Virtually complete E-selective α,β-unsaturated ester synthesis by Hg(OTf)2-catalyzed hydration of sec-ethoxyalkynyl acetate

Article abstract of DOI:10.1021/ol702548r

The reaction of alkyl-substituted sec-ethoxyalkynyl acetates with water catalyzed by Hg(OTf)₂ afforded α,β-unsaturated esters in excellent yield with high catalytic turnover up to 1000 times under very mild reaction conditions with virtually complete E-selectivity, superior even to that of the HWE reaction.

Full text of DOI:10.1021/ol702548r

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5577-5580
Virtually Complete E-Selective
-Unsaturated Ester Synthesis by
Hg(OTf)2-Catalyzed Hydration of
sec-Ethoxyalkynyl Acetate
r,â
Mugio Nishizawa,* Hiroko Hirakawa, Yuki Nakagawa, Hirofumi Yamamoto,
Kosuke Namba, and Hiroshi Imagawa
Faculty of Pharmaceutical Sciences, Tokushima Bunri UniVersity, Yamashiro-cho,
Tokushima 770-8514, Japan
mugi@ph.bunri-u.ac.jp
Received October 19, 2007
ABSTRACT
The reaction of alkyl-substituted sec-ethoxyalkynyl acetates with water catalyzed by Hg(OTf)2 afforded
r
,
â
-unsaturated esters in excellent
yield with high catalytic turnover up to 1000 times under very mild reaction conditions with virtually complete E-selectivity, superior even to
that of the HWE reaction.
R,â-Unsaturated esters, which have functional importance
as versatile building blocks in organic synthesis and as
constituents of biologically active compounds, are mostly
prepared by Wittig reaction or Horner-Wadsworth-
Emmons (hereafter HWE) reaction in a generally E-selective
manner.1 Although a number of alternative procedures to
overcome the drawbacks of the Wittig reaction have been
reported, E-selectivity is not always very high, and even the
HWE reaction affords small amounts of Z-isomer. Thus,
troublesome separation of two isomers is required.2 Acid-
catalyzed rearrangement of propargyl alcohol to an R,â-
unsaturated carbonyl compound is an important synthetic
procedure known as the Meyer-Shuster and Rupe rear-
rangement.3 However, these reactions have been applicable
only for tert- and sec-alcohols. We have recently found that
the mercuric triflate [hereafter Hg(OTf)2] showed highly
efficient catalytic activity for the hydration of propargyl
acetate 1 leading to enone 2 that corresponds to a Meyer-
Schuster-type reaction applicable to a primary alcohol
(Scheme 1).4 This effective catalytic activity is based upon
Scheme 1
a significant π-philicity of Hg(OTf)2 as well as an efficient
protodemercuration sequence to regenerate the catalyst.5
Engel and Dudley recently reported a gold(III)-catalyzed
Meyer-Schuster rearrangement of ethoxyalkynyl alcohol 3
to give R,â-unsaturated ester 4.6 However, this procedure
generates a mixture of E- and Z-isomers. In this communica-
tion, we describe Hg(OTf)2-catalyzed hydration of alkyl-
(1) (a) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863-927.
(b) Rein, T.; Reiser, O. Acta Chem. Scand. 1996, 50, 369-379. (c)
Dambacher, J.; Zhao, W.; El-Batta, A.; Anness, R.; Jiang, C.; Bergdahl,
M. Tetrahedron Lett. 2005, 46, 4473-4477.
(2) (a) List, B.; Doehring, A.; Fonseca, M. T. H.; Job, A.; Torres, R. R.
Tetrahedron 2006, 62, 476-482. (b) Sun, W.; Yu, B.; Kuhn, F. E.
Tetrahedron Lett. 2006, 47, 1993-1996. (c) Zeitler, K. Org. Lett. 2006, 8,
637-640. (d) Concellon, J. M.; Concellon, C.; Mejica, C. J. Org. Chem.
2005, 70, 6111-6113. Further references are cited therein.
10.1021/ol702548r CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/28/2007

