Synthesis of chlorinated bicyclic C-fused tetrahydrofuro[3,2- c ]azetidin-2-ones

Article abstract of DOI:10.1021/jo101045z

Some bicyclic C-fused chlorinated tetrahydrofuro[3,2-c]azetidin-2-ones were prepared by a fairly general route involving Staudinger reaction of allylic/propargylic imidates with dichloroketene followed by highly diastereoselective CuCl/PMDETA-catalyzed 5-

Full text of DOI:10.1021/jo101045z

pubs.acs.org/joc
and modify its biological activity. Accordingly, some apparently
Synthesis of Chlorinated Bicyclic C-Fused
Tetrahydrofuro[3,2-c]azetidin-2-ones
otherwise nonactivated monocyclic N-aryl-R-chloro-β-lactams3
have been reported to exhibit promising antibacterial,3a-e anti-
fungal,3a-e and antitubercular3e activities and activities against
nonmicrobial diseases such as antitumor,1a anticonvulsant,3f
anti-Parkinson,3f CNS,3f and HLE inhibitory activities.3g Some
6-chloropenams possess β-lactamase inhibitory activities4 and
7-chlorocephems display anticancer5 and HLE- and PPE-
inhibitory1a activities.
Ram N. Ram,* Neeraj Kumar, and Nem Singh†
Department of Chemistry, Indian Institute of Technology,
Delhi, Hauz Khas, New Delhi 110016, India. †Contributed to
the analysis of crystallographic data.
3,4-Fused (C-fused) bicyclic β-lactams, in which the lac-
tam nitrogen is not pyramidal, are apparently nonactivated
and have received much less attention6 as compared to their
celebrated N-fused analogues. They have rather been used as
intermediates for the synthesis of the N-fused bicyclic
β-lactams.7 However, some activated β-lactams C-fused with
a cyclopentene,8a pyrrolidine,8b,c or thiazolidine7b ring were
found to possess promising β-lactamase inhibitory activities,
and recently, some otherwise additionally nonactivated bi-
cyclic β-lactams C-fused with carbocycles and a sugar unit9
have been reported to exhibit promising nonclassical biolo-
gical activities against malaria,9a leishmaniasis,9b and several
types of cancer.9c Moreover, new applications in the synthe-
sis of non-β-lactam molecules of biological significance
have also been discovered.6a,10 Although the tetrahydro-
furan structural unit is abundant in bioactive natural and
rnram@chemistry.iitd.ernet.in
Received June 3, 2010
Some bicyclic C-fused chlorinated tetrahydrofuro[3,2-c]aze-
tidin-2-ones were prepared by a fairly general route involving
Staudinger reaction of allylic/propargylic imidates with di-
chloroketene followed by highly diastereoselective CuCl/
PMDETA-catalyzed 5-exo-trig/dig chlorine atom transfer
radical cyclization. An oxepan-fused β-lactam was also pre-
pared similarly by 7-endo-trig cyclization. Synthetic applica-
tion of the side chain chlorine atom of the products was
demonstrated by its substitution in one of the products with
azide followed by azide-alkyne click reaction with phenyla-
cetylene to obtain a 1,2,3-triazolyltetrahydrofuro[3,2-c]aze-
tidin-2-one.
(4) Knowle, J. R. Acc. Chem. Res. 1985, 18, 97.
(5) Vorona, M.; Veinberg, G.; Shestakova, I.; Kanepe, I.; Petrova, M.;
Liepinsh, E.; Lukevics, E. Chem. Heterocycl. Compd. 2007, 43, 1567.
(6) Reviews: (a) Alcaide, B.; Almendros, P. Curr. Med. Chem. 2004, 11,
1921. (b) Alcaide, B.; Almendros, P. Curr. Org. Chem. 2002, 6, 245. (c)
Gomez-Gallego, M.; Mancheno, M. J.; Sierra, M. A. Tetrahedron 2000, 56,
5743. Some other references: (d) Zhang, Z.; Zhang, Q.; Ni, Z.; Liu, Q. Chem.
Commun. 2010, 46, 1269 and references cited therein. (e) Alcaide, B.;
Almendros, P.; del Campo, T. M.; Soriano, E.; Marco-Contelles, J. L.
