Nickel-catalyzed highly regioselective multicomponent coupling of ynamides, aldehydes, and silane: A new access to functionalized enamides

Article abstract of DOI:10.1021/ol801534e

(Chemical Equation Presented) A new method for preparation of functionalized enamides by a nickel-catalyzed multicomponent coupling of ynamides, aldehydes, and silane has been developed. The coupling reaction proceeded in the presence of a nickel-IMes catalyst to give the corresponding γ-silyloxyenamide derivative, which has an allylic alcohol moiety in the molecule, in a highly stereoselective manner.

Full text of DOI:10.1021/ol801534e

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3829-3832
Nickel-Catalyzed Highly Regioselective
Multicomponent Coupling of Ynamides,
Aldehydes, and Silane: A New Access
to Functionalized Enamides
Nozomi Saito, Tomoyuki Katayama, and Yoshihiro Sato*
Faculty of Pharmaceutical Sciences, Hokkaido UniVersity, Sapporo 060-0812, Japan
biyo@pharm.hokudai.ac.jp
Received July 7, 2008
ABSTRACT
A new method for preparation of functionalized enamides by a nickel-catalyzed multicomponent coupling of ynamides, aldehydes, and silane
has been developed. The coupling reaction proceeded in the presence of a nickel-IMes catalyst to give the corresponding γ-silyloxyenamide
derivative, which has an allylic alcohol moiety in the molecule, in a highly stereoselective manner.
Enamide is recognized as one of the important fragments
found in some biologically active natural products1 as well
as a valuable substrate for the synthesis of optically active
amines via asymmetric hydrogenation.2 Therefore, many
protocols for enamide synthesis have been developed to date.
Recently, enamides have been synthesized with transition
metal catalysis including isomerization of N-allylamide,3
hydroamidation of alkynes,4 vinylation of amides,5,6 oxida-
tive amidation of alkenes,7 and co-oligomerization of N-
vinylamides with alkenes or alkynes.8 Furthermore, enamides
can be synthesized by transition metal-catalyzed ynamide
transformation:9 hydrogenation,10 hydro-, carbo-, and bis-
metalation,11 as well as cycloaddition.12 On the other hand,
catalytic multicomponent coupling13 with ynamides as a
(5) For a review, see: Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun.
2005, 973, and referencescited therein
.
(6) Bolshan, Y.; Batey, R. A. Angew. Chem., Int. Ed. 2008, 47, 2019.
(7) (a) Hosokawa, T.; Takano, M.; Kuroki, Y.; Murahashi, S.-i.
Tetrahedron Lett. 1992, 33, 6643. (b) Timokhin, V. I.; Anastasi, N. R.;
Stahl, S. S. J. Am. Chem. Soc. 2003, 125, 12996. (c) Brice, J. L.; Harang,
J. E.; Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc. 2005,
127, 2868.
(1) For recent reviews on natural products including enamide structure,
see: (a) Yet, L. Chem. ReV. 2003, 103, 4283. (b) Joullie´, M. M.; Richard,
D. J. Chem. Commun. 2004, 2011. (c) Tan, N.-H.; Zhu, J. Chem. ReV. 2006,
106, 840.
(2) For reviews on asymmetric hydrogenation, see: (a) Ohkuma, T.;
Kitamura, M.; Noyori, R. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima,
I., Ed.; Wiley-VCH, Inc.: New York, 2000; pp 1-110. (b) Kitamura, M.;
Noyori, R. In Ruthenium in Organic Synthesis; Murahashi, S.-i., Ed.; Wiley-
VCH, Inc.: New York, 2002; pp 3-52. (c) Chi, Y.; Tang, W.; Zhang, X.
In Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-
VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2004; pp 1-31.
(3) (a) Stille, J. K.; Becker, Y. J. Org. Chem. 1980, 45, 2139. (b)
Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A. Angew. Chem., Int.
Ed. 2002, 41, 4732. (c) Krompiec, S.; Pigulla, M.; Krompiec, M.; Baj, S.;
Mrowiec-Bialon, J.; Kasperczyk, J. Tetrahedron Lett. 2004, 5257, and
references cited therein.
(8) Tsujita, K.; Ura, Y.; Matsuki, S.; Wada, K.; Mitsudo, T.; Kondo, T.
Angew. Chem., Int. Ed. 2007, 46, 5160.
(9) For recent reviews on chemistry of ynamine and ynamide, see: (a)
Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.; Wei, L.-L.
