Highly stereoselective ring expansion of enantiopure α-hydroxyalkyl azetidines

Article abstract of DOI:10.1016/S0040-4039(03)01227-9

Stereodefined α-hydroxyalkyl azetidines, prepared in a few steps from enantiopure β-amino alcohols, are chlorinated or transformed into methanesulfonyloxymethyl derivatives in good yields. Heating of these compounds in chloroform or dimethylformamide induces a stereospecific ring enlargement to give 3-chloro or 3-methanesulfonyloxy pyrrolidines. The ease of this rearrangement depends on the nature of the migrating group (Cl^- or MsO^-), of the class of the starting alcohol (primary or secondary) and of the relative stereochemistry of the starting material.

Full text of DOI:10.1016/S0040-4039(03)01227-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5209–5212
Highly stereoselective ring expansion of enantiopure
a-hydroxyalkyl azetidines
Franc¸ois Couty,* Franc¸ois Durrat and Damien Prim
Laboratoire SIRCOB, UMR CNRS 8086, Baˆtiment Lavoisier, Universite´ de Versailles, 45, avenue des Etats-Unis,
F-78035 Versailles Cedex, France
Received 3 April 2003; revised 12 May 2003; accepted 19 May 2003
Abstract—Stereodefined a-hydroxyalkyl azetidines, prepared in a few steps from enantiopure b-amino alcohols, are chlorinated or
transformed into methanesulfonyloxymethyl derivatives in good yields. Heating of these compounds in chloroform or dimethylform-
amide induces a stereospecific ring enlargement to give 3-chloro or 3-methanesulfonyloxy pyrrolidines. The ease of this
rearrangement depends on the nature of the migrating group (Cl− or MsO−), of the class of the starting alcohol (primary or
secondary) and of the relative stereochemistry of the starting material. © 2003 Elsevier Science Ltd. All rights reserved.
Ring enlargements of nitrogen heterocycles are useful
reactions because they can provide an original access to
target molecules which are otherwise difficult to pre-
pare.1 These reactions frequently involve strained nitro-
gen rings in which the strain release acts as a driving
force for the enlargement. As a result, numerous exam-
ples of aziridine expansions have been reported.2
Recent work has shown that five- to six-membered ring
enlargement can also produce functionalized piperidi-
nes in an enantiospecific way3 and this was successfully
applied to the preparation of (−)-parotexine4a or zami-
fenamicin.4b The strain release in these reactions is not
always necessary and expansion of larger nitrogen hete-
rocycles has also been reported through various path-
ways.5 The azetidine ring however, despite its strain
which is a favourable factor for a ring expansion, has
been less studied. Some scarce reports describe the
Pd-catalysed rearrangement of N-tosyl-2-alkenyl aze-
tidines into piperidines (4 to 6 enlargement),6 the four
to six-membered ring enlargement of 2-thioacetal aze-
tidines under the action of a Lewis acid,7 and the use of
N-tosyl azetidines as a 1,4 dipole in cycloaddition
reactions (4 to 6 enlargement).8 These isolated examples
reflect the difficulty of access to azetidines, especially in
enantiomerically pure form.9 Very recently,10 the ther-
mic ring enlargement of racemic 2-halomethylazetidines
into 3-halopyrrolidines was reported (Fig. 1). This
prompted us to disclose herein our asymmetric version
of this rearrangement.
In order to study this ring expansion, we prepared a
series of primary, secondary and tertiary a-hydroxy-
alkyl azetidines from 2-cyano azetidines, for which we
have recently described an efficient preparation starting
from commercially available enantiomerically pure b-
amino alcohols.11
Primary a-hydroxyalkyl azetidines 1–4 were prepared in
good yields from the corresponding 2-cyano azetidines
following a two-step sequence involving transformation
into the corresponding ethyl ester, followed by LiAlH4-
mediated reduction. No detectable epimerisation could
be observed during this sequence. Secondary anti-a-
hydroxyalkyl azetidines 5 and 6 were prepared as previ-
ously reported12 through the diastereoselective
reduction of the intermediate ketone. Finally, tertiary
azetidinic alcohol 8 was prepared by addition of
methylmagnesium bromide to the corresponding ester 7
whilst 9 was prepared as previously described12 (Scheme
1).
Having in hand the required substrates, we next began
to investigate their ring enlargements. Chlorination of
primary alcohols 3 and 4 gave good yields of the
corresponding chlorides 10 and 11 as stable com-
* Corresponding author. Tel.: 33(0)1 39254455; fax: 33(0)1 39254452.
Figure 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01227-9

