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ARTICLEdoi:10.1038/nature14006
Functionalized olefin cross-coupling toconstruct carbon––carbon bondsJulian C. Lo1*, Jinghan Gui1*, Yuki Yabe1, Chung-Mao Pan1 & Phil S. Baran1
Carbon–carbon (C–C) bonds form the backbone of many important molecules, including polymers, dyes and pharma-ceutical agents. The development of new methods to create these essential connections in a rapid and practical fashionhas been the focus of numerous organic chemists. This endeavour relies heavily on the ability to form C–C bonds in thepresence of sensitive functional groups and congested structural environments. Here we report a chemical trans-formation that allows the facile construction of highly substituted and uniquely functionalized C–C bonds. Using asimple iron catalyst, an inexpensive silane and a benign solvent under ambient atmosphere, heteroatom-substitutedolefins are easily reacted with electron-deficient olefins to create molecular architectures that were previously difficultor impossible to access. More than 60 examples are presented with a wide array of substrates, demonstrating thechemoselectivity and mildness of this simple reaction.
New methods for the construction of C–C bonds have the potential toshift paradigms in retrosynthetic analysis (the strategy used to designsyntheses of molecules)1. Historically, those that have been most suc-cessful feature simple experimental procedures, exhibit broad scopeand allow access to chemical space previously deemed challenging orinaccessible. A recent exercise in total synthesis drew our attention toradical-based olefin hydrofunctionalizations of the sorts pioneered inrefs 2–9. Those illuminating studies led to the invention of a reductivecoupling10–12 of simple olefins with electron-deficient olefins such asthat depicted in Fig. 1a13. In that work, an adduct bearing an all-carbonquaternary centre such as A could be easily accessed in minutes and inan open flask from olefin B, presumably via the intermediacy of radicalA9. Although a useful and practical method, the compounds it producedcould already be obtained from readily accessible functionalized hydro-carbons such as alkyl halides14, alcohols15,16 and carboxylic acids17 viaconventional radical-generating processes.
In contrast, the functionalized hydrocarbons required to access adductssuch as C, D and E (Fig. 1a) would either require extensive functionalgroup (FG) manipulations or are unfeasible donors owing to FG incom-patibilities and chemoselectivity difficulties arising from the heteroa-toms present (B, S and I). By analogy to previous work, if olefins couldbe used as a surrogate for the intermediate radicals C9, D9 and E9, easilyaccessible compounds such as F could be employed directly, avoidingFG manipulations completely.
Development of functionalized olefin cross-couplingAlthough this idea is conceptually simple, examining the hypotheticalmechanistic pathway revealed numerous obstacles that would need tobe addressed, as shown in Fig. 1b. The initiating step, radical forma-tion from the donor olefin G by an in situ-generated Fe hydride, couldbe complicated by issues of both regioselectivity and chemoselectivity.Furthermore, depending on the nature of the X substituent, several com-peting pathways could arise involving the Fe complexes in the catalyticcycle (for example, transmetallation of a C–B bond, desulfurization ofa C–S bond, and oxidative addition of a C–I bond). If the first step didoccur as intended, the intermediate radical H could be prone to pre-mature reduction18–20, trapping with O2 (ref. 2), or homodimerization.
Provided that H undergoes the desired conjugate addition to the electron-deficient olefin coupling partner, the newly generated radical I couldundergo homodimerization, intramolecular hydrogen atom abstrac-tion or consecutive conjugate additions leading to uncontrollable oli-gomerization. Formation of J from a single-electron reduction of I wouldresult in a substantially basic and nucleophilic site that could prove tobe incompatible with the X group and its substituents. In order for thereaction to prove successful, the conditions must be mild enough totolerate both the various intermediate species in the catalytic cycle, aswell as the final coupled product K.
