Tandem blaise-alkenylation with unactivated alkynes: One-pot synthesis of α-vinylated β-enaminoesters from nitriles

Article abstract of DOI:10.1021/ol901241s

The in situ generated Blaise reaction intermediate, a zinc bromide complex of β-enaminoester, reacts with various unactivated terminal alkynes and an internal alkyne under mild conditions to afford α-vinylated β-enaminoesters in good to excellent yields.

Full text of DOI:10.1021/ol901241s

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3414-3417
Tandem Blaise-Alkenylation with
Unactivated Alkynes: One-Pot Synthesis
of r-Vinylated ꢀ-Enaminoesters from
Nitriles
Yu Sung Chun,† Young Ok Ko,† Hyunik Shin,*,‡ and Sang-gi Lee*,†
Department of Chemistry and Nano Science (BK21), Ewha Womans UniVersity,
Seoul 120-750, Korea, and Chemical DeVelopment DiVision, LG Life Sciences,
Ltd./R&D, Daejeon 305-380, Korea
sanggi@ewha.ac.kr;hisin@lgls.com
Received June 3, 2009
ABSTRACT
The in situ generated Blaise reaction intermediate, a zinc bromide complex of ꢀ-enaminoester, reacts with various unactivated terminal alkynes
and an internal alkyne under mild conditions to afford r-vinylated ꢀ-enaminoesters in good to excellent yields.
Tandem and cascade reactions have attracted significant
attention because of their undeniable benefits such as atom
economy and one-pot operation with maximization of
molecular complexicity.1 Indeed, the device and implementa-
tion of tandem reactions is a challenging facet and has
become increasingly important in organic synthesis. Recently,
we were intrigued by the possible tandem use of the Blaise
reaction intermediate, a zinc bromide complex of ꢀ-enami-
noester,2 as a nitrogen isostere of the zinc enolate of
ꢀ-ketoester and developed a highly efficient tandem synthesis
of R-acyl-ꢀ-enaminoesters.3 Herein, we report unprecedented
tandem nucleophilic addition of the Blaise reaction inter-
mediate to unactivated terminal alkynes and an internal
alkyne, which allow direct use of nitriles for effective one-
pot synthesis of R-vinylated ꢀ-enaminoesters under mild
conditions. Considering the importance of amine-function-
alized 1,3-dienes as versatile building blocks in organic
synthesis as well as in polymer chemistry, our protocol
provides a highly efficient alternative method for this class
of compounds.4
Nucleophilic 1,2-addition of metal enolates to unactivated
alkynes represents the most popular method for the synthesis
of R-vinylated 1,3-dicarbonyl compounds, and has received
great attention in recent years. Although its early intramo-
† Ewha Womans University.
‡ LG Life Sciences, Ltd/R&D.
(1) (a) Ho, T.-L. Tandem Organic Reactions; Wiley: New York, 1992.
(b) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2006. (c) Nicolaou, K. C.; Edmonds,
D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (d) Fu¨rstner,
A. Angew. Chem., Int. Ed. 2009, 48, 1364. (e) Parsons, P. J.; Penkett, C. S.;
Shell, A. J. Chem. ReV. 1996, 96, 195.
(3) (a) Chun, Y. S.; Lee, K. K.; Ko, Y. O.; Shin, H.; Lee, S.-g. Chem.
Commun. 2008, 5098. (b) Ko, Y. O.; Chun, Y. S.; Park, C.-L.; Kim, Y.;
Shin, H.; Ahn, S.; Hong, J.; Lee, S.-g. Org. Biomol. Chem. 2009, 7, 1132.
