TTMPP catalyzed one-pot silyl ketene acetal-imine condensation route to β-lactams

Article abstract of DOI:10.1246/cl.2004.1626

Highly nucleophilic phosphine, tris(2,4,6-trimethoxy phenyl) phosphine (TTMPP) catalyzes a unique one-pot cyclization reaction between silyl ketene acetal and aldimine, resulting in β-lactam. Copyright

Full text of DOI:10.1246/cl.2004.1626

1626
Chemistry Letters Vol.33, No.12 (2004)
TTMPP Catalyzed One-pot Silyl Ketene Acetal–Imine Condensation Route to ꢀ-Lactams
Satoru Matsukawaà and Kayoko Obu
Department of Science, Faculty of Education, Ibaraki University, Mito, 310-8512
(Received September 28, 2004; CL-041143)
Highly nucleophilic phosphine, tris(2,4,6-trimethoxy phen-
yl) phosphine (TTMPP) catalyzes a unique one-pot cyclization
reaction between silyl ketene acetal and aldimine, resulting in
ꢀ-lactam.
lyzed aldol reaction proceeded smoothly, and the one-pot forma-
tion of ꢀ-lactam was observed.8
Next, we investigated the mechanism of this one-pot forma-
tion of ꢀ-lactam. It is well recognized that ꢀ-lactams are directly
formed from metal enolates and aldimines.1a Under these condi-
tions, ꢀ-amino ester was generally obtained in shorter reaction
times and/or at lower temperatures, whereas ꢀ-lactam was ob-
tained in longer reaction times and/or at higher temperatures.
These results were interpreted as evidence for a two-step con-
densation-cyclization mechanism in which cyclization was rate
determining. To confirm the mechanism, this TTMPP catalyzed
reaction was carried out under various conditions. The product
was obtained in lower yields when the reaction time was re-
duced, but the selectivity remained fairly constant. Longer reac-
tion times did not increase the selectivity (Table 1, Entries 2 vs
6–8). Furthermore, the ꢀ-lactam selectivity was found to be al-
most the same, regardless of the temperature(Table 1, Entries 2
vs 9, 10).
On the basis of these results, it seems that cyclization is not
rate determining for this TTMPP catalyzed reaction. In the pres-
ent reaction, naked enolate (a)9 was produced via nucleophilic
O–Si bond cleavage by TTMPP.7 Then reacted with aldimine
to produce naked anion intermediate (b). This anion intermediate
is unstable, so that it rapidly cyclize to afford ꢀ-lactam
(Scheme 1). In this reaction, we consider that the condensation
step, espacially in the O–Si bond cleavage step, is rate determin-
ing, unlike in the reaction of metal enolate.
The addition of silyl ketene acetals to aldimines is an impor-
tant synthetic method for the preparation of ꢀ-lactams.1,2 There-
fore, numerous kinds of activators have been developed,3 and
highly enantioselective reactions have been reported.4 In these
reactions, ꢀ-amino ester is obtained as a precursor of ꢀ-lactam.
On the other hand, reactions using metal-free and uncharged or-
ganic molecules as activators have recently attracted attention
from the viewpoint of their environmentally benign nature.5 In
our previous study, highly nucleophilic phosphine, tris(2,4,6-tri-
methoxyphenyl)phosphine (TTMPP)6 was shown to catalyze the
aldol reaction of silyl ketene acetal and aldehydes.7 Herein, we
report an unprecedented one-pot cyclization reaction between
silyl ketene acetal and aldimine catalyzed by TTMPP to afford
ꢀ-lactam.
