images.nature.com€¦ · NATURE CHEMISTRY | . 1. SUPPLEMENTARY INFORMATION. DOI: 10.1038/NCHEM.1836. K. S. L. Chan et al. 1. Ligand-e. nabled . c. ross-c

NATURE CHEMISTRY | www.nature.com/naturechemistry 1

SUPPLEMENTARY INFORMATIONDOI: 10.1038/NCHEM.1836

K. S. L. Chan et al.

1

Ligand-enabled cross-coupling of C(sp3)–H bonds with arylboron reagents via

Pd(II)/Pd(0) catalysis

Kelvin S. L. Chan, Masayuki Wasa, Ling Chu, Brian N. Laforteza, Masanori Miura

& Jin-Quan Yu

Table of Contents

General Information SI 2

Experimental Section

A. Substrates SI 3

B. Synthesis of Pd(OTf)2(MeCN)4 SI 9

C. Ligand-Accelerated Pd(II)-Catalyzed Cross-Coupling of Alkyl SI 10

C(sp3)–H Bonds with Organoboron Reagents: Optimization

D. Products SI 16

E. Deprotection SI 35

References SI 36

NMR Spectra SI 37

K. S. L. Chan et al.

1

Ligand-Enabled Cross-Coupling of C(sp3)–H Bonds with Arylboron Reagents via

Pd(II)/Pd(0) Catalysis

Kelvin S. L. Chan, Masayuki Wasa, Ling Chu, Brian N. Laforteza, Masanori Miura & Jin-Quan

Yu

Table of Contents

General Information SI 2


A. Substrates SI 3

B. Synthesis of Pd(OTf)2(MeCN)4 SI 9

C. Ligand-Accelerated Pd(II)-Catalyzed Cross-Coupling of Alkyl SI 10

C(sp3)–H Bonds with Organoboron Reagents: Optimization

D. Products SI 16

E. Deprotection SI 35

References SI 36

NMR Spectra SI 37

© 2014 Macmillan Publishers Limited. All rights reserved.


SUPPLEMENTARY INFORMATIONDOI: 10.1038/NCHEM.1836K. S. L. Chan et al.

2

General Information

Solvents were obtained from Sigma-Aldrich, Alfa-Aesar, Acros and EMD Chemicals and used

directly without further purification. Palladium catalysts were obtained from Sigma-Aldrich,

Pressure Chemical Company, and Strem Chemicals. Amines and amino acids were obtained

from Sigma-Aldrich, Alfa-Aesar, Acros, Bachem, and Oakwood, and used to prepare

corresponding triflamides. Trifluoromethanesulfonic anhydride was purchased from Oakwood,

and arylboron reagents were purchased from Boron Molecular, Frontier Scientific, and Combi-

Blocks. Trifluoromethanesulfonamide is abbreviated to triflamide. Tert-amyl alcohol is

abbreviated to tAmylOH.

Analytical thin layer chromatography was performed on 0.25 mm silica gel 60-F254. Preparative

thin layer chromatography was performed on 0.5 mm silica gel purchased from Analtech.

Visualization was carried out with UV light and Vogel’s permanganate. NMR spectra were

recorded on a Bruker AMX-400 instrument (400 MHz for 1H; 100 MHz for 13C), Bruker DRX-

500 instrument (500 MHz for 1H; 125 MHz for 13C), or Bruker DRX-600 instrument (600 MHz

for 1H; 150 MHz for 13C) equipped with a 5 mm DCH cryoprobe. Calibration was done using

residual undeuterated solvent or SiMe4 as an internal reference for 1H and 13C. The following

abbreviations (or combinations thereof) were used to explain multiplicities: s = singlet, d =

doublet, t = triplet, q = quartet, m = multiplet, br = broad. High-resolution mass spectra (HRMS)

were recorded on an Agilent Mass spectrometer using ESI-TOF (electrospray ionization-time of

flight). IR spectra were recorded on a Perkin Elmer Spectrum BX FTIR spectrometer.

Enantiomeric excess values were determined on a Hitachi LaChrom Elite HPLC system using

commercially available chiral columns.




3


A. Substrate Preparation

Figure F1

General procedure A for the preparation of triflyl-protected methyl ester amino acid:

A methyl ester amino acid hydrochloride (20 mmol), either purchased or prepared from the

corresponding amino acid and thionyl chloride, was dissolved in CH2Cl2 (0.5 M), and the

reaction mixture was cooled to –78 °C. Triethylamine (2.0 equiv) was added and the reaction

mixture was stirred –78 °C for 5 minutes. Trifluoromethanesulfonic anhydride (1.05 equiv) was

then added dropwise and the reaction mixture was stirred at –78 °C for 1 to 2 hours, before

quenching with ice. The organic layer was separated, and the aqueous layer was extracted twice

with CH2Cl2. The combined organics were washed with brine, dried over Na2SO4, filtered, and

then concentrated in vacuo. The products were purified by column chromatography with hexanes

and ethyl acetate as an eluent.

General procedure B for the preparation of triflyl-protected amines:

An amine (20 mmol) was dissolved in CH2Cl2 (0.5 M), and the reaction mixture was cooled to –

78 °C. Triethylamine (1.0 equiv) was added and the reaction mixture was stirred –78 °C for 5

minutes. Trifluoromethanesulfonic anhydride (1.05 equiv) was then added dropwise and the

reaction mixture was stirred at –78 °C for 1 to 2 hours, before quenching with ice. The organic

layer was separated, and the aqueous layer was extracted twice with CH2Cl2. The combined

organics were washed with brine, dried over Na2SO4, filtered, and then concentrated in vacuo.

The products were purified by column chromatography with hexanes and ethyl acetate as an

eluent.

NH2

CO2H

H

NH2•HCl

CO2Me

HSOCl2

MeOHNHTf

CO2Me

HTf2O, Et3N

CH2Cl2-78 °C

R R R




4

Supplementary Table S1 | Substrate structures

Data:

(S)-methyl 2-(trifluoromethylsulfonamido)butanoate (1)

Substrate 1 was prepared from L-homoalanine using General Procedure A. 1H NMR (600 MHz, CDCl3) ! 5.90 (br s, 1H), 4.21 (t, J = 6.1 Hz, 1H), 3.82 (s, 3H), 1.98 to 1.92

(m, 1H), 1.85 to 1.77 (m, 1H), 1.00 (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) ! 171.49,

119.60 (q, J = 320.8 Hz), 58.27, 53.23, 26.94, 9.23.

(R)-2-acetamido-3,3-dimethylbutanoic acid (3)

To a solution of D-tert-leucine (1.0 g, 7.6 mmol) in acetic acid (8 mL) was added acetic

anhydride (0.85 mL, 9.1 mmol) and the reaction mixture stirred overnight at room temperature.

The solvent was removed in vacuo to afford compound 3 as a white solid (1.29 g, 98%). No

purification was necessary. Characterization data matched reported data.

NHTf

CO2Me

H

H

NHTf

CO2Me

H

H

MeNHTf

H

MeO2CNHTf

CO2Me

H

Et

NHTf

H

TBSONHTf

H

OBn

NHTf

H

EtNHTf

H

NHTf

CO2Me

H

1 5 6 7 8

9 10 11 12

NHTf

CO2Me

H

NHAc

CO2H

tBu




5

(R)-methyl 2-(trifluoromethylsulfonamido)butanoate (4)

Substrate 4 was prepared from D-homoalanine using General Procedure A. 1H NMR and 13C NMR identical to 1.

(S)-methyl 3-methyl-2-(trifluoromethylsulfonamido)butanoate (5) Substrate 5 was prepared from L-valine methyl ester hydrochloride using General Procedure A. 1H NMR (500 MHz, CDCl3) ! 6.68 (br s, 1H), 4.07 (d, J = 5.1 Hz, 1H), 3.81 (s, 3H), 2.28 to 2.19

(m, 1H), 1.04 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 7.0 Hz, 3H); 13C NMR (150 MHz, CDCl3) !

171.36, 119.64 (q, J = 321.1 Hz), 62.57, 52.95, 31.62, 18.78, 17.05.

(S)-methyl 3,3-dimethyl-2-(trifluoromethylsulfonamido)butanoate (6) Substrate 6 was prepared from L-tert-Leucine using General Procedure A. 1H NMR (600 MHz, CDCl3) ! 5.76 (br s, 1H), 3.90 (s, 1H), 3.80 (s, 3H), 1.03 (s, 9H); 13C NMR

(150 MHz, CDCl3) ! 170.74, 119.66 (q, J = 321.4 Hz), 65.61, 52.68, 34.97, 26.40.