(4) Examples for transition metal-mediated or catalyzed synthesis of
aminodienes, see: (a) Tsujita, H.; Ura, Y.; Matsuki, S.; Wada, K.; Mitsudo,
T.-a.; Kondo, T. Angew. Chem., Int. Ed. 2007, 46, 5160. (b) Mori, M.;
Wakamatsu, H.; Saito, N.; Narita, R.; Sato, Y.; Fujita, R. Tetrahedron 2006,
62, 3872. (c) Tanaka, R.; Hirano, S.; Urabe, H.; Sato, F. Org. Lett. 2003,
5, 67. (d) Vallin, K. S. A.; Zhang, Q.; Larhed, M.; Curran, D. P.; Hallberg,
A. J. Org. Chem. 2003, 68, 6639.
(2) (a) Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132, 478. (b)
Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132, 987. (c) Rathke,
M. W.; Weipert, P. In Zinc Enolates: The Reformatsky and Blaise Reaction
in ComprehensiVe Organic Reactions; Trost, B. M., Ed.; Pergram: Oxford,
1991; Vol. 2, pp 277-299. (d) Rao, H. S. P.; Rafi, S.; Padmavathy, K.
Tetrahedron 2008, 64, 8037.
10.1021/ol901241s CCC: $40.75
Published on Web 07/02/2009
 2009 American Chemical Society

lecular version (Conia-ene reaction) was of limited use due
to its high reaction temperature,5 employment of various
metal catalysts such as Au(I),6 Ni(II)-Yb(OTf)3,7 Pd(II)-
Yb(OTf)3,8 and In(III)9 made the reaction possible under
(1.5 equiv) to a solution of benzonitrile (1a, R1 ) Ph) (1.0
equiv) and zinc powder (2.0 equiv preactivated by using 5.0
mol % of CF3SO3H)13 in THF at reflux temperature or in
dioxane at 80 °C for 1 h (>97% conversion of nitrile by
GC). For the preparation of the butylzinc complex 2b, an
equivalent amount of n-BuLi was added to the formed Blaise
reaction intermediate 2a at 0 °C. The alkenylations were
carried out by addition of the phenyl acetylene 3a to the
zinc complex solution all at once at either reflux in THF or
80 °C in dioxane (entries 7-9, Table 1).
As shown in Table 1, the intact zinc bromide complex 2a
showed superb reactivity. Thus, the tandem reaction of 2a
with phenylacetylene has been completed within 1.5 h to
provide, after workup with aqueous sat. NH4Cl solution, the
R-vinylated ꢀ-enaminoester 4a in 91% yield (entry 1, Table
1).14 The reaction also proceeded smoothly at room tem-
perature with almost the same yield after 24 h (entry 2, Table
1). In contrast, the alkenylation of the butylzinc complex
2b required an excess amount of 3a and prolonged reaction
time to achieve reasonable yield (entries 3-6, Table 1).15
The yields were increased slightly by the addition of 20 mol
% of Lewis acids such as Sc(OTf)3 (79%, entry 7, Table 1),
Yb(OTf)3 (70%, entry 8, Table 1), and In(OTf)3 (89%, entry
9, Table 1), where a mixture of 1,4-dioxane and CH2Cl2 (1/
1, v/v) was used since the reaction was sluggish in THF or
in dioxane only. However, excess of alkyne was still
necessary for good yield.16 These results suggested that the
zinc bromide complex 2a may have balanced propensity to
play dual functions of a nucleophile as well as a Lewis acid
activating alkyne. In contrast, the reaction was significantly
retarded when the more electron-donating butyl group is
milder conditions. Recent development of In(III) or Re(I)10e
-
catalyzed intermolecular variants, mostly by Nakamura and
co-workers, significantly expanded the synthetic scope of this
reaction.10 It has been also indicated that zinc enolates of
1,3-dicarbonyls and N-monosubstituted ꢀ-enaminoesters or
ꢀ-enaminoamides could be effective nucleophiles for 1,2-
addition to unactivated terminal alkynes with careful choice
of Zn(II) species.10b-d,11 For example, ethylzinc enolates of
N-monosubstituted ꢀ-aminocrotonamides, generated in situ
from ꢀ-aminocrotonamides and diethylzinc, reacted with
unactivated terminal alkynes to afford the corresponding
R-alkylidene ꢀ-carbonyl amides, whereas the combined use
of a stoichiometric amount of Zn(OTf)2 and Et3N showed
much lower reactivity.10b Although an alternative synthetic
pathway to obtain trisubstituted alkenes via In(NTf)3-
catalyzed vinylation of 1,3-dicarbonyl compounds with
1-iodoalkyne followed by Pd-catalyzed cross-coupling
with phenylboronic acid,12 these reactions were not effective
with unactivated internal alkynes. Moreover, there is no
report on the reaction profile of N-unsubstituted ꢀ-ami-
noacrylate toward alkenylation with unactivated alkynes.
