Stereoselective synthesis of 3-substituted 4-(formyloxy)-2-azetidinones by the unusual Baeyer-Villiger reaction of β-lactam aldehydes. Scope and synthetic applications

Article abstract of DOI:10.1021/jo9612685

The Baeyer-Villiger oxidation of 4-formyl-β-lactams 1 with m-CPBA gave 4-(formyloxy) β-lactams 2 in a simple, efficient, and totally stereoselective process. This reaction is one of the scarce examples of the preferred migration of a carbon moiety in an aliphatic aldehyde. The influence of the substituents at N1 and C3 of the four-membered ring in the Baeyer-Villiger rearrangement has been studied. Thus, alkyl, alkenyl, aryl, and alkyloxy 3-substituted-1-(p-anisyl)-2-azetidinones 1 form exclusively 4-(formyloxy) β-lactams 2. Amide or acetoxy substituents at C3 of the four membered ring produce mixtures of 4-(formyloxy) β-lactams 2 and 4-carboxy β-lactams 5. The exclusive formation of carboxy derivatives is observed sometimes for 1-alkyl-substituted-2-azetidinones 1. 4-(Formyloxy) β-lactams 2 are suitable starting materials to prepare different 4-unsubstituted β-lactams 9 using β-hydroxy amides 8 as isolable intermediates. The overall transformation 4-formyl-2-azetidinone to 4-unsubstituted β-lactam is an easy and convenient stereoselective route to these interesting types of compounds.

Full text of DOI:10.1021/jo9612685

J . Org. Chem. 1996, 61, 8819-8825
8819
Ster eoselective Syn th esis of 3-Su bstitu ted
4-(F or m yloxy)-2-a zetid in on es by th e Un u su a l Ba eyer -Villiger
Rea ction of â-La cta m Ald eh yd es. Scop e a n d Syn th etic
Ap p lica tion s
Benito Alcaide,* Moustafa F. Aly,† and Miguel A. Sierra
Departamento de Quı´mica Orga´nica I, Facultad de Quı´mica, Universidad Complutense,
28040 Madrid, Spain
Received September 4, 1996X
The Baeyer-Villiger oxidation of 4-formyl-â-lactams 1 with m-CPBA gave 4-(formyloxy) â-lactams
2 in a simple, efficient, and totally stereoselective process. This reaction is one of the scarce examples
of the preferred migration of a carbon moiety in an aliphatic aldehyde. The influence of the
substituents at N1 and C3 of the four-membered ring in the Baeyer-Villiger rearrangement has
been studied. Thus, alkyl, alkenyl, aryl, and alkyloxy 3-substituted-1-(p-anisyl)-2-azetidinones 1
form exclusively 4-(formyloxy) â-lactams 2. Amide or acetoxy substituents at C3 of the four-
membered ring produce mixtures of 4-(formyloxy) â-lactams 2 and 4-carboxy â-lactams 5. The
exclusive formation of carboxy derivatives is observed sometimes for 1-alkyl-substituted-2-
azetidinones 1. 4-(Formyloxy) â-lactams 2 are suitable starting materials to prepare different
4-unsubstituted â-lactams 9 using â-hydroxy amides 8 as isolable intermediates. The overall
transformation 4-formyl-2-azetidinone to 4-unsubstituted â-lactam is an easy and convenient
stereoselective route to these interesting types of compounds.
Ch a r t 1
In tr od u ction
One of the well established principles in the oxidation
of aldehydes with peracids is the formation of carboxylic
acids due to the preferential migration of hydrogen over
the carbon moiety.2 Formates, formed by migration of
the carbon group, are the alternative reaction products,
but this rearrangement seldom occurs. In fact, to the
best of our knowledge, electron-rich aromatic3 and het-
eroaromatic4 aldehydes and R-oxygen-substituted alde-
hydes5 are the main exceptions to the general rule and
are converted to formate esters upon peroxy acid treat-
ment. The bizarre behavior of the 2-azetidinone ring,
exemplified by different unique transformations,6 pro-
vides a new example of preferential carbon migration on
the Baeyer-Villiger rearrangement of aldehydes. We
recently reported1 that â-lactam aldehydes 1 (Chart 1)
exclusively yield 4-(formyloxy) â-lactams 2 after Baeyer-
Villiger oxidation. This transformation represents one
of the scarce examples of the preferred migration of a
carbon group in an aliphatic aldehyde.3-5
Total synthesis of mono- and bicyclic â-lactam antibiot-
ics often rests on the modification of monocyclic 2-azeti-
dinones having acyloxy substituents at the C4 of the four-
membered ring.7 Elimination of the ester group promotes
the nucleophilic substitution through acyliminium inter-
mediates,8 and different functionalized nucleophiles are
thus attached to the â-lactam ring. Among others,
4-acetoxy-2-azetidinones 3 are recognized as universal
key intermediates7 to obtain biologically active â-lactams.
Compounds 3 have been prepared by the classical isocy-
anate-olefin cycloaddition9 using chlorosulfonyl isocy-
anate and different vinyl acetates. However, this ap-
† Permanent address: Chemistry Department, Faculty of Science
at Qena, South Valley University, Qena-Egypt.
proach is often
a low yielding, unselective step,
X Abstract published in Advance ACS Abstracts, November 15, 1996.
incompatible with different functional groups needed for
further synthetic steps.10 Alternative entries to 4-ac-
etoxy-2-azetidinones have been developed, for example,
by oxidation of 2-azetidinones lacking substituents at
(1) For
a preliminary communication of part of this work see:
Alcaide, B.; Aly, M. F.; Sierra, M. A. Tetrahedron Lett. 1995, 36, 3401-
4.
(2) For recent reviews of Baeyer-Villiger reaction, see: (a) Krow,
G. R. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon
Press: New York, 1991; Vol. 7, p 671. (b) Krow, G. R. Organic
Reactions; Paquette, L. A., Ed.; J ohn Willey and Sons: New York, 1993;
Vol. 43, p 251. (c) Krow, G. R. Tetrahedron 1981, 37, 2697. For recent
papers, see: (a) Kaneda, K.; Ueno, S.; Imanaka, T.; Shimotsuma, E.;
Nishiyama, Y.; Ishii, Y. J . Org. Chem. 1994, 59, 2915. (b) Chida, N.;
Tobe, T.; Ogawa, S. Tetrahedron Lett. 1994, 35, 7249.
(3) See, for example: (a) Grosby, D. G. J . Org. Chem. 1961, 26, 1215.
(b) Ogata, Y.; Sawaki, Y. J . Org. Chem. 1969, 34, 3985. (c) Godfrey, I.
M.; Sargent, M. V.; Elix, J . A. J . Chem. Soc., Perkin Trans. 1 1974,
1353. (d) Camps, F.; Coll, J .; Messeguer, A.; Perica´s, M. A. Tetrahedron
Lett. 1981, 22, 3895. (e) Gammill, R. B.; Hyde, B. R. J . Org. Chem.
1983, 48, 3863. (f) Nelson, W. L.; Burke, T. R. J . Med. Chem. 1979,
22, 1082.
(6) See, for example: (a) Ojima, I. Adv. Asymm. Synth. 1995, 1, 95.
(b) Manhas, M. S.; Wagle, D. R.; Chiang, J .; Bose, A. K. Heterocycles
1988, 27, 1755. (c) Alcaide, B.; Miranda, M.; Pe´rez-Castells, J .; Sierra,
M. A. J . Org. Chem. 1993, 58, 297. (d) Alcaide, B.; Mart´ın-Cantalejo,
Y.; Rodr´ıguez-Lo´pez, J .; Sierra, M. A. J . Org. Chem. 1993, 58, 4767.
(e) Alcaide, B.; Pe´rez-Castells, J .; Polanco, C.; Sierra, M. A. J . Org.
Chem., 1995, 60, 6012.
