Novel Diethylaluminum Chloride Promoted Reactions of the Azetidine Ring: Efficient and Stereocontrolled Entry to Functionalized Olefins, Pyrrolidines, and Pyrroles

Article abstract of DOI:10.1021/jo991203c

The first examples of Lewis acid promoted fragmentation or rearrangement of the azetidine ring are reported. Azetidine precursors, cis-β-lactams, were easily available as single cis-diastereoisomers by the Staudinger reaction. Both cis- and trans-4-formyl-β-lactams react with the appropriate diol or dithiol under acid catalysis to yield dioxolanes or dithiolanes, while reaction with trimethyl orthoformate or benzenethiol gave 4-acetal or thioacetal β-lactams, respectively. Azetidines were smoothly obtained by reduction of easily available β-lactams with monochloroalane (AlH₂Cl), generated in situ from LiAlH₄/AlCl₃. The chemical reactivity of azetidines with AlEt₂Cl was further investigated. Different substituted azetidines showed varied behavior on product formation during diethylaluminum chloride promoted reactions. Azetidines having 4-methoxyphenyl or 2-furyl groups at C2 and a benzyl or allyl substituent at nitrogen efficiently reacted with AlEt₂Cl to give olefins stereoselectively through a fragmentation process, while acetal or thioacetal azetidines under the standard reaction conditions afforded in a stereocontrolled manner pyrrolidines as the sole product. Furthermore, thioacetal azetidines bearing a substituent at C3 on the azetidine ring that can promote aromatization (phenoxy or exocyclic double bond) gave pyrroles by reaction with AlEt₂Cl.

Full text of DOI:10.1021/jo991203c

9596
J . Org. Chem. 1999, 64, 9596-9604
Novel Dieth yla lu m in u m Ch lor id e P r om oted Rea ction s of th e
Azetid in e Rin g: Efficien t a n d Ster eocon tr olled En tr y to
F u n ction a lized Olefin s, P yr r olid in es, a n d P yr r oles
Benito Alcaide,* Pedro Almendros, Cristina Aragoncillo, and Nati R. Salgado
Departamento de Quı´mica Orga´nica I, Facultad de Quı´mica, Universidad Complutense,
28040-Madrid, Spain
Received J uly 27, 1999
The first examples of Lewis acid promoted fragmentation or rearrangement of the azetidine ring
are reported. Azetidine precursors, cis-â-lactams, were easily available as single cis-diastereoisomers
by the Staudinger reaction. Both cis- and trans-4-formyl-â-lactams react with the appropriate diol
or dithiol under acid catalysis to yield dioxolanes or dithiolanes, while reaction with trimethyl
orthoformate or benzenethiol gave 4-acetal or thioacetal â-lactams, respectively. Azetidines were
smoothly obtained by reduction of easily available â-lactams with monochloroalane (AlH2Cl),
generated in situ from LiAlH4/AlCl3. The chemical reactivity of azetidines with AlEt2Cl was further
investigated. Different substituted azetidines showed varied behavior on product formation during
diethylaluminum chloride promoted reactions. Azetidines having 4-methoxyphenyl or 2-furyl groups
at C2 and a benzyl or allyl substituent at nitrogen efficiently reacted with AlEt2Cl to give olefins
stereoselectively through a fragmentation process, while acetal or thioacetal azetidines under the
standard reaction conditions afforded in a stereocontrolled manner pyrrolidines as the sole product.
Furthermore, thioacetal azetidines bearing a substituent at C3 on the azetidine ring that can
promote aromatization (phenoxy or exocyclic double bond) gave pyrroles by reaction with AlEt2Cl.
In tr od u ction
trisubstituted azetidines, on heating, form alkenes through
a Hoffmann-type elimination.6 Some activated 3-imi-
noazetidines undergo a slow ring opening to give 2-aza-
1,3-dienes.7 Ring opening of 3-substituted 4-arylaze-
tidines to give the corresponding amino alcohols takes
place upon catalytic hydrogenation on palladium or
Raney nickel.8 The Beckmann rearrangement of 3-(me-
syloxyimino)azetidines over alumina gives 4-imidazoli-
dinones,9 and 2-pyrrolidinones are obtained both by
cobalt carbonyl catalyzed carbonylation of azetidines10
and through intramolecular acylation in (3-azetidinyl)-
acetic acids.11 Finally, photolysis of 3-acylazetidines
results in the formation of pyrroles.12 During the course
of our ongoing project directed toward developing efficient
routes to prepare bi- and polycyclic â-lactam systems,13
Since the discovery of the â-lactam ring as the essential
feature of the â-lactam antibiotics,1 much has been
learned about the chemical reactivity of this four-
membered heterocycle. Thus, processes of ring opening,
fragmentation, and rearrangement involving any of the
four bonds of the 2-azetidinone ring have been reported,2
and developed to a synthetically useful level to prepare
different kinds of compounds.3 However, the chemistry
of azetidines has been much less investigated. While
much of the effort involving the azetidine nucleus has
been directed toward its synthesis,4 as it is a component
of many biologically active drugs and natural products,5
few examples of rearrangements or fragmentations of the
azetidine ring are known. It has been shown that 1,2,2′-
(5) Selected examples: (a) Kobayashi, J .; Ishibashi, M. Heterocycles
1996, 42, 943. (b) Shuman, R. T.; Rothenberger, R. B.; Campbell, C.
S.; Smith, G. F.; Gifford-Moore, D. S. J . Med. Chem. 1995, 38, 4446.
(c) Frigola, J .; Torrens, A.; Castrillo, J . A.; Mas, J .; Van˜o´, D.; Berrocal,
J . M.; Calvet, C.; Salgado, L.; Redondo, J .; Garc´ıa-Granda, S.; Valent´ı,
E.; Quintana, J . R. J . Med. Chem. 1994, 37, 4195. (d) Frigola, J .; Pares,
J .; Corbera, J .; Vano, D.; Merce, R. J . Med. Chem. 1993, 36, 801. (e)
Dure´ault, A.; Portal, M.; Carreaux, F.; Depezay, J . C. Tetrahedron
1993, 49, 4201. (f) Kobayashi, J .; Cheng, J . F.; Isibashi, M.; Wa¨lchli,
M. R.; Yamamura, S.; Ohizumi, Y. J . Chem. Soc., Perkin Trans. 1 1991,
1135. (g) Kozikowski, A. P.; Tueckmantel, W.; Reynolds, I. J .; Wrob-
lewski, J . T. J . Med. Chem. 1990, 33, 801, 1561. (h) Isono, K. J .
Antibiot. 1988, 41, 1711. (i) Isono, K.; Asahi, K.; Suzuki, S. J . Am.
Chem. Soc. 1969, 91, 7490.
(6) De Kimpe, N.; Tehrani, K. A.; Fonck, G. J . Org. Chem. 1996,
61, 6500.
(7) Charrier, J .; Foucaud, A.; Person, H.; Loukakou, E. J . Org. Chem.
1983, 48, 481.
(8) (a) Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K.; Yamashita,
M.; Abe, R. J . Org. Chem. 1991, 56, 5263. (b) Yamashita, M.; Ojima,
I. J . Am. Chem. Soc. 1991, 105, 6339.
(9) (a) Nitta, Y.; Kanamori, Y. Heterocycles 1986, 24, 2467. (b) Nitta,
Y.; Kanamori, Y. Heterocycles 1986, 24, 25.
(1) For some reviews on â-lactam antibiotics, see: (a) Du¨rckheimer,
W.; Blumbach, J .; Lattrell, R.; Scheunemann, K. H. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 180. (b) Chemistry and Biology of â-Lactam
Antibiotics; Morin, R. B., Gorman, M., Eds.; Academic Press: New
York, 1982; Vols. 1-3. (c) Soughgate, R.; Branch, C.; Coulton, S.; Hunt,
E. In Recent Progress in the Chemical Synthesis of Antibiotics and
Related Microbial Products; Lukacs, G., Ed.; Springer: Berlin, 1993;
Vol. 2, p 621. (d) Soughgate, R. Contemp. Org. Synth. 1994, 1, 417. (e)
The Chemistry of â-Lactams; Page, M. I., Ed.; Chapman and Hall:
London, 1992.
(2) For reviews, see: (a) The Organic Chemistry of â-Lactams, Georg,
G. I., Ed.; VCH: New York, 1993. (b) Manhas, M. S.; Wagle, D. R.;
Chiang, J .; Bose, A. K. Heterocycles 1988, 27, 1755.(c) Ojima, I. Adv.
Asymm. Synth. 1995, 1, 95.
