Michael addition of allenoates to electron-deficient olefins: Facile synthesis of 2-alkynyl-substituted glutaric acid derivatives

Article abstract of DOI:10.1021/ol801411b

(Chemical Equation Presented) A Michael addition of allenoates to electron-deficient olefins was mediated efficiently by a catalytic amount of commercial tetra-n-butylammonium fluoride (TBAF) under mild conditions. And 2-alkynyl substituted glutaric acid derivatives, which may be potential building blocks in organic synthesis, were obtained in good to excellent yields from these reactions. The mechanism for the Michael addition reaction may involve the formation of an alkynylenolate intermediate.

Full text of DOI:10.1021/ol801411b

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3887-3890
Michael Addition of Allenoates to
Electron-Deficient Olefins: Facile
Synthesis of 2-Alkynyl-Substituted
Glutaric Acid Derivatives
Le-Ping Liu, Bo Xu, and Gerald B. Hammond*
Department of Chemistry, UniVersity of LouisVille, LouisVille, Kentucky 40292
gb.hammond@louisVille.edu
Received June 22, 2008
ABSTRACT
A Michael addition of allenoates to electron-deficient olefins was mediated efficiently by a catalytic amount of commercial tetra-n-butylammonium
fluoride (TBAF) under mild conditions. And 2-alkynyl substituted glutaric acid derivatives, which may be potential building blocks in organic
synthesis, were obtained in good to excellent yields from these reactions. The mechanism for the Michael addition reaction may involve the
formation of an alkynylenolate intermediate.
The Michael addition reaction is one of the most powerful
methods for the generation of 1,5-dicarbonyl compounds,
Scheme 1. Aldol Reaction of Allenoates or Propargylic Esters
which are of general synthetic interest in organic synthesis.
Enolates or stabilized carbanions could be regarded as proper
nucleophiles for conjugate addition reactions.1 Recently, we
reported an aldol reaction of allenoates or propargylic esters
that we regarded to occur via a common alkynylenolate
intermediate A (Scheme 1).2 When the intermediate
Asgenerated by the action of tetra-n-butylammonium fluo-
ride (TBAF)sreacted with an aldehyde, the reaction favored
(1) For selected recent reviews on conjugate addition reactions, see: (a)
Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Perga-
mon: Oxford, UK, 1992. (b) Sibi, M. P.; Manyem, S. Tetrahedron 2000,
56, 8033–8061. (c) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–353. (d)
Woodward, S. Chem. Soc. ReV. 2000, 29, 393–401. (e) Alexakis, A.;
Benhaim, C. Eur. J. Org. Chem. 2002, 3221–3236. (f) Lopez, F.; Minnaard,
A. J.; Feringa, B. L. Acc. Chem. Res. 2007, 40, 179–188. (g) Sulzer-Mosse,
S.; Alexakis, A. Chem. Commun. 2007, 3123–3135.
exclusively the thermodynamically preferred γ-product,
namely the carbinol allenoate shown in Scheme 1 (top right).
To probe further the reactivity of this alkynylenolate
intermediate A, we decided to investigate the reaction of the
allenoatesswhich are suitable precursors of intermediate A3
and easily prepared using textbook methodologies4swith
(2) Xu, B.; Hammond, G. B. Angew. Chem., Int. Ed. 2008, 47, 689–
692.
(3) For the generation and reaction of allenyl/propargyl anions, see: (a)
Marshall, J. A.; Gung, B. W.; Grachan, M. L. In Modern Allene Chemistry;
Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, Germany,
2004; Vol. 1, Chapter 9. (b) Back, T. G. Tetrahedron 2001, 57, 5263–
5301. (c) Pasto, D. J. Tetrahedron 1984, 40, 2805–2827.
10.1021/ol801411b CCC: $40.75
Published on Web 07/25/2008
2008 American Chemical Society

