Thermal rearrangements of α-(ω-azidoalkyl) enones

Article abstract of DOI:10.1016/S0040-4039(02)01077-8

The thermal rearrangement of α-(ω-azidoalkyl) enones has been investigated. A variety of these substrates were synthesized and subjected to thermal rearrangement to investigate the scope and generality of their transformation to bicyclic lactams.

Full text of DOI:10.1016/S0040-4039(02)01077-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5385–5388
Thermal rearrangements of a-(v-azidoalkyl) enones
Gary A. Molander* and Christopher T. Bibeau
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
PA 19104-6323, USA
Received 5 June 2002; accepted 7 June 2002
Abstract—The thermal rearrangement of a-(v-azidoalkyl) enones has been investigated. A variety of these substrates were
synthesized and subjected to thermal rearrangement to investigate the scope and generality of their transformation to bicyclic
lactams. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
described by Aube´1 and two substrates were investi-
gated that gave different products from those reported
by Sha under both disparate and similar conditions
(vide infra).
Nitrogen heterocycles comprise the vast majority of
medicinals on the market today. With this in mind, we
began investigations into the scope and mechanism of
the thermal rearrangement of a-(v-azidoalkyl) enones,
a reaction that provides ready access to unsaturated
bicyclic lactams. To our knowledge, there have been
relatively few investigations into the thermal rearrange-
ments of a-(v-azidoalkyl) a,b-unsaturated enones.
Notable exceptions are the studies of Aube´,1 Schultz,2
and Sha.3–5 The rearrangements reported herein
provide products that are complementary to those pro-
vided by the Lewis acid catalyzed rearrangement
2. Results and discussion
Aromatic a-(v-azidoalkyl) enone 2 (Eq. (1)) was the
first substrate we subjected to thermal rearrangement
conditions. We selected this compound based on its
similarity to an intermediate that had undergone an
analogous thermal rearrangement in our synthetic route
to the natural product cephalotaxine.6 Substrate 2 was
synthesized via a Suzuki coupling7 of known substrates
1 and 2-iodo-3-methylcyclopent-3-en-1-one, 4, followed
by treatment of the coupled alkyl chloride with NaN3
in DMF.
Table 1. Effect of solvent on the thermal rearrangement
of 2
Entry
Conditions
% Isolated yield of 3
1
2
3
4
5
DMF, reflux, 15 h
Xylenes, reflux, 15 h
DMSO, 145°C, 15 h
DMSO, 110°C, 48 h
Neat, 145°C
76
65
45
0
We initially tested several temperatures and solvents to
optimize the reaction conditions for the rearrangement
(2 to 3, Eq. (1)) as outlined in Table 1. Both DMF and
xylenes worked reasonably well. Performing the reac-
tions in DMSO or neat led to dramatic decreases in the
0
(1)
Keywords: triazoline; rearrangement; a-(v-azidoalkyl) enone.
* Corresponding author. E-mail: gmolandr@sas.upenn.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01077-8