Tetrahedron 2001, 57, 7575. (b) Hsung, R. P., Ed. In Tetrahedron Symposia-
in-Print No. 118. Tetrahedron 2006, 62, 3783.
(10) Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.; Kurtz, K. C. M.;
Oppenheimer, J.; Petersen, M. E.; Sagamanova, I. K.; Shen, L.; Tracey,
M. R. J. Org. Chem. 2006, 71, 4170.
(11) (a) Hoffmann, R. W.; Bru¨ckner, D. New J. Chem. 2001, 25, 369.
(b) Timbart, L.; Cintrat, J.-C. Chem. Eur. J. 2002, 8, 1637. (c) Chechik-
Lankin, H.; Livshin, S.; Marek, I. Synlett 2005, 2098. (d) Buissonneaud,
D.; Cintrat, J.-C. Tetrahedron Lett. 2006, 47, 3139.
(4) (a) Kondo, T.; Tanaka, A.; Kotachi, S.; Watanabe, Y. J. Chem. Soc.,
Chem. Commun. 1995, 413. (b) Goossen, L. J.; Rauhaus, J. E.; Deng, G.
Angew. Chem., Int. Ed. 1995, 44, 4042. (c) Yudha S., S.; Kuninobu, Y.;
Takai, K. Org. Lett. 2007, 9, 5609.
(12) (a) Riddell, N.; Villeneuve, K.; Tam, W. Org. Lett. 2005, 7, 3681.
(b) Villeneuve, K.; Riddell, N.; Tam, W. Tetrahedron 2006, 62, 3823.
10.1021/ol801534e CCC: $40.75
Published on Web 08/06/2008
2008 American Chemical Society

platform could also be an attractive methodology for the
synthesis of functionalized enamides.
Scheme 1
.
Plan for Multicomponent Coupling of Ynamides,
Aldehydes, and Silane by Ni(0) Catalyst
We have demonstrated nickel-catalyzed multicomponent
coupling of 1,3-dienes, aldehydes, and silanes, in which the
stereoselectivity was controlled by the property of the
ligands.14-16 With this as a background, we planned nickel-
catalyzed multicomponent coupling of ynamides, aldehydes,
and silanes as a new method for stereoselective synthesis of
functionalized enamides (Scheme 1). Thus, oxidative cy-
cloaddition of ynamides 1 and aldehydes 2 to a zerovalent
nickel complex could proceed to give oxanickelacycle I or
II. The reaction of the nickelacycle with silane would afford
the corresponding three-component coupling product ꢀ-alky-
lated enamide III or R-alkylated enamide IV.17,18 In
particular, γ-alkoxy enamide III is known as a useful
substrate for the synthesis of some important organic
molecules.19
IMes·HCl, and KOtBu, was carried out in THF at room
temperature for 1 h. As a result, an enamide derivative 4aa
was obtained in 42% yield as a single isomer,21 and no other
regio- and stereoisomer was observed. However, the alk-
enylsilane 5, which might be formed by hydrosilylation of
1a,22 and significant amounts of the complex mixture of
polymeric products of 1a were also produced at the same
time (Scheme 2).
First of all, the reaction of oxazolidinone-derived ynamide
1a,20 benzaldehyde (2a), and Et3SiH (3) in the presence of
Ni(0)-NHC catalyst, which was generated from Ni(cod)2,
(13) (a) Zhu, J.; Bienayme´, H., Eds. In Multicomponent Reactions;
Wiley-VCH Verlag Gmbh and Co. KGaA: Weinheim, Germany, 2005. (b)
Ramo´n, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602.
(14) (a) Takimoto, M.; Hiraga, Y.; Sato, Y.; Mori, M. Tetrahedron Lett.
1998, 39, 4543. (b) Sato, Y.; Sawaki, R.; Mori, M. Organometallics 2001,
20, 5510. (c) Sawaki, R.; Sato, Y.; Mori, M. Org. Lett. 2004, 6, 1131. (d)
Sato, Y.; Hinata, Y.; Seki, R.; Oonishi, Y.; Saito, N. Org. Lett. 2007, 9,
5597. For Ni-catalyzed reductive coupling of 1,3-diene and aldehyde with
iBu2Al(acac), see: (e) Sato, Y.; Sawaki, R.; Saito, N.; Mori, M. J. Org.
Chem. 2002, 67, 656. For three-component coupling with Me3SiSnBu3
instead of silane, see: (f) Sato, Y.; Saito, N.; Mori, M. Chem. Lett. 2002,
Scheme 2
.
