A simple and efficient preparation of propargylic β-keto esters through transesterification

Full text of DOI:10.1021/jo9818172

1
380
J . Org. Chem. 1999, 64, 1380-1382
A Sim p le a n d Efficien t P r ep a r a tion of
however, a mild and broadly applicable transesterifica-
tion procedure, inspired by the work of Bader and
collaborators,3b has been found for the efficient prepara-
tion of propargylic â-keto esters. The procedure involves
equilibrium displacement without catalysis and is effec-
tive with methyl, ethyl, and tert-butyl â-keto esters, C-2
substituted or not, and with primary and secondary
propargylic alcohols7 (Table 1). Mechanistic studies
have suggested that the transformation most likely
proceeds via a ketene intermediate.
P r op a r gylic â-Keto Ester s th r ou gh
Tr a n sester ifica tion
Christophe Mottet, Olivier Hamelin, Geraldine Garavel,
J ean-Pierre Depr e´ s,* and Andrew E. Greene
3e
LEDSS, Universit e´ J oseph Fourier, B aˆ timent Chimie
Recherche, 301 rue de la Chimie, BP 53,
3
8041 Grenoble Cedex 9, France
Witzeman3 has reported that transesterification of
tert-butyl acetoacetate is considerably faster than the
more commonly used methyl and ethyl esters. In our
work, however, the tert-butyl â-keto esters were found
to be only slightly more reactive than the methyl and
ethyl esters. â-Keto esters unalkylated at C-2 (Table 1,
e
Received September 8, 1998
In connection with a program in our laboratory on
1
bakkenolide synthesis, we needed to prepare a propar-
gylic â-keto ester intermediate. Propargylic â-keto esters
have generally been synthesized by using diketene- or
2
3c,d
dioxinone-based methods, but these procedures were ill-
entries 1-3) were with propargyl alcohol, as expected,
suited and a direct transesterification protocol was
sought. To our surprise, in view of the number of methods
that were available for the often-effected transesterifi-
cation of â-keto esters,3 we were unable to find any
pertinent examples with propargylic alcohols,4 even
though several of the reported methods were effective
with allylic alcohols.3
substantially more reactive (e24 h) than those monoaky-
lated at C-2. 2-Cyclopentanonecarboxylate derivatives
were also transformed quite rapidly (Table 1, entries 9
and 10). Transesterifications with secondary propargylic
alcohols were found to be similar in rate to that with
propargyl alcohol with the same â-keto ester (Table 1,
entries 11 and 12 vs 5). Finally, it is important to point
out that this procedure is not at all limited to propargylic
alcohols. With a variety of alcohols excellent results are
obtained, generally much superior to those found in the
d-f
Transesterification of â-keto esters with propargylic
alcohols, we have discovered, in general is not trivial.
5
6
Conventional acid- or base-moderated transesterifica-
tion reactions with propargylic alcohols provided in most
cases low yields of the propargylic â-keto esters; further-
3
literature (Table 2). For example, ethyl acetoacetate with
benzyl alcohol and menthol (Table 2, entries 2 and 3)
afforded the expected â-keto esters in purified yields of
96% and 90%, respectively, and the â-keto ester 1d , a
more difficult substrate due to C-2 substitution, with
4-pentyn-2-ol gave the anticipated product in 82% puri-
fied yield (Table 2, entry 4).
3
c
more, the Taber procedure, as well as a modified
version,3d produced considerable tarring. Fortunately,
(1) Hamelin, O.; Depr e´ s, J .-P.; Greene, A. E.; Tinant, B.; Declerq,
J .-P. J . Am. Chem. Soc. 1996, 118, 9992-9993. Hamelin, O.; Depr e´ s,
J .-P.; Heidenhain, S.; Greene, A. E. Nat. Prod. Lett. 1997, 10, 99-103
and references therein.
The transesterification procedure is extremely simple
experimentally: a mixture of the â-keto ester and the
alcohol in toluene is merely heated to reflux, with a short
tube in place of the usual condenser. The equilibrium is
thus shifted due to the loss of the relatively volatile
methyl, ethyl, or tert-butyl alcohol from the reaction
(2) For examples of diketene-based preparations, see: Lacey, R. N.
J . Chem. Soc. 1954, 827-832. Sturzenegger, A.; Zelauskus, J .; Ofner,
A. J . Org. Chem. 1963, 28, 920-922. Kato, T.; Chiba, T. Chem. Pharm.
Bull. 1975, 23, 2263-2267. Kinder, F. R.; Padwa, A. Tetrahedron Lett.