With these potential difficulties in mind, we used the model systemdepicted in Fig. 2a, with silyl enol ether 1 serving as the donor andcyclohexenone (2) as the acceptor, to develop a functionalized olefincross-coupling. Application of conditions similar to those previouslydeveloped, using Fe(acac)3 (4, acac, acetylacetonate) as a catalyst andPhSiH3 as a stoichiometric reductant3,13, formed the reductively coupledproduct 3 in 53% yield based on GC/MS (gas chromatography/massspectrometry) using an internal standard. Analysis of the side productsfrom the model system and related reactions led to the identification ofcompounds 14–17 (Fig. 2b). As 16 and 17 presumably arise from path-ways where Fe(acac)3 behaves as a Lewis acid21, we hoped to attenuatethe Lewis acidity of the catalyst by increasing the amount of steric shield-ing of the Fe centre. Increasing the size of the substitution on the dioneligands (5–9) led to decreased amounts of 16, with Fe(dibm)3 (5, dibm,diisobutyrylmethane)22 providing the best balance between reactivityand steric shielding. Although attempts to alter the electronic structureof the ligand with electron-deficient (10 and 11) and electron-rich (12and 13) substituents eliminated reactivity, the addition of Na2HPO4 in-creased the yield of the desired product 3 from 69% to 78% when usingFe(dibm)3 as the catalyst. The use of about 45 other inorganic and aminebases as additives did not result in increased yields, suggesting thatNa2HPO4 does not simply serve as a buffering agent. Additionally,Fe(dibm)3 enabled product formation with donors that were unreac-tive with Fe(acac)3 (18, Fig. 2c), which instead provided significant quan-tities of by-products 16 and 17. Over the course of the project, it wasfound that Fe(dibm)3 provided the highest yields when the heteroa-tom substitution on the donor olefin contained Lewis-basic lone pairs,
*These authors contributed equally to this work.
1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
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whereas Fe(acac)3 proved superior in the absence of such moieties (seebelow).
Scope and functional group toleranceThe optimized conditions were then applied to a wider variety of donorand acceptor olefins, initially focusing on enol ethers (Fig. 3a). UsingFe(dibm)3 (5 mol%), silyl enol ethers could be coupled to cyclic andacyclic enones, an enal and an acrylamide to generate adducts 3 and20–25 with yields that generally increased with decreasing substitutionon the silicon atom (19 and 22–24). Remarkably, even a severely con-gested oestrone derivative could undergo addition to methyl vinyl ketoneto generate steroidal adduct 25 with the stereochemistry of the newlyformed neopentyl quaternary stereocentre corresponding to that obtainedthrough a conventional organometallic addition of an alkyl group tooestrone23. Alkyl and aryl vinyl ethers could also be used, although higheryields were generally obtained by using the donor olefin in excess (26–33).
Endocyclic enol ethers were also tolerated, as shown by the formationof 30–33.
Additionally, enecarbamates and enamides could undergo cross-coupling under the reaction conditions (Fig. 3b). Adducts 34 and 35were formed by the coupling of a Cbz (benzyloxycarbonyl)-protecteddihydropyrrole with benzyl acrylate and cyclopent-2-enone, respectively,although these couplings necessitated larger amounts of PhSiH3 thanthe enol ethers. The amount of PhSiH3 needed could be decreased byusing more electronically activated acceptors, as the formation of 36and 37 demonstrated. Other cyclic and acyclic enecarbamates could alsobe employed and added to various acceptor olefins (38, 39 and 41–46),although higher loadings (15 mol%) of Fe(dibm)3 were typically requiredfor useful yields. The formation of 40 also demonstrated that the nitro-gen atom present on the donor olefin could be protected as an amideinstead of a carbamate. Mono- and 1,1-disubstituted acyclic donor ole-fins were competent donors (41–46), however attempts to control thestereochemistry of the cross-coupling by usinga-phenylethylamine asa chiral auxiliary24 provided only modest amounts of diastereoselec-tivity (45 and 46).