Chem.;Eur. J. 2009, 15, 1901. (f) Alcaide, B.; Almendros, P.; del Campo,
T. M. Angew. Chem., Int. Ed. 2007, 46, 6684. (g) Alcaide, B.; Almendros, P.;
Rodriguez-Acebes, R. Synthesis 2005, 2335. (h) Alcaide, B.; Almendros, P.;
Aragoncillo, C. Org. Lett. 2003, 5, 3795. (i) Alcaide, B.; Almendros, P.; Luna,
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Am. Chem. Soc. 2008, 130, 418. (k) Alcaide, B.; Almendros, P.; Aragoncillo,
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2713.
The well-known antibacterial and most of the nonantibac-
terial1 activities of β-lactams rest on some additional activation
of the β-lactam ring toward nucleophilic enzymatic ring-open-
ing. This additional activation is brought in by a pyramidal
lactam nitrogen through 1,4-fusion (N-fusion) with another
ring, electron-withdrawing (-R or -I) N-substituent, and/or a
nucleofugal group.1 A chlorine substituent at the R position of
the β-lactam ring is expected to increase its chemical reactivity2
_
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Kazimierski, A.; Chmielewski, M. Curr. Med. Chem. 2004, 11, 1813. (b) Ren
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that additional activation of the β-lactam ring may not be absolutely essential
for its biological activity, particularly with regard to the biological activities
other than antibacteria.l (d) Kvrn, L.; Werder, M.; Hauser, H.; Carreira,
E. M. J. Med. Chem. 2005, 48, 6035.
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7408 J. Org. Chem. 2010, 75, 7408–7411
Published on Web 09/27/2010
DOI: 10.1021/jo101045z
r
2010 American Chemical Society

Ram et al.
JOCNote
synthetic molecules,11 very few examples of C-fused tetrahydro-
furo-β-lactams are known in the literature. They are mostly tetra-
hydrofuro[2,3-c]azetidin-2-ones having a C3-O linkage.6a-f,10c
The isomeric tetrahydrofuro[3,2-c]azetidin-2-ones with a
C4-O linkage which are also isomeric to oxapenams are
scarcely known.12
SCHEME 1. Synthesis of Chlorinated Monocyclic and C-Fused
Bicyclic β-Lactams via Copper(I)-Catalyzed ATRC
Therefore, in view of the importance of the R-chlorine
substituent on the β-lactam ring and the emerging prospect
of the C-fused β-lactams, we wish to report the synthesis of
some chlorinated C-fused tetrahydrofuro[3,2-c]azetidin-2-
ones in this paper. The synthesis uses Cu(I)-catalyzed chlor-
ine atom transfer radical cyclization (ATRC)13 as the key
step for the construction of the tetrahydrofuran ring on a
preformed β-lactam ring.14 Copper(I)-catalyzed ATRC does
not suffer from the limitations of the organotin hydride-
mediated radical cyclizations prevalent6a-c,g-i,15 in bicyclic
β-lactam synthesis, namely tedious separation of the product
from the toxic tin residues, direct reduction of the halide
precursor, and loss of the valuable halogen functionality,
which may otherwise be useful for further transformation of
the product.
The synthesis of the chlorinated C-fused bicyclic β-lactams
3 is shown in Scheme 1. The allylic imidates 1 were prepared
by reaction of easily accessible imidoyl chlorides with allylic
alcohols in the presence of NaH in quantitative yields.
Staudinger reaction16 of the crude sensitive allylic imidates
1 without further purification with dichloroacetyl chloride in
the presence of Et3N in benzene at ambient temperatures
TABLE 1. Ligand Screening for ATRC of Representative β-Lactamsa
product 3
yield (%)
recovered
2 (%)
(11) Reviews: (a) Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261. (b)
Norcrosst, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041. Some recent
references: (c) Xu, X.; Han, X.; Yang, L.; Hu, W. Chem.;Eur. J. 2009, 15,
12604. (d) Pedduri, Y.; Williamson, J. S. Tetrahedron Lett. 2008, 49, 6009. (e)
Ghosh, A. K.; Takayama, J. Tetrahedron Lett. 2008, 49, 3409. (f) Luesse,
S. B.; Wells, G.; Nayek, A.; Smith, A. E.; Kusche, B. R.; Bergmeier, S. C.;
McMills, M. C.; Priestley, N. D.; Wright, D. L. Bioorg. Med. Chem. Lett.