NHTf

CO2Me

H

NHTf

CO2Me

H

H

NHTf

CO2Me

H

H

Me




6

(2S,3S)-methyl 3-methyl-2-(trifluoromethylsulfonamido)pentanoate (7)

Substrate 7 was prepared from L-isoleucine using General Procedure A. 1H NMR (600 MHz, CDCl3) ! 4.13 (d, J = 4.8 Hz, 1H), 3.81 (s, 3H), 1.97 to 1.90 (m, 1H), 1.47

to 1.40 (m, 1H), 1.23 to 1.16 (m, 1H), 1.00 (d, J = 6.9 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H); 13C

NMR (150 MHz, CDCl3) ! 171.11, 119.64 (q, J = 321.2 Hz), 61.77, 52.99, 38.68, 24.60, 15.37,

11.50.

(R)-methyl 2-methyl-3-(trifluoromethylsulfonamido)propanoate (8) Substrate 8 was prepared from (R)-3-amino-2-methylpropionic acid using General Procedure A.1 1H NMR (400 MHz, CDCl3) ! 5.89 (br s, 1H), 3.74 (s, 3H), 3.41 (dq, J = 6.1, 13.8 Hz, 2H), 2.83

to 2.74 (m, 1H), 1.26 (d, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) ! 175.47, 119.78 (q, J =

321.0 Hz), 52.50, 46.28, 39.98, 14.62.

N-(2-((tert-butyldimethylsilyl)oxy)propyl)-1,1,1-trifluoromethanesulfonamide (9) To a solution of 1-amino-2-propanol (1.50 g, 20 mmol) and triethylamine (5.56 mL, 40 mmol) in

CH2Cl2 (20 mL) at 0 °C was added dropwise a solution of tert-butyldimethylsilyl chloride (3.01

g, 20 mmol) in CH2Cl2 (20 mL). The reaction mixture was allowed to warm to room temperature

and stirred overnight. The reaction mixture was quenched with NH4Cl (sat. aq.), extracted with

CH2Cl2, and the combined organics washed with brine, dried over Na2SO4, filtered, and

NHTf

CO2Me

H

Et

NHTf

H

MeO2C

NHTf

H

TBSO




7

concentrated in vacuo to afford the product as a colorless oil (99.9%). No purification was

necessary.1

Substrate 9 was thereafter prepared from the crude amine using General Procedure B. 1H NMR (400 MHz, CDCl3) ! 5.11 (br s, 1H), 4.04 to 3.97 (m, 1H), 3.33 (dd, J = 3.6, 13.0 Hz,

1H), 3.13 (dd, J = 6.4, 12.9 Hz, 1H), 1.18 (d, J = 6.2 Hz, 3H), 0.90 (s, 9H), 0.10 (s, 6H); 13C

NMR (100 MHz, CDCl3) ! 119.81 (q, J = 321.0 Hz), 67.30, 51.13, 25.85, 20.87, 18.09, -4.30, -

4.84.

N-(3-(benzyloxy)-2-methylpropyl)-1,1,1-trifluoromethanesulfonamide (10) A solution of 2-methylpropane-1,3-diol (1.80 g, 20 mmol) in THF (10 mL) was added dropwise

to a suspension of NaH in THF (50 mL). After the addition was complete, the mixture was

stirred at 50 °C for 1 h. Benzyl bromide (2.44 mL, 20.4 mmol) was then added dropwise and the

resulting mixture was stirred at 65 °C overnight. The reaction was quenched by addition of

NH4Cl (sat. aq.). The reaction mixture was diluted with ethyl acetate, washed with NH4Cl (sat.

aq.), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by

column chromatography and 3-(benzyloxy)-2-methylpropan-1-ol was afforded as a colorless oil

(2.50 g, 70%).2

To a solution of 3-(benzyloxy)-2-methylpropan-1-ol (1.00 g, 5.55 mmol),

trifluoromethanesulfonamide (1.65 g, 11.1 mmol), and triphenylphosphine (2.91 g, 11.1 mmol)

in THF (50 mL) at 0 °C was added neat diethyl diazodicarboxylate (1.93 g, 11.1 mmol). The

reaction mixture was stirred at room temperature overnight, and was quenched with water, then

diluted with ethyl acetate. The organics were separated, then washed with NaHCO3 (sat.) and

brine. The combined organics were then dried over Na2SO4, filtered, and concentrated in vacuo.

The crude residue was purified by column chromatography to afford substrate 10 as a colorless

oil (780 mg, 45 %).3

NHTf

H

OBn




8

1H NMR (500 MHz, CDCl3) ! 7.35 to 7.32 (m, 2H), 7.29 to 7.26 (m, 3H), 6.13 (br s, 1H), 4.50 to

4.45 (m, 2H), 3.51 (dd, J = 9.4, 4.0 Hz, 1H), 3.26 to 3.27 (m, 2H), 3.17 (ddd, J = 12.4, 7.8, 3.9

Hz), 2.10 to 2.01 (m, 1H), 0.90 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) ! 137.54,

128.64, 128.04, 127.75, 119.90 (q, J = 321.4 Hz), 74.81, 73.47, 49.32, 33.57, 14.28.

1,1,1-trifluoro-N-(2-methylbutyl)methanesulfonamide (11)

Substrate 11 was prepared from 2-methylbutylamine using General Procedure B. 1H NMR (400 MHz, CDCl3) ! 5.42 (br s, 1H), 3.21 (dt, J = 11.7, 5.6 Hz, 1H), 3.08 (dt, J = 12.8,

6.2 Hz, 1H), 1.67 to 1.56 (m, 1H), 1.49 to 1.39 (m, 1H), 1.25 to 1.14 (m, 1H), 0.95 (d, J = 6.7

Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) ! 119.84 (q, J = 321.1 Hz),

50.00, 35.24, 26.38, 16.54, 10.98.

1,1,1-trifluoro-N-(o-tolyl)methanesulfonamide (12) Substrate 12 was prepared from o-toluidine using General Procedure B. 1H NMR (500 MHz, CDCl3) ! 7.36 (d, J = 6.9 Hz, 1H), 7.26 to 7.19 (m, 3H), 2.35 (s, 3H); 13C

NMR (125 MHz, CDCl3) ! 134.20, 132.19, 131.32, 128.51, 127.24, 126.65, 119.94 (q, J = 322.3

Hz), 17.83.

NHTf

H

Et

NHTf

H




9

B. Synthesis of Pd(OTf)2(MeCN)44

To a dark orange solution of palladium(II) acetate (2.04 g, 9.09 mmol) in acetonitrile (172 mL),

neat trifluoromethanesulfonic acid (2.35 mL, 26.52 mmol) was added dropwise while stirring.

The reaction mixture subsequently changed to a pale yellow color. Diethyl ether (240 mL) was

then added, and a fine pale yellow powder precipitated. The suspension was set aside for 2 h and

the supernatant liquid was decanted. The residual powder was washed with diethyl ether and

dried under a stream of nitrogen to afford Pd(OTf)2(MeCN)4 as a pale yellow powder (3.75 g,

73%).




10

C. Ligand-Accelerated Pd(II)-Catalyzed Cross-Coupling of Alkyl C(sp3)–H Bonds with

Organoboron Reagents

Supplementary Table S2 | Further illustration of match/mismatch effect using D-substrate

NB: L-ligand performs better with D-substrate 4, compared to the D-ligand.

NHTf

CO2Me

H

CO2Me

BPin

cat. Pd(OAc)2 cat. Ac-tLeu-OH

Ag2CO3, NaHCO3BQ, DMSO, H2O

tAmylOH100 °C, N2, 18 h

NHTf

CO2Me

CO2Me

Entry Yield* (%)

Experiments were performed with D-subtrate 4 (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (0.02 mmol), ligand (0.04 mmol), NaHCO3 (1.2 mmol), Ag2CO3 (0.4 mmol), 1,4-benzoquinone (BQ) (0.1 mmol), dimethylsulfoxide (0.08 mmol), water (1.0 mmol) in tAmylOH (1 mL) for 18 h at 100 °C under N2 atmosphere. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard.

4 2 4a

1 542 65

Ligand

Ac-D-tLeu-OHAc-L-tLeu-OH

(R)(R)




11

Optimization:

Supplementary Table S3 | Optimization of bases

Entry Base Yield* (%)

1 33NaH2PO42 72Na2HPO43 70Na3PO44 23KH2PO456

41K2HPO4

738K3PO4

81KOtBu

910

0NaOtBu

11

0LiOtBu

12

55LiOTf

13

0CsF

14

21KF

1516

53NaOAc

17

6KOAc0CsOAc65Na2CO369Li2CO3

Equiv.