(3) See, for example: (a) Alcaide, B.; Mart´ın-Cantalejo, Y.; Pe´rez-
Castells, J .; Sierra, M. A.; Monje, A. J . Org. Chem. 1996, 61, 9156. (b)
Alcaide, B.; Pe´rez-Castells, J .; Polanco, C.; Sierra, M. A. J . Org. Chem.
1995, 60, 6012. (b) Alcaide, B.; Mart´ın-Cantalejo, Y.; Rodr´ıguez-Lo´pez,
J .; Sierra, M. A. J . Org. Chem. 1993, 58, 4767 and references therein.
(4) For reviews on the synthesis and chemistry of azetidines, see:
(a) De Kimpe, N. In Comprehensive Heterocyclic Chemistry II; Padwa,
A., Eds; Elsevier: Oxford, 1996; Vol. 1B, Chapter 1.18, pp 507-589.
(b) Moore, J . A.; Ayers, R. S. In Chemistry of Heterocyclic Compounds-
Small Ring Heterocycles; Hassner, A., Ed.; Wiley: New York, 1983;
Part 3, pp 1-217. (c) Cromwell, N. H.; Phillips, B. Chem. Rev. 1979,
79, 331.
(10) Roberto, D.; Alper, H. J . Am. Chem. Soc. 1989, 111, 7539.
(11) Bartholomew, D. J .; Stocks, M. Tetrahedron Lett. 1991, 32,
4799.
(12) Padwa, A.; Gruber, R. J . Am. Chem. Soc. 1970, 92, 100.
10.1021/jo991203c CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/24/1999

Novel Reactions of the Azetidine Ring
J . Org. Chem., Vol. 64, No. 26, 1999 9597
Ta ble 1. Dieth yla lu m in u m Ch lor id e Med ia ted F r a gm en ta tion of Azetid in es 2
â-lactam
R1
R2
R3
azetidine
yielda (%)
olefin
E/Zb
yielda (%)
57
cis-1a
cis-1b
cis-1c
cis-1d
trans-1d
cis-1e
cis-1f
trans-1g
trans-1h
cis-1i
PhO
PhO
PhO
PhO
PhO
PhO
PhO
Ph
4-MeOC6H4
Ph
4-NO2C6H4
2-furyl
2-furyl
2-furyl
Bn
Bn
Bn
allyl
allyl
Bn
cis-2a
cis-2b
cis-2c
cis-2d
trans-2d
cis-2e
cis-2f
trans-2g
trans-2h
cis-2i
91
91
91
97
85
85
57
54
91
73
3a
0:100
NRc
NRc
3b
0:100
67:33
0:100
58
61
53
3b
3b
2-furyl
4-MeOC6H4
NRc
3c
4-MeOC6H4
4-MeOC6H4
styryl
Bn
Bn
Bn
100:0
100:0
0:100
68
76
72
vinyl
PhO
3d
3e
a
b
Yield of pure, isolated product with correct analytical and spectral data. The ratio based on the 1H NMR spectra of the crude reaction
mixtures before purification. c NR ) no reaction was observed. Unreacted starting azetidine 2 was recovered.
we undertook a parallel study on the azetidine nucleus14
to check the electronic and/or steric effects involved in
the cyclization processes, because the planarity of the
amide nitrogen imposed by the amide resonance is
excluded in azetidines.15 We now report full details of two
new, hitherto unprecedented diethylaluminum chloride
promoted reactions of the azetidine ring, namely, its
fragmentation to form olefins and its rearrangement to
form pyrrolidines, fused pyrrolidines, and pyrroles.
vinyl ethers 3a ,b during purification. The stereochem-
istry of the azetidine was transferred unaltered to the
olefin in the tested cases, except for trans-azetidine 2d ,
which gave an E/Z mixture of olefins. The E/Z geometry
of the double bonds in these compounds was consistent
with vinylic coupling constants of ca. 7.0 and 14.0 Hz for
the Z- and E-isomers, respectively, in their 1H NMR
spectra (Table 1).
These examples show that azetidines 2a ,d ,e,g-i hav-
ing 4-methoxyphenyl, 2-furyl, or styryl groups at C2 and
benzyl or allyl substituents at nitrogen efficiently reacted
with AlEt2Cl, while azetidines 2b,c,f bearing phenyl or
4-nitrophenyl groups at C2 and 4-methoxyphenyl sub-
stituents at nitrogen were unreactive. The above results
strongly suggest that an electron donor group able to
stabilize a positive charge at the C2 position and a basic
azetidine nitrogen are necessary for the fragmentation
to occur.
Next, acetal and thioacetal azetidines 6 were selected
as suitable substrates to react with diethylaluminum
chloride. Starting substrates, cis- and trans-acetal aze-
tidines 6, were prepared from the corresponding 4-formyl-
â-lactams 4 in two steps using standard methodology. cis-
4-Formyl-â-lactams, cis-4,17 suffered regiospecific C4-
epimerization to yield trans-4-formyl-â-lactams, trans-
4, through a dimethylamine promoted heterogeneous
process recently developed in our group.18 Reaction of
aldehydes 4 with the appropriate diol or dithiol under
acidic catalysis gave the corresponding cyclic acetals
5a -e or dithioacetals 5f-k in good to excellent yields
(42-99%) (Table 2). Treatment of aldehydes 4 with
trimethyl orthoformate or benzenethiol, in the presence
of an acidic catalyst, yielded 4-acetal â-lactams 7a -c
(43-88%) or 4-dithioacetal â-lactams 7d -h (31-89%),
respectively (Table 3). Reaction of compounds 5 and 7
with AlH2Cl formed the required acetal azetidines 6 and
8, respectively (Tables 2 and 3).
Resu lts a n d Discu ssion
To test the behavior of the azetidine nucleus under the
influence of diethylaluminum chloride, we prepared a set
of different substituted azetidines. Azetidines 2 were
smoothly obtained by reduction of easily available â-lac-
tams 12a,16 with monochloroalane (AlH2Cl), generated in
situ from LiAlH4/AlCl3, following the procedure reported
by Ojima.8a The reaction was instantaneous at room
temperature, and the stereochemistry of the starting
monolactams remained unaltered during the process.
Azetidines 2 were further reacted with AlEt2Cl (1 M
solution in hexanes) in dichloromethane at room tem-
perature to give olefins 3, including vinyl ethers and
conjugated dienes. Pure compounds 3 were isolated in
fair to good yields (53-76%) by flash chromatography,
but some decomposition was observed for the sensitive
(13) See, among others: (a) Alcaide, B.; Almendros, P.; Aragoncillo,
C. Chem. Commun. 1999, 1913. (b) Alcaide, B.; Alonso, J . M.; Aly, M.
A.; Sa´ez, E.; Mart´ınez-Alca´zar, M. P.; Herna´ndez-Cano, F. Tetrahedron
Lett. 1999, 40, 5391. (c) Alcaide, B.; Almendros, P. Tetrahedron Lett.
1999, 40, 1015. (d) Alcaide, B.; Polanco, C.; Sierra, M. A. J . Org. Chem.
1998, 63, 6786. (e) Alcaide, B.; Rodr´ıguez-Vicente, A. Tetrahedron Lett.
1998, 39, 6589. (f) Alcaide, B.; Polanco, C.; Sa´ez, E.; Sierra, M. A. J .
Org. Chem. 1996, 61, 7125.
(14) For a preliminary communication of a part of this work, see:
Alcaide, B.; Salgado, N. R.; Sierra, M. A. Tetrahedron Lett. 1998, 39,
467.
(15) For some selected examples reporting the bizarre effects caused
by the inhibition of NCdO resonance in amides, especially in the so-
called anti-Bredt amides, see: (a) Alcaide, B.; Casarrubios, L.; Domı´ngu-
ez, G.; Sierra, M. A.; Monge, A. J . Am. Chem. Soc. 1995, 117, 5604. (b)
Brouillette, W. J .; Einspahr, H. M. J . Org. Chem. 1984, 49, 5113. (c)
Collins, T. J .; Coots, R. J .; Furutani, T. T.; Keech; J . T.; Peake, G. T.;
Santarsiero, B. D. J . Am. Chem. Soc. 1986, 108, 5333. (d) Somayaji,
V.; Brown, R. S. J . Am. Chem. Soc. 1987, 109, 4738. (e) Somayaji, V.;
Skorey, K. I.; Brown, R. S. J . Org. Chem. 1986, 51, 4866. Slebocka-
Tilk, H.; Brown, R. S. J . Org. Chem. 1987, 52, 805. (f) Williams, R. M.;
Lee, B. H.; Miller, M. M.; Anderson, O. P. J . Am. Chem. Soc. 1989,
111, 1073.
