Highly selective nickel-catalyzed three-component coupling of alkynes with enones and alkenyl boronic acids: A novel route to substituted 1,3-dienes

Article abstract of DOI:10.1021/ol101319f

A highly regio-and stereoselective nickel-catalyzed three-component coupling of alkynes with enones and alkenyl boronic acids to afford highly substituted 1,3-dienes is described. The reaction can also be extended to cyclization of enynes with coupling to alkenyl boronic acids. A possible reaction mechanism involving a five-membered nickelacycle as a key intermediate is proposed.

Full text of DOI:10.1021/ol101319f

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3610-3613
Highly Selective Nickel-Catalyzed
Three-Component Coupling of Alkynes
with Enones and Alkenyl Boronic Acids:
A Novel Route to Substituted 1,3-Dienes
Chun-Ming Yang, Masilamani Jeganmohan, Kanniyappan Parthasarathy, and
Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 30013, Taiwan
chcheng@mx.nthu.edu.tw
Received June 9, 2010
ABSTRACT
A highly regio- and stereoselective nickel-catalyzed three-component coupling of alkynes with enones and alkenyl boronic acids to afford
highly substituted 1,3-dienes is described. The reaction can also be extended to cyclization of enynes with coupling to alkenyl boronic acids.
A possible reaction mechanism involving a five-membered nickelacycle as a key intermediate is proposed.
Nickel-catalyzed three-component coupling of two different
π-components with an organometallic reagent is an efficient
method for constructing complex organic molecules.1 Previ-
ously, a number of three-component couplings involving
alkynes with alkenes and various organometallic reagents
or metal hydrides have been demonstrated.2-5 Among the
coupling reactions, only a few examples are known using
alkynes, enones, and various organometallic reagents. Thus,
Ikeda’s group found a series of nickel-catalyzed coupling
of alkynes, enones with organostannane, organozinc, and
organoaluminum reagents.2a-d In 2006, Shinokubo et al.
reported a rhodium-catalyzed coupling of aryl boronic acids
with internal alkynes and acrylates that led to the formation
of functionalized dienes.6 Recently, we have reported
intermolecular benzyne/alkene/organoboronic acid7a and
alkyne/enone/bis(pinacolate)diboron couplings.7b In addition,
Montgomery and co-workers reported the intramolecular
(1) Reviews and selected references: (a) Montgomery, J. Acc. Chem.
Res. 2000, 33, 467. (b) Ikeda, S. Acc. Chem. Res. 2000, 33, 511. (c) Ikeda,
S. Angew. Chem., Int. Ed. 2003, 42, 5120. (d) Montgomery, J. Angew.
Chem., Int. Ed. 2004, 43, 3890. (e) Miller, K. M.; Molinaro, C.; Jamison,
T. F. Tetrahedron: Asymmetry 2003, 14, 3619. (f) Montgomery, J.;
Sormunen, G. J. Top. Curr. Chem. 2007, 279, 1. (g) Moslin, R. M.; Moslin,
K. M.; Jamison, T. F. Chem. Commun. 2007, 43, 4441. (h) Li, W.; Herath,
A.; Montgomery, J. J. Am. Chem. Soc. 2009, 131, 17024.
(2) (a) Ikeda, S.; Sato, Y. J. Am. Chem. Soc. 1994, 116, 5975. (b) Ikeda,
S.; Kondo, K.; Sato, Y. J. Org. Chem. 1996, 61, 8248. (c) Ikeda, S.;
Yamamoto, H.; Kondo, K.; Sato, Y. Organometallics 1995, 14, 5015. (d)
Ikeda, S.; Cui, D.-M.; Sato, Y. J. Am. Chem. Soc. 1999, 121, 4712. (e)
Cui, D.-M.; Yamamoto, H.; Ikeda, S.; Hatano, K.; Sato, Y. J. Org. Chem.
