Reaction of Imines with Trichloroacetic Esters or Anhydride Promoted by Iron Carbonyl or Microwave Irradiation. Preparation of 3,3-Dichloro-β-Lactams

Article abstract of DOI:10.1039/a804314k

The synthesis of 3,3-dichloroazetidin-2-ones by the reaction of imines and methyl or trimethylsilyl trichloroacetate promoted by diiron nonacarbonyl or by microwave irradiation of imines and trichloroacetic anhydride is described.

Full text of DOI:10.1039/a804314k

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724 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 724±725$
Reaction of Imines with Trichloroacetic Esters or
Anhydride Promoted by Iron Carbonyl or Microwave
Irradiation. Preparation of 3,3-Dichloro-b-Lactams$
Mohammad S. Khajavi,* Fatemeh Sefidkon and
S. S. Sadat Hosseini
Department of Chemistry, Faculty of Science, Shahid Beheshti University, Tehran, Iran
The synthesis of 3,3-dichloroazetidin-2-ones by the reaction of imines and methyl or trimethylsilyl trichloroacetate
promoted by diiron nonacarbonyl or by microwave irradiation of imines and trichloroacetic anhydride is described.
Monocyclic b-lactams are an important class of hetero-
cyclic compounds because of their use in the synthesis of
biologically active classical or non-classical b-lactam anti-
biotics.1 The cycloaddition of substituted acetic acid deriva-
tives with imines has become one of the major routes for
the synthesis of b-lactams.2 Here we wish to report a novel
method for the synthesis of 3,3-dichloro-b-lactams by the
condensation of an imine with the methyl or trimethyl-
silyl ester of trichloroacetic acid (1a,b) promoted by diiron
nonacarbonyl through an enolate intermediate (2).
Noteworthy is that changing the trichloroacetate from
methyl (1a) to trimethylsilyl (1b) did not greatly improve the
yields of the desired b-lactams. A possible mechanism for
this dichloro-b-lactam formation is suggested in Scheme 2.
The formation of iron(II) dichloro enolate (2) from the
methyl or trimethylsilyl ester of trichloroacetic acid has an
analogy in the mechanism of Noyori4 for the formation of
the iron enolate (4) in Scheme 1. The reaction of the in situ
prepared 2 with imines would be similar to the condensation
of lithium ester enolates with imines.7
The preparation of 3,3-dihalo-b-lactams by the reaction
of a Schi€ base with trimethylsilyl trihaloacetate and tri-
phenylphosphine has been described previously.3
Noyori et al. have described the reaction of dibromo
ketones with iron carbonyls to produce an oxyallyl-iron(II)
complex by the mechanism outlined in Scheme 1.4
Scheme 2
Furthermore, Sekiya8 has reported that the reaction of
trichloroacetic anhydride with imines in re¯uxing xylene
over a period of 1±8 h, led to 3,3-dichloro-b-lactams. As
part of our programme to study the highly accelerated
synthesis of heterocyclic compounds under microwave
irradiation,9 we examined this reaction under such irra-
diation and it was found that the reaction of trichloroacetic
anhydride with the imines results in the rapid formation
of b-lactams (3a±g) in high yield when the reactions were
conducted in a tall beaker covered with a stemless funnel in
a microwave oven. The results are summarized in Table 1.
Scheme 1
Accordingly, we decided to extend this successful iron
carbonyl reduction of a,a'-dihalo ketones to iron(II) dichloro
enolate (2) formation. Our initial experiments showed that
imines reacted with methyl trichloroacetate in the presence
of diiron nonacarbonyl to a€ord poor yields of b-lactams
(3). Subsequently, it was found that the yields of the desired
b-lactams increase when the imines were treated with boron
tri¯uoride etherate. In the presence of BF3 the imines, to
some extent, cannot form a complex with diiron nona-
carbonyl.5 Kamiya has utilized the BF3 complex of
monomeric formaldehyde imines for the preparation of
4-unsubstituted b-lactams.6 Thus, it was found that when
a mixture of methyl or trimethylsilyl trichloroacetate (1a,b)
and diiron nonacarbonyl in dry benzene was treated
with an equimolar amount of the N-benzylideneaniline±
boron tri¯uoride complex at 50 8C, 3,3-dichloro-1,4-diphenyl
azetidin-2-one (3c) was isolated in 65% yield. A number
of 3,3-dichloro-b-lactams with various substituents were
prepared by this procedure (Table 1). To the best of our
knowledge, there have been no studies on the synthesis of
diahalo-b-lactams using the ester of trichloroacetic acid
promoted by iron carbonyl.
In conclusion, we have developed a new procedure for the
synthesis of 3,3-dichloro-b-lactams by the condensation of
iron(II) dichloro-enolate and imines; this is a rapid method
under microwave irradiation. Work is continuing in this
area to extend these reactions to other tri- and di-haloacetic
esters.
Experimental
IR spectra were recorded as KBr pellets on a Shimadzu IR-470
spectrophotometer. 1H NMR spectra were obtained on a Bruker
AC 80 or JEOL-EX-90 instrument. Microwave irradiations were
carried out in a National oven, Model 5250, at 2450 MHz. Melting
points are uncorrected and were determined in open capillary
tubes using Mel-Temp apparatus. Benzene and m-xylene were
dried over sodium and freshly distilled before use. Diiron nonacar-
bonyl (Aldrich), trichloroacetic anhydride (Fluka) and methyl
trichloroacetate (Aldrich) were used as received. Trimethylsilyl tri-
chloroacetate was readily prepared by the reaction of hexamethyl-
disilazane and trichloroacetic acid.11
*To receive any correspondence. Present address: Organization for
the Prohibition of Chemical Weapons, Johan de Wittlaan 32, 2517
JR, The Hague, The Netherlands.
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
For safety reasons all experiments with microwave ovens should
be performed in an ecient hood to avoid contact with vapours. If