Reaction of azetidines 6 with AlEt2Cl using different
experimental conditions, particularly by variation of the
amount of AlEt2Cl and the temperature, proceeded
selectively to afford fused pyrrolidines 9 as the sole
(17) (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 .; Rodr´ıguez-Lo´pez, J .; Sierra,
M. A.; Monge, A.; Pe´rez-Garc´ıa, V. J . Org. Chem. 1992, 57, 5921.
(18) Alcaide, B.; Aly, M.; Rodr´ıguez-Vicente, A. Tetrahedron Lett.
1998, 39, 5865.
(16) â-Lactams 1 were prepared in multigram quantities by stan-
dard acid chloride-imine cyclization, and were used as single cis- or
trans-diastereomers throughout this work.

9598 J . Org. Chem., Vol. 64, No. 26, 1999
Ta ble 2. Syn th esis of Cyclic Aceta l or Th ioa ceta l Azetid in es 6
Alcaide et al.
formyl-â-lactam
R1
Ph
Me
PhO
Ph
acidic catalyst
X
n
acetal â-lactam
yielda (%)
acetal azetidine
yielda (%)
cis-4a
cis-4b
cis-4c
trans-4a
4d
PTSA
PTSA
PTSA
PTSA
PTSA
O
O
O
O
O
1
1
1
1
1
cis-5a
cis-5b
cis-5c
trans-5a
5d
94
77
77
49
44
cis-6a
cis-6b
cis-6c
trans-6a
6d
85
97
94
71
69
cis-4b
cis-4a
cis-4b
cis-4c
cis-4e
Me
Ph
Me
PhO
PTSA
O
S
S
S
S
2
1
1
1
1
cis-5e
cis-5f
cis-5g
cis-5h
cis-5i
79
71
82
71
99
cis-6e
cis-6f
cis-6g
cis-6h
cis-6i
90
81
95
89
73
BF3(OEt)2
BF3(OEt)2
BF3(OEt)2
BF3(OEt)2
trans-4a
trans-4b
4d
Ph
Me
BF3(OEt)2
BF3(OEt)2
BF3(OEt)2
S
S
S
1
1
1
trans-5f
trans-5g
5j
85
99
42
trans-6f
trans-6g
6j
97
96
100
cis-4b
Me
BF3(OEt)2
S
2
cis-5k
84
cis-6k
100
a
Yield of pure, isolated product with correct analytical and spectral data. PMP ) 4-MeOC6H4.
Ta ble 3. Syn th esis of Acyclic Aceta l or Th ioa ceta l Azetid in es 8
formyl-
â-lactam
acidic
catalyst
acetal
â-lactam
acetal
azetidine
R1
Me
PhO
PhO
Ph
R2
reagent
X
R3
yielda (%)
yielda (%)
cis-4b
cis-4c
cis-4m
cis-4a
cis-4b
cis-4c
cis-4m
trans-4a
trans-4b
4d
PMP
PMP
Bn
PMP
PMP
PMP
Bn
PMP
PMP
PMP
amberlite
amberlite
amberlite
BF3(OEt)2
BF3(OEt)2
BF3(OEt)2
BF3(OEt)2
BF3(OEt)2
BF3(OEt)2
BF3(OEt)2
HC(OMe)3
HC(OMe)3
HC(OMe)3
PhSH
PhSH
PhSH
PhSH
PhSH
PhSH
PhSH
O
O
O
S
S
S
S
S
S
S
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
cis-7a
cis-7b
cis-7c
cis-7d
cis-7e
cis-7f
cis-7g
trans-7d
trans-7e
7h
88
43
55
72
89
76
31
64
72
66
cis-8a
cis-8b
cis-8c
cis-8d
cis-8e
cis-8f
cis-8g
trans-8d
trans-8e
8h
100
92
93
98
Me
100
100
66
97
74
PhO
PhO
Ph
Me
100
a
Yield of pure, isolated product with correct analytical and spectral data. PMP ) 4-MeOC6H4.
product (Table 4). This transformation tolerates alkyl,
alkenyl, and aryl substituents at C3 on the azetidine ring,
for both cyclic acetals and dithioacetals. The only excep-
tion was dithianyl azetidine cis-6k , which under the
reaction conditions of method A, after a few minutes, gave
a complex reaction mixture of unidentified products. The
behavior of 3-phenoxy and 3-isopropylidene derivatives
is worthy of note, showing a dramatic change in reactivity
due to the acetal moiety. Thus, while 2-dioxolanyl aze-
tidines cis-6c and 6d were unreactive under different
tested conditions, the corresponding 2-dithiolanyl aze-
tidines cis-6h and 6j smoothly gave pyrrole derivatives
19a and 19b, respectively (see later in Table 6).
The above results clearly show that diethylaluminum
chloride promoted reaction of azetidines 6 bearing a cyclic
acetal moiety is a stereoselective process for the prepara-
tion of bicyclic pyrrolidines 9, the reaction being slightly
faster when dithiolanyl azetidines 6f,g,i are used as
starting materials. It should be mentioned that the
stereochemistry of the starting azetidine has no influence
on the stereochemistry of the final product; e.g., fused
pyrrolidine 9e was obtained with similar yield by the
diethylaluminum chloride promoted rearrangement of
azetidine cis-6g or azetidine trans-6g. Formation of
olefins 3 and fused pyrrolidines 9 can be rationalized
through initial coordination of the lone electron pair of
nitrogen to AlEt2Cl to give the coordinate species 10. This
coordination should promote C2-N1 bond breakage to
form zwitterion 11.19 Intermediate 11 may react through
two different pathways depending on the nature of the
group attached to C2. For electron-donor aryl groups (R2
) furyl, p-anisyl), the C3-C4 bond would break to yield
the observed olefin 3, together with iminium salt 12.
Different behavior of azetidines 2 and 6 may be due to
the presence of a cyclic acetal or thioacetal group at C2
(19) 2-Alkoxy azetidines, putative intermediates in the transforma-
tion of â-chloroimines to â-(alkylamino)carbonyl compounds, have been
postulated to experience a related N1-C2 bond breakage, in basic
alkoxide media. Sulmon, P.; De Kimpe, N.; Schamp, N. Tetrahedron
1989, 45, 2937.

Novel Reactions of the Azetidine Ring
J . Org. Chem., Vol. 64, No. 26, 1999 9599
Ta ble 4. Syn th esis of F u sed P yr r olid in es 9
Ta ble 5. Syn th esis of P yr r olid in es 15
acetal
azetidine
fused
pyrrolidines
yieldb
(%)
acetal
azetidine R1
yieldb
(%)
R1
Ph
Me
Me
Ph
Me
Me
Me
X
n
methoda
time
2 d
12 d
6 d
12 h
19 h
5 min
30 min
1 h
R2 methoda
A
time
24 h
12 h
10 min
12 h
pyrrolidines
cis-6a
cis-6b
cis-6e
cis-6f
cis-6g
cis-6g
cis-6g
cis-6i
O
O
O
S
S
S
1
1
2
1
1
1
1
1
A
A
B
A
A
B
C
A
9a
9b
9c
9d
9e
9e
9e
9f
35
35
64
30
86
82
61
66
cis-8d
cis-8e
cis-8e
cis-8e
cis-8e
Ph Et
Me Et
Me Et
Me Et
Me Me
15a
15b
15b
15b
15c
67
31
72
63
38
A
B
C
B
10 min
a
Method A: The reaction was carried out at room temperature
with an azetidine:AlEt2Cl ratio of 1:1. Method B: The reaction
was carried out at reflux temperature with an azetidine:AlEt2Cl
ratio of 1:1. Method C: The reaction was carried out at reflux
S
S
cis-6i
S
1
B
3 h
9f
64
b
temperature with an azetidine:AlEt2Cl ratio of 1:2. Yield of pure,
isolated product with correct analytical and spectral data.
trans-6f Ph
trans-6g Me
S
S
1
1
A
A
12 h
19 h
9d
9e
30
71
products without involvement of chelated or unchelated
open-chain zwitterions. According to the proposed reac-
tion pathway, electron-donating groups attached at C2
should promote formation of a carbon-carbon double
bond to give compounds 3. The strong preference for the
rearrangement of the five-membered ring in compounds
6 may be due to the increased stability of the new
carbocation 14 formed.
a
Method A: The reaction was carried out at room temperature
with an azetidine:AlEt2Cl ratio of 1:1. Method B: The reaction
was carried out at reflux temperature with an azetidine:AlEt2Cl
ratio of 1:1. Method C: The reaction was carried out at reflux
b
temperature with an azetidine:AlEt2Cl ratio of 1:2. Yield of pure,
isolated product with correct analytical and spectral data. PMP
) 4-MeOC6H4.