Initially, the reaction of N-phenylaldimine and trimethylsil-
yl ketene acetal, derived from methyl isobutylate, was examined
in various solvents (Table 1, Entries 1–5). Interestingly, ꢀ-lac-
tam along with ꢀ-amino ester is obtained in THF. Furthermore,
with the use of DMF as the solvent, mainly ꢀ-lactam was
formed. Only trace amounts of product were obtained using
Et2O, CH3CN, and CH3OH. Thus, in DMF, the TTMPP cata-
In order to clarify the scope of this TTMPP catalyzed ꢀ-
lactam selective reaction, several aldimines were examined in
the presence of TTMPP (Table 2). ꢀ-Lactam was obtained in
good yields and with a high level of selectivity. Moderate trans
selectivity was observed irrespective of the geometry of the silyl
Table 1. Optimization of the reaction conditions
OMe
MeO
Ph
H
P
N
+
OMe
3
Ph
(TTMPP)
O
OSiMe3
PhNH
Ph
O
Ar3P+SiMe3
(20 mol%)
solvent
+
N
OMe
O–
OMe
Ph
Ph
H
TTMPP
N
Ph
Ph
rt
OSiMe3
OMe
+
+
1
2
OMe
(a)
R
N
Entry
Solvent
Time
Yield / %
(1:2)a
R
H
1
2
3
4
5
6
7
8
THF
DMF
Et2O
CH3OH
CH3CN
DMF
DMF
DMF
DMF
DMF
1 h
1 h
92
96
0
0
8
33
78
95
42
88
44:56
92:8
Ar3P+SiMe3
O
12 h
12 h
12 h
5 min
15 min
18 h
1 h
–
fast
PhN
O
+
MeO–
N
24:76
88:12
92:8
89:11
84:16
90:10
R
OMe
Ph
R
1
(b)
Ar3P+SiMe3 + MeO–
9b
10c
Ar P
MeOSiMe3
+
3
(TTMPP)
1 h
aRatio was determined by 1H NMR analysis. bat 0 ꢀC. c50 ꢀC.
Scheme 1.
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.12 (2004)
1627
Table 2. TTMPP catalyzed one-pot formation of ꢀ-lactams
1981, 545.
3
a) K. Ikeda, K. Achiwa, and M. Sekiya, Tetrahedron Lett., 24,
4707 (1983). b) E. W. Colvin and D. G. Mckarry, J. Chem.
Soc., Chem. Commun., 1985, 539. c) R. A. Pilli and D. J.
Russowsky, J. Chem. Soc., Chem. Commun., 1987, 1053.
d) T. Mukaiyama, K. Kashiwagi, and S. Matsui, Chem. Lett.,
1989, 1397. e) T. Mukaiyama, H. Akamatsu, and J. S. Han,
Chem. Lett., 1990, 889. f) M. Onaka, R. Ohno, N. Yanagiya,
and Y. Izumi, Synlett, 1993, 141. g) K. Ishihara, M.
Funahashi, N. Hanaki, M. Miyata, and H. Yamamoto, Synlett,
1994, 963. h) S. Kobayashi, M. Araki, H. Ishitani, and I.
Hachiya, Synlett, 1995, 233. i) S. Kobayashi and S.
Nagayama, J. Am. Chem. Soc., 119, 10049 (1997). j) R.
Hayakawa and M. Shimizu, Chem. Lett., 1999, 591. k) T.
Akiyama, J. Takaya, and H. Kagoshima, Synlett, 1999,
1045. l) K. Miura, K. Tamaki, T. Nakagawa, and A. Hosomi,
Angew. Chem., Int. Ed., 39, 1958 (1999). m) H. Fujisawa, E.
Takahashi, T. Nakagawa, and T. Mukaiyama, Chem. Lett.,
32, 1036 (2003).
Ph
N
O
R2
R1
H
TTMPP
NHPhO
(20 mol%)
+
+
N
R1
OMe
DMF, rt, 1h
OSiMe3
Ph
R1
R2
1
2
R2
OMe
Entry
R1
R2
Yield / %
(1:2)a
1
2
3
4
5
6
7
p-Tol
4-CF3Ph
4-ClPh
4-MeOPh
4-NO2Ph
1-Naphtyl
3-Pyridyl
Ph
Me
Me
Me
Me
Me
Me
Me
H
92
96
94
100
77
85
96
46
55
b
84:16
92:8
91:9
80:20
84:16
90:10
78:22
80c:20
76e:24
c
8b
9d
4
For asymmetric reactions, see: a) K. Ishihara, M. Miyata, K.
Hattori, T. Tada, and H. Yamamoto, J. Am. Chem. Soc., 116,
10520 (1994). b) H. Ishitani, M. Ueno, and S. Kobayashi,
J. Am. Chem. Soc., 119, 7153 (1997). c) S. Kobayashi, H.
Ishitani, and M. Ueno, J. Am. Chem. Soc., 120, 431 (1998).