View Online
J. CHEM. RESEARCH (S), 1998 725
Table 1 b-Lactams from trichloroacetic esters or anhydride and imines
Method A Method B, irradiation conditionsb
Yield (%)a (1)P/W t/min (2)P/W t/min Yield (%)a (T/8C)
Mp
Lit. mp
Entry Product R1
R2
(T/8C)
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
MeOC6H4
Ph
Ph
Ph
Ph
PhCH2
PhCH2
Ph
MeOC6H4
ClC6H4
Ph
60
64
65
75
68
72
78
70
70
70
70
70
70
70
1
1
2
1.5
2
210
210
210
210
210
210
210
1.5
1.5
1.5
1.5
2
72
68
80
84
74
79
77
104±106
46±48
±
45±468
16410
162±164
110±111
129±131
155±156
130±132
110.5±1128
131±1328
154±1558
130±1318
MeOC6H4
ClC6H4
1.5
2
2
2
3g
Ph
b
aYield of pure, isolated product based on imines. To control the reaction the irradiation was carried out in two stages, with a cooling
period between each irradiation.
a tall beaker covered with a watch glass or a small stemless funnel
We are grateful to the late Professor T. Kametani and
is used and the microwave irradiation period is interrupted with
a 5 min cooling period there is little vaporization and very high
work done at the Institute of Medicinal Chemistry at Hoshi
conversions can be observed.
Professor T. Honda for support of the early part of the
University in Tokyo.
Preparation of 3,3-Dichloro-ꢀ-lactams (Method A).ÐThe general
procedure is illustrated with 1-benzyl-3,3-dichloro-4-p-anisylazetidin-
2-one (3a). In a ¯ame-dried three-necked ¯ask, equipped with a
Received, 8th June 1998; Accepted, 29th July 1998
Paper E/8/04314K
dropping funnel, a condenser and a three-way stopcock attached to
a dry nitrogen inlet tube, was placed 3.64 g, 10 mmol of diiron non-
acarbonyl and the system was evacuated then ¯ushed with nitrogen.
To this were added 20 ml of dry benzene and then 1.8 g, 10 mmol
of methyl trichloroacetate or 2.36 g, 10 mmol of trimethylsilyl tri-
chloroacetate and the resultant mixture stirred at room temperature
while a benzene 30 ml solution of 2.25 g, 10 mmol of N-p-methoxy-
benzylidenebenzylamine and an equimolar amount of boron
tri¯uoride etherate was added dropwise over a 10 min period. The
resulting reaction mixture was stirred at 50 8C for 48 h. The precipi-
tates that formed were removed by ®ltration through a pad of
Celite. Evaporation of benzene gave the crude product which was
chromatographed on silica gel (100±200 mesh), using dichloro-
methane±hexane (50:50) as eluent gave the title compound in
60% yield, mp 104±106 8C (from hexane and diethyl ether) (Found:
C, 61.13; H, 4.53; N, 4.13. C17H15Cl2NO2 requires C, 60.73; H, 4.49;
References
1 (a) T. Kametani, Heterocycles, 1982, 17, 463; (b) R. B. Morin
and M. Gorman, Chemistry and Biology of ꢀ-Lactam Antibiotics,
Academic Press, New York, 1982, vols. 1±3; (c) T. Nagahara
and T. Kametani, Heterocycles, 1987, 25, 729.
2 (a) A. K. Bose, M. S. Manhas, J. M. Van Der Veen, S. G.
Amin, I. F. Firnandez, K. Gala, R. Gruska, J. C. Kapur, M. S.
Khajavi, J. Kreder, L. Mukkavilli, B. Ram, M. Sugiura and