4.02.01.54.02.01.54.04.04.04.04.04.04.04.04.02.02.0

18 K2CO3 2.0 4119 Cs2CO3 2.0 220 KHCO3 4.0 6321 NaHCO3 4.0 7022 Na3PO4 2.0 5823 Na2HPO4 3.0 6924 NaHCO3 6.0 74

Experiments were performed with 1 (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (0.02 mmol), 3 (0.04 mmol), base, Ag2CO3 (0.4 mmol), 1,4-benzoquinone (0.1 mmol), dimethylsulfoxide (0.08 mmol), water (1.1 mmol) in tAmylOH (1 mL) for 18 h at 100 °C under N2 atmosphere. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard.

NHTf

CO2Me

H

CO2Me

BPin

cat. Pd(OAc)2cat. Ac-D-tLeu-OH, 3

Ag2CO3, baseBQ, DMSO, H2O


NHTf

CO2Me

CO2Me1 2 1a




12

Supplementary Table S4 | Optimization of catalyst

Supplementary Table S5 | Optimization of Ag oxidant

Entry Catalyst Yield* (%)

1 74Pd(OAc)22 82Pd(OTf)2(MeCN)43 73Pd(TFA)24 57[Pd(allyl)Cl]2

Equiv.

0.10.10.10.05

Experiments were performed with 1 (0.2 mmol), 2 (0.4 mmol), Pd catalyst, 3 (0.04 mmol), NaHCO3 (6.0 equiv.), Ag2CO3 (0.4 mmol), 1,4-benzoquinone (0.1 mmol), dimethylsulfoxide (0.08 mmol), water (1.1 mmol) in tAmylOH (1 mL) for 18 h at 100 °C under N2 atmosphere. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard.

5 0none 0

NHTf

CO2Me

H

CO2Me

BPin

cat. Pdcat. Ac-D-tLeu-OH, 3



NHTf

CO2Me

CO2Me1 2 1a

cat. Pd(OTf)2(MeCN)4cat. Ac-D-tLeu-OH, 3

Ag salt, NaHCO3BQ, DMSO, H2O


Entry Yield* (%)

1 82Ag2CO32 51Ag2O3 32AgOAc4 15Ag3PO4

Equiv.

2.02.04.01.5

Experiments were performed with 1 (0.2 mmol), 2 (0.4 mmol), Pd(OTf)2(MeCN)4 (0.02 mmol), 3 (0.04 mmol), NaHCO3 (6.0 equiv.), Ag salt, 1,4-benzoquinone (0.1 mmol), dimethylsulfoxide (0.08 mmol), water (1.1 mmol) in tAmylOH (1 mL) for 18 h at 100 °C under N2 atmosphere. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard.

Ag

NHTf

CO2Me

H

CO2Me

BPin

NHTf

CO2Me

CO2Me1 2 1a




13

Supplementary Table S6 | Optimization of solvents



solvent100 °C, N2, 18 h

Entry Solvent Yield* (%)

1 0N,N-dimethylformamide (DMF)2 0N,N-dimethylacetamide3 281,2-dichloroethane4 481,2-dimethoxyethane56

1acetonitrile

727toluene

843ethyl acetate

910

54tetrahydrofuran

11

651,4-dioxane

12

64tBuOH

13

82tAmylOH76tAmylOH/dioxane (9:1)69tAmylOH/THF (9:1)

Experiments were performed with 1 (0.2 mmol), 2 (0.4 mmol), Pd(OTf)2(MeCN)4 (0.02 mmol), 3 (0.04 mmol), NaHCO3 (6.0 equiv.), Ag2CO3 (0.4 mmol), 1,4-benzoquinone (0.1 mmol), dimethylsulfoxide (0.08 mmol), water (1.1 mmol) in solvent (1 mL) for 18 h at 100 °C under N2 atmosphere. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard. †No dimethylsulfoxide was added. ‡N,N-dimethylformamide (0.08 mmol) was added instead of dimethylsulfoxide.

14 tAmylOH 7615 tAmylOH 6816 tAmylOH 017† tAmylOH 7818‡ tAmylOH 76

H2O (equiv.)

5.55.55.55.55.55.55.55.55.55.55.55.55.51.010505.55.5

NHTf

CO2Me

H

CO2Me

BPin

NHTf

CO2Me

CO2Me1 2 1a




14

Supplementary Table S7 | Optimization of other variables



tAmylOHtemperature, atmosphere, 18 h

Entry Temperature (°C) Yield* (%)

1 75802 821003 661204 76100

Experiments were performed with 1 (0.2 mmol), 2 (0.4 mmol), Pd(OTf)2(MeCN)4 (0.02 mmol), 3 (0.04 mmol), NaHCO3 (6.0 equiv.), Ag2CO3 (0.4 mmol), 1,4-benzoquinone (0.1 mmol), dimethylsulfoxide (0.08 mmol), water (1.1 mmol) in tAmylOH (1 mL) for 18 h at specified temperature under specified atmosphere. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard.

Atmosphere

N2N2N2O2

NHTf

CO2Me

H

CO2Me

BPin

NHTf

CO2Me

CO2Me1 2 1a




15

Supplementary Table S8 | Ligand optimization

Me

Me

Experiments were performed with 4 (0.2 mmol), 2 (0.4 mmol), Pd(OTf)2(MeCN)4 (0.02 mmol), ligand (0.04 mmol), NaHCO3 (1.2 mmol), Ag2CO3 (0.4 mmol), 1,4-benzoquinone (0.1 mmol), dimethylsulfoxide (0.08 mmol), water (1.1 mmol) in tAmylOH (1 mL) for 18 h at 100 °C under N2 atmosphere. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard.

Entry Ligand Yield* (%) Entry Ligand Yield* (%)R PG R PG

1 0 14 0iPr iPrMe Ts

2 18 15 31iPriPrFormyl

3 68iPr Ac

4 12iPr Boc

5 15iPr Fmoc

6 9iPr Cbz

7 0iPr Troc

NHTf

CO2Me

H

CO2Me

BPin

NHTf

CO2Me

CO2Me4 2 4a



HN

PGR

CO2H(S)

(R)(R)

8 31H Ac

9 50Me Ac

10 68nPr Ac

11 57iBu Ac

12 75tBu Ac

13 82Ac

OMe

O

O

16 43iPr F

O17 9iPr

18 8iPr

19 0iPr

20 6iPr

21 19iPr

22 58iPr

CF3

O

tBu

O

OMe

O

Bn

O

O

O

Me

Me

Ph

O

23 47iPr

24 0iPr

cat. Pd(OTf)2(MeCN)4




16

D. Products

Supplementary Table S9 | Complete coupling partner scope




NHTf

CO2Me1r, (23%)†‡

NHTf

CO2Me1s, (23%)†

Ac BocN

NHTf

CO2Me

H

BPin

X

NHTf

CO2Me

CO2Me1a, 82%

NHTf

CO2Me1b, 73%

NHTf

CO2Me1c, 64%

NHTf

CO2Me1d, 66%

NHTf

F

CO2Me1e, 62%

NHTf

CO2Me1f, 60%

NHTf

CF3

CO2Me1g, 71%

NHTf

CO2Me1h, 73%

NHTf

CF3

CO2Me1i, 60%

NHTf

F

CO2Me1j, 50%

NHTf

Cl

CO2Me1k, 63%

NHTf

CO2Me1l, 16%

NHTf

OMe

CO2Me1m, 54%

NHTf

CO2Me1n, 43%

NHTf

CO2Me1p, 61%

NHTf

CO2Me1q, 63%

F

CF3

CO2Me CO2Me

CO2Me

F CN

Br

OMe

OMe

Experiments were performed with 1 (0.2 mmol), arylboronic acid pinacol ester (0.4 mmol), Pd(OTf)2(MeCN)4 (0.02 mmol), 3 (0.04 mmol), NaHCO3 (1.2 mmol), Ag2CO3 (0.4 mmol), 1,4-benzoquinone (0.1 mmol), dimethylsulfoxide (0.08 mmol), water (1.1 mmol) in tAmylOH (1 mL) for 18 h at 100 °C under N2 atmosphere. *Isolated yields. †Product was not isolated and yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard. ‡Reaction was performed with Ac-D-Val-OH (0.04 mmol) instead of 3.

NHTf

CO2Me1o, 38%

NHAc

1

NHTf

CO2Me

X

1a–s




17

Supplementary Table S10 | Unreactive coupling partners

Figure F2 | Arylation with ArI

NHTf

CO2Me

Hcat. Pd(OTf)2(MeCN)4cat. Ac-D-tLeu-OH, 3



het

NHTf

CO2Me

1

het–BPin

Experiments were performed with 1 (0.2 mmol), arylboronic acid pinacol ester (0.4 mmol), Pd(OTf)2(MeCN)4 (0.02 mmol), 3 (0.04 mmol), NaHCO3 (1.2 mmol), Ag2CO3 (0.4 mmol), 1,4-benzoquinone (0.1 mmol), DMSO (0.08 mmol), H2O (1.1 mmol) in tAmylOH (1 mL) for 18 h at 100 °C under N2 atmosphere. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard.

