NaOH-catalyzed crossed Claisen condensation between ketene silyl acetals and methyl esters

Article abstract of DOI:10.1039/b504750a

We have developed a practical crossed Claisen condensation between ketene silyl acetals and methyl esters using catalytic NaOH to obtain α-monoalkylated β-keto esters and inacces-sible α,α- dialkylated β-keto esters. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b504750a

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NaOH-catalyzed crossed Claisen condensation between ketene silyl
acetals and methyl esters{
Akira Iida, Kenta Takai, Tomohito Okabayashi, Tomonori Misaki and Yoo Tanabe*
Received (in Cambridge, UK) 6th April 2005, Accepted 25th April 2005
First published as an Advance Article on the web 20th May 2005
DOI: 10.1039/b504750a
Table 1 Crossed Claisen condensation between methyl esters 1 and
KSAs 2 derived from using a-monoalkylated estersa
We have developed a practical crossed Claisen condensation
between ketene silyl acetals and methyl esters using catalytic
NaOH to obtain a-monoalkylated b-keto esters and inacces-
sible a,a-dialkylated b-keto esters.
The Claisen condensation is recognized as a fundamental and
useful C–C bond forming reaction to obtain b-keto esters in
organic syntheses.1 There are several methods for reactions
utilizing basic reagents such as NaOR, NaH, LDA, LiHMDS,
etc.1 and Lewis acid reagents such as TiCl2(OTf)2, TiCl4 and
ZrCl4.2 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
a-hydrogens, generally affords all four products. Recently, as
one solution to this problem, a Ti-crossed Claisen condensation
was disclosed.3
Entry Ester
1
KSA Base
Yieldb (%)
trace
2a
TBAF
2
3
4
5
6
7
8
K2CO3 trace
LiOH
CsOH
KOH
trace
14
30
NaOH 48
NaOH 64
NaOH 58
2b
2b
The method utilizing ketene silyl acetals (KSAs), the activated
substrate of esters, is regarded to be another promising candidate
for resolution of this problem. The reported crossed Claisen
condensation using KSAs,4 however, lacks generality: (i) use of
acid chlorides as the electrophile, (ii) limitation of the electrophile
to aromatic and/or a,b-unsaturated acid chlorides that do not
contain a-hydrogens. Recently, Mukaiyama and coworkers
developed several base-catalyzed aldol-type reactions utilizing enol
silyl ethers and KSAs with carbonyl acceptors.5
9
10
PhCO2Me
2b
2b
NaOH 61
NaOH 57
a
In DMF at 15–20 uC for 1 h. Molar ratio; 1:2:Base 5 1.0:3.0:0.05.
Isolated.
b
In connection with our studies on the development of practical
Ti- (or Zr-) Claisen condensations3 and related aldol addition,6
originally exploited by the Evans group,7 we report here the
NaOH-catalyzed crossed Claisen condensation of KSAs 2, 3, and
4 derived from both a-monomethyl and a,a-dialkylated esters,
with methyl esters 1 to afford a variety of a-monoalkylated and
a,a-dialkylated b-keto esters 5, respectively (Scheme 1).
propanoate 2b8 increased the yield (Entry 7), probably because the
undesirable self condensation was sufficiently circumvented for tBu
propanoate, which was simultaneously produced during the
reaction. The reaction of 2b with some methyl esters 1 proceeded
in moderate to good yields (Entries 7–10).
Next, we focused our attention on the reaction of KSAs 3 and 4
of a,a-dialkylated esters with methyl esters 1. The retro-Claisen
condensation of a,a-dialkylated b-ketoesters 8 usually predomi-
nates, because the reversible equilibrium barely shifts from 7 to the
favorable production of 81 (Scheme 2) due to the fact that 8 lacks
the ability to force the formation of the stable b-ketoester enolate.
Ph3C2Na+9and ZrCl4–iPr2NEt2e reagents are powerful enough to
conduct this type of Claisen condensation between a,a-dialkylated
esters. A few serious problems, however, remain: (i) limited to self
condensation between same simple esters, (ii) phenyl esters must be
used in the case of ZrCl4–iPr2NEt, and (iii) low to moderate
reaction yields.
The initial trial was guided by the reaction of the KSA of methyl
propanoate 2a with methyl decanoate (Table 1, Entries 1–6).
Among bases screened, NaOH (0.05 equiv) promoted the desired
t
crossed condensation (Entry 6). The use of the KSA of Bu
Scheme 1
To overcome these problems, we examined the use of KSAs 3
and 4 derived from a,a-dialkylated esters for the formation of
inaccessible b-keto esters 9. Table 2 lists the successful results under
optimized conditions, and the salient features are as follows. (i)
{ Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b5/b504750a/
*tanabe@kwansei.ac.jp
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Chem. Commun., 2005, 3171–3173 | 3171

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the reaction, because the sp3 stereogenic center will be maintained.
Indeed, two optically active substrates underwent the reaction
without racemization (Entries 19 and 20).
