I o ed. - Nature Research · sp, was maintained under nitrogen atmosphere. Melting points were recorded on a Thomas Hoover capillary melting point apparatus and are uncorrected Materials:

In the format provided by the authors and unedited.

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Supporting Information

Pd-catalyzed anti-Markovnikov selective oxidative amination

Daniel G. Kohler, Samuel N. Gockel, Jennifer L. Kennemur, Peter J. Waller, Kami L. Hull* Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, Illinois 61801

Table of Contents A. General Information .................................................................................................................. 2 B. Reaction Optimization .................................................................................................................. 3 C. Reagent Order Determination ..................................................................................................... 13 D. Probing Involvement of Pd Nanoparticles ................................................................................. 24 E. Isotope Labeling Experiments ..................................................................................................... 25 F. Hammett Study ............................................................................................................................. 35 G. Substrate Synthesis ....................................................................................................................... 41 H. Experimental Procedures and Characterization ....................................................................... 52 I. Palladate Crystal Structure ......................................................................................................... 82 J. References ...................................................................................................................................... 84 K. Spectral Data ................................................................................................................................ 85

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SUPPLEMENTARY INFORMATIONDOI: 10.1038/NCHEM.2904

NATURE CHEMISTRY | www.nature.com/naturechemistry 1

http://dx.doi.org/10.1038/nchem.2904


A. General Information

General Experimental Procedures:

All reactions were carried out in glassware not rigorously dried unless otherwise indicated. Air or moisture sensitive materials were synthesized or purchased and stored in a nitrogen filled glove box. Column chromatography was performed with silica gel from Grace Davison Discovery Sciences (35-75 µm), mixed as a slurry in eluent, packed and run under positive air pressure. Analytical thin-layer chromatography (TLC) was performed on pre-coated glass silica gel plates with F-254 indicator, purchased from EMD Chemicals Inc. Visualization was by short wave (254 nm) ultraviolet light or by staining with potassium permanganate followed by heating. Distillations were performed using a 3 cm short-path column either under reduced pressure or under positive pressure of nitrogen.

Instrumentation: 1H NMR and 13C NMR were recorded on a Varian Unity 400/500 MHz (100/125 MHz respectively for

13C) or a VXR-500 MHz spectrometer. Spectra were referenced using either CDCl3 with the residual solvent peak as the internal standard (1H NMR: δ 7.26 ppm, 13C NMR: δ 77.00 ppm for CDCl3). Chemical shifts were reported in parts per million and multiplicities are as indicated: s (singlet,) d (doublet,) t (triplet,) q (quartet,) p (pentet,) m (multiplet,) and br (broad). Coupling constants, J, are reported in Hertz and integration is provided, along with assignments, as indicated. Analysis by Gas Chromatography-Mass Spectrometry (GC-MS) was performed using a Shimadzu GC-2010 Plus Gas chromatograph fitted with a Shimadzu GCMS-QP2010 SE mass spectrometer using electron impact (EI) ionization after analytes traveled through a SHRXI–5MS- 30m x 0.25 mm x 0.25 µm column using a helium carrier gas. Data are reported in the form of m/z (intensity relative to base peak = 100). Gas Chromatography (GC) was performed on a Shimadzu GC-2010 Plus gas chromatograph with SHRXI–MS- 15m x 0.25 mm x 0.25 µm column with nitrogen carrier gas and a flame ionization detector (FID). Low-resolution Mass Spectrometry and High Resolution Mass Spectrometry were performed in the Department of Chemistry at University of Illinois at Urbana-Champaign. The glove box, MBraun LABmaster sp, was maintained under nitrogen atmosphere. Melting points were recorded on a Thomas Hoover capillary melting point apparatus and are uncorrected

Materials: Solvents used for extraction and column chromatography were reagent grade and used as received. Reaction solvents tetrahydrofuran (Fisher, unstabilized HPLC ACS grade), diethyl ether (Fisher, BHT stabilized ACS grade), methylene chloride (Fisher, unstabilized HPLC grade), dimethoxyethane (Fisher, certified ACS), toluene (Fisher, optima ACS grade), 1,4-dioxane (Fisher, certified ACS), and acetonitrile (Fisher, HPLC grade were dried on a Pure Process Technology Glass Contour Solvent Purification System using activated Stainless Steel columns while following manufacture’s recommendations for solvent preparation and dispensation unless otherwise noted. Pent-4-en-2-ol was acquired from Alfa Aesar and was used as received. Styrene was acquired from Sigma Aldrich and used as received. Allylbenzene, 4-allylanisole, and 1-allyl-4-(trifluoromethyl)benzene were acquired from Aldrich and used as received. 4-phenyl-1-butene was acquired from Finton Laboratories and used as received. Octene was acquired from Acros and used as received.

2


B. Reaction Optimization

Characterization of isomer mixture with homoallyl benzene

Supplementary Figure 1: Product mixture with addition of Bu4NOAc and Bu4NCl:

The crude mixture was purified by silica gel chromatography (5% to 10% to 20% ethyl acetate in hexanes) to afford the following make-up of fractions:

Fractions 23-30: isomer 3

Fractions 33-35: isomer 1 (some of 2 and 3)

Fractions 36-38: isomers 1, 2, 3, 4, 5 (18 : 15 : 1 : 23 : 43)

Fractions 39-5: isomer 5

Below, the 1H NMRs of each set of fractions are shown and the structure of isomers 1-5 is predicted based on this data.

Homoallyl benzene

1-methylnapthalene

Phthalimide

1 2

5

4 3

Bu3N

3


Supplementary Figure 2: 1H NMR of fractions 23-30 (isomer 3):


4



Supplementary Figure 5: 1H NMR Fractions 36-38: isomers 1, 2, 3, 4, 5 (18 : 15 : 1 : 23 : 43):

5


Supplementary Figure 6: Characterization of isomers 1-5:

6


Supplementary Figure 7: Reaction of 1a under published conditions.

7


Supplementary Figure 8: Reaction of 1m under published conditions.

8


Supplementary Figure 9: GC spectrum of crude mixture from the reaction of homoallyl benzene under the

optimized conditions.

1 2

5

4 3

9


Supplementary Table 1: Reaction Optimization.

Entry [Pd] (mol %) Olefin Equiv Bu4NOAc (mol %) Bu4NCl (mol %) T (°C) Total Yield (%) Yield 1a (%) a-M/M 1c 5 6 0 0 60 88 0 <1

2 c 5 6 5 5 60 15 3 <1

3 5 6 5 5 60 47 18 1

4 5 6 5 10 60 47 24 2

5 5 6 5 20 60 43 27 3

6 5 6 10 20 60 47 30 4

7 d 5 6 10 20 60 66 52 9

8 d 5 6 10 20 80 79 56 4

9 d 5 2 10 20 80 86 62 4

10 5 1 10 20 80 55 43 7

11 d 5 2 15 25 80 75 60 8

12d,e 10 2 30 50 80 71 58 36

13 d 5 2 20 30 80 24 21 130 a In situ yield determined by gas chromatographic analysis and comparison to an internal standard. b Conditions: olefin, nucleophile (0.10 mmol), Pd(OAc)2 (0.005 mmol), NBu4Cl (0.025 mmol), NBu4OAc (0.015 mmol), DMA (1.0 M), and a balloon of O2 (1 atm) at 80 °C for 24 h. c PhCN used as solvent d 5 Å MS (50 mg) added e 10 mol % Pd(OAc)2 .

10


Supplementary Table 2: Salt Additives.

Entry Additive (mol %) Total Yield (%)a Yield 1a (%)a a-M/Ma

1 None 20 <1 0.06

2 Bu4NCl (40 mol %) 95 68 3.0

3 LiCl (40 mol %) 32 18 1.4

4 CsCl (40 mol %) 13 2 0.2

5 Bu4NI (40 mol %) 80 24 2.3

6 Bu4NOAc (20 mol %) 59 26 1.3

7 NaOAc (20 mol %) 15 0 0.0

8 KOBz (20 mol %) 22 21 0.0 a In situ yield determined by gas chromatographic analysis and comparison to an internal standard

Supplementary Table 3: Solvents.

Entry Solvent Yield (%)a a-M/Ma

1 DMA 48 13

2 DMF 32 12

3 NMP 37 12

4 Diglyme 9 6

5 Mesitylene 26 21

6 PhCl 26 17

7 PhNO2 32 19 a In situ yield determined by gas chromatographic analysis and comparison to an internal standard

11


Supplementary Table 4: Oxidants.

Entry Solvent Yield (%)a a-M/Ma

1 CuCl2 0 NA

2 Benzoquinone 6 5

3 Duroquinone 14 9

4 O2 48 13

5 Air 26 13

6 Methyl Methacrylate 30 11 a In situ yield determined by gas chromatographic analysis and comparison to an internal standard

Supplementary Table 5: Additives.

Entry Additive Mol % Yield (%)a a-M/Ma

1 Bu4NCl 5% 9 5.0

2 Bu4NCl 10% 58 16.4

3 Bu4NCl 20% 77 29.7

4 Bu4NBr 20% 49 14.3

5 Bu4NI 20% 32 7.0

6 Bu4NCl 5% 9 5.0

7 Bu4NCl 10% 58 16.4 a

In situ yield determined by gas chromatographic analysis and comparison to an internal standard

12


Supplementary Table 6: Molecular Sieves.

Entry Mol. Sieve Yield (%)a a-M/Ma

1 0 mg 5 Å 19 5.8

2 10 mg 5 Å 36 11.1

3 20 mg 5 Å 45 12.2

4 50 mg 5 Å 65 17.1

5 50 mg 3 Å 54 20.7

6 50 mg 4 Å 0 NA a In situ yield determined by gas chromatographic analysis and comparison to an internal standard

Supplementary Table 7: Temperature.

Entry Temperature (°C) Time (h) Yield (%)a a-M/Ma

1 60 8 36 25.7

2 70 8 45 19.5

3 80 6 44 16.9

4 80 12 65 17.1

5 80 24 77 29.7 a In situ yield determined by gas chromatographic analysis and comparison to an internal standard

13


Supplementary Table 8: Equivalence.

Entry Nucleophile (mmol) Olefin (mmol) Yield (%)a a-M/Ma

1 0.1 0.1 68 18.8

2 0.1 0.12 56 18.4

3 0.1 0.15 63 19.2

4 0.1 0.2 54 14.1

5 0.1 0.5 50 13.1

6 0.12 0.1 64 12.6

7 0.15 0.1 69 10.6

8 0.2 0.1 68 10.3

9 0.5 0.1 71 9.8 a In situ yield determined by gas chromatographic analysis and comparison to an internal standard

14


C. Reagent Order Determination. General Procedure for Kinetic Experiments

Kinetic experiments were run in a manner modified from to that employed for the respective oxidative amination conditions, as follows. Data points represent the average of at least three independent runs, and measure rate of change of concentration divided by the change in time (Δ[Prod]/Δt), with 6 time points per concentration. Reagent order is calculated by fitting the data to a power curve and extracting the exponent factor.

Run Initial Rate (mM/min) Stdev

1 3.72 2 3.38 3 3.24

Average 3.45 0.252 Supplementary Figure 10: Representative kinetic measurement.

For homoallylbenzene (1a):

Bu4NCl, phthalimide, and 5Å molecular sieves (50 mg) were weighed into a 1-dram vial with a Teflon coated stir bar in a nitrogen-atmosphere glove box. A stock solution of Pd(OAc)2 and Bu4NOAc was freshly prepared in N,N-dimethylacetamide, and this was then added to the reaction vials. These were then sealed and removed from the glove box, 1a was added in one portion, and the vials were purged with oxygen gas and sealed again. The reaction was heated and stirred at 80 °C for the appropriate time. GC samples were obtained by addition of 1-methylnaphthalene followed by mixing and sampling, and yields calculated according to a calibration curve.

Order in Alkene:

The order in 1a was determined using the general amounts of Phthalimide (0.1 mmol, 14.7 mg) and Bu4NCl (0.025 mmol, 7.0 mg), and a stock solution was prepared of Pd(OAc)2 (0.15 mmol, 33.7 mg) and Bu4NOAc (0.45 mmol, 135.5 mg) in 3.0 mL N,N-dimethylacetamide. 100 µL of this solution was added to each vial and the reactions conducted as described above, for between 180 and 280 minutes with 20 minute time increments.

y = 3.7206x - 9.2809

0

40

80

120

0 5 10 15 20 25 30 35Con

cent

ratio

n 1m

(mM

)

Reaction time (minutes)

CatalystLoadingTimeStudy

15


Supplementary Figure 11: Order in olefin.

Order in Catalyst:

The order in catalyst was determined using the general amounts of Phthalimide (0.1 mmol, 14.7 mg), Bu4NCl (varied between 20-35 mol%, a fivefold excess relative to the palladium), and 1a (0.2 mmol, 30 µL), and a stock solution was prepared of Pd(OAc)2 (0.15 mmol, 33.7 mg) and Bu4NOAc (0.45 mmol, 135.5 mg) in 1.5 mL N,N-dimethylacetamide. Each vial was charged with the appropriate amount of solvent, followed by the remainder of this stock solution to achieve a total volume of 100 µL (60 µL DMA + 40 µL stock solution for 4 mol % catalyst, to 30 µL DMA + 70 µL stock solution for 7 mol % catalyst). The reactions were conducted as described above, for between 30 and 180 minutes with 30 minute time increments.

Supplementary Figure 12: Order in catalyst.

y = 0.0001x1.0633

R² = 0.96177

0

0.07

0.14

0.21

0 500 1000(Δ[2

a]/Δ

t) (m

M/m

in)

[1a] (mM)

y = 0.0014x1.4493

R² = 0.99951

0

0.2

0.4

0.6

0.8

0 20 40 60 80(Δ[2

a]/Δ

t) (m

M/m

in)

[Pd] (mM)

16


The order in catalyst was further investigated using the general amounts of Phthalimide (0.1 mmol, 14.7 mg), Bu4NCl (varied between 20-35 mol%, a fivefold excess relative to the palladium), and 1a (0.2 mmol, 30 µL), and a stock solution was prepared of Pd(OAc)2 (0.15 mmol, 33.7 mg) in 1.5 mL N,N-dimethylacetamide. Each vial was charged with the appropriate amount of solvent, followed by the remainder of this stock solution to achieve a total volume of 100 µL (60 µL DMA + 40 µL stock solution for 4 mol % catalyst, to 30 µL DMA + 70 µL stock solution for 7 mol % catalyst). The reactions were conducted as described above, for between 10 and 60 minutes with 10 minute time increments.

Supplementary Figure 13: Order in catalyst without additional Bu4NOAc.

Order in Nucleophile:

The order in nucleophile was determined using the general amounts of 1a (0.2 mmol, 30 µL) and Bu4NCl (0.025 mmol, 7.0 mg), and a stock solution was prepared of Pd(OAc)2 (0.15 mmol, 33.7 mg) and Bu4NOAc (0.45 mmol, 135.5 mg) in 3.0 mL N,N-dimethylacetamide. Each vial was charged with the appropriate amount of phthalimide, and then 100 µL of the catalyst stock solution. The reactions were conducted as described above, for between 30 and 180 minutes with 30 minute time increments.

Supplementary Figure 14: Order in nucleophile.

y = 0.0788x1.1258

R² = 0.99627

0

0.2

0.4

0.6

0.8

0 2 4 6 8(Δ[2

a]/Δ

t) (m

M/m

in)

[Pd] (mM)

y = 0.6652x-0.043

R² = 0.12236

0

0.3

0.6

0.9

0 500 1000 1500(Δ[2

a]/Δ

t) (m

M/m

in)

[PhthNH] (mM)

17


Effect of tetrabutylammonium additives:

Efforts were undertaken to explore the effects of the tetrabutylamonium additives in the reaction. Screening results demonstrated an optimal ratio between these and palladium, suggesting a change in catalyst composition. Attempts to get clear kinetic data on this were confounded by the fact that they produce a highly beneficial effect below a threshold, followed by an inhibitory effect beyond that point.

Supplementary Figure 15: Acetate equivalence for homoallylbenzene.

This result demonstrates that the addition of base is critical, as starting from a purely tetrachloropalladate produces no product whatsoever. Addition of base leads to product formation, and quickly inhibition of the Markovnikov isomer is observed at a ratio of about 2:1 Bu4NOAc:PdCl4, or what we would expect in our standard conditions beginning with Pd(OAc)2. A similar inhibition of the desired anti-Markovnikov isomer is found shortly thereafter, at a ratio of approximately 4:1 Bu4NOAc:PdCl4. This explains the role of added acetate in improving selectivity, as it inhibits the undesired pathway more rapidly than it does the desired pathway.

0

0.5

1

1.5

2

0 20 40 60(Δ[2

a]/Δ

t) (m

M/m

in)

[Bu4NOAc] (mM)

RateofFormationof2a

0

0.5

1

0 20 40 60(Δ[2

a']/Δ

t) (m

M/m

in)

[Bu4NOAc] (mM)

RateofFormationof2a'

18


Supplementary Figure 16: Chloride equivalence for homoallylbenzene.

In a similar fashion, addition of Bu4NCl was found to be critical for the success of this reaction under these conditions, with a peak rate for formation of the desired isomer being found at approximately 4:1 Bu4NCl:Pd(OAc)2. The addition of further chloride had a relatively small impact on the reaction efficiency with respect to the formation of 2a; however, inhibition of the undesired isomer 2a’ was found with further chloride, suggesting an inhibition of the reaction pathway leading to the Markovnikov isomer.

For homoallylic alcohol (1m):

Bu4NCl, phthalimide, and 5Å molecular sieves (50 mg) were weighed into a 1-dram vial with a Teflon coated stir bar in a nitrogen-atmosphere glove box. A stock solution of Pd(OAc)2 was freshly prepared in N,N-dimethylacetamide, and this was then added to the reaction vials. These were then sealed and removed from the glove box, 1m was added in one portion, and the vials were purged with oxygen gas and sealed again. The reaction was heated and stirred at 80 °C for the appropriate time. GC samples were obtained by addition of 1-methylnaphthalene followed by mixing and sampling, and yields calculated according to a calibration curve.

Order in Alkene:

The order in homoallylic alcohol (1m) was determined using the general amounts of Phthalimide (0.1 mmol, 14.7 mg) and Bu4NCl (0.020 mmol, 5.6 mg), and a stock solution was prepared of Pd(OAc)2 (0.15 mmol, 33.7 mg) in 3.0 mL N,N-dimethylacetamide. 100 µL of this solution was added to each vial and the reactions conducted as described above, for between 5 and 30 minutes with 5 minute time increments.

-0.5

0

0.5

1

1.5

2

0 20 40 60Δ[2a]/Δt)(mM/m

in)

Bu4NCl(mM)

RateofFormationof2a

0

0.2

0.4

0.6

0.8

0 20 40 60

Δ[2a']/Δt)(mM/m

in)

Bu4NCl(mM)

RateofFormationof2a'

19


Supplementary Figure 17: Order in olefin.

Order in Catalyst:

The order in catalyst was determined using the general amounts of Phthalimide (0.1 mmol, 14.7 mg) and 1m (0.1 mmol, 14.8 µL), and a stock solution was prepared of Pd(OAc)2 (0.15 mmol, 33.7 mg) in 1.5 mL N,N-dimethylacetamide. Each vial was charged with the appropriate amount of solvent, followed by the remainder of this stock solution to achieve a total volume of 100 µL (60 µL DMA + 40 µL stock solution for 4 mol % catalyst, to 30 µL DMA + 70 µL stock solution for 7 mol % catalyst). The reactions were conducted as described above, for between 5 and 30 minutes with 5 minute time increments.

Supplementary Figure 18: Order in catalyst.

y = 0.0045x0.9536

R² = 0.9988

0

1

2

3

4

0 500 1000

(Δ[2

m]/Δ

t) (m

M/m

in)

[1m] (mM)

y = 0.0631x1.0186

R² = 0.99684

0

2

4

6

0 20 40 60 80

(Δ[2

m]/Δ

t) (m

M/m

in)

[Pd] (mM)

20


Order in Nucleophile:

The order in nucleophile was determined using the general amounts of 1m (0.1 mmol, 14.8 µL) and Bu4NCl (0.020 mmol, 5.6 mg), and a stock solution was prepared of Pd(OAc)2 (0.15 mmol, 33.7 mg) in 3.0 mL N,N-dimethylacetamide. Each vial was charged with the appropriate amount of phthalimide, and then 100 µL of the catalyst stock solution. The reactions were conducted as described above, for between 5 and 30 minutes with 5 minute time increments.

Supplementary Figure 19: Order in nucleophile.

Effect of tetrabutylammonium additives:

Supplementary Figure 20: Acetate equivalence for homoallylic alcohol.

y = 3.4037x0.0294

R² = 0.23152

3.6

4

4.4

4.8

0 500 1000 1500

(Δ[2

m]/Δ

t) (m

M/m

in)

[PhthNH] (mM)

0

1

2

3

4

5

0 20 40 60(Δ[2

m]/Δ

t) (m

M/m

in)

[Bu4NOAc] (mM)

RateofFormationof2m

00.10.20.30.40.50.6

0 20 40 60

(Δ[2

m']/

Δt)

(mM

/min

)

[Bu4NOAc] (mM)

RateofFormationof2m'

21


As seen with 1a, this result demonstrates that the addition of base is critical, as starting from a purely tetrachloropalladate produces no product whatsoever. Addition of base leads to product formation, and quickly inhibition of the Markovnikov isomer is observed, consistent with the results obtained previously.

Supplementary Figure 21: Chloride equivalence for homoallylic alcohol.

In a similar fashion, addition of Bu4NCl was found to be critical for the success of this reaction under these conditions, with a peak rate for formation of the desired isomer being found at approximately 4:1 Bu4NCl:Pd(OAc)2.

