Powerful Ti-crossed Claisen condensation between ketene silyl acetals or thioacetals and acid chlorides or acids

Article abstract of DOI:10.1021/ol0619361

A powerful Ti-crossed Claisen condensation between ketene silyl acetals (KSAs) and acid chlorides was successfully performed to give α-monoalkylated esters and thermodynamically unfavorable (less accessible) α,α-dialkylated β-keto esters in good yield (46

Full text of DOI:10.1021/ol0619361

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5215-5218
Powerful Ti-Crossed Claisen
Condensation between Ketene Silyl
Acetals or Thioacetals and Acid
Chlorides or Acids
Akira Iida, Syogo Nakazawa, Tomohito Okabayashi, Atsushi Horii,
Tomonori Misaki, and Yoo Tanabe*
Department of Chemistry, School of Science and Technology, Kwansei Gakuin
UniVersity, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan
tanabe@kwansei.ac.jp
Received August 4, 2006
ABSTRACT
A powerful Ti-crossed Claisen condensation between ketene silyl acetals (KSAs) and acid chlorides was successfully performed to give
-monoalkylated esters and thermodynamically unfavorable (less accessible) -dialkylated -keto esters in good yield (46 examples; 41
98% yield). A closely related reaction between ketene silyl thioacetals (KSTAs) and acid chlorides also proceeded smoothly to give
r
r
,
r
â
−
r
-monoalkylated and
r
,
r
-dialkylated
â
-keto thioesters (21 examples; 61
−97% yield). The present protocol was extended to the direct condensation
of KSAs with carboxylic acids (14 examples; 71
−97% yield).
The Claisen condensation is recognized as a fundamental
and useful C-C bond-forming reaction for obtaining â-keto
esters in organic syntheses.1 This reaction is categorized into
two types: (i) traditional base-mediated condensations using
MOR (M ) Na, K), LDA, MHMDS (M ) Li, Na, K), and
MH (M ) Na, K)2 and (ii) the Ti-Claisen condensation.3
These methods, however, are limited to reactions of
R-monoalkylated ester substrates 1 and cannot be applied
to reactions of R,R-dialkylated esters 3 because the retro-
Claisen condensation generally predominates; 4 lacks the
ability to form stable â-keto ester metal enolates (Scheme
1).1,4,5
Scheme 1. Traditional Claisen Condensation Using R-Mono-
and R,R-Disubstituted Esters
A recently reported NaOH-catalyzed crossed Claisen
condensation of ketene silyl acetals (KSAs) with methyl
esters5 provides one solution to this issue.6 Two drawbacks,
however, remain: (i) 3 equiv of KSAs (vs esters) is generally
required to complete the reaction and (ii) the carbonyl
acceptor (methyl esters) should be simple and reactive. As
(1) (a) For examples, see: Smith, M. B.; March, J. AdVanced Organic
Chemistry, 5th ed.; John Wiley: New York, 2001; p 569. (b) Vollhardt, K.
P. C.; Schore, N. E. Organic Chemistry, 3rd ed.; Freeman: New York,
1999; p 1039. (c) Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. Organic
Chemistry; Oxford: New York, 2001; p 726. (d) Ku¨rti, L.; Czako´, B.
Strategic Applications of Named Reactions in Organic Synthesis; Elsevier:
Burlington, 2005; p 86 and p 138.
10.1021/ol0619361 CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/20/2006