2008, 18, 3946. (g) Du, Y.; Liu, J.; Linhardt, R. J. J. Org. Chem. 2007, 72,
3952. (h) Hirose, T.; Sunazuka, T.; Yamamoto, D.; Kaji, E.; Omura, S.
Tetrahedron Lett. 2006, 47, 6761.
(12) A few reported molecules of this type have a nonactivated β-lactam
ring and have been prepared by [2 þ 2] cycloaddition of aryl or alkyl
isocyantes to the parent 4,5-dihydrofuran. (a) Garcia-Martinez, C.; Taguchi,
Y.; Oishi, A.; Hayamizu, K. Tetrahedron: Asymmetry 1998, 9, 955. (b)
Garcia-Martinez, C.; Taguchi, Y.; Oishi, A.; Hayamizu, K. Magn. Reson.
Chem. 1998, 36, 429. (c) Taguchi, Y.; Tsuchiya, T.; Oishi, A.; Shibuya, I. Bull.
Chem. Soc. Jpn. 1996, 69, 1667. (d) Taguchi, Y.; Oishi, A.; Shibuya, I.;
Tsuchiya, T. Eur. Pat. EP 671398, 1995. Trichloroacetyl isocyanate to a few
furanoid glycals: (e) Abramski, W.; Badowska-Rosbnek, K.; Chmielewski,
M. Bioorg. Med. Chem. Lett. 1993, 3, 2403. (f) Abramski, W.; Urbanczyk-
Lipkowska, Z.; Chmielewski, M. J. Carbohydr. Chem. 1997, 16, 63. The
former suffers from low reactivity of the isocyanates and requires high
pressure (800 MPa at 100 °C), and the latter forms unstable products in
low yields accompanied by [4 þ 2] cycloadducts. The trichloroacetyl group
need be cleaved to obtain the stable products having no N-substituent. A
cyclization by nucleophilic alkylation of the β-lactam enolate at subzero
temperatures (-65 to -45 °C) has also been reported. (g) Murakami, M.;
Aoki, T.; Nagata, W. Synlett 1990, 684. For some refs of natural bioactive
bicyclic hemiaminal ethers see, ref 11h and: (h) Boal, B. W.; Schammel,
entry
lactam 2
ligand
bpy
bpy
TMEDA
TMEDA
PMDETA
PMDETA
time (h)
1
2
3
4
5
6
b
d
b
d
b
d
4
4
12
4
4
4
84
86
62
15
68
75
79
aThe yields are for the reactions performed with 10 mmol of 2 and 60
mol % each of CuCl and the ligand in DCE at reflux under a nitrogen
atmosphere.