Vinyl thioethers proved to be unique donor olefins, with the cross-couplings of those surveyed taking place at ambient temperature to gen-erate adducts 47–56 (Fig. 3c). Although the cross-coupling to form 49
a A new C–C bond formation method via cross-coupling
MeMe
R1
X
R2
Easily accessible donors
EWG
TBSO
Me I
R1
B(pin)
R1
SPh
R1
I
(pin)B
Me MeR2
R2
R2
PhS
Me EWG
EWG
EWG(this work)
b Postulated mechanism with potential complications
LnFem
LnFem–1
LnFem
H
R1R2
X
R2
X
R1
H
EWG
PhSiH3ROH
R1
R2X
H
EWG
R1
R2X
H
EWG
R2
R2X
H
EWG
H
ROH
ChemoselectivityRegioselectivity
Premature reductionTrapping with O
2
Homodimerization
Product stability to reaction conditions
HomodimerizationIntramolecular hydrogen atom abstractionOligomerization
Compatibility of X with intermediates
G H
IJ
K
A
C
D
E′
D′
C′
EWG
Acceptor
Nucleophilic radicals
H
Me
FG = I, OH,
CO2H, and so on
Me
FG
B
R1
X
R2
R1
I
R2
OH
for example,
FIdeal donor
FG
(prior work)
Difficult to access Unfeasible donors
A′
EFG = I, OH,
CO2H, and so on
Figure 1 | Functionalized olefin cross-coupling as a strategy for convergentchemical synthesis. a, Functionalized olefin cross-coupling would facilitatethe exploration of chemical space that has previously been difficult to access(for example, C–E). Such a strategy would use readily available heteroatom-substituted olefins as donors (F) to access nucleophilic radical intermediates(for example, C9–E9), which would couple with electrophilic acceptor olefins.This approach would avoid difficulties that could arise from the use of otherradical precursors (greyed box, bottom right). b, The functionalized olefincross-coupling would occur by the Fe hydride-mediated conversion of thedonor olefin G to the nucleophilic radical H, which would undergo conjugateaddition to the acceptor olefin to form intermediate I. Single-electron reductionto form the stabilized anion J followed by protonation would form the finalproduct K. Examination of the postulated mechanism for the cross-couplingreveals several potential complications (bulleted) that could arise due toeither the intermediacy of radicals or the heteroatom (X) present on thedonor olefin. EWG, electron-withdrawing group; FG, functional group;(pin), pinacolato; TBS, tert-butyldimethylsilyl; X, heteroatom; L, ligand.
Me
Me Me
Me
MeMe
N
SOO O
7 (36%)5 (69%, 78%*) 6 (56%)
Me
OOTBS
+
FeL3(5 mol% )
PhSiH3
EtOH, 60 °CMeMe
O
TBSO
4 (53%) 9 (9%)
13 (0%)
8 (8%)
12 (0%)11 (0%)
L = F3C
10 (0%)
1 3
a Ligand screen with corresponding yields of the coupled product
b Side products initially observed when using Fe(acac)3
Me Me
OTBS
15 17
OTBS
+
FeL3
(5 mol%)
PhSiH3Na2HPO4
EtOH, 60 °C
O
TBSO
c Two olefins unreactive with Fe(acac)3, but able to be coupled using Fe(dibm)3
O
O
TBSO
Me
Me
14
O
Catalyst
18 19
Yield
Fe(dibm)3 32%
Fe(acac)3 <1%
O
2
2
16
OEtTBSO
Figure 2 | Functionalized olefin cross-coupling optimization studies.a, Top row, reaction studied (ligand L shown bottom left). Altering the ligandson the Fe centre (by using compounds 4–13) had the greatest influence onthe outcome of the reaction, with Fe(dibm)3 (5) giving the highest yields.The addition of 1 equiv. Na2HPO4 further increased the yield. (Yields hereand in c are based on GC/MS analysis using 1,3,5-trimethoxybenzene as aninternal standard.) Greyed-out ligands gave 0% yield. b, Side products thatwere observed when Fe(acac)3 (4) was used as the catalyst. The formationof compounds 16 and 17 could be attributed to the Lewis acidity of 4. The useof 5 as the catalyst reduced the formation of compounds 16 and 17. c, Anexample where the use of 5 instead of 4 was essential in obtaining thedesired functionalized olefin cross-coupling reactivity. TBS,tert-butyldimethylsilyl; L, ligand; acac, acetylacetonate; dibm,diisobutyrylmethane; GC/MS, gas chromatography/mass spectrometry.
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proceeded in a higher yield when the reaction was heated at 60 uC, theyields of the other vinyl thioether cross-couplings did not benefit fromelevated temperatures. With the exception of 50, the coupling of thealkenyl thioether donors proceeded with 5 mol% of Fe(dibm)3; how-ever, increased amounts of PhSiH3 and acceptor olefin were required
for certain recalcitrant substrates (50, 51, 53 and 54). Syringe pumpaddition of the acceptor and PhSiH3 to the reaction mixture could alsoimprove yields in certain cases (51 and 55).
Boron substitution on the donor olefin could also be tolerated, with theuse of 5 mol% Fe(acac)3 providing slightly higher yields than Fe(dibm)3.