part of our ongoing project to develop practical Claisen
condensations,3-5 we present here an efficient powerful Ti-
crossed Claisen condensation of KSAs 5a-f, derived from
both R-monoalkylated and R,R-dialkylated esters, with
carboxylic acid chlorides or their parent acids (Scheme 2).
Table 2. Claisen Condensation between KSAs 5 and Acid
Chlorides
Scheme 2. Ti-Crossed Claisen Condensation Using Ketene
Silyl Acetals (KSAs) and Ketene Silyl Thioacetals (KSTAs)
In addition, a closely related condensation between ketene
silyl thioacetal acetals (KSTAs) 6a-e and acid chlorides was
performed. The present method, giving a variety of â-keto
esters and thioesters, proved to be the most powerful among
hitherto reported Claisen condensations.
The initial attempt was guided by the reaction between
KSA 5a (1.5 equiv) of methyl 2-methylpropionate and deca-
noyl chloride using several Lewis acid reagents (BF3·Et2O,
AlCl3, ZnBr2, SnCl4, ZrCl4, TiCl4) (Table 1). Although a BF3·
Table 1. Screening of Lewis Acids
Entry
Lewis acid
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
Yield/%a
1
2
3
4
5
6
7
8
BF3·Et2O
AlCl3
ZnBr2
SnCl4
ZrCl4
TiCl4
TiCl4
TiCl4
trace
61
57
23
66
80
72
85
chlorobenzene
1
a Determined by H NMR.
Et2O-promoted Claisen-type condensation between KSAs
and aryl-type acid chlorides was reported,7 the corresponding
reaction did not proceed (entry 1). Among five Lewis acids,
TiCl4 produced the best result (entry 6). Chlorobenzene, CH2-
Cl2, and toluene were used as solvents (entries 6-8).
Table 2 lists the successful results of the present Ti-crossed
Claisen condensation using a variety of KSAs 5a-f and acid
a Isolated.
chlorides. The salient features are as follows: (i) The
reaction, using both aliphatic and aromatic acid chlorides,
proceeded smoothly to give the corresponding â-keto esters
(2) (a) Fisher, N.; McElvain, S. M. J. Am. Chem. Soc. 1934, 56, 1766.
(b) Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001, 42, 7983.
(c) Cooke, M. P., Jr. J. Org. Chem. 1993, 58, 2910. (d) Loubinoux, B.;
Sinnes, J.-L.; O’Sullivan, A. C. J. Chem. Soc., Perkin Trans. 1 1995, 521.
(e) Lombart, H.-G.; Lubell, W. D. J. Org. Chem. 1994, 59, 6147. (f) Austad,
B. C.; Hart, A. C.; Burke, S. D. Tetrahedron 2002, 58, 2011. (g) Brown,
C. A. Synthesis 1975, 326. (h) McMurry, J. E.; Fleming, M. P.; Kees, K.
L.; Krepski, L. R. J. Org. Chem. 1978, 43, 3255.
(3) (a) Tanabe, Y. Bull. Chem. Soc. Jpn. 1989, 62, 1917. (b) Crane, S.
N.; Corey, E. J. Org. Lett. 2001, 3, 1395. (c) Tanabe, Y.; Makita, A.;
Funakoshi, S.; Hamasaki, R.; Kawakusu, T. AdV. Synth. Catal. 2002, 344,
507. (d) Tanabe, Y.; Manta, N.; Nagase, R.; Misaki, T.; Nishii, Y.;
Sunagawa, M.; Sasaki, A. AdV. Synth. Catal. 2003, 345, 967. (e) Hashimoto,
Y.; Konishi, H.; Kikuchi, S. Synlett 2004, 1264. (f) Misaki, T.; Nagase, R.;
Matsumoto, K. Tanabe, Y. J. Am. Chem. Soc. 2005, 127, 2854. Other
references cited therein.
5216
Org. Lett., Vol. 8, No. 23, 2006

in good to excellent yield (28 examples; 41-98%). (ii) KSA
equivalents of 5a were significantly reduced to 1.5, compared
with the NaOH-catalyzed method, in which 3 equiv was
used.5 (iii) Terminal double bond, δ-chloro, and methyl ester
functionalities were tolerated (entries 15-20) (note that
methyl esters function as electrophiles in the NaOH-catalyzed
method). (iv) Sterically congested KSA 5c bearing ethyl and
phenyl groups in R,R-positions resulted in a moderate yield
(entry 3). (v) R-Monoalkylated KSAs 5d-f, however, gave
the products in low yield) (vide infra, Table 4).
97%). Note that good yield was obtained using sterically
congested and R-monoalkylated KSTAs 6d and 6e (entries
4, 5, 7, 12, 15, and 19).
Next, to solve the lower yield problems referred to above
in (iv) and (v) using KSAs 5c-f, N-methylimidazole was
employed as a key cocatalyst because acid chlorides con-
dense with N-methylimidazole to form an activated acylam-
monium electrophilic intermediate 29.3f,8 As expected, the
yield was markedly improved using a combined reagent,
TiCl4/N-methylimidazole, giving the desired â-keto esters
(Table 4). We speculate that TiCl4 coordinates with the
The relevant reaction between KSTAs 6a-e and acid chlor-
ides was investigated. Table 3 lists the successful results.
Table 4. Ti-Crossed Claisen Condensation between Less
Reactive KSAs 5c-f and Acid Chlorides
Table 3. Claisen Condensation between KSTAs 6a-e and
Acid Chlorides
a Isolated. b Use of DMAP instead of N-methylimidazole. c 20-25 °C.
d -40 to -45 °C.
a Isolated. b 0-5 °C.
carbonyl oxygen of 29 to afford a highly reactive, double-
activated acylammonium intermediate 30. Terminal double
bond, Cl atom, and methyl ester functional groups were also
Similar to the case using KSAs, a variety of â-keto thioesters
were obtained in good to excellent yield (21 examples; 61-
Org. Lett., Vol. 8, No. 23, 2006
5217