Coupling of 1a, 2a, and 3 with Use of Ni(0)-IMes
Catalyst
18. (g) Saito, N.; Mori, M.; Sato, Y. J. Organomet. Chem. 2007, 692, 460
.
(15) For reviews on Ni(0)-catalyzed multicomponent coupling, see: (a)
Ikeda, S.-i. Acc. Chem. Res. 2000, 33, 511. (b) Montgomery, J. Acc. Chem.
Res. 2000, 33, 467. (c) Montgomery, J. Angew. Chem., Int. Ed. 2004, 43,
3890, and references cited therein
.
(16) For recent examples of Ni(0)-catalyzed multicomponent coupling,
see: (a) Terao, J.; Nii, S.; Chowdhury, F. A.; Nakamura, A.; Kambe, N.
AdV. Synth. Catal. 2004, 346, 905. (b) Kimura, M.; Miyachi, A.; Kojima,
K.; Tanaka, S.; Tamaru, Y. J. Am. Chem. Soc. 2004, 126, 14360. (c)
Shirakawa, E.; Yamamoto, Y.; Nakao, Y.; Oda, S.; Tsuchimoto, T.; Hiyama,
T. Angew. Chem., Int. Ed. 2004, 43, 3448. (d) Kimura, M.; Ezoe, A.; Mori,
M.; Tamaru, Y. J. Am. Chem. Soc. 2005, 127, 201. (e) Kimura, M.; Kojima,
K.; Tatsuyama, Y.; Tamaru, Y. J. Am. Chem. Soc. 2006, 128, 6332. (f)
Cozzi, P. G.; Rivalta, E. Angew. Chem., Int. Ed. 2005, 44, 3600. (g) Ng,
S.-S.; Ho, C.-Y.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 11513. (h)
Ho, C.-Y.; Jamison, T. F. Angew. Chem., Int. Ed. 2007, 46, 782. (i)
Chrovian, C. C.; Montgomery, J. Org. Lett. 2007, 9, 537. (j) Jayanth, T. T.;
Cheng, C.-H. Angew. Chem., Int. Ed. 2007, 46, 5921. (k) Herath, A.; Li,
It was thought that suppression of the formation of the
above byproduct was necessary to improve the yield of 4aa.
Therefore, we next investigated the impact of the reaction
procedure on byproduct formation (Table 1). First, a THF
solution of ynamide 1a and 2a was slowly added to a mixture
of Ni-IMes complex and Et3SiH (3) in THF over a period
of 14 h by a syringe pump (Method A). As a result, the yield
of the coupling product 4aa was improved to 69%, and no
polymeric product of 1a was observed. However, hydro-
silylation compound 5 was also obtained in 26% yield. Next,
slow addition of a THF solution of 1a to the mixture of Ni-
IMes catalyst, 2a, and 3 in THF was carried out over a period
of 14 h, giving the coupling product 4aa in 73% yield along
with starting ynamide 1a in 19% recovery (Method B).
W.; Montgomery, J. J. Am. Chem. Soc. 2008, 130, 469
.
(17) For Ni-catalyzed three-component coupling of alkynes, which have
alkyl, aryl, or silyl groups on the sp-hybridized carbon atom, aldehydes,
and silanes by Montgomery, see: (a) Mahandru, G. M.; Liu, G.; Mont-
gomery, J. J. Am. Chem. Soc. 2004, 126, 3698. (b) Sa-ei, K.; Montgomery,
J. Org. Lett. 2006, 8, 4441. (c) Chaulagain, M. R.; Sormunen, G. J.;
Montgomery, J. J. Am. Chem. Soc. 2007, 129, 9568. For other examples of
Ni-catalyzed reductive alkyne-aldehyde coupling, see: (d) Oblinger, E.;
Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065. (e) Huang, W.-S.;
Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221. (f) Miller, K. M.; Huang,
W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3422. (g) Luanphaisarn-
nont, T.; Ndubaku, C. O.; Jamison, T. F. Org. Lett. 2005, 7, 2937
(18) For a Ti-mediated reductive coupling of ynamides and aldehydes,
see: Tanaka, R; Hirano, S.; Urabe, H.; Sato, F. Org. Lett. 2003, 5, 67
.
.
(19) For recent examples of the preparation of γ-alkoxy enamide
derivatives and their synthetic application, see: (a) McAlonan, H.; Murphy,
J. P.; Nieuwenhuyzen, M.; Reynolds, K.; Sarma, P. K. S.; Stevenson, P. J.;
Thompson, N. J. Chem. Soc., Perkin Trans. 1 2002, 69. (b) Ylioja, P. M.;
Mosley, A. D.; Charlot, C. E.; Carbery, D. R. Tetrahedron Lett. 2008, 49,
1111.