(7) For comprehensive reviews, see: (a) Kametani, T.; Fukumoto,
K.; Ihara, M. Heterocycles 1982, 17, 463. (b) Nagahara, T.; Kametani,
T. Heterocycles 1987, 25, 729. (c) Davies, D. E.; Storr, R. C. In
Comprehensive Heterocyclic Chemistry; Lwowski, W., Ed.; Pergamon:
New York, 1984; Vol. 7, p 237. (d) Wild, H. In The Organic Chemistry
of â-Lactams; Georg, G. I., Ed.; VCH Publishers, Inc.: New York, 1993;
Chapter 2, p 49.
(4) See, for example: (a) Masman, J .-A. H.; Pensar, K. G. Synthesis
1985, 786. (b) Langendoen, A.; Koomen, G.-J .; Pandit, U. K. Hetero-
cycles 1987, 26, 91. (c) J efford, C. W.; J aggi, D.; Boukouvalas, J .
Tetrahedron Lett. 1989, 1237.
(8) Gavin˜a, F.; Costero, A. M.; Andreu, M. R. J . Org. Chem. 1990,
55, 434 and references cited therein.
(5) DeBoer, A.; Ellwanger, R. E. J . Org. Chem. 1974, 39, 77.
(9) Klaus, K.; Grimm, D.; Prossel, G. Liebigs Ann. Chem. 1974, 539.
S0022-3263(96)01268-6 CCC: $12.00 © 1996 American Chemical Society

8820 J . Org. Chem., Vol. 61, No. 25, 1996
Ta ble 1. Ba eyer -Villiger Oxid a tion of 4-F or m yl â-La cta m s 1 w ith m -CP BA
Alcaide et al.
yieldd,e (%)
entry
substratea
R1
R2
R3 b
product(s)
product ratio 2/5c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1b
1c
1d
1e
1f
1g
1h
1i
(+)-1i
1j
1k
1l
(+)-1m
1n
CH2dCH
CH2dC(Me)
H
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
Bn
2a
2b
2c
2d
2e
2f
2g
2h
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
88:12
75:25
65:35
35:65
50:50
0:100
91
70
90
94
94
72
87
93
94
94
80
73
57
10
45
Me2Cd
Ph
Et
i-Pr
H
H
H
H
i-Pr
CH3
H
H
H
H
H
H
H
CH3
BnO
BnO
AcO
Mdf
Ftg
2i
(+)-2i
2j/5a
2k /5b
2l/5c
(+)-2m /(+)-5d
2n /5e
(+)-5f
S-Oxh
BnO
S-Oxh
(+)-1o
H
Bn
a
Compounds (+)-1i, (+)-1m , and (+)-1o were used as optically pure materials with the configuration indicated in Chart 2. The remaining
compounds 1 were used as racemic mixtures of pure cis or trans diastereomers. PMP ) 4-methoxyphenyl. c Determined by integration
b
of well-resolved signals in the 1H NMR spectra of crude reaction mixtures. Yield of pure, isolated compound 2 with correct analytical
d
data. e Carboxylic acids 5 are better prepared by oxidation of compounds 1. See the Experimental Section. f Md ) Maleimido. Ft )
g
h
Phthalimido. (S)-4-Phenyl-2-oxo-1,3-oxazolidin-3-yl.
Ch a r t 2
C411 or oxidative degradation of 4-carboxy,12 4-benzoyl,13
and 4-acetyl â-lactams.14 In this context, the Baeyer-
Villiger oxidation of ketones has been used to prepare
4-acetoxy- and 4-(benzoyloxy)-2-azetidinones from the
corresponding 4-acyl derivatives.13,14 The close structural
relationship of the previously unknown formates 2 and
4-(acyloxy)-2-azetidinones 3 makes those compounds
attractive building blocks in â-lactam chemistry. This
paper reports in full the scope of this rearrangement, the
study of the factors modulating its regioselectivity, and
the use of formates 2 to prepare 4-unsubstituted â-lac-
tams.
2-azetidinones have been reported previously by us.
Compound 1n and optically pure 4-formyl-2-azetidinone
1o were prepared by reaction of (benzyloxy)acetyl chlo-
ride and the acid chloride derived from Evans’ oxazoli-
dinone and N-benzylcinnamylideneimine17 followed by
ozonolysis. The remaining optically pure cis-4-formyl
â-lactam (+)-1i18 was obtained from optically pure 2-aze-
tidinone 4 (Chart 2)19 by sequential hydrolysis of the
ketal and HIO4 oxidative cleavage. The compounds listed
on Table 1 cover a wide range of substituents as well as
both cis and trans stereochemistries on the 2-azetidinone
ring. Both benzyl and p-anisyl moieties, placed at the
lactam nitrogen, are among the most versatile groups in
â-lactam chemistry.
4-Formyl â-lactams 1 were submitted to m-chloroper-
benzoic (m-CPBA) acid treatment in CH2Cl2 at rt. The
results obtained are best understood by considering first
those compounds 1 having a p-anisyl group on the lactam
nitrogen. Compounds 1a -i gave smoothly the corre-
sponding 4-(formyloxy) â-lactams 2a -i in good to excel-
lent yields (Scheme 1 and Table 1, entries 1-10).
4-(Formyloxy) N-(p-anisyl)-â-lactams 2 having alkyl,
Resu lts a n d Discu ssion
Racemic and enantiomerically pure 4-formyl â-lactams
1 were synthetized by using standard methodology (Table
1). Cycloaddition of the corresponding acid chloride to
N,N-bis(p-methoxyphenyl)glyoxal diimine gave cis-4-
formyl â-lactams 1a -f and 1i-m .15 Lithium ester eno-
late-N,N-bis(p-methoxyphenyl)glyoxal diimine reaction
formed compounds 1g,h , with compound 1g having a
trans-2-azetidinone ring.16 Both approaches to 4-formyl-
(10) For reviews on CSI, see: (a) Rasmussen, J . K.; Hassner, A.
Chem. Rev. 1976, 76, 389. (b) Dhar, D. N.; Murthy, K. S. K. Synthesis
1986, 437. (c) Kamai, A.; Sattur, P. B. Heterocycles 1987, 26, 1051.
(11) See, for example: (a) Murahashi, S.-I; Naota, T.; Kawabara,
T.; Saito, T.; Kumobayashi, H.; Akutawa, S. J . Am. Chem. Soc. 1990,
112, 7820. (b) Easton, C. J .; Love, S. G.; Wang, P. J . Chem. Soc., Perkin
Trans. 1 1990, 277. (c) Mori, M.; Kagechica, K.; Tohjima, K.; Shibasaki,
M. Tetrahedron Lett. 1988, 29, 1409.
(12) (a) Kehagia, K.; Ugi, I. Tetrahedron 1995, 51, 9523. (b) Georg,
G. I.; Kant, J .; Gill, H. S. J . Am. Chem. Soc. 1987, 109, 1129. (c)
Cainelli, G.; Contento, M.; Giacomini, D.; Panunzio, M. Tetrahedron
Lett. 1985, 26, 937.
(13) (a) Tschaen, D. M.; Fuentes, L. M.; Lynch, J . E.; Laswell, W.
L.; Volante, R. P.; Shinkari, I. Tetrahedron Lett. 1988, 29, 2779. (b)
Altamura, M.; Ricci, M. Synth. Commun. 1988, 18, 2129.
(14) (a) Sheppard, A.; Miller, M. J . J . Chem. Soc., Perkin Trans. 1
1990, 2519. (b) Palomo, C.; Cossio, F. P.; Arrieta, A.; Odriozola, J . M.;
Oiarbide, M.; Ontoria, J . M. C. J . Org. Chem. 1989, 54, 5736. (c)
Arrieta, A.; Lecea, B.; Cossio, F. P.; Palomo, C. J . Org. Chem. 1988,
53, 3784.
