Functionalized olefin cross-coupling to construct carbon-carbon bonds

Article abstract of DOI:10.1038/nature14006

Carbon-carbon (C-C) bonds form the backbone of many important molecules, including polymers, dyes and pharmaceutical agents. The development of new methods to create these essential connections in a rapid and practical fashion has been the focus of numerous organic chemists. This endeavour relies heavily on the ability to form C-C bonds in the presence of sensitive functional groups and congested structural environments. Here we report a chemical transformation that allows the facile construction of highly substituted and uniquely functionalized C-C bonds. Using a simple iron catalyst, an inexpensive silane and a benign solvent under ambient atmosphere, heteroatom-substituted olefins are easily reacted with electron-deficient olefins to create molecular architectures that were previously difficult or impossible to access. More than 60 examples are presented with a wide array of substrates, demonstrating the chemoselectivity and mildness of this simple reaction.

Full text of DOI:10.1038/nature14006

ARTICLE
doi:10.1038/nature14006
Functionalized olefin cross-coupling to
construct carbon––carbon bonds
Julian 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 fashion
has been the focus of numerous organic chemists. This endeavour relies heavily on the ability to form C–C bonds in the
presence 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 a
simple iron catalyst, an inexpensive silane and a benign solvent under ambient atmosphere, heteroatom-substituted
olefins are easily reacted with electron-deficient olefins to create molecular architectures that were previously difficult
or impossible to access. More than 60 examples are presented with a wide array of substrates, demonstrating the
chemoselectivity and mildness of this simple reaction.
New methods for the construction of C–C bonds have the potential to Provided that Hundergoes the desired conjugate addition to the electron-
shift paradigms in retrosynthetic analysis (the strategy used to design deficient olefin coupling partner, the newly generated radical I could
syntheses of molecules)1. Historically, those that have been most suc- undergo homodimerization, intramolecular hydrogen atom abstrac-
cessful feature simple experimental procedures, exhibit broad scope tion or consecutive conjugate additions leading to uncontrollable oli-
and allow access to chemical space previously deemed challenging or gomerization. Formation of Jfromasingle-electronreductionofIwould
inaccessible. A recent exercise in total synthesis drew our attention to result in a substantially basic and nucleophilic site that could prove to
radical-based olefin hydrofunctionalizations of the sorts pioneered in be incompatible with the X group and its substituents. In order for the
refs 2–9. Those illuminating studies led to the invention of a reductive reaction to prove successful, the conditions must be mild enough to
coupling10–12 of simple olefins with electron-deficient olefins such as tolerate both the various intermediate species in the catalytic cycle, as
that depicted in Fig. 1a13. In that work, an adduct bearing an all-carbon well as the final coupled product K.
quaternary centre such as A could be easily accessed in minutes and in
an openflask fromolefinB, presumably viathe intermediacy of radical
A9. Althoughausefulandpracticalmethod, the compoundsit produced
could already be obtained from readily accessible functionalized hydro-
carbons such as alkyl halides14, alcohols15,16 and carboxylic acids17 via
conventional radical-generating processes.
With these potential difficulties in mind, we used the model system
depicted in Fig. 2a, with silyl enol ether 1 serving as the donor and
cyclohexenone (2) as the acceptor, to develop a functionalized olefin
cross-coupling. Application of conditions similar to those previously
developed, using Fe(acac)3 (4, acac, acetylacetonate) as a catalyst and
PhSiH3 as a stoichiometric reductant3,13, formed the reductively coupled
In contrast, the functionalized hydrocarbons required to access adducts product 3 in 53% yield based on GC/MS (gas chromatography/mass
such as C, D and E (Fig. 1a) would either require extensive functional spectrometry) using an internal standard. Analysis of the side products
group(FG)manipulationsorareunfeasibledonorsowingtoFGincom- from the model system and relatedreactions led to the identification of
patibilities and chemoselectivity difficulties arising from the heteroa- compounds 14–17(Fig. 2b). As 16 and 17 presumably arise frompath-
toms present (B, S and I). By analogy to previous work, if olefins could ways where Fe(acac)3 behaves as a Lewis acid21, we hoped to attenuate
be used as a surrogatefor the intermediate radicals C9, D9 and E9, easily theLewisacidityofthecatalystbyincreasingtheamountofstericshield-
accessible compounds such as F could be employed directly, avoiding ing of the Fe centre. Increasing the size of the substitution on the dione
FG manipulations completely.