Sch em e 1
To examine the rearrangement reaction on acyclic
thioacetals, we chose azetidines cis-8d ,e as precursors
for the reaction with AlEt2Cl or AlMe2Cl, and the process
succeeded in the stereoselective synthesis of pyrrolidines
15 (Table 5).20 However, when isomeric azetidines trans-
8d ,e were treated with AlEt2Cl under standard condi-
tions, complex mixtures of products were obtained (it
should be mentioned that azetidines cis-6 and trans-6
gave the same fused bicyclic pyrrolidines; see Table 4).
Interestingly, reaction of acetal azetidine cis-8a with
diethylaluminum chloride at reflux temperature of dichlo-
romethane, using an azetidine:AlEt2Cl molar ratio of 1:2,
proceeded selectively to give chloropyrrolidine 16 in
moderate yield (Scheme 2). However, azetidines cis-8b,c
were unreactive under different experimental conditions.
Sch em e 2
The relative stereochemistry of products 9, 15, and 16
is different, so the preferred formation of pyrrolidines 15
and 16 is inconsistent with participation of the same
suggested transition structures to form bicycles 9 (Scheme
1). Different behavior of azetidines trans-6 and trans-8
in compounds 6. This acetal moiety promotes the conver-
sion of intermediate 11 to a new carbocation 14, which
is, in turn, trapped intramolecularly by the nitrogen
atom, to yield the double rearranged product 9. The
stereochemical result can be tentatively interpreted
through species 13, a common intermediate for both cis-
and trans-azetidines 2 and 6, which suffers a rearrange-
ment to give 14, the nucleophilic moiety being delivered
from the less hindered face (Scheme 1). Alternatively, the
high selectivity observed in reactions of azetidines 2 or
6 may point to a concerted fragmentation of the alumi-
num coordinated azetidine 10 to form the reaction
(20) Because of the importance of substituted, stereoisomerically
pure pyrrolidines as building blocks for the synthesis of natural
products and pharmaceuticals, their stereocontrolled synthesis remains
an intensive research area. See, for example: (a) Lown, J . W. In 1,3-
Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York,
1984; Vol. 1, p 653. (b) Pearson, W. H. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: New York, 1988; Vol. 1,
Part A, p 323. (c) Kopach, M. E.; Fray, A. H.; Meyers, A. I. J . Am.
Chem. Soc. 1996, 118, 9876. (d) Barluenga, J .; Canteli, R. M.; Florez,
J . J . Org. Chem. 1996, 61, 3753. (e) Karlson, S.; Han, F.; Ho¨gberg,
H.-E.; Caldirola, P. Tetrahedron: Asymmetry 1999, 10, 2605.

9600 J . Org. Chem., Vol. 64, No. 26, 1999
Alcaide et al.
Ta ble 6. Syn th esis of P yr r oles 19
thioacetal
azetidine
R1
R2
R3
R4
H
R5
methoda
A
pyrrole
yieldb (%)
67
cis-6h
PhO
Dithc
PMP
19a
6j
Dithc
PMP
PMP
iPr
H
A
B
19b
19c
38
55
cis-8f
PhO
PhO
Ph
Ph
cis-8g
Bn
H
C
19d
72
a
Method A: The reaction was carried out at room temperature with an azetidine:AlEt2Cl ratio of 1:1. Method B: The reaction was
carried out at reflux temperature with an azetidine:AlEt2Cl ratio of 1:1. Method C: The reaction was carried out at reflux temperature
b
with an azetidine:AlEt2Cl ratio of 1:2. Yield of pure, isolated product with correct analytical and spectral data. PMP ) 4-MeOC6H4.
c Dith ) 1,3-dithiolan-2-yl.
Sch em e 3
Sch em e 4
in their reactions with AlEt2Cl may also point out that
formation of bicycles 9 and pyrrolidines 15 should not
be similar. We believe that for monocyclic compounds 15
and 16 the XR group at C2 in the former pyrrolidine 17
is eliminated to give an iminium salt 18, the alkyl moiety
being delivered from the organometallic reagent on the
less hindered face at the iminium cation (Scheme 3).
However, a clear explanation for the stereochemistry at
C4 has not yet been found. Azetidine cis-8a should evolve
into an intermediate bearing an oxygenated substituent
at C3. This intermediate should be coordinated by
another molecule of AlEt2Cl with further substitution for
a chlorine atom, yielding the chloropyrrolidine 16. As far
as we know this behavior of diethylaluminum chloride
is unprecedented. The difference in reactivity of di-
methylacetal azetidine cis-8a and diphenylthioacetal
azetidines cis-8d ,e may be due to the strong oxophilicity
of aluminum, allowing a better coordination with the
oxygen prior to the sulfur.
3-Phenoxy and 3-isopropylidene thioacetal azetidines
cis-6h , 6j, and cis-8f-g were treated with AlEt2Cl under
the above conditions to furnish pyrroles 19 in moderate
to good yields (38-72%) (Table 6). In this manner a new
methodology is available for the preparation of different
novel 3-thio-functionalized pyrrole derivatives. The in-
troduction of substituents at the 3-position of pyrroles is
of great importance in the synthesis of natural products,
while these pyrroles are not easily accessible.21
on standing for longer reaction time (45 min). The 1H
NMR spectrum of the crude reaction mixture showed the
expected azetidine cis-6h together with bicycle 20 (ratio
cis-6h :20 ) 65:35). After flash chromatography on silica
gel, bicycle 20 (25%), pyrrole 19a (20%), and phenol (20%)
were isolated. From this result it is evident that azetidine
cis-6h and not bicycle 20 was transformed into pyrrole
19a and phenol under chromatographic conditions. In an
independent experiment, when compound 20 was treated
with AlEt2Cl under the usual reaction conditions, un-
altered 20 was recovered, confirming that azetidine cis-
6h , and not bicycle 20, was the pyrrole precursor. The
stereochemistry of bicycle 20 and bicyclic pyrrolidines 9
is different at the C9 stereocenter, but it should be
mentioned that the origin is totally different (Scheme 4).
Formation of pyrroles 19a ,c,d can be illustrated fol-
lowing the scheme drawn for compound 19a . The main
difference between this mechanistic proposal and the
given explanation for the formation of bicyclic pyrro-
lidines 9 is the elimination of a molecule of phenol, giving
intermediate 21, which evolves to yield pyrrole 19a
(21) See, for example: (a) Pavri, N. P.; Trudell, M. L. J . Org. Chem.
1997, 62, 2649. (b) Tehrani, K. A.; Borremans, D.; De Kimpe, N.
Tetrahedron 1999, 55, 4133. (c) Kesteleyn, B.; Rosas Alonso, E.;
Stevens, Ch.; Dejaegher, Y.; Peristeropoulou, M.; Nguyen Van, T.;
Kulinkovich, O.; De Kimpe, N. Tetrahedron 1999, 55, 4153.
Of special interest in this context was the reaction of
acetal â-lactam cis-5h with monochloroalane (AlH2Cl),

Novel Reactions of the Azetidine Ring
J . Org. Chem., Vol. 64, No. 26, 1999 9601
Sch em e 5
F igu r e 1. Relative stereochemistry of fused pyrrolidines 9d ,
9f, and 20.
(Scheme 5). Pyrrole 19b should have a similar origin, but
now formation of pyrrole 19b must arise from the
isomerization of the ethylenic bond. A substituent at C3
on the azetidine ring that can promote aromatization
seems to be the driving force for pyrrole formation.
Con figu r a tion a l Assign m en t for P yr r olid in es 9,
15, 16, a n d 20. The structure and stereochemistry of
compounds 9, 15, 16, and 20 have been assigned by NMR
techniques. NOE irradiation of H1 on fused pyrrolidine
9d resulted in 11% enhancement in the signals corre-
sponding to H6 and the phenyl group, while NOE
irradiation of H6 resulted in enhancement of the signals
corresponding to H1 and the 4-methoxyphenyl group
(19% and 23%, respectively). On the basis of these data,
a syn-H1-H6/anti-H1-H9 relative stereochemistry was
assigned. Irradiation of H6 in compound 9f gave a NOE
enhancement of 15% on H1 and an enhancement of 20%
on the signals corresponding to the 4-methoxyphenyl
group, being assigned a syn relative disposition between
H1 and H6. Furthermore, NOE irradiation of H1 resulted
in enhancements of the signals corresponding to H6 and
the isopropylidene group (8% and 9%, respectively), being
assigned an anti-H1-H9 relative stereochemistry (Figure
1).
For compound 20, NOE enhancements of H1 (8%) and
the 4-methoxyphenyl group (12%) on irradiation of H6,
NOE enhancements of H6 (6%) and H9 (8%) on irradia-
tion of H1, and NOE enhancements of H1 (9%) and H8
(8%) on irradiation of H9 were consistent with a syn-H1-
H6/syn-H1-H9 relative stereochemistry (Figure 1).
