Reductive Ti-crossed Claisen condensation between methyl α-bromocarboxylates and acid chlorides utilizing a TiCl 4-PPh3-N-methylimidazole reagent

Article abstract of DOI:10.1246/cl.2007.48

Reductive Ti-crossed Claisen condensation between methyl α-bromocarboxylates and acid chlorides utilizing a TiCl ₄-PPh₃-N-methylimidazole reagent proceeded smoothly to give the α-monosubstituted and thermodynamically unfavorable α,α-

Full text of DOI:10.1246/cl.2007.48

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

Chemistry Letters Vol.36, No.1 (2007)
49
Table 2. Crossed Claisen condensation between methyl ꢀ-bro-
mo-ꢀ,ꢀ-disubstituted esters 1d–1f and acid chlorides
ꢀ-bromocarboxylates. The present method will provide a new
protocol for the synthesis of a variety of ꢀ-mono or ꢀ,ꢀ-disub-
stituted ꢁ-keto esters.
N
O
O
O
NMe
O
TiCl4 - PPh3
/ CH2Cl2,
-
R2
R3
+
R1
OMe
R1
Cl
OMe
This research was partially supported by Grant-in-Aids for
Scientific Research on Basic Areas (B) ‘‘18350056,’’ Priority
Areas (A) ‘‘17035087’’ and ‘‘18037068,’’ and Exploratory
Research ‘‘17655045’’ from MEXT.
R2 R3
Br
(1.0 equiv.)
(1.0 equiv.)
3
1e: R2= Me, R3= Et
1d: R2, R3= Me
1f: R2= Et, R3= Ph
Entry
1
2
3
4
5
6
7
8
Acid chloride
α
-Bromoester
Yield/%a
83
Dedicated to Prof. Teruaki Mukaiyama on the occasion of
his 80th birthday.
O
1d
1e
1f
1d
1e
1f
1d
1e
1f
1d
1e
1f
84
94
77
82
90
81
73
85
79
79
81
83
84
87
Cl
8
References and Notes
O
1
a) For examples: M. B. Smith, J. March, Advanced Organic
Chemistry, 5th ed., Benjamin, New York, 2001, p. 569. b)
K. P. C. Vollhardt, N. E. Schore, Organic Chemistry, 3rd ed.,
Freeman, New York, 1999, p. 1039. c) J. Clayden, N. Greeves,
S. Warren, P. Wothers, Organic Chemistry, Oxford University,
Cl
7
O
Cl
9
´
New York, 2001, p. 726. d) L. Kurti, B. Czako, Strategic Appli-
¨
O
10
11
12
13
14
15
cations of Named Reactions in Organic Synthesis, Elsevier,
Burlington, 2005, p. 86 and 138.
Cl
Cl
3
2
a) Y. Tanabe, Bull. Chem. Soc. Jpn. 1989, 62, 1917. b) Y.
Yoshida, R. Hayashi, H. Sumihara, Y. Tanabe, Tetrahedron
Lett. 1997, 38, 8727. c) Y. Yoshida, N. Matsumoto, R.
Hamasaki, Y. Tanabe, Tetrahedron Lett. 1999, 40, 4227. d) R.
Hamasaki, S. Funakoshi, T. Misaki, Y. Tanabe, Tetrahedron
2000, 56, 7423. e) Y. Tanabe, R. Hamasaki, S. Funakoshi,
Chem. Commun. 2001, 1674. f) Y. Tanabe, A. Makita, S.
Funakoshi, R. Hamasaki, T. Kawakusu, Adv. Synth. Catal.
2002, 507. g) Y. Tanabe, N. Manta, R. Nagase, T. Misaki,
Y. Nishii, M. Sunagawa, A. Sasaki, Adv. Synth. Catal. 2003,
345, 967.
O
O
1d
1e
1f
MeO
Cl
6
aIsolated.
2 (18 examples; 74–96%, cross:self = 97:3–99:1).9 Note that
the present reaction had consistently high cross-selectivity. This
result is consistent with the those of a Ti-crossed Claisen con-
densation.3 A terminal double bond, Cl atom, and methyl ester,
cyclopropane functionalities were tolerated during the present
reaction.