substituted sec-ethoxyalkynyl acetate to give R,â-unsaturated
esters in excellent yield under very mild conditions with high
catalytic turnover and virtually complete E-selectivity that
is superior not only to the Wittig reaction but also to the
HWE reaction from the standpoint of atom economy and
stereoselectivity.1,2
We first examined the reaction of 5 with 1.5 equiv of H2O
in the presence of 5 mol % of Hg(OTf)2 in acetonitrile at
room temperature (Scheme 2). The reaction was completed
Table 1. Hg(OTf)2-Catalyzed Hydration of 5
yield (%)a
Hg(OTf)2
H2O
time
entry
solvent
(mol %) (equiv) (min)
6
7
8
9
1
2
3
4
5
6
7
8
9
10
11
12
13
14
CH3CN
C6H5CH3
Et2O
5
5
5
5
5
10
1
1
1
1
1.5
1.5
1.5
1.5
1,5
1.5
1.5
1
5
1b
-
1
1
30 62
1440 51 19
150 34 44
2
5
1
21
-
-
-
-
-
-
-
-
-
-
-
-
-
5
CH3NO2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
40 72
30 76
10 75
20 88
20 94
15 76
20 86
20 25c
20 84
7
3
5
4
6
8
8
-
3
3
-
-
-
-
1
-
-
-
-
-
Scheme 2
1
1d
0.1
0.1d
300 85 11
300 20c
-
1
a NMR yield using 1,1,1-trichloroethane as an internal standard. b Reac-
tion in the presence of n-Bu4NOTf (1 equiv). c More than 70% of 5 was
recovered. d Reaction by using TfOH as catalyst.
vinylmercury product 8 (entry 5). Although an increase of
catalyst loading to 10 mol % did not increase the yield of 6,
1 mol % of catalyst resulted in an 88% yield within 20 min
(entries 6 and 7). The best result was obtained with the
reaction using 1 mol % of Hg(OTf)2 and 1 equiv of H2O for
20 min at room temperature in dichloromethane, affording
6 in 94% yield along with 6% of acetoxy ester 7 (entry 8).
The reaction was sensitive to the quantity of H2O: more
than 5 equiv of H2O significantly decreased the yield of 6
(entry 9). Addition of a phase transfer catalyst such as n-Bu4-
NOTf did not improve either reaction rate or yield of 6 (entry
10). Reaction under anhydrous condition also provided 6 in
25% yield along with 71% of starting material after 20 min
(entry 11). The reaction was shown to be also possible by
using TfOH, which gave rise to 6 in 84% yield with com-
plete E-selectivity along with 3% of 7 (entry 12);8 however,
the efficiency of Hg(OTf)2 over TfOH was evident when
the reaction was carried out by using 0.1 mol % of catalyst.
Hg(OTf)2 afforded 6 in 85% yield after 5 h (entry 13) along
with 11% of 7, whereas 0.1 mol % of TfOH gave 6 in 20%
yield along with 76% of starting material after 5 h (entry
14).9
within 30 min, and an R,â-unsaturated ester 6 was obtained
in 63% yield (NMR yield 62% by using 1,1,1-trichloroethane
as an internal standard)6b after column chromatography on
silica gel along with acetoxy ester 7 (2%), dimeric vinyl-
mercuric product 8 (5%), and Ritter-type byproduct 9 (21%)7
(Table 1, entry 1). The geometry of the double bond of 6
was probed to be E, and no trace of Z-isomer was detected.
While the generation of 9 was prevented by carrying out
the reaction in toluene, the reaction was very slow, giving
rise to 6 in 51% yield after 24 h (entry 2). The best solvent
was shown to be dichloromethane, which afforded 6 in 76%
yield along with 3% of 7 and negligible amounts of
(3) (a) Meyer, K. H.; Schuster, K. Chem. Ber. 1922, 55, 819-821. (b)
Rupe, H.; Kambli, E. HelV. Chim. Acta 1926, 9, 672. (c) Swaminathan, S.;
Narayanan, K. V. Chem. ReV. 1971, 71, 429-438. (d) Chabardes, P.
Tetrahedron Lett. 1988, 29, 6253-6256. (e) Narasaka, K.; Kusama, H.;
Hayashi, Y. Chem. Lett. 1991, 1413-1416. (f) Narasaka, K.; Kusama, H.;
Hayashi, Y. Tetrahedron 1992, 48, 2059-2068. (g) Mercier, C.; Chabardes,
P. Pure Appl. Chem. 1994, 66, 1509-1518. (h) Suzuki, T.; Tokunaga, M.;
Wakatsuki, Y. Tetrahedron Lett. 2002, 43, 7531-7533. (i) Cadierno, V.;
Diez, J.; Garcia-Garrido, S. E.; Gimeno, J. Chem. Commun. 2004, 2716-
2717. (j) Yu, M.; Zhang, G.; Zhang, L. Org. Lett. 2007, 9, 2147-2150.
(4) Imagawa, H.; Asai, Y.; Takano, H.; Hamagaki, H.; Nishizawa, M.
Org. Lett. 2006, 8, 447-450.
The proposed mechanism of this Hg(OTf)2-catalyzed
hydration is as shown in Scheme 3. The reaction is initiated
(5) (a) Nishizawa, M.; Skwarczynski, M.; Imagawa, H.; Sugihara, T.
Chem. Lett. 2002, 12-13. (b) Nishizawa, M.; Yadav, V. K.; Skwarczynski,
M.; Takao, H.; Imagawa, H.; Sugihara, T. Org. Lett. 2003, 5, 1609-1611.
(c) Nishizawa, M.; Takao, H.; Yadav, V. K.; Imagawa, H.; Sugihara, T.
Org. Lett. 2003, 5, 4563-4565. (d) Imagawa, H.; Kurisaki, T.; Nishizawa,
M. Org. Lett. 2004, 6, 3679-3681. (e) Imagawa, H.; Iyenaga, T.; Nishizawa,
M. Org. Lett. 2005, 7, 451-453. (f) Imagawa, H.; Iyenaga, T.; Nishizawa,
M. Synlett 2005, 703-705. (g) Imagawa, H.; Kinoshita, A.; Fukuyama, T.;
Yamamoto, H.; Nishizawa, M. Tetrahedron Lett. 2006, 47, 4729-4731.
(h) Yamamoto, H.; Nishiyama, M.; Imagawa, H.; Nishizawa, M. Tetrahe-
dron Lett. 2006, 47, 8369-8373. (i) Kurisaki, T.; Naniwa, T.; Yamamoto,
H.; Imagawa, H.; Nishizawa, M. Tetrahedron Lett. 2007, 48, 1871-1874.
(j) Yamamoto, H.; Sasaki, I.; Imagawa, H.; Nishizawa, M. Org. Lett. 2007,
9, 1399-1402. (k) Yamamoto, H.; Pandey, G.; Asai, Y.; Nakano, M.;
Kinoshita, A.; Namba, K.; Imagawa, H.; Nishizawa, M. Org. Lett. 2007, 9,
4029-4032.
(8) Li, Z.; Zhang, J.; Brouwer, C.; Yang, C. G.; Reich, N. W.; He, C.
Org. Lett. 2006, 8, 4175-4178.
(9) Typical procedure: To a solution of 5 (100 mg, 0.45 mmol) in
dichloromethane (4.5 mL) were sequentially added H2O (8.0 µL, 0.45 mmol)
and Hg(OTf)2 (0.1 M solution in acetonitrile, 45 µL, 0.0045 mmol) at room
temperature, and the mixture was stirred for 20 min at the same temperature.
After addition of NaHCO3 solution, organic material was extracted with
dichloromethane. Dried and concentrated extract was purified by flash
column chromatography on silica gel using hexane-ethyl acetate (15:1) as
an eluent to give 6 (74.7 mg, 92%, NMR yield 94%) as a colorless oil:
FTIR (neat) 2928, 2853, 1725, 1650, 1448, 1368, 1274, 1173, 1046, 983
cm-1; 1H NMR (200 MHz, CDCl3) δ 6.92 (dd, J ) 15.4, 6.6 Hz, 1H), 5.76
(dd, J ) 15.4, 1.6 Hz, 1H), 4.18 (q, J ) 7.2 Hz, 1H), 2.13 (m, 1H), 1.60-
1.85 (m, 6H), 1.29 (t, J ) 7.2 Hz, 1H), 1.01-1.45 (m, 4H); 13C NMR (50
MHz, CDCl3) δ 167.1, 154.2, 118.9, 60.1, 40.4, 31.7, 25.9, 25.7, 14.2;
(6) (a) Engel, D. A.; Dudley, G. B. Org. Lett. 2006, 8, 4027-4029. (b)
Lopez, S. S.; Engel, D. A.; Dudley, G. B. Synlett 2007, 949-953.
(7) Ritter, J. J.; Kalish, J. J. Am. Chem. Soc. 1948, 70, 4045-4048.
+
HRMS m/z calcd for C11H19O2 [M + H]+ 183.1386, found 183.1384.
5578
Org. Lett., Vol. 9, No. 26, 2007