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G. A. Molander, C. T. Bibeau / Tetrahedron Letters 43 (2002) 5385–5388
Scheme 1.
yields. Although the yield of the reaction in xylenes was
slightly less than the yield of the reaction in DMF, we
used xylenes during our subsequent studies because we
found the products difficult to separate from DMF.
After studying the effect of solvent and temperature on
this test substrate, we set out to elucidate the scope of
this rearrangement by synthesizing a variety of suitable
azides. In general, we synthesized the corresponding
alkyl chloride or alkyl mesylate, which yielded the
desired substrates upon treatment with NaN3 in DMF
at 60°C. Compounds 5a,b (Eq. (2)) were synthesized
according to a previously conveyed protocol.6 Sub-
strates 8a–c (Eq. (3)) were constructed according to the
method of Majetich.9 Enones 15 and 17 were accessed
according to the method of Johnson et al.10 g-Substi-
tuted enone 23 was prepared by treatment of the corre-
sponding alkyl chloride with NaI in acetone at reflux
followed by treatment with NaN3 in DMF at room
temperature. Azide 13 is known1 and was acquired by
adapting the method of Gassman11 for the preparation
of a-substituted a-phenylthiocycloalkanones, followed
by oxidation with m-CPBA and treatment with NaN3
in DMF at 60°C. The starting material 25 has been
previously reported4 and was available from ongoing
studies in our laboratory.
In previous investigations, Sha had ruled out a nitrene
mechanism in these reactions in favor of a 1,3-dipolar
mechanism that involved a triazoline intermediate
(Scheme 1).4 During the course of the current investiga-
tions, we used React-IR® to follow the disappearance
of the azide absorption at about 2100 cm−1, with con-
comitant formation of an amide carbonyl stretch at
1660 cm−1. On the basis of the NMR experiments of
Aube´1 and the dipolar cycloaddition mechanism put
forth by Sha,4,5 we had expected to observe the appear-
ance of an absorbance at 1620 cm−1 corresponding to a
transient triazoline.8 This intermediate could decom-
pose via a diradical process based on acyl radical
migration or via a process involving discrete betaine
intermediates (Scheme 1).4,5 However, no absorbance at
this frequency was observed during any of the experi-
ments listed in Table 1, indicating that the triazoline, if
formed, decomposed immediately on formation under
the reaction conditions.
Table 2 summarizes the results of our investigation into
the thermal rearrangement of the a-(v-azidoalkyl)
(2)
(3)

G. A. Molander, C. T. Bibeau / Tetrahedron Letters 43 (2002) 5385–5388
5387
enones. Of special interest are entries 7 and 8, in which
the enamide isomerizes, presumably through an
iminium ion intermediate. Entry 8 diverges from the
reactivity reported by Sha4 for his thermal rearrange-
ment of 9c (Eq. (5)). Entry 9 is noteworthy because it
reveals that this isomeric triazoline is stable under the
reaction conditions. The result in entry 10 complements
the investigations of Sha,3–5 who reported the same
product, 26, but as a minor constituent when the
rearrangement was performed in the polar solvents
MeOH or DMF. We were not able to isolate any other
products during this experiment.
described previously (Scheme 1). In the specific case
where 13 was subjected to the rearrangement conditions
(entry 4), we obtained a complex mixture which con-
tained neither 14 nor 26.
(4)
(5)
Significant is the fact that the substitution pattern of
the resultant products from these thermal rearrange-
ments differs from that obtained by Aube´1 in his Lewis
acid catalyzed rearrangement of 13 (Eq. (4)). In general,
the thermal rearrangements produce enamide substrates
whose structure can be predicted by the mechanism
In conclusion, the thermal rearrangement of a variety
of different a-(v-azidoalkyl) enones has been per-
formed. The products of these reactions are comple-
Table 2. Thermal rearrangement of a-(v-azidoalkyl) enones

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G. A. Molander, C. T. Bibeau / Tetrahedron Letters 43 (2002) 5385–5388
mentary to those provided by the Lewis-acid promoted
processes previously developed by Aube´. The reaction
is of synthetic value, and may be a useful tool in
assembling nitrogen heterocyclic intermediates for the
total synthesis of natural products.
5. Sha, C.-K.; Ouyang, S.-L.; Hsieh, D.-Y.; Hseu, T.-H.
Chem. Commun. 1984, 492.
6. Molander, G. A.; Hiersemann, M. Tetrahedron Lett.
1997, 38, 4347.
7. Black, W. C.; Brideau, C.; Chan, C.-C.; Charleson, S.;
Chauret, N.; Claveau, D.; Ethier, D.; Gordon, R.; Greig,
G.; Guay, J.; Hughes, G.; Jolicoeur, P.; Leblanc, Y.;
Nicoll-Griffith, D.; Ouimet, N.; Riendeau, D.; Visco, D.;
Wang, Z.; Xu, L.; Prasit, P. J. Med. Chem. 1999, 42,
1274.
8. Kadaba, P. K.; Stanovnik, B.; Tisler, M. In Advances in
Heterocyclic Chemistry; Katritzky, A. R., Ed. D2-1,2,3-
Triazolines; Academic Press: Orlando, 1984; Vol. 37, p.
217.
Acknowledgements
We thank Merck Research Laboratories for their gen-
erous support of this research.
References
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