0

1

2

3

4

5

0 20 40 60(Δ[2

m]/Δ

t) (m

M/m

in)

[Bu4Cl] (mM)

RateofFormationof2m

00.10.20.30.40.50.6

0 20 40 60

(Δ[2

m']/

Δt)

(mM

/min

)

[Bu4NCl] (mM)

RateofFormationof2m'

22


Tetrabutylammonium Acetate as Catalytic Base:

The precise role of the acetate was further investigated by 1H-NMR in DMF-d7. It was found that the 1:1 combination of this additive with the nucleophile in these reactions produced an upfield shift in the proton signals of the aryl ring in phthalimide, and apparently suppressed the N–H signal entirely, suggesting its competence in this polar solvent of either strong hydrogen bonding or equilibrium exchange, supporting its efficacy as a base in this transformation.

Supplementary Figure 22: a) Phthalimide in DMF-d7, b) 1:1 Phthalimide and Bu4NOAc in DMF-d7

a)

b)

23


D. Probing Involvement of Pd Nanoparticles.

Our reactions conditions are similar to those presently reported, typically employed for the Heck arylation and known as Jeffery’s conditions, and those have been shown to involve the intermediacy of colloidal palladium species. Their involvement in catalyst stability and reactivity are of interest, and to this end we explored the similarity in our catalytic system to those previously reported.1 Key features of those reactions involving nanoparticulate palladium are:

a) Catalyst deactivation via addition of Hg0, and; b) An induction period as the pre-catalyst is converted to the active particulate species.

To probe these two features, we first looked at the addition of Hg0. Our reactions were set up in the same manner as usual, except that directly before addition of olefin, a drop of Hg0 was added. After the prescribed reaction period, the reactions were analyzed by GC analysis as usual.

Supplementary Figure 23: Adding Hg0 to the standard conditions.

A diminished yield was observed relative to that expected under these conditions. This result is somewhat inconclusive, as it indicates the intermediacy of Pd0 as expected by our catalytic cycle, but not necessarily nanoparticles as the yield still accounted for greater than one turnover of the catalyst.

To probe the possibility of an induction period, we undertook initial rate kinetics. These results clearly indicate that there is no induction period in the formation of an active catalyst.

Run Initial Rate (mM/min)

Stdev

1 0.426 2 0.442

Average 0.435 0.002

Supplementary Figure 24: Investigating the potential for an induction period under standard conditions.

Taken together, these results are indicative of a molecular PdII/Pd0 catalytic cycle, with long-enough lived Pd0 to be amalgamated by Hg0.

y=0.4261x+3.7188R²=0.9861

010203040506070

0 50 100 150

Con

cent

ratio

n 2a

(m

M)

Time (min)

Initial Rate Proteo

24


E. Isotope Labeling Experiments.

Supplementary Figure 25: Synthesis of (Z)-β-Deuterostyrene.

Step 1: Synthesis of Phenylacetylene-d.

An oven-dried schlenk flask equipped with a stir bar was charged with phenylacetylene (2.2 mL, 20 mmol, 1.0 equiv) and anhydrous THF (30 mL, 0.67 M). The solution was cooled to -78 ºC and nBuLi (1.6 M in hexanes, 13 mL, 21 mmol, 1.05 equiv) was added in a dropwise fashion over 5 min. The solution was stirred at -78 ºC for 20 min after which point it was warmed to rt and stirred for an additional 20 min. The mixture was then cooled to -78 ºC and D2O (2 mL, excess) was added. The mixture is allowed to warm to rt and stirred for 20 min. The reaction was quenched with 3M HCl and extracted with diethyl ether (3x20 mL). The combined organic extracts were dried with MgSO4, filtered, and the solvent was carefully removed with use of a rotary evaporator (no heating, product is volatile) to give phenylacetylene-d as a clear oil (1.71 g, 83% yield). 1H NMR indicated the presence of THF in the final product. Otherwise, the spectra matched those previously reported.2

1H NMR signals for the 1% unlabeled material are indicated in square brackets [ ]. 1H NMR (500 MHz, CDCl3): δ 7.52–7.47 (m, 2H), 7.38–7.29 (m, 3H), [3.08 (s, 0.01H)]. 13C NMR (125 MHz, CDCl3): δ 132.32, 128.97, 128.51, 122.33, 83.40 (t, J = 9.4 Hz), 77.16 (t, J = 47.5 Hz), 68.16, 25.83. HRMS (ESI-TOF) m/z: [M+] calculated for C8H5D, 103.0532; found, 103.0529. Step 2: Synthesis of (Z)-β–Deuterostyrene.

In the glove box, an oven-dried flask was charged with phenylacetylene-d (1.12 g, 10.9 mmol) and anhydrous methylene chloride (31 mL, 0.35 M). The solution was cooled to 0 ºC using the glove box cold well. Schwartz’s Reagent (2.98 g, 11.5 mmol, 1.05 equiv) was then added in two equal portions (1.49 g each) in rapid succession. The orange mixture was allowed to stir at 0 ºC for 5 min, then removed from the cold well and stirred at rt in the dark for 2 h. The flask was then removed from the glove box, cooled to 0 ºC, quenched with H2O (1.5 mL) and

i). nBuLi

ii). D2O

Di). Schwartz’s Reagent

ii). H2O D

Step 1 Step 2

DHi). nBuLi, THF -78 ºC rt 1.5 h

ii). D2O -78 ºC rt

Di). Cp2Zr(H)(Cl) CH2Cl2 0 ºC rt, 2 h

ii). H2O, 1 h

D

25


stirred vigorously at rt for 2 h. MgSO4 was then added, and the mixture was filtered. The solution was carefully concentrated with the use of a rotary evaporator (product is volatile, no heating) until ca 15-20 mL remained. Hexane was added and the mixture was pulled through a celite pad to remove the white precipitate. The filter cake was rinsed with hexane and the solution was again concentrated with use of the rotary evaporator. The crude product was purified by pulling through a short silica column with methylene chloride. Careful concentration of the fractions with the use of a rotary evaporator gave (Z)-β-deuterostyrene (307.4 mg, 27% yield), which contained a small amount of hexane and other solvent impurities. The spectra matched those previously reported.2 The product was stored in the glove box freezer without the addition of a stabilizer. 1H NMR signals for the 1% unlabeled material are indicated in square brackets [ ]. 1H NMR (500 MHz, CDCl3): δ 7.45–7.40 (m, 2H), 7.36–7.30 (m, 2H), 7.29–7.22 (m, 1H), 6.72 (dt, J = 10.9, 2.6 Hz, 1H), [5.75 (dd, J = 17.6, 7.5, 0.01H)], 5.24 (d, J = 10.9 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 137.81, 137.05, 128.78, 128.05, 126.47, 113.82 (t, J = 23.8 Hz). HRMS (ESI-TOF) m/z: [M+] calculated for C8H7D, 105.0689; found, 105.0688. Oxidative Amination of (Z)-β-deuterostyrene

A 4-mL vial equipped with a stir bar was charged with Pd(OAc)2 (2.2 mg, 10 µmol, 5 mol%), nBu4NCl (11.2 mg, 40 µmol, 20 mol%), 5Å molecular sieves (100 mg), phthalimide (32.4 mg, 0.22 mmol, 1.1 equiv), and DMA (0.2 mL, 1.0 M in alkene). The headspace was purged with O2 and the vial was sealed. (Z)-b-deuterostyrene (21 mg, 0.20 mmol, 1.0 equiv) was added via syringe through the septum. An O2 balloon was then installed by placing the needle through the same hole through which the alkene had been added. The mixture was stirred at 80 ºC for 24 h after which point it was diluted with ethyl acetate (3 mL) and adsorbed onto celite. Purification via flash column chromatography on silica gel, eluting with 5% ethyl acetate in hexanes, yielded the aminated product as a bright yellow solid (14.6 mg, 29% yield). Rf (19:1 Hexanes:Ethyl Acetate): 0.21 m.p. 182.8-184.0 ºC. (lit.3 174-175 ºC) 1H NMR (500 MHz, CDCl3): δ 7.90 (dd, J = 5.4, 3.1 Hz, 2H), 7.76 (dd, J = 5.5, 3.0 Hz, 2H), 7.65 (s, 0.87H), 7.48 (d, J = 7.0 Hz, 2H), 7.36 (t, J = 7.7 Hz, 2.13H), 7.26 (t, J = 7.3 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 166.70, 136.20, 134.81, 131.96, 129.00, 127.91, 127.90, 126.49, 126.47, 123.94, 117.73 (t, J = 55 Hz).

+

NH

OO

Pd(OAc)2 5 mol%Bu4NCl (20 mol%)

MS 5Å (50 mg), O2DMA (1 M), 80 ºC, 24 h

1.1 equiv1.0 equiv

N

O

O

D

D

HN

O

OH

D

N

O

OH

H

A77.4%

B11.6%

C9.6%

N

O

OD

D

D1.4%

26


IR (neat): 3062, 3032, 2926, 1772, 1707, 1626, 1451, 1464 cm-1. HRMS (ESI-TOF) m/z: [M+H+] calculated for C16H11DNO2, 251.0931; found, 251.0935. Determination of Products and Their Ratios: Shown in Figure 26 are the products that were detected from the oxidative amination of (Z)-β-deuterostyrene. It should be noted that cis products were not observed in the GC trace of a crude reaction mixture or in the 1H NMR spectrum of the final product.

Supplementary Figure 26: Products observed from oxidative amination of (Z)-β-deuterostyrene.

Confirmation of deuterium at both vinylic positions can be seen in the 1H NMR (Figure 27). In the product mixture, the doublet for the β-proton (Figure 2, 7.36 ppm3) has disappeared underneath the triplet for the meta protons. The doublet for the α-proton (7.67 ppm3) has been converted into a broad singlet. These data suggest A is the major component of the product mixture. A small amount of a doublet at 7.67 ppm can be clearly seen, indicating a small amount of C is also present.

N

O

OD

HN

O

OH

DN

O

OH

HN

O

OD

D

A B C D

27


Supplementary Figure 27: 1H NMR of pure C and the deuterated product mixture.

7.107.157.207.257.307.357.407.457.507.557.607.657.707.757.807.857.907.958.008.058.10f1 (ppm)

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

04JLK54.1c1STANDARD PROTON PARAMETERS

1.0

3

2.9

9

2.0

4

1.0

0

1.9

9

2.0

3

7.2

57.2

57.2

67.2

77.2

77.2

87.2

87.2

87.3

47.3

57.3

67.3

67.3

77.3

87.4

77.4

77.4

77.4

97.4

9

7.6

5

7.6

8

7.7

67.7

67.7

77.7

7

7.9

07.9

17.9

17.9

2

7.057.107.157.207.257.307.357.407.457.507.557.607.657.707.757.807.857.907.95f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

SNG-IV-262-1H-1STANDARD PROTON PARAMETERS

1.0

5

2.2

1

2.0

3

0.8

4

0.0

4

2.0

2

2.0

0

7.2

57.2

57.2

67.2

6 C

DC

l37.2

77.2

87.2

87.2

87.3

47.3

57.3

67.3

7

7.4

77.4

77.4

77.4

87.4

9

7.6

5

7.6

7

7.7

57.7

67.7

77.7

7

7.9

07.9

07.9

17.9

1

1H NMR (zoomed) of pure C.

1H NMR (zoomed) of the product mixture.

Residual peaks from C

28


The integrations also confirm the presence of deuterium. The triplet at 7.36 ppm in the product mixture integrates to slightly more than 2, whereas it integrates to 3 for C. The singlet at 7.67 ppm also integrates for slightly less than one, indicating a small amount of B is also present. To determine the exact amounts of A, B, C, and D in the mixture, isotope ratio mass spectrometry and 2H NMR were employed. A walkthrough of the calculations is shown below (Figure 28 and 29). An isotope ratio mass spectrum of the product mixture was obtained. The experimental ratio of the [M+H+], [M+H++1], and [M+H++2] peaks were compared with the theoretical ratios of the pure components. This allows for the relative amounts of (A+B), C, and D to be calculated.

Supplementary Figure 28: Isotope Pattern for the Oxidative Amination Product:

m/z249 250 251 252 253 254 255

%

0

100SNG-IV-262 275 (6.900) Cn (Cen,5, 80.00, Ht); Sm (SG, 2x0.80); Cm (230:292-28:58) Scan ES+

4.74e4251.247359

250.25027

252.28780

[M+H+]=251.2

Mass Area Intensity 250.2 5027 8.2% 251.2 47359 77.4% 252.2 8780 14.4%

29


Supplementary Figure 29: Calculation of relative amounts of (A+B), C, and D.

N

O

OH

H

250(1.0)

251(0.173) 252

(0.014)

Theoretical Isotope Pattern for C:

m/z(rel. intensity)

251(1.0)

252(0.173) 253

(0.014)

N

O

O

Theoretical Isotope Pattern for A and/or B:

D

m/z(rel. intensity)

250(8.2)

251(77.4)

252(14.4)

Calculations Based on Theoretical Isotope Pattern for C:

m/z(intensity)

Raw data from isotoperatio mass spectrum.

Calculating C: 8.2x1 =8.2

8.2x0.173 =1.4

8.2x0.014 =0.1

These are the amountsthat C contributes to theoverall observed isotope pattern.

Calculating C:

251(1.4)

252(0.1)

250(8.2)

250(8.2)

251(77.4)

252(14.4)

Calculating (A+B): 76.0x1 =76.0

76.0x0.173 =13.1

These are the amountsthat (A+B) contributes to the observed isotope pattern.

Calculating (A+B):

251(76.0)

252(14.3)

251(76.0)

252(13.1)

Subtracting Out C: 8.2-8.2 =0

77.4-1.4 =76.0

14.4-0.1 =14.3

Substracting out C fromthe overall isotope pattern.The remaining intensitiescome from (A+B) and D.

Subtracting Out C:

251(76.0)

252(14.3)

Subtracting out (A+B): 76.0-76.0 =0

14.3-13.1 =1.2

Subtracting out (A+B) leaves the amount of D as the remainder.

252(1.2)

(A+B): 76.0/(76.0+8.2+1.2)x100 = 89.0%C: 8.2/(76.0+8.2+1.2)x100 = 9.6%D: 1.2/(76.0+8.2+1.2)x100 = 1.4%

Calculating Percentages of (A+B), C, and D:

Step 2

Step 1

Step 3

Step 4

Step 5

30


The relative amounts of A and B can be further elucidated from the 2H NMR spectrum (Figure 30).

Supplementary Figure 30: 2H NMR of the product mixture.

2H NMR indicates a ratio of 87:13 A:B. Extrapolating these values to the overall mixture gives 77.4% A, 11.6% B, 9.6% C, and 1.4% D. Analysis of Results:

Supplementary Figure 31. Product distribution.

+

NH

OO

Pd(OAc)2 5 mol%Bu4NCl (20 mol%)

MS 5Å (50 mg), O2DMA (1 M), 80 ºC, 24 h

1.1 equiv1.0 equiv

N

O

O

D

D

HN

O

OH

D

N

O

OH

H

A77.4%

B11.6%

C9.6%

N

O

OD

D

D1.4%

-2.0-1.5-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000SNG-IV-262-DeuteriumNMR-Acetone-9932scansSTANDARD PROTON PARAMETERS

0.8

70

.13

2.0

4 A

ceto

ne

7.3

97

.63

7.27.37.47.57.67.77.8f1 (ppm)

-200

0

200

400

600

800

0.8

7

0.1

3

7.3

9

7.6

3B

AA

31


Isotope ratio mass spectrometry data indicates that the mono-deuterated products A and B are major, making up 89.0% of the overall product mixture. 2H NMR indicates a ratio of 87% A and 13% B, making A and B 77.4% and 11.6% of the overall mixture, respectively. The non-deuterated and the di-deuterated products are minor, making up only 9.6% and 1.4%, respectively. The results are summarized in Figure S25 above. Mechanistically, product A would most likely form via a trans aminopalladation pathway (Figure 32). Trans aminopalladation of styrene forms a benzylic-Pd(II) species I. From here, bond rotation can occur to form pre-trans and pre-cis intermediates. The pre-trans intermediate is preferred, as the phthalimide unit is anti to the phenyl ring. This leads to b-hydride elimination and formation of the major product A. Therefore, because A is the major product observed, it is likely that the oxidative amination reaction reported herein proceeds through such a mechanism.

Supplementary Figure 32: Trans-aminopalladation pathway.

Enrichment of deuterium at the α-carbon (product B) could occur through several pathways. One involves the less likely instance where trans aminopalladation/b-deuteride elimination occurs to give cis-d0 (Figure 32, lower pathway). However, cis products were not detected in the GC of a crude reaction or in 1H NMR of the final product. Therefore, it seems plausible that a [Pd]–D mediated isomerization could occur to convert cis-d0 into B (Figure 33).

Supplementary Figure 33: Cis-to-trans isomerization of cis-d0 by a [Pd]–D.

Alternatively, cis aminopalladation/b-deuteride elimination could occur to form C (Figure 34). Incorporation of deuterium in the benzylic position followed by isomerization of the resulting cis-d1 product by a [Pd]–H could afford B.

D

NPhthPh

H

[Pd]H

PhH

[Pd]D

NPhth

H -[Pd]–H Ph

H

D

NPhth60º rotation

I

A

PhH

[Pd]NPhth

H

D -[Pd]–D Ph

H

NPhth

H60º rotation

cis-d0

pre-trans

pre-cis

Major

Not detected

Ph +[Pd]+ PhthNH

D

Ph

H

NPhth

H +[Pd]–DPh

H

DNPhth

H

[Pd] -[Pd]–H Ph

D

H

NPhth

Not detectedBcis-d0

32


Supplementary Figure 34: Alternative Pathways to Form B.

A final pathway for the production of B could involve scrambling of the deuterium within the starting material or product by a [Pd]–H. Taken together, the 1H and 2H NMR and isotope ratio data strongly suggest that a trans aminopalladation mechanism is the major pathway in operation, with the major products observed likely being formed through such a mechanism. C–H Activation Probe Substrate:

Supplementary Figure 35: C–H Activation Probe.

In a dry 20mL vial charged with Teflon-coated stir bar was added D2O (2.5 mL), 3-phenylpropanal (2.64mL, 20 mmol), and 4-dimethylaminopyridine (244mg, 2 mmol). The vessel was sealed and heated to 100 °C for 4h. After cooling, the reaction was extracted with methylene chloride (3x5mL), washed with HCl (1x10mL), NaHCO3 (1x10mL), and brine (1x10mL). The aldehyde was used directly in the next step.

To a dry 250mL round bottom flask containing a Teflon-coated stir bar was added methyltriphenylphosphonium bromide (1.79g, 5 mmol). THF (60 mL) was added, and the flask cooled to 0 °C. nBuLi (1.6M in hexanes, 3.13mL, 5 mmol) was added dropwise. The reaction was stirred at 0 °C for 30 min, then aldehyde was added and the reaction allowed to warm to room temperature. The reaction was stirred for 12h at room temperature, then quenched by addition of NH4Cl (sat.), and extracted with diethyl ether (3x50mL). The product was obtained after silica gel chromatography with hexanes as a colorless liquid in 34% overall yield.

-[Pd]–D Ph

H

H

NPhthPh +[Pd]+ PhthNHD

PhH

[Pd]DH

NPhth

-[Pd]–H

PhH

DHNPhth

[Pd]

+[Pd]–H

+[Pd]–D

Ph

D

NPhth

HPh

D

[Pd]NPhthH

H-[Pd]–HPh

D

H

NPhth

B cis-d1

cisaminopalladation

C

33


Supplementary Figure 36: NMR of 1a-d2

34


Supplementary Figure 37: Oxidative Amination of 1a-d2.

35


Kinetic Isotope Effect:

Phthalimide (0.1 mmol, 14.7 mg) and Bu4NCl (0.025 mmol, 7.0 mg) were weighed into a 1-dram vial, and a stock solution was prepared of Pd(OAc)2 (0.15 mmol, 33.7 mg) and Bu4NOAc (0.45 mmol, 135.5 mg) in 3.0 mL N,N-dimethylacetamide. 100 µL of this solution was added to each vial, then they were sealed and removed from the glove box. 1a (26.4 mg) or 1a-d2 (26.8 mg) was added in one portion, and the vials were purged with oxygen gas and sealed again. The reaction was heated and stirred at 80 °C for the appropriate time. GC samples were obtained by addition of 1-methylnaphthalene followed by mixing and sampling, and yields calculated according to a calibration curve. The reactions were conducted in duplicate, for between 20 and 120 minutes with 20 minute time increments.

Run Initial Rate (mM/min) Stdev Run Initial Rate (mM/min) Stdev

1 0.426 1 0.430 2 0.442 2 0.426

Average 0.435 0.002 Average 0.428 0.002 Supplementary Figure 38: Initial Rate Kinetic Isotope Effect.

y = 0.4261x + 3.7188R² = 0.9861

0102030405060

0 50 100 150

Conc

entra

tion

2a (m

M)

Time

Initial Rate Proteoy = 0.4302x + 3.5123

R² = 0.9819

0102030405060

0 50 100 150

Conc

entra

tion

2a-d

2(m

M)

Time

Initial Rate Deutero

36


F. Hammett Study.

To better understand the reaction mechanism, a Hammett study was conducted in conjunction with order studies. Initial rate kinetics were obtained for substrates 1a-1e, and these rates were compared against one another.

Phthalimide (0.1 mmol, 14.7 mg) and Bu4NCl (0.025 mmol, 7.0 mg) were weighed into a 1-dram vial, and a stock solution was prepared of Pd(OAc)2 (0.15 mmol, 33.7 mg) and Bu4NOAc (0.45 mmol, 135.5 mg) in 3.0 mL N,N-dimethylacetamide. 100 µL of this solution was added to each vial, then they were sealed and removed from the glove box. Olefin was added (0.2 mmol) in one portion, and the vials were purged with oxygen gas and sealed again. The reaction was heated and stirred at 80 °C for the appropriate time. GC samples were obtained by addition of 1-methylnaphthalene followed by mixing and sampling, and yields calculated according to a calibration curve. The reactions were conducted in duplicate, for between 15 and 180 minutes with equidistant time increments.