ligands (5–9) led todecreased amountsof 16, with Fe(dibm)3 (5, dibm,
diisobutyrylmethane)22 providing the best balance between reactivity
and steric shielding. Although attempts to alter the electronic structure
of the ligand with electron-deficient (10 and 11) and electron-rich (12
and 13) substituentseliminated reactivity, the addition ofNa2HPO4 in-
creased the yield of the desired product 3 from 69% to 78% when using
Fe(dibm)3 asthecatalyst.Theuseof about45other inorganicandamine
bases as additives did not result in increased yields, suggesting that
Na2HPO4 does not simply serve as a buffering agent. Additionally,
Fe(dibm)3 enabled product formation with donors that were unreac-
tivewith 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 was
found that Fe(dibm)3 provided the highest yields when the heteroa-
tom substitution on the donor olefin contained Lewis-basic lone pairs,
Development of functionalized olefin cross-coupling
Although this idea is conceptually simple, examining the hypothetical
mechanistic pathway revealed numerous obstacles that would need to
be addressed, as shown in Fig. 1b. The initiating step, radical forma-
tion from the donor olefin G by an in situ-generated Fe hydride, could
be complicated by issues of both regioselectivity and chemoselectivity.
Furthermore, dependingonthenatureof the Xsubstituent, severalcom-
peting pathways could arise involving the Fe complexes in the catalytic
cycle (for example, transmetallation of a C–B bond, desulfurization of
a C–S bond, and oxidative addition of a C–I bond). If the first step did
occur as intended, the intermediate radical H could be prone to pre-
mature reduction18–20, trapping with O2 (ref. 2), or homodimerization.
1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
*These authors contributed equally to this work.
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RESEARCH ARTICLE
a A new C–C bond formation method via cross-coupling
a Ligand screen with corresponding yields of the coupled product
FG
Me
O
Me
Me
(prior work)
O
Me
FeL3
OTBS
(5 mol%
)
+
EWG
FG = I, OH,
CO2H, and so on
B
PhSiH3
TBSO
Me Me
Me
A
A′
EtOH, 60 °C
Easily accessible donors
B(pin)
(pin)B
1
2
3
R2
R2
EWG
R1
R1
Me Me
X
EWG
EWG
Me
Me
(this work)
C′
C
R2
R1
Me
SPh
Me Me
6 (56%)
Me
5 (69%, 78%*)
PhS
Me
F
Acceptor
Ideal donor
4 (53%)
7 (36%)
8 (8%)
9 (9%)
H
I
D′
D
E
TBSO
O
S
O
O
X
FG
for example,
I
R2
I
OH
F3C
L =
R1
R2
R2
N
R1
R1
Me
FG = I, OH,
EWG
10 (0%)
11 (0%)
12 (0%)
13 (0%)
E′
CO2H, and so on
Unfeasible donors
Difficult to access
Nucleophilic radicals
b Side products initially observed when using Fe(acac)3
Me
O
b Postulated mechanism with potential complications
H
O
TBSO OEt
R2
R2
TBSO
R1
R1
OTBS
O
X
G
X
Me
Me
LnFem
H
H
Me
Chemoselectivity
Regioselectivity
Premature reduction
Trapping with O2
Homodimerization
14
15
16
17
LnFem–1
PhSiH3
ROH
c Two olefins unreactive with Fe(acac)3, but able to be coupled using Fe(dibm)3
EWG
LnFem
O
H
H
OTBS
O
FeL3
(5 mol%)
Yield
Fe(acac)3 <1%
Catalyst
R1
R1
+
TBSO
Compatibility of X
with intermediates
X
R2
J
X
R2
EWG
EWG
PhSiH3
Na2HPO4
Fe(dibm)3
32%
I
Homodimerization
H
EtOH, 60 °C
18
2
19
Intramolecular hydrogen
atom abstraction
H
R2
ROH
Oligomerization
Figure 2
|
Functionalized olefin cross-coupling optimization studies.