NOE irradiation of H3 on pyrrolidine 15b resulted in
enhancements of the signals corresponding to H4 and the
ethyl moiety (13% and 15%, respectively). Furthermore,
a 2% enhancement of the C4-methyl group was observed
on irradiation of H2, which is in agreement with the
proposed stereochemistry (Figure 2). The stereochemistry
for chloropyrrolidine 16 was immediately deduced by
comparison with the above results. Thus, NOE enhance-
ments of 15%, 12%, and 14% were observed on CH2CH3,
CH2CH3, and H4, respectively, when H3 was irradiated,
which is consistent with an anti-H2-H3/syn-H3-H4
relative stereochemistry (Figure 2).
F igu r e 2. Relative stereochemistry of pyrrolidines 15b and
16.
rangement reactions promoted by diethylaluminum chlo-
ride. These results show that diethylaluminum chloride
promoted reactions on the azetidine nucleus, namely, its
fragmentation and its rearrangement, are efficient and
stereocontrolled processes which can be used to prepare
different types of interesting functionalized compounds,
including olefins, monocyclic pyrrolidines, fused bicyclic
pyrrolidines, and pyrroles. Furthermore, as far as we
know, these are the first examples of Lewis acid promoted
fragmentation or rearrangement on the azetidine nucleus.
Notwithstanding the mechanistic dichotomy on mono-
cyclic pyrrolidine formation, the different behavior of
acetal azetidines reported herein is significant and will
have a bearing on their application in organic synthesis.
Other aspects of the novel reactivity of the azetidine ring
are under investigation.
Exp er im en ta l Section
Gen er a l Meth od s. General experimental data and proce-
dures have been previously reported.13f All NMR spectra were
recorded in CDCl3 solutions with TMS as the internal standard
unless otherwise stated. All commercially available compounds
were used without further purification. 4-Formyl-â-lactams 4
were used in all cases as single cis-17 or trans-isomers.18
Gen er a l Meth od for th e Syn th esis of Azetid in es 2, 6,
a n d 8. A solution of anhydrous AlCl3 (3 mmol) in dry Et2O
(10 mL) was added via syringe to a well-stirred suspension of
LiAlH4 (3 mmol) in anhydrous Et2O (10 mL). The mixture was
refluxed for 30 min, cooled to rt, and transferred via cannula
to a solution of the corresponding â-lactam 1, 5, or 7 (1 mmol),
in dry Et2O (5 mL). Inmediately, after the end of the addition,
TLC analysis showed the complete transformation of the
starting material. The reaction mixture was cooled to 0 °C and
then quenched with water (10 mL), diluted with Et2O (15 mL),
Con clu sion s. The present study provides the first
insight into the manner in which a variety of different
substituted azetidines undergo fragmentation and rear-

9602 J . Org. Chem., Vol. 64, No. 26, 1999
Alcaide et al.
and washed with brine (20 mL). The organic layer was dried
(MgSO4) and the solvent removed under reduced pressure. The
crude products were used without any further purification.
Representative examples for the preparation of azetidines
follow.22
mixture was cooled (0 °C), and then saturated aqueous
NaHCO3 (10 mL) was added. The mixture was allowed to
warm to room temperature before being diluted with CH2Cl2
(15 mL). The organic layer was separated and dried (MgSO4)
and the solvent removed under reduced pressure. Residues
were purified by flash chromatography eluting with EtOAc/
hexanes mixtures.
Meth od C. To a solution of the appropriate azetidine 6 or
8 (1.0 mmol) in CH2Cl2 (5 mL) was added, via syringe, a
solution of AlEt2Cl (0.24 g, 2.0 mmol) in hexane (2.0 mL). The
reaction was stirred under argon at room temperature until
complete disappearance of the azetidine (TLC). The reaction
mixture was cooled (0 °C), and then saturated aqueous
NaHCO3 (10 mL) was added. The mixture was allowed to
warm to room temperature before being diluted with CH2Cl2
(15 mL). The organic layer was separated and dried (MgSO4)
and the solvent removed under reduced pressure. Residues
were purified by flash chromatography eluting with EtOAc/
hexanes mixtures. Representative examples for the prepara-
tion of olefins 3, pyrrolidines 9, 15, and 16, and pyrroles 19
following different methods follow.
ci s-2-(1′,3′-D it h io la n -2-y l)-1-(p -m e t h o x y p h e n y l)-3-
p h en oxya zetid in e, cis-6h . From acetal â-lactam cis-5h (0.35
g, 0.94 mmol), AlCl3 (0.37 g, 2.81 mmol), and LiAlH4 (0.11 g,
2.81 mmol), 0.30 g (89%) of azetidine cis-6h was obtained as
a colorless oil. 1H NMR: δ 3.27 (m, 4 H), 3.75 (s, 3 H), 3.99
(dd, 1 H, J ) 8.8, 7.3 Hz), 4.19 (dd, 1 H, J ) 9.2, 4.4 Hz), 4.42
(dd, 1 H, J ) 8.5, 7.7 Hz), 5.02 (dt, 1 H, J ) 7.3, 4.0 Hz), 5.24
(d, 1 H, J ) 8.8 Hz), 6.76 (m, 4 H), 6.90 (m, 2 H), 7.19 (m, 3
H). 13C NMR: δ 156.9, 152.7, 144.7, 129.6, 121.6, 116.3, 115.7,
114.9, 73.4, 68.4, 59.9, 55.8, 53.3, 38.5, 38.1. IR (CHCl3): ν
1430, 1220. Anal. Calcd for C19H21NS2O2: C, 63.48; H, 5.89;
N, 3.90; S, 17.84. Found: C, 63.28; H, 5.95; N, 3.50; S, 17.57.
tr a n s-2-(1′,3′-Dit h iola n -2-yl)-1-(p -m et h oxyp h en yl)-3-
m eth yla zetid in e, tr a n s-6g. From acetal â-lactam trans-5g
(0.11 g, 0.37 mmol), AlCl3 (0.15 g, 1.11 mmol) and LiAlH4 (44
mg, 1.11 mmol), 0.10 g (96%) of azetidine trans-6g was
1
obtained as a colorless oil. H NMR: δ 1.23 (d, 3 H, J ) 7.0
(Z)-2-(p-Meth oxyph en yl)-1-ph en oxyeth en e, 3a . Meth od
A. From azetidine cis-2a (80 mg, 0.20 mmol) and AlEt2Cl (0.20
mL, 0.20 mmol), 20 mg (57%) of alkene 3a was obtained as a
pale yellow oil after purification by flash chromatography
Hz), 2.76 (m, 1 H), 3.11 (t, 1 H, J ) 6.6 Hz), 3.24 (m, 4 H),
3.67 (s, 3 H), 3.73 (d, 1 H, J ) 5.9 Hz), 4.10 (t, 1 H, J ) 6.6
Hz), 5.00 (d, 1 H, J ) 5.2 Hz), 6.63 (dd, 2 H, J ) 8.9 Hz), 6.79
(dd, 2 H, J ) 8.8, 2.2 Hz). 13C NMR: δ 152.5, 146.2, 114.5,
113.5, 75.3, 58.1, 57.9, 55.8, 38.6, 38.4, 29.9, 19.8. IR (CHCl3):
ν 1520. Anal. Calcd for C14H19NS2O: C, 59.75; H, 6.80; N, 4.98;
S, 22.78. Found: C, 59.35; H, 6.40; N, 4.58; S, 23.38.