Supplementary Figure 39: Initial rate for 1a.

y=0.4352x+3.323R²=0.98612

-20

0

20

40

60

0 50 100

Conc

entra

tion

2a (m

M)

Time(min)

37


Supplementary Figure 40: Initial rate for 1b.

Supplementary Figure 41: Initial rate for 1c.

y = 0.1067x - 0.0608R² = 0.9916

-5 0

5

10

15

20

25

0 50 100 150 200Conc

entra

tion

2b (m

M)

Time (min)

y=0.3932x+1.4575R²=0.984880

20

40

60

0 50 100Conc

entra

tion

2c (m

M)

Time(min)

38


Supplementary Figure 42: Initial rate for 1d.

Supplementary Figure 43: Initial rate for 1e.

y = 0.7268x + 3.8086R² = 0.99070

20

40

60

80

0 50 100Conc

entra

tion

2d (m

M)

Time (min)

y = 0.7819x + 7.0558R² = 0.9790

20406080

100120

0 50 100Conc

entra

tion

2e (m

M)

Time(min)

39


Supplementary Figure 44: Hammett plot for series 1a-1e.

The combined results show a positive ρ value, indicating a large partial negative charge build-up before or during the rate limiting step. This is consistent with the binding of the alkene to an anionic catalyst, which is also in keeping with our other mechanistic data.

y=0.878x- 0.0932R²=0.67444

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

-0.4 -0.2 0 0.2 0.4 0.6

Log(kX/kH

)

Sigma

1a

1b

1c

1d1e

40


G. Substrate Synthesis

1-(but-3-en-1-yl)-4-methoxybenzene (1b)

In a dry Schlenk flask charged with a stir bar, 1-(chloromethyl)-4-methoxybenzene (15 mmol, 1.0 equiv, 2.03 mL) and THF (38 mL) were added under N2 and the mixture was cooled to -78 ºC. Allylmagnesium chloride (2.0 M in THF, 25.5 mmol, 1.7 equiv, 15.0 mL) was added dropwise over 5 minutes. The reaction was stirred for 20 hours at room temperature using GC to monitor progress. When complete, the reaction was quenched at 0 ºC with saturated ammonium chloride, then extracted with methylene chloride, washed with water and brine, dried over MgSO4 and the solvent evaporated under reduced. Silica gel chromatography (1 % EtOAc in hexanes) afforded the product (2.30 g, 95% yield) as a colorless liquid. The 1H and 13C NMR spectra matched those previously reported.4 1H NMR (500 MHz, CDCl3) δ 7.11 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 5.86 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.04 (dq, J = 17.1, 1.6 Hz, 1H), 4.98 (ddt, J = 10.2, 2.1, 1.2 Hz, 1H), 3.79 (s, 3H), 2.66 (t, J = 8.0 Hz, 2H), 2.39 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 158.04, 138.48, 134.25, 129.58, 115.12, 113.98, 55.53, 36.06, 34.77.

1-(but-3-en-1-yl)-4-(trifluoromethyl)benzene (1e)

In a dry Schlenk flask charged with a stir bar, 1-(chloromethyl)-4-(trifluoromethyl)benzene (10 mmol, 1.0 equiv, 1.48 mL) and THF (20 mL) were added under N2 at room temperature. Allylmagnesium chloride (2M, 15 mmol, 1.5 equiv, 7.5 mL) was added dropwise over 5 minutes. The reaction was stirred for 12 hours at room temperature. The reaction was quenched with saturated ammonium chloride, then extracted with ethyl ether, washed with water and brine, dried over MgSO4 and the solvent evaporated under reduced. Silica gel chromatography (100 % hexanes) afforded the product (843 mg, 42% yield) as a colorless liquid. 1H NMR (499 MHz, CDCl3) δ 7.53 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 5.83 (ddt, J = 16.9, 10.3, 6.6 Hz, 1H), 5.04 (dp, J = 17.2, 1.5 Hz, 1H), 5.00 (dd, J = 10.3, 1.5 Hz, 1H), 2.77 (t, J = 7.8 Hz, 2H), 2.39 (qt, J = 6.6, 1.4 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 145.89, 137.34, 128.74, 128.21 (q, J = 32.3 Hz), 125.20 (q, J = 3.8 Hz), 124.37 (q, J = 271.7 Hz), 115.44, 35.14, 35.08. 19F NMR (471 MHz, CDCl3) δ -62.37.

1-allyl-4-chlorobenzene (1d)

To a dry Schlenk flask with a magnetic stir bar was added 1-bromo-4-chlorobenzene (10 mmol, 1.91 g, 1 equiv), Ni(acac)2 (1 mmol, 257 mg, 0.1 equiv), zinc powder (20 mmol, 1.29 g, 2 equiv), Bu4NBr (10 mmol,

MeO

F3C

41


3.22 g, 1 equiv), and 4,4'-di-tert-butyl-2,2'-bipyridine (1 mmol, 268 mg, 0.1 equiv) in a nitrogen glovebox. This flask was sealed with a rubber septum and removed from the glovebox, and through the septum as added DMA (70 mL), pyridine (10 mmol, 0.8 mL, 0.1 equiv), and allyl acetate (20 mmol, 2.16 mL, 2 equiv). The flask was stirred at 60 °C for 12 h. The crude reaction was diluted with 200 mL DI H2O, then extracted with Et2O (5x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Mg2SO4, and concentrated by rotatory evaporation. The crude product was purified by column chromatography (100 % hexanes) followed by distillation (10 mm Hg). 1H NMR (500 MHz, CDCl3) δ 7.27 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 5.94 (ddt, J = 16.9, 10.3, 6.7 Hz, 1H), 5.12 – 5.04 (m, 2H), 3.36 (d, J = 6.8 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 138.42, 136.85, 131.81, 129.92, 128.47, 116.20, 39.47.

Pent-4-en-1-ylbenzene (1k)

In a dry Schlenk flask charged with a stir bar, (2-bromoethyl)benzene (22.5 mmol, 1.0 equiv, 3.0 mL) and THF (60 mL) were added under N2 at room temperature. Allylmagnesium chloride (2M, 37 mmol, 1.5 equiv, 18.5 mL) was added dropwise over 5 minutes. The reaction was stirred for 24 hours at reflux. The reaction was allowed to cool to room temperature, then quenched with saturated ammonium chloride, then extracted with ethyl ether, washed with water and brine, dried over MgSO4 and the solvent evaporated under reduced. Silica gel chromatography (100 % hexanes) afforded the product (2.81 g, 85% yield) as a colorless liquid. The spectral data matched that previously reported.5 1H NMR (500 MHz, CDCl3) δ 7.29 (td, J = 7.4, 1.3 Hz, 2H), 7.20 (d, J = 7.0 Hz, 3H), 5.85 (ddtd, J = 16.9, 10.2, 6.6, 1.3 Hz, 1H), 5.04 (dp, J = 17.1, 1.7 Hz, 1H), 4.99 (dp, J = 10.2, 1.5 Hz, 1H), 2.64 (t, J = 7.9 Hz, 3H), 2.11 (q, J = 7.3 Hz, 2H), 1.74 (pd, J = 7.6, 1.3 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 142.44, 138.59, 128.44, 128.25, 125.66, 114.68, 35.31, 33.29, 30.61.

2-(but-3-en-2-yl)isoindoline-1,3-dione (1ad)

In a pressure-rated reaction vessel was weighed potassium phthalimide (39 mmol, 7.2g, 1 equiv). To this was added DMF (40ml) and a Teflon-coated stir bar. 3-chloro-1-butene (5.9 mL, 1.5 equiv.) was added in one portion and the vessel screwed shut. The reaction was heated at 130 °C. After 20 h, the reaction was removed from heat and then added to DI water (10x volume of DMF), resulting in immediate precipitation of the product. The precipitate was collected by filtration, washed with water, then purified by silica gel chromatography (Hexanes:EtOAc = 9:1) yielding a white solid (7.04g, 90%). The spectral data matched that previously reported.6

1H NMR (500 MHz, CDCl3) δ 7.83 (dd, J = 5.4, 3.1 Hz, 2H), 7.70 (dd, J = 5.4, 3.0 Hz, 2H), 6.20 (ddd, J = 17.1, 10.3, 6.7 Hz, 1H), 5.23 (dt, J = 17.3, 1.3 Hz, 1H), 5.16 (dt, J = 10.3, 1.2 Hz, 1H), 4.93 (pt, J = 7.0, 1.4 Hz, 1H), 1.58 (d, J = 7.1 Hz, 3H).

42


13C NMR (126 MHz, CDCl3) δ 168.25, 137.09, 134.17, 132.31, 123.43, 116.66, 49.23, 18.53.

1-allylpyrrolidin-2-one (1ae)

To a round-bottomed flask equipped with a stir bar was added NaH (60% dispersion in mineral oil, 2.97 g, 74 mmol) and anhydrous THF (95 mL). The mixture was cooled to 0 ºC with an ice bath and 2-pyrrolidinone (5.0 mL, 66 mmol, 1.0 equiv) was added slowly. After bubbling had subsided, allyl bromide (5.65 mL, 66 mmol, 1.0 equiv) was added. The mixture was sealed and stirred at room temperature overnight. Then, the mixture was quenched with excess water and washed 3 x 20 mL with diethyl ether. The combined organic extracts were dried with MgSO4 and filtered. Removal of solvent with the aid of a rotary evaporator provided the crude product. Purification by column chromatography (10% ethyl acetate in hexanes ramped to 100% ethyl acetate) provided the pure product as a clear oil (6.4 g, 78% yield). The spectral data matched that previously reported.7 1H NMR (500 MHz, CDCl3) δ 5.71 (ddt, J = 15.8, 12.2, 6.1, 2.9 Hz, 1H), 5.12 - 5.20 (m, 2H), 3.84 - 3.93 (m, 2H), 3.33 (td, J = 7.1, 2.4 Hz, 2H), 2.39 (td, J = 8.2, 2.9 Hz, 2H), 1.91 - 2.11 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 175.01, 132.73, 118.02, 47.00, 45.47, 31.24, 18.06. 2-(but-3-en-1-yl)isoindoline-1,3-dione (1af)

In a pressure-rated reaction vessel was weighed phthalimide (10 mmol, 1.47g, 1 equiv) and K2CO3 (10 mmol, 1.38g, 1 equiv). To this was added DMF (10ml) and a Teflon-coated stir bar. 4-bromo-1-butene (1.52 mL, 1.5 equiv.) was added in one portion and the vessel screwed shut. The reaction was heated at 130 °C. After 16 h, the crude reaction was diluted with methylene chloride (100mL), washed with water (5x 20mL), then brine (1x20mL). The organic layer was dried over MgSO4 and the solvent removed. The crude was then purified by silica gel chromatography (Hexanes:EtOAc = 7:1) yielding a white solid (816mg, 40%). The spectral data matched that reported in the literature.8 1H NMR (500 MHz, CDCl3) δ 7.84 (dd, J = 5.4, 3.1 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 5.79 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.06 (dq, J = 17.1, 1.6 Hz, 1H), 5.02 (ddt, J = 10.2, 1.9, 1.1 Hz, 1H), 3.77 (t, J = 7.1 Hz, 2H), 2.45 (tdd, J = 7.0, 5.9, 1.2 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 168.62, 134.75, 134.16, 132.38, 123.48, 117.83, 37.62, 33.13.

General Procedure for Homoallylic Alcohol Synthesis

To a flame-dried schlenk flask with Teflon-coated stir bar was added allylmagnesium chloride (1.7 M, 1.5 equiv). This was cooled to 0 °C, followed by drop-wise addition of aldehyde (1 M in THF). This was allowed to stir for 2 hours at 0 °C, then warmed to room temperature and stirred until reaction was complete. The reaction was quenched with NH4Cl (sat.), extracted with ethyl acetate, washed with brine, dried over MgSO4, and solvent removed under reduced pressure. Products were purified by silica gel chromatography.

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1-phenylbut-3-en-1-ol (1m)

Compound 1m was prepared according to the general procedure with benzaldehyde (50. mmol, 1.0 equiv, 5.0 mL) and allylmagnesium chloride solution (75 mmol, 1.5 equiv, 44 mL). The crude product was purified by silica gel chromatography (9:1 hexanes:ethyl acetate) to afford 1m (7.1 g, 96% yield) as a viscous colorless liquid. The characteristic data matched that found in literature.9 1H NMR (499 MHz, CDCl3): δ 7.38 – 7.27 (m, 5H), 5.82 (ddt, J = 17.2, 10.3, 7.1 Hz, 1H), 5.21 – 5.13 (m, 2H), 4.74 (s, 1H), 2.59 – 2.46 (m, 2H), 2.13 (br, 1H), 2.13. 13C NMR (126 MHz, CDCl3): δ 143.84, 134.42, 128.37, 127.49, 125.78, 118.34, 73.27, 43.79.

1-(4-methoxyphenyl)but-3-en-1-ol (1n)

In a dry Schlenk flask charged with a stir bar, 4-methoxybenzaldehyde (50. mmol, 1.0 equiv, 6.1 mL) and diethyl ether (50.0 mL) were added under N2 and the solution cooled to 0 °C. Allylmagnesium chloride (100 mmol, 2.0 equiv, 59 mL) was added dropwise over 20 minutes, and the reaction was stirred for 2 hours at 0 °C and quenched with saturated ammonium chloride. The crude product was extracted with ethyl acetate, washed with water and brine, dried over MgSO4, and the solvent evaporated under reduced to afford 1n (7.9 g, 89% yield) as a viscous colorless liquid. The characteristic data matched that found in literature.9

1H NMR (499 MHz, CDCl3): δ 7.28 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 5.80 (ddt, J = 17.2, 10.2, 7.0 Hz, 1H), 5.19 – 5.09 (m, 2H), 4.68 (td, J = 6.6, 2.8 Hz, 1H), 3.80 (s, 3H), 2.50 (t, J = 6.9 Hz, 2H), 2.03 (br, 1H). 13C NMR (126 MHz, CDCl3): δ 159.00, 136.04, 134.59, 127.04, 118.16, 113.76, 72.96, 55.25, 43.72.

1-(o-tolyl)but-3-en-1-ol (1o)

Compound 1o was prepared according to the general procedure with 2-methylbenzaldehyde (20. mmol, 1.0 equiv, 2.3 mL) and allylmagnesium chloride solution (30. mmol, 1.5 equiv, 17.7 mL). The crude product was purified by silica gel chromatography (9:1 hexanes:ethyl acetate) to afford 1o (3.0 g, 91% yield) as a viscous colorless liquid. The characteristic data matched that found in literature.9

44


1H NMR (500 MHz, CDCl3): δ 7.49 (dd, J = 7.7, 1.5 Hz, 1H), 7.24 (td, J = 7.4, 1.6 Hz, 1H), 7.19 (td, J = 7.4, 1.5 Hz, 1H), 7.14 (dd, J = 7.4, 1.5 Hz, 1H), 5.87 (dddd, J = 16.7, 10.1, 7.7, 6.4 Hz, 1H), 5.24 – 5.13 (m, 2H), 5.00 – 4.95 (m, 1H), 2.55 – 2.49 (m, 1H), 2.50 – 2.41 (m, 1H), 2.35 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 141.89, 134.69, 134.30, 130.30, 127.19, 126.21, 125.12, 118.24, 69.62, 42.59, 19.03.

1-mesitylbut-3-en-1-ol (1p)

Compound 1p was prepared per the general procedure with 2,4,6-trimethylbenzaldehyde (25 mmol, 1.0 equiv, 3.7 mL) and allylmagnesium chloride solution (38 mmol, 1.5 equiv, 22 mL). The crude product was purified by silica gel chromatography (10% ethyl acetate in hexanes). The compound was distilled under reduced pressure to afford 1p (3.21 g, 68% yield) as a viscous colorless liquid. The characteristic data matched that found in literature.9 1H NMR (500 MHz, CDCl3): δ 6.87 (s, 2H), 5.89 (dddd, J = 16.7, 10.1, 8.0, 6.3 Hz, 1H), 5.25 – 5.15 (m, 3H), 2.81 – 2.70 (m, 1H), 2.53 (dddt, J = 14.2, 6.5, 5.3, 1.4 Hz, 1H), 2.46 (s, 6H), 2.31 (s, 3H), 2.06 (d, J = 2.6 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 136.82, 136.26, 135.59, 130.43, 117.94, 70.97, 40.61, 21.04. Only 8 peaks are reported due to coincidental carbons.

2-(1-hydroxybut-3-en-1-yl)phenol

3-(1-hydroxybut-3-en-1-yl)phenol was prepared according to the general procedure with 3-hydroxybenzaldehyde (40. mmol, 1.0 equiv, 4.9 g) and allylmagnesium chloride (80. mmol, 2.0 equiv, 47 mL). The crude product was purified by silica gel chromatography (1% to 5% methanol in dichloromethane) to afford 3-(1-hydroxybut-3-en-1-yl)phenol (4.3 g, 65% yield) as a tan solid. 1H NMR (500 MHz, DMSO-d6): δ 9.25 (s, 1H), 7.06 (t, J = 7.8 Hz, 1H), 6.79 – 6.67 (m, 2H), 6.59 (ddd, J = 8.0, 2.5, 1.0 Hz, 1H), 5.74 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.16 (d, J = 4.3 Hz, 1H), 5.04 – 4.87 (m, 2H), 4.51 – 4.41 (m, 1H), 2.41 – 2.22 (m, 2H). 13C NMR (126 MHz, DMSO-d6): δ 157.75, 147.86, 136.34, 129.50, 117.23, 117.19, 114.26, 113.42, 72.86, 44.36.

HRMS (ESI-TOF): m/z [M+H+] calculated C18H16NO2 = 187.0735; found mass = 187.0733

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2-(1-hydroxybut-3-en-1-yl)phenyl acetate (1q)

3-(1-hydroxybut-3-en-1-yl)phenol (5.0 mmol, 1.0 equiv, 0.82 g) and DIPEA (15 mmol, 3.0 equiv, 2.6 mL) were dissolved in DCM (75 mL) and cooled to 0 °C. Acetic anhydride (5.5 mmol, 1.1 equiv, 520 µL) was slowly added in a solution of 5.0 mL of DCM. The reaction was allowed to warm to room temperature and stirred for 16 h. After 16 h, aq. NH4Cl was added and the organic layer was extracted with DCM (3 x 100 mL). The combined organic layers were washed with H2O (3 x 100 mL). The organic layer was dried with MgSO4, filtered through Celite and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (10% to 20% ethyl acetate in hexanes) to afford 1q (842 mg, 82% yield) as a viscous colorless liquid. 1H NMR (500 MHz, Chloroform-d): δ 7.34 (d, J = 8.2 Hz, 1H), 7.21 (ddd, J = 7.6, 1.7, 0.9 Hz, 1H), 7.12 – 7.08 (m, 1H), 7.00 (ddd, J = 8.1, 2.4, 1.1 Hz, 1H), 5.80 (ddtd, J = 16.9, 10.3, 7.1, 6.6, 0.9 Hz, 1H), 5.19 – 5.11 (m, 2H), 4.72 (dd, J = 7.8, 5.1 Hz, 1H), 2.57 – 2.38 (m, 2H), 2.29 (s, 1H). 13C NMR (126 MHz, CDCl3): δ 169.80, 150.96, 146.11, 134.43, 129.58, 123.51, 120.79, 119.28, 118.76, 72.98, 43.94, 21.38.


3-(1-hydroxybut-3-en-1-yl)phenyl trifluoromethanesulfonate (1r)

3-(1-hydroxybut-3-en-1-yl)phenol (5.0 mmol, 1.0 equiv, 0.82 g) and DIPEA (15 mmol, 3.0 equiv, 2.6 mL) were dissolved in DCM (75 mL) and cooled to 0 °C. Trifluoromethanesulfonic anhydride (5.2 mmol, 1.05 equiv, 850 µL) was slowly added in a solution of 5 mL of DCM. The reaction was stirred at 0 °C for 2 h. The organic layer was washed with H2O (3 x 100 mL) and brine (1 x 100 mL). The organic layer was dried with MgSO4, filtered through Celite and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (9:1 hexanes:ethyl acetate) to afford 1r (770 mg, 52% yield) as a viscous, slightly tan liquid. 1H NMR (500 MHz, CDCl3): δ 7.43 (t, J = 7.9 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.31 (s, 1H), 7.18 (dd, J = 8.1, 2.6, 1H), 5.78 (dddd, J = 16.8, 10.6, 7.8, 6.5 Hz, 1H), 5.22 – 5.13 (m, 2H), 4.80 (dt, J = 7.9, 3.9 Hz, 1H), 2.54 (dddt, J = 13.9, 6.1, 4.6, 1.4 Hz, 1H), 2.45 (dt, J = 14.7, 8.0 Hz, 1H), 2.16 (d, J = 3.2 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 149.65, 146.98, 133.36, 130.12, 125.68, 120.12, 119.35, 118.72, 118.69 (q, JC,F = 320.7 Hz), 72.09, 43.86.19F NMR (470 MHz, CDCl3): δ -72.95.

HRMS (ESI-TOF): m/z [M+H+] calculated C11H11O4F3S = 295.0252; found = 295.0250.

