Practical and convenient synthesis of N-heterocycles: Stereoselective cyclization of N-alkenylamides with t-BuOl under neutral conditions

Article abstract of DOI:10.1021/ol061182q

tert-Butyl hypoiodite (t-BuOl) was found to be a powerful reagent for the cyclization of N-alkenylamides leading to a variety of N-heterocycles under extremely mild conditions. When N-alkenylsulfonamides were employed in the reaction, three- to six-member

Full text of DOI:10.1021/ol061182q

ORGANIC
LETTERS
2
006
Vol. 8, No. 15
335-3337
Practical and Convenient Synthesis of
N-Heterocycles: Stereoselective
3
Cyclization of N-Alkenylamides with
t-BuOI under Neutral Conditions
Satoshi Minakata,* Yoshinobu Morino, Yoji Oderaotoshi, and Mitsuo Komatsu*
Department of Applied Chemistry, Graduate School of Engineering, Osaka UniVersity,
Yamadaoka 2-1, Suita, Osaka 565-0871, Japan
minakata@chem.eng.osaka-u.ac.jp
Received May 14, 2006
ABSTRACT
tert-Butyl hypoiodite (t-BuOI) was found to be a powerful reagent for the cyclization of N-alkenylamides leading to a variety of N-heterocycles
under extremely mild conditions. When N-alkenylsulfonamides were employed in the reaction, three- to six-membered saturated N-heterocycles
were obtained in good to excellent yields with complete stereoselectivity. The method was applicable to the cyclization of alkenylbenzamide
derivatives to afford N-, O- or N-, S-heterocycles.
Nitrogen-containing heterocycles, including aziridines, aze-
tidines, pyrrolidines, piperidines, and related compounds, are
frequently present as substructures in natural products and
include the need for heavy metals and/or heating conditions
and difficulty in controlling the stereochemistry of the
products.
1
show potent biological activities. For these reasons, the
We recently reported on the novel ionic iodine atom
transfer cyclization by the reaction of 4-pentenyl iodides with
Chloramine-T, leading to the formation of iodomethylated
development of practical and convenient methods for the
2
construction of these heterocycles is highly desirable. Al-
6
though there are many approaches to the synthesis of het-
erocycles based on a cyclization mode, for example, hydro-
pyrrolidines with complete stereoselectivity. In the course
of the studies on clarification of the reaction pathway,
N-chloro-N-alkenylsulfonamides were found to be precursors
of the desired products, and the subsequent treatment with
NaI enabled the cyclization (Scheme 1).
3
4
amination catalyzed by transition metals or acids and radical
5
cyclization, these procedures have certain disadvantages that
(
1) See, for example: O’Hagen, D. Nat. Prod. Rep. 2000, 17, 435-
46.
2) For recent reviews, see: (a) Sundberg, R. J. In ComprehensiVe
Heterocyclic Chemistry II; Bird, C. W., Ed.; Pergamon: Oxford, 1996; Vol.
2
3
2
2
This finding stimulated us to investigate an alternative
cyclization of N-alkenylamides by exploiting tert-butyl
hypoiodite. While this reagent, which is generated by reacting
4
(
, pp 119-206. (b) Nadin, A. J. Chem. Soc., Perkin Trans. 1 1998, 3493-
513. (c) Nadin, A.; Mitchinson, A. J. Chem. Soc., Perkin Trans. 1 1999,
553-2581. (d) Nadin, A.; Mitchinson, A. J. Chem. Soc., Perkin Trans. 1
000, 2862-2892. (e) Gribble, G. W.; Gilchrist, T. L. Progress in
7
t-BuOCl with metal iodide salts or iodine, would be
(5) For recent reviews and examples of the cyclization of N-centered
radicals, see: (a) Esker, J. L.; Newcomb, M. AdV. Heterocycl. Chem. 1993,
58, 1-45. (b) Zard, S. Z. Synlett 1996, 1148-1154. (c) Fallis, A. G.; Brinza,
I. M. Tetrahedron 1997, 53, 17543-17594. (d) Uchiyama, K.; Hayashi,
Y.; Narasaka, K. Tetrahedron 1999, 55, 8915-8930. (e) Senboku, H.;
Kajizuka, Y.; Hasegawa, H.; Fujita, H.; Suginome, H.; Orito, K.; Tokuda,
M. Tetrahedron 1999, 55, 6465-6474. (f) Liu, J. F.; Heathcock, C. H. J.
Org. Chem. 1999, 64, 8263-8266. (g) Cossy, J.; Tresnard, L.; Gomez, P.
D. Eur. J. Org. Chem. 1999, 1925-1933.
(6) Minakata, S.; Kano, D.; Oderaotoshi, Y.; Komatsu, M. Org. Lett.
2002, 4, 2097-2099.
(7) Tanner, D. D.; Gidley, G. C.; Das, N.; Rowe, J. E.; Potter, A. J. Am.
Chem. Soc. 1984, 106, 5261-5267 and references therein.
Heterocyclic Chemistry; Pergamon: Oxford, 2001; Vol. 13.
3) See, for example: (a) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J.
(
Am. Chem. Soc. 2005, 127, 7690-7691. (b) Manzoni, M. R.; Zabawa, T.
P.; Kasi, D.; Chemler, S. R. Organometallics 2004, 23, 5618-5621. (c)
Pohlki, A.; Doye, S. Chem. Soc. ReV. 2003, 32, 104-114. (d) Nobis, M.;
Driessen-H o¨ lscher, B. Angew. Chem., Int. Ed. 2001, 40, 3983-3986. (e)
Brunet, J. J.; Neibecker, D. In Catalytic Heterofunctionalization; Togni,
A., Gr u¨ tzmacher, H., Eds.; Wiley-VCH: Weinheim, Germany, 2001; pp
9
1-141. (f) M u¨ ller, T. E.; Beller, M. Chem. ReV. 1998, 98, 675-703.
4) See, for example: (a) Schlummer, B.; Matwig, J. F. Org. Lett. 2002,
, 1471-1474. (b) Kumadaki, I.; Jonoshita, S.; Sato, K.; Omote, M.; Ando,
(
4
A. Heterocycles 2001, 54, 589-592.
1
0.1021/ol061182q CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/22/2006