(15) (a) Alcaide, B.; Mart´ın-Cantalejo, Y.; Plumet, J .; Rodr´ıguez-
Lo´pez, J .; Sierra, M. A. Tetrahedron Lett. 1991, 32, 803. (b) Alcaide,
B.; Mart´ın-Cantalejo, Y.; Pe´rez-Castells, J .; Rodriguez-Lo´pez, J .; Sierra,
M. A.; Monge, A.; Pe´rez-Garc´ıa, V. J . Org. Chem. 1992, 57, 5921.
(16) (a) Alcaide, B.; Go´mez, A.; Plumet, J .; Rodr´ıguez-Lo´pez, J .
Tetrahedron 1989, 45, 2751. (b) Alcaide, B.; Esteban, G.; Mart´ın-
Cantalejo, Y.; Plumet, J .; Rodr´ıguez-Lo´pez, J .; Monge, A.; Pe´rez-Garc´ıa,
V. J . Org. Chem. 1994, 59, 7994.
(18) For other enantiospecific syntheses of cis-4-formyl-2-azetidino-
nes see, for example: (a) J arayaman, M.; Deshmukh, A. R.- A. S.;
Bhawal, B. M. J . Org. Chem. 1994, 59, 5921. (b) Palomo, C.; Cossio,
F. P.; Cuevas, C.; Lecea, B.; Mielgo, A.; Roman, P.; Luque, A.; Mart´ınez-
Ripoll, M. J . Am. Chem. Soc. 1992, 114, 9360. (c) Evans, D. A.;
Williams, J . M. Tetrahedron Lett. 1988, 29, 5065.
(19) The stereochemical outcome of â-lactams derived from D-
glyceraldehyde acetonide has been determined both experimentally and
theoretically. For the experimental approach see: (a) Hubschwerelen,
C.; Schmid, G. Helv. Chim. Acta 1983, 66, 2206. (b) Welch, J . T.; Araki,
K.; Kawecki, R.; Wichtowski, J . A. J . Org. Chem. 1993, 58, 2454. (c)
Wagle, D. R.; Garai, C.; Chiang, J .; Monteleone, M. G.; Kurys, B. E.;
Strohmeyer, T. W.; Hedge, V. R.; Manhas, M. S.; Bose, A. K. J . Org.
Chem. 1988, 53, 4227 and references therein. For the theoretical
approach see, for example: Cossio, F. P.; Arrieta, A.; Lecea, B.; Ugalde,
J . M. J . Am. Chem. Soc. 1994, 116, 2085.
(17) Evans, D. A.; Sjogren, E. B. Tetrahedron Lett. 1985, 26, 3783.

Synthesis of 3-Substituted 4-(Formyloxy)-2-azetidinones
J . Org. Chem., Vol. 61, No. 25, 1996 8821
Sch em e 1
Sch em e 2
alkenyl, aryl, and alkyloxy substituents on position 3 are
formed in excellent yields. The regioisomeric 4-carboxy-
2-azetidinones 5 were not formed in any case as estab-
lished by 1H NMR analysis of the reaction mixtures. The
cis-trans stereochemistry of the starting compound 1 is
transferred unaltered to the final products. An attractive
feature of this transformation is its high chemoselectivity
and the fact that it occurs even in the presence of other
oxidizable groups (entries 1-3, Table 1).20
The presence of an acyloxy or amide group on C3 of
the starting material 1 produces different results. In fact,
these compounds yield mixtures of the formates 2 and
their regioisomers, 4-carboxy-2-azetidinones 5 (entries
11-14, Table 1). The nature of the substituent deter-
minates the relative ratio of the reaction products,
carboxylic acid formation increasing steadly from ester
to amide substituents. Interestingly, an oxazolidinone
group promoted the migration of hydrogen preferentially
over the carbon moiety (entry 14, Table 1). Finally, the
influence of the group attached to the lactam nitrogen
on the migratory aptitude was studied. 4-Carboxy
derivatives 5e,f were obtained either in equimolar
amounts (from 1n ) or exclusively (from 1o) (entries 15-
16, Table 1). Upon comparison of entries 9 and 14 in
Table 1 with entries 15 and 16 it is clear that an alkyl
group attached to the lactam nitrogen favors the migra-
tion of the hydrogen atom. The results obtained in Table
1 may be explained by the preferential migration of the
group with higher ability to support a positive charge
either by inductive effect or hyperconjugation. Provided
that special conformational factors are not present, this
fact is well established in the Baeyer-Villiger rearrange-
ment.2
related to 8 are intermediates in the synthesis of mal-
onamide derivatives as well as useful retroamide isos-
teres in biologically relevant peptidomimetics.23 In turn,
two important groups of monocyclic â-lactam antibiotics,
nocardicins 1024 and monobactams 11,25 and the glutamine
synthetase inhibitor, tabtoxin 12,26 are characterized by
the presence of a 2-azetidinone nucleus lacking substit-
uents at the 4-position of the â-lactam ring (Chart 3).
Ch a r t 3
To set analogies and differences between 4-(formyloxy)-
2-azetidinones 2 and the classical 4-acetoxy â-lactams 3,
some aspects of the chemistry of compounds 2 were
studied. Compatibility of the formyloxy substituent with
standard manipulations of the group attached at N1 was
established by effecting the oxidative cleavage with
cerium(IV) ammonium nitrate (CAN)21 of the p-methox-
yphenyl group attached to the lactam nitrogen. N-
Unsubstituted formates 6a -c were obtained in good
yields from compounds 2d , 2f, and 2h , respectively.
Compounds 6a , and 6c underwent also reductive reaction
with NaBH4 in aqueous 2-propanol or methanol at 0 °C
to give the corresponding C4-unsubstituted NH-â-lactams
7a ,b.22 Thus, standard manipulations can be effected on
4-(formyloxy) â-lactams (Scheme 2).
Reduction of 4-(formyloxy) â-lactams 2 with NaBH4 in
methanol at 0 °C gave the corresponding R-substituted
â-hydroxy amides 8 in high yields.27 The reduction of
the formyloxy group should occur sequentially through
R-formyl amides 13, the open tautomer of 4-hydroxy
â-lactams 14.28 These intermediates are further reduced
to give the final â-hydroxyamides 8 (Scheme 3). Some
R-formyl amides 13 can be obtained, independently, by
(23) Abouabdellah, A.; Welch, J . T. Tetrahedron: Asymmetry 1994,
5, 1005.
(24) (a) Aoki, H.; Sakai, H.; Kohsaka, M.; Konomi, T.; Hosoda, J .;
Kubochi, Y.; Iguchi, E.; Imanaka, H. J . Antibiot. 1976, 29, 492, 890.
(b) Hashimoto, M.; Komori, T.; Kamiya, T. J . Am. Chem. Soc. 1976,
98, 3023. (c) Hosoda, J .; Konomi, T.; Tani, N.; Aoki, H.; Imanaka, H.
Agric. Biol. Chem. 1977, 41, 2013.
The following approaches to â-hydroxy amides 8 and
different 4-unsubstituted â-lactams 9 illustrate the po-
tential of 4-(formyloxy)-2-azetidinones 2 as intermediates
in more elaborate â-lactam systems. â-Hydroxy amides
(20) The sole exception was the 3-(phenylthio)-4-formyl-2-azetidi-
none. This compound gave the corresponding sulfone after prolongued
reaction time. In this case the formyl group remained unaltered.
(21) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J . Org. Chem. 1982,
47, 2765.
(22) For NaBH4 reduction on related 4-acetoxy â-lactams, see:
Pfaendler, H. R.; Hoppe, H. Heterocycles 1985, 23, 265. For another
reduction method, see: Arrieta, A.; Lecea, B.; Cossio, F. P.; Palomo,
C. J . Org. Chem. 1988, 53, 3784.
(25) (a) Imada, A.; Kitano, K.; Kintaka, K.; Muroi, M.; Asai, M.