NHTf

CO2Me

0%

O

O

O NHTf

CO2Me

O

(S)(S)

0%

NHTf

CO2Me

NN

0%

Me

NHTf

CO2Me

0%

N

Experiment was performed with 11 (0.2 mmol), iodobenzene (0.6 mmol), Pd(OAc)2 (0.02 mmol), 3 (0.04 mmol), Ag2CO3 (0.4 mmol) in tBuOH (1 mL) for 18 h at 120 °C under air. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard. Comparable to yields from cross-coupling reaction with PhBPin.

NHTf

H

I

cat. Pd(OAc)2cat. Ac-D-tLeu-OH, 3

PhI, Ag2CO3tBuOH

120 °C, air, 18 h

NHTf

11 11a, 53%*

Et Et




18

General Procedure

In a 50 mL Schlenk tube, the starting material (0.2 mmol), arylboronic acid pinacol ester (0.4

mmol), Pd(OTf)2(MeCN)4 (11.4 mg, 0.02 mmol), Ac-D-tLeu-OH 3 (6.9 mg, 0.04 mmol),

NaHCO3 (100.8 mg, 1.2 mmol), Ag2CO3 (110.3 mg, 0.4 mmol), and 1,4-benzoquinone (10.8 mg,

0.1 mmol) were combined. The flask was evacuated and backfilled with N2 three times, before a

solution of dimethylsulfoxide (6.0 mg, 0.076 mmol), water (20 mg, 1.1 mmol), and tAmylOH (1

mL, 0.2M) was added. The reaction mixture was then stirred at 100 °C for 18 h. After being

allowed to cool to room temperature, the mixture was diluted with a 1:1 mixture of hexanes:ethyl

acetate, and filtered through a pad of celite. The filtrate was concentrated in vacuo, and the

resulting mixture purified by column chromatography using an eluent of hexanes: ethyl acetate.

Data:

(S)-methyl 4-(4-methoxy-4-oxo-3-(trifluoromethylsulfonamido)butyl)benzoate (1a)

Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 4-methoxycarbonylphenylboronic acid

pinacol ester (104.8 mg, 0.4 mmol) following the general procedure. After purification by

column chromatography, 1a was obtained as a pale yellow liquid (62.9 mg, 82 %). 1H NMR (600 MHz, CDCl3) ! 7.97 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.19 (br s, 1H),

4.28 to 4.26 (m, 1H), 3.91 (s, 3H), 3.78 (s, 3H), 2.80 (t, J = 8.0 Hz, 2H), 2.27 to 2.21 (m, 1H),

2.11 to 2.04 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.14, 167.21, 145.19, 130.11, 128.58,

119.59 (q, J = 321.0 Hz), 56.79, 53.35, 52.29, 34.73, 31.27; IR (neat) ! 3205, 2955, 1751, 1722,

1702, 1438, 1382, 1286, 1231, 1193, 1148, 1112, 990 cm–1; HRMS (ESI-TOF) Calcd for

C14H17F3NO6S (MH+): 384.0723; found: 384.0718.

NHTf

CO2Me

CO2Me




19

(S)-methyl 3-(4-methoxy-4-oxo-3-(trifluoromethylsulfonamido)butyl)benzoate (1b)



column chromatography, 1b was obtained as a pale yellow liquid (56.0 mg, 73 %). 1H NMR (600 MHz, CDCl3) ! 7.90 (dd, J = 6.6, 2.2 Hz, 1H), 7.88 (s, 1H), 7.40 to 7.36 (m, 2H),

6.12 (d, J = 9.0 Hz, 1H), 4.28 (dt, J = 4.8, 8.5 Hz, 1H), 3.92 (s, 3H), 3.79 (s, 3H), 2.84 to 2.76

(m, 2H), 2.28 to 2.22 (m, 1H), 2.12 to 2.06 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.20,

167.29, 140.13, 133.26, 130.56, 129.57, 128.87, 127.96, 119.59 (q, J = 321.0 Hz), 56.86, 53.37,

52.37, 34.97, 31.08; IR (neat) ! 3175, 2962, 1751, 1723, 1438, 1382, 1292, 1231, 1198, 1148,

1111, 989 cm–1; HRMS (ESI-TOF) Calcd for C14H17F3NO6S (MH+): 384.0723; found: 384.0722.

(S)-dimethyl 5-(4-methoxy-4-oxo-3-(trifluoromethylsulfonamido)butyl)isophthalate (1c) Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 3,5-bismethoxycarbonylphenylboronic

acid pinacol ester (128.1 mg, 0.4 mmol) following the general procedure. After purification by

column chromatography, 1c was obtained as an off-white solid (56.5 mg, 64 %). 1H NMR (600 MHz, CDCl3) ! 8.54 (s, 1H), 8.08 (s, 2H), 6.28 (d, J = 9.0 Hz, 1H), 4.29 (dt, J =

4.7, 8.6 Hz, 1H), 3.95 (s, 6H), 3.81 (s, 3H), 2.91 to 2.83 (m, 2H), 2.31 to 2.25 (m, 1H), 2.16 to

2.06 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.10, 166.39, 140.81, 133.93, 131.04, 129.11,

119.59 (q, J = 321.0 Hz), 56.85, 53.43, 52.62, 34.78, 31.03; IR (neat) ! 1727, 1436, 1383, 1337,

1253, 1198, 1148, 1001, 758 cm–1; HRMS (ESI-TOF) Calcd for C16H19F3NO8S (MH+): 442.0778;

found: 442.0769.

NHTf

CO2Me

CO2Me

NHTf

CO2Me

CO2Me

CO2Me




20

(S)-methyl 4-phenyl-2-(trifluoromethylsulfonamido)butanoate (1d)

Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with phenylboronic acid pinacol ester (81.6

mg, 0.4 mmol) following the general procedure. After purification by column chromatography,

1d was obtained as a pale yellow liquid (43.1 mg, 66 %). 1H NMR (600 MHz, CDCl3) ! 7.31 (t, J = 7.5 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.18 (dd, J = 7.8,

1.2 Hz, 2H), 5.79 (br s, 1H), 4.29 (dd, J = 7.5, 4.9 Hz, 1H), 3.77 (s, 3H), 2.73 (t, J = 8.0 Hz, 2H),

2.26 to 2.20 (m, 1H), 2.10 to 2.04 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.26, 139.66,

128.80, 128.52, 126.70, 119.59 (q, J = 320.9 Hz), 56.88, 53.32, 35.20, 31.16; IR (neat) ! 3252,

1735, 1436, 1381, 1231, 1195, 1146, 1103, 988 cm–1; HRMS (ESI-TOF) Calcd for

C12H15F3NO4S (MH+): 326.0668; found: 326.0674. The enantiomeric purity of the product was

determined by HPLC analysis (CHIRALCEL IC column, 2% isopropanol in hexanes, flow rate

0.3 mL/min, retention time 25.993 min (major) and 27.773 min (minor)), 96% ee.

DAD-CH1 results

Retention Time Area% 25.993 97.908 27.773 2.092 Total 100%

(S)-methyl 4-(4-fluorophenyl)-2-(trifluoromethylsulfonamido)butanoate (1e)

Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 4-fluorophenylboronic acid pinacol

ester (88.8 mg, 0.4 mmol) following the general procedure. After purification by column

chromatography, 1e was obtained as a pale yellow liquid (42.6 mg, 62 %).

NHTf

CO2Me

NHTf

F

CO2Me




21

1H NMR (600 MHz, CDCl3) ! 7.14 (dd, J = 5.4, 8.5 Hz, 2H), 6.99 (t, J = 8.7 Hz, 2H), 5.92 (br s,

1H), 4.26 (dd, J = 4.9, 7.7 Hz, 1H), 3.78 (s, 3H), 2.71 (t, J = 7.9 Hz, 2H), 2.22 to 2.16 (m, 1H),

2.06 to 2.00 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.29, 161.72 (d, J = 244.5 Hz), 135.28

(d, J = 3.3 Hz), 129.97 (d, J = 7.9 Hz), 119.58 (q, J = 320.9 Hz), 115.58 (d, J = 21.3 Hz), 56.73,

53.37, 35.32, 30.38; IR (neat) ! 3272, 2959, 1733, 1604, 1510, 1436, 1378, 1187, 1143, 1107,

1090, 987, 890, 827, 773 cm–1; HRMS (ESI-TOF) Calcd for C12H14F4NO4S (MH+): 344.0574;

found: 344.0590.

