Three-component assembly of conjugated enyne scaffolds via E-selective olefination of ynals

Article abstract of DOI:10.1021/ol3012277

Benefited by the accessible ynamido-lithium intermediates Ib from a Cu-catalyzed azide-alkyne cycloaddition in the presence of stoichiometric amounts of LiOH, a mild and flexible three-component route to conjugated enyne scaffolds was successfully achieved via a formal E-selective olefination strategy.

Full text of DOI:10.1021/ol3012277

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3146–3149
Three-Component Assembly of
Conjugated Enyne Scaffolds via
E-Selective Olefination of Ynals
Dong Cheng, Fei Ling, Zexiang Li, Weijun Yao, and Cheng Ma*
Department of Chemistry, Zhejiang University, 20 Yugu Road, Hangzhou 310027,
People’s Republic of China
mcorg@zju.edu.cn
Received May 5, 2012
ABSTRACT
Benefited by the accessible ynamidoꢀlithium intermediates Ib from a Cu-catalyzed azideꢀalkyne cycloaddition in the presence of stoichiometric
amounts of LiOH, a mild and flexible three-component route to conjugated enyne scaffolds was successfully achieved via a formal E-selective
olefination strategy.
Conjugated enynes are valuable compounds in organic
synthesis since these scaffolds not only are important units
in medicinal and material science but also serve as versatile
synthetic building blocks.1 Whereas significant progress
has been achieved, the stereocontrolled synthesis of multi-
substituted and functionalized conjugated enynes through
carbonyl olefination remains a challenging task.2 In this
context, the pioneering studies of Shindo and co-workers
on the torquoselective olefination of alkynyl alkyl ketones
oralkynoateswithpre-prepared ynolatesnotablyprovided
a convergent protocol to substituted (E)-2-en-4-ynoic acid
derivatives with high stereoselectivities, even under harsh
conditions (Scheme 1a).3
The Cu-catalyzed azideꢀalkyne cycloaddition (CuAAC)
reaction4 constitutes one of the most interesting examples
of the click reaction.5 On the other hand, over the past few
years, N-sulfonyl ketenimine species (ynamidoꢀcopper Ia
and ketenimine II), arising from a CuAAC reaction, have
been recognized as versatile synthons in multicomponent
(1) (a) Trost, B. M. Science 1991, 254, 1471. (b) Materials for Non-
linear Optics: Chemical Perspectives. ACS Symposium Series 455;
Marder, S. R., Stucky, G. D., Sohn, J. E., Eds.; American Chemical Society:
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V. A.; Wrasidlo, W. Science 1992, 256, 1172. (d) Parshall, G. W.; Ittel,
S. D. Homogeneous Catalysis, 2nd ed.; John Wiley: New York, 1992.
(e) Nicolaou, K. C.; Smith, A. L. In Modern Acetylene Chemistry; Stang,
P. J., Diederich, F., Eds.; VCH: Weinheim, Germany, 1995. (f) Trost, B. M.
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Chem. Rev. 2000, 100, 2901.
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Chem. 2006, 51.
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Applications; Wiley-VCH: Weinheim, Germany, 2004.For recent reviews,
see: (b) Korotchenko, V. N.; Nenajdenko, V. G.; Balenkova, E. S.; Shastin,
A. V. Russ. Chem. Rev. 2004, 73, 957. (c) Negishi, E.; Huang, Z.; Wang,
G.; Mohan, S.; Wang, C.; Hattori, H. Acc. Chem. Res. 2008, 41, 1474. (d)
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Kuhn, F. E.; Santos, A. M. Mini-Rev. Org. Chem. 2004, 1, 55. (e) Flynn,
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Valliant, J. F.; Schaffer, P.; Stephenson, K. A.; Britten, J. F. J. Org.
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r
10.1021/ol3012277
Published on Web 06/06/2012
2012 American Chemical Society