1998, 63, 2782. (f) Ikeda, S.; Cui, D.-M.; H.Sato, Y. J. Org. Chem. 1994,
59, 6877. (g) Cui, D.-M.; Yamamoto, H.; Ikeda, S.; Hatano, K.; Sato, Y. J.
Org. Chem. 1998, 63, 2782.
(4) Selected references for coupling of other π-components with
organometallic reagents: (a) Qi, X.; Montgomery, J. J. Org. Chem. 1999,
64, 9310. (b) Shimizu, K.; Takimoto, M.; Mori, M. Org. Lett. 2003, 5,
2323. (c) Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221.
(d) Saibata, K.; Kimura, M.; Shimizu, M.; Tamura, Y. Org. Lett. 2001, 3,
2181. (e) Kimura, M.; Ezoe, A.; Shibata, K.; Tamura, Y. J. Am. Chem.
Soc. 1998, 120, 4033. (f) Sato, Y.; Sawaki, R.; Saito, N.; Mori, M. J. Org.
Chem. 2002, 67, 656. (g) Kang, S.-K.; Yoon, S.-K. Chem. Commun. 2002,
22, 2634. (h) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed 2003, 42,
(3) Intramolecular coupling: (a) Montgomery, J.; Savchenko, A. V.
J. Am. Chem. Soc. 1996, 118, 2099. (b) Montgomery, J.; Oblinger, E.;
Savchenko, A. V. J. Am. Chem. Soc. 1997, 119, 4911. (c) Montgomery, J.;
Chevliakov, M. V.; Brielmann, H. L. Tetrahedron 1997, 53, 16449. (d)
Chevliakov, M. V.; Montgomery, J. Angew. Chem., Int. Ed. 1998, 37, 3144.
(e) Savchenko, A. V.; Montgomery, J. J. Org. Chem. 1996, 61. (f)
Montgomery, J.; Song, M. Org. Lett. 2002, 4, 4009. (g) Ni, Y.; Amarasinghe,
K. K. D.; Montgomery, J. Org. Lett. 2002, 4, 1743.
1364
.
(5) (a) Shintani, R.; Tsurusaki, A.; Okamoto, K.; Hayashi, T. Angew.
Chem., Int. Ed. 2005, 44, 3909. (b) Tsukamoto, H.; Suzuki, T.; Uchiyama,
T.; Kondo, Y. Tetrahedron Lett. 2008, 49, 4174
(6) kurahashi, T.; Shinokubo, H.; Osuka, A. Angew. Chem., Int. Ed.
2006, 45, 6336.
.
10.1021/ol101319f  2010 American Chemical Society
Published on Web 07/27/2010

sequential coupling of enynes with various organometallic
reagents.1d,3 However, to the best of our knowledge, there
have been no reports of using intermolecular coupling of
alkynes with enones and alkenyl boronic acids.
stereoselective with both double bonds in 4a being E
stereochemistry. This depends on the substituents R1 and R2
on the alkyne substrate. In most cases the two substituents
are cis to each other.
To find the optimized reaction conditions, the reaction
of 1a with 2a and 3a in the presence of Ni(cod)2 and PPh3
was examined with various additives and solvents. The
reaction in MeOH gave a three-component product 4a in
45% yield in addition to the 1,4-addition product of 2a
and 3a, E-PhCHdCH-(CH2)2COEt (5a)10 in 35% yield.
To improve the yield of 4a, various additives were
examined (see suppoting infomation). Among them, CsF
gave 4a in 96% NMR yield (Table 1, entry 1) along with
trace of 5a. Additives BEt3 and ZnCl2 are less effective
giving 4a in 51 and 15% yields with 5a in 15 and 5%
yields, respectively. The effect of solvents is also vital to
the catalytic reaction. The best solvent is MeOH in which
4a was obtained in 96% yield. CH3CN is also effective
giving 4a in 58% yield. Other solvents such as THF, DMF,
and toluene were totally ineffective for the catalytic
reaction (see the Supporting Information for detailed
studies). On the basis of these optimization studies, we
choose Ni(cod)2 (10 mol %), PPh3 (10 mol %), CsF (2.0
mmol) in MeOH at 80 °C for 16 h as the standard
conditions for the following catalytic reactions.
