48
Chemistry Letters Vol.36, No.1 (2007)
Reductive Ti-crossed Claisen Condensation between Methyl ꢀ-Bromocarboxylates
and Acid Chlorides Utilizing a TiCl4–PPh3–N-Methylimidazole Reagent
Akira Iida, Syogo Nakazawa, Hidefumi Nakatsuji, Tomonori Misaki, and Yoo TanabeÃ
Department of Chemistry, School of Science and Technology, Kwansei Gakuin University,
2-1 Gakuen, Sanda 669-1337
(Received September 20, 2006; CL-061095; E-mail: tanabe@kwansei.ac.jp)
O
O
O
Reductive Ti-crossed Claisen condensation between methyl
O
TiCl4 - PPh3 - additive
/ CH2Cl2, -45 oC, 1 h
+
ꢀ-bromocarboxylates and acid chlorides utilizing a TiCl4–PPh3–
N-methylimidazole reagent proceeded smoothly to give the
ꢀ-monosubstituted and thermodynamically unfavorable ꢀ,ꢀ-
disubstituted ꢁ-keto methyl esters in good to excellent yields
(33 examples; 73–96% yield).
Cl
OMe
OMe
Bu
Br
additive; none
DMAP
(33% yield, cross/self = 78/22)
(88% yield, cross/self = 95/5)
N
NMe
(89% yield, cross/self = 99/1)
Scheme 2.
The Claisen condensation is recognized as a fundamental
and useful C–C bond-forming reaction for obtaining ꢁ-keto
esters in organic syntheses.1 This reaction is categorized into
two types; (i) traditional base-mediated condensations using
MOR (M = Na and K), LDA, MHMDS (M = Li, Na, and K),
and MH (M = Na and K),1 and (ii) the Ti-Claisen condensa-
tion.2 The major problem of the Claisen condensation lies in
the difficulty in controlling the direction of the reaction: the
reaction of a mixture of two different esters, each of which
possesses an ꢀ-hydrogen, generally affords all four products.
To solve this problem, we recently reported a Ti-crossed Claisen
condensation3 and a NaOH-catalyzed crossed Claisen condensa-
tion.4
Hashimoto and co-workers reported an original reductive
Ti-crossed Claisen condensation and related reactions using
ꢀ-bromothioesters promoted by a Lewis acid–PPh3 reagent.5
This reductive Ti-crossed Claisen condensation,5a however, uses
less accessible and less atom-economical 2,4,6-triisopropyl-
phenyl ꢀ-bromothioesters and the yield of four examples was
moderate (50–78%). As part of our ongoing project to develop
practical Claisen condensations,2–4 we present here an efficient
reductive Ti-crossed Claisen condensation between a 1:1 mix-
ture of methyl ꢀ-bromocarboxylates 1 and acid chlorides using
a TiCl4–PPh3–N-methylimidazole reagent. The present method
provides not only accessible ꢀ-monosubstituted ꢁ-keto esters
2, but also thermodynamically unfavorable ꢀ,ꢀ-disubstituted
ꢁ-keto esters 3 (Scheme 1).
was employed as a co-catalyst, because acid chlorides are acti-
vated by these amines.3,7,8 As expected, the yield was markedly
increased (88 and 89%). N-methylimidazole was chosen as the
key co-catalyst based on its higher cross/self selectivity (99/1)
and cost-effectiveness.
Table 1 lists the successful results of the present reductive
Ti-crossed Claisen condensations between bromoesters 1a–1c
and acid chlorides to obtain various ꢀ-monoalkyl-ꢁ-ketoesters
Table 1. Crossed Claisen condensation between methyl ꢀ-
bromo-ꢀ-monosubstituted esters 1a–1c and acid chlorides
N
O
NMe
O
O
O
TiCl4 - PPh3
-
R2
R1
OMe
R1
Cl
+
OMe
/ CH2Cl2
R2
Br
(1.0 equiv.)
(1.0 equiv.)
1c: R2 = i-Pr
1a: R2 = Me 1b: R2 = Bu
2
α
-Bromo-
ester
Yield
/%a
95
Entry
Acid chloride
Cross/Self b
O
1
2
3
4
5
1a
1b
1c
1b
1c
1a
1b
98/2
99/1
99/1
99/1
99/1
96
86
93
86
Cl
8
O
Cl
7
O
6
7
81
76
99/1
99/1
Cl
The initial attempt was guided by the reaction between
methyl 2-bromohexanoate and cyclohexanecarbonyl chloride
using a TiCl4–PPh3 reagent (Scheme 2). The desired ꢁ-keto
ester, however, was obtained in low yield (33%) with ca. 10%
of undesirable self-condensation product, methyl 2-butyl-3-
oxooctanoate (mainly, decomposed cyclohexanecarboxylic
acid).6 To solve the problem, DMAP or N-methylimidazole
O
8
9
1b
1c
94
82
99/1
99/1
Cl
O
10
11
12
13
14
1a
1b
1c
1a
1b
1a
1b
1a
1b
90
77
83
85
93
99/1
99/1
99/1
99/1
99/1
Cl
O
Cl
Cl
3
N
NMe
O
O
O
O
O
TiCl4 - PPh3
-
O
15
16
84
91
97/3
99/1
R2
R3
R1
OMe
+
R1
OMe
MeO
Cl
6
Cl
Br
R2 R3
2: R2 = alkyl, R3 = H
3: R2 = alkyl, R3 = alkyl or phenyl
O
17
18
74
74
97/3
98/2
Cl
Cl
1
Cl
b
1
aIsolated. Determined by H NMR measurement.
Scheme 1.
Copyright Ó 2007 The Chemical Society of Japan