(25-30 °C) followed by purification of the product by
column chromatography furnished the R,R-dichloro-β-lac-
tams 2 in good yields. The CuCl-catalyzed ATRC of the
lactams 2 was found to be influenced by the nature of the
substituent at the lactam nitrogen and the nature of the
ligand used (Table 1). Thus, the cyclization of the lactams 2b
and 2d as representatives of N-alkyl and N-aryl β-lactams in
DCE at reflux under a nitrogen atmosphere using up to 60
mol % (1:1 molar equiv mixture) of CuCl and 2,20-bipyridine
(bpy), tetramethylethylenediamine (TMEDA), or penta-
methyldiethylenetriamine (PMDETA) as the ligand revealed
that bpy was ineffective, while TMEDA was effective in the
case of the N-phenyl-β-lactam 2d. Only PMDETA was
found to be a suitable ligand for the cyclization of both 2b
and 2d. Subsequently, all the lactams 2 listed in Table 2 and
the lactam 4 were successfully cyclized with CuCl/PMEDTA
(60 mol %, 1:1 molar equiv mixture) in DCE under reflux for
4 h by 5-exo-trig radical cyclization in a highly diastereose-
lective manner to afford the bicyclic β-lactams 3 and 5,
respectively, in good yields. In most of the cases, only one
diastereomer was isolated. The structures of all the com-
pounds were well supported by 1H and 13C NMR, IR, and
ꢀ
A. W.; Garg, N. K. Org. Lett. 2009, 11, 3458. (i) Menard-Moyon, C.; Taylor,
R. J. K. Eur. J. Org. Chem. 2007, 3698.
(13) (a) Clark, A. J. Chem. Soc. Rev. 2002, 31, 1. (b) Pattarozzi, M.;
Roncaglia, F.; Accorsi, L.; Parsons, A. F.; Ghelfi, F. Tetrahedron 2010, 66,
1357. (c) Ram, R. N.; Kumar, N. Tetrahedron Lett. 2008, 49, 799. (d) Ram,
R. N.; Tittal, R. K.; Upreti, S. Tetrahedron Lett. 2007, 48, 7994. (e) Ram,
R. N.; Charles, I. Chem. Commun. 1999, 2267.
(14) We could find only one example of application of CuCl/bpy-cata-
lyzed ATRC for the synthesis of an N-fused bicyclic β-lactam in poor yield
(28%). Penfold, D. J.; Pike, K.; Genge, A.; Anson, M.; Kitteringham, J.;
Kilburn, J. D. Tetrahedron Lett. 2000, 41, 10347.
(15) (a) Bachi, M. D.; Hoornaert, C. Tetrahedron Lett. 1981, 22, 2689.
€
(b) Leemans, E.; D’hooghe, M.; Dejaegher, Y.; Tornroos, K. W.; De Kimpe,
N. J. Org. Chem. 2008, 73, 1422.
(16) Review: Fu, N.; Tidwell, T. T. Tetrahedron 2008, 64, 10465.
J. Org. Chem. Vol. 75, No. 21, 2010 7409

Ram et al.
JOCNote
TABLE 2. Yields of the Monocyclic and Bicyclic β-Lactams
SCHEME 2. Cu(I)-Catalyzed Click Reaction of 3e
yield (%)
entry
1
R1
R2
R3
2a
3b
3c
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
n-Bu
i-Pr
c-Hex
C6H5
4-MeOC6H4
4-ClC6H4
i-Pr
i-Pr
i-Pr
H
H
H
H
H
H
OMe
Cl
NO2
H
H
H
H
H
H
H
H
H
78
84
82
78
84
76
76
80
78
76
72
77
75
74
79
72
66
73
74
79
84d
55e
60
63
61
62
60
50
55
59
62
64
40
case also, the two diastereomers arose probably due to the
stereogenic center in the side chain. However, the side chain in
these diastereomers was arguably oriented cis to the bridgehead
chlorine as suggested by considerably different values of the
vicinal coupling constants (1.8, 3.5 Hz) between the tetrahydro-
furan ring protons, probably due to difference in the puckering
of the THF ring. The trans relationship of the methyl and ben-
zylic side chain in both the diastereomers was also supported by
1H NOSEY and difference NOE spectra (Supporting Informa-
tion). The cyclization of the β-lactam 6having an alkynic radical
trap occurred exclusively by 5-exo-dig radical cyclization to
afford the lactam 7 with an E-exocyclic double bond.17 The
reaction of the lactam 8 having a substituted homoallyic group
as the radical trap was mostly incomplete under similar condi-
tions. The 7-endo-trig radical cyclization product 9 and the
H
n-Pr
Ph
10
11
j
k
C6H5
C6H5
H
aOne step (1 f 2). bOne step (2 f 3). cTwo steps (1 f 3). dMixture of
diastereomers. eOnly one diastereomer could be isolated.
