Cobalt-catalyzed reductive coupling of saturated alkyl halides with activated alkenes

Article abstract of DOI:10.1021/jo052065w

An efficient cobalt-catalyzed reductive coupling reaction of alkyl halides with electron-withdrawing alkenes (CH₂=CR¹EWG, EWG = electron-withdrawing group) in the presence of water and zinc powder in acetonitrile to give the corresponding Michael-type addition product (RCH ₂CR¹EWG) was described. The methodology is versatile such that unactivated primary, secondary, and tertiary alkyl bromides and iodides and various conjugated alkenes including acrylates, acrylonitrile, methyl vinyl ketone, and vinyl sulfone all successfully participate in this coupling reaction. For the alkyl halides used in the reaction, the iodides generally gave heller yields compared to those of the corresponding bromides. It is a unique method employing CoI₂dppe, zinc, and alkyl halides, affording conjugate addition products in high yields. Mechanistically, the reaction appears to follow an oxidative addition driven route rather than the previously reported radical route.

Full text of DOI:10.1021/jo052065w

Cobalt-Catalyzed Reductive Coupling of Saturated Alkyl Halides
with Activated Alkenes
Paritosh Shukla, Yun-Chu Hsu, and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 30043, Taiwan
chcheng@mx.nthu.edu.tw
ReceiVed October 3, 2005
An efficient cobalt-catalyzed reductive coupling reaction of alkyl halides with electron-withdrawing alkenes
1
(
CH
2
dCR EWG, EWG ) electron-withdrawing group) in the presence of water and zinc powder in
1
2
acetonitrile to give the corresponding Michael-type addition product (RCH CR EWG) was described.
The methodology is versatile such that unactivated primary, secondary, and tertiary alkyl bromides and
iodides and various conjugated alkenes including acrylates, acrylonitrile, methyl vinyl ketone, and vinyl
sulfone all successfully participate in this coupling reaction. For the alkyl halides used in the reaction,
the iodides generally gave better yields compared to those of the corresponding bromides. It is a unique
method employing CoI dppe, zinc, and alkyl halides, affording conjugate addition products in high yields.
2
Mechanistically, the reaction appears to follow an oxidative addition driven route rather than the previously
reported radical route.
Introduction
metal complexes. Broadly, there have been two main transition-
metal-mediated approaches to the construction of Csp -Csp
3
3
Transition-metal catalysts have a well-established niche in
C-C bond-forming reactions. Specifically, the catalytic cou-
pling of aryl and alkenyl halides with alkenes or nucleophiles
has been extensively investigated. However, the use of unac-
tivated alkyl halides to construct Csp -Csp bonds catalyzed by
transition-metal complexes is particularly challenging in view
bonds. The first one involves the catalytic reductive coupling
of an alkyl halide and an alkene. Most previous accounts of
related reductive couplings necessitated stoichiometric amounts
1
2
4
of metal. Although some nickel-catalyzed reductive couplings
3
3
of saturated alkyl halides with electron-withdrawing alkenes
were reported, they were of limited scope for saturated alkyl
3
of the difficulty in overcoming â-hydrogen elimination and the
low reactivity of unactivated alkyl halides toward transition-
5
a
halides, requiring the use of stoichiometric amounts of
5
b
6
pyridine or requiring the use of a polymer resin. The second
(
1) (a) Trost, B. M., Fleming, I., Eds. ComprehensiVe Organic Synthesis;
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1
4
(
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4
3
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(
3) For an overview of the difficulty of achieving coupling reactions of
Csp3-X electrophiles, see: (a) C a´ rdenas, D. J. Angew. Chem., Int. Ed. 2003,
4
3
1
2, 384-387. (b) C a´ rdenas, D. J. Angew. Chem., Int. Ed. 1999, 38, 3018-
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1
0.1021/jo052065w CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/15/2005
J. Org. Chem. 2006, 71, 655-658
655

Shukla et al.
1
SCHEME 1
was detected in the H NMR spectrum of the reaction mixture.
When the amount of acrylate used was increased to 4 equiv,
along with the addition of 1 equiv of water, the yield increased
to 74% (Table 1, entry 1). Control experiments revealed that,
in the absence of either a cobalt catalyst or zinc powder, no
product was observed. Other cobalt complexes such as CoI2-
(PPh3)2, CoCl2(PPh3)2, CoCl2(dppe), and CoI2(dppm) were
inferior to CoI2(dppe), giving 3a in 26, 41, 48, and 25% yields,
respectively. Among the solvents that were tested, including
THF, CH3CN, methylene chloride, toluene, and DMF, CH3CN
gave the highest yield of product 3a.
approach, currently much in vogue, utilizes cross-coupling7
reactions of alkyl electrophiles (halides, sulfonates, etc.) with
main group metal alkyls catalyzed by Pd, Ni, Fe, and so forth.
Several cobalt-catalyzed reactions, reported by Oshima et al.,
that are closely related to our work are the Heck reaction of
alkyl halides with styrene in the presence of a Grignard
reagent,8 a three-component coupling of an alkyl halide, a 1,3-
The CoI2(dppe) system also catalyzes the reductive coupling
of n-decyl bromide with ethyl acrylate (2b) forming 3b in good
yield (entry 3, Table 1). Similarly, phenyl 3-bromopropyl ether
(1c) reductively coupled with 2a to yield product 3c (entry 4),
thereby showing that an ether functionality can be tolerated
under the reaction conditions. Remarkably, secondary bromide
a
1
d also gave the reductive Heck-type product 3d, albeit in a
8b
diene, and a silylmethylmagnesium chloride, and a cross-
coupling reaction of an alkyl halide with an allylic or benzylic
Grignard reagent.8 All of the above cobalt-catalyzed reactions
required the use of a Grignard reagent and involved the addition
of an alkyl radical to a C-C double bond. In addition, the
method cannot be used for the coupling of an alkyl halide with
an electron-withdrawing alkene as a result of the presence of
the Grignard reagent, which shows high reactivity toward
lower yield. Substitutions at the R- or â-positions tend to make
alkene insertion sluggish not only for palladium-catalyzed Heck
c
9
a
reactions but also for cobalt-catalyzed couplings. However,
in our protocol, R-substituted methacrylate 2d reacted smoothly
with 1a to form 3e (entry 5) in 64% yield.
The reaction appeared sluggish with alkyl chlorides while
alkyl iodides were more reactive than the corresponding alkyl
bromides in the present cobalt-catalyzed reaction. The reductive
couplings with alkyl iodides were complete in 6 h and produced
higher yields with just 5 mol % of the cobalt catalyst (entries
9
activated alkenes. Our interest in cobalt-catalyzed reactions
prompted us to explore the coupling of alkyl halides with
3
alkenes. Herein, we describe an efficient cobalt-catalyzed Csp -
2
and 7-11, Table 1). Thus, 1-hexyl iodide (1f) reacted with
3
Csp bond-forming process via the reductive coupling of primary,
n-butyl acrylate forming 3f in 92% yield (entry 7). Similarly,
sec-butyl iodide (1g) reacted with 2c to afford the γ-substituted
ester 3g in excellent yield (entry 8). Also, the very long chain
ester n-butyl nonadecanoate (3h) was formed in 91% yield (entry
9). Even t-butyl iodide also yielded the expected product (3i,
entry 10) in 78% yield. Finally, treating 4-iodobutyl acetate (1j)
with 2c under similar conditions afforded the expected product
secondary, and tertiary alkyl halides with electron-withdrawing
alkenes under mild conditions (Scheme 1). The catalytic
mechanism appears to be different from that proposed previously
involving the addition of an alkyl radical to a C-C double
bond.4,6-8,10
Results and Discussion
3
m in good yield (entry 11).
Treatment of (2-bromoethyl)benzene (1a, 1.0 mmol) with
methyl acrylate (2a, 1.2 mmol) in the presence of CoI2(dppe)
The present strategy can be further extended to other
conjugated alkenes (Table 2). As depicted in Table 2, acryloni-
trile reacted with (2-iodoethyl)benzene to form 5-phenylpen-
tanenitrile (3j) in excellent yield (entry 1, Table 2). In the same
vein, methyl vinyl ketone (entry 2) reacted with 1e to form the
reductively coupled ketone 3k. In addition, phenyl vinyl sulfone
reacted with n-butyl acrylate to form 3l in good yield under
similar reaction conditions (entry 3, Table 2).
(0.10 mmol, 10 mol %) and zinc powder (2.5 mmol) in
acetonitrile (2.5 mL) at 80 °C for 12 h gave methyl 5-phenyl-
pentanoate (3a) in 61% isolated yield. Surprisingly, only a trace
amount of the Heck product, that is, the R,â-unsaturated ester,
(
7) For reviews of metal-catalyzed cross-coupling reactions, see: (a)
Metal-catalyzed Cross-coupling Reactions; Diederich, P., Stang, P. J., Eds.;
Wiley-VCH: Weinheim, Germany, 1998; p 12. (b) Cross-Coupling
Reactions: A Practical Guide; Miyaura, N., Ed.; Topics in Current
Chemistry Series 219; Springer-Verlag: New York, 2002. (c) Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E.-I., Ed.;
Wiley-Interscience: New York, 2002. For leading references, see: (a) ref
Mechanistic Considerations. To understand the nature of
the present cobalt-catalyzed reaction, several experiments were
carried out and the results are summarized below. First, the
reaction of 6-bromo-1-hexene with n-butyl acrylate, under
standard catalytic conditions, yielded no cyclized product
3
1
7
b. (b) Netherton, M. R.; Fu, G. C. AdV. Synth. Catal. 2004, 346, 1525-
532. (c) Powell, D. A.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 7788-
789 and references therein.
(Scheme 2) but instead yielded a carbon-carbon double bond
isomerized product of the reductive coupling of 6-bromo-1-
hexene and the acrylate. The reaction of cyclopropylmethyl
bromide with benzyl acrylate gave a complicated mixture that
was difficult to characterize; there was no expected ring-opening
addition product, benzyl 6-heptenoate, detected in the mixture.
Second, competition reactions of n-propyl iodide and isopropyl
iodide for benzyl acrylate under the standard catalytic conditions
gave only the reductive coupling product of isopropyl iodide
and the acrylate. Surprisingly, competition reactions of isopropyl
iodide and tert-butyl iodide for benzyl acrylate again afforded
chemoselectively the reductive coupling product of isopropyl
(8) (a) Ikeda, Y.; Nakamura, T.; Yorimitsu, H.; Oshima, K. J. Am. Chem.
Soc. 2002, 124, 6514-6515. (b) Fujioka, T.; Nakamura, T.; Yorimitsu, H.;
Oshima, K. Org. Lett. 2002, 4, 2257-2259. (c) Ohmiya, H.; Tsuji, T.;
Yorimitsu, H.; Oshima, K. Chem.sEur. J. 2004, 10, 5640-5648 and
references therein.
(
9) (a) Wang, C. C.; Lin, P. S.; Cheng, C. H. J. Am. Chem. Soc. 2002,
1
(
6
24, 9696-9697. For precedents similar to the proposed mechanism, see:
b) Wang, C. C.; Lin, P. S.; Cheng, C. H. Tetrahedron Lett. 2004, 45, 6203-
206. (c) Chang, K. J.; Rayabarapu, D. K.; Cheng, C. H. Org. Lett 2003,
5
, 3963-3966. (d) Chang, K. J.; Rayabarapu, D. K.; Cheng, C. H. J. Org.
Chem. 2004, 69, 4781-4787 and references therein.
(10) Wakabayashi, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc.
2
001, 123, 5374-5375.
656 J. Org. Chem., Vol. 71, No. 2, 2006

Cobalt-Catalyzed Coupling of Alkyl Halides with Alkenes
TABLE 1. Results of the Cobalt-Catalyzed Reductive Coupling of Alkyl Halides with Acrylatesa
a
Unless stated otherwise, all reactions were carried out in a sealed tube or a sidearm flask, consisting of an alkyl halide (1.0 mmol), acrylate (2-5 mmol),
CoI2(dppe) (0.10 mmol, 10 mol %), H2O (1.0 mmol), and Zn (2.5 mmol) in CH3CN (2.5 mL) at 80 °C under N2 for 12 h. b Isolated yields. c Reaction time
was 6 h and only 5 mol % of the Co catalyst was used.
TABLE 2. Cobalt-Catalyzed Reductive Coupling with Other
Conjugated Alkenesa
SCHEME 2
led to a substantial amount of the hydrogenation product of
acrylate, benzyl propionate, and styrene. The observation
suggests that â-hydride elimination of the phenylethyl-Co
species in the catalytic cycle competes strongly with the addition
of the phenylethyl group to the acrylate. The Co-H that is
formed then reacts with acrylate to give the reduced product 4.
Similar reduced products of the acrylates were also observed
for the different alkyl halides and acrylates used. Fourth, the
a
Reaction conditions: similar to those in Table 1. b Isolated yields
iodide and the acrylate. These competition experiments indicate
that isopropyl iodide is much more reactive than n-propyl iodide
and t-butyl iodide. Third, the reaction of 2-phenylethyl iodide
1e) with benzyl acrylate under the standard catalytic conditions
and at a high 2-phenylethyl iodide/benzyl acrylate ratio (g1:1)
(
J. Org. Chem, Vol. 71, No. 2, 2006 657

Shukla et al.
SCHEME 3
by the observation of a substantial amount of the hydrogenation
product of the acrylate at high alkyl iodide/acrylate ratios. The
proposed protonation step is supported by the fact that the
addition of 1 equiv of water increases the product yield.
An alternative mechanism involving the addition of the alkyl
radical to acrylate cannot be entirely excluded. In the recent
reports of transition-metal-catalyzed additions of unactivated
alkyl halides to C-C double bonds, an addition of the alkyl
radical generated from the reaction of the alkyl halide with the
low-valent transition-metal complex to the C-C double bond,
4
,6-8,10
was proposed by several authors.
A mechanism similar
to that proposed by Oshima et al., involving an electron transfer
from the Co(I) complex to an alkyl halide to generate an alkyl
radical, followed by the addition of the radical to acrylate and
then trapping by the cobalt species to give a Co(III) intermediate,
as shown in Scheme 2, can also account for the observed
reductive coupling reaction, but it is more difficult to explain
the observed hydrogenation product of acrylate at a high alkyl
halide/acrylate ratio. It should be noted that in the mechanism
proposed by Oshima et al., a Co(0) anion was used for the
electron transfer to the alkyl halide.
reaction of alkyl halides with acrylates under the standard
catalytic conditions at low alkyl halide/acrylate ratio (e1:3) in
the reaction led clearly to the observation of the corresponding
reductive dimerization product of acrylate 5. The linear reductive
9
b
dimerization of acrylates was reported by us previously.
Finally, the reaction of the cobalt(I) complex CoCl(PPh3)3 with
-iodoethylbenzene (1e) and n-butyl acrylate (2a) stoichiomet-
2
rically in acetonitrile at 80 °C afforded the reductive coupling
product 3a in 63% yield.
Conclusion
We have reported an effective utilization of a cobalt catalyst
for the reductive coupling of primary, secondary, and tertiary
alkyl bromides and iodides with a wide variety of conjugated
alkenes such as acrylates, acrylonitrile, vinyl ketone, vinyl
sulfone, and so forth, in good to excellent yields. To accomplish
these cobalt-catalyzed reactions, mild conditions were employed.
Also, our protocol involves the use of an easily prepared cobalt
complex, namely, CoI2(dppe). Furthermore, the reaction appears
to undergo an oxidative addition driven route rather than the
expected radical route.