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F. Couty et al. / Tetrahedron Letters 44 (2003) 5209–5212
Scheme 3. Mesylation of primary alcohols followed by ring
expansion.
The behavior of the secondary alcohols was somewhat
different (Scheme 4). Chlorination of benzylic alcohols
5 and 6 was not stereoselective and gave unrearranged
chlorides 22–25. In both cases chlorination occurred
predominantly with inversion of configuration to give
syn-chlorides 22 and 24 as major products. The syn and
anti isomers could be separated by chromatography
and showed a different reactivity with regard to the ring
expansion. Indeed, heating a solution of the minor
anti-isomer 23 or 25 in chloroform induced the ring
Scheme 1. Synthesis of a-hydroxyalkyl azetidinic substrates.
pounds. Overnight heating of these chlorides in reflux-
ing chloroform left them unchanged whilst heating in
DMF (120°C, 10 h) smoothly gave 3-chloropyrrolidines
12 and 13 in fair to modest yields (Scheme 2).
On the other hand, mesylation of 1–4 gave the corre-
sponding mesylates 14–17 with trace amounts (10–15%)
of rearranged mesylates 18–21. In this case, heating of
these mixtures in chloroform completed the ring expan-
sion to give 3-mesyloxy pyrrolidines in good overall
yields (Scheme 3).
Scheme 4. Chlorination or mesylation of secondary alcohols
followed by ring expansion.
Scheme 2. Chlorination of primary alcohols followed by ring
expansion.

F. Couty et al. / Tetrahedron Letters 44 (2003) 5209–5212
5211
oxymethyl derivatives (most reactive) and chlorides is in
accordance with the higher leaving group ability of the
methanesulfonate anion compared to the chloride. The
ease of the rearrangement is further enhanced if the
leaving group is held at a benzylic position (note the
facile production of 26 and 27 without isolation of the
intermediate unrearranged methanesulfonate deriva-
tives). Furthermore, the difference of reactivity between
syn-22, 24 and anti-23, 25 benzylic chlorides can be
easily explained by examination of the corresponding
rearrangement transition states, depicted in Figure 3 for
the rearrangements of 24 and 25. It is clear that if the
phenyl group is oriented in an endo position, such as
for the rearrangement involving 24, the steric strain is
important, and the reaction will require higher thermic
activation.
expansion to give 26 or 27, respectively, but left the
syn-isomers 22 and 24 unchanged. However, upon
heating in refluxing DMF, compound 24 rearranged to
give 29, whilst 22 gave trace amounts of rearranged
pyrrolidine 28 along with unidentified byproducts. On
the other hand, mesylation of 5 and 6 afforded directly
rearranged chlorides 26 and 27 with no detectable
amount of the corresponding intermediate mesylate.
The relative configurations in the produced pyrrolidines
were determined by careful NOE experiments. As
examples, some observed NOE enhancements for com-
pounds 19, 27, and 29 are shown in Figure 2. The
determination of the relative configurations of pyrro-
lidines 26–29 allowed the determination of the stereo-
chemistries of the chlorinated stereocentre in the
starting azetidines 22–25.
The above discussion supposes that this rearrangement
involves a concerted pathway and not a transient azeti-
dinium ion (34 in Fig. 4) resulting from intramolecular
alkylation. A similar intermediate (35 in Fig. 4) was
postulated in a related ring expansion involving pyrro-
lidinemethanol derivatives.3a
Finally, tertiary alcohols also showed a different behav-
ior. Treatment of 8 with thionyl chloride, followed by
alkaline workup gave in fair yield (60%) a roughly
equimolar mixture of alkene 31 and amino ketone 33
(Scheme 5). The formation of the compound 31 can be
explained by the occurrence of a transient carbenium
species 30 that undergoes elimination, whilst a 1,2-
hydride shift giving an iminium ion 32 followed by ring
opening accounts for the formation of 33. Under the
same conditions, diphenyl substrate 9 gave only starting
material as an isolable compound: clearly the stable
carbenium species does not rearrange, but gives the
corresponding chloride that undergoes hydrolysis upon
workup.
Our preliminary experimental observations are consis-
tent with a concerted mechanism. First, AM1 calcula-
tions performed on both of these bicyclic ammonium
ions show a very high energy difference, reflecting the
steric strain of the azabicyclo [2.1.0] pentane frame,
although this skeleton was reported in one case.13 We
feel that, unlike 35, the strained ion 34 is not produced.
Furthermore, we were not able to detect by NMR such
azetidinium ions upon treatment of unrearranged ben-
zylic chloride 24 with AgBF4 in CDCl3. Another exper-
imental observation in favor of the concerted pathway
is the absence of rearrangement when a-azetidine carbe-
nium species are involved. Although further experimen-
The relative reactivity of these substrates with regard to
the ring expansion can be explained as follows. The
difference of reactivity between methanesulfonyl-
Figure 2.
Figure 3.
Scheme 5. Chlorination of a tertiary alcohols: no ring expan-
sion takes place.
Figure 4.