Our continued interest in metal-catalyzed three-component
coupling reactions8 prompted us to explore an efficient
method for the intermolecular coupling of alkynes with
enones and alkenylboronic acids. Thus, treatment of 1-phen-
yl-1-propyne (1a) with ethyl vinyl ketone (2a) and (E)-
styrylboronic acid (3a) in the presence of Ni(cod)2 (10 mol
%), PPh3 (10 mol %) and CsF in MeOH at 80 °C for 16 h
provided a highly substituted 1,3-diene 4a in 89% isolated
yield (Table 1, entry 1). 1,3-Dienes are very useful synthetic
Table 1. Results of the Reaction of Enones, Alkenyl Boronic
Acid with Various Alkynesa
A variety of alkynes 1b-j were successfully used for the
three-component reaction with 2a and 3a under the standard
reaction conditions (Table 1, eq 1). Symmetrical alkynes 1b-e
all gave exclusively only one stereoisomeric three-component
product 4b-e, respectively, in 78-89% yield (entries 2-5).
Surprisingly, acetylene gas (1 atm) (1f) also reacted smoothly
with 2a and 3a to give 4f in 95% yield (entry 6). In addition to
1a, other unsymmetrical internal alkyne and terminal alkynes
(1g-j) were also examined. However, the regioselectivity of
the products using these alkynes as substrates are lower. Ethyl
phenylpropiolate (1g) afforded two regioisomeric products 4g/
4g′ in a 67/33 ratio in a 63% combined yield (entry 7). Similar
to 1g, phenyl acetylene (1h) and 2-ethynyl thiophene (1i) gave
regioisomeric products 4h/4h′ and 4i/4i′ in 88/12 and 85/15
ratios with 73% and 71% combined yields (entries 8 and 9). In
the major products 4h and 4i, the unsubstituted carbon of
terminal alkyne moiety is connected to the ꢀ-carbon of vinyl
ketone 2a. There is essentially no regioselectivity for 1-hexyne
providing regioisomeric products 4j/4j′ in a 50/50 ratio in a
67% combined yield (entry 10).
The scope of present reaction was further extended to
various enones 2b-j (Table 2, eq 2). R-Methyl and ꢀ-methyl
or phenyl substituted enones 2b-d, underwent coupling with
1a and 2a to give 4k-m in good to excellent yields (entries
11-13). Phenyl vinyl ketone (2e) and cyclohexyl vinyl
ketone (2f) provided coupling products 4n and 4o in
moderate yields (entries 14 and 15). 1-Cyclopentenyletha-
none (2g) also participated in the reaction to give 4p in 58%
yield (entry 16). Cyclic enones 2h-j also underwent three-
component coupling efficiently with 1a and 2a. Thus,
2-cyclopentenone (2h), 2-cyclohexenone (2i), and 2-cyclo-
a Unless otherwise mentioned, all reactions were carried out using alkyne
1 (1.5 mmol), enone 2a (1.0 mmol) and alkenyl boronic acid (3) (1.5 mmol)
in the presence of Ni(cod)2 (10 mol %), PPh3 (10 mol %), CsF (2.0 mmol)
in MeOH at 80 °C for 16 h. b Isolated yields; the yield in parentheses was
1
determined by H NMR method using mesitylene as an internal standard.
c Acetylene gas balloon. d Two regioisomeric products, 4 and 4′, exist with
4 the major and 4′ the minor isomer.
intermediates in many organic transformations.9 The catalytic
reaction is highly regioselective with the styryl group of 3a
adding very selectively at the phenyl substituted alkyne
carbon, and the other C-C bond formation occurs at the
methyl substituted alkyne carbon of 1a and the ꢀ-carbon of
vinyl ketone 2a. The catalytic reaction is also highly
(7) (a) Jayanth, T. T.; Cheng, C.-H. Angew. Chem., Int. Ed. 2007, 46,
5921. (b) Mannathan, S.; Jeganmohan, M.; Cheng, C.-H. Angew. Chem.,
Int. Ed. 2009, 48, 2192.