In this context, we initially anticipated that the ligating
group to the zinc of the Blaise reaction intermediate would
exert significant influence on the reactivity, and thus,
investigated the reactivity profiles of the intact zinc bromide
intermediate 2a and the butylzinc complex 2b toward
unactivated alkyne in their R-vinylation reaction (Table 1).
To began our investigations, a Blaise reaction intermediate
2a was prepared in situ by addition of ethyl bromoacetate
(5) Conia, J. M.; Le Perchec, P. Synthesis 1975, 1.
(6) (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem.
Soc. 2004, 126, 4526. (b) Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D.
Angew. Chem., Int. Ed. 2004, 43, 5350. (c) Ochida, A.; Ito, H.; Sawamura,
M. J. Am. Chem. Soc. 2006, 128, 16486. (d) Ito, H.; Makida, Y.; Ochida,
A.; Ohmiya, H.; Sawamura, M. Org. Lett. 2008, 10, 5051.
Table 1. Optimization Study for Tandem Reaction of the Blaise
(7) Gao, Q.; Zheng, B.-F.; Li, J.-H.; Yang, D. Org. Lett. 2005, 7, 2185.
(8) Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168.
(9) (a) Tsuji, H.; Yamagata, K.-i.; Itoh, Y.; Endo, K.; Nakamura, M.;
Nakamura, E. Angew. Chem., Int. Ed. 2007, 46, 8060. (b) Itoh, Y.; Tsuji,
H.; Yamagata, K.-i.; Endo, K.; Tanaka, I.; Nakamura, M.; Nakamura, E.
J. Am. Chem. Soc. 2008, 130, 17161.
Intermediate with Phenylacetylenea
(10) (a) Nakamura, M.; Endo, K.; Nakamura, E. J. Am. Chem. Soc. 2003,
125, 13002. (b) Nakamura, M.; Fujimoto, T.; Endo, K.; Nakamura, E. Org.
Lett. 2004, 6, 4837. (c) Endo, K.; Hatakeyama, T.; Nakamura, M.;
Nakamura, E. J. Am. Chem. Soc. 2007, 129, 5264. (d) Fujimoto, T.; Endo,
K.; Tsuji, H.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2008, 130,
4492. (e) Kuninobu, Y.; Kawata, A.; Takai, K. Org. Lett. 2005, 7, 4823.
(f) Tsuji, H.; Fujimoto, T.; Endo, K.; Nakamura, M.; Nakamura, E. Org.
Lett. 2008, 10, 1219.
time
yield
entry
2
3 (equiv)
solvent
THF
THF
THF
THF
THF
THF
(h) additiveb (%)c
(11) Nakamura, M.; Liang, C.; Nakamura, E. Org. Lett. 2004, 6, 2015.
(12) Tsuji, H.; Fujimoto, T.; Endo, K.; Nakamura, M.; Nakamura, E.
Org. Lett. 2008, 10, 1219.