A plausible reaction mechanism (catalytic cycle) is proposed in
Scheme 3 as exemplified by the reaction between KSA 3 and
a-monoalkylated linear methyl ester 10 (Scheme 3). First, the ester
enolate 11 generated by HO2 condenses with 10 to give the
b-ketoester 12 with the elimination of MeO2. Next, MeO2 attacks
3 to give 11, which in turn condenses with 12 to give ketone enolate
13. 13 receives the TMS group from 3 to give the desired TMS
enolate 14 by reforming 11. Thus, more than 2 equiv of KSA were
required to complete the reaction.
Scheme 2
Surprisingly, the crossed-Claisen condensation using KSAs 3 and
4, which looked like less reactive nucleophiles than KSAs 2,
proceeded smoothly and the yields were good to excellent in every
case examined. (ii) As an apparent tendency, the reaction using
linear esters 1 (R2 5 H) predominantly gave enol silyl enolates
form 9A of the parent b-keto esters, whereas that of branched
esters (R1 and R2 ? H) exclusively afforded b-keto esters 9B. (iii)
Silyl enolates 9A was easily converted to b-keto esters form 9B on
treatment with aqueous 1 M HCl. (iv) Several functionalities, such
as an acetal, an epoxide, a tert-butyl ester, a cyclopropane, and an
indole, and a benzyloxy, tolerated the reaction conditions (Entries
9–18). (v) Feature (ii) ensures that the use of optically active methyl
lactate and alanine methyl ester analogs will not racemize during
Finally, we planned the Mukaiyama aldol reaction (Method A)
and Ti-direct aldol reaction (Method B) for further useful
functionalization of both the obtained a,a-dialkylated b-keto
esters 9A and their TMS enolates 9B, all of which are novel
compounds. Table 3 lists these results. All six examples were
successfully performed: a9-octyl substrate predominantly gave syn
aldol-adducts (Entries 1–4), whereas a-benzyloxy substrate gave
anti aldol-adducts (Entries 5 and 6). This stereoselectivity was
significantly enhanced by the Ti-direct method B. We propose that
Table 2 NaOH-catalyzed crossed Claisen condensation between methyl esters 1 and KSAs 3, 4 derived from a,a-dialkylated estersa
Entry Ester
KSA Yieldb (%) A:B
Entry Ester
KSA Yieldb (%) A:B
1
2
3
4
99
98
82:18
92:8
13
14
3
4
85
90
51:49
54:46
3
4
3
4
88
87
59:41
93:7
15
16
3
4
89
88
0:100
0:100
5
6
PhCO2Me
3
4
85c
94c
—
—
17
3
67e
—
7
8
3
4
83
82
0:100
0:100
18
3
3
85
85
100:0
9
3
4
88d
91d
77:23
86:14
19f
0:100g
10
11
12
3
4
83
92
42:58
27:73
20f
3
89g
0:100h
a
b
c
d
In DMF at 15–20 uC for 1 h. Molar ratio; 1:3 (or 4) :NaOH 5 1.0:2.4:0.05. Isolated. KSA 3 or 4 is 1.2 equiv. Reaction time is 3 h.
e
f
Because 9A and 9B were not separable, the mixture was treated with 1 M HCl to convert 9A into 9B. Reaction temperature is 0 uC.
97% ee by HPLC analysis. 95% ee by HPLC analysis.
g
h
3172 | Chem. Commun., 2005, 3171–3173
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extension of the present method. Because the Claisen condensation
of a,a-dialkylated esters is very difficult, the present method
provide a new avenue for the preparation of inaccessible
b-ketoesters.{
We thank Kuraray Co. Limited, for generous gift of methyl
dichlorovinylcrysanthemate.
Akira Iida, Kenta Takai, Tomohito Okabayashi, Tomonori Misaki and
Yoo Tanabe*
Department of Chemistry, School of Science and Technology, Kwansei
Gakuin University, 2-1 Gakuen, Sanda, Hyogo, 669-1337, Japan.
E-mail: tanabe@kwansei.ac.jp; Fax: (+81)79-565-9077;
Tel: (+81)79-565-8394
Notes and references
{ Typical procedure: [(1-Methoxy-2-methyl-1-butenyl)oxy]trimethylsilane
(452 mg, 2.40 mmol) was added to a stirred solution of methyl decanoate
(186 mg, 1.0 mmol) and NaOH (crushed powder prepared under dry
atmosphere; 2 mg, 0.05 mmol) in DMF (0.2 cm3) at 15–20 uC under an Ar
atmosphere, and the reaction mixture was stirred at that temperature for
1 h. Water was added to the reaction mixture, which was extracted with
ether. The organic phase was washed with water, brine, dried (Na2SO4) and
concentrated. The obtained crude product was purified by silica-gel column
chromatography (hexane:ether 5 30:1 y 100:1) to give methyl 2,2-
dimethyl-3-(trimethylsiloxyl)dodec-3-enoate (A) (colorless oil, 270 mg, 82%)
and methyl 2,2-dimethyl-3-oxododecanoate (B) (colorless oil, 44 mg, 17%).