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1-(3-chlorophenyl)but-3-en-1-ol (1s)

Compound 1s was prepared according to the general procedure with 3-chlorobenzaldehyde (25 mmol, 1.0 equiv, 3.5 g) and allylmagnesium chloride (37.5 mmol, 1.5 equiv, 22.1). The crude product was purified by silica gel chromatography (10% ethyl acetate in hexanes). The compound was distilled under reduced pressure to afford 1s (2.4 g, 53% yield) as a viscous colorless liquid. The characteristic data matched that found in literature.10 1H NMR (500 MHz, CDCl3): δ 7.33 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 5.87 – 5.71 (m, 1H), 5.22 – 5.10 (m, 2H), 4.70 (ddd, J = 7.8, 5.1, 2.3 Hz, 1H), 2.54 – 2.40 (m, 2H), 2.33 (d, J = 2.7 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 142.37, 134.06, 133.20, 128.60, 127.30, 118.89, 72.66, 43.91.

1-(4-(trifluoromethyl)phenyl)but-3-en-1-ol (1t)

Compound 1t was prepared according to the general procedure with 4-(trifluoromethyl)benzaldehyde (25 mmol, 1.0 equiv, 3.3 mL) and allylmagnesium chloride solution (38 mmol, 1.5 equiv, 22 mL). The crude product was purified by silica gel chromatography (10% ethyl acetate in hexanes). The compound was distilled under reduced pressure to afford 1t (3.0 g, 56% yield) as a viscous colorless liquid. The characteristic data matched that found in literature.9

1H NMR (500 MHz, CDCl3): δ 7.60 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 5.84 – 5.73 (m, 1H), 5.19 (m, 1H), 5.17 – 5.14 (m, 1H), 4.78 (dd, J = 8.1, 4.8 Hz, 1H), 2.57 – 2.50 (m, 1H), 2.49 – 2.42 (m, 1H), 2.33 (s, 1H). 13C NMR (126 MHz, CDCl3): δ 147.87, 133.80, 129.79 (q, J = 32.2 Hz), 126.20, 125.45 (q, J = 3.7 Hz), 124.28 (d, J = 272.0 Hz), 119.28, 72.66, 44.00. 19F NMR (376 MHz, CDCl3): δ -65.60.

1-(3,5-bis(trifluoromethyl)phenyl)but-3-en-1-ol (1u)

Compound 1u was prepared according to the general procedure with 3,5-bis(trifluoromethyl)benzaldehyde (10 mmol, 1.0 equiv, 2.4 g) and allylmagnesium chloride (15, 1.5 equiv, 8.8 mL). The crude product was purified

47


by silica gel chromatography (0-20% Ethyl acetate in hexanes) to afford 1u (2.1 g, 75% yield) as a viscous colorless liquid. The characteristic data matched that found in literature.11

1H NMR (500 MHz, CDCl3): δ 7.83 (s, 2H), 7.79 (s, 1H), 5.80 (dddd, J = 16.8, 10.3, 7.9, 6.3 Hz, 1H), 5.27 – 5.17 (m, 2H), 4.88 (dd, J = 8.4, 4.4 Hz, 1H), 2.59 (dddt, J = 14.1, 5.9, 4.3, 1.3 Hz, 1H), 2.45 (dtt, J = 14.1, 8.2, 1.1 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 146.29, 132.98, 131.60 (q, J = 33.3 Hz), 126.02, 121.36 (hept, J = 3.9 Hz), 122.33 (q, J = 273.6, 272.7, 272.1 Hz), 119.90, 71.88, 43.96.

19F NMR (470 MHz, CDCl3): δ -62.88.

1-(furan-2-yl)but-3-en-1-ol (1v)

Compound 1v was prepared according to the general procedure with 2-furaldehyde (25 mmol, 1.0 equiv, 2.1 mL) and allylmagnesium chloride (38 mmol, 22 mL). The crude product was purified by silica gel chromatography (10% ethyl acetate in hexanes). The compound was vacuum distilled to afford 1v (2.5 g, 72% yield) as a colorless liquid. The characteristic data matched that found in literature.9 1H NMR (500 MHz, CDCl3): δ 7.34 (dd, J = 1.8, 0.9 Hz, 1H), 6.30 (dd, J = 3.2, 1.8 Hz, 1H), 6.21 (dt, J = 3.2, 0.8 Hz, 1H), 5.76 (ddt, J = 17.2, 10.2, 7.1 Hz, 1H), 5.17 – 5.03 (m, 2H), 4.73 – 4.63 (m, 1H), 2.79 (s, 1H), 2.65 – 2.51 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 156.11, 141.86, 133.81, 118.22, 110.10, 106.08, 66.89, 40.00.

1-(thiophen-2-yl)but-3-en-1-ol (1w)

Compound 1w was prepared according to the general procedure with thiophene-2-carboxaldehyde (30 mmol, 2.63 mL). The crude product was purified by silica gel chromatography (30% methylene chloride in hexanes) affording 1w (1.7 g, 37% yield) as a yellow oil. Spectra matched those previously reported.9

Rf: (30% methylene chloride in hexanes): 0.37 1H NMR (400 MHz, CDCl3): δ 7.28–7.24 (m, 1H), 7.04–6.94 (m, 2H), 5.84 (ddt, J = 17.2, 10.2, 7.1 Hz, 1H), 5.28–5.13 (m, 2H), 5.05–4.93 (m, 1H), 2.69–2.57 (m, 2H), 2.17 (d, J = 4.1 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 148.03, 134.07, 126.90, 124.85, 123.96, 119.15, 69.62, 44.07.

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(E)-1-phenylhexa-1,5-dien-3-ol (1x)

Compound 1x was prepared according to the general procedure with cinnamaldehyde (20. mmol, 1.0 equiv, 2.5 mL) and allylmagnesium chloride solution (30. mmol, 1.5 equiv, 18 mL). The crude product was purified by silica gel chromatography (9:1 hexanes:ethyl acetate) to afford 1x (3.5 g, 81% yield) as a viscous colorless liquid. The characteristic data matched that found in literature.9 1H NMR (499 MHz, CDCl3): δ 7.39 (dt, J = 8.2, 1.8 Hz, 2H), 7.32 (td, J = 6.9, 6.5, 1.6 Hz, 2H), 7.25 (tt, J = 7.3, 1.2 Hz, 1H), 6.62 (d, J = 15.9, 1H), 6.25 (dd, J = 15.9, 6.3 Hz, 1H), 5.87 (ddt, J = 17.2, 10.2, 7.1 Hz, 1H), 5.23 – 5.14 (m, 2H), 4.37 (q, J = 5.7 Hz, 1H), 2.52 – 2.30 (m, 2H), 1.88 (br, 1H). 13C NMR (101 MHz, CDCl3): δ 136.58, 133.99, 131.48, 130.30, 128.53, 127.62, 126.43, 118.50, 71.66, 41.97.

1-cyclohexylbut-3-en-1-ol (1y)

Compound 1y was prepared according to the general procedure with cyclohexanecarboxaldehyde (25 mmol, 3.0 mL). The crude product was purified by silica gel chromatography (50% methylene chloride in pentane) yielded 1y as a clear oil (1.3 g, 33%). Spectra matched those previously reported.9

Rf (methylene chloride): 0.32 1H NMR (500 MHz, CDCl3): δ 5.84 (ddd, J = 15.8, 11.0, 6.2 Hz, 1H), 5.18–5.05 (m, 2H), 3.46–3.31 (m, 1H), 2.46–2.24 (m, 1H), 2.20–2.06 (m, 1H), 1.90-1.81 (m, 1H), 1.81–1.72 (m, 2H), 1.72–1.63 (m, 2H) 1.54 (d, J = 4.0 Hz, 1H), 1.43–1.31 (m, 1H), 1.30–0.93 (m, 5H). 13C NMR (125 MHz, CDCl3): δ 135.75, 118.26, 75.00, 43.37, 39.11, 29.37, 28.41, 26.80, 26.57, 26.43.

2,2-dimethylhex-5-en-3-ol (1z)

Compound 1z was prepared according to the general procedure with pivaldehyde (20. mmol, 2.2 mL). The crude product was purified by silica gel chromatography (50% methylene chloride in pentane) yielded 1z as a volatile clear oil (620 mg, 24%). Spectra matched those previously reported.9

Rf (50% methylene chloride in pentane): 0.24

49


1H NMR (400 MHz, CDCl3): δ 5.86 (ddd, J = 18.2, 10.8, 5.6 Hz, 1H), 5.22–5.08 (m, 2H), 3.26 (ddd, J = 10.6, 3.4, 2.1 Hz, 1H), 2.37 (m, 1H), 1.98 (m, 1H), 1.59 (d, J = 3.5 Hz, 1H), 0.92 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 136.84, 118.08, 78.38, 36.84, 34.90, 26.03.

9-((tert-butyldimethylsilyl)oxy)non-1-en-4-ol (1ab)

Compound 1ab was prepared according to the general procedure with 6-((tert-butyldimethylsilyl)oxy)hexanal (6.1 mmol, 1.4 g). The crude product was purified by silica gel chromatography (15% ethyl acetate in hexanes) yielded 1ab (1.20 g, 75% yield) as a clear oil. Spectra matched those previously reported.12

Rf (15% ethyl acetate in hexanes): 0.46 1H NMR (400 MHz, CDCl3): δ 5.89–5.77 (m, 1H), 5.22–5.10 (m, 2H), 3.68–3.63 (m, 1H), 3.60 (t, J = 6.6 Hz, 2H), 2.37–2.24 (m, 1H), 2.20–2.08 (m, 1H), 1.60–1.44 (m, 6H), 1.39–1.31 (m, 3H), 0.89 (s, 9H), 0.04 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 135.15, 118.41, 70.88, 68.26, 63.47, 42.24, 37.09, 33.09, 26.27, 26.14, 25.77, -4.97.

non-8-ene-1,6-diol

Under nitrogen, the monoprotected diol (1x above, 17 mmol, 4.75 g) and anhydrous THF (8.5 mL, 2.0 M) were added to an oven-dried schlenk flask equipped with a stir bar. The solution was cooled to 0 ºC, tetrabutylammonium fluoride (1.0 M, in THF, 26 mL, 26 mmol, 1.5 equiv) was added, and the mixture was stirred at rt for 4 h. The reaction was quenched with H2O and extracted with 4 x 50 mL ethyl acetate. Drying with MgSO4, filtering, and removing the solvent under reduced pressure afforded the crude unprotected diol. Column chromatography on silica gel (30% ethyl acetate in hexanes to 100% ethyl acetate) afforded pure unprotected diol as a viscous clear oil (2.2 g, 81%). The spectra matched those previously reported.12

Rf (100% ethyl acetate): 0.57 1H NMR (500 MHz, CDCl3): δ 5.82 (dddd, J = 20.0, 9.5, 8.0, 6.5, 1H), 5.13 (m, 2H), 3.79–3.50 (m, 3H), 2.37–2.23 (m, 1H), 2.21–2.08 (m, 1H), 1.71–1.52 (m, 4H), 1.52–1.44 (m, 3H), 1.43–1.33 (m, 3H). 13C NMR (125 MHz, CDCl3): δ 135.07, 118.44, 70.79, 63.13, 42.27, 36.95, 32.93, 26.01, 25.70.

50


(1-methoxybut-3-en-1-yl)benzene (1ac)

In a dry Schlenk flask charged with a stir bar, anhydrous acetonitrile (10mL) was combined with trifluoroacetic acid (0.5 mmol, 0.1 equiv., 38 µL). To this was added (dimethoxymethyl)benzene (5 mmol, 1 equiv., 750 µL) and allyltrimethylsilane (7.5 mmol, 1.5 equiv., 1.19 mL). This was stirred at room temperature for 24 hours, then added to brine and extracted with Et2O. The combined organic layers were washed with sat. NaHCO3, then brine, and dried of MgSO4 followed by filtration. Column chromatography (19:1 hexanes:ethyl acetate) afforded the product (268.1 mg, 31%). Spectral data matched that previously reported.13 1H NMR (400 MHz, CDCl3): δ 7.39 – 7.33 (m, 2H), 7.33 – 7.26 (m, 3H), 5.77 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.12 – 4.98 (m, 2H), 4.17 (dd, J = 7.5, 5.8 Hz, 1H), 3.22 (s, 3H), 2.57 (pt, J = 7.2, 1.2 Hz, 1H), 2.41 (dddt, J = 14.1, 7.0, 5.8, 1.4 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 141.62, 134.75, 128.30, 127.55, 126.67, 116.82, 83.58, 56.57, 42.49.

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H. Experimental Procedures and Characterization General Procedure for anti-Markovnikov Oxidative Amination

Procedure 1

Pd(OAc)2 (5.6 mg, 0.025 mmol, 0.050 equiv), Bu4NCl (35 mg, 0.125 mmol, 0.25 equiv), Bu4NOAc (23 mg, 0.075 mmol, 0.15 equiv), nucleophile (0.5 mmol, 1 equiv), and 5Å molecular sieves (250 mg) were weighed into a 20 mL vial with a Teflon coated stir bar. N,N-dimethylacetamide (0.50 mL) was added, followed by olefin (1.0 mmol, 2.0 equiv) in one portion. This vial was purged with oxygen gas, then sealed with a septum-lined cap and an oxygen-filled balloon was affixed through the septum. The reaction was heated and stirred at 80 °C for 24 h. GC samples were obtained by addition of 1-methylnaphthalene followed by mixing and sampling, whereas isolation was achieved by solid-loading the crude mixture onto celite, followed by silica gel chromatography using a mixture of hexanes:EtOAc, unless otherwise noted.

Procedure 2

Pd(OAc)2 (11.1 mg, 0.05 mmol, 0.10 equiv), Bu4NCl (56 mg, 0.20 mmol, 0.4 equiv), Bu4NOAc (15 mg, 0.050 mmol, 0.10 equiv), nucleophile (0.5 mmol, 1 equiv), and 5Å molecular sieves (250 mg) were weighed into a 20 mL vial with a Teflon coated stir bar. N,N-dimethylacetamide (0.50 mL) was added, followed by olefin (1.0 mmol, 2.0 equiv) in one portion. This vial was purged with oxygen gas, then sealed with a septum-lined cap and an oxygen-filled balloon was affixed through the septum. The reaction was heated and stirred at 80 °C for 24 h. GC samples were obtained by addition of 1-methylnaphthalene followed by mixing and sampling, whereas isolation was achieved by solid-loading the crude mixture onto celite, followed by silica gel chromatography using a mixture of hexanes:EtOAc, unless otherwise noted.

(Note – A high surface area-to-volume ratio and rapid stirring (800 rpm) is critical to the success of this reaction, as attempts to use smaller reaction vessels led to catalyst decomposition. Similarly, when performed on 5 mmol scale, a 250 mL round bottom flask was used)

(E)-2-(4-phenylbut-3-en-1-yl)isoindoline-1,3-dione (2a)

Compound 2a was prepared according to General Procedure 1 with 4-phenyl-1-butene (1.0 mmol, 132 mg) and phthalimide (0.5 mmol, 74 mg). The crude mixture (11:1 a-M:M crude selectivity) was purified by silica gel chromatography (10% ethyl acetate in hexanes) to afford 2a (79 mg, 57% yield) as a white solid.

Rf (9:1 Hexanes:Ethyl Acetate): 0.20

m.p.: 130-134 °C 1H NMR (500 MHz, CDCl3): δ 7.84 (dt, J = 6.9, 3.4 Hz, 2H), 7.71 (dp, J = 6.7, 3.6 Hz, 2H), 7.34 – 7.26 (m, 4H), 7.23 – 7.19 (m, 1H), 6.45 (d, J = 16.1 Hz, 1H), 6.20 (dt, J = 15.8, 7.1 Hz, 1H), 3.86 (t, J = 7.1 Hz, 2H), 2.63 (qd, J = 7.2, 1.5 Hz, 2H).

52


13C NMR (126 MHz, CDCl3) δ 168.48, 137.38, 134.04, 132.74, 132.23, 128.61, 127.36, 126.30, 126.28, 123.37, 37.73, 32.38.

IR (neat): 3025 (s), 1771 (s), 1702 (s), 1615 (s) cm-1.

HRMS (ESI-TOF): m/z [M+H+] calculated C18H16NO2 = 278.1181; found mass = 278.1178.

(E)-2-(4-(4-methoxyphenyl)but-3-en-1-yl)isoindoline-1,3-dione (2b)

Compound 2b was prepared according to General Procedure 1 with 4-(4-methoxyphenyl)-1-butene (1.0 mmol, 162 mg) and phthalimide (0.50 mmol, 74 mg). The crude mixture (10:1 a-M:M selectivity) was purified by silica gel chromatography (7.5-10% ethyl acetate in hexanes) gave 2b (83 mg, 54% yield) as a white solid.

Rf (10% ethyl acetate in hexanes): 0.30

m.p.: 139.3-140.5 °C (lit.14 136.5-138.0 ºC). 1H NMR (500 MHz, CDCl3): δ 7.83 (dd, J = 5.4, 3.1 Hz, 2H), 7.69 (dd, J = 5.5, 3.0 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 6.37 (d, J = 15.8 Hz, 1H), 6.03 (dt, J = 15.7, 7.1 Hz, 1H), 3.83 (t, J = 7.1 Hz, 2H), 3.79 (s, 3H), 2.58 (dt, J = 7.1, 1.4 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 168.50, 159.07, 134.02, 132.25, 132.10, 130.23, 127.40, 124.07, 123.36, 114.04, 55.42, 37.87, 32.37. IR (neat): 3034, 2937, 2842, 1771, 1704, 1606 cm-1.


(E)-2-(4-(p-tolyl)but-3-en-1-yl)isoindoline-1,3-dione (2c)

Compound 2c was prepared according to General Procedure 1 with 1-(but-3-en-1-yl)-4-methylbenzene (1.0 mmol, 146 mg) and phthalimide (0.5 mmol, 74 mg). The crude mixture (14:1 a-M:M selectivity) was purified by silica gel chromatography (5% to 7.5% ethyl acetate in hexanes) to afford 2c (75 mg, 51% yield) as a white solid.


N

O

O

MeO

53


m.p.: 112-114 °C 1H NMR (500 MHz, CDCl3): δ 7.85 (dd, J = 5.4, 3.0 Hz, 2H), 7.72 (dd, J = 5.5, 3.0 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 7.9 Hz, 2H), 6.42 (d, J = 15.9 Hz, 1H), 6.14 (dt, J = 15.7, 7.1 Hz, 1H), 3.86 (t, J = 7.2 Hz, 2H), 2.62 (qd, J = 7.2, 1.4 Hz, 2H), 2.33 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 168.49, 137.13, 134.02, 132.59, 132.25, 129.31, 126.18, 125.22, 123.37, 37.80, 32.37, 21.30.

IR (neat): 3026, 2932, 1771 (s), 1706 (s), cm-1.

HRMS (ESI-TOF): m/z [M+H+] calculated C19H18NO2 =292.1338; found mass =292.1328

(E)-2-(4-(4-chlorophenyl)but-3-en-1-yl)isoindoline-1,3-dione (2d)

Compound 2d was prepared according to General Procedure 1 with 1-(but-3-en-1-yl)-4-chlorobenzene (1.0 mmol, 167 mg) and phthalimide (0.5 mmol, 74 mg). The crude mixture (27:1 a-M:M selectivity) was purified by silica gel chromatography (5% to 7.5% ethyl acetate in hexanes) to afford 2d (105 mg, 67% yield) as a white solid.


m.p.: 120-122 °C 1H NMR (500 MHz, CDCl3): δ 7.83 (dd, J = 5.4, 3.1 Hz, 2H), 7.70 (dd, J = 5.5, 3.0 Hz, 2H), 7.25 – 7.19 (m, 4H), 6.37 (dt, J = 15.9, 1.4 Hz, 1H), 6.15 (dt, J = 15.8, 7.1 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 168.47, 135.86, 134.09, 132.97, 132.19, 131.52, 128.76, 127.49, 127.11, 123.40, 37.62, 32.38.

IR (neat): 1773 (s), 1701 (s), 1490, 1400 (s) cm-1.

HRMS (ESI-TOF): m/z [M+H+] calculated C18H15ClNO2 =312.0791; found mass =312.0793

(E)-2-(4-(4-(trifluoromethyl)phenyl)but-3-en-1-yl)isoindoline-1,3-dione (2e)

Compound 2e was prepared according to General Procedure 1 with 1-(but-3-en-1-yl)-4-(trifluoromethyl)benzene (1.0 mmol, 200 mg) and phthalimide (0.50 mmol, 74 mg). The crude mixture (8:1 a-

54


M:M selectivity) was purified by silica gel chromatography (7.5% ethyl acetate in hexanes) gave 2e (97 mg, 56% yield) as a white solid.


m.p.: 140-142 °C 1H NMR (500 MHz, CDCl3) δ 7.83 (dd, J = 5.4, 3.0 Hz, 2H), 7.70 (dd, J = 5.4, 3.0 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 6.45 (d, J = 15.8 Hz, 1H), 6.28 (dt, J = 15.6, 7.1 Hz, 1H), 3.87 (t, J = 6.9 Hz, 2H), 2.64 (q, J = 7.0 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 168.44, 140.78, 134.11, 132.15, 131.44, 129.25, 129.18 (q, J = 32.4 Hz), 126.40 125.57 (q, J = 3.8 Hz), 125.42, 124.34 (q, J = 271.1), 123.40, 37.47, 32.43. 19F NMR (470 MHz, CDCl3) δ -62.55.

IR (neat): 2938, 1775, 1701, 1615, 1397 cm-1.

HRMS (ESI-TOF): m/z [M+H+] calculated C19H15F3NO2 = 346.1055; found mass = 346.1048.