1
(AcOEt/hexanes, 1:20). H NMR: δ 3.81 (s, 3 H), 5.59 (d, 1 H,
J ) 6.9 Hz), 6.54 (d, 1 H, J ) 6.9 Hz), 6.87 (d, 2 H, J ) 9.0
Hz), 7.10 (d, 1 H, J ) 10.8 Hz), 7.12 (d, 1 H, J ) 8.7 Hz), 7.31
(m, 4 H), 7.63 (d, 2 H, J ) 8.7 Hz). 13C NMR: δ 140.3, 129.6,
127.7, 123.1, 114.2, 113.7, 113.5, 110.2, 55.3, 29.7. IR
(CHCl3): ν 1600, 1510. Anal. Calcd for C15H14O2: C, 79.62; H,
6.24. Found: C, 79.22; H, 6.64.
cis-2-Dim eth oxym eth yl-1-(p-m eth oxyp h en yl)-3-m eth -
yla zetid in e, cis-8a . From acetal â-lactam cis-7a (0.19 g, 0.72
mmol), AlCl3 (0.28 g, 2.15 mmol), and LiAlH4 (86 mg, 2.15
mmol), 0.17 g (100%) of azetidine cis-8a was obtained as a pale
yellow oil. 1H NMR: δ 1.36 (d, 3 H, J ) 7.3 Hz), 2.72 (m, 1 H),
3.46 and 3.49 (s, each 3 H), 3.60 (dd, 1 H, J ) 7.0, 4.0 Hz),
3.69 (dd, 1 H, J ) 8.8, 7.0 Hz), 3.75 (s, 3 H), 3.97 (t, 1 H, J )
8.8 Hz), 4.59 (d, 1 H, J ) 7.7 Hz), 6.72 (s, 4 H). 13C NMR: δ
152.5, 146.9, 114.3, 114.2, 106.5, 66.8, 59.1, 57.3, 55.8, 53.8,
(E)-1-(p-Meth oxyp h en yl)-2-p h en yleth en e, 3c. Meth od
A. From azetidine trans-2g (0.15 g, 0.45 mmol) and AlEt2Cl
(0.45 mL, 0.45 mmol), 60 mg (68%) of alkene 3c was obtained
as a colorless solid after purification by flash chromatography
1
(EtOAc/hexanes, 1:10). Mp: 131-134 °C. H NMR: δ 3.74 (s,
3 H), 6.83 (t, 2 H, J ) 8.8 Hz), 6.97 (d, 2 H, J ) 14.3 Hz), 7.15
(m, 2 H), 7.26 (m, 2 H), 7.36 (m, 3 H). 13C NMR: δ 159.2, 137.6,
130.1, 128.6, 128.1, 127.7, 127.2, 126.5, 126.2, 114.1, 55.3, 29.7.
IR (KBr): ν 1510, 1250. Anal. Calcd for C15H14O: C, 85.68; H,
6.71. Found: C, 85.82; H, 6.85.
26.6, 15.7. IR (CHCl3): ν 1430, 1230. Anal. Calcd for C14H21
-
NO3: C, 66.91; H, 8.42; N, 5.57. Found: C, 67.31; H, 8.82; N,
5.97.
c i s -3-I s o p r o p y li d e n -1-(p -m e t h o x y p h e n y l)-2-b i s -
(p h en ylth iom eth yl)a zetid in e, 8h . From acetal â-lactam 7h
(126 mg, 0.28 mmol), AlCl3 (0.11 g, 0.84 mmol) and LiAlH4
(34 mg, 0.84 mmol), 0.12 g (100%) of azetidine 8h was obtained
as a colorless oil. 1H NMR: δ 1.59 and 1.70 (s, each 3 H), 3.75
(s, 3 H), 4.07 and 4.66 (d, each 1 H, J ) 11.0 Hz), 4.79 (s, 1 H),
4.96 (br s, 1 H), 6.47 and 6.75 (d, each 2 H, J ) 9.0 Hz), 7.21
(m, 7 H), 7.40 (m, 3 H). 13C NMR: δ 152.3, 144. 7, 135.4, 133.4,
132.3, 129.0, 127.9, 127.5, 126.3, 124.1, 114.5, 113.6, 74.0, 64.4,
59.8, 55.8, 19.9, 19.3. IR (CHCl3): ν 1430, 1220. Anal. Calcd
for C26H27NS2O2: C, 72.02; H, 6.28; N, 3.23; S, 14.79. Found:
C, 71.99; H, 6.17; N, 3.35; S, 14.85.
(E)-1-(p-Meth oxyph en yl)bu tadien e, 3d. Meth od A. From
azetidine trans-2h (0.13 g, 0.46 mmol) and AlEt2Cl (0.46 mL,
0.46 mmol), 60 mg (76%) of alkene 3d was obtained as a pale
yellow oil after purification by flash chromatography (EtOAc/
hexanes, 1:5). 1H NMR: δ 3.73 (s, 3 H), 5.03 (dd, 1 H, J ) 9.5,
1.5 Hz), 5.20 (dd, 1 H, J ) 16.5, 1.5 Hz), 6.40 (dd, 1 H, J )
16.5, 10.3 Hz), 6.44 (dd, 1 H, J ) 16.9, 2.5 Hz), 6.60 (dd, 1 H,
J ) 14.7, 10.6 Hz), 6.78 and 7.25 (d, each 2 H, J ) 9.0 Hz). 13
C
NMR: δ 159.3, 137.4, 132.4, 129.9, 127.6 (3 C), 116.4, 114.1,
55.3. IR (KBr): ν 1510, 1250. Anal. Calcd for C11H12O: C,
91.61; H, 8.39. Found: C, 91.21; H, 8.69.
Gen er a l Meth od for th e Rea ction of Azetid in es w ith
Dieth yla lu m in u m Ch lor id e. Meth od A. To a solution of the
appropriate azetidine 2, 6, or 8 (1.0 mmol) in CH2Cl2 (5 mL)
was added, via syringe, a cooled solution of AlEt2Cl (0.12 g,
1.0 mmol) in hexane (1.0 mL). The reaction was stirred under
argon at room temperature until complete disappearance of
the azetidine (TLC). The reaction mixture was cooled (0 °C),
and then saturated aqueous NaHCO3 (10 mL) was added. The
mixture was allowed to warm to room temperature before
being diluted with CH2Cl2 (15 mL). The organic layer was
separated dried (MgSO4) and the solvent removed under
reduced pressure. Residues were purified by flash chromatog-
raphy eluting with EtOAc/hexanes mixtures.
(1E,4Z)-1-P h en oxy-4-p h en ylbu ta d ien e, 3e. Meth od A.
From azetidine cis-2i (89 mg, 0.26 mmol) and AlEt2Cl (0.26
mL, 0.26 mmol), 42 mg (72%) of alkene 3e was obtained as a
colorless oil after purification by flash chromatography (EtOAc/
hexanes, 1:7). 1H NMR: δ 5.64 (dd, 1 H, J ) 11.4, 6.3 Hz),
6.48 (d, 1 H, J ) 6.3 Hz), 6.55 (d, 1 H, J ) 15.8 Hz), 7.08 (m,
3 H), 7.19 (m, 6 H), 7.45 (m, 2 H). IR (CHCl3): ν 1510, 1250.
Anal. Calcd for C11H12O: C, 91.61; H, 8.39. Found: C, 91.31;
H, 8.49.
(1R*,6R*,9R*)-2,5-Dioxa -7-(p-m eth oxyp h en yl)-9-p h en -
yl-7-a za byciclo[4,3,0]n on a n e, 9a . Meth od A. From azeti-
dine cis-6a (34 mg, 0.10 mmol) and AlEt2Cl (0.10 mL, 0.10
mmol), 12 mg (35%) of compound 9a was obtained as a
colorless oil after purification by flash chromatography (AcOEt/
hexanes, 1:8). 1H NMR: δ 3.49 (ddd, 1 H, J ) 8.8, 5.7, 2.3
Hz), 3.75 (s, 3H), 3.77 (dd, 1 H, J ) 4.8, 1.8 Hz), 3.79 (m, 1 H),
3.82 (d, 1 H, J ) 6.2 Hz), 3.90 (ddd, 1 H, J ) 9.4, 4.8, 1.8 Hz),
3.96 (m, 2 H), 4.04 (m, 2 H), 4.72 (d, 1 H, J ) 4.4 Hz), 6.68
and 6.76 (d, each 2 H, J ) 9.0 Hz), 7.29 (m, 5 H). 13C NMR:
δ 152.2, 142.2, 138.1, 128.9, 128.4, 127.4, 115.0, 114.9, 104.5,
65.5, 64.8, 57.2, 55.7, 49.0, 45.6. IR (CHCl3): ν 1720. Anal.
Meth od B. To a solution of the appropriate azetidine 6 or
8 (1.0 mmol) in CH2Cl2 (5 mL) was added, via syringe, a
solution of AlEt2Cl (0.12 g, 1.0 mmol) in hexane (1.0 mL). The
reaction was stirred under argon at reflux temperature until
complete disappearance of the azetidine (TLC). The reaction
(22) Full spectroscopic and analytical data for compounds not
included in the Experimental Section are described in the Supporting
Information.

Novel Reactions of the Azetidine Ring
J . Org. Chem., Vol. 64, No. 26, 1999 9603
Calcd for C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C,
73.43; H, 6.94; N, 4.64.
112.1, 68.4, 56.8, 55.5, 54.5, 35.3, 26.2, 14.0, 10.5. MS (EI):
m/z 327 (M+, 63), 189 (100). Anal. Calcd for C20H25NSO: C,
73.35; H, 7.69; N, 4.28; S, 9.79. Found: C, 73.75; H, 8.09; N,
4.68; S, 10.19.
(2S *,3R *,4R *)-2,4-Dim e t h yl-1-(p -m e t h oxyp h e n yl)-3-
p h en ylth iop yr r olid in e, 15c. Meth od B. From azetidine cis-
8e (0.10 g, 0.25 mmol) and AlMe2Cl (0.25 mL, 0.25 mmol), 30
mg (38%) of compound 15c was obtained as a colorless oil after
purification by flash chromatography (AcOEt/hexanes, 1:19).