X
R2
EWG
a, Top row, reaction studied (ligand L shown bottom left). Altering the ligands
on the Fe centre (by using compounds 4–13) had the greatest influence on
the outcome of the reaction, with Fe(dibm)3 (5) giving the highest yields.
The addition of 1 equiv. Na2HPO4 further increased the yield. (Yields here
and in c are based on GC/MS analysis using 1,3,5-trimethoxybenzene as an
internal standard.) Greyed-out ligands gave 0% yield. b, Side products that
were observed when Fe(acac)3 (4) was used as the catalyst. The formation
of compounds 16 and 17 could be attributed to the Lewis acidity of 4. The use
of 5 as the catalyst reduced the formation of compounds 16 and 17. c, An
example where the use of 5 instead of 4 was essential in obtaining the
desired functionalized olefin cross-coupling reactivity. TBS,
K
Product stability to reaction conditions
Figure 1
|
Functionalized olefin cross-coupling as a strategy for convergent
chemical synthesis. a, Functionalized olefin cross-coupling would facilitate
the 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 other
radical precursors (greyed box, bottom right). b, The functionalized olefin
cross-coupling would occur by the Fe hydride-mediated conversion of the
donor olefin G to the nucleophilic radical H, which would undergo conjugate
addition to theacceptor olefin to form intermediate I. Single-electron reduction
to form the stabilized anion J followed by protonation would form the final
product K. Examination of the postulated mechanism for the cross-coupling
reveals several potential complications (bulleted) that could arise due to
either the intermediacy of radicals or the heteroatom (X) present on the
donor olefin. EWG, electron-withdrawing group; FG, functional group;
(pin), pinacolato; TBS, tert-butyldimethylsilyl; X, heteroatom; L, ligand.
tert-butyldimethylsilyl; L, ligand; acac, acetylacetonate; dibm,
diisobutyrylmethane; GC/MS, gas chromatography/mass spectrometry.
Endocyclic enol ethers were also tolerated, as shown by the formation
of 30–33.
Additionally, enecarbamates and enamides could undergo cross-
coupling under the reaction conditions (Fig. 3b). Adducts 34 and 35
were formed by the coupling of a Cbz (benzyloxycarbonyl)-protected
dihydropyrrole with benzyl acrylate and cyclopent-2-enone, respectively,
although these couplings necessitated larger amounts of PhSiH3 than
the enol ethers. The amount of PhSiH3 needed could be decreased by
using more electronically activated acceptors, as the formation of 36
and37demonstrated. Othercyclicandacyclicenecarbamatescouldalso
be employed and added to various acceptor olefins (38, 39 and 41–46),
although higher loadings (15 mol%) of Fe(dibm)3 were typically required
for useful yields. The formation of 40 also demonstrated that the nitro-
gen atom present on the donor olefin could be protected as an amide
instead of a carbamate. Mono- and 1,1-disubstituted acyclic donor ole-
fins were competent donors (41–46), however attempts to control the
stereochemistry of the cross-coupling by using a-phenylethylamine as
a chiral auxiliary24 provided only modest amounts of diastereoselec-
tivity (45 and 46).
whereas Fe(acac)3 proved superior in the absence of such moieties (see
below).
