N-Acylation of 4-alkylidene-β-lactams: Unexpected results

Article abstract of DOI:10.1016/S0040-4039(03)01533-8

This paper describes the different reactivity of E- and Z-4-alkylidene-β-lactams in acylation reactions under basic conditions. The E isomer is readily acylated, whereas the Z reacted sluggishly rearranging to the corresponding oxazin-6-one. The N-acylation of Z isomers was successfully obtained with oxalyl- or malonyl chlorides in benzene at reflux.

Full text of DOI:10.1016/S0040-4039(03)01533-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6269–6272
N-Acylation of 4-alkylidene-b-lactams: unexpected results
Gianfranco Cainelli, Daria Giacomini,* Massimo Gazzano, Paola Galletti* and Arianna Quintavalla
Department of Chemistry ‘G. Ciamician’, University of Bologna and ISOF (C.N.R.), Via Selmi 2, Bologna 40126, Italy
Received 9 June 2003; revised 18 June 2003; accepted 19 June 2003
Abstract—This paper describes the different reactivity of E- and Z-4-alkylidene-b-lactams in acylation reactions under basic
conditions. The E isomer is readily acylated, whereas the Z reacted sluggishly rearranging to the corresponding oxazin-6-one. The
N-acylation of Z isomers was successfully obtained with oxalyl- or malonyl chlorides in benzene at reflux.
© 2003 Elsevier Ltd. All rights reserved.
The chemistry of b-lactams has been offering a continu-
ous occasion to get a lot of new synthetic methods and
transformations. b-Lactams, in fact, have gained sub-
stantial interest in the scientific community not only
due to their meaningful biological activity, but also as
reactive intermediates and as starting materials in a
wide range of syntheses.1
In a typical procedure compound 1 or 2 (0.31 g, 1
mmol) and benzylchloroformate (0.15 mL, 1 mmol),
were dissolved in anhydrous acetone (10 mL); K2CO3
(0.14 g, 1 mmol for 1 and 2 mmol for 2) was added and
the reaction mixture was stirred for 1 h for 1 and
overnight for 23. Then K2CO3 was filtered off, the
solvent was removed and the crude oily residue was
immediately purified by flash chromatography.
Aqueous work-up of the crude must be avoided
because of product decomposition. The structures of
3a–d and 4a–d were established by IR, 1H and 13C
In the progress of a study on new b-lactams as
inhibitors of serine-dependent enzymes and matrix
metalloproteases, we found active over human leuko-
cyte elastase and gelatinases MMPs some 4-alkylidene-
b-lactam derivatives.2 Their synthesis was accomplished
starting from 4-acetoxy-azetidinones and acyldiazo
compounds with a Lewis acid promotion (Scheme 1).
By this method we obtained different amounts of E-
and/or Z-4-alkylideneazetidinones depending on the
Lewis acid and on the diazocompound.
Scheme 1.
In a tentative acylation reaction of the b-lactam nitro-
gen atom, we found a completely different behaviour of
E and Z isomers. N-Acetylation of the E isomer 1 with
acetic anhydride and solid K2CO3 in acetone was rapid,
giving product 3a, whereas, unexpectedly, the Z isomer
2 reacted sluggishly rearranging to the corresponding
oxazin-6-one 4a (Scheme 2, Table 1). Compound 2, in
fact, requires at least 2 equiv. of K2CO3 for satisfactory
yields of oxazin-6-ones, with 1 equiv. of the base only
traces of 4a, together with unreacted 2, was detected in
the reaction mixture. This different behaviour persisted
with some other acylating agents such as CbzCl or
benzylisocyanate.