See ESI for NMR data.
Scheme 3
Table 3 Ti-Aldol reactions of crossed Claisen adduct 9A and 9B with
aldehydes
Method A (Mukaiyama Aldol Reaction)a
1 (a) For example, M. B. Smith and J. March, Advanced Organic
Chemistry, Benjamin, New York, 5 th edn., 2001, p. 569; (b) K. P.
C. Vollhardt and N. E. Schore, Organic Chemistry, 3rd edn., Freeman,
New York, 1999, p. 1039; (c) J. Clayden, N. Greeves, S. Warren and
P. Wothers, Organic Chemistry, Oxford University, New York, 2001,
p. 726.
Method B (Ti - Direct Aldol Reaction)b
2 (a) Y. Tanabe, Bull. Chem. Soc. Jpn., 1989, 62, 1917; (b) Y. Yoshida,
R. Hayashi, H. Sumihara and Y. Tanabe, Tetrahedron Lett., 1997, 38,
8727; (c) Y. Yoshida, N. Matsumoto, R. Hamasaki and Y. Tanabe,
Tetrahedron Lett., 1999, 40, 4227; (d) R. Hamasaki, S. Funakoshi,
T. Misaki and Y. Tanabe, Tetrahedron, 2000, 56, 7423; (e) Y. Tanabe,
R. Hamasaki and S. Funakoshi, Chem. Commun., 2001, 1674; (f)
Y. Tanabe, A. Makita, S. Funakoshi, R. Hamasaki and T. Kawakusu,
Adv. Synth. Catal., 2002, 507; (g) Y. Tanabe, N. Manta, R. Nagase,
T. Misaki, Y. Nishii, M. Sunagawa and A. Sasaki, Adv. Synth. Catal.,
2003, 345, 967; (h) Y. Hashimoto, H. Konishi and S. Kikuchi, Synlett,
2004, 1264.
Entry R1
R2
Method Product Yieldc (%) syn:antid
1
2
3
4
5
6
a
Octyle Ph
A
B
A
B
A
B
73
78
80
83
67
80
93:7
93:7
72:28
.99:1
25:75
2:98
Pentyl
BnOf Ph
3 T. Misaki, R. Nagase, K. Matsumoto and Y. Tanabe, J. Am. Chem.
Soc., 2005, 127, 2854.
4 (a) M. W. Rathke and D. F. Sullivan, Tetrahedron Lett., 1973, 15, 1297;
(b) M. H. Stefaniak, Synlett, 1997, 677.
In CH2Cl2, 245 to 250 uC for
1
h. Molar ratio;
b
5 (a) H. Fujisawa and T. Mukaiyama, Chem. Lett., 2002, 182; (b)
H. Fujisawa and T. Mukaiyama, Chem. Lett., 2002, 858; (c)
T. Mukaiyama and H. Fujisawa, Helv. Chim. Acta, 2002, 85, 4518.
6 (a) Y. Tanabe, N. Matusmoto, S. Funakoshi and N. Manta, Synlett,
2001, 1959; (b) Y. Tanabe, N. Matsumoto, T. Higashi, T. Misaki, T. Itoh,
M. Yamamoto, K. Mitarai and Y. Nishii, Tetrahedron, 2002, 58, 8269; (c)
Y. Tanabe, K. Mitarai, T. Higashi, T. Misaki and Y. Nishii, Chem.
Commun., 2002, 2542.
7 (a) D. A. Evans, F. Urpi, T. C. Somers, J. S. Clark and M. T. Bilodeau,
J. Am. Chem. Soc., 1990, 112, 8215; (b) D. A. Evans, D. L. Rieger,
M. T. Bilodeau and F. Urpi, J. Am. Chem. Soc., 1991, 113, 1047; (c)
D. A. Evans, J. S. Clark, R. Metternich, V. J. Novack and
G. S. Sheppard, J. Am. Chem. Soc., 1990, 112, 866.
9A:aldehydes:TiCl4 5 1.0:1.2:1.2. In CH2Cl2, 0–5 uC for 2 h.
Molar ratio; 9B:aldehydes:TiCl4:Bu3N 5 1.0:1.2:1.2:1.4. Isolated.
c
d
e
f
Determined by 1H-NMR. 9A (E:Z 5 1:.99) was used. 9A
(E:Z 5 5:95) was used.
the syn mechanism utilizes the conventional six-membered chair
transition state, whereas the anti mechanism utilizes a benzoyloxy-
coordination boat mechanism (See ESI{).
In conclusion, we developed a new mild, catalytic, practical and
efficient method for preparing various b-ketoesters using a-mono
or a,a-dialkylated KSAs and catalytic NaOH. Further functiona-
lization utilizing two Ti-aldol reactions demonstrates a notable
8 J. Otera, Y. Fujita and S. Fukuzumi, Synlett, 1994, 213.
9 C. R. Hauser and W. B. Renfrow, Jr., J. Am. Chem. Soc., 1937, 59, 1823.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 3171–3173 | 3173