tolerated during this reaction (entries 5-13). Greenwald and
co-workers reported a relevant mechanism during an efficient
esterification of tertiary alcohols utilizing a double-activated
acylammonium intermediate, derived from a Sc(OTf)3/
DMAP reagent.9
Screening of sulfonyl chlorides revealed that 2,5-dichlo-
robenzenesulfonyl chloride gave the best result (entry 7).
Note that DMAP (82%) produced somewhat better results
than N-methylimidazole (73%) under conditions identical to
those of entry 7.
The three methods presented here have a higher reactivity
than the related NaOH-catalyzed method between KSAs and
methyl ester. Indeed, the reactions using 5c-f in the NaOH-
catalyzed method did not proceed (low yield).
Finally, the present protocol was extended to Ti-crossed
Claisen condensation using parent carboxylic acids as the
electrophile. We expected the formation of double-activated
acylammonium intermediate 33, which was coordinated with
TiCl4 (Table 5). A plausible mechanism is as follows: Mixed
On the basis of this result, Ti-crossed Claisen condensa-
tions between KSAs 5a-c and several carboxylic acids were
successfully performed to give the desired â-keto esters in
good to excellent yield (Table 6) (14 examples; 71-97%
yield).
Table 6. Ti-Crossed Claisen Condensation between KSAs and
Carboxylic Acids
Table 5. Screening of Sulfonyl Chlorides for the Reaction of
Carboxylic Acids
a Isolated.
In conclusion, we developed a Ti-crossed Claisen con-
densation between a number of KSAs (or KSTAs) of
R-monoalkylated esters and less accessible R,R-dialkylated
esters and acid chlorides (or acids) (81 examples total). The
present method exhibited high reactivity and generality,
which will provide a new avenue for the Claisen condensa-
tion.
a Determined by 1H NMR. b Parentheses indicate the cases using
N-methylimidazole instead of DMAP.
anhydride 31 is initially formed in situ between decanoic
acid and a sulfonyl chloride in the presence of Et3N as an
acid scavenger. Similar to the reaction shown in Table 4, 31
is transformed to reactive intermediate 33 through acylam-
monium 32 with DMAP.
Acknowledgment. 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.
(4) ZrCl4-mediated condensation of aryl R,R-dialkylated esters was
reported; however, it was limited to self-Claisen condensation. Tanabe, Y.;
Hamasaki, R.; Funakoshi, S. Chem. Commun. 2001, 1674.
(5) Iida, A.; Takai, K.; Okabayashi, T.; Misaki, T.; Tanabe, Y. Chem.
Commun. 2005, 3171.
(6) Recently, a catalytic enantioselective version was disclosed. Mer-
menrian, A. H.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 5804.
(7) Stefaniak, M. H. Synlett 1997, 677.
Supporting Information Available: The experimental
procedure and compound characterization data. This material
is available free of charge via the Internet at http://
pubs.acs.org.
(8) Wakasugi, K.; Iida, A.; Misaki, T.; Nishii, Y.; Tanabe, Y. AdV. Synth.
Catal. 2003, 345, 1209.
(9) Zhao, H.; Pendri, A.; Greenwald, R. B. J. Org. Chem. 1998, 63, 7559.
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