(8) Selected references: (a) Jeganmohan, M.; Cheng, C.-H. Chem.
Commun. 2008, 27, 3101. (b) Jeganmohan, M.; Bhuvaneswari, S.; Cheng,
C.-H. Angew. Chem., Int. Ed. 2009, 48, 77.
(9) For 1,3-dienes application: (a) Oppolzer, W. In ComprehensiVe
Organic Chemistry; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 5, Chapter 4.1, pp 315-400. (b) Trost, B. M.; Pinkerton, A. B.
J. Am. Chem. Soc. 1999, 121, 4068. (c) Kinoshita, A.; Sakakibara, N.; Mori,
M. J. Am. Chem. Soc. 1997, 119, 12388. (d) Murakami, M.; Ubukata, M.;
Ito, Y. Tetrahedron Lett. 1998, 39, 7361. (e) Trost, B. M.; Pinkerton, A. B.;
Seidel, M. J. Am. Chem. Soc. 2001, 123, 12466, and references therein. (f)
Hilt, G.; Janikowski, J.; Hess, W. Angew. Chem., Int. Ed. 2006, 45, 5204,
and references therein.
(10) Lin, P. S.; Jeganmohan, M.; Cheng, C.-H. Chem. Asian J. 2007, 2,
1409.
Org. Lett., Vol. 12, No. 16, 2010
3611

alkene exclusively in Z-stereoselectvity and tetrasubstituted
alkene in E-stereoselectivity (entry 20). On the other hand,
(E)-prop-1-enylboronic acid (3c) produced coupling product
4u in 70% yield with the two carbon-carbon double bonds
exclusively in E-stereoselectivity (entry 21). Other (E)-
alkenyl boronic acids including (E)-pent-1-enyl, (E)-2-
cyclohexylviny, (E)-3-phenylprop-1-enyl, and (E)-4-meth-
oxystyryl boronic acids 3d-g, respectively, afforded coupling
products 4v-y in good yields with similar stereochemistry
as 4u (entries 22-25). It is interesting to note that in these
three-component coupling products 4, the two substituents
from the alkyne moiety were always cis to each other and
retention of stereochemistry of the alkenyl group of 3 in the
product was observed.
Table 2. Results of the Reaction of Alkynes, Alkenyl Bronic
Acid with Various Enonesa
The synthetic utility of our reaction was further exempli-
fied by the synthesis of different stereochemical dienes from
acetylene gas. Thus, acetylene gas 1f was treated with enone
2c and (Z)-prop-1-enylboronic acid (3b) under the standard
reaction condition to give (Z,Z)-diene 4fa in 73% yield.
Similarly, the reaction of 1f with (E)-3-phenylprop-1-
enylboronic acid (3f) and enone 2a gave (Z,E)-diene 4fb in
78% yield (Scheme 1). In these two diene syntheses, the
reactions are stereospecific.
a Unless otherwise mentioned, all reactions were carried out using alkyne
1a (1.5 mmol), enone 2 (1.0 mmol), and alkenyl boronic acid 3a (1.5 mmol)
in the presence of Ni(cod)2 (10 mol %), PPh3 (10 mol %), and CsF (2.0
mmol) in MeOH at 80 °C for 16 h. b Isolated yields.
Scheme 1
.
Nickel-Catalyzed Stereospecific Synthesis of Dienes
4fa,b
heptenone (2j) produced 4q-s in excellent 95%, 91%, and
90% yield, respectively (entries 17-19).