Next, we turned our attention to the reaction using methyl
ꢀ-bromo-ꢀ,ꢀ-disubstituted carboxylates 1d–1f. Because the
desired ꢁ-keto ester product 3 lacks the ability to form stable
ꢁ-keto ester metal enolates, the retro-Claisen condensation gen-
erally predominates.1 Nonetheless, the desired reaction proceed-
ed smoothly. Table 2 lists the successful results of the present
protocol for obtaining various ꢀ,ꢀ-dialkyl-ꢁ-ketoesters 3 (15
examples; 73–94%).9
A plausible reaction mechanism is as follows. Acid chro-
rides couple with N-methylimidazole to form reactive acyl-
ammonium intermediate 4. As Hashimoto’s group proposed,5
titanium enolate 5 is generated from ꢀ-bromoesters 1 by the
action of TiCl4–Ph3P. Finally, Ti-Claisen condensation between
4 and 5 proceeds to give ꢁ-ketoesters 2 or 3 (Scheme 3).
In conclusion, we developed a reductive Ti-crossed Claisen
condensation between a 1:1 mixture of acid chlorides and methyl
3
a) T. Misaki, R. Nagase, K. Matsumoto, Y. Tanabe, J. Am.
Chem. Soc. 2005, 127, 2854. b) A. Iida, S. Nakazawa, T.
Okabayashi, A. Horii, T. Misaki, Y. Tanabe, Org. Lett., in press.
A. Iida, K. Takai, T. Okabayashi, T. Misaki, Y. Tanabe, Chem.
Commun. 2005, 3171.
a) Y. Hashimoto, H. Konishi, S. Kikuchi, Synlett 2004, 1264.
b) H. Kagoshima, Y. Hashimoto, K. Saigo, Tetrahedron Lett.
1998, 39, 8465. c) Y. Hashimoto, S. Kikuchi, Chem. Lett.
2002, 126.
4
5
6
7
At present, the reason for obtaining of self-condensation product
is not so clear.
DMAP: a) W. Steglich, G. Hoefle, Angew. Chem., Int. Ed. 1969,
8, 981. b) E. F. V. Scriven, Chem. Soc. Rev. 1983, 12, 129. c)
A. C. Spivey, S. Arseniyadis, Angew. Chem., Int. Ed. 2004,
43, 5436.
8
9
N-Methylimidazole: a) A. K. Saha, P. Schultz, H. Rapoport, J.
Am. Chem. Soc. 1989, 111, 4856. b) F. S. Gibson, H. Rapoport,
J. Org. Chem. 1995, 60, 2615. c) K. Wakasugi, A. Iida, T.
Misaki, Y. Nishii, Y. Tanabe, Adv. Synth. Catal. 2003, 345,
1209. d) H. Nakatsuji, J. Morita, T. Misaki, Y. Tanabe, Adv.
Synth. Catal. 2006, 348, in press.
General procedure: PPh3 (210 mg, 0.8 mmol) in CH2Cl2
(1.0 mL) and TiCl4 (323 mg, 1.7 mmol) were successively added
to a stirred solution of an acid chloride (0.5 mmol), N-methyl-
imidazole (49 mg, 0.6 mmol), and an ꢀ-bromoester (0.5 mmol)
in CH2Cl2 (2.0 mL) at À45–À50 ꢀC under an Ar atmosphere,
followed by being stirred at same temperature for 1–2 h. The
mixture was quenched with water (5.0 mL), which was extracted
twice with ether. The combined organic phase was washed with
water, brine, dried (Na2SO4) and concentrated. The obtained
crude product was purified by SiO2-column chromatography
(Hexane/Et2O = 3:1–80:1) to give the desired product.
Cl-
O
O
R1
+
N
NMe
N
NMe
R1
Cl
+
O
O
4
R1
OMe
R2 R3
TiCl4
TiCl3
TiCl4
PPh3
-
2 or 3
O
O
R2
R3
R2
OMe
1
OMe
R3
Br
5
Ph3PBrCl
Ph3P
Scheme 3.
Published on the web (Advance View) December 16, 2006; doi:10.1246/cl.2007.48