1
990, 31, 6835-6838. Padwa, A.; Dean, D. C.; Fairfax, D. J .; Xu, S. L.
J . Org. Chem. 1993, 58, 4646-4655. For examples of dioxinone-based
preparations, see: Cruciani, P.; Stammler, R.; Aubert, C.; Malacria,
M. J . Org. Chem. 1996, 61, 2699-2708. Weingarten, M. D.; Padwa, A.
Synlett, 1997, 189-190. For a method based on Rh(II)-catalyzed
cyclization of 2-alkynyl 2-diazo-3-oxobutanoates, see: Padwa, A.;
Kinder, F. R. J . Org. Chem. 1993, 58, 21-28.
8
mixture. Although the reaction times, not unexpectedly,
can be lengthy with certain C-2 alkylated substrates, the
reactions are nonetheless typically clean and high-
yielding under these mild, neutral conditions. It is
expected that the method will find general application
(3) (a) For a general review on transesterification, see: Otera, J .
Chem. Rev. 1993, 1449-1470. (b) Bader, A. R.; Cummings, L. O.; Vogel,
H. A. J . Am. Chem. Soc. 1951, 73, 4195-4197. Bader, A. R.; Vogel, H.
A. Ibid. 1952, 74, 3992-3994. (c) Taber, D. F.; Amedio, J . C., J r.; Patel,
Y. K. J . Org. Chem. 1985, 50, 3618-3619. (d) Gilbert, J . C.; Kelly, T.
A. J . Org. Chem. 1988, 53, 449-450. (e) Witzeman, J . S.; Nottingham,
W. D. J . Org. Chem. 1991, 56, 1713-1718. (f) Balaji, B. S.; Sasidharan,
M.; Kumar, R.; Chanda, B. J . Chem. Soc., Chem. Commun. 1996, 707-
9
for the preparation of these useful compounds.
Exp er im en ta l Section
Gen er a l P r oced u r e. In a 100-mL flask fitted with a 10-cm
tube, a stirred mixture of the â-keto ester (5.0 mmol) and the
alcohol (1.2-5.0 equiv) in toluene (35 mL) was heated so the
toluene refluxed halfway up the tube (120-130 °C, bath tem-
7
08.
4) (a) For a high-temperature aluminum isopropoxide-based pro-
(
cedure, see: Kugatova-Shemyakina, G. P.; Kazlauskas, D. A. Bull. Soc.
Acad. Sci. USSR, Div. Chem. Sci. 1966, 262-269 and 480-485.
McAndrew, B. A.; Riezebos, G. J . Chem. Soc., Perkin Trans. 1, 1972,
1
perature), until no starting material remained ( H NMR, 12 h
3
67-369. (b) The â-keto ester 3b has since been synthesized in 51%
to 12 days). If propargyl alcohol (bp 114-115 °C) was used it
yield by clay-catalyzed transesterification. This procedure also gave
â-keto ester 3m from methyl acetoacetate and benzyl alcohol in 86%
yield but failed to give 3n in the case of methyl acetoacetate and
menthol: Ponde, D. E.; Deshpande, V. H.; Bulbule, V. J .; Sudalai, A.;
Gajare, A. S. J . Org. Chem. 1998, 63, 1058-1063.
(7) With tertiary propargylic alcohols the yields are low, presumably
because of the Carroll rearrangement of the â-keto ester products
(Carroll, M. F. J . Chem. Soc. 1940, 704-706; 1941, 507-511. Kimel,
W.; Cope, A. C. J . Am. Chem. Soc. 1943, 65, 1992-1998) in addition
to other side reactions.
(
5) The â-keto ester was refluxed in toluene in the presence of a
catalytic amount of p-toluenesulfonic acid and with slow distillation.
While this procedure was initially used in the synthesis of 9-acetoxy-
fukinanolide, the method described in this paper has since been found
to be far superior.
(8) In the case of propargyl alcohol, however, an excess is necessary
to compensate for its volatility (bp 114-115 °C).
(9) We have found, for example, that a range of propargylic â-keto
esters undergo smooth â-methylene-γ-butyrolactonization in the pres-
ence of manganese(III) acetate (manuscript in preparation).
1
(
6) The â-keto ester in propargyl alcohol was treated with 3-5 equiv
of base (LiH, NaH, or K CO ).