1
monoreductive dechlorination product were detected by H
NMR in 25:75 ratio. However, when the cyclization was carried
out in benzene under reflux, no reduction product was formed
and the bicyclic β-lactam 9 was isolated as a single diastereomer
in 62% yield. The 7-endo-trig cyclization was probably favored
due to steric hindrance for the 6-exo-trig cyclization. The
stereostructures of the bicyclic β-lactams 7 and 9 were also
supported by X-ray diffraction spectroscopy.
FIGURE 1. ORTEP diagram of bicyclic β-lactam 3k.
In order to demonstrate the utility of the side-chain chlorine
atom in further elaboration of the bicyclic β-lactams, 3e was con-
verted to the azide 10 (Scheme 2) by treatment with sodium azide
which on copper(I)-catalyzed azide-alkyne click reaction18 with
phenylacetylene followed by purification by column chroma-
tography furnished the triazolyl β-lactam 11. 1,2,3-Triazole-con-
taining molecules possess a wide range of biological activi-
ties,11f,18,19 and even though 1,2,3-triazolyl-β-lactam antibiotic
cefatrizine,19c the β-lactamase inhibitors tazobactam and BRL
42715,19a and the anti-inflammatory coenzyme A-independent
transacylase inhibitor SB 21204719d have been known for a long
time, triazolyl-β-lactams have since been rarely revisited.20
Curiously, relatively few reports describe Staudinger reac-
tion of dichloroketene,21 very few of acyclic imidates7a,22 and
1
HRMS data. Thus, in the H NMR spectra of 3, the THF
OCH2 protons appeared in the range δ 4.90-4.64 as a dd
(J = 10.2-9.8, 7.8-7.4 Hz, 1H) and in the range δ 4.17-3.86
as a triplet (J = 11.3-10.6 Hz, 1H). In the case of 3a and 3f,
the dd collapsed to triplet (J = 8.6 Hz). The THF CH proton
appeared as a multiplet in the range δ 3.06-2.77. Understand-
ably, it showed up as a dt (J = 11.1-10.8, 7.5 Hz) in the side-
chain substituted derivatives 3j,k. Single-crystal X-ray diffrac-
tion of 3d and 3k showed cis ring fusion and a trans relationship
between the bridgehead chlorine atom and the adjacent side
chain on the tetrahydrofuran ring. The similarity of their NMR
spectra and the vicinal coupling constants of the THF ring
protons (10.8-7.4 Hz) with those of the other bicyclic β-lactams
3 (11.3-7.5 Hz) indicated that probably all the bicyclic β-
lactams 3 had similar stereostructures. In the case of 3j, a
mixture of two diastereomers was obtained in 91:9 ratio due
to the formation of an additional stereogenic center in the side
chain which could not be separated. However, in the case of 3k,
1H NMR indicated the formation of four diatereoisomeric
products in 76:9:8:7 ratio due to different orientations (exo,
endo) of the side chain and configurations of the stereogenic
center in it. Of these, only the major diastereomer could be
separated and purified by column chromatography in 55%
yield. Its stereostructure, as shown in 3k, was established by
single-crystal X-ray diffraction. The ORTEP diagram is shown
in Figure 1. Single-crystal X-ray diffraction also revealed that the
monocyclic β-lactam 4 was an RR and SS enantiomeric mixture
of a single diastereoisomer. Thus, it was formed by a highly
diastereoselective Staudinger reaction. On ATRC, it furnished a
78:22 mixture of two not easily separable diastereomers 5.Inthis
(17) See ref 11d and references cited therein for synthetic applications of
β-alkylidenetetrahydrofurans and for such a natural bioactive compound.
(18) Meldal, M.; Tornoe, C. W. Chem. Rev. 2008, 108, 2952.
(19) Reviews: (a) Tron, G. C.; Pirali, T.; Billington, R. A.; Canonico, P. L.;
Sorba, G.; Genazzani, A. A. Med. Res. Rev. 2008, 28, 278. (b) Krivopalov, V. P.;
Shkurko, O. P. Russ. Chem. Rev. 2005, 74, 339. Triazolyl-β-lactams: (c) Neu, H.;
Fu, K. Antimicrob. Agents Chemother. 1979, 15, 209. (d) Winkler, J. D.; Sung,
C.-M.; Chabot-Flecher, M.; Griswold, D. E.; Marshall, L. A.; Chilton, F. H.;
Bondinell, W.; Mayer, R. J. Mol. Pharmacol. 1998, 53, 322.