2-cinnamylisoindoline-1,3-dione (2f)

Compound 2f was prepared according to General Procedure 2 with allyl benzene (1.0 mmol, 118 mg) and phthalimide (0.5 mmol, 74 mg). The crude mixture (47:1 a-M:M selectivity) was purified by silica gel chromatography (5% to 10% ethyl acetate in hexanes) to afford 2f (65 mg, 47% yield) as a white solid.


m.p.: 142-152 °C 1H NMR (500 MHz, CDCl3): δ 7.85 (dt, J = 6.8, 3.4 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 7.35 (d, J = 7.3 Hz, 2H), 7.28 (t, J = 7.5 Hz, 3H), 7.24 – 7.21 (m, 1H), 6.66 (d, J = 15.8 Hz, 1H), 6.26 (dt, J = 15.8, 6.5 Hz, 1H), 4.45 (dd, J = 6.4, 1.4 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 168.10, 136.38, 134.12, 133.95, 132.33, 128.67, 128.03, 126.67, 123.46, 122.87, 39.83.

IR (neat): 3044 (s), 3025 (s), 1770 (s), 1701 (br), 1611 (s) cm-1.


55


(E)-2-(3-(4-methoxyphenyl)allyl)isoindoline-1,3-dione (2g)

Compound 2g was prepared according to General Procedure 2 with 4-vinylanisole (1.0 mmol, 148 mg) and phthalimide (0.5 mmol, 74 mg). The crude mixture (6:1 a-M:M selectivity) was purified by silica gel chromatography (5% to 10% ethyl acetate in hexanes) to afford 2g (85 mg, 54% yield) as a white solid.


m.p.: 118-132 °C 1H NMR (500 MHz, CDCl3): δ 7.86 (dd, J = 5.5, 3.1 Hz, 2H), 7.72 (dd, J = 5.6, 3.1 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 15.8 Hz, 1H), 6.13 (dt, J = 15.8, 6.6 Hz, 1H), 4.43 (d, J = 6.6 Hz, 2H), 3.79 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 168.14, 159.56, 134.07, 133.52, 132.36, 129.17, 127.88, 123.42, 120.61, 114.07, 55.41, 39.92.

IR (neat): 3029 (s), 1768 (s), 1706 (s), 1606 (s) cm-1.


(E)-2-(3-(p-tolyl)allyl)isoindoline-1,3-dione (2h)

Compound 2h was prepared according to General Procedure 2 with 1-allyl-4-methylbenzene (1.0 mmol, 132 mg) and phthalimide (0.5 mmol, 74 mg). The crude mixture (37:1 a-M:M selectivity) was purified by silica gel chromatography (10% ethyl acetate in hexanes) to afford 2h (94 mg, 68% yield) as a white solid.


m.p.: 154-157 °C 1H NMR (500 MHz, CDCl3): δ 7.86 (dd, J = 5.4, 3.0 Hz, 2H), 7.72 (dd, J = 5.5, 3.0 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 7.09 (d, J = 7.9 Hz, 2H), 6.63 (d, J = 16.0 Hz, 1H), 6.20 (dt, J = 15.8, 6.5 Hz, 1H), 4.43 (dd, J = 6.6, 1.3 Hz, 2H), 2.31 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 168.14, 137.89, 134.10, 133.89, 133.61, 132.36, 129.37, 126.58, 123.45, 121.79, 39.90, 21.35.

IR (neat): 3046 (s), 2914 (s), 1771 (s), 1696 (s) cm-1.


56


(E)-2-(3-(4-chlorophenyl)allyl)isoindoline-1,3-dione (2i)

Compound 2i was prepared according to General Procedure 2 with 1-allyl-4-chlorobenzene (1.0 mmol, 153 mg) and phthalimide (0.5 mmol, 74 mg). The crude mixture (24:1 a-M:M selectivity) was purified by silica gel chromatography (10% ethyl acetate in hexanes) to afford 2i (74 mg, 50% yield) as a white solid.


m.p.: 146-149 °C 1H NMR (500 MHz, CDCl3): δ 7.87 (dd, J = 5.4, 3.0 Hz, 2H), 7.73 (dd, J = 5.5, 3.0 Hz, 2H), 7.31 – 7.22 (m, 6H), 6.60 (d, J = 15.8 Hz, 1H), 6.23 (dt, J = 15.8, 6.4 Hz, 1H), 4.44 (d, J = 6.4 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 168.08, 134.89, 134.19, 133.70, 132.65, 132.29, 128.85, 127.89, 123.61, 123.52, 39.71.

IR (neat): 3028 (s), 2918 (s), 1770 (s), 1698 (s) cm-1.

HRMS (ESI-TOF): m/z [M+H+] calculated C17H13ClNO2 = 298.0635; found mass = 298.0632

(E)-2-(3-(4-(trifluoromethyl)phenyl)allyl)isoindoline-1,3-dione (2j)

Compound 2j was prepared according to General Procedure 2 with 4-(trifluoromethyl)allylbenzene (1.0 mmol, 186 mg) and phthalimide (0.5 mmol, 74 mg). The crude mixture (57:1 a-M:M selectivity) was purified by silica gel chromatography (5% to 10% ethyl acetate in hexanes) to afford 2j (68 mg, 41% yield) as a white solid.


m.p.: 140-143 °C 1H NMR (500 MHz, CDCl3): δ 7.87 (dd, J = 5.4, 3.1 Hz, 2H), 7.73 (dd, J = 5.5, 3.0 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 6.66 (d, J = 15.9 Hz, 1H), 6.35 (dt, J = 15.9, 6.3 Hz, 1H), 4.47 (dd, J = 6.4, 1.4 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 168.02, 139.81, 134.22, 132.33, 132.20, 129.77 (q, J = 32.6 Hz), 126.81, 125.67, 125.61 (q, J = 4.0 Hz), 124.22 (d, J = 271.9 Hz), 123.52, 39.59. 19F NMR (470 MHz, CDCl3): δ -62.94.

IR (neat): 3027 (s), 1769 (s), 1698 (s), 1616 (s) cm-1.

HRMS (ESI-TOF): m/z [M+H+] calculated C18H13F3NO2 = 332.0898; found mass = 332.0896.

57


(E)-2-(5-phenylpent-4-en-1-yl)isoindoline-1,3-dione (2k)

Compound 2k was prepared according to General Procedure 1 with pent-4-en-1-ylbenzene (1.0 mmol, 146 mg) and phthalimide (0.50 mmol, 74 mg). The crude mixture (8:1 a-M:M selectivity) was purified by silica gel chromatography (7.5% ethyl acetate in hexanes) to afford 2k (a-M) (34 mg, 23% yield) as a white solid.


m.p.: 78-80 °C 1H NMR (500 MHz, CDCl3) δ 7.83 (dd, J = 5.4, 3.0 Hz, 2H), 7.69 (dd, J = 5.5, 3.0 Hz, 2H), 7.32 – 7.27 (m, 3H), 7.20 – 7.15 (m, 1H), 6.41 (dt, J = 15.7, 1.5 Hz, 1H), 6.20 (dt, J = 15.8, 6.8 Hz, 1H), 3.75 (t, J = 7.1 Hz, 2H), 2.29 (ddd, J = 14.8, 7.0, 1.3 Hz, 2H), 1.88 (p, J = 7.4 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 168.60, 137.63, 134.01, 132.26, 130.79, 129.28, 128.57, 127.07, 126.09, 123.31, 37.78, 30.50, 28.15.

IR (neat): 3032, 2937, 1769, 1695, 1433, 1400 cm-1.


General Procedure for anti-Markovnikov Oxidative Amination of Homoallylic Alcohols:

Pd(OAc)2 (5.6 mg, 0.025 mmol, 0.050 equiv), Bu4NCl (28 mg, 0.10 mmol, 0.20 equiv), nucleophile (0.55 mmol, 1.1 equiv), and 5Å molecular sieves (250 mg) were weighed into a 20 mL vial with a Teflon coated stir bar. N,N-dimethylacetamide (0.50 mL) was added, followed by olefin (0.50 mmol, 1.0 equiv) in one portion via syringe. This vial was purged with oxygen gas, then sealed with a septum-lined cap and an oxygen-filled balloon was affixed through the septum. The reaction was heated and stirred at 80 °C for 24 h. GC samples were obtained by addition of 1-methylnaphthalene followed by mixing and sampling, whereas isolation was achieved by solid-loading the crude mixture onto celite, followed by silica gel chromatography using a mixture of hexanes:EtOAc, unless otherwise noted.

Note – for alpha alkyl homoallylic alcohols, an additional 5 mol % Bu4NOAc was added via a stock solution in DMA.

Note – A high surface area-to-volume ratio and rapid stirring (800 rpm) is critical to the success of this reaction, as attempts to use smaller reaction vessels led to catalyst decomposition. Similarly, when performed on 5 mmol scale, a 250 mL round bottom flask was used.

2-(4-oxo-4-phenylbutyl)isoindoline-1,3-dione (2m)

58


Compound 2m was prepared according to the general procedure for homoallylic alcohols with 1m (0.50 mmol, 74 mg) and phthalimide (0.55 mmol, 81 mg). The crude mixture (14:1 a-M:M selectivity) was purified by silica gel chromatography (7:1 Hexanes:Ethyl Acetate) then washed with NaOH (to remove co-eluting phthalimide) to afford 2m (110 mg, 75% yield) as a white solid.

This procedure was modified to 10x the standard scale, as follows:

Pd(OAc)2 (56 mg, 0.25 mmol, 0.050 equiv), Bu4NCl (278 mg, 1.0 mmol, 0.20 equiv), phthalimide (5.5 mmol, 810 mg, 1.1 equiv), and 5Å molecular sieves (2.50 g) were weighed into a 250 mL round bottom flask equipped with a Teflon coated stir bar. N,N-dimethylacetamide (5.0 mL) was added, followed by 1i (5.0 mmol, 740 mg, 1.0 equiv) in one portion via syringe. This flask was purged with oxygen gas, then sealed with a septum and 4 oxygen-filled balloons were affixed through the septum. The reaction was heated and stirred at 80 °C for 24 h. The crude product was purified by silica gel chromatography (7:1 Hexanes:Ethyl Acetate) then washed with NaOH (to remove co-eluting phthalimide) to afford 2i (1.12 g, 77% yield) as a white solid.


m.p.: 128-130 °C 1H NMR (500 MHz, CDCl3): δ 7.92 (dd, J = 8.4, 1.4 Hz, 2H), 7.84 (dd, J = 5.4, 3.1 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 7.55 (tt, J = 7.5, 7.4, 1.3, 1.2 Hz, 1H), 7.44 (dd, J = 8.3, 7.2 Hz, 2H), 3.83 (t, J = 6.8 Hz, 2H), 3.06 (t, J = 7.3 Hz, 2H), 2.15 (p, J = 7.0 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 198.96, 168.59, 136.89, 134.09, 133.19, 132.21, 128.71, 128.12, 123.40, 37.61, 35.92, 23.30.

IR (neat): 2955, 2925, 2852, 1771, 1702, 1693 cm-1.


2-(4-(4-methoxyphenyl)-4-oxobutyl)isoindoline-1,3-dione (2n)

Compound 2n was prepared according to the general procedure for homoallylic alcohols with 1j (0.50 mmol, 89 mg) and phthalimide (0.55 mmol, 81 mg). The crude mixture (14:1 a-M:M selectivity) was purified by silica gel chromatography (4:1 Hexanes:Ethyl Acetate) to afford 2n (90 mg, 56% yield) as a white solid.


m.p.: 112-113 °C 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 8.9 Hz, 2H), 7.84 (dd, J = 5.4, 3.0 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 3.86 (s, 3H), 3.81 (t, J = 6.9 Hz, 2H), 3.00 (t, J = 7.3 Hz, 2H), 2.13 (p, J = 7.1 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 197.35, 168.42, 163.39, 133.90, 132.08, 130.24, 129.87, 123.22, 113.67, 55.44, 37.54, 35.40, 23.33.

59


IR (neat): 2941, 1770, 1702, 1671, 1598 cm-1.


2-(4-oxo-4-(o-tolyl)butyl)isoindoline-1,3-dione (2o)

Compound 2o was prepared according to the general procedure for homoallylic alcohols with 1o (0.50 mmol, 81 mg) and phthalimide (0.55 mmol, 81 mg). The crude mixture (20:1 a-M:M selectivity) was purified by silica gel chromatography (7:1 Hexanes:Ethyl Acetate) then washed with NaOH (to remove co-eluting phthalimide) to afford 2o (98 mg, 64% yield) as a white solid.


m.p.: 105-107 °C 1H NMR (500 MHz, CDCl3): δ 7.84 (dd, J = 5.4, 3.1 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 7.61 (dd, J = 7.7, 1.4 Hz, 1H), 7.35 (td, J = 7.5, 1.4 Hz, 1H), 7.25 – 7.21 (m, 2H), 3.81 (t, J = 6.8 Hz, 2H), 2.97 (t, J = 7.2 Hz, 2H), 2.46 (s, 3H), 2.11 (p, J = 7.0 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 202.99, 168.59, 138.17, 137.91, 134.08, 132.21, 132.05, 131.36, 128.51, 125.80, 123.40, 38.73, 37.57, 23.38, 21.38.

IR (neat): 3103, 3046, 1774, 1699, 1676 cm-1.


2-(4-mesityl-4-oxobutyl)isoindoline-1,3-dione (2p)

Compound 2p was prepared according to the general procedure for homoallylic alcohols with 1p (0.50 mmol, 95 mg) and phthalimide (0.55 mmol, 81 mg). The crude mixture (18:1 a-M:M selectivity) was purified by silica gel chromatography (15% ethyl acetate in hexanes) then washed with NaOH (to remove co-eluting phthalimide) to afford 2p (52 mg, 31% yield) as a white solid.


m.p.: 145-150 °C 1H NMR (500 MHz, CDCl3): δ 7.83 (dd, J = 5.4, 3.1 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 6.80 (s, 2H), 3.78 (t, J = 7.0 Hz, 2H), 2.75 (t, J = 7.4 Hz, 2H), 2.25 (s, 3H), 2.16 (s, 6H), 2.10 (p, J = 7.2 Hz, 2H).

60


13C NMR (126 MHz, CDCl3): δ 209.60, 168.59, 139.59, 138.62, 134.23, 132.75, 132.28, 128.72, 123.50, 42.20, 37.72, 22.98, 21.28, 19.41.

IR (neat): 3035 (s), 1762 (s), 1699 (s), 1609 (s) cm-1.


3-(4-(1,3-dioxoisoindolin-2-yl)butanoyl)phenyl acetate (2q)

Compound 2q was prepared according to the general procedure for homoallylic alcohols with 1q (0.50 mmol, 103 mg) and phthalimide (0.55 mmol, 81 mg). The crude mixture (>20:1 a-M:M selectivity) was purified by silica gel chromatography (20% to 50% ethyl acetate in hexanes) to afford 2q (134 mg, 76% yield) as a white solid.


m.p.: 120-124 °C 1H NMR (500 MHz, CDCl3): δ 7.83 (dd, J = 5.4, 3.1 Hz, 2H), 7.79 (dt, J = 7.8, 1.3 Hz, 1H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 7.63 (t, J = 2.0 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.28 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 3.81 (t, J = 6.8 Hz, 2H), 3.03 (t, J = 7.2 Hz, 2H), 2.31 (s, 3H), 2.14 (p, J = 7.0 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 197.74, 169.29, 168.48, 150.92, 138.24, 134.03, 132.10, 129.70, 126.46, 125.48, 123.32, 121.18, 37.43, 35.93, 23.10, 21.14.

IR (neat): 3046 (s), 1759 (s), 1702 (s), 1679 (s), 1586 (s) cm-1.


3-(4-(1,3-dioxoisoindolin-2-yl)butanoyl)phenyl trifluoromethanesulfonate (2r)

Compound 2r was prepared according to the general procedure for homoallylic alcohols with 1r (0.50 mmol, 148 mg) and phthalimide (0.55 mmol, 81 mg). The crude mixture (10:1 a-M:M selectivity) was purified by silica gel chromatography (5:1 Hexanes:Ethyl Acetate) to afford 2r (107 mg, 49% yield) as a white solid.


m.p.: 50-52 °C

61


1H NMR (500 MHz, CDCl3): δ 7.94 (dt, J = 7.8, 1.2 Hz, 1H), 7.84 (dd, J = 5.4, 3.1 Hz, 2H), 7.81 (dd, J = 2.6, 1.5 Hz, 1H), 7.72 (dd, J = 5.5, 3.0 Hz, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.47 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 3.83 (t, J = 6.7 Hz, 2H), 3.06 (t, J = 7.1 Hz, 2H), 2.16 (p, J = 6.9 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 196.62, 168.40, 149.73, 138.90, 133.97, 131.93, 130.61, 127.77, 125.65, 123.22, 120.69, 118.60 (q, J = 321.0 Hz), 37.15, 35.86, 22.81. In the 13C NMR there is slight C,H coupling observed due to incomplete decoupling by the instrument with concentrated samples. The peaks have been reported at the center of the observed doublets. 19F NMR (470 MHz, CDCl3): δ -72.80.

IR (neat): 2928, 2942, 1770, 1711, 1683, 1579 cm-1.

HRMS (ESI-TOF): m/z [M+H+] calculated C19H15NO6F3S = 442.0572; found mass = 442.0565.

2-(4-(3-chlorophenyl)-4-oxobutyl)isoindoline-1,3-dione (2s)

Compound 2s was prepared according to the general procedure for homoallylic alcohols with 1s (0.5 mmol, 91 mg) and phthalimide (0.55 mmol, 81 mg). The crude mixture (16:1 a-M:M selectivity) was purified by silica gel chromatography (15% ethyl acetate in hexanes) then washed with NaOH (to remove co-eluting phthalimide) to afford 2s (129 mg, 79% yield) as a white solid.


m.p.: 120-122 °C

1H NMR (500 MHz, CDCl3): δ 7.83 – 7.79 (m, 2H), 7.78 (dd, J = 5.4, 3.1 Hz, 2H), 7.67 (dd, J = 5.5, 3.0 Hz, 2H), 7.37 – 7.32 (m, 2H), 3.77 (t, J = 6.7 Hz, 2H), 2.99 (t, J = 7.2 Hz, 2H), 2.10 (p, J = 7.0 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 197.55, 168.42, 139.42, 135.08, 133.99, 132.04, 129.42, 128.87, 123.25, 37.37, 35.72, 23.07. There are two fewer signals reported due to coincidental carbons.

IR (neat): 3089 (s), 1765 (s), 1705 (s), 1679 (s), 1580 (s) cm-1.

HRMS (ESI-TOF):: m/z [M+H+] calculated C20H18NO5 = 328.0662; found mass = 328.0698.

2-(4-oxo-4-(4-(trifluoromethyl)phenyl)butyl)isoindoline-1,3-dione (2t)

62


Compound 2t was prepared according to the general procedure for homoallylic alcohols with 1t (0.50 mmol, 108 mg) and phthalimide (0.55 mmol, 81 mg). The crude mixture (19:1 a-M:M selectivity) was purified by silica gel chromatography (15% ethyl acetate in hexanes) then washed with NaOH (to remove co-eluting phthalimide) to afford 2t (130 mg, 72% yield) as a white solid.


m.p.: 160-163 °C 1H NMR (500 MHz, CDCl3): δ 8.00 (d, J = 8.1 Hz, 2H), 7.81 (dd, J = 5.4, 3.1 Hz, 2H), 7.73 – 7.65 (m, 4H), 3.81 (t, J = 6.7 Hz, 2H), 3.07 (t, J = 7.1 Hz, 2H), 2.15 (p, J = 6.9 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 197.94, 168.56, 139.51, 134.40 (q, J = 32.7 Hz), 134.12, 132.12, 128.41, 125.76 (q, J = 3.8 Hz), 123.69 (q, J = 272.7 Hz), 123.38, 37.38, 36.13, 23.04. 19F NMR (376 MHz, CDCl3): δ -63.52.

IR (neat): 1774 (s), 1707 (s), 1691 (s), 1618 (s) cm-1.

HRMS (ESI-TOF): m/z [M+H+] calculated C19H15NO3F3 = 362.1004; found mass = 362.1001.

2-(4-(3,5-bis(trifluoromethyl)phenyl)-4-oxobutyl)isoindoline-1,3-dione (2u)

Compound 2u was prepared according to the general procedure for homoallylic alcohols with 1u (0.50 mmol, 142 mg) and phthalimide (0.55 mmol, 81 mg). The crude mixture (>20:1 a-M:M selectivity) was purified by silica gel chromatography (9:1 Hexanes:Ethyl Acetate) to afford 2u (121 mg, 56% yield) as a white solid.


m.p.: 112-114 °C 1H NMR (500 MHz, CDCl3): δ 8.33 (s, 2H), 8.06 (s, 1H), 7.83 (dd, J = 5.4, 3.1 Hz, 2H), 7.72 (dd, J = 5.5, 3.0 Hz, 2H), 3.84 (t, J = 6.6 Hz, 2H), 3.11 (t, J = 6.9 Hz, 2H), 2.20 (p, J = 6.8 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 195.97, 168.45, 138.17, 134.04, 132.25 (q, J = 34.0 Hz), 131.94, 127.96, 126.22, 123.26, 122.84 (q, J = 273.0 Hz), 37.03, 35.77, 22.69. 19F NMR (470 MHz, CDCl3): δ -62.98.

IR (neat): 2985, 1775, 1766, 1703, 1614 cm-1.

HRMS (ESI-TOF): m/z [M+H+] calculated C20H14NO3F6 = 430.0878; found mass = 430.0882.

63


2-(4-(furan-2-yl)-4-oxobutyl)isoindoline-1,3-dione (2v)

Compound 2v was prepared according to the general procedure for homoallylic alcohols with 1v (0.50 mmol, 69 mg) and phthalimide (0.55 mmol, 81 mg). The crude mixture (14:1 a-M:M selectivity) was purified by silica gel chromatography (20% ethyl acetate in hexanes) then washed with NaOH (to remove co-eluting phthalimide) to afford 2v (98 mg, 69% yield) as a white solid.


m.p.: 122-125 °C

1H NMR (500 MHz, CDCl3): δ 7.82 (dd, J = 5.4, 3.1 Hz, 2H), 7.70 (dd, J = 5.5, 3.0 Hz, 2H), 7.53 (dd, J = 1.7, 0.8 Hz, 1H), 7.15 (dd, J = 3.6, 0.8 Hz, 1H), 6.50 (dt, J = 3.5, 1.7 Hz, 1H), 3.78 (t, J = 6.9 Hz, 2H), 2.89 (dd, J = 8.2, 6.7 Hz, 2H), 2.10 (p, J = 7.0 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 188.14, 168.46, 152.61, 146.38, 134.05, 132.15, 123.34, 117.06, 112.30, 37.53, 35.70, 23.06.