addition of t-BuOCl and NaI to an acetonitrile solution of
the alkenylamide led to the direct cyclization to afford an
iodomethylated N-tosylpyrrolidine 2a in 98% yield within
only 5 h (eq 1).
Scheme 1. A Representative Example of Previous Studies on
the Synthesis of a Pyrrolidine
To verify the superiority of the system, iodine or IPy
2
-
BF , which would be potential reagents, was evaluated for
4
the cyclization of 1a. Although the reaction proceeded under
the same conditions, the efficiencies were rather low to afford
2a in 61% (by I ) and 77% (by IPy BF ), respectively. Since
the t-BuOCl/NaI system was found to be a powerful tool
for the construction of an N-heterocycle, a variety of
alkenylsulfonamides were employed in the cyclization to
establish the generality of the reaction (Table 1). Both trans-
expected to be a powerful iodinating agent, there are only a
few examples where it is used in organic reactions. Among
these, the addition reaction of t-BuOI to styrene is known,
2
2
4
8
but the use of UV light or Lewis acid is required for the
9
reaction to proceed. If t-BuOI were to be utilized in the
reaction with an alkenylamide, the reagent would first induce
the iodination of the amide nitrogen and not the addition to
the olefin moiety. The resulting N-iodinated alkenylamide
would cyclize via iodine atom transfer from the amido
nitrogen to the olefin, whose phenomenon might be explained
by the stability of an iodonium ion. Namely, we anticipated
that the reaction of N-alkenylamides with t-BuOI would
directly afford the desired cyclic products under neutral
conditions (Scheme 2). Although a similar transformation
Table 1. Cyclization of a Variety of Alkenylsulfonamides
Using the t-BuOCl/NaI Systema
Scheme 2. Proposed Cyclization of N-Alkenylamides with
t-BuOI
for construction of aziridines has been studied by Taguchi’s
group, the method suffers from drawbacks of the requirement
for a strong base and difficulty in the complete control of
10
the stereochemistry. In this paper, we report on a practical
and convenient synthesis of three- to six-membered N-
heterocycles from N-alkenylamides utilizing t-BuOI, in which
the cyclization proceeds with complete stereoselectivity under
extremely mild conditions.
6
As mentioned in a previous report, the reaction of N-(4-
pentenyl)-p-toluenesulfonamide (1a) with t-BuOCl in aceto-
nitrile at room temperature for 24 h gave only an N-chlori-
nated compound in quantitative yield. The simultaneous
a
Reaction conditions: alkenylsulfonamide (0.17 mol/L), t-BuOCl, NaI
(
8) (a) Barton, D. H. R.; Beckwith, A. L. J.; Goosen, A. J. Chem. Soc.
b
(
(
1 equiv), MeCN, rt, 5 h. t-BuOCl, NaI (1.2 equiv), 24 h. c t-BuOCl, NaI
1
9
1
4
965, 181-190. (b) Tanner, D. D.; Gidley, G. C. J. Am. Chem. Soc. 1968,
0, 808-809. (c) Kametani, T.; Watt, D. S.; Ji, T.; Fitz, T. J. Org. Chem.
985, 50, 5384-5387. (d) Montro, R.; Wirth, T. Org. Lett. 2003, 5, 4729-
731.
1.3 equiv), 24 h. d Alkenylsulfonamide (0.09 mol/L), t-BuOCl, NaI (1.2
equiv), 24 h.
(
9) Heasley, V. L.; Berry, B. R.; Holmes, S. L.; Holstein, L. S., III;
Milhoan, K. A.; Sauerbrey, A. M.; Teegarden, B. R.; Shellhamer, D. F. J.
Org. Chem. 1988, 53, 198-201.
and cis-N-(4-hexenyl)-p-toluenesulfonamides (1b and 1c)
were efficiently converted to the corresponding pyrrolidines
(
10) Kitagawa, O.; Taguchi, T. Synlett 1999, 8, 1191-1199.
3336
Org. Lett., Vol. 8, No. 15, 2006

