Base-catalyzed highly stereoselective conversion of γ-hydroxy- α,β-acetylenic esters to γ-acetoxy dienoates

Article abstract of DOI:10.1002/chem.200802355

γ-Hydroxy-α,β-acetylenic esters can be conveniently prepared from the reaction of methyl propiolate with aldehydes in the presence of ZnEt₂ and N-methylimidazole at room temperature. It is discovered that the γ-hydroxy-α,β-acetylenic esters can

Full text of DOI:10.1002/chem.200802355

DOI: 10.1002/chem.200802355
Base-Catalyzed Highly Stereoselective Conversion of g-Hydroxy-a,b-
acetylenic Esters to g-Acetoxy Dienoates
Yang Yue,[a, b] Xiao-Qi Yu,*[b] and Lin Pu*[a]
Abstract: g-Hydroxy-a,b-acetylenic esters can be conveniently prepared from the
reaction of methyl propiolate with aldehydes in the presence of ZnEt2 and N-
methylimidazole at room temperature. It is discovered that the g-hydroxy-a,b-ace-
tylenic esters can be catalyzed by p-N,N-dimethylaminopyridine (DMAP) in acetic
anhydride to generate the g-acetoxy dienoates with high stereo control. The mech-
anism of this conversion is investigated by NMR ananlyses and isotope labeling
experiments. An intramolecular Diels–Alder reaction of a g-acetoxy dienoate is
conducted to show the synthetic potential of these compounds.
Keywords: alkyne addition · dien-
oates · hydroxyacetylenic esters ·
stereoselective synthesis · synthetic
methods
Introduction
a novel reaction takes place to generate g-acetoxy dienoates.
Herein, we report a convenient synthesis of the g-hydroxy-
a,b-acetylenic esters and their highly stereoselective conver-
sion to the g-acetoxy dienoates.
g-Hydroxy-a,b-acetylenic esters represent a class of highly
functional organic molecules that are very useful in organic
synthesis.[1] For example, recently, Koide and Sonye found
that a g-hydroxy-a,b-acetylenic ester can be converted to a
g-oxo-a,b-enoate in the presence of DABCO in DMSO
(Scheme 1).[2,3] This reaction is found to be limited to aryl-
Results and Discussion
Previously, g-hydroxy-a,b-acetylenic esters were synthesized
by treatment of methyl propiolate with nBuLi at extremely
low temperature (À1208C) followed by the addition of alde-
hydes.[1a] In 2004, Koide and Shahi reported that treatment
of methyl propiolate with AgOTf and [Cp2ZrCl2] followed
by the addition of aldehydes can be conducted at room tem-
perature.[4] In 2006, we found that in the presence of 1,1’-bi-
Scheme 1.
2-naphthol (BINOL), ZnEt2, [TiACHTUNRTGNEUNG(OiPr)4], and hexamethyl-
phosphoramide (HMPA), the reaction of methyl propiolate
with aldehydes proceeded at room temperature with both
good yields and high enantioselectivity.[5] In 2007, You and
co-workers used a similar procedure, in which they replaced
HMPA with a catalytic amount of N-methylimidazole and
obtained good yield and enantioselectivity for the reaction
of methyl propiolate with benzaldehyde.[6] It is, however,
not clear whether the use of the Lewis acid complex gener-
substituted substrates only. When R is an alkyl substituent,
almost no reaction occurs.[2a] We find that when the alkyl-
substituted g-hydroxy-a,b-acetylenic esters are treated with
p-N,N-dimethylaminopyridine (DMAP) in acetic anhydride,
[a] Y. Yue, L. Pu
Department of Chemistry, University of Virginia
Charlottesville, Virginia 22904 (USA)
ated from BINOL and [TiACTHNUTRGNE(NUG OiPr)4] is necessary when only
[b] Y. Yue, X.-Q. Yu
the racemic products are desired. We have therefore tested
the reaction of methyl propiolate with aldehydes in the pres-
ence of ZnEt2 and N-methylimidazole without BINOL and
Department of Chemistry, Key Laboratory of Green Chemistry and
Technology
Sichuan University, Chengdu, 610064 (China)
E-mail: lp6n@virginia.edu
[TiACTHNUTRGEN(UGN OiPr)4] (Scheme 2). We find that N-methylimidazole
alone can activate ZnEt2 to deprotonate methyl propiolate
to generate the corresponding alkynylzinc reagent. In addi-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802355.