IR (neat): 3132 (s), 1763 (s), 1702 (s), 1667 (s), 1569 (s), 1566 (s) cm-1.


2-(4-oxo-4-(thiophen-2-yl)butyl)isoindoline-1,3-dione (2w)

Compound 2w was prepared according to the general procedure for homoallylic alcohols with 1w (0.50 mmol, 77 mg) and phthalimide (0.55 mmol, 81 mg). The crude mixture (>20:1 a-M:M selectivity) was purified by silica gel chromatography (10-20% ethyl acetate in hexanes) to afford 2w as an off-white powder (117 mg, 78%).


mp: 121-123 ºC (lit.15 118.5-121.5 ºC). 1H NMR (500 MHz, CDCl3): δ 7.82 (dd, J = 5.4, 3.0 Hz, 2H), 7.70 (dd, J = 5.5, 3.0 Hz, 2H), 7.68 (dd, J = 3.9, 1.2 Hz, 1H), 7.60 (dd, J = 5.0, 1.2 Hz, 1H), 7.10 (dd, J = 5.0, 3.8 Hz, 1H), 3.80 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 7.3 Hz, 2H), 2.14 (p, J = 7.1 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 191.84, 168.50, 144.09, 134.07, 133.68, 132.15, 131.99, 128.18, 123.36, 37.52, 36.57, 23.50.

IR (neat): 3100, 2954, 2952, 2926, 1770, 1701, 1692 cm-1.

64


HRMS (ESI-TOF): m/z [M+H+] calculated for C16H14NO3S, 300.0694; found, 300.0967.

(E)-2-(4-oxo-6-phenylhex-5-en-1-yl)isoindoline-1,3-dione (2x)

Compound 2x was prepared according to the general procedure for homoallylic alcohols with 1x (0.50 mmol, 87 mg) and phthalimide (0.55 mmol, 81 mg). The crude mixture (>20:1 a-M:M selectivity) was purified by silica gel chromatography (5:1 Hexanes:Ethyl Acetate) to afford 2x (92 mg, 53% yield) as a white solid.


m.p.: 121-122 °C 1H NMR (500 MHz, CDCl3): δ 7.84 (dd, J = 5.4, 3.0 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 7.55 – 7.49 (m, 3H),7.40 – 7.36 (m, 3H), 6.73 (d, J = 16.2 Hz, 1H), 3.79 (t, J = 6.8 Hz, 2H), 2.75 (t, J = 7.3 Hz, 2H), 2.09 (p, J = 7.0 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 198.90, 168.58, 142.74, 134.58, 134.09, 132.22, 130.60, 129.06, 128.45, 126.01, 123.40, 38.21, 37.60, 23.29.

IR (neat): 3041, 1770, 1707, 1692, 1665, 1617 cm-1.


2-(4-oxopentyl)isoindoline-1,3-dione (2y)

Compound 2y was prepared according to the general procedure for homoallylic alcohols with the 1y (0.50 mmol, 69 mg) and phthalimide (0.55 mmol, 81 mg) and Bu4NOAc (7.5 mg, 0.05 equiv). The crude mixture (9:1 a-M:M selectivity) was purified by silica gel chromatography (4:1 Hexanes:Ethyl Acetate) to afford 2y (76 mg, 66% yield as a white solid.


m.p.: 71-72 °C 1H NMR (500 MHz, CDCl3): δ 7.84 (ddd, J = 5.4, 3.1, 0.8 Hz, 2H), 7.71 (ddd, J = 5.4, 3.0, 0.7 Hz, 2H), 3.70 (t, J = 6.6 Hz, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.14 (s, 3H), 1.95 (p, J = 7.0 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 207.60, 168.60, 134.12, 132.18, 123.38, 40.69, 37.34, 30.09, 22.82.

IR (neat): 2925, 1770, 1711, 1608 cm-1.

65



2-(4-cyclohexyl-4-oxobutyl)isoindoline-1,3-dione (2z)

Compound 2z was prepared according to the general procedure for homoallylic alcohols with 1z (0.50 mmol, 77 mg) and phthalimide (0.55 mmol, 81 mg) and Bu4NOAc (7.5 mg, 0.05 equiv). The crude mixture (13:1 a-M:M selectivity) was purified by silica gel chromatography (5-10% ethyl acetate in hexanes) to afford 2z as a white powder (107 mg, 71%)


m.p.: 86-87.5 ºC 1H NMR (500 MHz, CDCl3): δ 7.84 (dd, J = 5.4, 3.0 Hz, 2H), 7.71 (dd, J = 5.4, 3.0 Hz, 2H), 3.70 (t, J = 6.8 Hz, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.37-2.35 (m, 1H), 1.94 (p, J = 7.0 Hz, 2H), 1.86-1.70 (m, 4H), 1.69-1.59 (m, 1H), 1.37-1.11 (m, 5H). 13C NMR (125 MHz, CDCl3): δ 212.85, 168.58, 134.06, 132.22, 123.36, 50.85, 37.81, 37.56, 28.63, 25.96, 25.79, 22.76.

IR (neat): 2935, 2851, 1770, 1697, 1614 cm-1.

HRMS (ESI-TOF): m/z [M+H+] calculated for C18H22NO3, 300.1605; found, 300.1600.

2-(5,5-dimethyl-4-oxohexyl)isoindoline-1,3-dione (2aa)

Compound 2aa was prepared according to the general procedure for homoallylic alcohols with 1aa (0.50 mmol, 64 mg) and phthalimide (0.55 mmol, 81 mg) and Bu4NOAc (7.5 mg, 0.05 equiv). The crude mixture (>20:1 a-M:M selectivity) was purified by silica gel chromatography (5-10% ethyl acetate in hexanes) to afford 2aa as a white solid (98 mg, 72%).


m.p.: 53-54.3 ºC. 1H NMR (500 MHz, CDCl3): δ 7.79 (dd, J = 5.4, 3.1 Hz, 2H), 7.68 (dd, J = 5.5, 3.0 Hz, 2H), 3.66 (t, J = 6.9 Hz, 2H), 2.54 (t, J = 7.1 Hz, 2H), 1.90 (p, J = 7.0 Hz, 2H), 1.09 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 214.72, 168.45, 133.98, 132.12, 123.25, 44.06, 37.50, 33.74, 26.62, 22.95.

IR (neat): 2969, 2949, 2913, 2870, 1776, 1772, 1699 cm-1.

66


HRMS (ESI-TOF): m/z [M+H+] calculated for C16H20NO3, 274.1443; found, 274.1443.

2-(9-((tert-butyldimethylsilyl)oxy)-4-oxononyl)isoindoline-1,3-dione (2ab)

Compound 2ab was prepared according to the general procedure for homoallylic alcohols with 1ab (0.50 mmol, 137 mg) and phthalimide (0.55 mmol, 81 mg) and Bu4NOAc (7.5 mg, 0.05 equiv). The crude mixture (10:1 a-M:M selectivity) was purified by silica gel chromatography (5-10% ethyl acetate in hexanes) to afford 2ab as a clear oil (151 mg, 72%).

Rf (4:1 Hexanes:Ethyl Acetate): 0.36 1H NMR (500 MHz, CDCl3): δ 7.83 (dd, J = 5.4, 3.1 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 3.69 (t, J = 6.7 Hz, 2H), 3.57 (t, J = 6.5 Hz, 2H), 2.46 (t, J = 7.2 Hz, 2H), 2.39 (t, J = 7.4 Hz, 2H), 1.95 (p, J = 7.0 Hz, 2H), 1.55 (p, J = 7.6 Hz, 2H), 1.49 (p, J = 6.8 Hz, 2H), 1.29 (m, 2H), 0.87 (s, 9H), 0.02 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 209.78, 168.56, 134.07, 132.19, 123.35, 63.12, 42.90, 39.82, 37.43, 32.74, 26.10, 25.58, 23.65, 22.81, 18.49, -5.14.

IR (neat): 2926, 2857, 1774, 1711 cm-1.

HRMS (ESI-TOF): m/z [M+H+] calculated for C23H36NO4Si, 418.2414; found, 418.2409.

5-(4-chlorophenyl)-3,4-dihydro-2H-pyrrole (6s)

A 25 mL round bottomed flask equipped with a stir bar was charged with 2s (125.0 mg, 0.38 mmol, 1.0 equiv), methanol (0.5 mL, 0.76 M), and hydrazine hydrate (86.41 µL, 1.14 mmol, 3.0 equiv). A reflux condenser was attached, the mixture placed under an N2 atmosphere, and heated at 60 ºC. After 6 h, the reaction was complete (by GCMS). The mixture was taken up in methylene chloride and the resulting cloudy mixture was filtered. The filtrate was washed with aqueous NaOH (2 M, 3 x 10 mL). The aqueous layer was then back-extracted with methylene chloride (3 x 10 mL). The combined organic extracts were dried (MgSO4), filtered, and the solvent was removed under reduced pressure with the aid of a rotary evaporator to give the product 6s (53.8 mg, 78% yield). The spectral data matched that previously reported.16 1H NMR (500 MHz, CDCl3): δ 7.76 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 4.05 (tt, J = 7.3, 2.1 Hz, 2H), 2.89 (ddt, J = 8.1, 7.3, 2.1 Hz, 2H), 1.98-2.08 (m, 2H).

13C NMR (125 MHz, CDCl3): δ 172.41, 136.53, 133.31, 129.12, 128.87, 61.87, 35.12, 22.96.

Cl

ONPhth NH2NH2•H2O (3 equiv)

MeOH, 60 ºC, 6 h Cl

N

2s 6s

67


(E/Z)-2-(4-methoxy-4-phenylbut-3-en-1-yl)isoindoline-1.3-dione (2ac)

Compound (E/Z)-2ac-(a-M) was prepared according to the general procedure for homoallylic alcohols with 1ac (0.50 mmol, 81 mg). The crude product was analyzed by GC and GC/MS to show a mixture of isomers formed (Figure 45a). To obtain a crude NMR of this isomer mixture without DMA, the reaction was extracted with ethyl acetate (3x 10mL), then washed with 2M NaOH (5 mL) followed by brine (10mL) (Figure S44b). The combined organic layers were dried over MgSO4, then filtered to afford the isomer mixture as a yellow oil (89.2 mg, 58%).

a)

b)

Supplementary Figure 45: a) GC trace of crude mixture of 2y b) GC trace of extracted mixture of 2ac

These peaks contain diagnostic signals associated with isomers of the (E/Z)-2ac-(a-M), and in many cases the molecular ion is also visible. In the case of the amination of 1m, we see fragmentation supporting the regiochemical outcome of the reaction in the form of fragmentation next to nitrogen the give a 160 fragment for the cleavage of phthalimide plus one methylene, along with a small amount of a 174 fragment representing cleavage one carbon further.

68


Supplementary Figure 46: Fragmentation of anti-Markovnikov isomer 2m.

Importantly, in the case of the Markovnikov functionalized product, we do not see this 160 fragment, and only see the 174 fragment. The isomer mixture of (E/Z)-2ac-(a-M) is indicative of anti-Markovnikov functionalization, with all GC peaks giving a strong 160 peak and no 174 peak; however, without isolation to support the identity of these peaks, this cannot be definitely proved and therefore we are only reporting what we were able to identify through isolation and are reporting the remaining as a mixture of constitutional and stereoisomers.

Supplementary Figure 47: Fragmentation of Markovnikov isomer 2m’.

69


a) Peak 1

b) Peak 2

c) Peak 3

70


d) Peak 4

Supplementary Figure 48: Fragmentation patterns of individual peaks

71


Supplementary Figure 49: NMR of extracted mixture of 2ac:

Isomers (E/Z)-2ac-(a-M) were obtained as a mixture via column chromatography, and were by assigned by 1H NMR (Figure 50-51).

Supplementary Figure 50a: Characterization of purified (E/Z)-2ac-(a-M)

72


NMR Characterization of diastereomers: 1H NMR (400 MHz, CDCl3) δ 7.84 (dt, J = 4.6, 2.2 Hz, 2H), 7.70 (dd, J = 5.3, 3.0 Hz, 2H), 7.48 – 7.26 (m, 5H), 5.23 (t, J = 7.4 Hz, 1H), 3.82 (t, J = 7.0 Hz, 2H), 3.39 (s, 3H), 2.66 (q, J = 7.1 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 168.41, 156.94, 135.42, 133.94, 133.82, 132.16, 132.09, 128.43, 128.31, 128.00, 126.90, 126.62, 126.23, 123.30, 123.11, 109.74, 109.49, 95.41, 58.46, 55.08, 38.61, 37.73, 26.72, 24.98.

Supplementary Figure 50b: Characterization of purified (E/Z)-2ac-(a-M) (figure continued)

73


Supplementary Figure 51a: NMR assignment of isomers in purified (E/Z)-2ac-(a-M)

74


Supplementary Figure 51b: NMR assignment of isomers in purified (E/Z)-2ac-(a-M) (Figure continued)

75


Upon sitting, this mixture completely decomposed to compound 2m and MeOH, further confirming the identity as (E/Z)-2ac-(a-M) (Figure 52-53).

Supplementary Figure 52: GC of mixture upon sitting, showing conversion to 2m

Supplementary Figure 53: GC of 2m obtained via amination of 1m for comparison

76


Supplementary Figure 54: 1H NMR of mixture after sitting, identical to that of 2m

(E)-2,2'-(but-1-ene-1,3-diyl)bis(isoindoline-1,3-dione) (2ad)

Pd(OAc)2 (1.12 mg, 0.005 mmol, 0.050 equiv), Bu4NCl (4.2 mg, 0.015 mmol, 0.15 equiv), phthalimide (0.10 mmol, 14.7 mg), and 5Å molecular sieves (50 mg) were weighed into a 4 mL vial with a Teflon coated stir bar. N,N-dimethylacetamide (0.10 mL) was added, followed by 2-(but-3-en-2-yl)isoindoline-1,3-dione (0.2 mmol, 40.2 mg). This vial was purged with oxygen gas, then sealed with a septum-lined cap and an oxygen-filled balloon was affixed through the septum. The reaction was heated and stirred at 80 °C for 24 h. The crude mixture (>20:1 a-M:M selectivity) was purified by silica gel chromatography (15% ethyl acetate in hexanes) to afford 2ad (a-M) (28.7 mg, 83% yield) as a white solid.

m.p. 153.5-157.4 ºC

Rf = 0.15 (20% EtOAc in hexanes) 1H NMR (500 MHz, CDCl3) δ 7.84 (ddd, J = 13.2, 5.4, 3.0 Hz, 4H), 7.71 (ddd, J = 15.0, 5.5, 3.0 Hz, 4H), 7.08 (dd, J = 14.8, 7.8 Hz, 1H), 6.91 (dd, J = 14.9, 1.1 Hz, 1H), 5.07 (dq, J = 13.9, 7.1 Hz, 1H), 1.68 (d, J = 7.0 Hz, 3H).

77


13C NMR (126 MHz, CDCl3) δ 167.92, 166.36, 134.64, 134.05, 132.21, 131.72, 123.81, 123.37, 120.07, 119.45, 47.69, 19.04.

IR (neat): 3000, 2966, 1774, 1705, 1680 cm-1.

HRMS (ESI-TOF): m/z [M+H+] calculated C20H15N2O4 = 347.1032; found mass = 347.1026.

(E)-2-(3-(2-oxopyrrolidin-1-yl)allyl)isoindoline-1,3-dione (2ae)

Pd(OAc)2 (5.6 mg, 0.025 mmol, 0.050 equiv), Bu4NCl (28 mg, 0.10 mmol, 0.20 equiv), phthalimide (0.50 mmol, 74 mg), and 5Å molecular sieves (250 mg) were weighed into a 20 mL vial with a Teflon coated stir bar. N,N-dimethylacetamide (0.50 mL) was added, followed by 1-allylpyrrolidin-2-one (1.0 mmol, 125 mg). This vial was purged with oxygen gas, then sealed with a septum-lined cap and an oxygen-filled balloon was affixed through the septum. The reaction was heated and stirred at 80 °C for 24 h. The crude mixture (>20:1 a-M:M selectivity) was purified by silica gel chromatography (50% ethyl acetate in hexanes) to afford 2ae (a-M) (83 mg, 62% yield) as a white solid.

Rf = 0.14 (50% EtOAc in hexanes)

m.p. 147-149 ºC 1H NMR (500 MHz, CDCl3) δ 7.84 (dd, J = 5.4, 3.1 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 7.21 (d, J = 14.4 Hz, 1H), 5.03 (dt, J = 14.1, 6.9 Hz, 1H), 4.33 (dd, J = 7.0, 1.1 Hz, 2H), 3.46 (t, J = 7.2 Hz, 2H), 2.46 (dd, J = 8.6, 7.7 Hz, 2H), 2.08 (p, J = 7.7 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 173.39, 168.03, 134.10, 132.34, 127.90, 123.43, 104.73, 45.19, 37.88, 31.26, 17.59. IR (neat): 3464 , 1758, 1700, 1658, 1400 cm-1.

HRMS (ESI-TOF): m/z [M+H+] calculated C15H15N2O3 =271.1083; found mass=271.1084.

(E)-2,2'-(but-2-ene-1,4-diyl)bis(isoindoline-1,3-dione) (2af)

Pd(OAc)2 (5.6 mg, 0.025 mmol, 0.050 equiv), Bu4NCl (28 mg, 0.10 mmol, 0.25 equiv), phthalimide (0.50 mmol, 74 mg), and 5Å molecular sieves (250 mg) were weighed into a 20 mL vial with a Teflon coated stir bar. N,N-dimethylacetamide (0.50 mL) was added, followed by 2-(but-3-en-1-yl)isoindoline-1,3-dione (1.0 mmol,

78


201 mg). This vial was purged with oxygen gas, then sealed with a septum-lined cap and an oxygen-filled balloon was affixed through the septum. The reaction was heated and stirred at 80 °C for 24 h. The crude mixture (>20:1 a-M:M selectivity) was purified by silica gel chromatography (3% ethyl acetate in methylene chloride) to afford 2af (86 mg, 50% yield) as a white solid and (E)-2,2'-(but-1-ene-1,4-diyl)bis(isoindoline-1,3-dione) (2af’) (30 mg, 17% yield). The double bond geometry was confirmed by comparison against authentic (Z)-2,2'-(but-2-ene-1,4-diyl)bis(isoindoline-1,3-dione), prepared from potassium phthalimide and (Z)-1,4-dichlorobut-2-ene, affording a different GC retention time as well as different NMR chemical shifts.

The crude yield of this transformation was 68% of 2af and <1% of 2af’; however, some isomerization was observed on silica gel to afford 2af’, which was isolated separately.

Data for 2af

m.p. 217.3-221.0 ºC

Rf = 0.46 (5% EtOAc in CH2Cl2) 1H NMR (500 MHz, CDCl3) δ 7.82 (dd, J = 5.4, 3.1 Hz, 4H), 7.71 (dd, J = 5.4, 3.0 Hz, 4H), 5.79 (t, J = 3.2 Hz, 2H), 4.25 (d, J = 3.7 Hz, 4H). 13C NMR (126 MHz, CDCl3) δ 167.92, 134.12, 132.22, 127.48, 123.48, 38.89.

IR (neat): 2930, 2860, 1765, 1708, 1612 cm-1.


Data for 2af’

m.p. 232.0-234.7 ºC

Rf = 0.61 (5% EtOAc in CH2Cl2) 1H NMR (500 MHz, CDCl3) δ 7.84 (dd, J = 5.6, 2.9 Hz, 4H), 7.71 (dd, J = 5.5, 3.0 Hz, 4H), 6.69 (dt, J = 14.6, 1.1 Hz, 1H), 6.60 (dt, J = 14.6, 7.2 Hz, 1H), 3.83 (dd, J = 7.8, 6.6 Hz, 2H), 2.56 (ddt, J = 7.2, 1.1 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 168.38, 166.54, 134.50, 134.06, 132.24, 131.78, 123.72, 123.44, 119.92, 117.88, 37.86, 30.67.

IR (neat): 3085, 2928, 2856, 1772, 1701, 1616 cm-1.


N N

O

O

O

O

N N

O

O

O

O

79


1-(4-oxo-4-phenylbutyl)pyrrolidine-2,5-dione (3m)

Compound 3m was prepared according to the general procedure for homoallylic alcohols with 1m (0.50 mmol, 74 mg) and succinimide (0.55 mmol, 55 mg). The crude mixture (14:1 a-M:M selectivity) was purified by silica gel chromatography (2:1 Hexanes:Ethyl Acetate) to afford 3m (73 mg, 60% yield) as a white solid.

Rf (Ethyl Acetate): 0.25

m.p.: 110-112 °C 1H NMR (500 MHz, CDCl3): δ 7.93 (dd, J = 8.3, 1.4 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 3.64 (t, J = 6.9 Hz, 2H), 3.03 (t, J = 7.1 Hz, 2H), 2.69 (s, 4H), 2.05 (p, J = 7.0 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 198.98, 177.49, 136.86, 133.26, 128.75, 128.09, 38.55, 36.10, 28.31, 22.26.

IR (neat): 2951, 1772, 1693 cm-1.