(21) Olefinic geometry was determined by an NOE experiment. See the
Supporting Information.
(20) In this work, the ynamides were synthesized by Hsung’s Cu-
catalyzed coupling reaction of haloalkynes and amides. Frederick, M. O.;
Mulder, J. A.; Tracey, M. R.; Hsung, R. P.; Huang, J.; Kurtz, K. C. M.;
Shen, L.; Douglas, C. J. J. Am. Chem. Soc. 2003, 125, 2368.
(22) For a hydrosilylation of alkyne with Ni-NHC catalyst, see:
Chaulagain, M. R.; Mahandru, G. M.; Montgomery, J. Tetrahedron 2006,
62, 7560.
3830
Org. Lett., Vol. 10, No. 17, 2008

(runs 3 and 4). When 4-chlorobenzaldehyde (2f) was used
for the coupling reaction, the corresponding enamide 4af was
obtained in 61% yield (run 5). 4-Fluorobenzaldehyde (2g)
reacted with 1a and 3, giving the enamide derivative 4ag in
64% yield (run 6), and the reaction with 3-fluorobenzalde-
hyde (2h) provided the coupling product 4ah in 96% yield
(run 7). When 2-naphthaldehyde (2i) was reacted with 1a
under the same reaction conditions, the enamide product 4ai
was obtained in 91% yield (run 8). An aliphatic aldehyde
such as isobutyraldehyde (2j) was also applicable to the
three-component coupling, and the corresponding enamide
derivative 4aj was obtained in 48% yield as a single isomer
(run 9).
Table 1. Optimization of the Reaction Procedure
yield (%)
methoda
4aa
5
1a
A
B
C
69
73
91
26
19
a Method A: Slow addition of 1a and 2a in THF over a period of 14 h.
Method B: Slow addition of 1a in THF over a period of 14 h. Method C:
Slow addition of 1a in THF over a period of 7 h.
Next, we turned our attention to investigation of the three-
component coupling using various ynamides (Table 3). When
Finally, the only desired enamide derivative 4aa was obtained
in 91% by slow addition of the solution of 1a in THF over
a period of 7 h (Method C).
Table 3. Scope of Ynamide Structure in the Three-Component
Couplinga
Using the optimal reaction procedure (Method C), study
of the scope and limitations of aldehyde structure in the three-
component coupling was conducted (Table 2). The reaction
Table 2. Scope of Aldehyde Structure in the Three-Component
coupling.a
a Reaction procedure (Method C: for details, see the Supporting
Information): A solution of aldehyde 2 (3 equiv) in THF was added to a
solution of ynamide 1a (1 equiv), Et3SiH (5 equiv), Ni(cod)2 (10 mol %),
IMes·HCl (10 mol %), and KOtBu (12 mol %) in THF over a period of 7 h
by a syringe pump at room temperature. After the addition was finished,
the reaction mixture was stirred for an additional 0.5 h. b After the slow
addition was finished, the reaction mixture was stirred overnight.
methyl-substituted ynamide 1b and 2a were treated with 3,
coupling product 4ba was obtained in 91% yield. The
reaction of ynamides having a silylether tether (1c and 1d)
or acetal tether (1e and 1f) with 2a and 3 gave the
corresponding γ-silyloxyenamide derivatives 4ca-4fa in
moderate to good yield (runs 2-5). Ynamides having an ester
group 4g reacted with 2a and 3 to give the product 4ga in
53% yield (run 6).
The possible reaction course of the regioselective three-
component coupling of ynamides, aldehydes, and silane is
shown in Scheme 3. Under the conditions using Method C,
the aldehyde 2 coordinates to zerovalent Ni complex to give
η2-aldehydenickel intermediate 6.23 Next, the reaction of
ynamide 1 with the complex 6 would proceed to give
oxaniceklacycle 7 regioselectively. Then cleavage of the
a Reaction procedure (Method C: for details, see the Supporting
Information): A solution of aldehyde 2 (3 equiv) in THF was added to a
solution of ynamide 1a (1 equiv), Et3SiH (5 equiv), Ni(cod)2 (10 mol %),
IMes·HCl (10 mol %), and KOtBu (12 mol %) in THF over a period of 7 h
by a syringe pump at room temperature. After the addition was finished,
the reaction mixture was stirred for an additional 0.5 h. b After the slow
addition was finished, the reaction mixture was stirred overnight.
with 1a and aromatic aldehydes 2b and 2c, having an
electron-donating group, gave the corresponding enamide
derivatives 4ab and 4ac in low yield (runs 1 and 2). On the
other hand, the reaction of 1a and aldehyde 2d and 2e, which
had an electron-withdrawing group at the para position on
the aromatic ring, proceeded smoothly to give the coupling
products 4ad and 4ae in 99% and 94% yield, respectively
(23) For examples of the formation of η2-arylaldehydenickel complexes
from zerovalent nickel complex and aldehyde, see: (a) Walther, D. J.