reactions.6 However, previous studies in this area have been
predominantly focused on disclosing the diverse electro-
philic reactivities7 of these intermediates toward a tethered
or an extra nucleophile and subsequent tandem reactions.8
The feasibility of generating ynamidoꢀlithium intermedi-
ates Ib via a CuAAC reaction is still uncovered.9
most probably, upon the nucleophilicity of ynamidoꢀ
lithium (Ib) intermediates (Scheme 1b).11
Table 1. Optimization of Reaction Conditionsa
Scheme 1. Formal Olefination of Carbonyl Compounds
entry
base
solvent
temp (°C) t (h) yield (%)b
1
2
Et3N
THF
25
25
25
25
25
25
25
25
25
25
25
25
25
10
ꢀ5
12
12
5
2,6-lutidine THF
3
Cs2CO3
NaOH
Li2CO3
t-BuOLi
LiOH
LiOHc
LiOHd
LiOH
THF
49
31
11
41
58
51
31
55
48
<5
65
81
4
THF
2
5
THF
24
2
6
THF
7
THF
3
8
THF
12
6
9
THF
10
11
12
13
14
15
CH2Cl2
THF/H2Oe
MeCN
THF/t-BuOHe
THF/t-BuOHe
THF/t-BuOHe
7
LiOH
6
LiOH
7
LiOH
6
LiOH
3
LiOH
12
a Conditions: (1) 1a (0.45 mmol), 2a (0.45 mmol), 3a (0.3 mmol), CuI
(10 mol %), and Et4NI (10 mol %) for inorganic base in solvent (5.0 mL)
under N2, then base (1.2 equiv); (2) saturated aqueous NH4Cl (5 mL).
b Isolated yield of 4a. c In the absence of Et4NI. d LiOH (0.45 equiv) was
used. e Et4NI = tetraethylammonium iodide; v/v = 10:1.
We have previously disclosed a CuI-catalyzed cascade
reaction of terminal alkynes, sulfonyl azides, and aromatic
2-oxobut-3-ynoates, giving access to two types of five-
membered heterocyclic skeletons.10 Encouraged by this
result, we thus screened a variety of carbonyl compounds
as substrates instead of activated ynones and found that
β-substituted propiolaldehydes deliver good efficiency to
conduct an olefination reaction, which provides a highly
E-selective avenue to substituted conjugated enyne products,
Preliminary investigation of the reaction of alkyne 1a,
tosyl azide 2a, and 3-phenylpropiolaldehyde (3a) in the
presence of CuI (10 mol %) at 25 °C revealed that the
reaction outcomes strongly depend on the base used. As
shown in Table 1, both triethylamine and 2,6-lutidine, two
common bases employed in CuI-catalyzed reactions upon
ketenimine intermediates, did not furnish any coupling
products (Table 1, entries 1 and 2). In sharp contrast, a set
of inorganic bases in combination with Et4NI (10 mol %)
provided enyne 4a in varying yields (Table 1, entries 3ꢀ8).
Lithium hydroxide turned out to perform best for this
tandem reaction in terms of the product yield; the addition
of Et4NI should accelerate the formation of the product 4a
(Table 1, entry 7 versus 8). Nevertheless, when employing
substoichiometric amounts of LiOH, the reaction did not
reach completion even after 12 h (entry 9). Solvent screen-
ing (Table 1, entries 10ꢀ12) indicated that this reaction can
be achieved in CH2Cl2 as well as in a mixture of THF and
H2O with comparable results; notably, reactions in acet-
onitrile yielded only trace amounts of 4a. We also observed
that the presence of tert-butyl alcohol slightly facilitated
the olefination and therefore chose the mixtures of THF
(6) For leading reference, see: (a) Bae, I.; Han, H.; Chang, S. J. Am.
Chem. Soc. 2005, 127, 2038. (b) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S.
J. Am. Chem. Soc. 2005, 127, 16046. (c) Cassidy, M. P.; Raushel, J.;
Fokin, V. V. Angew. Chem., Int. Ed. 2006, 45, 3154.
(7) The electrophilicity of N-acyl ketenimine can be enhanced by
Cu(I) ions in the presence of tris(3,5-dimethyl-4-bromopyrazolyl)-
ꢀ
methane: Cano, I.; Alvarez, E.; Nicasio, M. C.; Perez, P. J. J. Am.
ꢀ
Chem. Soc. 2011, 133, 191.
(8) For elegant [2 þ 2] annulations of imines, see: (a) Whiting, M.;
Fokin, V. V. Angew. Chem., Int. Ed. 2006, 45, 3157. (b) Xu, X.; Cheng,
D.; Li, J.; Guo, H.; Yan, J. Org. Lett. 2007, 9, 1585. For iminopho-
sphoranes, see: (c) Cui, S.-L.; Wang, J.; Wang, Y. Org. Lett. 2008, 10,
1267. For recent examples, see: (d) Li, S.; Luo, Y.; Wu, J. Org. Lett. 2011,
13, 3190. (e) Wang, J.; Wang, J.; Zhu, Y.; Lu, P.; Wang, Y. Chem.
Commun. 2011, 47, 3275. (f) Namitharan, K.; Pitchumani, K. Org. Lett.
2011, 13, 5728. (g) Chen, Z.; Ye, C.; Gao, L.; Wu, J. Chem. Commun.
2011, 47, 5623.
(9) For reviews on ynamides, see: (a) De-Korver, K. A.; Li, H.;
Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev.
2010, 110, 5064. (b) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem., Int.
Ed. 2010, 49, 2840.
(10) (a) Yao, W.; Pan, L.; Zhang, Y.; Wang, G.; Wang, X.; Ma, C.
Angew. Chem., Int. Ed. 2010, 49, 9210. For our previous studies on
ketenes, see: (b) Ma, C.; Ding, H.; Zhang, Y.; Bian, M. Angew. Chem.,
Int. Ed. 2006, 45, 7793. (c) Ma, C.; Ding, H.; Wang, Y. Org. Lett. 2006, 8,
3133. (d) Ding, H.; Ma, C.; Yang, Y.; Wang, Y. Org. Lett. 2005, 7, 2125.
(11) For [2 þ 2] cycloaddition of N-alkyl ketenimines with aldehydes,
see: (a) Barbaro, G.; Battaglia, A.; Giorgianni, P. J. Org. Chem. 1988, 53,
5501. (b) Barbaro, G.; Battaglia, A.; Giorgianni, P. Tetrahedron Lett.
1987, 28, 2995.
Org. Lett., Vol. 14, No. 12, 2012
3147