2
3
1
0.1021/jo9818172 CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/28/1999

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1381
Ta ble 1. P r op a r gylic â-Keto Ester s by Tr a n sester ifica tion w ith ou t Ca ta lyst
1
1
was necessary to add an additional 2.5 equiv of the alcohol every
1747, 1687 cm- ; H NMR δ 8.0-7.6 (m, 5H), 4.81 (d, J ) 2.4
13
2
days. After being cooled to room temperature, the reaction
Hz, 2 H), 4.05 (s, 2 H), 2.49 (t, J ) 2.2 Hz, 1 H); C NMR δ
191.9, 166.7, 133.9, 128.8, 128.6, 128.5, 75.4, 52.8, 45.5.
P r op -2-yn yl 2-a llyl-3-oxobu ta n oa te (3d ): chromatography,
mixture was directly concentrated under reduced pressure (or
with propargyl alcohol worked up conventionally) to afford the
crude product, which was purified by column chromatography
on silica gel with increasing amounts of ethyl acetate or diethyl
ether in hexane.
1
1
ether/hexane 10:90-12:88; IR 3290, 2130, 1750, 1718 cm
; H
NMR δ 5.86-5.62 (m, 1 H), 5.16-5.04 (m, 2 H), 4.74 (d, J ) 2.5
Hz, 2 H), 3.58 (t, J ) 7.4 Hz, 1H), 2.66-2.56 (m, 2 H), 2.51 (t, J
) 2.5 Hz, 1 H), 2.26 (s, 3 H); 13C NMR δ 201.7, 166.5, 133.9,
117.8, 77.0, 75.5, 58.9, 52.7, 32.1, 29.2; mass spectrum (EI) m/z
P r op -2-yn yl 3-oxoh exa n oa te (3a ): chromatography, ethyl
-
1 1
acetate/hexane 8:92-10:90; IR 3282, 2130, 1751, 1717 cm ; H
NMR δ 4.74 (d, J ) 2.5 Hz, 2 H), 3.50 (s 2 H), 2.53 (t, J ) 7.3
Hz, 2 H), 2.52 (t, J ) 2.5 Hz, 1 H), 1.64 (pseudo sext, J ) 7.3
+
+
181 (M + 1, 2.7), 180 (M , 2), 43 (100), 39 (HCdCdCH
Anal. Calcd for C10
H, 6.49.
2
, 71).
12 3
H O : C, 66.65; H, 6.71. Found: C, 66.43;
1
3
Hz, 2 H), 0.93 (t, J ) 7.3 Hz, 3 H); C NMR δ 202.2, 166.5,
7
1
C
7.1, 75.0, 52.6, 48.9, 44.9, 16.9, 13.5; mass spectrum (EI) m/z
P r op -2-yn yl 2-ben zyl-3-oxobu ta n oa te (3e): chromatogra-
phy, ethyl acetate/hexane 10:90-12:88; IR 3287, 2128, 1745,
+
68 (M , 2.9), 71 (100), 39 (HCdCdCH
: C, 64.27; H, 7.19. Found: C, 64.01; H, 7.14.
Bu t-2-yn yl 3-oxoh exa n oa te (3b): chromatography, ethyl
2
, 53). Anal. Calcd for
9
H
12
O
3
1720 cm-1
; H NMR δ 7.32-7.12 (m, 5 H), 4.67 (pseudo t, J )
1
2.5 Hz, 2 H), 3.82 (pseudo t, J ) 7.6 Hz, 1 H), 3.17 (pseudo d, J
-
1
1
13
acetate/hexane 6:94-7.5:92.5; IR 2244, 1748, 1718 cm
;
H
) 7.6 Hz, 2 H), 2.47 (pseudo t, J ) 2.5 Hz, 1 H), 2.18 (s, 3H);
C
NMR δ 4.70 (q, J ) 2.4 Hz, 2 H), 3.47 (s, 2 H), 2.53 (t, J ) 7.2
NMR δ 201.7, 168.3, 137.8, 128.8, 128.6, 126.8, 76.9, 75.5, 60.9,
+
Hz, 2 H), 1.85 (t, J ) 2.0 Hz, 3 H), 1.63 (pseudo sext, J ) 7.4
52.7, 33.9, 29.6; mass spectrum (EI) m/z 230 (M , 4.7), 187 (61),
1
3
Hz, 2 H), 0.93 (t, J ) 7.4 Hz, 3 H). C NMR δ 202.3, 166.7,
43 (100), 39 (HCdCdCH
73.02; H, 6.13. Found: C, 73.24; H, 6.20.