1
2a
2a
2b
2b
2b
2b
2b
2b
2b
1.1
1.1
1.1
2.0
4.0
5.0
5.0
5.0
5.0
1.5
24
12
12
12
12
-
-
-
-
-
-
91
90
20
24
57
70
79
70
89
2d
3
(13) (a) Shin, H.; Choi, B. S.; Lee, K. K.; Choi, H.-W.; Chang, J. H.;
Lee, K. W.; Nam, D. H.; Kim, N.-S. Synthesis 2004, 2629. (b) Choi, B. S.;
Chang, J. H.; Choi, H.-w.; Kim, Y. K.; Lee, K. K.; Lee, K. W.; Lee, J. H.;
Heo, T.; Nam, D. H.; Shin, H. Org. Process Res. DeV. 2005, 9, 311.
(14) When the reaction was workup with 3N aqueous HCl solution, the
R-alkylidene ꢀ-ketoester 5 was isolated in 85% yield (see Supporting
Information).
4
5
6
7e
8e
9e
Dioxane/CH2Cl2 12
Dioxane/CH2Cl2 12
Dioxane/CH2Cl2 12
Sc(OTf)3
Yb(OTf)3
In(OTf)3
a Reaction was carried out on a 7.6 mmol scale of 1a at reflux in THF
(4 mL) under the conditions described in the text unless otherwise noted.
b Additive (20 mol %) was used. c After silica column chromatography.
d Reaction was carried out at room temperature. e Reaction was conducted
at 80 °C (bath temperature) in a mixture of 1.4-dioxane/CH2Cl2 (1/1, v/v).
(15) Similar results were obtained with ethylzinc complex of ꢀ-enami-
noester, which was prepared in situ from the isolated ꢀ-enaminoester and
diethylzinc.
Org. Lett., Vol. 11, No. 15, 2009
3415

ligated in 2b lowering Lewis acidity, but the reactivity of
which can be restored marginally through the activation of
alkyne by using additional Lewis acid catalyst.
alkyne. However, other internal alkynes 3g and 3h did not
react at all with 2a (entries 19 and 20 in Table 2).
Finally, to acquire an insight into the reaction mechanism,
the tandem Blaise reaction of 1a with 1.1 equiv of deuterium
labeled 3a-d was carried out to afford a mixture of isotopi-
cally discriminated 4a-DD, 4a-DH, 4a-HD, and 4a-HH with
a 3:2:2:5 ratio in 90% yield. The scrambling of proton and
deuterium atoms at the terminal vinyl group clearly indicated
the generation of unlabeled 3a, and its incorporation into
the reaction as shown in the proposed pathways (Figure 1).
We next explored the substrate scope of the reaction, and
the results are summarized in Table 2.17 A wide range of
Table 2. Tandem Blaise-Alkenylation with Terminal and
Internal Alkynesa
Figure 1. Possible reaction pathways.
In path a, the Blaise reaction intermediate 2a reacted with
3a-d to form vinylzinc bromide A, which abstracted the
deuterium from the second 3a-d resulting in zinc acetylide
3a-ZnBr. The inter- and/or intramolecular deprotonation of
the acidic proton by 3a-ZnBr could generate 3a and the zinc
bromide complex C, which hydrolyzed to form 4a-DD.
Proton transfer from the generated 3a to the vinylzinc
a For reaction conditions, see ref 17. b t1: time for >97% conversion of
nitrile to the Blaise intermediate, t2: time for the disappreance of the Blaise
intermediate. c After silica column chromatography. d 3a was added after
80% conversion of nitrile.
aromatic (1a-1g), heteroaromatic (1h and 1i), and aliphatic
(1j-1m) nitriles could be transformed efficiently to the
corresponding R-vinylated ꢀ-enaminoesters 4a-4m with
good to excellent yields through the tandem alkenylation of
the Blaise reaction intermediate with phenylacetylene 1a
(entries 1-13, Table 1). The sterically more demanded
isobutyronitrile 1l showed diminished reactivity in both
Blaise (ca. 80% conversion of nitrile) and alkenylation (ca.