2-(4-oxo-4-phenylbutyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (4m)

Compound 4m was prepared according to the general procedure for homoallylic alcohols with 1m (0.50 mmol, 74 mg) and saccharin (0.55 mmol, 101 mg). The crude mixture (19:1 a-M:M selectivity) was purified by silica gel chromatography (4:1 Hexanes:Ethyl Acetate) to afford 4m (128 mg, 78% yield) as a white solid.


m.p.: 119-121 °C 1H NMR (500 MHz, CDCl3): δ 8.06 (d, J = 7.4 Hz, 1H), 7.96 (dd, J = 8.2, 1.0 Hz, 2H), 7.93 (d, J = 7.3 Hz, 1H), 7.87 (td, J = 7.5, 1.3 Hz, 1H), 7.83 (td, J = 7.4, 1.3 Hz, 1H), 7.55 (tt, J = 7.4, 1.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 3.94 (t, J = 6.8 Hz, 2H), 3.15 (t, J = 7.1 Hz, 2H), 2.31 (p, J = 6.9 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 198.74, 159.29, 137.82, 136.89, 134.91, 134.49, 133.24, 128.73, 128.15, 127.49, 125.35, 121.12, 39.05, 35.59, 22.82.

IR (neat): 3090, 1725, 1681, 1596 cm-1.

HRMS (ESI-TOF): m/z [M+H+] calculated C17H16NO4S = 330.0800; found mass = 330.0807.

80


5-nitro-2-(4-oxo-4-phenylbutyl)isoindoline-1,3-dione (5m)

Compound 5m was prepared according to the general procedure for homoallylic alcohols with 1m (0.50 mmol, 74 mg) and 4-nitrophthalimide (0.55 mmol, 106 mg). The crude mixture (>20:1 a-M:M selectivity) was purified by silica gel chromatography (10-30% ethyl acetate in hexanes) to afford 5m as a white solid (106 mg, 63%).


m.p.: 147-149 ºC. 1H NMR (500 MHz, CDCl3): δ 8.65 (d, J = 1.9 Hz, 1H), 8.60 (dd, J = 8.1, 2.0 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 7.4 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 3.88 (t, J = 6.8 Hz, 2H), 3.08 (t, J = 7.0 Hz, 2H), 2.18 (p, J = 7.0 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 198.65, 166.36, 166.10, 151.79, 136.71, 136.60, 133.56, 133.28, 129.33, 128.71, 128.02, 124.54, 118.74, 38.35, 35.79, 22.91.

IR (neat): 3105, 2952, 2865, 1783, 1717, 1707 cm-1.

HRMS (ESI-TOF): m/z [M+H+] calculated for C18H15N2O5, 339.0978; found, 339.0981.

81


I. Data for Palladate Crystal Structure

Tetrabutylammonium tetrachloropalladate

In a 25mL round bottom flask charge with Teflon-coated stir bar was added PdCl2 (177mg, 1 mmol) and Bu4NCl (556mg, 2 mmol). To this was added dry acetone (10mL), and this was stirred at room temperature for 30 minutes. In a separate flask was added 125mL dry Et2O and, with stirring, the acetone solution was added dropwise to precipitate the product. The precipitate was collected by filtration and washed with dry Et2O, and then dried by under vacuum to provide a pale orange powder (610mg, 83% yield). This product was characterized by CHN analysis and X-ray analysis of a single crystal to confirm the structure.

Anal. Calcd for C32H72Cl4N2Pd (733.16):

C, 52.42; H, 9.90; N, 3.82. Found: C, 51.80; H, 9.88; N, 3.83.

82


Supplementary Figure 55: ORTEP representation of tetrabutylammonium tetrachloropalladate. Hydrogen atoms omitted for clarity. Thermal ellipsoids are drawn at 50% probability level.

Supplementary Table S9. Crystallographic data for tetrabutylammonium tetrachloropalladate Empirical formula C32H72N2Cl4P2 Formula weight 733.12 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Orthorhombic Space group Fdd2 Unit cell dimensions a = 30.7385(16) b = 34.7003(19) c = 14.7046(8) α = 90°, β = 90°, γ = 90° Volume 15684.4(15) Z 16 Density (calculated) 1.242 g/cm3 Absorption coefficient 0.768 mm-1 F(000) 6272.0 Crystal size 0.152 x 0.142 x 0.096 mm3 Theta range for data collection 2.237 to 27.237° Index ranges -39<=h<=39, -44<=k<=44, -

15<=l<=15

Reflections collected 8229 Independent reflections 7251 [R(int) = 0.0293] Completeness to theta 0.94 Absorption correction Multi-scan Refinement method Full-matrix least-squares on F2 Data/ restraints/ parameters 7251/ 0/ 360 Goodness-of-fit on F2 1.024 Final R indices [I>2sigma(I)] R1 = 0.0293, wR2 = 0.0573

83


J. References

1A. H. M. de Vries, F. J. Parlevliet, L. Schmeder-van de Vondervoort, J. H. M. Mommers, H. J. W. Hendrickx and M. A. N. Walet, Adv. Synth. Catal. 344, 996–1002 (2002).2 Ball, L. T.; Lloyd-Jones, G. C.; Russell, C. A. Chem. Eur. J. 18, 2931-2937 (2012). 3 Nájera, F.; García-Segura, R.; Pérez-Inestrosa, E.; Sánchez-Sánchez, C.; Suau, R. Photochem. Photobiol. 82, 248-253 (2006). 4 Onodera, G.; Yamamoto, E.; Tonegawa, S.; Iezumi, M.; Takeuchi, R. Adv. Synth. Catal. 353, 2013-2021 (2011). 5 Coulter, M. M.; Kou, K. G. M.; Galligan B.; Dong, V. M. J. Am. Chem. Soc. 132, 16330-16333 (2010). 6 Weiner, B.; Baeza, A.; Jerphagnon, T.; Feringa, B. L. J. Am. Chem. Soc. 131, 9473–9474 (2009). 7 Würdemann, M.; Christoffers, J. Org. Biomol. Chem. 8, 1894–1898 (2010). 8 Vermeulen, M.; Zwanenburg, B.; Chittenden, G. J. F.; Verhagen, H. Eur. J. Med. Chem. 38, 729–737 (2003). 9 Denmark, S. E.; Nguyen, S. T. Org. Lett. 11, 781 (2009). 10 Srivastaava, V. P.; Patel, R.; Yadav, L. D. S. Adv. Synth. Catal. 353, 695 (2011). 11 Doucet, H.; Santelli, M. Tetrahedron: Asymmetry, 11, 4163–4169 (2000). 12 Lee, K. S.; Ready, J. M. Angew. Chem. Int. Ed. 50, 2111–2114 (2011). 13 Ratnikov, M. O.; Tumanov, V. V.; Smit, W. A. Angew. Chem. Int. Ed. 47, 9739-9742 (2008). 14 McEwen, W. E.; Cooney, J. V. J. Org. Chem. 48, 983-987 (1983). 15 Jansen, A. B. A.; Spencer, K. E. V. 1-Diethylamino-6-phthalimidohexan-3-one US3308135, 1967. 16 Chen, F.; Ding, Z.; Qin, J.; Wang, T.; He, Y.; Fan, Q.-H. Org. Lett. 13, 4348-4351 (2011).

84

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

2.09

2.08

1.02

1.00

1.01

4.79

2.16

2.14

2.59

2.59

2.60

2.61

2.62

2.62

2.63

2.64

3.83

3.85

3.86

5.30

7.17

7.17

7.18

7.18

7.19

7.19

7.19

7.20

7.20

7.21

7.25

7.26

CDC

l37.

267.

277.

277.

287.

287.

297.

297.

297.

307.

317.

697.

697.7

07.7

07.

827.

837.

837.

84

DCM

H2O grease

NPhth

2a, 1H NMR, CDCl3

85

102030405060708090100110120130140150160170180190200210f1 (ppm)

0

50

100

150

200

250

300

350

400

450

500

550

600

650

700

32.3

8

37.7

3

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

123.

3712

6.28

126.

3012

7.36

128.

6113

2.23

132.

7413

4.04

137.

38

168.

48

NPhth

2a, 13C NMR, CDCl3

86

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

700

750

800

850

2.00

3.00

2.00

1.00

1.00

2.00

2.00

2.00

2.00

1.56

Wat

er

2.56

2.56

2.57

2.58

2.59

2.59

2.60

2.60

3.79

3.81

3.83

3.84

6.00

6.01

6.03

6.03

6.04

6.06

6.35

6.35

6.38

6.39

6.80

6.82

7.22

7.24

7.26

CDC

l37.

687.

697.

697.7

07.

827.

837.

837.

84

NPhth

OCH3

2b, 1H NMR, CDCl3

H2O

grease

87

0102030405060708090100110120130140150160170180190200210f1 (ppm)

-20-100102030405060708090100110120130140150160170180190200210

32.3

7

37.8

7

55.4

2

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

114.

04

123.

3612

4.07

127.

4013

0.23

132.

1013

2.25

134.

02

159.

07

168.

50

NPhth

OCH3

2b, 13C NMR, CDCl3

88

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.5f1 (ppm)

-200

0

200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

2800

3000

3200

3400

3600

3.35

2.15

2.14

1.10

1.11

2.00

1.94

1.98

1.92

2.31

2.57

2.57

2.59

2.59

2.60

2.60

2.61

2.62

3.82

3.83

3.85

6.09

6.10

6.11

6.12

6.13

6.15

6.38

6.41

7.07

7.08

7.18

7.20

7.26

CDC

l37.

687.

697.

697.7

07.

827.

827.

837.

84

NPhth

CH3

2c, 1H NMR, CDCl3H2O

grease

89

102030405060708090100110120130140150160170180190200210220f1 (ppm)

-10

0

10

20

30

40

50

60

70

80

90

100

21.3

0

32.3

7

37.8

0

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

123.

3712

5.22

126.

1812

9.31

132.

2513

2.59

134.

0213

7.13

168.

49

NPhth

CH3

2c, 13C NMR, CDCl3

90

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000

7500

2.10

2.08

1.03

1.00

3.97

2.11

2.04

2.58

2.58

2.59

2.60

2.61

2.61

2.62

2.62

3.83

3.84

3.85

6.11

6.12

6.13

6.13

6.14

6.15

6.15

6.17

6.18

6.18

6.35

6.36

6.36

6.38

6.39

6.39

6.40

7.20

7.20

7.21

7.22

7.22

7.22

7.23

7.24

7.24

7.24

7.24

7.26

CDC

l37.

697.7

07.7

07.7

17.

827.

837.

837.

84

NPhth

Cl

2d, 1H NMR, CDCl3

H2O

grease

91

102030405060708090100110120130140150160170180190200210220f1 (ppm)

-10

0

10

20

30

40

50

60

70

80

90

100

110

32.3

8

37.6

2

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

123.

4012

7.11

127.

4912

8.76

131.

5213

2.19

132.

9713

4.09

135.

86

168.

47

NPhth

Cl

2d, 13C NMR, CDCl3

92

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-2000

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

2.03

2.02

1.01

1.00

2.02

2.00

1.82

1.76

1.61

HDO

2.61

2.62

2.63

2.63

2.64

2.64

2.66

2.66

3.82

3.85

3.86

3.88

6.25

6.27

6.28

6.28

6.30

6.31

6.43

6.43

6.43

6.46

6.46

6.47

7.26

CDC

l37.

367.

377.

387.

507.

517.

517.

527.

527.

677.

687.

687.

697.7

07.7

07.7

17.7

17.7

27.

817.

817.

827.

837.

837.

847.

857.

85NPhth

F

FF

2e, 1H NMR, CDCl3

93

102030405060708090100110120130140150160170180190200210f1 (ppm)

-200-10001002003004005006007008009001000110012001300140015001600170018001900200021002200

32.4

3

37.4

7

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

121.

1012

3.26

123.

4012

5.42

125.

5312

5.56

125.

5912

5.62

126.

4012

7.58

128.

7912

9.05

129.

2512

9.31

129.

5613

1.44

132.

1513

4.11

140.

78

168.

44

NPhth

F

FF

2e, 13C NMR, CDCl3

94

-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-100f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

700

750

800

-113

.15

-62.

55

NPhth

F

FF

2e, 19F NMR, CDCl3

fluorobenzene

95

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

0

5000

10000

15000

20000

25000

30000

35000

2.03

1.01

1.00

0.98

2.02

2.04

2.02

1.96

4.44

4.44

4.45

4.46

6.23

6.24

6.26

6.26

6.27

6.29

6.65

6.68

7.20

7.21

7.21

7.22

7.22

7.22

7.23

7.23

7.24

7.26

CDC

l37.

277.

277.

287.

287.

297.

297.

307.

307.7

17.7

27.7

27.7

37.

867.

867.

877.

87

NPhth

2f, 1H NMR, CDCl3

H2O

96

102030405060708090100110120130140150160170180190200210f1 (ppm)

0

100

200

300

400

500

600

700

800

900

1000

39.8

3

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

122.

8712

3.46

126.

6712

8.03

128.

6713

2.33

133.

9513

4.12

136.

38

168.

102f, 13C NMR, CDCl3

NPhth

97

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

110000

3.01

2.01

1.01

1.00

1.99

2.04

2.00

1.90

3.78

4.41

4.41

4.42

4.43

6.09

6.10

6.12

6.12

6.14

6.15

6.60

6.63

6.80

6.81

6.81

6.82

6.83

6.83

7.26

CDC

l37.

277.

287.

287.

297.

297.

307.7

07.7

17.7

17.7

27.

857.

857.

867.

86

NPhth

OCH3

2g, 1H NMR, CDCl3

H2O

98

102030405060708090100110120130140150160170180190200210f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

39.9

2

55.4

1

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

114.

07

120.

6112

3.42

127.

8812

9.17

132.

3613

3.52

134.

07

159.

56

168.

14

NPhth

OCH3

2g, 13C NMR, CDCl3

99

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.5f1 (ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

3.23

2.10

1.02

1.00

1.88

1.98

2.12

1.98

2.31

4.42

4.43

4.44

4.44

6.17

6.19

6.20

6.21

6.22

6.23

6.61

6.65

7.08

7.10

7.24

7.25

7.26

CDC

l37.7

17.7

27.7

27.7

37.

857.

867.

867.

87

NPhth

CH3

2h, 1H NMR, CDCl3

H2O

100

102030405060708090100110120130140150160170180190200210220f1 (ppm)

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

21.3

5

39.9

0

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

121.

7912

3.45

126.

5812

9.37

132.

3613

3.61

133.

8913

4.10

137.

89

168.

14

NPhth

CH3

2h, 13C NMR, CDCl3

101

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

2.09

0.99

1.00

5.79

2.12

2.07

1.25

1.56

4.43

4.45

6.20

6.21

6.23

6.23

6.25

6.26

6.59

6.62

7.24

7.25

7.25

7.26

7.26

CDC

l37.

277.

277.

287.

297.7

27.7

37.7

37.7

47.

867.

877.

877.

88

NPhth

Cl

2i, 1H NMR, CDCl3

H2O

grease

102

102030405060708090100110120130140150160170180190200210220f1 (ppm)

-20

0

20

40

60

80

100

120

140

160

180

200

220

240

260

280

300

320

340

360

39.7

1

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

123.

5212

3.61

127.

8912

8.85

132.

2913

2.65

133.

7013

4.19

134.

89

168.

08

NPhth

Cl

2i, 13C NMR, CDCl3

103

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

0

100

200

300

400

500

600

700

800

900

1000

2.10

1.02

1.00

2.07

2.02

2.04

1.91

4.47

4.47

4.48

4.48

6.32

6.33

6.35

6.35

6.36

6.38

6.65

6.68

7.26

CDC

l37.

437.

457.

537.

547.7

37.7

47.7

47.7

57.7

57.

867.

877.

877.

887.

88

H2O

grease

NPhthF

FF

2j, 1H NMR, CDCl3

104

102030405060708090100110120130140150160170180190200210220f1 (ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000

39.5

9

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

120.

9712

3.14

123.

5212

5.30

125.

5712

5.60

125.

6312

5.67

126.

8112

7.46

129.

3812

9.64

129.

8913

0.15

132.

2013

2.33

134.

2213

9.81

168.

02

grease

NPhthF

FF

2j, 13C NMR, CDCl3

105

-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-100f1 (ppm)

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

-164

.90

-65.

74

NPhthF

FF

2j, 19F NMR, CDCl3

hexafluorobenzene

106

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

0

500

1000

1500

2000

2500

3000

3500

4000

4500

2.19

2.19

2.13

1.02

1.00

0.95

2.85

2.17

2.02

1.85

1.87

1.88

1.90

1.91

2.26

2.27

2.28

2.28

2.29

2.29

2.31

2.31

3.74

3.75

3.77

6.17

6.18

6.20

6.20

6.22

6.23

6.39

6.39

6.40

6.41

6.42

6.43

6.43

7.16

7.16

7.16

7.17

7.17

7.18

7.18

7.19

7.19

7.24

7.25

7.26

7.26

7.26

CDC

l37.

277.

287.

297.

297.

297.

307.

307.

317.

317.

687.

687.

697.

697.

827.

827.

837.

83

NPhth

2k, 1H NMR, CDCl3

H2O

grease

107

102030405060708090100110120130140150160170180190200210220f1 (ppm)

-200

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

28.1

530

.50

37.7

8

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

2 CD

Cl3

123.

3112

6.09

127.

0712

8.57

129.

2813

0.79

132.

2613

4.01

137.

63

168.

60

NPhth

2k, 13C NMR, CDCl3

108

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-20

0

20

40

60

80

100

120

140

160

180

200

220

240

260

280

300

3.00

17.5

2

89.2

5

1.99

2.76

0.82

-0.0

50.

080.

040.

136.

700.

743.

83

14.0

10.

820.

29

16.5

115

.71

0.64

0.66

0.67

0.76

0.84

0.84

0.85

0.86

0.88

0.93

1.12

1.13

1.24

1.25

1.26

1.27

1.28

1.29

1.30

1.30

1.31

1.32

1.33

1.33

1.34

1.35

1.36

1.37

1.39

1.44

1.45

1.46

1.46

1.48

1.53

1.54

1.56

1.59

1.60

1.60

1.73

1.90

1.91

1.93

1.95

1.96

1.97

1.99

2.00

2.02

2.03

2.03

2.05

5.35

5.36

5.36

5.37

5.37

5.38

5.39

5.40

5.42

7.26

CDC

l37.

677.

677.

687.

687.

697.

697.7

07.7

07.7

87.7

87.7

97.

807.

807.

817.

827.

827.

837.

83

CH3 N

O

O

2l Mixture of isomers, 1H NMR, CDCl3

109

0102030405060708090100110120130140150160170180190200210f1 (ppm)

-200

0

200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

2800

3000

3200

3400

13.4

513

.76

13.8

213

.99

14.0

318

.01

18.3

518

.82

18.8

518

.90

19.1

822

.14

22.5

322

.71

25.5

725

.68

26.4

126

.87

26.9

228

.19

28.4

128

.55

29.1

929

.82

30.0

231

.26

31.5

531

.80

31.9

032

.19

32.2

132

.25

32.4

633

.32

33.4

334

.57

34.7

437

.22

37.7

937

.92

38.0

738

.13

47.1

647

.46

47.4

847

.58

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

123.

0712

3.11

123.

1412

3.16

123.

2312

3.25

123.

3212

5.34

125.

7212

6.33

127.7

512

8.56

128.

8213

0.95

131.

4313

2.09

132.

1213

2.16

132.

2513

2.29

132.

7113

2.98

133.

8313

3.87

133.

8913

3.91

133.

9413

3.96

134.

0416

8.55

168.

6416

8.65

2l Mixture of isomers, 13C NMR, CDCl3

CH3 N

O

O

110

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-200

0

200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

2800

3000

3200

3400

2.14

2.13

2.12

2.01

1.00

2.03

1.85

1.99

2.12

2.14

2.15

2.16

2.18

3.05

3.05

3.06

3.07

3.08

3.81

3.83

3.84

7.26

CDC

l37.

437.

437.

447.

447.

447.

457.

467.

537.

537.

537.

547.

557.

557.

567.

567.

567.

697.7

07.7

07.7

17.7

17.7

27.7

37.7

37.

837.

847.

847.

857.

917.

927.

927.

937.

937.

937.

94

O

NPhth

2m, 1H NMR, CDCl3

DCM

H2O

111

102030405060708090100110120130140150160170180190200210220f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

700

750

800

23.3

0

35.9

237

.61

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

2 CD

Cl3

123.

4012

8.12

128.

7113

2.21

133.

1913

4.09

136.

89

168.

59

198.

96O

NPhth

2m, 13C NMR, CDCl3

112

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

2.03

2.01

2.00

2.90

1.96

1.93

1.89

1.96

2.10

2.12

2.13

2.13

2.14

2.15

2.16

2.99

2.99

3.00

3.01

3.02

3.02

3.80

3.81

3.83

3.86

6.90

6.92

7.26

CDC

l37.7

07.7

17.7

17.7

27.

837.

837.

847.

847.

907.

91

O

NPhth

OCH3

2n, 1H NMR, CDCl3

H2O

113

0102030405060708090100110120130140150160170180190200210220f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

23.4

9

35.5

637

.70

55.6

0

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

113.

83

123.

38

130.

0313

0.40

132.

2413

4.06

163.

55

168.

58

197.

51O

NPhth

OCH3

2n, 13C NMR, CDCl3

114

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-200

0

200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

2.14

3.06

2.11

2.11

1.99

0.97

1.00

2.01

1.92

2.08

2.10

2.11

2.12

2.13

2.14

2.46

2.96

2.96

2.97

2.98

2.99

3.79

3.81

3.82

7.21

7.21

7.22

7.22

7.22

7.22

7.22

7.22

7.22

7.23

7.23

7.23

7.23

7.23

7.23

7.24

7.24

7.24

7.25

7.25

7.25

7.25

7.26

CDC

l37.