Meth yl p r op -2-yn yl 2-a cylbu ta n ed ioa te (3f): chromatog-
raphy, ethyl acetate 17:83-20:80; IR 3282, 2130, 1730, 1720
cm ; H NMR δ 4.76 (d, J ) 2.4 Hz, 1 H), 4.75 (d, J ) 2.4 Hz,
1 H), 4.03 (X of ABX, dd, J ) 7.8, 6.6 Hz, 1 H), 3.69 (s, 3 H),
2 14 3
, 23). Anal. Calcd for C14H O : C,
8
3.7, 72.7, 53.5, 52.2, 49.0, 16.9, 13.5, 3.6; mass spectrum (EI)
+
m/z 182 (M , 1.4), 71 (66), 53 (HCdCdCCH
3
, 100). Anal. Calcd
for C10 : C, 65.91; H, 7.74. Found: C, 65.46; H,7.79.
14 3
H O
4
b
-1 1
P r op -2-yn yl 3-p h en yl-3-oxop r op a n oa te (3c): chroma-
tography, ethyl acetate/hexane 10:90-12:88; IR 3290, 2131,

1
382 J . Org. Chem., Vol. 64, No. 4, 1999
Ta ble 2. Tr a n sester ifica tion of â-Keto Ester s w ith Va r iou s Alcoh ols
Notes
2
.99 (A of ABX, dd, J ) 18.0, 7.8 Hz, 1 H), 2.85 (B of ABX, dd,
H), 2.14-2.00 (m, 3 H), 1.6-1.2 (m, 8 H), 1.25 (s, 3 H); 13C NMR
(major diastereomer) δ 211.4, 169.2, 75.3, 55.8, 52.7, 52.2, 39.4,
J ) 18.0, 6.6 Hz, 1 H), 2.54 (pseudo t, J ) 2.4 Hz, 1 H), 2.38 (s,
1
3
3
2
7
H); C NMR δ 200.9, 171.6, 167.7, 75.7, 54.4, 53.1, 52.1, 32.0,
36.6, 34.2, 25.1, 22.4, 21.4, 20.7; mass spectrum (EI) m/z 234
+
+
+
9.9; mass spectrum (CI) m/z 230 (M + 18, 100), 213 (M + 1,
(M , 8), 219 (32), 81 (100), 39 (HCdCdCH
2
, 86). Anal. Calcd for
: C, 71.77; H, 7.74. Found: C, 71.77; H, 7.84.
1-P h en ylp r op -2-yn yl 2-ben zyl-3-oxobu ta n oa te (3k ): 1:1
mixture of diastereomers; chromatography, ethyl acetate/hexane
8). Anal. Calcd for C10 : C, 56.60; H, 5.70. Found: C, 56.31;
H
12
O
5
14 18 3
C H O
H, 5.84.
P r op -2-yn yl 2-isop r op yl-3-oxobu ta n oa te (3g): chroma-
tography, ether/hexane 8:92-10:90; IR 3282, 2130, 1746, 1717
cm ; H NMR δ 4.73 (d, J ) 2.5 Hz, 2 H), 3.25 (d, J ) 9.4 Hz,
1
1
1
-
1
1
8:92-10:90; IR 3290, 2129, 1745, 1718 cm ; H NMR δ 7.5-
7.1 (m, 10 H), 6.44 (pseudo t, J ) 6.5 Hz, 1 H), 3.16 (m, 2 H),
2.68 and 2.64 (2 d, J ) 2.2 Hz, 1 H), 2.18 and 2.08 (2 s, 3 H);
-
1 1
H), 2.51 (t, J ) 2.5 Hz, 1 H), 2.54-2.34 (m, 1 H), 2.24 (s, 3 H),
.00 (d, J ) 6.7, 3 H), 0.95 (d, J ) 6.7 Hz, 3H); 13C NMR δ 202.4,
68.4, 75.3, 67.1, 52.4, 29.3, 28.8, 20.5, 20.3; mass spectrum (CI)
+
mass spectrum (EI) m/z 306 (M , 1.5), 115 (HCdCdCHPh, 97),
43 (100). Anal. Calcd for C19
C, 78.40; H, 5.78.
24 3
H O : C, 78.41; H, 5.92. Found:
+
+
m/z 200 (M + 18), 183 (M + 1, 100). Anal. Calcd for C10
C, 65.91; H, 7.74. Found: C, 66.31; H, 7.47.