Nature (London) 1981, 289, 590. (b) Sykes, R. B.; Cimarusti, C. M.;
Bonner, D. P.; Bush, K.; Floyd, D. M.; Georgopapadakou, N. H.; Koster,
W. H.; Liu, W. C.; Parker, W. L.; Principe, P. A.; Rathnum, M. L.;
Slusarchyk, W. A.; Trejo, W. H.; Wells, J . S. Nature (London) 1981,
291, 489. (c) Wells, J . S.; Hunter, J . C.; Astle, G. L.; Sherwood, J . C.;
Ricca, C. M.; Trejo, W. H.; Bonner, D. P.; Sykes, R. B. J . Antibiot. 1982,
35, 814.
(26) Stuart, W. W. Nature (London) 1971, 229, 174.

8822 J . Org. Chem., Vol. 61, No. 25, 1996
Alcaide et al.
Sch em e 3
Sch em e 4
NaOH treatment of compounds 2 and are reduced to
hydroxy amides 8 by treatment with NaBH4. The
synthesis of a 4-hydroxy â-lactam (type 14) has been
reported previously from (3R)-4-acetoxy-3-benzyl-3-fluoro-
â-lactam.23 In our hands, when compounds 2f and 2h
were submitted to analogous reaction conditions, the
open-chain aldehyde tautomers 13a and 13b, respec-
tively, were obtained in excellent yield.29 Therefore,
4-formyl â-lactams 1 are efficiently transformed into
compounds 8 in two steps following our procedure. The
reported method to prepare compounds analogous to 8
starting from a 4-acetoxy-2-azetidinone requires four
steps to effect the same overall transformation.
Our intended approach to 4-unsubstituted â-lactams
makes use of a ketene-imine cycloaddition to build the
starting 4-(formyloxy) â-lactam 2 and an intramolecular
C4-N bond formation reaction on R-substituted â-hy-
droxy amides 8 (Scheme 4). This mixed route employs
both general approaches to this class of compounds: the
ketene-imine cycloaddition based on unstable, in situ
generated, formaldehyde imines30 or formaldehyde imine
equivalents31 and the intramolecular displacement of an
activated leaving group attached to the â-position of an
acid derivative, usually an amide, under basic condi-
tions.32 Thus, the hydroxyl group of N-(4-methoxyphe-
nyl)amides 8 was activated as its imidosulfonate,27b which
undegoes the intramolecular displacement by the amide
nitrogen upon base treatment to yield the desired com-
pounds 9 (Scheme 4). The overall transformation occurs
in good yields and without lost of the stereochemical
integrity of the starting material when optically pure
starting material was used.33 Alkyl-, aryl-, and alkoxy
groups are tolerated in this transformation. â-Hydroxy
amide 8a having a vinyl group forms 3-ethylidenyl-2-
azetidinone 9a . The isomerization of the double bond
should occur upon base treatment.15b This sequence,
4-formyl-2-azetidinones 1 to C4-unsubstituted 2-azetidi-
nones 9, represents a simple, stereoselective, and high-
yielding entry to this interesting type of compounds.
Finally, CAN dearylation of compounds 9 gives the
corresponding N-unsubstituted â-lactams 7.
In conclusion, the Baeyer-Villiger oxidation of 4-formyl
â-lactams 1 has been studied. This reaction represents
one of the scarce examples of the preferred migration of
a carbon moiety in an aliphatic aldehyde and is an
efficient and totally stereoselective entry to 4-(formyloxy)
â-lactams 2, which in turn are suitable building blocks
for â-lactam antibiotics. The influence of the substituents
at N1 and C3 of the four-membered ring in the Baeyer-
Villiger rearrangement have been studied. 4-(Formyloxy)
â-lactams 2 are suitable starting materials to prepare
different 4-unsubstituted â-lactams 9 using â-hydroxy
amides 8 as isolable intermediates. The overall trans-
formation of 4-formyl-2-azetidinone 1 to 4-unsubstituted
â-lactam 9 is a simple and convenient route to this
interesting type of compounds.
(27) â-Hydroxy N-arylamides related to 6 have been used for the
synthesis of relevant C4-unsubstituted-â-lactams. See, for example:
(a) Bose, A. K.; Sahu, D. P.; Manhas, M. S. J . Org. Chem. 1981, 46,
1229. (b) Hanessian, S.; Couture, C.; Wyss, H. Can. J . Chem., 1985,
63, 3613.
(28) R-Formylacetanilides related to 13 have been obtained from
4-amino-â-lactams. See, for instance: (a) Perelman, E.; Mizsak, S. A.
J . Am Chem. Soc. 1962, 84, 4988. (b) Opitz, G.; Koch, J . Angew. Chem.
1963, 75, 167. (c) Bose, A. K.; Kugajevsky, I. Tetrahedron 1967, 23,
957.
(29) Reduction (NaBH4/Methanol/0 °C) of isolated compound 13a
gave the corresponding â-hydroxy amide 8d in quantitative yield.
(30) See, for example: (a) Overmann, L. E.; Osawa, T. J . Am Chem.
Soc. 1985, 107, 1698. (b) Nakaguchi, O.; Oku, T.; Takeno, H.;
Hashimoto, M.; Kamiya, T. Chem. Pharm. Bull. 1987, 35, 3985. (c)
Hegedus, L. S.; D’Andrea, S. J . Org. Chem. 1988, 53, 3113.
(31) Selected examples: (a) Kamiya, T.; Hashimoto, M.; Nakaguchi,
O.; Oku, T. Tetrahedron 1979, 35, 323. (b) Curran, W. V.; Sassiver, M.
L.; Ross, A. S.; Fields, T. L.; Boothe, J . H. J . Antibiot. 1985, 35, 329.
(c) Narukawa, Y.; J uneau, K.; Snustad, D.; Miller, D. B.; Hegedus J .
Org. Chem. 1992, 57, 5453.
Exp er im en ta l Section 34
Gen er a l P r oced u r e. General experimental data and
procedures have been reported previously.15b 4-Formyl â-lac-
tams 1 were used in all cases as single cis- or trans-isomers.
Except as otherwise stated, spectroscopic data (1H- and 13C-
(32) Ternansky, R. J .; Morin, J . M. In The Organic Chemistry of
â-Lactams; Georg, G. I., Ed.; VCH Publishers, Inc.: New York, 1993;
Chapter 5, p 4257.
(33) All enantiomerically pure compounds with a single stereocenter
were checked against partial or total racemization by using chiral shift
reagents. See the Experimental Section.

Synthesis of 3-Substituted 4-(Formyloxy)-2-azetidinones
J . Org. Chem., Vol. 61, No. 25, 1996 8823
NMR) were obtained in CDCl3 solutions. Specific rotation [R]D
is given in deg per dm at the specified temperature, and the
concentration (c) is expressed in g per 100 mL in the given
solvent. The optical purity of those compounds having a single
Calcd for C14H15NO4: C, 64.36; H, 5.79; N, 5.36. Found: C,
64.15; H, 5.72; N, 5.09.
ci s-1-(p -An is y l)-4-(fo r m y lo x y )-3-p h e n y l-2-a ze t id i-
n on e, 2d . Reaction time: 18 h. Yield: 0.56 g (94%). White
solid. Mp: 98-100 °C. 1H NMR: δ 7.78 (s, 1H), 7.36 (m ,
7H), 6.92 (d, 2H, J ) 9.0 Hz), 6.77 (d, 1H, J ) 4.3 Hz), 4.86 (d,
1H, J ) 4.3 Hz), 3.81 (s, 3H). 13C NMR: δ 163.6, 159.3, 157.1,
130.1, 129.8, 129.7, 128.7, 128.5, 118.8, 114.7, 78.2, 60.9, 55.6.
1
chiral center was checked by H NMR using tris[(3-heptafluo-
ropropyl)hydroxymethylene-d-camphorate]europium(III), Eu-
(hfc)3, as the chiral shift reagent, both in the racemic and
optically pure compound. Except as otherwise stated all
compounds are racemic.