J. E. Vincent, Tetrahedron, 1981, 37, 2321, and references cited
therein; (b) M. S. Manhas, A. K. Bose and M. S. Khajavi,
Synthesis, 1981, 209.
3 M. S. Manhas, M. S. Khajavi, S. S. Bari and A. K. Bose,
Tetrahedron Lett., 1983, 24, 2323.
4 (a) R. Noyori, Y. Hayakawa, H. Takaya, S. Murai, R. Kobayashi
and N. Sonoda, J. Am. Chem. Soc., 1978, 100, 1759; (b) R. Noyori
and Y. Hayakawa, Tetrahedron, 1985, 41, 5879, and references
cited therein.
1
N, 4.16%); ꢁmax/cm (KBr) 1786; ꢂH (CDCl3) 3.75 (s, 3 H, OCH3),
3.87 (d, 1 H, J 13.7 Hz), 4.82 (s, 1 H, C4-H), 4.91 (d, 1 H, J
13.7 Hz), 6.87±7.46 (m, 9 H, Ar-H).
Preparation of 3,3-Dichloro-ꢀ-lactams (Method B).ÐThe general
procedure is illustrated with 3,3-dichloro-1,4-diphenylazetidin-2-one
(3c). A mixture of N-benzylideneaniline (1.81 g, 10 mmol) and
trichloroacetic anhydride (3.4 g, 11 mmol) in 8 ml of m-xylene con-
tained in a tall beaker was placed in the microwave oven and the
beaker was covered with a stemless funnel and irradiated for 2 min
at 70 W, and after 10 min (during this time the mixture cools slowly
to room temperature) it was irradiated again at 210 W for 1.5 min.
The solvent was evaporated under reduced pressure. Trituration of
the crude residue with diethyl ether led to the title compound which
was recrystallized from ethanol and hexane to give an 80% yield
of 3c, mp 162±164 8C (lit.,10 164 8C); ꢁmax/cm1 (KBr) 1767; ꢂH
(CDCl3) 5.59 (s, 1 H, C4-H), 7.11±7.48 (m, 10 H, Ar-H).
5 For a similar improvement in yields see H. Takaya, S. Makino,
Y. Hayakawa and R. Noyori, J. Am. Chem. Soc., 1978, 100,
1765.
6 T. Kamiya, T. Oku, O. Nakaguchi, H. Takeno and M. Hashimoto,
Tetrahedron Lett., 1978, 5119.
7 (a) A. K. Bose, M. S. Khajavi and M. S. Manhas, Synthesis,
1982, 407; (b) F. H. van der Steen, H. Kleijn, A. L. Spek and
G. van Koten, J. Org. Chem., 1991, 56, 5868; (c) L. E. Overman
and T. Osawa, J. Am. Chem. Soc., 1985, 107, 1698; for reviews
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Heterocycles, 1989, 29, 2225; (e) D. J. Hart and D.-C. Ha,
Chem. Rev. 1989, 89, 1447.
8 M. Sekiya and T. Morimoto, Chem. Pharm. Bull., 1975, 23,
2353.
9 (a) M. S. Khajava, N. Montazari and S. S. Sadat Hosseini,
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and R. Naderi, J. Chem. Res. (S), 1996, 92.
10 E. Ziegler, Th. Wimmer and H. Mittelbach, Monatsh. Chem.,
1968, 99, 2128.
11 G. A. Gornowicz and J. W. Ryan, J. Org. Chem., 1966, 31,
3439.
1
3b: ꢁmax/cm (KBr) 1782; dH (CDCl3) 3.82 (d, 1 H, J 13.6 Hz),
4.71 (s, 1 H, C4-H), 4.86 (d, 1 H, J 13.6 Hz), 6.85±7.61 (m, 10 H,
Ar-H).
1
3d: ꢁmax/cm (KBr) 1776; dH (CDCl3) 3.73 (s, 3 H, OCH3), 5.45
(s, 1 H, C4-H), 6.82±7.93 (m, 9 H, Ar-H).
1
3e: ꢁmax/cm (KBr) 1785; dH (CDCl3) 5.48 (s, 1 H, C4-H), 7.21±
7.67 (m, 9 H, Ar-H).
1
3f: ꢁmax/cm (KBr) 1770; dH (CDCl3) 3.78 (s, 3 H, OCH3), 5.41
(s, 1 H, C4-H), 6.63±7.45 (m, 9 H, Ar-H).
1
3g: ꢁmax/cm (KBr) 1774; dH (CDCl3) 5.48 (s, 1 H, C4-H), 7.05±
7.63 (m, 9 H, Ar-H).