To further explore the scope of the coupling reaction,
various alkenylboronic acids 3b-g were examined for the
reaction with 1a and 2a (Table 3, eq 3). (Z)-Prop-1-
Table 3. Results of the Reaction of Alkynes, Enones with
Various Alkenyl Bronic Acidsa
The application of diene 4f in the Diels-Alder reaction
was demonstrated in Scheme 2. Thus, treatment of 4f with
Scheme 2. Applications in Diels-Alder Reactions
maleic anhydride gave highly stereoselective Diels-Alder
adduct 7a in 67% yield. Highly substituted benzene 7b was
readily prepared from the Diels-Alder reaction of 4f with
dimethyl acetylenedicarboxylate followed by DDQ aroma-
tization (Scheme 2).
a Similar reaction conditions as in Table 1footnote a except various
alkenyl boronic acids were used. b Isolated yields.
enylboronic acid (3b) reacted smoothly to give a highly
substituted 1,4-diene 4t in 73% yield with the disubstituted
An intramolecular version of the coupling of enynes with
alkenyl boronic acid also worked very well under the
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Org. Lett., Vol. 12, No. 16, 2010

optimized reaction conditions (Scheme 3). Thus, the reaction
of enyne 6a with 3a gave a five-membered cyclic product
in the catalytic reaction and also suggests that the resulted
methoxy anion can be used for the base-promoted trans-
metalation.
A possible reaction mechanism involving a five-membered
nickelacycle as a key intermediate is proposed (Scheme 5).
Scheme 3
.
Results of Nickel-Catalyzed Intramolecular Coupling
Reactions
Scheme 5
.
Possible Catalytic Pathways of the Three-Component
Coupling Reaction
8a in 85% yield in a highly regio- and steroselective manner.
In a similar fashion, enynes 6b-e also efficiently participated
in the reaction to give cyclic coupling products 8b-e in 85%,
94%, 87%, and 65% yields.
To understand the role of MeOH and to help elucidate
the mechanism of the present catalytic reaction, isotope-
labeling experiments using CD3OD to replace normal
methanol for the coupling of ethyl vinyl ketone 2a with
alkyne 1a and (E)-styrylboronic acid 3a were carried out.
The reactions gave product 4a with various degree of
deuteration at the R-carbons to the ketone group as shown
in Scheme 4. The reaction without CsF afforded 4a in 45%
Highly regioselective cyclometalation of alkyne and enone
with Ni(0) gives a five-membered nickelacycle 9.7 Selective
protonation of the R-carbon of ketone moiety in 9 by MeOH
provides intermediate 10.1,7 Highly stereoselective trans-
metalation of alkenyl boronic acid 3 with intermediate 10
in the presence of MeO- or CsF gives alkenyl-nickel
intermediate 11.7 Reductive elimination of intermediate 11
affords product 4 and regenerates the Ni(0) catalyst.
In conclusion, we have developed a highly regio- and
stereoselective nickel-catalyzed three-component reductive
coupling of alkynes with enones and alkenyl boronic acids
to provide substituted 1,3-dienes in good to excellent yields.
The scope of the catalytic reaction was successfully dem-
onstrated with various alkynes, enones, and alkenyl boronic
acids. An intramolecular version of coupling of enynes with
alkenyl boronic acid was also described. Further extension
of coupling of two different π-components with an organo-
metallic reagent, and the detailed mechanistic investigation
are in progress.
Scheme 4. Deuterium-Labeling Studies
yield with 40% deuterium incorporation at the inner R-carbon
to the ketone group. The experiment with CsF presence
afforded 4a with >98% deuteration at both R-carbons to the
ketone group. The observed extensive deuteration of 4a in
the presence of weak base CsF is likely due to a base-assisted
H/D exchange occurring in the enolate acidic positions. The
observed 40% deuterium incorporation of the product in the
absence of CsF indicates that methanol acts as proton source
Acknowledgment. We thank the National Science Council
of Republic of China (NSC 96-2113-M-007-020-MY3) for
support of this research.
Supporting Information Available: General experimental
procedure and characterization details. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL101319F
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