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FULL PAPER
slowly converted to a g-acetoxy dienoate 3 and a pyridinium
salt 4 in a 1:3 ratio (Scheme 3). Compound 4 cannot be con-
verted to 3 at room temperature over an extended period of
Scheme 2.
tion, for the subsequent reaction with aldehydes, an addi-
tional Lewis acid catalyst like BINOL-[TiACTHNURTGNENG(U OiPr)4] is not
needed to activate the aldehydes, and the in situ produced
alkynylzinc reagent is nucleophilic enough for the addition.
As shown in Table 1, using this method can give various
alkyl-substituted g-hydroxy-a,b-acetylenic esters under very
mild conditions in good yields.
Scheme 3.
Table 1. Synthesis of g-hydroxy-a,b-acetylenic esters from the reaction of
methyl propiolate with aldehydes.[a]
time and is thus not an intermediate from 1 to 3. The g-oxo-
a,b-enoate 5 is not observed in this reaction and cannot be
obtained by using DABCO in DMSO because of the alkyl
substituent of 1.[2a] We have prepared 5 from the reaction of
3 with methanol in the presence of acid (see the Supporting
Information) and found that it cannot be converted to 3 in
the presence of DMAP and acetic anhydride at room tem-
perature.
We have further studied the reaction of 1 in the presence
of DMAP, and found that when 1 is treated with 10 mol%
of DMAP in acetic anhydride at 858C for 48 h, the g-ace-
toxy dienoate product 3 is obtained in good yield.[7] The
NOESY NMR spectrum of 3 supports its (2E,4Z)-diene
stereo structures. When DABCO is used in place of DMAP,
no diene product is generated. The reactions of other alkyl-
substituted g-hydroxy-a,b-acetylenic esters in the presence
of DMAP and acetic anhydride were conducted under the
same conditions, and the results are summarized in Table 2.
Generally, the reactions proceed smoothly to give the g-ace-
toxy dienoate products with good yields and high stereose-
lectivity. The sterically more hindered substrates such as
those shown in entries 11 and 12 in Table 2 normally give
lower yields than the less sterically demanding compounds.
To gain further insight into the mechanism of this novel
conversion, we have prepared the d-deuteriated substrate
[D2]-1 and studied its reaction in the presence of DMAP
and acetic anhydride. The 1H and 2H NMR spectra of the re-
Entry
Aldehyde
g-Hydroxy-a,b-acetylenic ester
Isolated
yield [%]
1
2
3
4
5
6
7
78
71
73
73
74
55
73
8
9
68
67
10
11
12
63
75
74
[a] Reactions were conducted at room temperature with the use of
methyl propiolate (1.2 equiv), ZnEt2 (1.2 equiv), N-methylimidazole
(5 mol%), and an aldehyde.
sulting [D]-3 show no deuterium incorporation into either
the a or b position. In addition, the g-position of [D]-3 con-
tains only 50% deuterium. This indicates that there is par-
tial H–D exchange in the course of the reaction. We have
also prepared the g-deuteriated substrate [D]-1 and subject-
ed it to the reaction conditions with DMAP and acetic anhy-
When compound 1, a g-hydroxy-a,b-acetylenic ester, is
treated with DMAP and acetic anhydride (2 equiv) in
CDCl3 at room temperature, 1H NMR analysis shows a
rapid formation of an acetate intermediate 2, which is then
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L. Pu, X.-Q. Yu and Y. Yue
Table 2. Base-catalyzed conversion of g-hydroxy-a,b-acetylenic esters to
g-acetoxy dienoates.
nance-stabilized anion 6. Protonation of 6 at the a-position
will give 7. A base-promoted deprotonation at the d position
together with protonation at the b position of 7 could gener-
ate the g-acetoxy dienoate product. This step should be re-
versible, leading to the partial H–D exchange observed in
the conversion of [D2]-1 to [D]-3. The reactions of both
[D2]-1 and [D]-1 do not support an intramolecular 1,3-hy-
drogent shift. The acidic proton involved in the protonation
of the intermediates in this reaction mechanism can have
multiple sources such as water and acetic acid that are nor-
mally present in acetic anhydride. We have dried and dis-
tilled acetic anhydride over Na to remove any water and
acetic acid. When the g-deuteriated substrate [D]-1 is treat-
ed with DMAP and acetic anhydride under the rigorously
dry conditions under nitrogen, we still observe no deuterium
incorporation in the g-acetoxy dienoate product. Thus, the
a-protons of acetic anhydride could also be the proton
source. We have also conducted the experiment in the pres-
ence of trifluoroacetic anhydride. However, when DMAP is
added to the solution of compound 1 in trifluoroacetic anhy-
dride, it reacts with trifluoroacetic anhydride to form a
white precipitate and stops further reaction.