Scope and functional group tolerance
Theoptimizedconditions were thenappliedtoa widervariety of donor
and acceptor olefins, initially focusing on enol ethers (Fig. 3a). Using
Fe(dibm)3 (5 mol%), silyl enol ethers could be coupled to cyclic and
acyclic enones, an enal and an acrylamide to generate adducts 3 and
20–25 with yields that generally increased with decreasing substitution
on the silicon atom (19 and 22–24). Remarkably, even a severely con-
gested oestrone derivative could undergo addition to methyl vinyl ketone
to generate steroidal adduct 25 with the stereochemistry of the newly
formed neopentyl quaternary stereocentre corresponding to that obtained
through a conventional organometallic addition of an alkyl group to
Vinyl thioethers proved to be unique donor olefins, with the cross-
oestrone23. Alkyland arylvinyl ethers could also be used, although higher couplingsofthose surveyedtakingplaceatambienttemperaturetogen-
yields were generally obtained by using the donor olefin in excess (26–33). erate adducts 47–56 (Fig. 3c). Although the cross-coupling to form 49
3 4 4
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ARTICLE RESEARCH
R2
R2
R4
R4
Fe(dibm)3 or Fe(acac)3
(5–100 mol%)
• Heteroatoms (X) tolerated on donor:
O, N, S, B, Si, F, Cl, Br, I
R3
EWG
EWG
R1
+
R1
(1 equiv.)
• 60 examples
Na2HPO4 (1 equiv.)
PhSiH3 (2–6 equiv.)
ROH, RT–80 °C
R3
X
• Air and moisture compatible
• Typically complete in under 1 h
X
(3 equiv.)
Nitrogen: 5 mol% Fe(dibm)3, 2 equiv. PhSiH3, EtOH, 60 °C
b
a Oxygen: 5 mol% Fe(dibm)3, 2 equiv. PhSiH3, EtOH, 60 °C
O
MeO
O
BnO
O
O
Me
O
TBSO
Me Me
20 (69%)
TBSO
N
Me
H
N
O
TBSO
N
Cbz
Cbz
Me Me
21 (40%)
Cbz
MeO
36 (75%)
O
Me Me
3 (78%)*
34 (65%)†
35 (75%)†
TBSO
Me
O
O
Me
EtO
O
Cbz
N
O
OR
O
Me
Cbz
N
H
H
O
Me
N
H
On-C4H9
26 (51%)*
Cbz
O
n-C5H11
Me OEt
22: R = TMS (46%)*
23: R = TES (33%)*
19: R = TBS (37%)*
24: R = TIPS (9%)*
37 (88%)
38 (55%, 1:1.5 d.r.)†,‡,II
39 (61%)
25 (43%, >99:1 d.r.)†,‡,§
O
MeO
O
Me Me
Me
R
EtO
O
EtO
O
N
Bn
OMe
Cbz
N
Me
N
OPh
27: R = CN (59%)*
28: R = CO2Me (58%)*
29: R = C(O)Me (31%)*
O
O
Boc
R
O
O
O
O
Me
42: R = H (48%)†,II,¶
43: R = Bn (79%, 1:1.3 d.r.)†,‡,II
Me OEt
30 (54%, 1:1.2 d.r.)
Me OEt
31 (76%, 1:1.8 d.r.)
40 (70%)†,II,¶
41 (70%)*
Boron: 5 mol% Fe(acac)3,
3 equiv. PhSiH3, EtOH, 60 °C
O
d
c
Sulfur: 5 mol% Fe(dibm)3,
2 equiv. PhSiH3, EtOH, RT
O
OBn
O
OMe
MeO
MeO
OMe
O
Ph Me
Ph Me
O
Me
R
R2B
O
Ph
Me
Me
NMe2
N
Cbz
Me
N
R
S
Me
O
Me Me
45: R = Cbz (69%, 1:1.5 d.r.)†,‡,II
32 (43%)*
33 (64%, >99:1 d.r.)†,‡
57: R2 = (pin) (70%)
58: R2 = (MIDA) (58%)§
59: R2 = (dan) (71%)
44 (73%) 46: R = Boc (55%, 1:1.4 d.r.)†,‡,II
47: R = CN (65%)
48: R = C(O)NMe2 (67%)
n-C4H9S
O
NHBoc
O
OTBS
O
Ph
n-C6H13
R
n-C12H25
S
CN
(dan)B
OMe
NMe2
OMe
Me
49 (48%)#
Me Me
Me B(pin)
S
CN
Me B(pin)
51: R = C(O)Me (49%)†,‡
52: R = CN (50%)
60 (86%)
61 (47%)
62 (32%)
50 (40%)†,II,¶
e Silicon: 50 mol% Fe(acac)3, 2 equiv. PhSiH3, n-PrOH, 80 °C
PhMe2Si
O
NMe2
PhMe2Si
R
PhMe2Si
R
PhS
R
n-C6H13
4-MeOPh
55 (35%)†,‡
Me Me
Me Me
Me
N
S
O
NMe2
Me
O
Me
63: R = CO2Me (61%)
64: R = CO2Bn (54%)
65: R = CN (84%, 51% ) 69: R = C(O)NMe2 (70%)
66: R = SO2Ph (35%)**
67: R = CO2H (53%)††
S
68: R = C(O)Me (60%)‡
70 (51%)‡
S
Me
53: R = CN (67%)†
54: R = C(O)NMe2 (48%)†
56 (54%)