Michael acceptors such as alkyl acrylate, methyl vinyl ketone,
acrylonitrile, and N,N-dimethyl acrylamide. Herein, we wish
to report a highly attractive Michael addition of allenoates5
to electron-deficient carbon-carbon double bonds that
provides a convenient entry into 2-alkynyl-substituted glutaric
acid derivatives. Although glutaric acid derivatives have been
used extensively in organic synthesis,6 the synthetically more
useful 2-alkynyl-substituted glutaric acid derivatives rarely
have been reported in the literature.7
Table 1. Optimization of Reaction Conditionsa
entry
base
X (equiv) solvent
yieldb (%)
Using ethyl R-methyl-γ-(n-hexyl)-allenoate 1a as the
substrate, we studied its Michael addition to methyl acrylate
2a under similar conditions employed for the γ-selective
aldol reaction.2 We were pleased to observe that the reaction
proceeded smoothly at rt in 12 h yielding exclusively the
R-selective adduct8 3a in 55% yield (Table 1, entry 1). When
conducted at higher temperature (50 °C), the reaction could
be completed in 2 h and gave a much higher yield (Table 1,
entry 2). Water did not prevent the reaction from occurring
since a very good yield of 3a was obtained when using TBAF
trihydrate as the base (Table 1, entry 3). Other bases, either
inorganic or organic, were also examined in this reaction,
but the yields of product dropped sharply. In most of these
cases, only traces of the product were found by TLC and
most of the starting material remained (Table 1, entries
4-13). Solvent effects were also investigated. We found that
compound 3a could be isolated in very good yields in toluene
(Table 1, entry 14), but when 1,2-dichloroethane (DCE),
dichloromethane (DCM), and diethyl ether were employed,
the reaction was severely retarded (Table 1, entries 15-17).
The reaction could also take place in polar aprotic solvents
such as acetonitrile, N,N-dimethylformamide (DMF), and
dimethyl sulfoxide (DMSO) and the product 3a could be
obtained in moderate to good isolated yields (Table 1, entries
18-20). Reducing the amount of TBAF to as low as 0.1
equiv of the allenoate did not decrease the yield of the
product (Table 1, entries 21-24). This clearly marked a
substantial improvement to our methodology.
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
TBAFd
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
0.5
0.2
0.1
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
55
80
82
TBAFd
TABF·3H2O
(n-Bu4N+)-OAc
(n-Bu4N+)-Br
K2CO3
Cs2CO3
CsF
KOtBu
NaOAc
Et3N
PyH
DBU
trace
no reaction
trace
trace
trace
complex mixture
trace
trace
trace
complex mixture
TBAF·3H2O
TBAF·3H2O
TBAF·3H2O
TBAF·3H2O
TBAF·3H2O
TBAF·3H2O
TBAF·3H2O
TBAFd
toluene 81
DCE
DCM
Et2O
CH3CN 84
DMF 42
DMSO 59
THF
THF
THF
THF
trace
trace
trace
79
81
77
83
TBAFd
TBAFd
TBAFd
a Reaction conditions: allenoate 1a (0.3 mmol), methyl acrylate 2a (0.36
mmol), solvent (2.0 mL). b Isolated yields; c Conducted at rt for 12 h. d 1.0
M solution in THF.
With optimal reaction conditions in hand, we explored the
scope of this Michael reaction. By using allenoate 1a as a
fixed substrate, we carried out the reactions with various