1H NMR: δ 1.22 and 1.27 (d, each 3 H, J ) 6.8 Hz), 2.82 (m,
1 H), 3.12 (t, 1 H, J ) 8.8 Hz), 3.55 (m, 2 H), 3.67 (s, 3 H), 3.75
(m, 1 H), 6.39 and 6.75 (d, each 2 H, J ) 9.0 Hz), 7.15 (m, 5
H). MS (EI): m/z 313 (M+, 98), 189 (100). Anal. Calcd for
(1R*,7R*,10R*)-2,6-Dioxa-8-(p-m eth oxyph en yl)-10-m eth -
yl-8-a za bicyclo[5,3,0]d eca n e, 9c. Meth od C. From azetidine
cis-6e (90 mg, 0.32 mmol) and AlEt2Cl (0.70 mL, 0.70 mmol),
59 mg (64%) of compound 9c was obtained as a colorless oil
after purification by flash chromatography (AcOEt/hexanes,
1
1:5). H NMR: δ 1.03 (d, 3 H, J ) 6.8 Hz), 1.23 (m, 1 H), 1.99
(m, 1 H), 2.26 (m, 1 H), 3.40 (dd, 1 H, J ) 10.6, 5.9 Hz), 3.56
(m, 3 H), 3.67 (s, 3 H), 3.70 (m, 2 H), 4.05 (td, 2 H, J ) 10.7,
5.9 Hz), 4.58 (d, 1 H, J ) 2.9 Hz), 6.59 and 6.69 (d, each 2 H,
J ) 9.0 Hz). 13C NMR: δ 152.2, 142.0, 115.2, 114.9, 101.7, 66.9
(2 C), 57.8, 55.7, 48.8, 36.7, 25.8, 14.2. IR (CHCl3): ν 1730.
MS (EI): m/z 263 (M+, 8), 212 (100). Anal. Calcd for C15H21
-
C
19H23NSO: C, 72.80; H, 7.40; N, 4.47; S, 10.23. Found: C,
NO3: C, 68.42; H, 8.04, N, 5.32. Found: C, 68.82; H, 8.44; N,
5.72.
73.20; H, 7.80; N, 4.87; S, 10.63.
(2S*,3R*,4R*)-3-Ch lor o-2-eth yl-1-(p-m eth oxyp h en yl)-4-
m eth ylp yr r olid in e, 16. Meth od C. From azetidine cis-8a
(0.10 g, 0.39 mmol) and AlEt2Cl (0.78 mL, 0.78 mmol), 30 mg
(36%) of compound 16 was obtained as a colorless oil after
purification by flash chromatography (AcOEt/hexanes, 1:14).
1H NMR (C6D6): δ 0.68 (t, 3 H, J ) 7.5 Hz), 0.72 (d, 3 H, J )
7.8 Hz), 1.57 (m, 1 H), 1.62 (m, 1 H), 2.22 (m, 1 H), 2.88 (dd,
1 H, J ) 10.7, 8.5 Hz), 3.13 (dd, 1 H, J ) 8.5, 7.1 Hz), 3.43 (s,
3 H), 3.72 (dd, 1 H, J ) 10.0, 3.7 Hz), 3.82 (d, 1 H, J ) 4.4
Hz), 6.53 and 6.87 (d, each 2 H, J ) 9.4 Hz). 13C NMR: δ 119.4,
115.2 (4 C), 112.3, 67.9, 61.9, 56.0, 36.3, 29.7, 26.8, 13.2, 10.9.
MS (CI): m/z 255 (M+ + 2, 39), 253 (M+, 100). Anal. Calcd for
(1R*,6R*,9R*)-2,5-Dith ia -7-(p-m eth oxyp h en yl)-9-m eth -
yl-7-a za bicyclo[4,3,0]n on a n e, 9e. Meth od A. From azeti-
dine cis-6g (0.18 g, 0.64 mmol) and AlEt2Cl (0.64 mL, 0.64
mmol), 0.16 g (86%) of compound 9e was obtained as a colorless
oil after purification by flash chromatography (AcOEt/hexanes,
1:8).
Meth od B. From azetidine cis-6g (48 mg, 0.17 mmol) and
AlEt2Cl (0.17 mL, 0.17 mmol), 40 mg (82%) of compound 9e
was obtained as a colorless oil after purification by flash
chromatography (AcOEt/hexanes, 1:17).
Meth od C. From azetidine cis-6g (42 mg, 0.15 mmol) and
AlEt2Cl (0.30 mL, 0.30 mmol), 26 mg (61%) of compound 9e
was obtained as a colorless oil after purification by flash
chromatography (AcOEt/hexanes, 1:8).
C
14H20NClO: C, 66.26; H, 7.94; N, 5.52; Cl, 13.97. Found: C,
65.86; H, 7.54; N, 5.12; Cl, 13.57.
3-(1′,4′-Dith ia bu tyl)-1-(p-m eth oxyp h en yl)p yr r ole, 19a .
Meth od A. From azetidine cis-6h (70 mg, 0.18 mmol) and
AlEt2Cl (0.18 mL, 0.18 mmol), 30 mg (67%) of compound 19a
was obtained as a colorless oil after purification by flash
Meth od A. From azetidine trans-6g (185 mg, 0.66 mmol)
and AlEt2Cl (0.66 mL, 0.66 mmol), 132 mg (71%) of compound
9e was obtained as a colorless oil after purification by flash
1
chromatography (AcOEt/hexanes, 1:8). H NMR: δ 1.24 (d, 3
1
chromatography (AcOEt/hexanes, 1:2). H NMR: δ 1.73 (dd,
H, J ) 7.0 Hz), 2.47 (dd, 1 H, J ) 8.3, 2.5 Hz), 2.75 (dd, 1 H,
J ) 10.7, 4.4 Hz), 2.81 (dd, 1 H, J ) 13.6, 4.4 Hz), 2.94 (m, 4
H), 3.52 (m, 1 H), 3.74 (s, 3 H), 5.18 (d, 1 H, J ) 4.4 Hz), 6.67
and 6.83 (d, each 2 H, J ) 9.0 Hz). 13C NMR: δ 151.9, 138.9,
114.9, 113.1, 61.4, 55.8, 53.8, 47.1, 33.7, 29.9, 23.9, 16.2. IR
(CHCl3): ν 1720. MS (EI): m/z 281 (M+, 62), 174 (100). Anal.
Calcd for C14H19NS2O: C, 59.75; H, 6.80; N, 4.98; S, 22.78.
Found: C, 59.35; H, 7.20; N, 6.40; S, 22.38.
J ) 8.1, 7.7 Hz), 2.72 (m, 2 H), 2.88 (m, 2 H), 3.84 (s, 3 H),
6.34 (m, 1 H), 6.95 (m, 3 H), 7.06 (ddd, 1 H, J ) 4.0, 2.2, 1.8
Hz), 7.27 (dd, 2 H, J ) 9.0, 2.0 Hz). 13C NMR: δ 158.0, 133.7,
124.1, 123.8, 122.1, 120.7, 115.1, 114.7, 112.6, 55.6, 40.8, 24.5.
MS (EI): m/z 265 (M+, 83), 205 (100). Anal. Calcd for C13H15
-
NS2O: C, 58.84; H, 5.70; N, 5.28; S, 24.16. Found: C, 59.24;
H, 5.30; N, 5.68; S, 24.56.
3-(1′,4′-Dith ia bu tyl)-4-isop r op yl-1-(p-m eth oxyp h en yl)-
p yr r ole, 19b. Meth od A. From azetidine 6j (0.11 g, 0.37
mmol) and AlEt2Cl (0.37 mL, 0.37 mmol), 40 mg (38%) of
compound 19b was obtained as a colorless oil after purification
by flash chromatography (AcOEt/hexanes, 1:6). 1H NMR: δ
1.16 (d, 6 H, J ) 7.9 Hz), 1.71 (dd, 1 H, J ) 8.0, 7.7 Hz), 2.70
(m, 2 H), 2.81 (m, 2 H), 3.03 (m, 1 H), 3.76 (s, 3 H), 6.77 (d, 1
H, J ) 2.6 Hz), 6.92 (dd, 2 H, J ) 8.8, 2.2 Hz), 7.03 (d, 1 H, J
) 2.6 Hz), 7.27 (dd, 2 H, J ) 8.8, 2.2 Hz). 13C NMR: δ 157.7,
135.9, 134.0, 124.4, 121.7, 116.0, 114.6, 111.3, 55.6, 40.8, 25.4,
24.5, 24.1. MS (EI): m/z 307 (M+, 94), 232 (100). Anal. Calcd
for C16H21NS2O: C, 62.50; H, 6.88; N, 4.56; S, 20.85. Found:
C, 62.90; H, 7.12; N, 4.96; S, 21.25.