337.

347.

357.

357.

367.

377.

607.

617.

627.

627.

697.

697.7

07.7

07.7

17.7

17.7

27.7

27.7

37.7

37.

827.

827.

837.

847.

847.

857.

857.

86

H2Ogrease

EtAc

EtAc

EtAc

O

NPhth

CH3

2o, 1H NMR, CDCl3

115

102030405060708090100110120130140150160170180190200210220f1 (ppm)

-100

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

700

750

21.3

823

.38

37.5

738

.73

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

123.

4012

5.80

128.

5113

1.36

132.

0513

2.21

134.

0813

7.91

138.

17

168.

59

202.

99O

NPhth

CH3

2o, 13C NMR, CDCl3

116

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

2.13

5.81

3.00

1.96

2.00

1.89

1.94

1.84

2.07

2.09

2.10

2.12

2.13

2.16

2.25

2.74

2.75

2.77

3.77

3.78

3.80

6.80

7.26

CDC

l37.

697.7

07.7

17.7

17.7

27.7

27.7

37.

817.

827.

827.

837.

847.

84

grease

O

NPhth

CH3CH3

CH3

2p, 1H NMR, CDCl3

117

102030405060708090100110120130140150160170180190200210220f1 (ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

19.2

621

.13

22.8

4

37.5

8

42.0

5

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

123.

3512

8.57

132.

1413

2.61

134.

0813

8.48

139.

45

168.

45

209.

45

grease

2p, 13C NMR, CDCl3

O

NPhth

CH3CH3

CH3

118

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

2.02

2.89

2.02

2.00

0.95

0.97

0.86

1.92

0.96

1.90

2.11

2.12

2.14

2.15

2.16

2.31

3.02

3.03

3.05

3.80

3.81

3.82

7.26

CDC

l37.

277.

277.

277.

287.

297.

297.

297.

297.

447.

457.

477.

627.

637.

637.7

07.7

07.7

17.7

27.7

87.7

87.7

87.7

97.7

97.

807.

837.

837.

847.

84

DCMH2O

O

NPhth

OO

CH3

2q, 1H NMR, CDCl3

119

0102030405060708090100110120130140150160170180190200210220f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

110021.2

223

.16

36.0

037

.49

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

121.

2512

3.40

125.

5512

6.53

129.

7713

2.17

134.

0913

8.29

150.

97

168.

5616

9.37

197.7

9O

NPhth

OO

CH3

2q, 13C NMR, CDCl3

120

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

2.06

2.02

2.00

0.94

0.99

1.94

0.93

1.84

0.97

2.14

2.15

2.16

2.18

2.19

3.04

3.06

3.07

3.82

3.83

3.84

7.26

CDC

l37.

467.

467.

467.

467.

477.

487.

487.

487.

557.

577.

587.7

17.7

27.7

27.7

37.

807.

817.

817.

817.

817.

837.

847.

847.

857.

937.

947.

947.

957.

957.

95

H2OEtAc

O

NPhth

OS

O

O

F

F

F

2r, 1H NMR, CDCl3

EtAcEtAc

121

102030405060708090100110120130140150160170180190200210220f1 (ppm)

0

500

1000

1500

2000

2500

3000

22.9

7

36.0

237

.31

76.8

4 CD

Cl3

77.1

6 CD

Cl3

77.4

8 CD

Cl3

113.

9811

7.17

120.

3612

0.85

123.

3812

3.55

125.

8112

7.93

130.

7713

2.09

134.

1313

9.06

149.

89

168.

56

196.

78O

NPhth

OS

O

O

F

F

F

2r, 13C NMR, CDCl3

122

-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-100f1 (ppm)

-20-100102030405060708090100110120130140150160170180190200

-113

.18

-113

.17

-113

.16

-113

.15

-113

.14

-113

.13

-72.

80

O

NPhth

OS

O

O

F

F

F

2r, 19F NMR, CDCl3

fluorobenzene

123

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

700

750

800

850

2.03

2.02

2.00

1.81

1.80

3.78

2.07

2.08

2.10

2.11

2.13

2.97

2.99

3.00

3.76

3.77

3.78

7.26

CDC

l37.

347.

347.

357.

367.

367.

377.

667.

677.

677.

687.7

77.7

87.7

87.7

97.

807.

807.

817.

827.

827.

82

DCMgrease

O

NPhth

Cl

2s, 1H NMR, CDCl3

124

0102030405060708090100110120130140150160170180190200210220f1 (ppm)

0

500

1000

1500

2000

2500

3000

3500

23.0

7

35.7

237

.37

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

123.

25

128.

8712

9.42

132.

0413

3.99

135.

0813

9.42

168.

42

197.

55

grease

O

NPhth

Cl

2s, 13C NMR, CDCl3

125

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

0

50

100

150

200

250

300

350

400

450

2.01

2.03

2.00

3.72

1.75

1.92

2.12

2.14

2.15

2.16

2.18

3.06

3.07

3.08

3.80

3.81

3.83

7.26

CDC

l37.

687.

697.7

07.7

07.7

17.7

27.7

27.7

97.

807.

807.

817.

827.

827.

837.

838.

008.

01

DCMH2O

grease

O

NPhth

F

FF

2t, 1H NMR, CDCl3

126

102030405060708090100110120130140150160170180190200210220f1 (ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

23.0

4

36.1

337

.38

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

2 CD

Cl3

120.

4412

2.61

123.

3812

4.78

125.

7212

5.75

125.

7812

5.81

126.

9512

8.41

132.

1213

4.12

134.

1513

4.27

134.

5313

9.51

168.

56

197.

94

grease

O

NPhth

F

FF

2t, 13C NMR, CDCl3

127

-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-100f1 (ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

-164

.90

-66.

22

O

NPhth

F

FF

2t, 19F NMR, CDCl3

hexafluorobenzene

128

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

700

750

800

1.99

1.97

2.00

1.88

1.78

0.88

1.82

2.17

2.19

2.20

2.21

2.23

3.10

3.11

3.13

3.83

3.84

3.86

7.26

CDC

l37.7

27.7

27.7

37.7

37.

837.

837.

847.

848.

068.

33

O

NPhth

F

F

F

FF

F

2u, 1H NMR, CDCl3

H2O

129

102030405060708090100110120130140150160170180190200210220f1 (ppm)

-200-1000100200300400500600700800900100011001200130014001500160017001800190020002100

22.8

5

35.9

337

.19

76.8

4 CD

Cl3

77.1

6 CD

Cl3

77.4

8 CD

Cl3

118.

9312

1.64

123.

4212

4.35

126.

3812

7.07

128.

1213

1.90

132.

1013

2.24

132.

5813

2.92

134.

2013

8.33

168.

61

196.

13O

NPhth

F

F

F

FF

F

2u, 13C NMR, CDCl3

130

-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-100f1 (ppm)

-20

0

20

40

60

80

100

120

140

160

180

200

220

240

260

280

300-113

.18

-113

.17

-113

.16

-113

.15

-113

.14

-113

.13

-113

.12

-62.

98

O

NPhth

F

F

F

FF

F

2u, 19F NMR, CDCl3

fluorobenzene

131

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-100010020030040050060070080090010001100120013001400150016001700180019002000

2.02

2.01

2.00

0.87

0.84

0.83

1.88

1.79

2.09

2.11

2.11

2.12

2.12

2.13

2.13

2.15

2.89

2.90

2.91

2.91

2.92

3.78

3.79

3.81

6.51

6.51

6.51

6.52

7.16

7.16

7.16

7.17

7.26

CDC

l37.

547.

547.

557.

557.

697.

697.7

07.7

07.7

17.7

17.7

27.7

37.7

37.

827.

827.

827.

837.

837.

847.

847.

85

H2O

grease

O

NPhthO

2v, 1H NMR, CDCl3

132

0102030405060708090100110120130140150160170180190200210220f1 (ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000

7500

23.0

6

35.7

037

.53

76.9

0 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

112.

30

117.

06

123.

34

132.

1513

4.05

146.

38

152.

61

168.

46

188.

14

grease

O

NPhthO

2v, 13C NMR, CDCl3

133

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

2.00

2.00

2.00

0.93

0.92

3.00

1.88

2.11

2.13

2.14

2.14

2.15

2.16

2.17

2.97

2.99

3.00

3.79

3.80

3.81

7.09

7.10

7.10

7.11

7.26

CDC

l37.

597.

607.

607.

617.

687.

687.

687.

697.

697.7

07.7

17.7

17.

817.

827.

837.

83

DCM H2O

O

NPhthS

2w, 1H NMR, CDCl3

134

0102030405060708090100110120130140150160170180190200210f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

23.5

0

36.5

737

.52

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

123.

3612

8.18

131.

9913

2.15

133.

6813

4.07

144.

09

168.

50

191.

84O

NPhthS

2w, 13C NMR, CDCl3

135

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

2.13

2.11

2.05

0.97

2.88

3.00

2.12

1.99

2.06

2.08

2.08

2.09

2.10

2.10

2.12

2.73

2.75

2.76

3.78

3.79

3.80

6.71

6.74

7.26

CDC

l37.

387.

397.

397.

507.

527.

537.

537.

547.

547.7

07.7

17.7

17.7

27.

837.

847.

847.

85

H2OEtAc

EtAcEtAc

O

NPhth

2x, 1H NMR, CDCl3

136

102030405060708090100110120130140150160170180190200210220f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

100023.2

9

37.6

038

.21

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

123.

4012

6.01

128.

4512

9.06

130.

6013

2.22

134.

0913

4.58

142.

74

168.

58

198.

90O

NPhth

2x, 13C NMR, CDCl3

137

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

1900

2.07

2.99

2.01

2.00

2.05

1.83

1.93

1.94

1.95

1.97

1.98

2.14

2.48

2.50

2.51

3.69

3.69

3.70

3.72

3.72

7.26

CDC

l37.7

07.7

07.7

17.7

17.7

17.7

27.7

27.7

27.

837.

837.

837.

837.

847.

847.

847.

85

CH3

O

NPhth

2y, 1H NMR, CDCl3

138

102030405060708090100110120130140150160170180190200210220f1 (ppm)

-100

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

700

750

22.8

2

30.0

9

37.3

440

.69

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

123.

38

132.

1813

4.12

168.

60

207.

60

CH3

O

NPhth

2y, 13C NMR, CDCl3

139

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

0

100

200

300

400

500

600

700

800

900

5.00

1.00

4.00

2.00

0.98

2.00

1.87

1.96

1.82

1.18

1.18

1.20

1.20

1.21

1.23

1.23

1.24

1.25

1.25

1.25

1.26

1.26

1.26

1.27

1.27

1.27

1.28

1.28

1.29

1.29

1.29

1.31

1.31

1.62

1.63

1.63

1.63

1.64

1.65

1.65

1.65

1.65

1.66

1.66

1.73

1.73

1.74

1.74

1.75

1.76

1.76

1.77

1.78

1.78

1.79

1.79

1.79

1.80

1.80

1.80

1.81

1.81

1.81

1.82

1.82

1.82

1.91

1.93

1.94

1.96

1.97

2.29

2.31

2.31

2.34

2.49

2.50

2.52

3.69

3.70

3.71

7.26

CDC

l37.7

07.7

17.7

17.7

27.

837.

837.

847.

85

O

NPhth

2z, 1H NMR, CDCl3

140

0102030405060708090100110120130140150160170180190200210f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

22.7

625

.79

25.9

628

.63

37.5

637

.81

50.8

5

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

123.

36

132.

2213

4.06

168.

58

212.

85

O

NPhth

2z, 13C NMR, CDCl3

141

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

0

500

1000

1500

2000

2500

3000

3500

4000

9.00

2.00

2.00

2.00

2.00

2.00

1.08

1.09

1.88

1.90

1.91

2.52

2.54

2.55

3.65

3.66

3.68

7.26

CDC

l37.

677.

677.

687.

687.7

97.7

97.

807.

80

O

NPhth

CH3

CH3

CH3

2aa, 1H NMR, CDCl3

142

0102030405060708090100110120130140150160170180190200210f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

700

750

800

850

22.9

526

.62

33.7

437

.50

44.0

6

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

123.

25

132.

1213

3.98

168.

45

214.

72

O

NPhth

CH3

CH3

CH3

2aa, 13C NMR, CDCl3

143

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

6.00

9.00

2.00

2.00

2.00

2.00

2.00

2.00

2.00

2.00

2.00

2.00

0.02

0.87

1.24

1.26

1.27

1.29

1.30

1.32

1.46

1.47

1.49

1.50

1.52

1.53

1.55

1.56

1.58

1.94

1.95

1.96

2.38

2.39

2.40

2.44

2.46

2.47

3.56

3.57

3.58

3.68

3.69

3.71

7.26

CDC

l37.7

07.7

07.7

17.7

27.

827.

837.

837.

84

O

NPhthO

Si

CH3

CH3

CH3

CH3

CH3

6

2ab, 1H NMR, CDCl3

144

0102030405060708090100110120130140150160170180190200210f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

18.4

922

.81

23.6

525

.58

26.1

0

32.7

437

.43

39.8

242

.90

63.1

2

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

123.

35

132.

1913

4.07

168.

56

209.

78

grease

O

NPhthO

Si

CH3

CH3

CH3

CH3

CH3

6

2ab, 13C NMR, CDCl3

145

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

0

500

1000

1500

2000

2500

3000

3500

4000

0.79

2.04

0.44

2.81

0.71

2.06

0.35

1.00

9.91

3.76

3.76

2.44

2.45

2.47

2.48

2.64

2.65

2.67

2.68

3.27

3.39

3.70

3.72

3.81

3.82

3.84

4.68

4.70

4.71

5.22

5.23

5.25

7.23

7.26

7.26

CDC

l37.

267.

277.

277.

287.

287.

297.

307.

317.

317.

317.

327.

327.

337.

347.

347.

357.

367.

367.

697.7

07.7

07.7

17.7

97.

807.

807.

817.

837.

847.

857.

85

OCH3

NPhth

2ac, 1H NMR, CDCl3

146

102030405060708090100110120130140150160170180190200210220f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

700

750

25.1

426

.88

37.8

938

.77

55.2

458

.62

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

95.5

7

109.

6510

9.90

123.

2712

3.46

126.

3912

6.78

127.

0612

8.16

128.

4712

8.59

132.

2513

2.32

133.

9813

4.10

135.

58

157.

10

168.

57

OCH3

NPhth

2ac, 13C NMR, CDCl3

147

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.5f1 (ppm)

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

0.12

3.00

1.00

0.04

0.04

1.00

1.00

4.00

4.00

1.68

1.69

5.03

5.04

5.05

5.05

5.06

5.06

5.07

5.08

5.09

5.09

6.89

6.90

6.92

6.93

7.06

7.08

7.09

7.11

7.26

CDC

l37.

697.7

07.7

07.7

17.7

27.7

37.7

37.7

47.

827.

827.

837.

847.

857.

857.

867.

86

N

CH3

NO

O

O

O

2ad, 1H NMR, CDCl3

grease

148

0102030405060708090100110120130140150160170180190200210f1 (ppm)

0

5

10

15

20

25

30

35

19.0

4

47.6

9

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

119.

4512

0.07

123.

3712

3.81

131.

7213

2.21

134.

0513

4.64

166.

3616

7.92

N

CH3

NO

O

O

O

2ad, 13C NMR, CDCl3

149

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

2.16

2.13

2.06

2.04

1.03

1.00

2.07

2.01

2.04

2.06

2.08

2.09

2.11

2.45

2.46

2.46

2.48

3.44

3.46

3.47

4.32

4.32

4.33

4.33

5.00

5.02

5.03

5.04

5.06

7.19

7.22

7.26

CDC

l37.7

07.7

17.7

17.7

27.

837.

847.

847.

85

H2O

O

N

N

O

O

2ae, 1H NMR, CDCl3

150

102030405060708090100110120130140150160170180190200210220f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

17.5

9

31.2

6

37.8

8

45.1

9

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

104.

73

123.

4312

7.90

132.

3413

4.10

168.

03

173.

39

O

N

N

O

O

2ae, 1H NMR, CDCl3

151

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

4.00

2.00

4.00

4.00

4.25

4.26

5.78

5.79

5.80

7.26

CDC

l37.

697.7

07.7

17.7

17.

817.

827.

837.

83

2af, 1H NMR, CDCl3

N

O

N

O

O

O

grease

152

0102030405060708090100110120130140150160170180190200210f1 (ppm)

-20-100102030405060708090100110120130140150160170180190200

38.8

9

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

123.

4812

7.48

132.

2213

4.12

167.

92

2af, 13C NMR, CDCl3

N

O

N

O

O

O

153

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

2.00

2.00

0.04

1.00

1.00

4.00

4.00

2.54

2.54

2.56

2.56

2.57

2.57

2.59

2.59

3.82

3.83

3.84

3.85

5.30

DCM

6.57

6.59

6.60

6.62

6.63

6.67

6.67

6.68

6.70

6.70

6.70

7.26

CDC

l37.7

07.7

07.7

17.7

17.7

17.7

27.7

27.7

37.

837.

847.

847.

857.

862af', 1H NMR, CDCl3

N

O

N

O

O

O

greaseH2O

154

0102030405060708090100110120130140150160170180190200210f1 (ppm)

-100102030405060708090100110120130140150160170180190200

30.6

7

37.8

6

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

117.

8811

9.92

123.

4412

3.72

131.

7813

2.24

134.

0613

4.50

166.

5416

8.38

2af', 13C NMR, CDCl3

N

O

N

O

O

O

155

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

0.09

0.42

0.13

0.03

1.05

2.21

2.03

0.84

0.04

2.02

2.00

0.88

Gre

ase

1.25

Gre

ase

1.57

Wat

er

5.30

CH2

Cl2

7.26

7.26

CDC

l37.

277.

287.

287.

287.

347.

357.

367.

377.

477.

477.

477.

487.

497.

657.

677.7

57.7

67.7

77.7

77.

907.

907.

917.

91

N

O

OH/D

H/D

2ag-d1, 1H NMR, CDCl3

156

0102030405060708090100110120130140150160170180190200210f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

117.

6012

0.19

123.

8112

6.34

126.

3612

7.77

127.7

812

8.87

131.

8313

4.68

136.

07

166.

57

117118119120121f1 (ppm)

0

500

1000117.

6211

7.73

117.

84

120.

3012

0.47

N

O

OH/D

H/D

2ag-d1, 13C NMR, CDCl3

157

-2.0-1.00.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

0.87

0.13

2.04

Ace

tone

7.39

7.63

7.27.37.47.57.67.77.8f1 (ppm)

-200

0

200

400

600

800

0.87

0.13

7.39

7.63

N

O

OH/D

H/D

2ag-d1, 2H NMR, CDCl3

158

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

2.00

1.97

2.00

1.81

0.89

0.93

0.93

0.90

1.77

0.86

1.55

2.28

2.30

2.31

2.32

2.33

2.34

3.14

3.15

3.17

3.93

3.94

3.95

7.26

CDC

l37.

447.

457.

477.

547.

547.

547.

557.

557.

567.

577.

577.

577.

827.

827.

837.

847.

857.

857.

867.

867.

877.

877.

897.

897.

927.

937.

957.

957.

977.

978.

058.

058.

068.

078.

078.

078.

07

H2O

O

N

O

O

3m, 1H NMR, CDCl3

159

102030405060708090100110120130140150160170180190200210220f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

22.2

6

28.3

1

36.1

038

.55

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

128.

0912

8.75

133.

2613

6.86

177.

49

198.

98

O

N

O

O

3m, 13C NMR, CDCl3

160

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-200-1000100200300400500600700800900100011001200130014001500160017001800190020002100

2.07

2.03

2.00

1.87

0.91

0.96

0.96

0.93

1.83

0.89

2.28

2.30

2.31

2.32

2.33

2.34

3.14

3.15

3.17

3.93

3.94

3.95

7.26

CDC

l37.

447.

457.

477.

547.

547.

547.

557.

557.

567.

577.

577.

577.

827.

827.

837.

847.

857.

857.

867.

867.

877.

877.

897.

897.

927.

937.

957.

957.

977.

978.

058.

058.

068.

078.

078.

078.

07

H2O

O

N

SO

O

O

4m, 1H NMR, CDCl3

161

102030405060708090100110120130140150160170180190200210220f1 (ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

22.8

2

35.5

939

.05

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

2 CD

Cl3

121.

1212

5.35

127.

4912

8.15

128.

7313

3.24

134.

4913

4.91

136.

8913

7.82

159.

29

198.

74

O

N

SO

O

O

4m, 13C NMR, CDCl3

162

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

-200-10001002003004005006007008009001000110012001300140015001600170018001900200021002200

2.00

2.00

2.00

2.00

1.00

2.00

1.00

1.00

0.96

2.15

2.17

2.17

2.18

2.19

2.20

2.20

2.21

3.07

3.08

3.08

3.09

3.10

3.87

3.87

3.88

3.89

3.90

7.26

CDC

l37.

267.

897.

907.

907.

917.

917.

917.

917.

928.

028.

028.

038.

048.

048.

048.

598.

598.

598.

598.

608.

618.

618.

618.

658.

658.

658.

65

H2O

O

N

O

O

N+ O

O-

5m, 1H NMR, CDCl3

grease

163

0102030405060708090100110120130140150160170180190200210f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

700

22.9

1

35.7

938

.35

76.9

1 CD

Cl3

77.1

6 CD

Cl3

77.4

1 CD

Cl3

118.

7412

4.54

128.

0212

8.71

129.

3313

3.28

133.

5613

6.60

136.

71

151.

79

166.

1016

6.36

198.

65

O

N

O

O

N+ O

O-

5m, 13C NMR, CDCl3

164

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I o ed. - Nature Research · sp, was maintained under nitrogen atmosphere. Melting points were recorded on a Thomas Hoover capillary melting point apparatus and are uncorrected Materials: