Cobalt-catalyzed reductive coupling of activated alkenes with alkynes

Article abstract of DOI:10.1021/ja073604c

Cobalt complex/Zn systems effectively catalyze the reductive coupling of activated alkenes with alkynes in the presence of water to give substituted alkenes with very high regio- and stereoselectivity in excellent yields. While the intermolecular reaction

Full text of DOI:10.1021/ja073604c

Published on Web 09/11/2007
Cobalt-Catalyzed Reductive Coupling of Activated Alkenes
with Alkynes
Hong-Tai Chang, Thiruvellore Thatai Jayanth, Chun-Chih Wang, and
Chien-Hong Cheng*
Contribution from the Department of Chemistry, National Tsing Hua UniVersity,
Hsinchu 30013, Taiwan
Received May 19, 2007; E-mail: chcheng@mx.nthu.edu.tw
Abstract: Cobalt complex/Zn systems effectively catalyze the reductive coupling of activated alkenes with
alkynes in the presence of water to give substituted alkenes with very high regio- and stereoselectivity in
excellent yields. While the intermolecular reaction of acrylates, acrylonitriles, and vinyl sulfones with alkynes
takes place in the presence of CoI
2 3 2
(PPh ) /Zn, the reaction of enones and enals with alkynes requires the
use of the CoI (dppe)/Zn/ZnI system. The intramolecular reductive coupling of activated alkenes (enones,
2
2
enals, acrylates, and acrylonitriles) with alkynes also works efficiently. Further a variety of cyclic lactones
and lactams were prepared using this methodology. Possible mechanistic pathways are proposed based
on a deuterium-labeling experiment carried out in the presence of D O.
2
6
Introduction
hydropalladation of alkenes is also known. Krische has reported
related reductive couplings of alkynes with carbonyl compounds
or imines under hydrogenation conditions using rhodium as a
Catalytic reactions that effect carbon-carbon bond formation
by uniting readily available π-components in a highly atom-
economical way is very important to the development of organic
7
catalyst. The efficacy of these types of reaction leading to
highly substituted alkenes heavily depends on the selectivity
that can be achieved.
1
synthesis. Among these the coupling of alkynes and a double
bonded component leading to highly substituted alkenes is
particularly interesting. The Alder-ene reaction of alkynes with
alkenes catalyzed by ruthenium to form dienes has been
extensively studied by Trost’s group. Another variant involves
2
Cobalt also has been employed as highly reactive catalysts
for the carbon-carbon bond forming reaction by Oshima,
8a-c
3
8d,e
8f,g
8h-j
Knochel,
Gosmini,
our group
and others. In this
catalytic reductive couplings. Most widely studied in this type
is the nickel-catalyzed reductive coupling of alkynes with
carbonyl compounds or imines leading to allylic alcohols or
context, we have earlier reported a cobalt-catalyzed intermo-
lecular reductive coupling of alkynes and conjugated alkenes
in a highly chemo-, regio-, and stereoselective fashion. To the
9
4
amines. Nickel-catalyzed reductive coupling of alkynes and
alkenes involving an organometallic reagent as a third compo-
nent is known, but simple reductive couplings are unknown.
Coupling of alkenes and alkynes via palladium-catalyzed
(
5) For very recent examples, see: (a) Ho, C.-Y.; Jamison, T. F. Angew. Chem.,
Int. Ed. 2007, 46, 782. (b) Ng, S.-S.; Ho, C.-Y.; Jamison, T. F. J. Am.
Chem. Soc. 2006, 128, 11513. (b) Song, M.; Montgomery, J. Tetrahedron
2005, 61, 11440. (c) Ng, S.-S.; Jamison, T. F. Tetrahedron 2005, 61, 11405.
5
(
d) Takimoto, M.; Kajima, Y.; Sato, Y.; Mori, M. J. Org. Chem. 2005, 70,
(
1) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 259. (c) Trost, B. M. Acc. Chem. Res. 2002, 35,
8605. (e) Ng, S.-S.; Jamison, T. F. J. Am. Chem. Soc. 2005, 127, 7320. (f)
Hratchian, H. P.; Chowdhury, S. K.; Gutierrez-Garcia, V. M.; Amarasinghe,
K. K. D.; Heeg, M. J.; Schlegel, H. B.; Montgomery, J. Organometallics
2004, 23, 4636. (g) Kimura, M.; Ezoe, A.; Mori, M.; Tamaru, Y. J. Am.
Chem. Soc. 2005, 127, 201. (h) Shirakawa, E.; Yamamoto, Y.; Nakao, Y.;
Oda, S.; Tsuchimoto, T.; Hiyama, T. Angew. Chem., Int. Ed. 2004, 43,
3448. For earlier references, see ref 2c. See also: (i) Yi, C. S.; Lee, D.
W.; Chen, Y. Organometallics 1999, 18, 2043. (j) Ikeda, S.; Yamamoto,
H.; Kondo, K.; Sato, Y. Organometallics 1995, 14, 5015. (k) Ikeda, S.;
Cui, D. M.; Sato, Y. J. Am. Chem. Soc. 1999, 121, 4712.
6
95. (c) Wender, P. A.; Bi, F. C.; Gamber, G. G.; Gosselin, F.; Hubbard,
R. D.; Scanio, M. J. C.; Sun, R.; Williams, T. J.; Zhang, L. Pure Appl.
Chem. 2002, 74, 25. (d) Wender, P. A.; Handy, S. T.; Wright, D. L. Chem.
Ind. (London) 1997, 765. (e) Wender, P. A.; Miller, B. L. In Organic
Synthesis: Theory and Applications; Huldicky, T., Ed.; JAI Press:
Greenwich, 1993; Vol. 2, p 27.
(
2) (a) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. ReV. 2000, 101,
2
067. (b) Ikeda, S.-I. Angew. Chem., Int. Ed. 2003, 42, 5120. (c)
Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890. (d) Tang, X. Q.;
Montgomery, J. J. Am. Chem. Soc. 1999, 121, 6098. (e) Huang, W.-S.;
Chen, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221. (f) Colby, E. A.; Jamison,
T. F. J. Org. Chem. 2003, 68, 156. (g) Miller, K. M.; Huang, W.-S.;
Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442. (h) Takai, K.; Sakamoto,
S.; Isshiki, T. Org. Lett. 2003, 5, 653.
(6) (a) Zhao, L.; Lu, X. Org. Lett. 2002, 4, 3903. (b) Zhao, L.; Lu, X.; Xu, W.
J. Org. Chem. 2005, 70, 4059.
(7) (a) Jang, H.-Y.; Krische, M. J. Eur. J. Org. Chem. 2004, 19, 3953. (b)
Jang, H.-Y.; Krische, M. J. Acc. Chem. Res. 2004, 37, 653. (c) Komanduri,
V.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 16448.
(8) (a) Yorimitsu, H.; Oshima, K. Pure Appl. Chem. 2006, 78, 441. (b) Ohmiya,
H.; Wakabayashi, K.; Yorimitsu, H.; Oshima, K. Tetrahedron 2006, 62,
2207. (c) Shinokubo, H.; Oshima, K. Eur. J. Org. Chem. 2004, 10, 2081.
(d) Korn, T. J.; Schade, M. A.; Wirth, S.; Knochel, P. Org. Lett. 2006, 8,
725. (e) Korn, T. J.; Cahiez, G.; Knochel, P. Synlett 2003, 1892. (f)
Kazmierski, I.; Gosmini, C; Paris, J.-M; Perichon, J. Synlett 2006, 881. (g)
Amatore, M.; Gosmini, C.; Perichon, J. J. Org. Chem. 2006, 71, 6130. (h)
Chang, H.-T.; Jeganmohan, M.; Cheng, C.-H. Chem. Commun. 2005, 4955
(i) Chang, K.-J.; Rayabarapu, D. K.; Cheng, C.-H. J. Org. Chem. 2004,
69, 4781. (j) Chang, K.-J.; Rayabarapu, D. K; Cheng, C.-H. Org. Lett.
2003, 5, 3963.
(
3) (a) Trost, B. M.; Frederiksen, M. U.; Rudd, M. T. Angew. Chem., Int. Ed.
2
005, 44, 6630. (b) Trost, B. M.; Huang, X. Chem.sAsian J. 2006, 1,
69.
4
(
4) (a) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2003, 42, 1364. (b)
Sato, Y.; Takimoto, M.; Hayashi, K.; Katsuhara, T.; Takagi, K.; Mori, M.
J. Am. Chem. Soc. 1994, 116, 9771. (c) Oblinger, E.; Montgomery, J. J.
Am. Chem. Soc. 1997, 119, 9065. (d) Kimura, M.; Ezoe, A.; Shibata, K.;
Tamaru, Y. J. Am. Chem. Soc. 1998, 120, 4033. (e) Montgomery, J. Acc.
Chem. Res. 2000, 33, 467. (f) Ikeda, S. Acc. Chem. Res. 2000, 33, 511. (g)
Ni, Y.; Amarasinghe, K. K. D.; Montgomery, J. Org. Lett. 2002, 4, 1743.
12032
9
J. AM. CHEM. SOC. 2007, 129, 12032-12041
10.1021/ja073604c CCC: $37.00 © 2007 American Chemical Society

Co-Catalyzed Reductive Coupling of Alkenes with Alkynes
A R T I C L E S
Scheme 1. Co-Catalyzed Reductive Coupling of Acrylates,
Acrylonitriles, and Vinyl Sulfones with Alkynes
Table 1. Optimization Studies for the Co-Catalyzed Reductive
Coupling of Enones with Alkynesa
entry
catalyst
additive
yield (%)b
1
2
3
4
5
6
7
8
9
Zn
-
-
0
0
CoI2(PPh3)2, Zn, 3PPh3
CoI2(PPh3)2, Zn, 3 PPh3
CoI2(dppe), Zn
ZnCl2
-
trace
22
75
71
70
70
63
94
36
85
64
0
CoI2(dppe), Zn
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnI2
Zn(OAc)2
CuI
CuCl
LiCl
CoI2(dppe), Zn, dppe
CoCl2(dppe), Zn
CoCl2(dppm), Zn
CoCl2(dppb), Zn
CoI2(dppe), Zn
CoI2(dppe), Zn
CoI2(dppe), Zn
CoI (dppe), Zn
CoI2(dppe), Zn
best of our knowledge this is the first and only catalytic
intermolecular reductive ene-yne coupling known until now.
In this article we disclose a significantly expanded scope of
this cobalt-catalyzed reductive coupling. In the preliminary
communication, the alkene used was restricted to acrylates,
acrylonitriles, and vinyl sulfones. Herein, we report that, by a
suitable modification of the reaction conditions, enones and enals
were successfully employed in this reductive coupling. An
intramolecular version of this reaction was also accomplished.
Further, we also wish to describe some useful applications of
this reductive coupling methodology via synthesis of six- and
seven-membered lactones and lactams.
1
1
1
0
1
2
13
2
1
1
4
5
CoI2(dppe), Zn
MgCl2
0
a
Reaction conditions: alkyne (1.00 mmol), alkene (1.20 mmol), cobalt
complex (0.050 mmol; 5.0 mol %), Zn (2.75 mmol), additive (0.10 mmol),
H2O (2.0 mmol), CH3CN (2.0 mL) at 80 °C for 24 h. Isolated yields.
b
in 74% yield (entry 3). Dieneyne 1j gave the corresponding
diene 5d in 81% yield (entry 4). Dialkylalkynes 1c also coupled
smoothly (entry 5). A heteroaromatic alkyne, 2-pyridine-1-
propyne (1k), also reacted successfully with 4a to give the
corresponding substituted alkene 5f in 84% yield (entry 6).
Similarly, various enones underwent the expected reductive
coupling. For example, phenyl vinyl ketone (4c) coupled with
Results and Discussion
Earlier we found that internal alkynes and alkenes especially
acrylates, acrylonitrile, and vinyl sulfones undergo reductive
coupling in the presence of a cobalt catalyst to give highly
substituted alkenes (Scheme 1). In order to widen the scope of
this reaction, enones were employed as the alkene partner. But
when methylphenylacetylene (1a) was treated with methyl vinyl
ketone (4a) under the same reaction conditions (entry 2, Table
1
a providing 5i in 74% yield (entry 9). Enal 4e also reacted
efficiently with alkyne 1a under the standard reaction conditions
to afford 5k, albeit in a lower yield (entry 11). Cyclic enones,
like cyclopentenone and cyclohexenone, were compatible for
this coupling (entries 13-17). While all the above reductive
coupling reactions occurred in a highly regio- and stereoselective
fashion, the corresponding reductive coupling of propiolates 1f
and 1g with enone 4a took place with low regioselectivity
leading to two regioisomers (entries 18 and 19).
1) employed for the reductive coupling of acrylates with alkynes,
no expected reductive coupling product was observed. During
our search for suitable reaction conditions for the alkyne-enone
coupling, we observed that the use of ZnCl2 gave a trace amount
of the reductive coupling product 5a (entry 3). The use of CoI2-
Intramolecular reductive coupling of an alkyne and an
activated alkene group was also possible under the standard
reaction conditions. The reaction worked equally well with both
cis and trans isomers of 6 to give the reductive coupling product
in almost the same yields (Table 3, entries 1, 2, 4, 5, 7, and 8).
Compounds E-6a, Z-6a, and 6b (E form), terminal alkynes
tethered with enones, underwent intramolecular enyne coupling
to give 7a and 7b in very high yields (Table 3, entries 1 to 3).
It is interesting to note that for the intermolecular version of
enyne reductive coupling, terminal alkynes generally do not react
with activated alkenes to give the expected products (see Table
(
2
dppe) and Zn gave the reductive coupling product obtained in
2% yield (entry 4). When CoI2(dppe)/Zn/H2O was employed
along with ZnCl2, the yield of reductive coupling product was
increased to 75% yield (entry 5). Subsequently, a variety of
Lewis acids were tried. The use of ZnI2 gave the highest yield
of 5a with complete regio- and stereoselectivity (entry 10). As
shown in entries 12 and 13, CuCl and CuI also worked well
for this reaction.
A variety of internal alkynes reacted with enones to give the
reductive coupling product in good yields in a regio- and
stereoselective manner. The regio- and stereochemistry of the
products was determined by NOE experiments. Table 2 il-
lustrates the scope of this coupling reaction. Diphenylacetylene
2
). Internal alkynes with an aryl or alkyl substituent were com-
patible for the present intramolecular reductive coupling. Both
electron-withdrawing and electron-donating phenyl substituents
worked equally well (entries 4-9). 1-Naphthyl and 2-thienyl
substituted alkynes tethered to an enone group formed the five-
membered ring product in good yields (entries 10-12). Tether
length can also be increased to form a cyclohexane derivative
(
1b) coupled with methyl vinyl ketone (4a) to give 5b in 88%
yield (entry 2). Naphthyl-1-propyne (1i) also reacted well with
a to afford the corresponding reductive coupling product 5c
4
(
9) (a) Wang, C.-C.; Lin, P.-S.; Cheng, C.-H.; J. Am. Chem. Soc. 2002, 124,
9
696. For a recent report on Co-catalyzed reductive cycloaddition of allenes
(entry 13). Oxygen tethered enynes also underwent reductive
and enones, see: (b) Chang, H. -T.; Jayanth, T. T.; Cheng, C. -H.; J. Am.
Chem. Soc. 2007, 129, 4166. For related cobalt-catalyzed reductive
couplings from our lab, see: (c) Shukla, P.; Hsu, Y.-C.; Cheng, C.-H. J.
Org. Chem. 2006, 71, 655. (d) Wang, C.-C.; Lin, P.-S.; Cheng, C.-H.
Tetrahedron Lett. 2004, 45, 6203.
coupling to afford substituted tetrahydrofurans in very good
yields (entries 14 and 15). Similarly, acrylonitrile and acrylate
tethered alkynes also worked efficiently (entries 16 and 17).
J. AM. CHEM. SOC.
9
VOL. 129, NO. 39, 2007 12033

A R T I C L E S
Chang et al.
Table 2. Co-Catalyzed Intermolecular Reductive Coupling of Enones and Enals with Alkynesa
12034 J. AM. CHEM. SOC.
9
VOL. 129, NO. 39, 2007

Co-Catalyzed Reductive Coupling of Alkenes with Alkynes
A R T I C L E S
Table 2. (Continued)
a
Reaction conditions: alkyne (1.00 mmol), alkene (1.20 mmol), CoI2(dppe) (0.050 mmol; 5.0 mol %), Zn (2.75 mmol), ZnI2 (0.10 mmol), H2O (2.0
b
mmol), CH3CN (2.0 mL) at 80 °C for 24 h. Isolated yields.
The success of the reductive coupling reaction of alkynes
with both acrylates and enones encouraged us to look for further
utility of this reaction. The highly atom-economical nature and
complete regio- and stereoselectivity of this reductive coupling
as well as the use of acrylates compelled us to think that a
strategic positioning of a hydroxyl group in the alkyne moiety
will lead to lactones. In this context, we have also reported
When phenyl propargyl alcohol (8a) was treated with methyl
acrylate (2d) under the reaction conditions shown in Scheme
1, the expected lactone formed albeit in a very low yield of
20%. After a series of attempts to optimize the reaction
conditions, we found that CoI (dppe) and a proper ratio of CH -
2
3
CN and 1,4-dioxane as solvent gave the six-membered ring
several metal-catalyzed coupling/lactonization strategies to
(
11) (a) Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. ReV. 2006, 106, 911.
synthesize a variety of interesting lactones.10 Small and medium
(b) El Ali, B.; Alper, H. Synlett. 2000, 161. (c) Shiina, I. Chem. ReV. 2007,
107, 239.
ring lactones are very important in organic chemistry, as they
(12) (a) Rousseau, G. Tetrahedron 1995, 51, 2777. (b) Bringmann, G.; Hinrichs,
J.; Henschel, P.; Peters, K.; Peters, E.-M. Synlett 2000, 1822. (c) Hosmi,
F.; Rousseau, G. J. Org. Chem. 1998, 63, 5255. (d) Grigg, R.; Khalil, H.;
Levett, P.; Virica, J.; Sridharan, V. Tetrahedron Lett. 1994, 35, 3197. (e)
Ali, B. E.; Okura, K.; Vasapolla, G.; Alper, H. J. Am. Chem. Soc. 1996,
118, 4264. (f) Williams, A. S.; Firmenich, S. A. Synthesis 1999, 10, 1707.
(g) Wang, Y.; Tennyson, R. L.; Romo, D. Heterocycles 2004, 64, 605. (h)
Yoneda, E.; Zhang, S. W.; Onitsuka, K.; Takahashi, S. Tetrahedron Lett.
2001, 42, 5459.
11,12
are contained in an ever-growing number of natural products.
(
10) (a) Rayabarapu, D. K.; Sambaiah, T.; Cheng, C.-H. Angew. Chem., Int.
Ed. 2001, 40, 1286. (b) Rayabarapu, D. K.; Cheng, C.-H. J. Am. Chem.
Soc. 2002, 124, 5630. (c) Rayabarapu, D. K.; Shukla, P.; Cheng, C.-H.
Org. Lett. 2003, 5, 4903. (d) Chang, H.-T.; Jeganmohan, M.; Cheng, C.-
H. Chem. Commun. 2005, 39, 4955.
J. AM. CHEM. SOC.
9
VOL. 129, NO. 39, 2007 12035

A R T I C L E S
Chang et al.
Table 3. Co-Catalyzed Intramolecular Reductive Coupling of Activated Alkenes with Alkynesa
12036 J. AM. CHEM. SOC.
9
VOL. 129, NO. 39, 2007

Co-Catalyzed Reductive Coupling of Alkenes with Alkynes
A R T I C L E S
Table 3. (Continued)
a
Reaction conditions: enyne 6 (1.00 mmol), CoI2(dppe) (0.050 mmol; 5.0 mol %), Zn (2.75 mmol), ZnI2 (0.10 mmol), H2O (2.0 mmol), CH3CN (2.0
b
mL) at 80 °C for 8 h. Isolated yields.
lactone in high 80% yield (Table 4, entry 1). The generality of
this reaction is demonstrated by the successful extension to a
variety of propargyl alcohols (entries 2-4). More importantly,
substitution at the propargylic position also gave the corre-
sponding six-membered ring lactones (entries 5-8). The Z
stereochemistry of the exo-double bond of the lactone was
confirmed by NOE experiments. When phenyl propargyl amine
was used, no lactam was observed. Introduction of a suitable
protecting group (BOC) to the amine group gave the reductive
coupling in high yields (Scheme 2). The lactamization was
realized by heating the reductive coupling product in the
presence of TFA for 1 h. Both electron-donating and electron-
withdrawing group substituted phenyl propargyl amines 10
formed the six-membered lactams 11. 9-Phenanthrenyl propargyl
amine (10b) gave the expected product 11b in 73% yield.
When 8i, a phenyl propargyl alcohol possessing an ester group
at the ortho position of the phenyl ring, was treated with acrylate
formation of seven-membered ring lactones was further con-
firmed by comparing the chemical shifts in the H NMR. The
1
protons of the methylene group on the lactone ring of all the
seven-membered ring lactones (Table 5) including 12a appeared
between 4.36 and 4.47 ppm, whereas the protons of the
methylene group of the six-membered ring lactones (Table 4)
appeared between 5.05 and 5.13 ppm. The formation of seven-
membered lactone could be effected with different alkenes like
acrylonitrile 2b, vinyl sulfone 2c, and diethylacryl amide 2e
(entries 2-5). Alkynes with different substituents (8j-l) at the
propargylic position formed the seven-membered ring lactones
in modest yields (entries 6-9). The high stereo- and regiose-
lectivity of the reductive coupling alkyne and alkene is very
crucial for the success of the synthesis of the six- and seven-
membered ring lactones. For example, the lack of regioselec-
tivity for the reaction of 8d and 2d (entry 4, Table 4) leads to
two products, and one of the products fails to lactonize.
Mechanistic Discussion. To understand the role of water and
to help elucidate the mechanism of the present catalytic reaction,
an isotope-labeling experiment using D2O (99.9%) to replace
normal water for the reductive coupling of ethyl vinyl ketone
4b with alkyne 1a to give product 5g-d was carried out. The
results show that the olefinic proton and one of the protons
2
a the corresponding seven-membered ring lactone 12a was
obtained in 65% yield (Table 5, entry 1). The formation of
another possible product, a six-membered cyclic lactone, was
not observed. This was inferred from the presence of the n-butyl
group of the acrylate on the product and no methyl group of
the ester on the ortho position of the aromatic ring. The
J. AM. CHEM. SOC.
9
VOL. 129, NO. 39, 2007 12037

A R T I C L E S
Chang et al.
Table 4. Synthesis of Six-Membered Cyclic Lactone via Co-Catalyzed Intermolecular Reductive Coupling/Lactonization of Acrylates with
Propargyl Alcoholsa
a
Reaction conditions: propargyl alcohol (1.00 mmol), methyl acrylate (1.20 mmol), CoI2(dppe) (0.05 mmol; 5.0 mol %), Zn (2.75 mmol), H2O (2.0
b
mmol), CH3CN (0.80 mL), 1,4-dioxane (2.20 mL) at 80 °C for 12 h. Isolated yields.
attached to the R-carbon atom of ketone in 5g-d were
deuterated in 84 and 80%, respectively. No deuterium-labeling
for other protons in this product was observed. The isotope
spectrum of 5g-d reveals two characteristic deuterium coupled
triplets at 125.3 and 40.6 ppm for the olefin and methylene
carbons, respectively.
1
abundance was determined by the H NMR integration method.
A similar D2O study involving the reaction of phenyl vinyl
1
13
8
In agreement with the results of H NMR analysis, the C NMR
sulfone (2c) with alkyne 1a also gave analogous results. The
12038 J. AM. CHEM. SOC.
9
VOL. 129, NO. 39, 2007

Co-Catalyzed Reductive Coupling of Alkenes with Alkynes
A R T I C L E S
Scheme 2. Synthesis of Six-Membered Cyclic Lactams via
Co-Catalyzed Intermolecular Reductive Coupling/Lactamization of
Acrylates with Propargyl Amines
addition reactions of enones. 1,4-Addition of organometallic
reagents to R,â-unsaturated ketones is one of the basic synthetic
reactions often used for the carbon-carbon bond formation.1
The reaction presented here, especially in Table 2, offers a more
efficient route to 1,4 addition products because these reactions
do not require the use of an organometallic reagent (Scheme
4,15
1
6
4
).
The ruthenium-catalyzed Alder-ene reaction involves the
formation of a diene from the reaction of an alkyne and alkene.
The high atom economy offered by this reaction has led to many
useful applications of this reaction toward total synthesis of
naturally occurring compounds. The present cobalt-catalyzed
reductive coupling also involves the reaction of simple alkenes
and alkynes to give highly substituted alkenes. The pre-catalyst
CoI2(dppe) is easy to prepare, handle, and store. Cobalt salts
are relatively cheap and environmentally friendly. The very mild
reducing agent zinc is used. The simplest hydrogen source water
is employed. Thus, this methodology, the one that offers a
simple and highly atom-economical approach to carbon-carbon
bond formation, will find wide applications in organic synthesis.
mechanism of the present reductive coupling is interesting in
view of the ability of the catalyst to assemble an alkyne and an
alkene molecule for coupling and hydrogenation in one pot in
a regio- and stereoselective fashion. A straightforward route that
can explain well the observed regio- and stereochemistry is the
formation of a cobaltacyclopentene intermediate from cyclo-
metalation of an alkyne and alkene to the cobalt(I) center
followed by protonation of the intermediate by water (Scheme
Conclusion
In conclusion, we have developed a novel simple method for
the assembling of an alkene and alkyne via a cobalt-catalyzed
reductive-coupling mode. This reaction is highly chemo-, regio-,
and stereoselective. The generality of the reaction was demon-
strated by the employment of various activated alkenes like
acrylates, acrylonitriles, vinyl sulfones, enones (cyclic and
acyclic), and enals and of a wide range of alkynes. Both inter-
and intramolecular versions work very well. The methodology
was used to synthesize six- and seven-membered cyclic lactones.
Further studies toward the asymmetric version and application
of this methodology in total synthesis and the use of cobalt
catalyst for carbon-carbon bond formation are underway in our
laboratories.
3, Cycle I). Such a metallocyclopentene species has been
proposed as a key intermediate in the ene-yne coupling
2
catalyzed by ruthenium and nickel complexes. The results of
the above deuterium isotope-labeling experiment strongly sup-
port this pathway. An alternative mechanism involves a cobalt-
(III) hydride generated from protonation of cobalt(I) by water
followed by insertion of an alkene into the metal-hydride bond
giving a five-membered ring species (Cycle 2). A similar five-
membered ketone chelate complex of rhodium and palladium
1
3
has been isolated However, in the present case, this pathway
can be ruled out considering that the five-membered ring
intermediate generated by a cyclic enone such as 2-cyclopenten-
Experimental Section
1
-one would contain a strained five-membered ring.
The role of ZnI2 is believed to be twofold: (1) to remove
A few representative examples are listed here. Experimental
procedures and spectroscopic data for all compounds can be found in
the Supporting Information.
Typical Procedure for the Reductive Coupling of Enones with
2
Alkynes: A round-bottom sidearm flask containing CoI (dppe) (0.0500
the iodide from the Co(I)(dppe)I complex (generated from the
one-electron reduction of pre-catalyst Co(dppe)I2) thereby
generating a more active cationic cobalt complex; (2) to activate
the vinyl ketone by Lewis acid catalysis.
mmol), zinc powder (2.75 mmol), and zinc iodide (0.100 mmol) was
evacuated and purged with nitrogen gas three times. Freshly distilled
High selectivities were obtained for the formation of a seven-
membered ring over a six-membered ring in entries 1 and 4,
Table 5. These results are interesting in view of the fact that
the formation of a six-membered ring is generally more
favorable than a seven-membered ring. The seven-membered
ring lactonization is more entropically favorable due to a
transition state arising from a near planar structure of the styrenyl
moiety 12a′. However, we did not observe any 12a′ while
monitoring the reaction at various time intervals. Thus the
possibility of cobaltacyclopentene intermediate 12a-C formed
for the reaction of 8i and 2a in entry 1, Table 5 forming a seven-
membered ring lactone 12a (even before the catalytic cycle is
complete) without going through 12a′ cannot be ruled out
completely.
3
CH CN (2.0 mL), alkyne 1 (1.00 mmol), ketone 4 (1.20 mmol), and
H
2
O (2.00 mmol) were added via syringes. The reaction mixture was
heated with stirring at 80 °C for 24 h and was then cooled, diluted
with dichloromethane, and stirred in the air 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 hexane-ethyl acetate as eluent to
afford the desired product 5.
Intramolecular reductive coupling was performed following the above
procedure with 6 instead of 1 and 4.
(
14) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1992. (b) Schmalz, H.-G. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
1
7
991; Vol. 4. (c) Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992, 92,
71.
Some of the products obtained via the present cobalt-catalyzed
reductive coupling invite an interesting comparison with 1,4-
(15) (a) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829. (b) Krause,
N.; Hoffmann-Roder, A. Synthesis 2001, 171. (c) Sibi, M. P.; Manyem, S.
Tetrahedron 2000, 56, 8033. (d) Kanai, M.; Shibasaki, M. In Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley: New York, 2000; p
569.
(13) DiRenzo, G. M.; White, P. S.; Brookhart, M. J. Am. Chem. Soc. 1996,
1
18, 6225 and references therein.
(16) Takaya, Y.; Ogasawara, M.; Hayashi, T. Tetrahedron Lett. 1998, 39, 8479.
J. AM. CHEM. SOC.
9
VOL. 129, NO. 39, 2007 12039

A R T I C L E S
Chang et al.
Table 5. Synthesis of Seven-Membered Cyclic Lactone via Co-Catalyzed Intermolecular Reductive Coupling/Lactonizationa
a
Reaction conditions: alkynes (1.00 mmol), alkenes (1.20 mmol), CoI2(dppe) (0.050 mmol; 5.0 mol %), Zn (2.75 mmol), H2O (2.0 mmol), CH3CN (3.0
b
mL) at 80 °C for 24 h. Isolated yields.
12040 J. AM. CHEM. SOC.
9
VOL. 129, NO. 39, 2007

Co-Catalyzed Reductive Coupling of Alkenes with Alkynes
A R T I C L E S
Scheme 3. Plausible Mechanistic Pathways
Scheme 4. Comparison of 1,4-Addition and Reductive Coupling
12 h and was then cooled, diluted with dichloromethane, and stirred in
the air 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 hexane-
ethyl acetate as eluent to afford the desired product 9.
Similar procedures were employed to prepare 11a′-c′ from 10 and
d. Compounds 11a′-c′ were deprotected followed by lactamization
2
to the corresponding 11a-c by refluxing in THF in the presence of
trifluoroacetic acid.
1
5
-[(Z)-1-Phenylmethylidene]tetrahydro-2H-2-pyranone (9a). H
NMR (400 MHz, CDCl
3
): δ 7.34 (t, J ) 7.2 Hz, 2H), 7.27 (t, J ) 7.2
Hz, 1H), 7.08 (d, J ) 7.2 Hz, 2H), 6.55 (s, 1H), 5.06 (s, 2H), 2.78-
2
1
2
.75 (m, 2H), 2.70-2.67 (m, 2H). 13C NMR (100 MHz, CDCl
71.68, 135.74, 131.04, 128.44 (2C), 127.53, 127.34, 68.02, 30.34,
7.83. HRMS calcd for C12 188.0837; found 188.0844.
-[(Z)-1-(4-Methoxyphenyl)methylidene]-2-piperidinone (11a). H
NMR (400 MHz, CDCl ): δ 7.06 (d, J ) 9.2 Hz, 2H), 6.87 (d, J )
.2 Hz, 2H), 6.84 (s, 1H), 6.25 (br, 1H), 4.22 (s, 2H), 3.79 (s, 3H),
.62 (t, J ) 6.4 Hz, 2H), 2.45 (t, J ) 6.4 Hz, 2H). 13C NMR (100
): δ 173.10, 158.52, 130.24, 129.76, 128.85, 125.56,
13.75, 55.21, 43.62, 32.32, 30.51. HRMS calcd for C13
17.1103; found 217.1110.
Butyl 3-(1-Oxo-1,3-dihydro-2-benzoxepin-4-yl)propanoate (12a).
3
): δ
12 2
H O
1
5
3
9
2
1
(
E)-5-Methyl-6-phenylhex-5-en-2-one (5a). H NMR (400 MHz,
MHz, CDCl
1
2
3
3
CDCl ): δ 7.30 (t, J ) 7.2 Hz, 2H), 7.20 (d, J ) 7.2 Hz, 2H), 7.17 (t,
H15NO
2
J ) 7.2 Hz, 1H), 6.26 (s, 1H), 2.64 (t, J ) 8.0 Hz, 2H), 2.43 (t, J )
3
8
.0 Hz, 2H), 2.17 (s, 3H), 1.84 (s, 3H). 1 C NMR (100 MHz, CDCl
3
):
δ 208.31, 138.10, 137.32, 128.75, 128.00, 126.02, 125.36, 42.22, 34.36,
1
H NMR (400 MHz, CDCl
.0 Hz, 1H), 7.36 (t, J ) 8.0 Hz, 1H), 7.20 (d, J ) 8.0 Hz, 1H), 6.65
s, 1H), 4.43 (s, 2H), 4.08 (t, J ) 6.4 Hz, 2H), 2.70 (t, J ) 6.4 Hz,
3
): δ 7.97 (d, J ) 8.0 Hz, 1H), 7.50 (t, J )
2
9.94, 17.77. HRMS calcd for C13
H
16O 188.1201; found 188.1207.
8
(
1
2-(2-Methylenecyclopentyl)-1-phenylethanone (7a). H NMR (400
MHz, CDCl
7
1
3
): δ 7.95 (dd, J ) 7.2 Hz, J ) 5.2 Hz, 2H), 7.54 (tt, J )
.2 Hz, J ) 1.2 Hz, 1H), 7.44 (t, J ) 8.0 Hz, 2H), 4.91 (d, J ) 2.0 Hz,
H), 4.80 (dd, J ) 2.0 Hz, J ) 2.0 Hz, 1H), 3.22 (dd, J ) 15.2 Hz, J
3.2 Hz, 1H), 2.96-2.90 (m, 2H), 2.44-2.30 (m, 2H), 2.06-1.98
m, 1H), 1.76-1.71 (m, 1H), 1.70-1.54 (m, 1H), 1.32-1.23 (m, 1H).
2
0
1
6
H), 2.59 (t, J ) 6.4 Hz, 2H), 1.62-1.55 (m, 2H), 1.37-1.32 (m, 2H),
13
.90 (t, J ) 7.2 Hz, 3H). C NMR (100 MHz, CDCl ): δ 172.36,
3
70.13, 141.62, 135.66, 132.58, 132.17, 130.87, 130.21, 128.69, 127.86,
6.34, 64.63, 32.81, 31.44, 30.64, 19.10, 13.63. HRMS calcd for
)
(
C
17
H
20
O
4
288.1362; found 288.1358.
1
3
C NMR (100 MHz, CDCl
28.54, 128.06, 104.62, 43.61, 39.79, 33.35, 32.92, 24.08. HRMS calcd
16O 200.1201; found 200.1195.
Typical Procedure for the Synthesis of Six-Membered Ring
Lactones: A round-bottom sidearm flask containing CoI (dppe) (0.0500
mmol) and zinc powder (2.75 mmol) was evacuated and purged with
nitrogen gas three times. Freshly distilled CH CN (0.8 mL) and 1,4-
dioxane (2.2 mL), propargyl alcohol 8 (1.00 mmol), methyl acrylate
d (1.20 mmol), and H O (2.00 mmol) were added to the flask via
syringes. The reaction mixture was heated with stirring at 80 °C for
3
): δ 199.75, 155.85, 137.21, 132.90,
1
Acknowledgment. We thank the National Science Council
for C14H
of Republic of China (NSC 95-2119-M-007-005) for support
of this research.
2
Supporting Information Available: General experimental
procedure and characterization details. This material is available
free of charge via the Internet at http://pubs.acs.org.
3
2
2
JA073604C
J. AM. CHEM. SOC.
9
VOL. 129, NO. 39, 2007 12041