* Corresponding author. Fax: +39 051 209 9456; e-mail: giacomin@
ciam.unibo.it; paolag@ciam.unibo.it
Scheme 2.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01533-8

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G. Cainelli et al. / Tetrahedron Letters 44 (2003) 6269–6272
Table 1. E-N-Acyl-b-lactams (3) and oxazin-6-ones (4) starting from 4-alkylidene-azetidinones according to Scheme 2
Entry
Substrate
Acylating reagents and conditions
R
Product
Yielda (%)
1
2
3
4
5
6
7
8
1
1
1
1
2
2
2
2
Ac2O, K2CO3 acetone
CH3
3a
3b
3c
3d
4a
4b
4c
4d
80
69
60
63
77
54
60
47
Benzylchloroformate, K2CO3 acetone
Benzylisocyanate, K2CO3 acetone
Benzoyl chloride, K2CO3 acetone
Ac2O, K2CO3 acetone
Benzylchloroformate, K2CO3 acetone
Benzylisocyanate, K2CO3 acetone
Benzoyl chloride, K2CO3 acetone
OCH2Ph
NHCH2Ph
Ph
CH3
OCH2Ph
NHCH2Ph
Ph
a Yields after flash chromatography.
NMR.4 Quite characteristic is the IR absorption of the
4-alkylidene-b-lactam carbonyl group at 1818–1853
cm−1 while in oxazin-6-ones there is a shift at 1739–
1752 cm−1.
O-Deprotection of 4b with H2 and Pd on carbon in
THF gave the oxazin-2,6-dione 5, a stable, crystalline
compound whose structure was definitively confirmed
by X-ray diffraction analysis (Scheme 3, Fig. 1).5
Rearrangements of b-lactams into oxazines or of oxazi-
nes into b-lactams have already been observed.6 Ala-
jarin et al.7 investigated the mechanism for the oxazine
formation from N-acyl-4-acetoxy-b-lactams throughout
the formation of a highly unstable N-acyl azetone that
rearranges into the six membered ring. Under our
reaction conditions (K2CO3, acetone) we suppose an
initial formation of N-acyl-Z-4-alkylideneazetidinone
(Scheme 4, intermediate A) followed by a base-induced
endocyclic isomerization of the CꢀC bond giving the
corresponding N-acyl azetone (B).8 This intermediate
should quickly rearrange into the oxazin-6-one D via a
ketene-acylimine intermediate C.
Figure 1. Crystal data for 5: C16H27NO6Si, M=357.48,
orthorhombic, P212121, a=7.306(5), b=16.415(5), c=
3
,
,
16.766(5) A, V=2010.7(2) A , Z=4, T=293(2)°C, v(Mo-
Ka)=0.144 mm−1, 15557 reflections measured, 2919 unique
(Rint=0.0892), R1=0.0784, wR2=0.2133.
detected in the reaction mixture.9 Moreover, treatment
of E isomer of N-acetyl derivative (3a) with an excess
of K2CO3 at room temperature gave the corresponding
oxazin-6-one 4a.
We have indirect evidence that the allylic isomerization
follows the acylation of the b-lactam nitrogen atom, in
fact, a longstanding treatment of E-4-alkylidene-b-lac-
tam 1 with K2CO3/acetone without any acylating agent
leads to isomerization into the Z isomer 2, which results
stable in these reaction conditions. No traces of azetone
or any other decomposition products have been
The endocyclic double bond rearrangement under basic
conditions, depends on the E or Z geometry of the CꢀC
bond and on the C-3 side chain. For instance, treat-
ment of the two E- and Z-4-alkylidene-b-lactams
unsubstituted on the C-3 position (azetidinones 6 and 7,
Scheme 5) with acetic anhydride in acetone with solid
K2CO3 resulted in the formation of the sole oxazin-6-
one 8.
A careful exploration of the reaction conditions (start-
ing b-lactam, acylating agent and solvent), allowed us
to successfully obtain Z isomers of N-acyl-4-alkylidene-
azetidinones (Table 2). Critical resulted the use of
mono chloro oxalyl esters or ethyl malonyl chloride as
acylating agents in benzene at reflux.10 The reaction of
b-lactam 9 and mono chloro oxalyl esters gave good
yields, and the products can be directly recovered by
evaporation, under reduced pressure, of volatile compo-
nents from the crude (Scheme 6 and Table 2).
In summary, we have developed a new route to N-acyl-
4-alkylidene-azetidin-2-ones Z and E. The reaction con-
Scheme 3.

G. Cainelli et al. / Tetrahedron Letters 44 (2003) 6269–6272
6271
Scheme 6.
ditions depend on the Z or E isomer. Under basic
conditions (K2CO3, acetone) the E isomer is readily
acylated whereas Z isomer rearranges into oxazines.