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F. Couty et al. / Tetrahedron Letters 44 (2003) 5209–5212
tal work will be needed, we therefore think that this
ring expansion occurs through a concerted pathway.
J.; Dumas, C.; Gomez Pardo, D. Bioorg. Med. Chem.
Lett. 1997, 7, 1343–1344.
5. (a) Wasserman, H. H.; Robinson, R. P.; Matsuyama, H.
Tetrahedron Lett. 1980, 21, 3493–3497; (b) Lednicer, D.;
Hauser, C. R. J. Am. Chem. Soc. 1957, 79, 4449–4451; (c)
Manhas, M. S.; Amin, S. G.; Bose, A. K. Heterocycles
1976, 5, 669–673.
6. Fugami, K.; Miura, K.; Morizawa, Y.; Oshima, K.;
Utimoto, K.; Nozaki, H. Tetrahedron 1989, 45, 3089–
3098.
7. Alcaide, B.; Almendros, P.; Aragoncillo, C.; Salgado, N.
R. J. Org. Chem. 1999, 64, 9596–9604. See also references
cited therein for other 4 to 5 ring enlargements.
8. Ungureanu, I.; Klotz, P.; Schoenfelder, A.; Mann, A. J.
Chem. Commun. 2001, 958–959.
In conclusion, we have described in this letter a
straightforward access to enantiopure 2-halomethyl or
2-methanesulfonyloxymethyl azetidines and 3-chloro14
or 3-methanesulfonyloxy pyrrolidines, and we have
examined the scope of the rearrangement of the former
four- into five-membered rings. Further functionalisa-
tion of these heterocycles is under active investigation
in our group.
Acknowledgements
9. (a) Agami, C.; Couty, F.; Rabasso, N. Tetrahedron Lett.
2002, 43, 4633–4636; (b) Carlin-Sinclair, A.; Couty, F.;
Rabasso, N. Synlett 2003, 726–729.
10. Outurquin, F.; Pannecoucke, X.; Berthe, B.; Paulmier, C.
Eur. J. Org. Chem. 2002, 1007–1014.
CNRS is acknowledged for generous financial support
(Soutien jeune e´quipe). The authors wish to thank Drs.
C. Robert-Labarre and M. J. Pouet for their help in the
conduction of NOE experiments.
11. Agami, C.; Couty, F.; Evano, G. Tetrahedron: Asymme-
try 2002, 297–302.
12. Couty, F.; Prim, D. Tetrahedron: Asymmetry 2002, 13,
2619–2624.
References
1. Hesse, M. Ring Enlargements in Organic Chemistry;
VCH: Weinheim; New York; Basel; Cambridge, 1991.
2. For some recent examples see: (a) Papa, C.; Tomasini, C.
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14. Selected data: Compound 27: H NMR (300 MHz): 3.01
1
(t, J=9.5 Hz, 1H, H5), 3.19 (d, J=13.1 Hz, 1H,
CHHPh), 3.26 (dd, J=9.5 and 3.3 Hz, 1H, H5%), 3.50
(ddd, J=3.3, 7.1, 9.5 Hz, 1H, H4), 3.73 (d, J=8.5 Hz,
1H, H2), 3.96 (d, J=13.1 Hz, 1H, CHHPh), 4.03 (dd,
J=7.1 and 8.4 Hz, 1H, H3), 7.21–7.48 (m, 13H, Ar), 7.63
(d, J=7.5 Hz, 2H, Ar). Compound 29: 1H NMR (300
MHz): 2.48 (t, J=9.8 Hz, 1H, H5), 3.21 (d, J=13.1 Hz,
1H, CHHPh), 3.50 (dd, J=9.5 and 7.5 Hz, 1H, H5%), 3.66
(ddd, J=6.5, 7.5, 9.5 Hz, 1H, H4), 4.01 (d, J=13.1 Hz,
1H, CHHPh), 4.07 (d, J=7.9 Hz, 1H, H2), 4.52 (dd,
J=6.5 and 7.9 Hz, 1H, H3), 7.21–7.60 (m, 15H, Ar).