(2S*,3R*,4R*)-2-Eth yl-1-(p-m eth oxyp h en yl)-4-p h en yl-
3-p h en ylth iop yr r olid in e, 15a . Meth od A. From azetidine
cis-8d (0.13 g, 0.29 mmol) and AlEt2Cl (0.29 mL, 0.29 mmol),
76 mg (67%) of compound 15a was obtained as a colorless oil
after purification by flash chromatography (AcOEt/hexanes,
1
1:9). H NMR: δ 0.79 (t, 3 H, J ) 7.3 Hz), 1.52 and 1.80 (m,
each 1 H), 3.66 (m, 1 H), 3.80 (dd, 2 H, J ) 8.8, 4.9 Hz), 3.81
(s, 3 H), 3.90 (dd, 1 H, J ) 5.8, 1.9 Hz), 4.03 (m, 1 H), 6.54 and
6.86 (d, each 2 H, J ) 9.0 Hz), 7.26 (m, 10 H). 13C NMR: δ
132.9, 129.1, 128.9, 128.7, 128.6, 128.4, 128.2, 127.7, 127.5,
127.1, 115.1, 112.5, 68.1, 57.0, 55.9, 51.4, 45.6, 26.4, 10.3. MS
(EI): m/z 389 (M+, 49), 251 (100). Anal. Calcd for C25H27NSO:
C, 77.08; H, 6.99; N, 3.60; S, 8.23. Found: C, 77.48; H, 7.39;
N, 4.01; S, 8.63.
1-(p-Meth oxyph en yl)-3-ph en ylth iopyr r ole, 19c. Meth od
B. From azetidine cis-8f (80 mg, 0.18 mmol) and AlEt2Cl (0.18
mL, 0.18 mmol), 20 mg (55%) of compound 17c was obtained
as a colorless oil after purification by flash chromatography
(2S*,3R*,4R*)-2-Eth yl-1-(p-m eth oxyp h en yl)-4-m eth yl-
3-p h en ylth iop yr r olid in e, 15b. Meth od A. From azetidine
cis-8e (90 mg, 0.22 mmol) and AlEt2Cl (0.22 mL, 0.22 mmol),
22 mg (31%) of compound 15b was obtained as a colorless oil
after purification by flash chromatography (AcOEt/hexanes,
1:21).
Meth od B. From azetidine cis-8e (45 mg, 0.11 mmol) and
AlEt2Cl (0.11 mL, 0.11 mmol), 26 mg (72%) of compound 15b
was obtained as a colorless oil after purification by flash
chromatography (AcOEt/hexanes, 1:21).
1
(AcOEt/hexanes, 1:6). H NMR: δ 3.75 (s, 3 H), 6.42 (dd, 1 H,
J ) 2.9, 1.8 Hz), 6.97 (dd, 2 H, J ) 8.8, 2.1 Hz), 7.08 (m, 2 H),
7.22 (m, 4 H), 7.32 (dd, 2 H, J ) 8.8, 2.2 Hz). 13C NMR: δ
158.1, 140.2, 133.7, 128.7, 126.0, 125.4, 124.8, 122.1, 121.2,
115.9, 114.8, 110.6, 55.6. MS (EI): m/z 281 (M+, 100). Anal.
Calcd for C17H15NSO: C, 72.57; H, 5.37; N, 4.98; S, 11.39.
Found: C, 72.17; H, 5.77; N, 4.48; S, 11.79.
Meth od C. From azetidine cis-8e (78 mg, 0.19 mmol) and
AlEt2Cl (0.38 mL, 0.38 mmol), 39 mg (63%) of compound 15b
was obtained as a colorless oil after purification by flash
chromatography (AcOEt/hexanes, 1:17). 1H NMR (C6D6): δ
0.39 (t, 3 H, J ) 7.4 Hz), 1.41 (d, 3 H, J ) 6.8 Hz), 1.09 and
1.51 (m, each 1 H), 2.33 (m, 1 H), 2.83 (dd, 1 H, J ) 9.5, 9.0
Hz), 3.07 (m, 1 H), 3.21 (m, 1 H), 3.25 (s, 3 H), 3.44 (d, 1 H J
) 7.9 Hz), 6.35 and 7.11 (d, each 2 H, J ) 9.0 Hz), 6.76 (m, 5
H). 13C NMR: δ 150.6, 142.2, 135.4, 132.4, 128.9, 126.9, 114.9,
1-Ben zyl-3-p h en ylth iop yr r ole, 19d . Meth od C. From
azetidine cis-8g (40 mg, 0.09 mmol) and AlEt2Cl (0.18 mL, 0.18
mmol), 17 mg (72%) of compound 19d was obtained as an oil
after purification by flash chromatography (AcOEt/hexanes,
1:16). 1H NMR: δ 5.08 (s, 2 H), 6.29 (dd, 1 H, J ) 2.7, 1.7 Hz),
6.76 (dd, 1 H, J ) 2.6, 2.2 Hz), 6.90 (t, 1 H, J ) 2.0 Hz), 7.07
(m, 7 H), 7.28 (m, 3 H). 13C NMR: δ 140.7, 137.2, 128.8, 128.6,
128.0, 127.2 (3 C), 125.7, 124.6, 122.7, 115.1, 53.8, 30.9. MS
(EI): m/z 265 (M+, 87), 91 (100). Anal. Calcd for C17H15NS:

9604 J . Org. Chem., Vol. 64, No. 26, 1999
Alcaide et al.
C, 76.94; H, 5.70; N, 5.28; S, 12.08. Found: C, 77.34; H, 5.30;
N, 5.14; S, 12.25.
1 H, J ) 8.8, 3.3 Hz), 4.24 (dd, 1 H, J ) 6.3, 6.6 Hz), 5.07 (td,
1 H, J ) 7.0, 2.9 Hz), 5.53 (d, 1 H, J ) 5.1 Hz), 6.74 (d, 2 H,
J ) 9.0 Hz), 6.83 (m, 4 H), 6.91 (td, 1 H, J ) 7.2, 1.1 Hz), 7.21
(d, 2 H, J ) 9.0 Hz). 13C NMR: δ 157.2, 152.6, 114.8, 129.5,
121.4, 115.2, 114.5, 113.7, 102.8, 69.6, 67.9, 65.4, 65.1, 59.2,
55.8. IR (CHCl3): ν 1730. MS (EI): m/z 359 (M+, 2), 254 (100).
Anal. Calcd for C19H21NO2S2: C, 63.48; H, 5.89; N, 3.90; S,
17.84. Found: C, 63.88; H, 6.29; N, 4.30; S, 18.24.
Mon och lor oa la n e P r om oted Rea ction of â-La cta m cis-
5h . A solution of anhydrous AlCl3 (0.35 g, 2.65 mmol) in
anhydrous Et2O (8 mL) was added via syringe to a well stirred
suspension of LiAlH4 (0.11 mg, 2.65 mmol) in anhydrous Et2O
(8 mL). The mixture was refluxed for 30 min, cooled to rt, and
transferred via cannula to a solution of acetal â-lactam cis-5h
(0.33 g, 0.88 mmol) in dry Et2O (4 mL). The reaction was
stirred under argon at room temperature for 45 min, cooled
to 0 °C, and then quenched with water (8 mL), diluted with
Et2O (13 mL), and washed with brine (2 × 5 mL). The organic
layer was dried (MgSO4) and the solvent removed under
reduced pressure, and after purification by flash chromatog-
raphy (AcOEt/hexanes, 1:12), 47 mg (20%) of the less polar
compound 19a (identical to that obtained from azetidine cis-
6h ), 17 mg (20%) of phenol, and 79 mg (25%) of the more polar
product 20 were obtained.
Ack n ow led gm en t. Support for this work by the
DGES-MEC (Project PB96-0565) is gratefully acknowl-
edged. P. A. thanks the DGES (MEC, Spain) for a
“Contrato de Incorporacio´n”.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
analytical data for isomerically pure compounds 1a -i, 2a -i,
3b, 5a -k , 6a -g, 6i-k , 7a -h , 8b-g, 9b, 9d , and 9f. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(1R *,6R *,9S *)-2,5-D it h ia -7-(p -m e t h o x y p h e n y l)-9-
1
p h en oxy-7-a za bicyclo[4,3,0]n on a n e, 20. H NMR: δ 3.76
(s, 3 H), 3.96 (m, 4 H), 4.10 (dd, 1 H, J ) 6.2, 3.7 Hz), 4.15 (dd,
J O991203C