Ph
H
aRatio was determined by H NMR analysis. 75% E. cis/
1
trans = 34:66. d88% Z. cis/trans = 37:63.
e
Ph
N
d) R. Muller, H. Goesmann, and H. Waldmann, Angew.
¨
Chem., Int. Ed., 38, 184 (1999). e) E. Hagiwara, A. Fujii,
and M. Sodeoka, J. Am. Chem. Soc., 120, 2474 (1998).
f) D. Ferraris, B. Young, T. Dudding, and T. Lectka, J. Am.
Chem. Soc., 120, 4548 (1998). g) S. Xue, S. Yu, Y. Deng,
and W. D. Wulff, Angew. Chem., Int. Ed., 40, 2271 (2001).
h) S. Kobayashi, T. Hamada, and K. Manabe, J. Am. Chem.
Soc., 124, 5640 (2002). i) B. M. Trost and L. R. Terrell,
J. Am. Chem. Soc., 125, 338 (2003). j) S. Matsunaga, N.
Kumagai, S. Harada, and M. Shibasaki, J. Am. Chem. Soc.,
125, 4712 (2003). k) T. Akiyama, J. Itoh, K. Yokota, and
K. Fuchibe, Angew. Chem., Int. Ed., 43, 1566 (2004).
a) S. Kobayashi, C. Ogawa, H. Konishi, and M. Sugiura,
J. Am. Chem. Soc., 125, 6610 (2003). b) C. Ogawa, M.
Sugiura, and S. Kobayashi, Chem. Commun., 2003, 192.
a) M. Wada and S. Higashizaki, J. Chem. Soc., Chem. Com-
mun., 1984, 482; Recent report of the reaction using TTMPP,
Ar3P+SiMe3
Me
O
–
PhN
O
R
H
N
–O
OMe
R
OMe
Ph
R
Ar3P+–SiMe3
trans
Scheme 2.
ketene acetal, which was derived from methyl propionate
(Table 2, Entries 8, 9). This observed stereoselectivity was deter-
mined in the condensation step. It can be reasonably explained
by considering an extended transition state (Scheme 2). A typical
experimental procedure is as follows: To a solution of aldimine
(1 mmol) and TTMPP (0.2 mmol) in DMF (2 mL), silyl ketene
acetal (1.5 mmol) was added at room temperature. The reaction
was monitored by TLC. After one hour, the mixture was
quenched with water. A general work-up and purification by
flash column chromatography resulted in the desired product.
In summary, we disclose that TTMPP catalyzes a unprece-
dented one-pot cyclization reaction between silyl ketene acetal
and aldimine to afford ꢀ-lactam. Further investigations along
these lines, including stereoselective reactions, are currently un-
derway.
5
6
see: b) S. Roper, R. Wartchow, and M. R. Hoffmann, Org.
¨
Lett., 4, 3179 (2002). c) H. Kawabata and M. Hayashi,
Tetrahedron Lett., 43, 5645 (2002). d) K. Yoshimoto, H.
Kawabata, N. Nakamichi, and M. Hayashi, Chem. Lett.,
2001, 934. e) S. M. Maddock and M. G. Finn, Organometal-
lics, 19, 2684 (2000).
S. Matsukawa, N. Okano, and T. Imamoto, Tetrahedron Lett.,
41, 103 (2000).
Other phsophines, such as triphenylphosphine, tricyclohexyl
phosphine, tributylphosphine and triisopropylphosphine, did
not catalyze this reaction.
a) I. Kuwajima and E. Nakamura, J. Am. Chem. Soc., 97,
3257 (1975). b) R. Noyori, K. Yokoyama, J. Sakata, I.
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7
8
References and Notes
1
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E. F. Kleinman, in ‘‘Comprehensive Organic Synthesis,’’
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Hassner, Wiley, New York (1983), Vol. 42, p 219. e) N.
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9
2
a) I. Ojima, S. Inaba, and K. Yoshida, Tetrahedron Lett., 18,
3643 (1977). b) I. Ojima, S. Inaba, and M. Nagai, Synthesis,
´
C. J. J. Reye, Tetrahedron, 39, 999 (1983).
Published on the web (Advance View) November 20, 2004; DOI 10.1246/cl.2004.1626