14 3
H O :
1-P en tylp r op -2-yn yl 2-ben zyl-3-oxobu ta n oa te (3l): 1:1
P r op -2-yn yl cycloh exa n on e-2-ca r boxyla te (3h ): chroma-
mixture of diastereomers; chromatography, ethyl acetate/hexane
-
1 1
tography, ether/hexane 6:94; IR 3290, 2130, 1752, 1711, 1655,
8:92-12:88; IR 3288, 2125, 1748, 1718 cm ; H NMR δ 7.35-
7.10 (m, 5 H), 5.40-5.25 (m, 1 H), 3.86-3.70 (m, 1 H), 3.20-
3.10 (m, 2 H), 2.44 (m, 1 H), 2.22 and 2.18 (2 s, 3 H), 1.80-1.55
(m, 2 H), 1.5-1.1 (m, 6 H), 0.95-0.78 (m, 3 H); mass spectrum
-
1 1
1
2
1
7
1
6
616 cm ; H NMR (enolic form) δ 11.96 (s, 1 H), 4.77 (d, J )
.5 Hz, 2 H), 2.50 (t, J ) 2.5 Hz, 1 H), 2.34-2.20 (m, 4 H), 1.76-
1
3
.50 (m, 4 H); C NMR (enolic form) δ 173.3, 171.7, 97.3, 77.9,
+
+
4.8, 51.6, 29.2, 22.3, 21.8; mass spectrum (CI) m/z 198 (M
+
(EI) m/z 300 (M , 7.5), 149 (50), 43 (100). Anal. Calcd for
+
8, 4), 181 (M + 1, 10). Anal. Calcd for C10
H
12
O
3
: C, 66.65; H,
C
19
H
24
O
3
: C, 75.97; H, 8.05. Found: C, 75.84; H, 8.09.
1-Meth ylbu t-3-yn yl 2-ben zyl-3-oxobu ta n oa te (3o): 1:1
mixture of diastereomers; chromatography, ethyl acetate/hexane
.71. Found: C, 66.59; H, 6.84.
P r op -2-yn yl 1-in d a n on e-2-ca r boxyla te (3i): 25% enolic
form; chromatography, ethyl acetate/hexane 15:85-20:80; mp
4-45 °C; IR 3290, 2130, 1748, 1713 cm-1; 1H NMR (only ketone
form) δ 7.80-7.35 (m, 4 H), 4.78 (pseudo t, J ) 2.3 Hz, 2 H),
.78 (X of ABX, dd, J ) 8.2, 4.3 Hz, 1 H), 3.58 (B of ABX, dd, J
-
1 1
1:9; IR 3290, 2122, 1738, 1715 cm ; H NMR δ 7.35-7.15 (m,
5 H), 5.00 (q, J ) 6.2 Hz, 1 H), 3.79 and 3.78 (2 pseudo t, J )
2.7 Hz, 1 H), 3.20-3.10 (m, 2 H), 2.41 and 2.35 (2 dd, J ) 5.9,
2.6 Hz, 2 H), 2.21 and 2.20 (2 s, 3 H), 1.99 and 1.95 (2 pseudo t,
4
3
)
2
1
3
3
4
1
3
17.3, 4.3 Hz, 1 H), 3.40 (A of ABX, dd, J ) 17.3, 8.2 Hz, 1 H),
J ) 2.6 Hz, 1 H), 1.29 and 1.21 (2 d, J ) 6.3 Hz, 3 H); C NMR
.51, (pseudo t, J ) 2.5 Hz, 1 H); 13C NMR (only ketone form) δ
δ 202.1, 168.5, 138.0, 128.8, 128.5, 126.6, 79.3, 70.8, 69.7, 61.3,
+
98.7, 168.4, 153.4, 135.5, 127.8, 126.5, 124.7, 75.4, 75.1, 52.9,
33.8, 29.5, 25.3, 18.8, 18.7; mass spectrum (EI) m/z (258, M ,
+
0.2; mass spectrum (EI) m/z 214 (M , 22), 130 (93), 71 (100),
7), 215 (51), 149 (70), 43 (100). Anal. Calcd for C16
74.39; H, 7.02. Found: C, 74.33; H, 7.06.
18 3
H O : C,
9 (HCdCdCH
.71. Found: C, 72.77; H, 4.80.
P r op -2-yn yl 1-m eth ylbicyclo[4.3.0]n on a n e-7-on e-8-ca r -
boxyla te (3j): 3:1 mixture of diastereomers; chromatography,
2 10 3
, 40). Anal. Calcd for C13H O : C, 72.89; H,
Ack n ow led gm en t. We thank Prof. J . Lhomme for
his interest in our work. Financial support from the
CNRS (UMR 5616) is gratefully acknowledged.
-
1
1
ethyl acetate/hexane 1:9; IR 3290, 2130, 1747, 1730 cm
NMR (major diastereomer) δ 4.73 (pseudo t, J ) 2.2 Hz, 2 H),
.37 (pseudo t, J ) 9.8 Hz, 1 H), 2.49 (pseudo t, J ) 2.5 Hz, 1
; H
3
J O9818172