Entry g-Hydroxy-a,b-acetylenic
g-Acetoxy dienoate
product
Isolated
Yield
[%]
ester
1
2
3
4
5
6
7
78
62
73
65
80
65
53
8
9
59
67
We have studied the thermally promoted Diels–Alder re-
action of the g-acetoxy dienoate 8 prepared in entry 9 of
Table 2. At 1908C, 8 undergoes an intramolecular cycliza-
tion to give the bicyclic g-ketoester 9 in 40% yield
(Scheme 5). The structure of 9 is depicted as one of the two
10
11
12
63
52
41
Scheme 5.
dride. No deuterium incorporation is observed in the g-ace-
toxy dienoate product. This is different from what was ob-
served by Koide and Sonye for the reaction shown in
Scheme 1. They found that the g-H of the starting material
migrates to the a-position in the product.[8]
On the basis of our isotope labeling experiments and
NMR analyses, a mechanism is proposed in Scheme 4 for
the base-catalyzed conversion of the g-hydroxy-a,b-acety-
lenic esters to the g-acetoxy dienoates. In the first step, an
acetate is produced from the reaction with acetic anhydride.
Then, DMAP can remove the g-proton to generate the reso-
enantiomers generated from an exo cyclization pathway.
The COESY and NOESY NMR analyses support the trans
configuration between the 3- and 4-positions, but the trans-
fused bicyclic structure cannot be confirmed by the NMR
study. The synthesis of 9 demonstrates that starting from
methyl propiolate and an aldehyde, a structurally elaborated
and highly functionalized product can be obtained readily.
Conclusions
In summary, we have shown that g-hydroxy-a,b-acetylenic
esters can be conveniently prepared from the reaction of
methyl propiolate with aldehydes in the presence of ZnEt2
and N-methylimidazole at room temperature. We have dis-
covered that the g-hydroxy-a,b-acetylenic esters can be cata-
lyzed by DMAP in acetic anhydride to generate the g-ace-
toxy dienoates with high stereo control. A mechanism for
this conversion is proposed on the basis of NMR analyses
and isotope labeling experiments. An intramolecular Diels–
Alder reaction of a g-acetoxy dienoate occurs. The synthetic
Scheme 4.
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Strereoselective Synthesis of g-Acetoxy Dienoates
FULL PAPER
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application of the g-acetoxy dienoates is currently being ex-
plored further.
[3] Other reports on similar conversions: a) D. Ma, X. Lu, Tetrahedron
Lett. 1989, 30, 2109–2112; b) M. K. Eddine Saiah, R. Pellicciari, Tet-
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[4] S. P. Shahi, K. Koide, Angew. Chem. 2004, 116, 2579–2581; Angew.
Chem. Int. Ed. 2004, 43, 2525–2527.
Acknowledgements
Partial support of this work from the US National Science Foundation
(CHE-0717995), the donors of the Petroleum Research Fund adminis-
tered by the American Chemical Society, the National Science Founda-
tion of China (Nos. 20725206 and 20732004), and the Specialized Re-
search Fund for the Doctoral Program of Higher Education in China are
gratefully acknowledged. Y.Y. also thanks the fellowship from the China
[5] G. Gao, Q. Wang, X.-Y. Yu, R.-G. Xie, L. Pu, Angew. Chem. 2006,
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lenic esters to give dienoates: C. Guo, X. Lu, J. Chem. Soc. Chem.
Commun. 1993, 394–395; b) Ph3P can also catalyze the conversion of
a,b-acetylenic esters to dienoates: B. M. Trost, U. Kazmaier, J. Am.
Chem. Soc. 1992, 114, 7933–7935.
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Received: November 13, 2008
Published online: March 25, 2009
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