B(pin)Me
OMe
O
61 (47%)
NMe2
Me B(pin)
O
62 (32%)
NHBoc
R2BNMe2
Me Me
O
57: R2 = (pin) (70%)
58: R2 = (MIDA) (58%)§
59: R2 = (dan) (71%)
(dan)BOMe
Me Me
O
60 (86%)
22: R = TMS (46%)*
23: R = TES (33%)*
19: R = TBS (37%)*
24: R = TIPS (9%)* MeO
MeTBSO
RMe
OPh
O
H
H
H
MeO
O
Me
32 (43%)*
27: R = CN (59%)*
28: R = CO2Me (58%)*
29: R = C(O)Me (31%)*
25 (43%, >99:1 d.r.)†,‡,§ O
42: R = H (48%)†,II,¶
43: R = Bn (79%, 1:1.3 d.r.)†,‡,II
N
Me
45: R = Cbz (69%, 1:1.5 d.r.)†,‡,II
46: R = Boc (55%, 1:1.4 d.r.)†,‡,II
41 (70%)*
44 (73%)
N
O
Me
O
40 (70%)†,II,¶
71 (48%)
PhMe2Si R
Me Me
PhMe2Si
Me
63: R = CO2Me (61%)
64: R = CO2Bn (54%)
65: R = CN (84%, 51% )
66: R = SO2Ph (35%)**
70 (51%)‡
PhS R
Me
n-C4H9S
R
S
R
n-C12H25S CN
Me S
53: R = CN (67%)†
54: R = C(O)NMe 2 (48%)†
51: R = C(O)Me (49%)†,‡
52: R = CN (50%)
55 (35%)†,‡
47: R = CN (65%)
48: R = C(O)NMe2 (67%)
49 (48%)# 50 (40%)†,II,¶
N
BnO O
N
34 (65%)† 35 (75%)†
O
R
OTBSPh
CN
n-C6H13
38 (55%, 1:1.5 d.r.)†,‡,II
O
N
Me
Me
+ EWGR1
R2
X
EWGR3
R2
R1
R3 X
R4 R4Fe(dibm)3 or Fe(acac)3
(5–100 mol%)
Na2HPO4 (1 equiv.)PhSiH3 (2–6 equiv.)
ROH, RT–80 °C
TBSO
20 (69%)
Me Me
Me
O
O
TBSO
Me Me3 (78%)*
Me
On-C4H9
26 (51%)*
Me
O
N
EtO O
37 (88%)
Me OEt
O
N
36 (75%)
OMeO
O
EtO O
30 (54%, 1:1.2 d.r.)
Me
O
OEt
EtO O
31 (76%, 1:1.8 d.r.)
Me
O
OEt
O
Oxygen: 5 mol% Fe(dibm)3, 2 equiv. PhSiH3, EtOH, 60 °C Nitrogen: 5 mol% Fe(dibm)3, 2 equiv. PhSiH3, EtOH, 60 °C
Sulfur: 5 mol% Fe(dibm)3,2 equiv. PhSiH3, EtOH, RT
Boron: 5 mol% Fe(acac)3,
3 equiv. PhSiH3, EtOH, 60 °C
Silicon: 50 mol% Fe(acac)3, 2 equiv. PhSiH3, n-PrOH, 80 °C
Halogens: 100 mol% Fe(acac)3, 3 equiv. PhSiH3, EtOH, 60 °C
BnN
MeMe
O
OMe
• Heteroatoms (X) tolerated on donor: O, N, S, B, Si, F, Cl, Br, I
• 60 examples• Air and moisture compatible• Typically complete in under 1 h
PhMe2Si R
Me Me
67: R = CO2H (53%)††
68: R = C(O)Me (60%)‡
69: R = C(O)NMe2 (70%)56 (54%)
39 (61%)
72: R = NMe2 (60%)
73: R = OH (46%)††
76 (42%)†,‡ 77 (37%)†,‡74 (67%) 75 (50%)††
N
OMeO
n-C6H13
S4-MeOPh
S
N
S Me
(1 equiv.) (3 equiv.)