(S)-methyl 4-(3-fluorophenyl)-2-(trifluoromethylsulfonamido)butanoate (1f) Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 3-fluorophenylboronic acid pinacol


chromatography, 1f was obtained as a pale yellow liquid (41.2 mg, 60 %). 1H NMR (600 MHz, CDCl3) ! 7.27 (dt, J = 6.1, 8.0 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.94 to

6.88 (m, 2H), 5.84 (d, J = 8.9 Hz, 1H), 4.28 (dt, J = 4.8, 8.3 Hz, 1H), 3.80 (s, 3H), 2.77 to 2.70

(m, 2H), 2.25 to 2.19 (m, 1H), 2.09 to 2.02 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.17,

163.09 (d, J = 246.1 Hz), 142.17 (d, J = 7.3 Hz), 130.28 (d, J = 8.3 Hz), 124.21 (d, J = 2.7 Hz),

119.58 (q, J = 321.0 Hz), 115.41 (d, J = 21.2 Hz), 113.65 (d, J = 20.7 Hz), 56.75, 53.41, 34.94,

30.91; IR (neat) ! 3266, 2960, 1733, 1618, 1590, 1489, 1438, 1380, 1230, 1192, 1143, 1104,

988, 942, 869, 784 cm–1; HRMS (ESI-TOF) Calcd for C12H14F4NO4S (MH+): 344.0574; found:

344.0568.

NHTf

CO2Me

F




22

(S)-methyl 4-(4-(trifluoromethyl)phenyl)-2-(trifluoromethylsulfonamido)butanoate (1g)

Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 4-trifluoromethylphenylboronic acid


column chromatography, 1g was obtained as a pale yellow liquid (55.8 mg, 71 %). 1H NMR (500 MHz, CDCl3) ! 7.57 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 5.75 (d, J = 8.9

Hz, 1H), 4.28 (dt, J = 4.8, 8.3 Hz, 1H), 3.79 (s, 3H), 2.85 to 2.75 (m, 2H), 2.28 to 2.21 (m, 1H),

2.11 to 2.03 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.02, 143.75, 128.91, 125.75 (q, J = 3.6

Hz), 124.28 (q, J = 272.0 Hz), 119.59 (q, J = 321.0 Hz), 56.72, 53.47, 34.97, 31.02; ; IR (neat) !

3274, 2930, 1735, 1619, 1438, 1380, 1324, 1231, 1192, 1145, 1120, 1067, 1019, 988, 848, 825

cm–1; HRMS (ESI-TOF) Calcd for C13H13F6NO4SNa (MNa+): 416.0362; found: 416.0357.

(S)-methyl 4-(3-(trifluoromethyl)phenyl)-2-(trifluoromethylsulfonamido)butanoate (1h)

Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 3-trifluoromethylphenylboronic acid


column chromatography, 1h was obtained as a pale yellow liquid (57.4 mg, 73 %). 1H NMR (500 MHz, CDCl3) ! 7.49 (d, J = 7.6 Hz, 1H), 7.44 – 7.41 (m, 2H), 7.38 (d, J = 7.4 Hz,

1H), 5.86 (d, J = 8.8 Hz, 1H), 4.28 (dt, J = 4.8, 8.3 Hz, 1H), 3.79 (s, 3H), 2.81 (t, J = 7.9 Hz,

2H), 2.29 to 2.22 (m, 1H), 2.12 to 2.04 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.09, 140.59,

132.01, 131.14 (q, J = 33.2 Hz), 129.28, 125.22 (q, J = 3.8 Hz), 124.19 (q, J = 272.2 Hz), 123.64

(q, J = 3.8 Hz), 119.59 (q, J = 321.0 Hz), 56.74, 53.46, 34.99, 31.04; IR (neat) ! 3264, 2921,

NHTf

CF3

CO2Me

NHTf

CO2Me

CF3




23

2852, 1735, 1439, 1380, 1330, 1231, 1196, 1145, 1122, 1073, 987, 902, 802 cm–1; HRMS (ESI-

TOF) Calcd for C13H13F6NO4SNa (MNa+): 416.0362; found: 416.0350.

(S)-methyl 4-(3-fluoro-4-(trifluoromethyl)phenyl)-2-(trifluoromethylsulfonamido) butanoate (1i)

Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 3-fluoro,4-trifluoromethyl

phenylboronic acid pinacol ester (116.0 mg, 0.4 mmol) following the general procedure. After

purification by column chromatography, 1i was obtained as a pale yellow liquid (49.4 mg, 60

%). 1H NMR (400 MHz, CDCl3) ! 7.54 (t, J = 7.7 Hz, 1H), 7.06 (dd, J = 9.8, 13.5 Hz, 2H), 5.75 (br

s, 1H), 4.27 (dd, J = 4.8, 7.8 Hz, 1H), 3.82 (s, 3H), 2.84 to 2.74 (m, 2H), 2.29 to 2.20 (m, 1H),


(d, J = 8.0 Hz), 127.61 to 127.53 (m), 124.24 (d, J = 3.4 Hz), 122.72 (q, J = 272.2 Hz), 119.58

(q, J = 321.1 Hz), 116.96, 116.82, 56.60, 53.56, 34.65, 30.90; IR (neat) ! 3271, 2921, 1738,

1631, 1585, 1512, 1434, 1380, 1324, 1230, 1178, 1128, 1046, 988, 877, 832 cm–1; HRMS (ESI-

TOF) Calcd for C13H12F7NO4SNa (MNa+): 434.0267; found: 434.0261.

(S)-methyl 4-(3-cyano-4-fluorophenyl)-2-(trifluoromethylsulfonamido)butanoate (1j) Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 3-cyano,4-fluorophenylboronic acid

pinacol ester (98.8 mg, 0.4 mmol) following the general procedure. After purification by column

chromatography, 1j was obtained as a pale yellow liquid (36.8 mg, 50 %).

NHTf

CF3

CO2Me

F

NHTf

F

CO2Me

CN




24

1H NMR (600 MHz, CDCl3) ! 7.47 to 7.43 (m, 2H), 7.17 (tt, J = 1.1, 8.4 Hz, 1H), 5.93 (br s,

1H), 4.24 (dd, J = 4.7, 8.1 Hz, 1H), 3.83 (s, 3H), 2.78 (t, J = 8.0 Hz, 2H), 2.26 to 2.18 (m, 1H),


(d, J = 3.8 Hz), 135.38 (d, J = 8.1 Hz), 133.15, 119.56 (d, J = 321.0 Hz), 116.87 (d, J = 19.5 Hz),

113.97, 101.69 (d, J = 15.6 Hz), 56.51, 53.57, 34.88, 30.12; IR (neat) ! 3233, 1746, 1502, 1439,

1380, 1255, 1229, 1192, 1146, 1114, 990, 899, 835, 774 cm–1; HRMS (ESI-TOF) Calcd for

C13H13F4N2O4S (MH+): 369.0527; found: 369.0509.

(S)-methyl 4-(4-chlorophenyl)-2-(trifluoromethylsulfonamido)butanoate (1k)

Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 4-chlorophenylboronic acid pinacol


chromatography, 1k was obtained as a pale yellow liquid (45.3 mg, 63 %). 1H NMR (600 MHz, CDCl3) ! 7.27 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 5.69 (br s, 1H),

4.26 (dd, J = 7.7, 4.8 Hz, 1H), 3.79 (s, 3H), 2.74 to 2.67 (m, 2H), 2.23 to 2.17 (m, 1H), 2.06 to

2.00 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.07, 138.05, 132.52, 129.90, 128.92, 119.58 (q,

J = 320.7 Hz), 56.70, 53.42, 35.18, 30.52; IR (neat) ! 3244, 2960, 1735, 1493, 1437, 1381, 1231,

1196, 1146, 1093, 1015, 989, 896, 811, 759 cm–1; HRMS (ESI-TOF) Calcd for C12H14ClF3NO4S

(MH+): 360.0279; found: 360.0296.

(S)-methyl 4-(4-bromophenyl)-2-(trifluoromethylsulfonamido)butanoate (1l)

NHTf

Cl

CO2Me

NHTf

CO2Me

Br




25

Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 4-bromophenylboronic acid pinacol


chromatography, 1l was obtained as a pale yellow liquid (12.9 mg, 16 %). 1H NMR (600 MHz, CDCl3) ! 7.43 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 8.3 Hz, 2H), 5.66 (br s, 1H),

4.26 (br s, 1H), 3.79 (s, 3H), 2.73 to 2.65 (m, 2H), 2.23 to 2.17 (m, 1H), 2.06 to 2.00 (m, 1H); 13C

NMR (150 MHz, CDCl3) ! 171.04, 138.58, 131.88, 130.29, 120.53, 119.58 (q, J = 321.0 Hz)

56.69, 53.43, 35.11, 30.59; IR (neat) ! 3248, 2958, 1737, 1489, 1437, 1381, 1231, 1197, 1146,

1094, 1073, 1011 cm–1; HRMS (ESI-TOF) Calcd for C12H13BrF3NO4SNa (MNa+): 425.9593;

found: 425.9572.