and tert-butyl alcohol (10:1) for further exploration.12
It was shown that the temperature has a critical effect on
this reaction (Table 1, entries 13ꢀ15): while the yield of 4a
increased to 81% by lowering the temperature to 10 °C,
further decrease in temperature resulted in a very slow
conversion to provide almost no detectable amount of 4a
after 12 h.
Table 3. Scope of Monosubstituted Ethynes 1a
The scope of this formal olefination reaction was next
investigated under the optimized conditions (Tables 2 and
3). Accordingly, a variety of substituted propiolaldehydes
3 carrying aryl or alkyl substituents achieved the tandem
reaction with 1a and 2a smoothly, and all gave good yields
with consistently high stereoselectivities (Table 2, entries
1ꢀ5). Nevertheless, an extended reaction time was re-
quired for 3-(4-fluorophenyl)propiolaldehyde to afford
4c in a slightly lower yield (entry 3). Moreover, variation
of the sulfonyl azide component (R2 = 4-AcNHC6H4 and
Me) was also tolerated; the corresponding products 4f
and 4g were obtained in 72 and 65% yield, respectively
(Table 2, entries 6 and 7).
a Conditions: (1) 1a (0.45 mmol), 2 (0.45 mmol), 3 (0.3 mmol), CuI
(10 mol %), and Et4NI (10 mol %) in THF/t-BuOH (10:1, 5 mL) under
N2 at 10 °C, then LiOH (0.36 mmol); (2) saturated aqueous NH4Cl
(5 mL). b Yield of isolated 4. c Detected by the 1H NMR spectra of the
crude reaction product.
Furthermore, this reaction also tolerated 5-chloropent-
1-yne (5), affording the targeted product 4o in 56% yield;
only trace amounts of subsequent cyclization product 6
were detected after 12 h. An intramolecular N-alkylation
of 4o by potassium carbonate in acetonitrile did give
(E)-3-(3-phenylprop-2-ynylidene)-1-tosylpiperidin-2-one (6)
in 95% yield with retained E-configuration of the double
bond according to the NOESY spectrum of 6 (Scheme 2).
To gain insight into the reaction mechanism, a control
test of 1-sulfonyltriazole 7 and 3a was conducted in THF
(Scheme 3). After decomposition of 7 by n-butyllithium
Table 2. Scope of Ynals 3 and Sulfonyl Azides 2 with 1aa
entry
R2
R3
time (h)
4, yieldb (%)
1
2
3
4
5
6
7
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-AcNHC6H4
Me
Ph
3
5
4a, 81
4b, 78
4c, 65
4d, 74
4e, 86
4f, 72
4g, 65
4-CH3Ph
4-FC6H4
n-Bu
11
6
Scheme 2. Formation of Enyne Scaffolds 4o and 6
2-thienyl
Ph
4
7
Ph
3
a Conditions: (1) 1a (0.45 mmol), 2 (0.45 mmol), 3 (0.3 mmol), CuI
(10 mol %), and Et4NI (10 mol %) in THF/t-BuOH (10:1, 5 mL) under
N2 at 10 °C, then LiOH (0.36 mmol); (2) Saturated aqueous NH4Cl
(5 mL). b Yield of isolated 4. Almost only E-configuration product of 4
was formed according to the 1H NMR spectra of the crude reaction
product.
Subsequently, we investigated the formation of enynes
4 by using a variety of monosubstituted ethynes 1. As de-
picted in Table 3, the targeted products 4hꢀn were ob-
tainedin reasonably good yieldsunder mild conditions. All
tested ethynes with various substituted phenyl, alkyl, and
alkenyl groups were cleanly converted into their corre-
sponding derivatives with high stereoselectivity, reflecting
wide scope of this reaction. In addition, the E-configura-
tion of the newly formed double bond of 4l was confirmed
by single-crystal X-ray diffraction analysis.
Scheme 3. Formation of 4a from 1-Sulfonyltriazole 7
(12) The action of tert-butyl alcohol is currently not clear; presum-
ably, the solvent mixtures could facilitate the formation of lithium
ynamidate intermediates.
3148
Org. Lett., Vol. 14, No. 12, 2012