N-Acylation of Z isomers was successfully achieved
with oxalyl or malonyl monoester chlorides in benzene
at reflux.
Scheme 4.
Biological activity of these new N-acyl-4-alkylidene aze-
tidin-2-ones is actively under investigation.
Acknowledgements
We thank Mrs. Elisa Bertoletti for experimental assis-
tance. This work was supported by MURST (60% and
COFIN) and the University of Bologna (funds for
selected topics).
Scheme 5.
Table 2. N-Acyl-b-lactams (12–21) starting from 4-alkylidene-azetidinones according to Scheme 6
Entry
1
Substrate
R%
R
Product
Yielda (%)
30
1
OEt
CH2COOEt
2
3
4
5
6
7
8
9
2
2
9
9
9
9
9
10
10
OEt
OEt
SPh
SPh
SPh
SPh
SPh
Ph
CH2COOEt
COOEt
COOEt
COOpNO2Bn
COOtBu
COOCH2CHꢀCH2
COOBn
COOEt
COOCH2CH2SiMe3
COOEt
13
–
29b
–
14
15
16
17
18
19
20
85
80
83
80
89
90
90
50
10
11
Ph
SPh
a Conversion determined by 1H NMR analyses of the crude.
b A 20% of the corresponding oxazin-6-one was detected in the crude by NMR analyses.

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G. Cainelli et al. / Tetrahedron Letters 44 (2003) 6269–6272
1.36 (d, 3H, J=6.6 Hz), 1.62 [bs, 1H, NH), 3.88 (d, 1H,
References
C=CCHAHBCO2, JAB=17.2 Hz), 4.08 (d, 1H, C=
CCHAHBCO2, JAB=17.2 Hz), 4.26 (q, 2H, J=7.2 Hz),
5.10 (q, 1H, CH3CHOSi, J=6.6 Hz)—13C NMR (75.5
MHz, CDCl3): l −5.2, −5.1, 14.0, 18.0, 24.3, 25.8, 33.4,
62.5, 64.3, 111.6, 147.4, 159.1, 159.2, 168.5. 8: IR
(CH2Cl2): 1762, 1746, 1635, 1581 cm−1—1H NMR (200
MHz, CDCl3): l 1.28 (t, 3H, J=7.4 Hz), 2.40 (s, 3H,
CH3CꢀN), 3.46 (s, 2H, CH2CO2Et), 4.24 (q, 2H,
CH3CH2CO2, J=7.4 Hz), 6.12 (s, 1H, CHꢀC)—13C
NMR (50 MHz, CDCl3): l 14.1, 21.6, 29.7, 42.2, 61.6,
107.7, 158.8, 160.7, 167.2, 168.1. 19: IR (CH2Cl2): 1853,
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1757, 1717, 1679, 1618 cm−1 1H NMR (200 MHz,
.
3. The sequence in reagent addition is quite important. In
fact addition of the acylating agent to the acetone suspen-
sion of 1 and K2CO3 resulted in the formation of the sole
oxazin-6-one 4a, because the acylation follows the prelim-
inary basic isomerization of 1 in 2.
CDCl3): l 0.12 (s, 3H), 0.17 (s, 3H), 0.91 (s, 9H), 1.23 (d,
3H, J=6.3 Hz), 1.40 (t, 3H, J=7.0 Hz), 4.44 (q, 2H,
CH3CH2CO2, J=7.0 Hz), 4.52 (dd, 1H, CH3CHOSi,
J=1.4 Hz, J=4.4 Hz), 4.76 (dq, 1H, J=4.4 Hz, J=6.3
Hz), 7.65 (d, 1H, CH=C, J=1.4 Hz), 7.53 (m, 3H), 7.98
(m, 2H)—13C NMR (50 MHz, CDCl3): l −5.2, −4.8,
13.7, 17.8, 20.4, 25.5, 63.4, 64.9, 65.5, 66.5, 105.2, 128.2,
128.3, 128.6, 133.3, 137.6, 147.7, 163.8, 189.2.