(S)-methyl 4-(4-methoxyphenyl)-2-(trifluoromethylsulfonamido)butanoate (1m) Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 4-methoxyphenylboronic acid pinacol


chromatography, 1m was obtained as a pale yellow liquid (38.4 mg, 54 %). 1H NMR (600 MHz, CDCl3) ! 7.10 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 8.3 Hz, 2H), 5.70 (d, J = 8.8

Hz, 1H), 4.27 (dt, J = 5.0, 8.4 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 2.67 (t, J = 7.8 Hz, 3H), 2.23 to

2.16 (m, 1H), 2.11 to 1.99 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.27, 158.39, 131.62,

129.50, 119.59 (q, J = 321.0 Hz), 114.20, 56.82, 55.43, 53.31, 35.45, 30.26; IR (neat) ! 3244,

2929, 2853, 1748, 1613, 1513, 1439, 1381, 1232, 1195, 1147, 1100, 1035, 991, 823, 767 cm–1;

HRMS (ESI-TOF) Calcd for C13H17F3NO5S (MH+): 356.0774; found: 356.0764.

NHTf

OMe

CO2Me




26

(S)-methyl 4-(3,5-dimethoxyphenyl)-2-(trifluoromethylsulfonamido)butanoate (1n)

Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 3,5-bismethoxyphenylboronic acid


column chromatography, 1n was obtained as a pale yellow liquid (33.1 mg, 43 %). 1H NMR (600 MHz, CDCl3) ! 6.34 (s, 3H), 5.73 (d, J = 9.0 Hz, 1H), 4.28 (dt, J = 4.6, 8.4 Hz,

1H), 3.79 (s, 3H), 3.78 (s, 6H), 2.67 (t, J = 7.9 Hz, 2H), 2.24 to 2.18 (m, 1H), 2.08 to 1.99 (m,

1H); 13C NMR (150 MHz, CDCl3) ! 171.24, 161.10, 142.02, 119.58 (q, J = 321.1 Hz), 106.62,

98.59, 56.83, 55.45, 53.33, 35.05, 31.48; IR (neat) ! 3244, 2927, 2843, 1748, 1598, 1461, 1433,

1381, 1295, 1231, 1198, 1148, 1103, 1059, 992, 837 cm–1; HRMS (ESI-TOF) Calcd for

C14H19F3NO6S (MH+): 386.0880; found: 386.0872.

(S)-methyl 4-(4-acetamidophenyl)-2-(trifluoromethylsulfonamido)butanoate (1o)

Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 4-acetamidophenylboronic acid pinacol


chromatography with a eluent of dichloromethane:acetone (4:1), 1o was obtained as a pale

yellow solid (29.1 mg, 38 %). 1H NMR (600 MHz, CDCl3) ! 7.62 (br s, 1H), 7.38 (br s, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.02 (d,

J = 8.3 Hz, 2H), 4.15 (dt, J = 4.5, 9.0 Hz, 1H), 3.68 (s, 3H), 2,74 to 2.66 (m, 1H), 2.60 to 2.53

(m, 1H), 2.14 (s, 3H), 2.10 to 2.02 (m, 1H), 2.00 to 1.90 (m, 1H); 13C NMR (150 MHz, CDCl3) !

171.48, 169.64, 136.46, 136.04, 129.02, 120.49, 119.70 (q, J = 321.0 Hz), 57.18, 53.05, 34.78,

31.22, 24.44; IR (neat) ! 3378, 3293, 3045, 2932, 1748, 1665, 1602, 1535, 1438, 1413, 1376,

NHTf

CO2Me

OMe

OMe

NHTf

NHAc

CO2Me




27

1320, 1229, 1194, 1149, 1099, 1001, 837 cm–1; HRMS (ESI-TOF) Calcd for C14H18F3N2O5S

(MH+): 383.0883; found: 383.0884.

(S)-methyl 4-(naphthalen-2-yl)-2-(trifluoromethylsulfonamido)butanoate (1p) Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 2-napthaleneboronic acid pinacol ester

(101.7 mg, 0.4 mmol) following the general procedure. After purification by column

chromatography, 1p was obtained as a pale yellow liquid (45.8 mg, 61 %). 1H NMR (600 MHz, CDCl3) ! 7.79 (q, J = 8.3, 7.3 Hz, 3H), 7.63 (s, 1H), 7.48 to 7.43 (m, 2H),

7.30 (dd, J = 8.4, 1.8 Hz, 1H), 5.77 (d, J = 5.8 Hz, 1H), 4.33 (q, J = 6.6 Hz, 1H), 3.76 (s, 3H),

2.93 to 2.86 (m, 2H), 2.35 to 2.29 (m, 1H), 2.18 to 2.12 (m, 1H); 13C NMR (150 MHz, CDCl3) !

171.25, 137.07, 133.66, 132.35, 128.49, 127.78, 127.62, 126.93, 126.90, 126.35, 125.74, 119.61

(q, J = 320.7 Hz), 56.89, 53.36, 35.15, 31.32; IR (neat) ! 3257, 2954, 1730, 1436, 1379, 1316,

1230, 1193, 1147, 1099, 991, 858, 821, 751 cm–1; HRMS (ESI-TOF) Calcd for C16H17F3NO4S

(MH+): 376.0825; found: 376.0809.

(S)-methyl 4-(naphthalen-1-yl)-2-(trifluoromethylsulfonamido)butanoate (1q)

Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 1-napthaleneboronic acid pinacol ester

(101.7 mg, 0.4 mmol) following the general procedure. After purification by column

chromatography, 1q was obtained as a pale yellow liquid (47.3 mg, 63 %). 1H NMR (600 MHz, CDCl3) ! 7.93 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.2

Hz, 1H), 7.54 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.50 (ddd, J = 8.0, 6.8, 1.3 Hz, 1H), 7.40 (dd, J =

NHTf

CO2Me

NHTf

CO2Me




28

8.2, 7.0 Hz, 1H), 7.33 (d, J = 6.9 Hz, 1H), 5.76 (d, J = 8.8 Hz, 1H), 4.42 to 4.38 (m, 1H), 3.77 (s,

3H), 3.23 to 3.15 (m, 2H), 2.38 to 2.32 (m, 1H), 2.23 to 2.17 (m, 1H); 13C NMR (150 MHz,

CDCl3) ! 171.16, 135.77, 134.07, 131.60, 129.15, 127.60, 126.39, 125.87, 125.71, 123.21,

119.64 (q, J = 321.0 Hz), 57.19, 53.37, 34.46, 28.43; IR (neat) ! 3288, 2956, 1733, 1436, 1381,

1231, 1196, 1146, 1103, 986, 894, 798, 780 cm–1; HRMS (ESI-TOF) Calcd for C16H17F3NO4S

(MH+): 376.0825; found: 376.0811.




29

Products from Table 4 of paper:

Methyl 4-((3S)-4-methoxy-2-methyl-4-oxo-3-(trifluoromethylsulfonamido)butyl) benzoate (5a)



column chromatography, mono-arylated 5a was obtained as a mixture of diastereomers in a form

of a pale yellow liquid (45.1 mg, 57 %), and in a d.r. of 4.7:1. In addition, di-arylated 5b was

also isolated as an off-white solid (41.7 mg, 39 %).

1H NMR (600 MHz, CDCl3) Major diastereomer: ! 7.98 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz,

2H), 5.85 (br s, 1H), 4.18 (d, J = 3.9 Hz, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 2.82 (dd, J = 5.1, 13.2

Hz, 1H), 2.48 (dd, J = 9.5, 13.1 Hz, 1H), 2.46 to 2.35 (m, 1H), 0.96 (d, J = 6.6 Hz, 3H); 13C

NMR (150 MHz, CDCl3) Major diastereomer: ! 170.49, 167.07, 144.16, 130.02, 129.21, 128.76,

119.61 (q, J = 321.3 Hz), 61.37, 53.23, 52.27, 38.95, 38.41, 15.79; IR (neat) ! 3207, 2957, 1749,

1722, 1612, 1439, 1382, 1286, 1233, 1194, 1147, 1114, 1021, 966, 760 cm–1; HRMS (ESI-TOF)

Calcd for C15H19F3NO6S (MH+): 398.0880; found: 398.0877.