Halogens: 100 mol% Fe(acac)3, 3 equiv. PhSiH3, EtOH, 60 °C
f
HO2C
OTBS
O
OTBS
O
OH
O
O
OTBS
O
OTBS
O
NMe2
R
NMe2
4-MeOPh
O
NMe2
NMe2
77 (37%)†,‡
Me
F
Me Cl
Me Cl
Me Cl
75 (50%)††
Me Br
Me
I
71 (48%)
72: R = NMe2 (60%)
73: R = OH (46%)††
74 (67%)
76 (42%)†,‡
Figure 3
|
Adducts synthesized by functionalized olefin cross-coupling.
acceptor used. 1THF used as a cosolvent.
|
|
15 mol% [Fe] used. "Second
Top, the reaction studied. The donor component is shown in green and the
acceptor component is shown in blue. Couplings using donor olefins with
heteroatom substitution containing Lewis basic lone pairs (a, O; b, N; c, S)
proceeded in higher yields with Fe(dibm)3 whereas couplings without such
moieties (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.
portion of [Fe], acceptor and PhSiH3 added after 1 h. #Heated at 60 uC.
qRun on gram-scale. **100mol% [Fe] used. {{Na2HPO4 omitted. TMS,
trimethylsilyl; TES, triethylsilyl; TIPS, triisopropylsilyl; Bn, benzyl; Cbz,
benzyloxycarbonyl; Boc, tert-butyloxycarbonyl; (MIDA),
N-methyliminodiacetate; (dan), 1,8-diaminonaphthyl.
proceeded in a higher yield when the reaction was heated at 60 uC, the for certain recalcitrant substrates (50, 51, 53 and 54). Syringe pump
yields of the other vinyl thioether cross-couplings did not benefit from addition of the acceptor and PhSiH3 to the reaction mixture could also
improve yields in certain cases (51 and 55).
elevated temperatures. With the exception of 50, the coupling of the
alkenyl thioether donors proceeded with 5 mol% of Fe(dibm)3; how-
Boron substitution on the donor olefin could also be tolerated, with the
ever, increased amounts of PhSiH3 and acceptor olefin were required useof5 mol%Fe(acac)3 providingslightlyhigheryieldsthanFe(dibm)3.
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RESEARCH ARTICLE
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 THFas a cosolvent was required to solubilize the MIDA
boronate. Additionally, methyl acrylate could be used as an acceptor
(60and 61), and oxygen- and nitrogen-containing functionalities could
be tolerated at allylic positions (61 and 62).
a Comparison of olefin cross-coupling and traditional routes to 79
Olefin cross-coupling
1 step, 68% isolated
30 mol% Fe(dibm)3
mild heating
O
O
BnO
BnO
78
BnO
BnO
O
Me
Vinyl silanes could also be used as donor olefins, although highest
yields were obtained using a substoichiometric amount (50 mol%) of
Fe(acac)3. Additionally, switching the solvent from EtOH to n-PrOH
and heating the reactions to 80 uC instead of 60 uC resulted in higher
yields. With these slight modifications, an isopropenyl and vinyl silane
could be coupled to a wide variety of acceptor olefins to form 63–70
(Fig. 3e), although the coupling to obtain the phenyl vinylsulfone adduct
66 required a stoichiometric amount of Fe(acac)3. With the omission
of Na2HPO4, unprotected acrylic acid could be used as an acceptor to
provide the coupled product 67 in a transformation difficult to achieve
OBn
OBn
79
Conventional route 27
3 steps, 52% overall
Excess HCl(g), n-Bu3SnCl,
LiNap, n-BuLi
cryogenic temperatures
b Limitations of olefin cross-coupling
Examples of currently unexpected regiochemistry
O
using conventional conjugate addition techniques28,29
.