Although the details of the catalytic steps are not clear,9c,d
based on the above observations, we propose the following
mechanism to account for this cobalt-catalyzed reductive
coupling reaction. The catalytic cycle is likely initiated by the
reduction of CoI2(dppe) to Co(I) by zinc powder followed by
the oxidative addition of an alkyl halide to give an alkyl cobalt-
Experimental Section
General Procedure for the Reductive Coupling of Unactivated
Alkyl Halides (1) with Electron-Withdrawing Alkenes (2).
Synthesis of Methyl 5-Phenylpentanoate (3a). A sealed tube (20
(III) intermediate (Scheme 3). Subsequent coordination of the
conjugated alkene, insertion into the Co-alkyl bond, and
protonation gives rise to the final reductive coupling product
mL) containing CoI
mmol) was evacuated and purged with nitrogen three times. Freshly
distilled CH CN (2.5 mL), (2-bromoethyl)benzene 1a (1.0 mmol),
2
(dppe) (0.10 mmol) and zinc powder (2.5
3
. Reduction of the Co(III) species by zinc powder regenerates
the active Co(I) catalyst.
3
The proposed oxidative addition of alkyl halides with Co(I)
species in the mechanism gains strong support as M(I) (M )
Co, Rh, and Ir) reacts readily with various unactivated alkyl
methyl acrylate 2a (4.0 mmol), and H O (1.0 mmol) were added
to the sealed tube via syringes. The reaction mixture was heated
2
with stirring at 80 °C for 12 h and was then cooled, diluted with
dichloromethane, and stirred in an air atmosphere for 10 min. The
mixture was filtered through a Celite and silica gel pad and washed
with dichloromethane. The filtrate was concentrated, and the residue
was purified on a silica gel column using hexanes-ethyl acetate
as eluent to afford the desired product 3a as a colorless liquid in
halides to give M(III) oxidative addition products.1
1,12
Particu-
larly, Co(I) complexes are known to be supernucleophiles,
13
reacting with an alkyl halide via an SN2 mechanism. Further-
more, as indicated in the foregoing experiment, the involvement
of Co(I) in the present catalytic cycle is evidenced by the fact
74% isolated yield.
14
that CoCl(PPh3)3 reacts with 1e and acrylate 2a stoichiomet-
rically to give the reductive coupling product 3a. Indirect
evidence for the presence of the alkyl-Co species was shown
Products 3b-m were prepared according to similar procedures,
except when the iodo compounds were used, the reaction time was
reduced to 6 h and only 5 mol % of CoI (dppe) and 2 to 3 equiv
2
of acrylate (2.0-3.0 mmol) were employed.
(
11) (a) Labinger, J. A.; Osborn, J. A. Inorg. Chem. 1980, 19, 3230-
3
1
236. (b) Labinger, J. A.; Osborn, J. A.; Coville, N. J. Inorg. Chem. 1980,
Acknowledgment. We thank the National Science Council
of the Republic of China (NSC 93-2113-M-007-033) for the
support of this research.
9, 3236-3242.
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12) (a) Branchaud, B. P.; Yu, G. X. Organometallics 1991, 10, 3795-
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(
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c) Cheng, C. H.; Spivack, B. D.; Eisenberg, R. J. Am. Chem. Soc. 1977,
Supporting Information Available: General experimental
procedures, spectral data, and 1H and C NMR spectra for
compounds 3a-m. This material is available free of charge via
the Internet at http://pubs.acs.org
9, 3003-3011. (d) Collman, J. P. Acc. Chem. Res. 1968, 1, 136-143.
13) Schrauzer, G. N.; Deutsch, R. J. Am. Chem. Soc. 1969, 91, 3341-
350 and the references therein.
14) Wakatsuki, Y.; Yamazaki, H. In Mononuclear Transition Metal
13
(
3
(
Complexes Part III. Metallocycle Complexes; Kaesz, H. D., Ed.; Inorganic
Syntheses Series 26; John Wiley and Sons: New York, 1989.
JO052065W
658 J. Org. Chem., Vol. 71, No. 2, 2006