4. Selected data 3a: [h]D25=−180 (c 0.13, CHCl3). IR (film):
2959, 1832, 1726, 1660, cm−1 1H NMR (200 MHz,
.
CDCl3): l −0.07 (s, 3H), 0.03 (s, 3H), 0.80 (s, 9H), 1.30 (t,
J=6.8 Hz, 3H), 1.40 (d, J=6.4 Hz, 3H), 2.42 (s, 3H),
4.05 (dd, J=1.4 Hz, J=1.6 Hz, 1H), 4.20 (q, J=6.8 Hz,
2H), 4.73 (dq, J=6.4 Hz, J=1.6 Hz, 1H), 6.52 (d, J=1.4
Hz, 1H).13C NMR (CDCl3, 50.29 MHz): l −5.5, −4.4,
14.4, 17.7, 22.0, 24.1, 25.5, 60.3, 65.0, 65.6, 99.6, 150.3,
165.7, 166.5, 166.7. 4a: [h]2D5=+24 (c 0.5, CHCl3). IR
(film): 1739, 1639, 1586, 1076, 943 cm−1—1H NMR (300
MHz, CDCl3): l 0.02 (s, 3H), 0.09 (s, 3H), 0.88 (s, 9H),
1.28 (t, 3H, J=7.2 Hz), 1.39 (d, 3H, J=6.6 Hz), 2.37 (s,
3H), 3.83 (d, 1H, C=CCHAHBCO2, JAB=16.0 Hz), 4.10
(d, 1H, C=CCHAHBCO2, JAB=16.0 Hz), 4.19 (dq, 2H,
CH3CH2CO2, J=7.2 Hz, J=1.2 Hz), 5.20 (q, 1H,
CH3CHOSi, J=6.3 Hz). 13C NMR (75.5 MHz, CDCl3):
l −5.2, −5.1, 14.1, 18.0, 21.2, 23.7, 25.8, 39.6, 61.0, 63.9,
123.4, 156.5, 159.6, 163.9, 169.2. 4c: IR (CH2Cl2): 1739,
1627, 1567, 1301, 1255, 911, 738 cm−1—1H NMR (200
MHz, CDCl3): l 0.02 (s, 3H), 0.09 (s, 3H), 0.89 (s, 9H),
1.26 (t, 3H, J=7.4 Hz), 1.38 (d, 3H, J=6.6 Hz), 3.83 (d,
1H, CꢀCCHAHBCO2, JAB=16.0 Hz), 4.09 (d, 1H, C=
5. Crystallographic data (excluding structure factors) for
compound 5 have been deposited with the Cambridge
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tion no. CCDC 211163. Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (fax: +44 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk).
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CCHAHBCO2,
CH3CH2CO2, J=7.2 Hz, J=2.6 Hz), 5.15 (q, 1H,
CH3CHOSi, J=6.6 Hz), 5.33 (d, 1H, OCHAHBPh, JAB
JAB=16.0 Hz), 4.18 (dq, 2H,
=
9. Compound 2 results thermodynamically more stable than
1 because of the intramolecular hydrogen bond between
the NH and the COOEt in the side chain, see for instance
Ref. 2.
10. (a) Brodney, M. A.; Padwa, A. J. Org. Chem. 1999, 64,
556–565; (b) Padwa, A.; Prein, M. Tetrahedron 1998, 54,
6957–6976.
12.0 Hz), 5.39 (d, 1H, OCHAHBPh, JAB=12.0 Hz), 7.30
(m, 5H)—13C NMR (50 MHz, CDCl3): l −5.2, −5.0,
14.1, 18.0, 24.0, 25.8, 40.2, 61.0, 64.1, 71.4, 117.9, 128.2,
128.5, 128.7, 134.0, 156.9, 159.2, 159.7, 169.0. 5: [h]2D5=+
28 (c 0.5, CHCl3)—IR (Nujol): 3250, 3204, 1765, 1739,
1719, 1646 cm−1—1H NMR (300 MHz, CDCl3): l 0.03 (s,
3H), 0.10 (s, 3H), 0.89 (s, 9H), 1.33 (t, 3H, J=7.2 Hz),