Scheme 3. Proposed Mechanism of Hg(OTf)2-Catalyzed
Table 2. Hg(OTf)2-Catalyzed Hydration of Ethoxypropargyl
Acetates in Dichloromethane
Hydration of Ethoxyalkynyl Acetate
by π-complexation of alkyne with Hg(OTf)2, as shown in
10, and generates oxonium cation 11 via participation of the
acetyl group. Nucleophilic addition of water to 11 affords
vinylmercury intermediate 12. Protonation by TfOH formed
in situ generates alternative oxonium cation 13, which
undergoes demercuration to produce the orthoester-type
intermediate 14 and the regenerated catalyst Hg(OTf)2. A
6-π electrocyclic fragmentation should yield R,â-unsaturated
ester 6. When the illustrated fragmentation of 15 takes place
prior to the protonation, the byproduct 8 should form via 16
that does not favor for the protodemercuration sequence
(Scheme 4).
Scheme 4. Possible Transition States Leading to (E)-6 and
(Z)-6
a NMR yield using 1,1,1-trichloroethane as an internal standard.
18; however, this was a 12.5:1 mixture of E- and Z-isomers
(see NMR charts in Supporting Information). This result
indicates that our procedure is characterized by the generation
of conjugate esters with complete E-selectivity. Although
the reaction of long alkyl chain analogue 21 also provided
conjugate ester 22 in 95% yield,6b reaction of heptyn-3-ol
derivative 19 resulted in only 60% yield of 20,6b together
with an unidentified byproduct.10 Substituted alkyl analogues
23, 25, and 27 afforded esters 24,2b 26,11a and 28,11b
respectively, in satisfactory yields. Reaction of tert-butyl-
substituted 29 resulted in modest yield of 30.6b While phenyl-
substituted 31 also afforded ester 32 in 77% yield;6b however,
the product was an 1:1 mixture of E- and Z-isomers.
p-Nitrophenyl-substituted 33 gave 342b in quantitative yield
with E/Z 5:1 selectivity, though this required a long reaction
time.
The virtually complete E-selectivity could be explained
by considering the transition state that is in an equilibrium
between an equatorial 14a and an axial 14b conformation.
The stability of 14a over 14b is obvious and leads to
preferential formation of (E)-6.
The hydration of various ethoxyalkynyl acetates was next
examined. The reaction of 4-ethoxy-3-butyn-2-ol deriva-
tive 17 with H2O (1 equiv) in the presence of 1 mol % of
Hg(OTf)2 in dichloromethane at room temperature for 30
min afforded the well-known (E)-ethyl crotonate (18) in 95%
yield (NMR using 1,1,1-trichloroethane as the internal
standard) (Table 2). The Z-isomer was not detected at all.
When acetaldehyde was reacted with diethyl phosphono-
acetate under the standard HWE conditions, this afforded
(10) This reaction was repeated five times, and 20 was obtained in 55-
60% yield.
(11) (a) Chang, M. Y.; Chen, C. Y.; Chen, S. T.; Chang, N. C.
Tetrahedron 2003, 59, 7547-7553. (b) Curran, D. P.; Liu, H. J. Chem.
Soc., Perkin Trans. 1 1994, 1377-1393. (c) Appella, D. H.; Moritani, Y.;
Shintani, R.; Ferreira, E. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999,
121, 9473-9474.
Org. Lett., Vol. 9, No. 26, 2007
5579