IR (KBr): ν 1755, 1735, 1595, 1515 cm-1
. Anal. Calcd for
All commercially available compounds were used without
further purification. The following starting materials were
prepared according to previously reported procedures: cis-1-
(p-anisyl)-4-formyl-3-vinyl-2-azetidinone,15b cis-(1-p-anisyl)-4-
(formy)-3-isopropenyl-2-azetidinone,15b cis-1-(p-anisyl)-4-(formyl-
oxy)-3-isopropylidene-2-azetidinone,15b cis-1-(p-anisyl)-4-formyl-
3-phenyl-2-azetidinone,15b cis-1-(p-anisyl)-3-ethyl-4-formyl-2-
azetidinone,15b cis-1-(p-anisyl)-3-isopropyl-4-formyl-2-azeti-
dinone,15b trans-1-(p-anisyl)-3-isopropyl-4-formyl-2-azetidinone,16a
1-(p-anisyl)-3,3-dimethyl-4-formyl-2-azetidinone,16a cis-1-(p-
anisyl)-3-(benzyloxy)-4-formyl-2-azetidinone,15b cis-3-acetyl-1-
(p-anisyl)-4-formyl-2-azetidinone,15b cis-1-(p-anisyl)-3-maleimido-
4-formyl-2-azetidinone,15b cis-1-(p-anisyl)-4-formyl-3-phthalimido-
2-azetidinone,15b (+)-cis-1-(p-anisyl)-4-formyl-3-[(S)-4-phenyl-
2-oxooxazolidin-3-yl)]-2-azetidinone,15b cis-1-benzyl-3-(benzyloxy)-
4-formyl-2-azetidinone,17 (+)-cis-1-benzyl-4-formyl-3-[(S)-4-
phenyl-2-oxooxazolidin-3-yl)]-2-azetidinone,17 (+)-(3R,4S)-cis-
1-(p-anisyl)-3-(benzyloxy)-4-[(S)-2,2-dimethyl-1,3-dioxolan-4-
yl]-2-azetidinone.19c
Gen er a l P r oced u r e for th e Syn th esis of cis-3-Su bsti-
tu ted 4-(For m yloxy)-2-azetidin on es 2. A mixture of 4-formyl
â-lactam 1 (2 mmol) and m-CPBA (calcd 0.414 g, 2.4 mmol,
50-60%) in CH2Cl2 (DCM) (40 mL) was stirred at room
temperature until total consumption of the starting material
(TLC). The reaction mixture was then washed with 5%
aqueous NaHCO3 solution (2 × 30 mL) and brine (2 × 30 mL)
and finally dried over anhydrous Na2SO4. Removal of the
solvent under reduced pressure afforded a residue that was
purified by silica gel chromatography with hexane-EtOAc (3:
1) to give the corresponding analytically pure product 2. In
those cases in which mixtures of compounds 2 and carboxylic
acids 5 were obtained, chromatographic separation afforded
analytically pure 2-azetidinones 2. Compounds 5 were not
obtained in pure form by this procedure. Pure compounds 5
were prepared as described below by J ones’ oxidation of the
corresponding 4-formyl â-lactams 1. Spectroscopic and ana-
lytical data for some representative forms of 2 follow.34
cis-1-(p-An isyl)-4-(for m yloxy)-3-vin yl-2-azetidin on e, 2a.
Reaction time: 3 h. Yield: 0.45 g (91%). White solid. Mp:
105-107 °C (DCM/hexanes). 1H NMR: δ 8.15 (s, 1H), 7.36
(d, 2H, J ) 9.0 Hz), 6.88 (d, 2H, Ar, J ) 9.0 Hz), 6.67 (dd, 1H,
J 1 ) 4.3 Hz, J 2 ) 0.6 Hz), 5.77-5.91 (m, 1H), 5.39-5.45 (m,
2H), 4.24 (dd, 1H, J 1 ) 8.0 Hz, J 2 ) 4.3 Hz), 3.79 (s, 3H). 13C
NMR: δ 163.4, 159.7, 157.1, 129.5, 126.4, 123.0, 118.8, 114.6,
77.6, 58.7, 55.6. IR (KBr): ν 1770, 1730, 1560, 1520. Anal.
Calcd for C13H13NO4: C, 63.15; H, 5.30; N, 5.66. Found: C,
62.89; H, 5.31; N, 5.58.
C17H15NO4: C, 68.68; H, 5.09; N, 4.71. Found: C, 68.39; H,
5.10; N, 4.60.
cis-1-(p -An isyl)-3-isop r op yl-4-(for m yloxy)-2-a zet id i-
n on e, 2f. Reaction time: 4 h. Yield: 0.45 g (85%). White
solid. Mp: 120-122 °C (DCM/hexanes). 1H NMR: δ 8.23 (s,
1H), 7.32 (d, 2H, J ) 9.0 Hz), 6.87 (d, 2H, J ) 9.0 Hz), 6.84 (d,
1H, J ) 4.3 Hz), 3.78 (s, 3H), 3.23 (dd, 1H, J 1 ) 9.7 Hz, J 2
)
4.3 Hz), 2.21 (m, 1H), 1.22 (d, 3H, J ) 6.7 Hz), 0.96 (d, 3H, J
) 6.7). 13C NMR: δ 165.3, 160.2, 156.7, 129.3, 118.6, 114.5,
75.77, 61.2, 55.5, 25.3, 21.6, 20.2. IR (KBr): ν 1760, 1725,
1520. Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32.
Found: C, 63.78; H, 6.47; N, 5.25.
tr a n s-1-(p-An isyl)-3-isop r op yl-4-(for m yloxy)-2-a zetid i-
n on e, 2g. Reaction time: 4 h. Yield: 0.46 g (87%). White
solid. Mp: 106-107 °C (DCM/hexanes). 1H NMR: δ 8.15 (s,
1H), 7.33 (d , 2H, J ) 9.3 Hz), 6.87 (d, 2H, J ) 9.3 Hz), 6.45
(d, 1H, J ) 0.9 Hz), 3.78 (s, 3H), 3.11 (dd, 1H, J 1 ) 0.9 Hz, J 2
) 7.5 Hz), 2.17 (m, 1H), 1.13 (d, 3H, J ) 6.6 Hz), 1.09 (d, 3H,
J ) 6.9 Hz). 13C NMR: δ 164.5, 159.8, 156.7, 129.3, 118.5,
114.4, 77.8, 64.9, 55.4, 26.7, 20.2, 19.6. IR (KBr): ν 2960, 1760,
1730, 1530. Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51;
N, 5.32. Found: C, 63.75; H, 6.74; N, 5.19.
cis-(+)-3-(Ben zyloxy)-4-(for m yloxy)-2-a zetid in on e, (+)-
2i. Reaction time: 2 h. Yield: 0.62 g (94%). White solid.
Mp: 88-90 °C (DCM/hexanes). [R]25D ) +128.26 (c 1, CHCl3).
1H NMR: δ 8.18 (s, 1H), 7.36 (m, 7H), 6.89 (d, 2H, J ) 9.0
Hz), 6.61 (d, 1H, J ) 3.4 Hz), 4.94 (d, 1H, J ) 3.4 Hz), 4.78
(AB, 2H, J ) 11.7 Hz), 3.79 (s, 3H). 13C NMR: δ 163.5, 160.0,
157.4, 136.5, 129.1, 128.7, 128.4, 128.2, 119.1, 114.7, 82.1, 79.4,
74.0, 55.6. IR (KBr): ν 1780, 1730, 1520 cm-1. Anal. Calcd
for C18H17NO5: C, 65.77; H, 5.27; N, 4.24. Found: C, 66.05;
H, 5.23; N, 4.28.
cis-3-Ace t oxy-1-(p -a n isyl)-4-(for m yloxy)-2-a ze t id i-
n on e, 2j, a n d cis-3-Acetoxy-1-(p-a n isyl)-4-ca r boxy-2-a ze-
tid in on e, 5a . Following the standard procedure, after 3 h, a
crude reaction mixture containing compounds 2j and 5a (88:
12) was obtained. From this mixture 0.45 g (80%) of 2j was
obtained as a white solid. Mp: 128-130 °C (DCM/hexanes).