types of olefins bearing an electron-withdrawing group
(EWG); the results are outlined in Table 2. EWG could be
esters (Table 2, entries 1-3), ketone (Table 2, entry 4), nitrile
(Table 2, entry 5), or amide (Table 2, entry 6). In all these
cases we found that the corresponding products could
be obtained in good yields. When using acrylates having a
methyl group substituted at R- or ꢀ-positions, such as methyl
methacrylate (Table 2, entry 7) and methyl crotonate (Table
2, entry 8), higher temperatures and prolonged times were
needed for the reactions to occur and lower yields were
obtained. This clearly indicated that the reaction was
susceptible to steric effects.
We then proceeded to examine the Michael addition
reactions of various allenoates with methyl acrylate; the
results are summarized in Table 3. As can be seen from this
table, aromatic and aliphatic substituted allenoates reacted
with methyl acrylate smoothly and the corresponding prod-
ucts were isolated, again in very good yields. For the
aromatic group-substituted substrates (Table 3, entries 1-3),
either an electron-donating or electron-withdrawing group
(4) For preparation of allenoates, see: Lang, R. W.; Hansen, H.-J. Org.
Synth., Collect. 1990, 7, 232.
(5) Selected recent papers on allenoates, see: (a) Elsner, P.; Bernardi,
L.; Dela Salla, G.; Overgaard, J.; Jorgensen, K. A. J. Am. Chem. Soc. 2008,
130, 4897–4905. (b) Singh, L.; Ishar, M. P. S.; Elango, M.; Subramaniam,
V.; Gupta, V.; Kanwal, P. J. Org. Chem. 2008, 73, 2224–2233. (c) Shi,
M.; Tang, X.-Y.; Yang, Y.-H. Org. Lett. 2007, 9, 4017–4020. (d) Cowen,
B. J.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 10988–10989. (e) Li, C.-
Y.; Sun, X.-L.; Jing, Q.; Tang, Y. Chem. Commun. 2006, 2980–2982. (f)
Klein, A.; Miesch, M. Synthesis 2006, 2613–2617.
(6) For selected recent papers on glutaric acid derivatives, see: (a) Yan,
J.; Travis, B. R.; Borhan, B. J. Org. Chem. 2004, 69, 9299–9302. (b) Tagat,
J. R.; McCombie, S. W.; Nazareno, D. V.; Boyle, C. D.; Kozlowski, J. A.;
Chackalamannil, S.; Josien, H.; Wang, Y.; Zhou, G. J. Org. Chem. 2002,
67, 1171–1177. (c) Vera, M.; Almontassir, A.; Rodr´ıguez-Gala´n, A.;
Puiggal´ı, J. Macromolecules 2003, 36, 9784–9796. For glutaric acid
derivatives used in total synthesis, see: (d) Nayyar, N. K.; Hutchison, D. R.;
Martinelli, M. J. J. Org. Chem. 1997, 62, 982–991. (e) Colobert, F.; Mazery,
R. D.; Solladie´, G.; Carren˜o, M. C. Org. Lett. 2002, 4, 1723–1725. (f) Zhu,
C.; Tang, P.; Yu, B. J. Am. Chem. Soc. 2008, 130, 5872–5873.
(7) To the best of our knowledge, there is only one report on 2-alkynyl-
substituted glutaric acid derivatives, see:Casara, P.; Metcalf, B. W.
Tetrahedron Lett. 1978, 19, 1581–1584.
(8) For a recent example of alkynyl-substituted cyclization products from
sulfonylallene derivatives by base treatment, see: (a) Kitagaki, S.; Teramoto,
S.; Mukai, C. Org. Lett. 2007, 9, 2549-2552, and references cited therein.
For a palladium-catalyzed alkylation of vinyl oxiranes with allenoates, see:
(b) Nanayakkara, P.; Alper, H. J. Org. Chem. 2004, 69, 4686–4691.
3888
Org. Lett., Vol. 10, No. 17, 2008