78%) reactions, resulted in a slightly lower yield of R-vi-
nylated ꢀ-enaminoester 3l (entry 12, Table 1). The nature
of terminal alkyne did not affect the efficiency of the reaction
as well, and thus the tandem reaction with aromatic and
aliphatic terminal alkynes proceeded efficiently, as clearly
shown in entries 14-17 in Table 2. Importantly, the Blaise
reaction intermediate 2a reacts with an internal alkyne,
methyl phenyl acetylene 3f, to afford the corresponding
trisubstituted alkene 4r, but required prolonged reaction time
(63% yield, entry 18 in Table 2). This is the first intermo-
lecular alkenylation of metal enolate with unactivated internal
(16) The reaction of the isolated ꢀ-enaminoester with phenylacetylene
in the presence of 20 mol % of In(OTf)3 only or a stoichiometric mixture
of In(OTf)3 and Et3N did not proceeded efficiently, and less than 10% of
4a was obtained after 24 h.
(17) A typical procedure for the tandem alkenylation of the Blaise
reaction intermediate: To a stirred suspension of commercial zinc dust (1.0
g, 15.3 mmol) was added methansulfonic acid (3.7 mg) in anhydrous THF
(4.0 mL). After 10 min reflux, benzonitrile (1a, 0.8 mL, 7.6 mmol) was
added. While maintaining the reflux temperature, ethyl bromoacetate (1.26
mL, 11.4 mmol) was added over 1 h by using a syringe pump, and the
reaction mixture was further refluxed for 1 h. To this reaction mixture,
phenylacetylene (3a, 0.92 mL, 8.4 mmol) was added, and the reaction
mixture was refluxed for 1.5 h. The reaction was quenched with saturated
aqueous NH4Cl at room temperature. After evaporation of THF, the residue
was extracted with ethyl acetate (20 mL × 3), and the combined organic
layer was dried with anhydrous MgSO4 and filtered then concentrated under
reduced pressure. The residue was purified by silica chromatography (eluent:
n-hexane/EtOAc ) 5:1) to afford viscous yellowish liquid 4a (2.03 g, 91%);
1H NMR (250 MHz, CDCl3) δ 0.90 (t, J ) 7.1 Hz, 3H), 4.00 (q, J ) 7.1
Hz, 2H), 4.76 (d, J ) 1.5 Hz, 1H), 5.36 (d, J ) 1.5 Hz, 1H), 7.20∼7.33
(m, 8H), 7.39∼7.43 (m, 2H) ppm; 13C NMR (63 MHz, CDCl3) δ 14.0,
59.2, 98.4, 118.2, 126.1, 126.8, 127.4, 128.0, 128.2, 128.8, 138.8, 143.0,
144.5, 160.8, 170.2 ppm; HRMS calcd for [M + H]+: C19H20NO2: 294.1494.
Found: 294.1500.
3416
Org. Lett., Vol. 11, No. 15, 2009

complex A afforded 4a-DH + 4a-HD. The generated 3a in
path a reacts with the Blaise intermediate 2a to form the
vinylzinc D, which was then converted to 4a-HH and 4a-
HD + 4a-DH via proton and deuterium transfer from 3a
and 3a-d, respectively (path b).
In conclusion, we have developed unprecedented tandem
alkenylation of the Blaise reaction intermediate with unac-
tivated terminal and internal alkynes in a one-pot operation
under mild conditions. This discovery opens a new direct
method for the synthesis of various R-vinylated ꢀ-enami-
noesters from nitrile. These results underscore the potential
of the Blaise reaction intermediate as an organozinc nucleo-
phile as well as a Lewis acid for the formation of carbon-
carbon bonds. Studies extending the range of tandem Blaise
reactions by modulating the Blaise reaction intermediate are
currently underway in our laboratory.
Acknowledgment. This work was supported by the grants
from Korea Research Foundation (KRF-2006-312-C00587)
and the Center for Intelligent Nano-Bio Materials at Ewha
Womans University. We thank Professor J. Hong for his
HRMS analysis.
Supporting Information Available: Experimental details
1
and spectral data of 4a-4r and their H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL901241S
Org. Lett., Vol. 11, No. 15, 2009
3417