(20) (a) Vatmurge, N. S.; Hazra, B. G.; Pore, V. S.; Shirazi, F.;
Deshpande, M. V.; Kadreppa, S.; Chattopadhyay, S.; Gonnade, R. G.
Org. Biomol. Chem. 2008, 6, 3823. (b) Auberger, S.; Gerardin, C.; Rodehuser,
L.; Finance, C.; Nicolazzi, C.; Perez, L.; Infante, M.-R.; Manresa, M.-A.;
Selve, C. Prog. Colloid Polym. Sci. 2001, 118, 145.
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7410 J. Org. Chem. Vol. 75, No. 21, 2010

Ram et al.
JOCNote
practically none involving the two together.23 Regarding
exploiting the synthetic potentiality of the gem-dichlorofunc-
tionality of the R,R-dichloro-β-lactams, only reductive
monodehalogenation and alkylation via chlorine-lithium
exchange24 and a transformation to aziridines25 have been
reported. The present work describes the generation of a
radical center for the first time.
In conclusion, Staudinger reaction of allylic imidates with
dichloroketene followed by copper(I)-catalyzed ATRC con-
stituted a diastereoselective method for the synthesis of novel
chlorinated tetrahydrofuro[3,2-c]azetidin-2-ones. The meth-
od used readily available and inexpensive starting materials.
It is quite general for the synthesis of a variety of bicyclic
β-lactams C-fused with a substituted tetrahydrofuran ring
and with an aliphatic or aromatic substituent at the lactam
nitrogen. The synthesis involves some rarely exploited reac-
tions in β-lactam chemistry and the products have some
attractive structural attributes to merit attention.
over Na2SO4, and evaporated under reduced pressure on a
rotary evaporator. The residue was purified by column chro-
matography (neutral alumina, n-hexane/EtOAc = 95:5 v/v)
followed by recrystallization from n-hexane-diethyl ether to
obtain the pure 4-(allyloxy)-3,3-dichloro-1,4-diphenylazetidin-
2-one 2d (2.71 g, 78%) as a white solid: mp 62-64 °C; 1H NMR
(300 MHz, CDCl3) δ 7.47-7.19 (m, 10H), 6.03-5.90 (m, 1H),
5.39 (dd, J = 17.1, 1.5 Hz, 1H), 5.25 (dd, J = 10.5, 1.5 Hz, 1H),
4.74 (dd, J = 12.3, 4.8 Hz, 1H), 4.18 (dd, J = 12.3, 5.4 Hz, 1H);
13C NMR (75.5 MHz, CDCl3) δ 159.1 (C), 135.6 (C), 133.7 (C),
132.5 (CH), 129.7 (CH), 129.3 (CH), 128.2 (CH), 127.4 (CH),
125.9 (CH), 118.5 (CH), 117.4 (CH2), 98.6 (C), 89.9 (C), 67.0
(CH2); IR (KBr) νmax 3063 (w), 2927 (w), 1784 (s), 1493 (m),
1371 (s), 1123 (m), 759 (m), 731 (m), 692 (m) cm-1; HRMS calcd
for [C18H15NO2Cl2 þ Na]þ 370.0378, found 370.0365.