Com p ou n d 2j. 1H NMR: δ 8.16 (s, 1H), 7.39 (d, 2H, J ) 9.0
Hz), 6.90 (d, 2H, J ) 9.0 Hz), 6.83 (d, 1H, J ) 3.7 Hz), 5.97 (d,
1H, J ) 3.7 Hz), 3.80 (s, 3H), 2.19 (s, 3H). 13C NMR: δ 169.1,
161.0, 159.4, 157.6, 128.6, 119.2, 114.7, 77.1, 75.0, 55.6, 20.4.
IR (KBr): ν 1770, 1730, 1515. Anal. Calcd for C13H13NO6:
C, 55.92; H, 4.69; N, 5.02. Found: C, 55.95; H, 4.74; N, 4.91.
cis-1-(p-An isyl)-4-(for m yloxy)-3-p h th a lim id o-2-a zetid i-
n on e, 2l, a n d cis-1-(p-An isyl)-4-ca r boxy-3-p h th a lim id o-
2-a zetid in on e, 5c. Following the standard procedure, after
7 h, a crude reaction mixture containing compounds 2l and
5c (65:35) was obtained. From this mixture 0.45 g (62%) of
2l was obtained as a white solid. Mp: 178-180 °C (DCM/
hexanes). Com p ou n d 2l. 1H NMR: δ 8.04 (s, 1H), 7.80 (m,
2H), 7.46 (m, 2H), 7.46 (d, 2H, J ) 9.0 Hz), 6.91 (d, 2H, J )
9.0 Hz), 6.87 (d, 1H, J ) 3.9 Hz), 5.72 (d, 1H, J ) 3.9 Hz),
3.80 (s, 3H). 13C NMR: δ 166.5, 160.2, 159.5, 157.4, 134.7,
131.6, 128.9, 124.1, 119.4, 114.5, 77.6, 57.6, 55.5. IR (KBr): ν
1790, 1775, 1735, 1715, 1520. Anal. Calcd for C19H14N2O6:
C, 62.30; H, 3.85; N, 7.65. Found: C, 62.08; H, 3.94; N, 7.58.
cis-1-Be n zyl-3-(b e n zyloxy)-4-(for m yloxy)-2-a ze t id i-
n on e, 2n , a n d cis-1-Ben zyl-3-(ben zyloxy)-4-ca r boxy-2-
a zetid in on e, 5e. Following the standard procedure, after 2.5
h, a crude reaction mixture containing compounds 2n and 5e
(50:50) was obtained. From this mixture 0.28 g (45%) of 2n
was obtained as a colorless thick oil. Com p ou n d 2n . 1H
NMR: δ 8.01 (s, 1H), 7.30 (m, 10H), 6.0 (d, 1H, J ) 3.4 Hz),
4.77 (d, 1H, J ) 3.4 Hz), 4.70 (AB, 2H, J ) 14.0 Hz), 4.58 (d,
1H, J ) 15.0 Hz), 4.19 (d, 1H, J ) 15.0 Hz). 13C NMR: δ 166.7,
160.2, 136.5, 134.8, 129.0, 128.7, 128.5, 128.4, 128.3, 128.2,
cis-1-(p-An isyl)-4-(for m yloxy)-3-isop r op en yl-2-a zetid i-
n on e, 2b. Reaction time: 20 h. Yield: 0.36 g (70%). White
solid. Mp: 62-64 °C (DCM/hexanes). 1H NMR: δ 8.14 (s,
1H), 7.34 (d, 2H, J ) 9.0 Hz), 6.86 (d, 2H, J ) 9.0 Hz), 6.69 (d,
1H, J ) 4.3 Hz), 5.15 (s, 1H), 5.09 (s, 1H), 4.18 (d, 1H, J ) 4.3
Hz), 3.75 (s, 3H), 1.81 (s, 3H). 13C NMR: 163.6, 159.9, 156.9,
135.2, 129.5, 118.7, 118.2, 114.5, 77.4, 61.5, 55.5, 21.9. IR
(KBr): ν 1770, 1720, 1520. Anal. Calcd for C14H15NO4: C,
64.36; H, 5.79; N, 5.36. Found: C, 64.19; H, 5.76; N, 5.17.
cis-1-(p-An isyl)-4-(for m yloxy)-3-isop r op ylid en e-2-a ze-
tid in on e, 2c. Reaction time: 2 h. Yield: 0.47 g (90%). White
solid. Mp: 104-106 °C (DCM/hexanes). 1H NMR: δ 8.24 (d,
1H, J ) 0.8 Hz), 7.35 (d, 2H, J ) 9.0 Hz), 7.15 (s, 1H), 6.89 (d,
2H, J ) 9.0 Hz), 3.79 (s, 3H), 2.14 (s, 3H), 1.84 (s, 3H). 13C
NMR: δ 160.8, 160.6, 156.6, 141.0, 131.6, 129.9, 118.2, 114.7,
78.3, 55.6, 21.0, 20.4. IR (KBr): ν 1760, 1720, 1520 cm-1. Anal.
(34) Full spectroscopic and analytical data of compounds not
included in this Experimental Section are described in the Supporting
Information.

8824 J . Org. Chem., Vol. 61, No. 25, 1996
Alcaide et al.
82.6, 79.9, 73.6, 44.8. IR (KBr): 1750, 1700, 1640. Anal.
Calcd for C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found: C,
69.07; H, 5.71; N, 4.47.
N-(p-An isyl)-3-h yd r oxy-2-p h en ylp r op a n a m id e, 8b. Re-
action time: 1 h. Yield: 0.23 g (85%). Colorless needles.
Mp: 144-146 °C. 1H-NMR: δ 7.37 (m, 7H), 7.16 (br s, 1H),
6.83 (d, 1H, J ) 9.0 Hz), 4.22 (m, 1H), 3.85 (m, 2H), 3.78 (s,
3H), 3.32 (t, 1H, J ) 8.4 Hz). 13C NMR: δ 171.7, 156.8, 136.4,
130.4, 129.4, 128.6, 128.2, 122.1, 114.2, 65.1, 55.6, 55.2. IR
(KBr): ν 3400, 3300, 1660, 1540, 1520. Anal. Calcd for
C16H17NO3: C, 70.83; H, 6.32; N, 5.16. Found: C, 70.55; H,
6.22; N, 5.04.
N-(p-An isyl)-3-h yd r oxy-2-isop r op ylp r op a n a m id e, 8d .
Reaction time: 0.5 h. Yield: 0.23 g (95%). White solid. Mp:
126-128 °C. 1H NMR: δ 7.64 (br s, 1H), 7.43 (d, 2H, J ) 9.0
Hz), 6.85 (d, 2H, J ) 9.0 Hz), 3.90 (m, 2H), 3.79 (s, 3H), 2.75
(br s, 1H), 2.13 (m, 2H), 1.03 (d, 3H, J ) 6.3 Hz) and 1.01 (d,
3H, J ) 6.3 Hz). 13C NMR: δ 173.4, 156.5, 130.6, 122.0, 114.1,
61.7, 56.4, 55.5, 27.7, 21.2, 20.3. IR (KBr): ν 3300, 1665, 1545,
1525. Anal. Calcd for C13H19NO3: C, 65.80; H, 8.07; N, 5.90.
Found: C, 65.94; H, 7.79; N, 5.85.
Gen er a l P r oced u r e for th e Syn th esis of 4-Ca r boxy-2-
a zetid in on es 5. J ones’ reagent was added dropwise to a
solution of 4-formyl-2-azetidinone 1 (1 mmol) in acetone (20
mL) cooled to 0 °C (ice bath). The reaction mixture was stirred
at 0 °C for 0.5 h; MeOH (1 mL) was added, and stirring was
continued for 5 min. The mixture was filtered through Celite,
and the solvent was removed under reduced pressure. The
residue was taken up in CHCl3 (30 mL), washed with H2O and
brine, and dried (MgSO4). Compound 5 was obtained upon
solvent removal under vacuum. Analytically pure compounds
were obtained by crystallization of the indicated solvent
mixture. Spectroscopic and analytical data for some repre-
sentative forms of 5 follow.34
cis-3-Acetoxy-1-(p-a n isyl)-4-ca r boxy-2-a zetid in on e, 5a .