2b and 2c in excellent yields (entries 1 and 2). It is
noteworthy that complete stereoselectivity as well as ste-
reospecificity was observed in the reaction when geometric
isomers were used. The cis-fused bicyclic pyrrolidines 2d-f
were readily synthesized from alkenylsulfonamides having
five- to seven-membered cycloalkenes 1d-f in extremely
high yields with complete stereoselectivity (entries 3-5). The
present method was applicable to the efficient synthesis of
iodomethylated aziridine 2g under neutral conditions in
contrast to the case with Taguchi’s method (entry 6). The
formation of azetidines by electrophilic cyclization appears
to be a difficult process, and only a limited number of
successes have been reported.11 Essentially all the reactions
were achieved by the introduction of some substituents to
homoallylamine derivatives (a phenyl group on the carbon
of the olefin and/or alkyl groups on the carbon R to the
nitrogen). However, the method enabled an unfunctionalized
homoallyl sulfonamide to cyclize to azetidine 2h (entry 7).
A six-membered ring, piperidine 2i, was also obtained in
good yield by this procedure (entry 8).
Scheme 4. Plausible Reaction Pathway Leading to a
Pyrrolidine
Table 2. Cyclization of Alkenylbenzamides Using the
t-BuOCl/NaI System
To clarify which moiety, the sulfonamide nitrogen or the
C-C double bond, was first iodinated by t-BuOI, the active
species, the following experiment was carried out (Scheme
1
2
3
). When a mixture of N-methyl-p-toluenesulfonamide
Scheme 3. Iodination Reaction: Sulfonamide versus Olefin
benzamide (6a) was treated with t-BuOCl and NaI in
acetonitrile at room temperature, cyclization proceeded
smoothly to afford an iodomethylated oxazoline 7a in 95%
yield, in which no detectable N-benzoylaziridine was pro-
duced. A six-membered ring, an oxazine derivative 7b, was
readily obtained from a benzamide having a homoallyl group
(
3
methyl; δ 2.41 ppm) and trans-2-octene in CD CN was
1
treated with t-BuOCl and NaI, the H NMR spectra showed
that the trans-2-octene signals remained unchanged, but a
new methyl singlet at δ 3.14 ppm appeared. The chemical
shift of the singlet was identified by comparison with that
of an authentic sample prepared by reacting N-methyl-p-
toluenesulfonamide and N-iodosuccinimide in CD CN. This
3
result indicates that t-BuOI first iodinates the nitrogen of
the sulfonamide.
6
b using the procedure. Thioamide derivatives were also
converted to the corresponding N-, S-heterocycles.
In summary, an efficient, simple, and practical method for
the synthesis of a variety of N-heterocycles from N-
alkenylamides by utilizing t-BuOI under neutral and very
mild conditions has been developed. Since the cyclization
pathway involved a cyclic iodonium ion, the stereochemistry
could be controlled completely. The application of the
potential reagent, t-BuOI, to other organic reactions is
currently in progress.
Thus, the most likely pathway for the present cyclization
is proposed to be as follows (Scheme 4). t-BuOI is generated
in situ by the reaction of t-BuOCl and NaI. The active
7
species iodinates the sulfonamide nitrogen, followed by
intramolecular iodonium ion transfer to the olefin moiety
leading to the three-membered iodonium ion 5, and the
cyclization of 5 then proceeds smoothly to afford the product.
The formation of the iodonium ion is supported by the
stereospecific and diastereoselective cyclizations shown in
Table 1.
The present method was successfully applicable to the
synthesis of other heterocycles from alkenylbenzamides or
alkenylbenzthioamides (Table 2). When N-(2-propenyl)-
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Japan Society for
Promotion of Science. Y.M. expresses his special thanks for
the 21st century center of excellence (21COE) program,
“Creation of Integrated EcoChemistry of Osaka University”.
We also wish to acknowledge the Instrumental Analysis
Center, Faculty of Engineering, Osaka University.
Supporting Information Available: Experimental details
and spectral data for the major products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(
11) Robin, S.; Rousseau, G. Eur. J. Org. Chem. 2002, 3099-3114.
(12) See Supporting Information.
OL061182Q
Org. Lett., Vol. 8, No. 15, 2006
3337