O
OMe
81 B(pin)
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 in
reasonable yields using stoichiometric amounts of Fe(acac)3. Alkenyl
fluorides, chlorides, bromidesand even iodides could allbe used as donors,
with the 2-haloallyl alcohol derivatives delivering products 71, 72, 76
and 77 (Fig. 3f), where thehalogen atom remained intact. Interestingly,
acrylic acid could once again be used as an acceptor (73, 75), and the
reaction proceeded readily with a free alcohol (74), demonstrating the
notable chemoselectivity of this method.
OMe
B(pin)
n-C6H13
n-C6H13
Olefin cross-
coupling
80
O
O
OMe
SiMe2Ph
82
PhMe2Si
OMe
Me
Me
Olefin cross-
coupling
83
Examples of currently unsuccessful acceptor olefins
To highlight the efficiency of the newly developed couplingreaction,
we chose to target glucal derivative 79 (Fig. 4a). This compound has
previouslybeenpreparedinthreestepsfromreadilyavailable78in52%
yield, although that route required the use of excess gaseous HCl, toxic
and harsh organometallic reagents and cryogenic temperatures30. By
contrast,olefincross-couplingallowedthedesiredproduct79tobesyn-
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 to
adverse conditions was evaluated by performing the reaction in a vari-
ety of unconventional solvents. As indicated by GC/MS, the coupling
to form silyl ether 20 proved to be successful in a selection of beer, wine
and various spirits (see Supplementary Table 2 and Supplementary
Figs 23–30). In addition to showing the ability of the reaction to pro-
ceed under aqueous conditions, theseresults demonstrate the reaction’s
tolerance of a host of organic compounds31 and microorganisms, sug-
gesting possible downstream applications to the area of bioconjugation32.
O
O
O
O
Me
H
Me
Me
Me
Me
Me
Me
84
Me
Me
85
86
87
c Mechanistic studies
Radical clock experiment
O
O
TBSO
Me
OTBS
OMe
OMe
O
OMe
Olefin cross-
coupling
88
89 (6%)
Labelling studies
TBSO
O
O
TBSO
Me
Me
Me Me
D
Me
D
91
90
Using PhSiD3
>99% D incorporation
Using C2H5OD or C2D5OD
>99% D incorporation
Discussion and limitations
From a strategic perspective, this methodology grants access to areas
of chemical space that, in most cases, were previously inaccessible. His-
torically, heteroatom-substitutedquaternarycentreshavebeen synthe-
sized with multiple FG manipulations and rarely, if ever, through a direct
C–C disconnectionasenabledhere. Thus, ,90%ofthecompounds listed
in Fig. 3 are new chemical entities despite their simplicity. In the case
of 30, 31 and 34–37, where a comparison to contemporary reactivity
modes couldbe made, it wasfound thatthe olefin cross-coupling route
offers 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 regards
to moisture or air exclusion, and reactions were typically done within a
few minutes to an hour. The reaction is also readily scalable, with the
coupling to form 65 being conducted on the gram scale (51% yield).
However, no reaction is without limitations. Although nearly all of
the 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 occurred
Figure 4
|
Additional functionalized olefin cross-coupling studies.
a, Functionalized olefin cross-coupling (top route) offers a direct route to glucal
derivative 79 that circumvents the harsh reagents, superstoichiometric
organometallic reagents and cryogenic temperatures used in conventional
approaches (bottom route). b, Top two rows: the use of certain 1,2-
disubstituted donor olefins (80 and 82) gave adducts where the C–C bond
formed distal instead of adjacent to the heteroatom (81 and 83). Bottom row:
the use of acceptors with excessive aliphatic substitution (84–87) gave trace or
no product. c, The use of vinyl cyclopropane 88 resulted in the isolation of
89, where the fragmentation of the cyclopropane ‘‘radical clock’’ supports
the formation of a radical adjacent to the heteroatom in the donor. Isolation of
compounds 90 and 91 from deuterium labelling studies further support
the mechanism depicted in Fig. 1b.