Organomet. Chem. 1980, 190, 393. (b) Ogoshi, S.; Kamada, H.; Kurosawa,
H. Tetrahedron 2006, 62, 7583.
Org. Lett., Vol. 10, No. 17, 2008
3831

HOMO of 1b exists on the carbon-carbon triple bond and
that ꢀ-carbon has a negative charge. This means that the
ꢀ-carbon would be more nucelophilic than the R-carbon.
On the basis of the above insight from the calculation
results, one reason for the highly regioselective formation
of oxanickelacycle 7 in the possible reaction mechanism
might be the electronic properties of ynamide (Scheme 4).
Scheme 3. Possible Reaction Course
Scheme 4
.
Possible Reason for Regioselective Formation of
Nickelacycle 7
nickel-oxygen bond by σ-bond metathesis (depicted as 8)
of the nickelacycle 7 with Et3SiH (3) would afford hydride-
nickel intermediate 9. Finally, the reductive elimination from
9 would occur to afford the γ-silyloxyenamide derivative 4
in a regio- and stereoselective manner.24,25
To gain an insight into the high regioselectivity of the
ynamide-aldehyde coupling, the structural and electronic
properties of ynamide were investigated by DFT calcula-
tion at the B3LYP/6-31G* level utilizing Spartan’06
(Wavefunction, Inc., Irvine, CA). Figure 1 illustrates the
highest occupied molecular orbital (HOMO) of geometrical
That is, at the oxanickelacycle formation stage, the reaction
would proceed as the negatively polarized carbon at the
ꢀ-position of ynamide 1 might interact with the positive
carbonyl carbon of aldehyde 2 (illustrated as 10) and
carbon-carbon bond formation would occur between those
two carbons.26 Consequently, only oxanickelacycle inter-
mediate 7 would be produced in a regioselective manner.
In summary, we have developed a new method for the
synthesis of functionalized enamides by a nickel-catalyzed
multicomponent coupling of ynamides, aldehydes, and silane.
The coupling reaction proceeded though carbon-carbon
bond formation between ꢀ-carbon of ynamides and carbonyl
carbon of aldehydes to afford γ-silyloxyenamide derivatives
in a highly regio- and stereoselective manner. Further studies
along this line are now in progress.
Acknowledgment. A part of this work was supported by
a Grant-in-Aid for Science Research on Priority Areas (No.
19027005, Synergy of Elements) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan
and by a Grant-in-Aid for Scientific Research (B) (No.
19390001) from the Japan Society for the Promotion of
Science (JSPS). N.S. acknowledges the Akiyama Foundation
for financial support.
Figure 1. HOMO of geometrically optimized ynamide 1b. The
values show natural charge at CR and Cꢀ positions.
optimized ynamide 1b along with the natural charge at CR
Supporting Information Available: Experimental details
and spectral data of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
and Cꢀ positions. The calculation results suggested that the
(24) Recently, oxanickelacyclopentene from zerovalent nickel, aldehyde,
and alkyne was isolated and its structure was elucidated by X-ray analysis,
see: Ogoshi, S.; Arai, T.; Ohashi, M.; Kurosawa, H. Chem. Commun. 2008,
OL801534E
1347
.
(25) Montgomery suggested the reaction mechanism via oxanickel-
acyclopentene formation followed by σ-bond metathesis with silane in his
three-component coupling of alkynes, aldehydes, and silanes using Ni-NHC
catalyst. See refs 17a and 17c.
(26) Similar regioselectivity has been observed in Lewis acid-mediated
coupling of ynamides and aldehydes or ketones demonstrated by Hsung,
see: You, L.; Al-Rashid, Z. F.; Figueroa, R.; Ghosh, S. K.; Li, G.; Lu, T.;
Hsung, R. P. Synlett 2007, 1656.
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Org. Lett., Vol. 10, No. 17, 2008