substituted glutaric acid derivatives 3qd but afforded instead
3qa, 3qb, and 3qc as the only products (Scheme 2).
Table 2. Michael Addition Reactions of Allenoate 1a with
Various Michael Acceptors 2a
Scheme 2. Michael Addition Reaction of Allenoate 1i with
Methyl Acrylate 2a under Optimized Conditions
entry
R1/R2
EWG
3, yieldc (%)
1
2
3
4
H/H
H/H
H/H
H/H
H/H
H/H
H/Me
Me/H
CO2nBu (2b)
CO2 Bu (2c)
3b, 81
3c, 78
3d, 72
3e, 70
3f, 84
3g, 69
3h, 58e
3i, 36e
t
CO2Allyl (2d)
COCH3 (2e)
CN (2f)
CON(CH3)2 (2g)
CO2Me (2h)
CO2Me (2i)
5
6
7d
8d
a Reaction conditions: allenoate 1a (0.3 mmol), Michael acceptor 2 (0.36
mmol), THF (2.0 mL). b 1.0 M solution in THF. c Isolated yields.
d Conducted under reflux for 6 h. e Total yield of two diastereoisomers.
A proposed mechanism for the formation of these products
is depicted in Scheme 3. Alkynylenolate intermediate2,9 B,
on the aromatic ring did not affect the reaction significantly.
For the aliphatic group-substituted substrates (Table 3, entries
4-6), steric hindrance did not prevent the reaction from
taking place, even when an isopropyl-substituted allenoate
was used as the substrate (Table 3, entry 5). An allenic
lactone 1h was also employed in this reaction and the
corresponding R-alkynyl-substituted lactone 3p was obtained
in 73% yield.
Scheme 3
.
Proposed Mechanism for the Formation of
Compounds 3qa, 3qb,and 3qc
When using ethyl γ-methylallenoate 1i as the substrate,
the reaction with methyl acrylate did not gave the 2-alkynyl-
Table 3. Michael addition reactions of allenoates 1 with methyl
acrylate 2aa
which was formed from substrate 1i under the mediation of
TBAF, added to the carbon-carbon double bond of methyl
acrylate with R-selectivity to give intermediate 3qd. How-
ever, under the reaction conditions, this intermediate rear-
ranged to the thermodynamically more stable product 3qa.10
Intermediate 3qd could be deprotonated once more, reacting
with another molecule of methyl acrylate to give the double
addition product 3qc. An alternative route to 3qc could
involve the reaction of 3qa with methyl acrylate in a similar
(9) (a) Lepore, S. D.; He, Y.; Damisse, P. J. Org. Chem. 2004, 69, 9171–
9175. (b) Petasis, N. A.; Teets, K. A. J. Am. Chem. Soc. 1992, 114, 10328–
10334
.
(10) It is well-known that allenic and propargylic esters tend to
interconvert to each other in the presence of base through a prototropic
rearrangement, see: (a) Sleeman, M. J.; Meehan, G. V. Tetrahedron Lett.
1989, 30, 3345–3348. (b) Clinet, J. C.; Linstrumelle, G. Synthesis 1981,
875–877. (c) Croudace, M. C.; Schore, N. E. J. Org. Chem. 1981, 46, 5357–
5363.
b,c
a Reaction conditions: allenoate 1 (0.3 mmol), methyl acrylate 2a (0.36
mmol), THF (2.0 mL). b 1.0 M solution in THF. c Isolated yields.
Org. Lett., Vol. 10, No. 17, 2008
3889

manner.11 Likewise, intermediate B added to methyl acrylate
with γ-selectivity to give the product 3qb.
organic synthesis, including its asymmetric variant, are
currently under investigation.
In surmmary, we found that allenoates react with various
types of Michael acceptors under the mediation of catalytic
amounts of a commercial solution of TBAF and mild
conditions. And the exclusive R-selective products, 2-alkynyl
substituted glutaric acid derivatives, which may have po-
tential application in organic synthesis, were obtained in very
good yields. The broader applications of this reaction in
Acknowledgment. We are grateful to the National Science
Foundation for financial support (CHE-0809683).
Supporting Information Available: 1H, 13C NMR spec-
troscopic data, MS, and analytic data of the compounds
shown in Tables 1–3 and Schemes 1–3, and detailed
description of experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) Compound 3qa was isolated and subjected to the reaction with
methyl acrylate under the same conditions, and compound 3qc was obtained
in 76% isolated yield as the only product.
OL801411B
3890
Org. Lett., Vol. 10, No. 17, 2008