O4-MeOPh
O
Me Cl
HO2COTBS
Me Br
OTBS
Me I
OH
Me Cl
OTBS
Me Cl
OTBS
Me F
MeO
NMe2O
n-C5H11O
O
OMeMeO
MeO O
Me
33 (64%, >99:1 d.r.)†,‡
NR
Ph MeO OMe
N
MeO OBn
Ph
TBSO
21 (40%)
Me Me
H
OMe
O
OR
NMe2 R
OO
NMe2
O
NMe2
O
NMe2
O
Ph
Me
O NMe2
Cbz
Cbz
Cbz
Boc
Cbz
Cbz
CbzCbz Cbz
a b
c
f
e
d
Figure 3 | Adducts synthesized by functionalized olefin cross-coupling.Top, the reaction studied. The donor component is shown in green and theacceptor component is shown in blue. Couplings using donor olefins withheteroatom substitution containing Lewis basic lone pairs (a, O; b, N; c, S)proceeded in higher yields with Fe(dibm)3 whereas couplings without suchmoieties (d, B; e, Si; f, halogens) proceeded in higher yields with Fe(acac)3.*3 equiv. donor and 1 equiv. acceptor used. {6 equiv. PhSiH3 used. {6 equiv.
acceptor used. 1THF used as a cosolvent. | | 15 mol% [Fe] used. "Secondportion of [Fe], acceptor and PhSiH3 added after 1 h. #Heated at 60 uC.qRun on gram-scale. **100 mol% [Fe] used. {{Na2HPO4 omitted. TMS,trimethylsilyl; TES, triethylsilyl; TIPS, triisopropylsilyl; Bn, benzyl; Cbz,benzyloxycarbonyl; Boc, tert-butyloxycarbonyl; (MIDA),N-methyliminodiacetate; (dan), 1,8-diaminonaphthyl.
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An isopropenyl pinacolato (pin) boronic ester, N-methyliminodiacetate(MIDA) boronate25,26, and a 1,8-diaminonaphthyl (dan) boronamide27
could all be coupled to N,N-dimethyl acrylamide (57–59; Fig. 3d), al-though the use of THF as a cosolvent was required to solubilize the MIDAboronate. Additionally, methyl acrylate could be used as an acceptor(60 and 61), and oxygen- and nitrogen-containing functionalities couldbe tolerated at allylic positions (61 and 62).
Vinyl silanes could also be used as donor olefins, although highestyields were obtained using a substoichiometric amount (50 mol%) ofFe(acac)3. Additionally, switching the solvent from EtOH to n-PrOHand heating the reactions to 80 uC instead of 60 uC resulted in higheryields. With these slight modifications, an isopropenyl and vinyl silanecould be coupled to a wide variety of acceptor olefins to form 63–70(Fig. 3e), although the coupling to obtain the phenyl vinyl sulfone adduct66 required a stoichiometric amount of Fe(acac)3. With the omissionof Na2HPO4, unprotected acrylic acid could be used as an acceptor toprovide the coupled product 67 in a transformation difficult to achieveusing conventional conjugate addition techniques28,29.
As a final testament to the mildness of this C–C bond forming reac-tion, alkenyl halides were found to take part in the cross-coupling inreasonable yields using stoichiometric amounts of Fe(acac)3. Alkenylfluorides, chlorides, bromides and even iodides could all be used as donors,with the 2-haloallyl alcohol derivatives delivering products 71, 72, 76and 77 (Fig. 3f), where the halogen atom remained intact. Interestingly,acrylic acid could once again be used as an acceptor (73, 75), and thereaction proceeded readily with a free alcohol (74), demonstrating thenotable chemoselectivity of this method.
To highlight the efficiency of the newly developed coupling reaction,we chose to target glucal derivative 79 (Fig. 4a). This compound haspreviously been prepared in three steps from readily available 78 in 52%yield, although that route required the use of excess gaseous HCl, toxicand harsh organometallic reagents and cryogenic temperatures30. Bycontrast, olefin cross-coupling allowed the desired product 79 to be syn-thesized directly from 78 in a single step over two hours in 68% iso-lated yield, although it did require the slow addition of a large excess(12 equiv.) of both methyl vinyl ketone and PhSiH3.
Finally, the resilience of the functionalized olefin cross-coupling toadverse conditions was evaluated by performing the reaction in a vari-ety of unconventional solvents. As indicated by GC/MS, the couplingto form silyl ether 20 proved to be successful in a selection of beer, wineand various spirits (see Supplementary Table 2 and SupplementaryFigs 23–30). In addition to showing the ability of the reaction to pro-ceed under aqueous conditions, these results demonstrate the reaction’stolerance of a host of organic compounds31 and microorganisms, sug-gesting possible downstream applications to the area of bioconjugation32.