(S)-dimethyl 4,4'-(2-(2-methoxy-2-oxo-1-(trifluoromethylsulfonamido)ethyl)propane-1,3-

diyl)dibenzoate (5b)

NHTf

CO2Me

CO2Me

Me

NHTf

CO2Me

CO2Me

MeO2C




30

1H NMR (600 MHz, CDCl3) ! 7.99 to 7.96 (m, 4H), 7.25 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.3 Hz,

2H), 5.75 (br s, 1H), 4.21(s, 1H), 3.91 (s, 6H), 3.67 (s, 3H), 2.86 (dd, J = 6.7, 13.6 Hz, 1H), 2.74

to 2.62 (m, 4H); 13C NMR (150 MHz, CDCl3) ! 170.26, 167.01, 166.89, 143.87, 143.51, 130.16,

130.13, 129.31, 129.20, 129.03, 128.96, 58.66, 53.41, 52.31, 52.27, 45.78, 36.68, 35.74; IR

(neat) ! 3174, 2922, 1748, 1722, 1611, 1438, 1384, 1282, 1233, 1194, 1147, 1112, 1020, 765

cm–1; HRMS (ESI-TOF) Calcd for C23H25F3NO8S (MH+): 532.1247; found: 532.1231.

(S)-methyl 4-(4-methoxy-2,2-dimethyl-4-oxo-3-(trifluoromethylsulfonamido) butyl)benzoate

(6a) Substrate 6 (55.5 mg, 0.2 mmol) was cross-coupled with 4-methoxycarbonylphenylboronic acid


column chromatography, both mono-arylated 6a (36.4 mg, 44 %) and di-arylated 6b were

isolated (41.9 mg, 38 %) as off-white solids.

1H NMR (600 MHz, CDCl3) ! 7.97 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H), 6.03 (br s, 1H),

4.05 (s, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 2.79 (d, J = 13.0 Hz, 1H), 2.63 (d, J = 13.0 Hz, 1H), 0.94

(d, J = 4.1 Hz, 6H); 13C NMR (150 MHz, CDCl3) ! 170.52, 167.16, 142.23, 130.99, 129.46,

128.77, 119.64 (q, J = 321.5 Hz), 65.42, 52.90, 52.26, 44.32, 38.69, 23.37, 22.82; IR (neat) !

3234, 2959, 1723, 1612, 1439, 1382, 1285, 1234, 1194, 1147, 1115, 1082, 1021, 767, 747, 715

cm–1; HRMS (ESI-TOF) Calcd for C16H21F3NO6S (MH+): 412.1036; found: 412.1034.

NHTf

CO2Me

CO2Me

Me

Me




31

(S)-dimethyl 4,4'-(2-(2-methoxy-2-oxo-1-(trifluoromethylsulfonamido)ethyl)-2-

methylpropane-1,3-diyl)dibenzoate (6b) 1H NMR (600 MHz, CDCl3) ! 7.98 to 7.95 (m, 4H), 7.27 to 7.23 (m, 4H), 4.18 (s, 1H), 3.92 (s,

3H), 3.91 (s, 3H), 3.88 (s, 3H), 3.03 (d, J = 13.3 Hz, 1H), 2.90 (d, J = 13.2 Hz, 1H), 2.73 (d, J =

13.3 Hz, 1H), 2.59 (d, J = 13.2 Hz, 1H), 0.88 (s, 3H); 13C NMR (150 MHz, CDCl3) ! 170.26,

167.08, 167.03, 141.56, 141.55, 131.17, 131.07, 129.70, 129.65, 129.11, 129.00, 119.49 (q, J =

321.6 Hz), 62.62, 53.09, 52.31, 52.28, 42.41, 42.05, 41.88, 22.00; IR (neat) ! 3223, 2955, 1721,

1611, 1438, 1383, 1284, 1233, 1196, 1147, 1112, 1020, 965, 767, 712 cm–1; HRMS (ESI-TOF)

Calcd for C24H27F3NO8S (MH+): 546.1404; found: 546.1404.

Methyl 4-((2R,3S)-2-ethyl-4-methoxy-4-oxo-3-(trifluoromethylsulfonamido) butyl)benzoate

(7a)



column chromatography, 7a was obtained as a pale yellow liquid (41.1 mg, 50 %). 1H NMR (400 MHz, CDCl3) ! 8.00 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 5.68 (br s, 1H),

4.21 (d, J = 2.9 Hz, 1H), 3.91 (s, 3H), 3.78 (s, 3H), 2.73 (d, J = 7.2 Hz, 2H), 2.25 to 2.18 (m,

1H), 1.41 to 1.33 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) ! 170.99,

167.13, 144.56, 130.06, 129.35, 128.72, 119.60 (q, J = 321.6 Hz), 58.95, 53.25, 52.24, 45.61,

36.46, 22.27, 11.77; IR (neat) ! 3211, 2959, 1748, 1723, 1611, 1439, 1382, 1284, 1231, 1194,

NHTf

CO2Me

CO2Me

MeO2C

Me

NHTf

CO2Me

CO2Me

Et




32

1147, 1114, 1020, 755 cm–1; HRMS (ESI-TOF) Calcd for C16H21F3NO6S (MH+): 412.1036;

found: 412.1019.

(R)-methyl 2-benzyl-3-(trifluoromethylsulfonamido)propanoate (8a)


mg, 0.4 mmol) following the general procedure using Ac-L-tLeu-OH (0.04 mmol) instead. After

purification by column chromatography, 8a was obtained as a pale yellow liquid (37.4 mg, 57

%). 1H NMR (600 MHz, CDCl3) ! 7.25 (dd, J = 6.6, 8.1 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.08 (d, J

= 7.2 Hz, 2H), 5.58 (br d, J = 4.6 Hz, 1H), 3.66 (s, 3H), 3.36 to 3.29 (m, 2H), 3.01 (dd, J = 6.0,

13.8 Hz, 1H), 2.94 to 2.89 (m, 1H), 2.78 (dd, J = 8.2, 13.8 Hz, 1H); 13C NMR (150 MHz, CDCl3)

! 174.37, 137.01, 128.97, 128.90, 127.29, 119.71 (q, J = 321.1 Hz), 52.55, 46.97, 44.25, 35.55;

IR (neat) ! 3254, 2957, 1721, 1495, 1440, 1378, 1231, 1193, 1147, 1082, 835, 746, 702 cm–1;

HRMS (ESI-TOF) Calcd for C12H15F3NO4S (MH+): 326.0668; found: 326.0661.

N-(2-((tert-butyldimethylsilyl)oxy)-3-phenylpropyl)-1,1,1-trifluoromethanesulfonamide (9a)


mg, 0.4 mmol) following the general procedure using Na2CO3 (42.4 mg, 0.4 mmol) instead.

After purification by column chromatography, 9a was obtained as a pale yellow liquid (44.6 mg,

56 %). 1H NMR (400 MHz, CDCl3) ! 7.31 (d, J = 7.2 Hz, 2H), 7.27 to 7.22 (m, 1H), 7.17 (d, J = 6.8 Hz,

2H), 5.08 (br s, 1H), 4.06 to 4.01 (m, 1H), 3.30 to 3.22 (m, 2H), 2.86 (dd, J = 6.4, 13.6 Hz, 1H),

NHTfMeO2C

NHTfTBSO




33

2.78 (dd, J = 7.1, 13.6 Hz, 1H), 0.88 (s, 9H), 0.04 (s, 3H), -0.09 (s, 3H); 13C NMR (150 MHz,

CDCl3) ! 136.93, 129.63, 128.80, 127.03, 119.79 (q, J = 321.4 Hz), 72.11, 48.63, 41.33, 25.88,

18.12, -4.77, -4.85; IR (neat) ! 3320, 2954, 2932, 2858, 1418, 1374, 1256, 1233, 1193, 1148,

1106, 1046, 988, 837, 808, 788, 749, 700 cm–1; HRMS (ESI-TOF) Calcd for C16H27F3NO3SSi

(MH+): 398.1427; found: 398.1423.