Ethoxyalkynyl acetates 17, 19, 21, 23, 25, 27, 29, 31, and
33 were prepared from the corresponding aldehydes by the
alkylation with Li acetylide of ethoxyacetylene and subse-
quent acetylation in excellent yields. Although naphthyl- and
p-methoxyphenyl-substituted acetates 35a and 35b were
prepared by the same procedure, these products were unstable
on silica gel column chromatography and decomposed to
give 1:1 mixtures of E and Z conjugate esters 36a and 36b,2d
respectively (Scheme 5). tert-Acetate 37 was more unstable
and decomposed to yield a 1:1 mixture of conjugate esters
38 during column chromatography on silica gel.11c These
results as well as the mixture formation of 32 from 31 suggest
that the reactions of these aromatic derivatives probably take
place via the Meyer-Shuster reaction by forming stable
propargylic cation 39 followed by hydration forming 40.
Thus this procedure is not applicable for substrates containing
cation stabilizing functionality.
Thus, we have established an efficient procedure for syn-
thesis of alkyl-substituted R,â-unsaturated esters by the hy-
dration of sec-ethoxyalkynyl acetate catalyzed by Hg(OTf)2
under the very mild reaction conditions with very high
catalytic turnover. The procedure is particularly noteworthy
in its virtually complete E-selectivity that is even higher than
that obtained with the HWE reaction.
Scheme 5. Silica Gel Induced Hydration via Stable Cation
Acknowledgment. This study was financially supported
by a Grant-in-Aid from the Ministry of Education, Culture,
Sports, Science, and Technology of the Japanese Govern-
ment, and a MEXT.HAITEKU, 2003-2007.
Supporting Information Available: Experimental details
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL702548R
5580
Org. Lett., Vol. 9, No. 26, 2007