Discussion and limitationsFrom a strategic perspective, this methodology grants access to areasof chemical space that, in most cases, were previously inaccessible. His-torically, heteroatom-substituted quaternary centres have been synthe-sized with multiple FG manipulations and rarely, if ever, through a directC–C disconnection as enabled here. Thus, ,90% of the compounds listedin Fig. 3 are new chemical entities despite their simplicity. In the caseof 30, 31 and 34–37, where a comparison to contemporary reactivitymodes could be made, it was found that the olefin cross-coupling routeoffers a complementary approach to the recently reported decarbox-ylative method33. Furthermore, the olefin cross-coupling reaction set-up was operationally simple, as no precautions were made with regardsto moisture or air exclusion, and reactions were typically done within afew minutes to an hour. The reaction is also readily scalable, with thecoupling to form 65 being conducted on the gram scale (51% yield).
However, no reaction is without limitations. Although nearly all ofthe substrate classes tested delivered the expected product, the 1,2-disubstituted vinyl boronic ester 80 and vinyl silane 82 exclusively pro-vided adducts 81 and 83, respectively, where bond formation occurreddistal to the heteroatom (Fig. 4b). Additionally, excessive alkyl substitution
on the acceptor olefin was not well tolerated, with trisubstituted accep-tors (for example, 84 and 85) and disubstituted acceptors containingaliphaticb branching (for example, 86 and 87) generally giving little orno product. Cases where the isolated yield was ,50% and below could beattributed to incomplete conversion, premature reduction or substrate
OBnO
BnO
OBn
OBnO
BnO
OBn
30 mol% Fe(dibm)3
mild heating
Conventional route 27
3 steps, 52% overall
Olefin cross-coupling1 step, 68% isolated
Excess HCl (g), n-Bu3SnCl,LiNap, n-BuLi
cryogenic temperatures
O Me
78 79
81Olefin cross-
coupling
OMe
O
Examples of currently unsuccessful acceptor olefins
Examples of currently unexpected regiochemistry
80
a Comparison of olefin cross-coupling and traditional routes to 79
b Limitations of olefin cross-coupling
89 (6%)
Olefin cross-coupling
OTBSOMe
O
OMe
OTBSO
Me
O
OMe
Labelling studies
Radical clock experiment
91Using C2H5OD or C2D5OD
>99% D incorporation
TBSO
Me Me
Me
O
D
90Using PhSiD3
>99% D incorporation
TBSO
Me
Me
O
D
88
c Mechanistic studies
O
Me
Me
O
Me
MeMe Me
H
O
85 86 87Me Me
Me
O
84
n-C6H13
B(pin)n-C6H13
B(pin)
OMe
O
83Olefin cross-
coupling
OMe
O
82
MeSiMe2Ph
MeOMe
O
PhMe2Si
Figure 4 | Additional functionalized olefin cross-coupling studies.a, Functionalized olefin cross-coupling (top route) offers a direct route to glucalderivative 79 that circumvents the harsh reagents, superstoichiometricorganometallic reagents and cryogenic temperatures used in conventionalapproaches (bottom route). b, Top two rows: the use of certain 1,2-disubstituted donor olefins (80 and 82) gave adducts where the C–C bondformed distal instead of adjacent to the heteroatom (81 and 83). Bottom row:the use of acceptors with excessive aliphatic substitution (84–87) gave trace orno product. c, The use of vinyl cyclopropane 88 resulted in the isolation of89, where the fragmentation of the cyclopropane ‘‘radical clock’’ supportsthe formation of a radical adjacent to the heteroatom in the donor. Isolation ofcompounds 90 and 91 from deuterium labelling studies further supportthe mechanism depicted in Fig. 1b.
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dimerization. It is finally worth noting that as Fig. 3 demonstrates, thestereochemical outcomes of this reaction are all currently substrate-controlled.