3-Chloro-4-chloromethyl-1,6-diphenyltetrahydrofuro[3,2-c]aze-
tidin-2-one 3d: Typical Procedure for the Synthesis of Bicyclic
β-Lactams. A flame-dried, two-necked, round-bottom flask was
charged with 4-(allyloxy)-3,3-dichloro-1,4-diphenylazetidin-2-one
2d (3.48 g,10 mmol), CuCl (0.6 g, 6 mmol), and degassed DCE
(40 mL) under a N2 atmosphere using Schlenk techniques. Into this
suspension was injected PMDETA (1.04 g, 1.25 mL, 6 mmol), and
the mixture was heated with stirring for 4 h. The mixture was then
cooled and filtered. The filtrate was evaporated under reduced
pressure, and the residual mass was purified by column chromatog-
raphy (silica gel, n-hexane/EtOAc = 90:10 v/v) followed by recrys-
tallization from n-hexane-diethyl ether to obtain 3-chloro-4-
chloromethyl-1,6-diphenyltetrahydrofuro[3,2-c]azetidin-2-one 3d
Experimental Section
4-(Allyloxy)-3,3-dichloro-1,4-diphenylazetidin-2-one 2d: Typi-
cal Procedure for the Synthesis of Monocyclic β-Lactams. To a
solution of the allylic imidate 1d (2.37 g,10 mmol) in benzene (50
mL) was added triethylamine (2.02 g, 2.8 mL, 20 mmol) through
a syringe at room temperature (22-30 °C). A solution of
dichloroacetyl chloride (2.9 g, 1.9 mL, 20 mmol) in benzene
(5 mL) was added to this solution dropwise over 15 min, and the
reaction mixture was stirred for 2 h at the same temperature.
After this time, TLC indicated the disappearance of the imidate.
The reaction mixture was filtered to separate the hydrochloride
salt, and the filtrate was washed with brine (3 ꢀ 10 mL), dried
1
(2.8 g, 79%) as a white solid: mp 130-132 °C; H NMR (300
MHz, CDCl3) δ7.52-7.43 (m, 7H), 7.30-7.25 (m, 2H), 7.13 (t, J=
7.4 Hz, 1H), 4.74 (dd, J = 10.1, 7.4 Hz, 1H), 4.04 (dd, J = 11.4, 4.2
Hz, 1H), 3.91 (t, J = 10.8 Hz, 1H), 3.72 (t, J = 11.4 Hz, 1H),
3.06-2.96 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ 159.5 (C),
134.7 (C), 131.6 (C), 130.0 (CH), 129.2 (CH), 128.7 (CH), 127.2
(CH), 125.5 (CH), 118.5 (CH), 101.7 (C), 81.3 (C), 70.3 (CH2), 51.3
(CH), 40.7 (CH2); IR (KBr) νmax 3008 (w), 2923 (w), 1770 (s), 1501
(m), 1384 (m), 1055 (m), 748 (m), 690 (w) cm-1; HRMS calcd for
[C18H15NO2Cl2 þ Na]þ 370.0378, found 370.0372.
(23) We could find only one report which described two examples of
cycloaddition of ethyl formimidates with dichloroketene to form the corre-
sponding 3,3-dichloro-β-lactams in negligible yields (7%). (a) Katagiri, N.;
Niwa, R.; Kato, T. Chem. Pharm. Bull. 1983, 31, 2899. A few reports
described cycloaddition of dichloroketene to some endocyclic imidates (5,6-
dihydro-1,3-oxazines): (b) Stajer, G.; Virag, M.; Szabo, A. E.; Bernath, G.;
Sohar, P.; Sillanpaa, R. Acta Chem. Scand. 1996, 50, 922. (c) Sohar, P.; Stajer,
G.; Pelczer, I.; Szabo, A. E.; Szunyog, J.; Bernath, G. Tetrahedron 1985, 41,
1721. Exocyclic imidates (maleic isoimides) have also been described: (d)
Capraro, H. G.; Winkler, T.; Martin, P. Helv. Chim. Acta 1983, 66, 362.
These compounds form N-fused bicyclic and spirocyclic β-lactams, respec-
tively.
Acknowledgment. Financial assistance by the CSIR,
New Delhi, and IIT, Delhi, is gratefully acknowledged.
Supporting Information Available: Detailed experimental
procedures, spectral data, and NMR spectra of all the new and
relevant compounds, CIF and ORTEP diagrams of 3d, 3k, 4, 7,
and 9. This material is available free of charge via the Internet
http://pubs.acs.org.
(24) Dejaegher, Y.; Denolf, B.; Stevens, C. V.; De Kimpe, N. Synthesis
2005, 193.
(25) Dejaegher, Y.; Mangelinckx, S.; De Kimpe, N. J. Org. Chem. 2002,
67, 2075.
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