Yield: 85%. White solid. Mp: 214-216 °C (AcOEt/DCM). 1H
NMR (DMSO-d6): δ 7.30 (d, 2H, J ) 8.9 Hz), 6.95 (d, Ar, J )
8.9 Hz), 6.16 (d, 1H, J ) 5.5 Hz), 5.02 (d, 1H, J ) 5.5 Hz),
3.72 (s, 3H), 2.09 (s, 3H). 13C-NMR (DMSO-d6): δ 168.7, 168.3,
160.7, 156.1, 130.2, 118.1, 114.3, 73.7, 57.8, 55.2, 20.1. IR
(KBr): ν 3100-2540, 1770, 1760, 1735, 1515. Anal. Calcd
for C13H13NO6: C, 55.92; H, 4.69; N, 5.02. Found: C, 56.08;
H, 4.58; N, 4.94.
(+)-N -(p -An isyl)-2-(b e n zyloxy)-3-h yd r oxyp r op a n a -
m id e, (+)-8f. Reaction time: 1 h. Yield: 0.27 g (87%). White
solid. Mp: 104-106 °C. [R]25 ) +54.92° (c 1, CHCl3). 1H-
D
NMR: δ 8.34 (br s, 1H), 7.43 (m, 7H), 6.86 (d, 2H, J ) 9.0
Hz), 4.74 (AB, 2H, J ) 11.6 Hz), 4.09 (t, 1H, J ) 4.9 Hz), 3.94
(t, 2H, J ) 6.0 Hz), 3.79 (s, 3H), 2.50 (t, 1H, J ) 6.3 Hz). 13C-
NMR: δ 168.9, 156.8, 136.7, 130.1, 129.0, 128.7, 128.3, 121.6,
114.3, 80.1, 73.5, 62.9, 55.6. IR (KBr): ν 3380, 3280, 1660,
1525 cm-1. Anal. Calcd for C17H19NO4: C, 67.76; H, 6.36; N,
4.65. Found: C, 67.55; H, 6.35; N, 4.52.
cis-1-(p -An isyl)-4-ca r b oxy-3-p h t h a lim id o-2-a ze t id i-
n on e, 5c. Yield: 87%. White solid. Mp: 260-262 °C (AcOEt/
DCM). 1H NMR (DMSO-d6): δ 7.93 (m, 4H), 7.44 (d, 2H, J )
8.9 Hz), 6.97 (d, 2H, J ) 8.9 Hz), 5.85 (d, 1H, J ) 6.3 Hz),
5.18 (d, 1H, J ) 6.3 Hz), 3.74 (s, 3H). 13C NMR (DMSO-d6):
δ 168.4, 166.5, 160.7, 155.8, 135.2, 131.0, 130.8, 123.7, 118.4,
Gen er a l P r oced u r e for th e P r ep a r a tion of 4-Un su b-
stitu ted 2-a zetid in on es 9. A solution of 3-hydroxy amide 8
(1 mmol) in DMF (15 mL) was added dropwise to a solution of
NaH (previously washed in hexanes) (0.05 g, 2 mmol) in DMF
(2.5 mL) cooled to 0 °C (ice bath). The resulting mixture was
cooled to -40 °C, and a solution of diimidazolyl sulfone (0.396
g, 2 mmol) in DMF (7.5 mL) was added dropwise over a 10
min period. After being stirred at -40 °C for 0.5 h the mixture
was allowed to reach room temperature. Methanol (0.5 mL)
and CHCl3 (125 mL) were successfully added to the reaction
mixture and then washed with brine and H2O and finally dried
over MgSO4. The organic solvent was removed under vacuum
to yield a residue whose 1H-NMR spectrum of the crude
reaction mixture showed a quantitative yield of the expected
product 9. Column chromatography (DCM/AcOEt/hexanes 12:
2:1) afforded analytically pure compounds 9. Spectroscopic
and analytical data for some representative forms of 9 follow.34
1-(p-An isyl)-3(E)-eth ylid en yl-2-a zetid in on e, 9a . Yield:
75%. White solid. Mp: 115-117 °C (DCM/hexanes). 1H
NMR: δ 7.32 (d, 2H, J ) 9.0 Hz), 6.88 (d, 2H, J ) 9.0 Hz),
6.28 (dq, 1H, J 1 ) 6.9 Hz, J 2 ) 0.7 Hz), 4.05 (d, 2H, J ) 0.6
Hz), 3.78 (s, 3H), 1.81 (d, 3H, J ) 7.0 Hz). 13C NMR: δ 160.2,
156.0, 136.8, 132.4, 122.9, 117.5, 114.5, 55.6, 46.6, 14.6. IR
(KBr): ν 1735, 1520. Anal. Calcd for C12H13NO2: C, 70.92;
H, 6.45; N, 6.89. Found: C, 70.72; H, 6.19; N, 6.83.
1-(p-An isyl)-3-p h en yl-2-a zetid in on e, 9b. Yield: 92%.
White solid. Mp: 124-126 °C (DCM/hexanes). 1H NMR: δ
7.33 (m, 7H), 6.90 (d, 2H, J ) 9.0 Hz), 4.50 (dd, 1H, J 1 ) 5.8,
J 2 ) 2.7 Hz), 4.03 (t, 1H, J ) 5.8 Hz), 3.80 (s, 3H), 3.64 (dd,
1H, J 1 ) 5.7 Hz, J 2 ) 2.8 Hz). 13C NMR: δ 164.9, 156.3, 135.6,
132.1, 129.0, 127.8, 127.5, 117.8, 114.5, 55.6, 35.7, 27.0. IR
(KBr): ν 1740, 1510. Anal. Calcd for C16H15NO2: C, 75.87;
H, 5.97; N, 5.53. Found: C, 75.63; H, 5.73; N, 5.51.
1-(p-An isyl)-3-isop r op yl-2-a zetid in on e, 9c. Yield: 87%.
White solid. Mp: 80-82 °C (DCM/hexanes). 1H NMR: δ 7.31
(d, 2H, J ) 9.0 Hz), 6.87 (d, 2H, J ) 9.0 Hz), 3.78 (s, 3H), 3.62
(t, 1H, J ) 5.6 Hz), 3.32 (dd, 1H, J 1 ) 5.7 Hz, J 2 ) 2.7 Hz),
3.11 (m, 1H), 2.07 (m, 1H) 1.12 (d, 3H, J ) 6.7 Hz), 1.01 (d,
3H, J ) 6.7 Hz). 13C NMR: δ 166.7, 156.0, 132.4, 117.5, 114.4,
55.8, 55.6, 42.5, 28.4, 20.2, 20.1. IR (KBr): ν 1720, 1510. Anal.
Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C,
71.24; H, 7.69; N, 6.37.
114.0, 56.8, 55.2, 55.1. IR (KBr): ν 1770, 1720, 1520 cm-1
.
Anal. Calcd for C19H14N2O6: C, 62.30; H, 3.85; N, 7.65.
Found: C, 62.56; H, 3.54; N, 7.72.
cis-1-Ben zyl-3-(ben zyloxy)-4-car boxy-2-azetidin on e, 5e.
Yield: 85%. White solid. Mp: 235-237 °C (DCM/hexanes).