Although a thorough mechanistic investigation has not been pur-sued, several observations are consistent with the mechanism depictedin Fig. 1b. Subjecting a donor olefin bearing a vinylcyclopropane (88,Fig. 4c) to the reaction conditions led to the isolation of adduct 89, aris-ing from cleavage of the cyclopropane ring. Furthermore, the utilizationof PhSiD3 instead of PhSiH3 resulted in the isolation of C6 deuteratedadduct 90. These two observations support the notion that a hydrogenatom originating from PhSiH3 is incorporated into donor olefin G(Fig. 1b) through a radical-based process. Boger has previously pro-posed a similar initiating step in his Fe-mediated oxidation of anhy-drovinblastine to vinblastine and originated the idea that Fe-mediatedMukaiyama-type hydrofunctionalizations may not occur via hydrome-tallation34. In recent work developing a mild thermodynamic olefin re-duction applicable to haloalkenes, Shenvi has suggested hydrogen atomtransfer (HAT) to be the initial step of these hydrofunctionalizations18.Taken together, these observations support the initiation of the func-tionalized olefin cross-coupling by HAT from an Fe hydride35 generatedin situ to the donor olefin G to form radical intermediate H (Fig. 1b).The protonation of intermediate J to the final coupled product K issupported by the isolation of adduct 91 (Fig. 4c) when using eitherethanol-d1 or ethanol-d6 as the solvent. Submitting undeuterated ana-logue 20 (Fig. 3a) to the reaction conditions using deuterated ethanoldid not lead to any deuterium incorporation, demonstrating that thedeuterium incorporation observed in the labelling studies occurred dur-ing the course of the reaction.
ConclusionIn summary, a new method for forming unique C–C bonds in a rapid,scalable and practical fashion has been described using an inexpensiveiron catalyst and a simple reaction set-up. From a retrosynthetic per-spective, this method requires the rethinking of the classic roles of somecommon building blocks in organic synthesis. For example, enol ethersand enamides need not be viewed as reacting as nucleophiles solelyat their b position36,37. Vinyl boronates, normally used to fashion newC(sp2) centres38, can now be viewed as potential progenitors to tertiaryboronates for a variety of Ni- and Pd-based C(sp3) couplings39. Vinylthioethers, rarely employed in molecule construction40, can now be viewed
in a different light. Vinyl silanes have been employed in cyclizations41
and C(sp2) cross-coupling chemistry42 but never as precursors to silyl-substituted quaternary centres. In the case of vinyl halides, the halide(F, Cl, Br and even I) no longer needs to be viewed as a disposable func-tionality for conventional transition-metal-mediated cross-coupling43,but rather as a spectator FG that can be incorporated into a final pro-duct. Functionalized olefin cross-coupling ultimately represents a methodof reversing the native reactivity44 of heteroatom-substituted olefins(Fig. 5), thus permitting the facile exploration of underdeveloped chem-ical space and serving as an alternative to other powerful retrosyntheticC–C bond disconnections45–47. Although achieving ligand control ofstereo- and regiochemical outcomes and a deeper understanding of themechanism are prominent future goals, potential applications of thismethod, even in its current form, to numerous areas of chemical sci-ence can be envisioned.
Received 13 September; accepted 20 October 2014.
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[Fe, silane]Formalpolarity reversal
SR
Cl
NR2
F
OR
Br
“δ–”
BR2
I
Induced reactivity
SiR3
SR
Cl
NR2
F
OR
Br
δ+ δ+ δ+
δ+ δ+ δ+
BR2
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δ+
δ+
Native reactivity
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Supplementary Information is available in the online version of the paper.
Acknowledgements Financial support for this work was provided by NIH/NIGMS(GM-097444). The National Science Foundation supported a predoctoral fellowshipfor J.C.L.; the Shanghai Institute of Organic Chemistry, Zhejiang Medicine Co. andPharmaron supported a postdoctoral fellowship for J.G.; and the Japan Society for thePromotion of Science supported a postdoctoral fellowship for Y.Y. We are grateful toD.-H. Huang and L. Pasternack (TSRI) for assistance with NMR spectroscopy, andA. L. Rheingold and C. E. Moore (UCSD) for X-ray crystallographic analysis. We thankR. A. Shenvi (TSRI) and Y. Ji (TSRI) for discussions.
Author Contributions J.C.L. and P.S.B. conceived the work; J.C.L. conducted initialfeasibility studies; J.C.L., J.G., Y.Y., C.-M.P. and P.S.B. designed the experiments andanalysed the data; J.C.L., J.G., Y.Y. and C.-M.P. performed the experiments; and J.C.L.and P.S.B. wrote the manuscript.
Author Information Crystallographic data for the structure of Fe(dibm)3 (5) is availablefree of charge from the Cambridge Crystallographic Data Centre under depositionnumber CCDC 1022625. Reprints and permissions information is available atwww.nature.com/reprints. The authors declare no competing financial interests.Readers are welcome to comment on the online version of the paper. Correspondenceand requests for materials should be addressed to P.S.B. ([email protected]).
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