ynamidate Ib presumably via a deprotonation reaction of
ketenimine II (path a) or direct transmetalation of copper-
(I) alkynamide Ia (path b) in the absence of ligands for
copper(I) complexes.13 The intermediate Ib then reacts
with ynal 3 to afford adduct III.14 Subsequent electronic
ring opening ofIII leads tothe formationof lithium saltIV;
the E/Z-selectivity of the newly formed double bond would
be determined in this step. Finally, the protonation of IV
with aqueous NH4Cl then furnishes enyne 4.
Scheme 4. Plausible Mechanism for the Formation of 4
In summary, making use of the easily accessible lithium
ynamidate intermediates from a CuAAC reaction in the
presence of stoichiometric amounts of LiOH, the present
protocol provided a mild and highly stereoselective access
to conjugated enyne scaffolds from simple substrates via a
formalE-selectiveolefination reactionof substituted ynals.
Experimental results suggest that the formation of lithium
ynamidate intermediates Ib by stoichiometric amounts of
LiOH is responsible for the current reaction outcome.
Additional studies on application and mechanism of the
reaction are now in progress.
at ꢀ78 °C, as expected, the resulting intermediate, lithium
ynamidate Ib0,8a smoothly reacted with 3a to give enyne 4a
in 56% isolated yield with high E-selectivity.
A plausible mechanism for this E-selective olefination
reaction is depicted in Scheme 4. Initially, a CuI-catalyzed
reaction of terminal alkyne 1 and azide 2 in the presence of
stoichiometric amounts of LiOH in THF generates lithium
Acknowledgment. We are grateful for financial support
from the Zhejiang Provincial Natural Science Foundation
of China (R4110055) and the Program for New Century
Excellent Talents in University.
Supporting Information Available. Experimental de-
tails and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(13) For studies on ligand-free CuAAC reaction, see: Rodionov,
V. O.; Fokin, V. V.; Finn, M. G. Angew. Chem., Int. Ed. 2005, 44, 2210.
(14) For a review on oxetanes, see: Burkhard, J. A.; Wagner, B.;
€
Fischer, H.; Schuler, F.; Muller, K.; Carreira, E. M. Angew. Chem., Int.
The authors declare no competing financial interest.
Ed. 2010, 49, 3524.
Org. Lett., Vol. 14, No. 12, 2012
3149