1H NMR (CDCl3): δ 9.46 (br s, 1H), 7.35-7.15 (m, 10 H), 4.91
(d, 1H, J ) 15.6 Hz), 4.86 (d, 1H, J ) 5.1 Hz), 4.70 (AB, 2H,
J ) 11.4 Hz), 4.14 (d, 1H, J ) 5.1 Hz), 4.12 (d, 1H, J ) 15.6
Hz). 13C NMR (CDCl3): δ 172.4, 166.7, 136.4, 134.1, 129.1,
128.7, 128.6, 128.3, 128.3, 128.2, 82.5, 73.4, 58.3, 45.2. IR
(KBr): ν 1760, 1530 cm-1
. Anal. Calcd for C18H17NO4: C,
69.44; H, 5.50; N, 4.50. Found: C, 69.28; H, 5.34; N, 4.65.
cis-1-Ben zyl-4-car boxy-3-[(S)-4-ph en yl-2-oxooxazolidin -
3-yl)]-2-a zetid in on e, 5f. Yield: 86%. White solid. Mp:
145-147 °C (DCM/hexanes). [R]25 ) +190.48 (c 1, CHCl3).
D
1H NMR (CDCl3): δ 7.74 (br s, 1H), 7.35 (m, 10H), 5.08 (m,
2H), 4.75 (t, 1H, J ) 8.7 Hz), 4.38 (d, 1H, J ) 14.7 Hz), 4.32
(d, 1H, J ) 5.6 Hz), 4.15 (m, 1H), 4.04 (d, 1H, J ) 5.6 Hz).
13C-NMR (CDCl3): δ 170.6, 163.9, 158.7, 135.9, 134.6, 129.8,
129.0, 128.9, 128.1, 127.7, 71.6, 61.0, 60.8, 55.4, 45.5. IR
(KBr): ν 3280, 1775, 1735. Anal. Calcd for C20H18N2O4: C,
68.56; H, 5.18; N, 8.00. Found: C, 68.84; H, 4.89; N, 7.75.
Gen er a l P r oced u r e for th e Syn th esis of 3-Hyd r oxy
a m id es 8. Fine granulated NaBH4 (0.46 g, 1.2 mmol) was
added to a solution of 4-(formyloxy)-2-azetidinone 2 (1 mmol)
in MeOH (40 mL) cooled to 0 °C (ice bath). The resulting
mixture was stirred at 0 °C until total consumption of the
starting material (TLC). The solvent was removed under
reduced pressure, and the residue was dissolved in DCM (30
mL), washed with H2O (20 mL) and brine (20 mL), and finally
dried (MgSO4). The solvent was removed under vacuo, and
unless otherwise stated the residue was crystallized from
DCM/hexanes mixtures to give analytically pure compounds
8. Spectroscopic and analytical data for some representative
forms of 8 follow.34
N-(p-An isyl)-3-h yd r oxy-2-vin ylp r op a n a m id e, 8a . Reac-
tion time: 1 h. Yield: 0.19 g (86%). White solid. Mp: 53-
55 °C. 1H NMR: δ 7.59 (br s, 1H), 7.40 (d, 2H, J ) 9.0 Hz),
6.86 (d, 2H, J ) 9.0 Hz), 5.96 (m, 1H), 5.39 (dd, 2H, J 1 ) 14.1,
J 2 ) 2.7 Hz), 3.91 (m, 2H), 3.79 (s, 3H), 3.25 (m, 1H), 3.17 (t,
1H, J ) 6.9 Hz). 13C NMR: δ, 171.0, 156.8, 133.3, 130.5, 122.0,
120.8, 114.2, 63.5, 55.6, 53.5. IR (KBr): ν 3280, 1660, 1640,
1520. Anal. Calcd for C12H15NO3: C, 65.14; H, 6.83; N, 6.33.
Found: C, 64.85; H, 6.52; N, 6.38.
(+)-1-(p -An isyl)-3-(b en zyloxy)-2-a zet id in on e, (+)-9d .
Yield: 90%. White solid. Mp: 102-104 °C (DCM/hexanes).
[R]25D ) +33.1 (c 1, CHCl3). 1H NMR: δ 7.37 (m, 7H), 7.30 (d,
2H, J ) 9.0 Hz), 6.87 (d, 2H, J ) 9.0 Hz), 4.91 (d, 1H, J )
11.4 Hz), 4.87 (dd, 1H, J 1 ) 4.9 Hz, J 2 ) 2.1 Hz), 4.70 (d, 1H,
J ) 11.5 Hz), 3.79 (s, 3H), 3.75 (dd, 1H, J 1 ) 6.0 Hz, J 2 ) 4.9

Synthesis of 3-Substituted 4-(Formyloxy)-2-azetidinones
J . Org. Chem., Vol. 61, No. 25, 1996 8825
Hz), 3.52 (dd, 1H, J 1 ) 6.0 Hz, J 2 ) 2.1 Hz). 13C-NMR: δ
could not be obtained. 1H-NMR: δ 9.63 (s, 1H), 8.05 (br s,
1H), 7.33 (d, 2H, J ) 9.0 Hz), 6.77 (d, 2H, J ) 9.0 Hz), 3.70 (s,
3H), 1.39 (s, 6H). 13C-NMR: δ 203.3, 169.4, 156.8, 130.5, 122.3,
114.2, 55.5, 53.8, 21.2. IR (KBr): ν 3340, 1740, 1655, 1520.
163.8, 156.5, 137.0, 131.5, 128.7, 128.4, 118.1, 114.5, 80.0, 72.6,
55.6, 47.5. IR (KBr): ν 1745, 1520. Anal. Calcd for C17H17
-
NO3: C, 72.07; H, 6.05; N, 4.94. Found: C, 71.98; H, 6.19; N,
4.77.
Gen er a l P r oced u r e for th e syn th esis of 3-Oxop r o-
p a n a m id es 13. NaOH (0.05 g, 1.25 mmol) in H2O (1 mL) was
added in a single portion to a solution of 2-azetidinone 2 (1
mmol) in MeOH (8 mL). The mixture was stirred at rt for 1
h, and DCM (17 mL) was added. The resulting heterogeneous
mixture was stirred for an additional period of 10 min. The
organic layer was separated, washed with brine, and dried
(MgSO4). The corresponding R-formyl amide 13 was obtained
upon solvent elimination under vacuo.
Ack n ow led gm en t. Support for this work by the
DGICYT (Project PB93-0442) is gratefully acknowl-
edged. One of us (M.F.A.) acknowledges the receipt of
a postdoctoral fellowship by the Ministerio de Educacio´n
y Ciencia (Spain). We also thank Alberto Rodr´ıguez-
Vicente for his colaboration in the preparation of this
manuscript.
N-(p-An isyl)-2-isop r op yl-3-oxop r op a n a m id e, 13a . Yield:
89%. White solid. Mp: 132-134 °C (DCM/hexanes). 1H
NMR: δ 9.79 (d, 1H, J ) 3.5 Hz), 7.95 (br s, 1H), 7.42 (d, 2H,
J ) 9.0 Hz), 6.86 (d, 2H, J ) 9.0 Hz), 3.79 (s, 3H), 3.00 (dd,
1H, J 1 ) 3.5, J 2 ) 8.5 Hz), 2.60 (m, 1H), 1.11 (d, 3H, J ) 6.76
Hz), 1.04 (d, 3H, J ) 6.8 Hz). 13C NMR: δ 201.5, 165.9, 156.9,
130.3, 122.2, 114.3, 67.6, 55.6, 29.5, 20.6, 20.3. IR (KBr): ν
3290, 1730, 1650. Anal. Calcd for C13H17NO3: C, 66.36; H,
7.28; N, 5.95. Found: C, 66.35; H, 7.16; N, 6.26.
Su p p or tin g In for m a tion Ava ila ble: Full spectral and
analytical data for compounds (+)-1i, 2e, 2h ,i,k , (+)-2m , 5b,
(+)-5d , 6a -c, 7a -c, (+)-7c, 8c, 8e-f, and 9d (6 pages). This
material is contained in libraries on microfiche, inmediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
N-(p-An isyl)-2,2-dim eth yl-3-oxopr opan am ide, 13b. Yield:
72%. Compound 13b was unstable, and correct analytical data
J O9612685