N-(2-benzyl-3-(benzyloxy)propyl)-1,1,1-trifluoromethanesulfonamide (10a) Substrate 10 (62.3 mg, 0.2 mmol) was cross-coupled with phenylboronic acid pinacol ester (81.6


After purification by column chromatography, 10a was obtained as a pale yellow liquid (47.3

mg, 61 %). 1H NMR (600 MHz, CDCl3) ! 7.38 (ddd, J = 7.5, 6.3, 1.5 Hz, 2H), 7.35 to 7.32 (m, 1H), 7.31 to

7.28 (m, 4H), 7.24 to 7.21 (m, 1H), 7.12 (dd, J = 8.1, 1.4 Hz, 2H), 5.99 (br s, 1H), 4.52 to 4.46

(m, 2H), 3.58 (dd, J = 9.6, 3.5 Hz, 1H), 3.44 to 3.40 (m, 2H), 3.31 to 3.27 (m, 1H), 2.64 (dq, J =

7.5, 13.9 Hz, 2H), 2.25 to 2.19 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 138.58, 137.29, 129.00,

128.83, 128.80, 128.32, 127.94, 126.76, 119.89 (q, J = 321.4 Hz), 73.78, 72.75, 48.02, 40.30,

35.36; IR (neat) ! 3313, 2916, 1453, 1425, 1375, 1231, 1192, 1148, 1066, 743, 700 cm–1; HRMS

(ESI-TOF) Calcd for C18H21F3NO3S (MH+): 388.1189; found: 388.1173.

N-(2-benzylbutyl)-1,1,1-trifluoromethanesulfonamide (11a)



NHTf

OBn

NHTfEt




34

After purification by column chromatography, 11a was obtained as a pale yellow liquid (31.9

mg, 54 %). 1H NMR (600 MHz, CDCl3) ! 7.32 (t, J = 7.3 Hz, 2H), 7.24 (t, J = 6.7 Hz, 1H), 7.16 (d, J = 6.9

Hz, 2H), 4.59 (br s, 1H), 3.28 to 3.17 (m, 2H), 2.72 (dd, J = 6.6, 13.9 Hz, 1H), 2.54 (dd, J = 7.9,

13.9 Hz, 1H), 1.89 to 1.79 (m, 1H), 1.45 to 1.38 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H); 13C NMR (150

MHz, CDCl3) ! 139.41, 129.05, 128.88, 126.72, 119.78 (q, J = 320.1 Hz), 47.29, 42.20, 38.23,

24.09, 10.95; IR (neat) ! 3314, 2966, 2932, 1430, 1371, 1231, 1192, 1147, 1061, 740, 701 cm–1;

HRMS (ESI-TOF) Calcd for C12H16F3NO2SNa (MNa+): 318.0746; found: 318.0743.

Methyl 4-(2-(trifluoromethylsulfonamido)benzyl)benzoate (12a) Substrate 12 (47.8 mg, 0.2 mmol) was cross-coupled with 4-methoxycarbonylphenylboronic acid

pinacol ester (104.8 mg, 0.4 mmol) following the general procedure but using Pd(OTf)2(MeCN)4

(0.01 mmol, 5 mol%), 3 (0.02 mmol, 10 mol%) and at a lowered temperature of 80 °C for only 8

h. After purification by column chromatography, 12a was obtained as a yellow liquid (52.7 mg,

71 %). 1H NMR (600 MHz, CDCl3) ! 7.94 (d, J = 8.3 Hz, 2H), 7.42 to 7.39 (m, 1H), 7.36 to 7.32 (m,

2H), 7.28 to 7.26 (m, 1H), 7.19 (d, J = 8.2 Hz, 2H), 4.16 (s, 2H), 3.88 (s, 3H); 13C NMR (150

MHz, CDCl3) ! 166.97, 144.13, 136.66, 132.33, 131.59, 130.44, 129.12, 128.91, 128.82, 128.46,

127.78, 119.83 (q, J = 322.2 Hz), 52.35, 38.15; IR (neat) ! 3159, 1700, 1612, 1493, 1434, 1370,

1290, 1221, 1194, 1143, 1114, 958, 752 cm–1; HRMS (ESI-TOF) Calcd for C16H15F3NO4S

(MH+): 374.0668; found: 374.0653.

NHTf

CO2Me




35

E. Deprotection5, 6

Figure 3

To a mixture of substrate (0.50 mmol, 219.2 mg) and K2CO3 (0.60 mmol, 82.9 mg) in acetone (2

mL) was added bromoacetonitrile (0.60 mmol, 72.0 mg) or 4-nitrobenzyl bromide (0.60 mmol,

129.6 mg). The reaction mixture was stirred at room temperature overnight, and the solvent was

removed in vacuo thereafter. Water (5 mL) was added and the mixture was extracted with ethyl

acetate, washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The

product was afforded as a colorless oil (129.1 mg for R= CN, and 177.2 mg for R = aryl, quant.

for both). No purification was required.

Figure 4

To a solution of substrate (0.5 mmol, 177.2 mg) in THF (3 mL) was added Cs2CO3 (0.66 mmol,

217.0 mg). The reaction mixture was warmed overnight at 30 °C and then cooled to room

temperature. The reaction mixture was then acidified with 1M HCl (aq) (2 mL), and the THF

was removed in vacuo. The aqueous layer was washed with ether (5 mL x 2) and the organics

discarded. The aqueous layer was then placed in an ice bath. 1N NaOH (5 mL) was added, and

benzoyl chloride (1.5 mmol, 210.8 mg) was added at 0 °C portionwise over 30 min, and the

reaction mixture was allowed to warm to room temperature. After stirring overnight, the reaction

mixture was extracted with ethyl acetate. The combined organics were washed with brine (5

mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by

column chromatography (0 ! 20% ethyl acetate in hexanes) and product was afforded as a

colorless oil (71.7 mg, 75%). Similar yields are obtained for R = CN.

Br RK2CO3

acetone

quant.

R = CN, or

NO2

Et

Me

NHTfEt

MeTfN R

Cs2CO3, THF 1. HCl (aq.)

2. PhCOCl, NaOH (aq)

75% over 3 steps

Et

MeTfN

Et

Me

NEt

MeHN Ph

O

NO2 NO2




36

References:

1. WO2011121350A1, page 125.

2. WO2010111353A1, PCT/US2010/028444 page 79.

3. Sakakura, A., Kondo, R., Matsumura, Y., Akakura, M. & Ishihara, K. J. Am. Chem. Soc. 131,

17762–17764 (2009).

4. E. Drent, J. A. M. van Broekhoven, M. J. Doyle, J. Organomet. Chem. 417, 235 (1991).

5. Hendrickson, J. B., Bergeron, R., Giga, A. & Stembach, D. J. Am. Chem. Soc. 95, 3412–3413

(1973).

6. Amos, D. T., Renslo, A. R. & Danheiser, R. L. J. Am. Chem. Soc. 125, 4970–4971 (2003).




37

NMR Spectra

NHTf

CO2Me

CO2Me

NHTf

CO2Me

CO2Me




38

NHTf

CO2Me

CO2Me

NHTf

CO2Me

CO2Me




39

NHTf

CO2Me

CO2Me

CO2Me

NHTf

CO2Me

CO2Me

CO2Me




40

NHTf

CO2Me

NHTf

CO2Me




41

NHTf

F

CO2Me

NHTf

F

CO2Me




42

NHTf

CO2Me

F

NHTf

CO2Me

F




43

NHTf

CF3

CO2Me

NHTf

CF3

CO2Me




44

NHTf

CO2Me

CF3

NHTf

CO2Me

CF3




45

NHTf

CF3

CO2Me

F

NHTf

CF3

CO2Me

F




46

NHTf

F

CO2Me

CN

NHTf

F

CO2Me

CN




47

NHTf

Cl

CO2Me

NHTf

Cl

CO2Me




48

NHTf

CO2Me

Br

NHTf

CO2Me

Br




49

NHTf

OMe

CO2Me

NHTf

OMe

CO2Me




50

NHTf

CO2Me

OMe

OMe

NHTf

CO2Me

OMe

OMe




51

NHTf

NHAc

CO2Me

NHTf

NHAc

CO2Me




52

NHTf

CO2Me

NHTf

CO2Me




53

NHTf

CO2Me

NHTf

CO2Me




54

NHTf

CO2Me

CO2Me

Me

NHTf

CO2Me

CO2Me

Me




55

NHTf

CO2Me

CO2Me

MeO2C

NHTf

CO2Me

CO2Me

MeO2C




56

NHTf

CO2Me

CO2Me

Me

Me

NHTf

CO2Me

CO2Me

Me

Me




57

NHTf

CO2Me

CO2Me

MeO2C

Me

NHTf

CO2Me

CO2Me

MeO2C

Me




58

NHTf

CO2Me

CO2Me

Et

NHTf

CO2Me

CO2Me

Et




59

NHTfMeO2C

NHTfMeO2C




60

NHTfTBSO

NHTfTBSO




61

NHTf

OBn

NHTf

OBn




62

NHTfEt

NHTfEt




63

NHTf

CO2Me

NHTf

CO2Me


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images.nature.com€¦ · NATURE CHEMISTRY | . 1. SUPPLEMENTARY INFORMATION. DOI: 10.1038/NCHEM.1836. K. S. L. Chan et al. 1. Ligand-e. nabled . c. ross-c