on the acceptor olefin was not well tolerated, with trisubstituted accep-
tors (for example, 84 and 85) and disubstituted acceptors containing
aliphaticb branching (for example, 86and 87) generally givinglittle or
no product. Cases where theisolated yield was ,50%andbelowcouldbe
distal to the heteroatom (Fig. 4b). Additionally, excessive alkyl substitution attributed to incomplete conversion, premature reduction or substrate
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ARTICLE RESEARCH
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 viewedas a disposablefunc-
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 method
of reversing the native reactivity44 of heteroatom-substituted olefins
(Fig. 5), thuspermitting the facile explorationofunderdeveloped chem-
ical space and serving as an alternative to other powerful retrosynthetic
C–C bond disconnections45–47. Although achieving ligand control of
stereo- and regiochemical outcomes and a deeper understanding of the
mechanism are prominent future goals, potential applications of this
method, even in its current form, to numerous areas of chemical sci-
ence can be envisioned.
dimerization. It is finally worth noting that as Fig. 3 demonstrates, the
stereochemical 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 depicted
in Fig. 1b. Subjecting a donor olefin bearing a vinylcyclopropane (88,
Fig. 4c) to the reaction conditions led to the isolation of adduct 89, aris-
ingfromcleavageofthecyclopropanering. Furthermore, theutilization
of PhSiD3 instead of PhSiH3 resulted in the isolation of C6 deuterated
adduct 90. These two observations support the notion that a hydrogen
atom 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-mediated
Mukaiyama-type hydrofunctionalizationsmaynot occurvia hydrome-
tallation34. In recent work developing a mild thermodynamic olefin re-
duction applicable to haloalkenes, Shenvi has suggested hydrogen atom
transfer (HAT) to be the initial step of these hydrofunctionalizations18.
Taken together, these observations support the initiation of the func-
tionalizedolefincross-couplingbyHATfromanFehydride35 generated
in situ to the donor olefin G to form radical intermediate H (Fig. 1b).
The protonation of intermediate J to the final coupled product K is
supported by the isolation of adduct 91 (Fig. 4c) when using either
ethanol-d1 or ethanol-d6 as the solvent. Submitting undeuterated ana-
logue 20 (Fig. 3a) to the reaction conditions using deuterated ethanol
did not lead to any deuterium incorporation, demonstrating that the
deuteriumincorporationobservedinthelabellingstudiesoccurreddur-
ing the course of the reaction.
Received 13 September; accepted 20 October 2014.
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Acknowledgements Financial support for this work was provided by NIH/NIGMS
(GM-097444). The National Science Foundation supported a predoctoral fellowship
for J.C.L.; the Shanghai Institute of Organic Chemistry, Zhejiang Medicine Co. and
Pharmaron supported a postdoctoral fellowship for J.G.; and the Japan Society for the
Promotion of Science supported a postdoctoral fellowship for Y.Y. We are grateful to
D.-H. Huang and L. Pasternack (TSRI) for assistance with NMR spectroscopy, and
A. L. Rheingold and C. E. Moore (UCSD) for X-ray crystallographic analysis. We thank
R. 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 initial
feasibility studies; J.C.L., J.G., Y.Y., C.-M.P. and P.S.B. designed the experiments and
analysed 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 available
free of charge from the Cambridge Crystallographic Data Centre under deposition
number CCDC 1022625. Reprints and permissions information is available at
www.nature.com/reprints. The authors declare no competing financial interests.
Readers are welcome to comment on the online version of the paper. Correspondence
and requests for materials should be addressed to P.S.B. (pbaran@scripps.edu).
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organoboron compounds. Chem. Rev. 95, 2457–2483 (1995).
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partners. Chem. Rev. 111, 1417–1492 (2011).
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