A new method for the generation and cyclization of iminyl radicals via the Hudson reaction

Article abstract of DOI:10.1021/ol990720e

(Matrix presented) A mild new synthetic procedure has been developed for in situ generation and cyclization of iminyl radicals onto pendant alkenes, followed by functionalization of the resulting carbon radical by one of a variety of trapping reagents. The key process in the method involves production of the iminyl radical via treatment of an aldoxime or ketoxime with readily available 2,6-dimethylbenzenesulfinyl chloride at -50°C to room temperature (Hudson reaction).

Full text of DOI:10.1021/ol990720e

ORGANIC
LETTERS
1999
Vol. 1, No. 4
637-639
A New Method for the Generation and
Cyclization of Iminyl Radicals via the
Hudson Reaction
Xichen Lin, Didier Stien, and Steven M. Weinreb*
Department of Chemistry, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
smw@chem.psu.edu
Received June 7, 1999
ABSTRACT
A mild new synthetic procedure has been developed for in situ generation and cyclization of iminyl radicals onto pendant alkenes, followed
by functionalization of the resulting carbon radical by one of a variety of trapping reagents. The key process in the method involves production
of the iminyl radical via treatment of an aldoxime or ketoxime with readily available 2,6-dimethylbenzenesulfinyl chloride at −50 °C to room
temperature (Hudson reaction).
During the past several years, cyclizations of various types
of nitrogen-based radicals onto pendant olefins have been
Scheme 1
recognized as a powerful method for construction of nitrogen
heterocycles.1,2 Iminyl radicals are especially useful in this
regard since the cyclization products are functionally dis-
posed for further elaboration into a variety of useful systems.
In particular, Zard and co-workers have pioneered in the
development of methodology for the generation and cycliza-
tion of iminyl radicals.3,4
In 1978, Hudson and co-workers described a general
method for the mild generation of N-sulfonylimines 4 from
that this transformation occurs via the homolytic fragmenta-
ketoximes 1 and arylsulfinyl chlorides (Scheme 1).5-7
tion-recombination mechanism shown in the scheme, in-
Convincing evidence has been provided by EPR experiments
volving initial formation of a transient sulfinate ester 2, which
upon warming to room temperature leads to the “caged”
(1) For an excellent review of nitrogen radicals, see: Fallis, A. G.; Brinza,
I. M. Tetrahedron 1997, 53, 17543.
diradical 3. We were intrigued that an iminyl radical is
(2) See also: Bowman, W. R.; Broadhurst, M. J.; Coghlan, D. R.; Lewis,
postulated as an intermediate in this process and considered
K. A. Tetrahedron Lett. 1997, 38, 6301.
(3) (a) Boivin, J.; Fouquet, E.; Schiano, A.-M.; Zard, S. Z. Tetrahedron
1994, 50, 1769. (b) Callier-Dublanchet, A.-C.; Quiclet-Sire, B.; Zard, S. Z.
Tetrahedron Lett. 1995, 36, 8791. (c) Boivin, J.; Callier-Dublanchet, A.-
C.; Quiclet-Sire, B.; Schiano, A.-M.; Zard, S. Z. Tetrahedron 1995, 51,
6517. (d) Le Tadic-Biadatti, M.-H.; Callier-Dublanchet, A.-C.; Horner, J.
H.; Quiclet-Sire, B.; Zard, S. Z.; Newcomb, M. J. Org. Chem. 1997, 62,
559. (e) Boivin, J.; Schiano, A.-M.; Zard, S. Z.; Zhang, H. Tetrahedron
Lett. 1999, 40, 4531.
(5) Brown, C.; Hudson, R. F.; Record, K. A. F. J. Chem. Soc., Perkin
Trans. 2 1978, 822.
(6) For related processes, see: (a) Bleeker, I. P.; Engberts, J. B. F. N.
Recl.: J. R. Neth. Chem. Soc. 1979, 121. (b) Bouma, W. J.; Engberts, J. B.
F. N. J. Org. Chem. 1976, 41, 143. (c) Hovius, K.; Engberts, J. B. F. N.
Tetrahedron Lett. 1972, 13, 181.
(7) For a comprehensive review of N-sulfonylimines, see: Weinreb, S.
M. Top. Curr. Chem. 1997, 190, 131.
(4) See also: El Kaim, L.; Meyer, C. J. Org. Chem. 1996, 61, 1556.
10.1021/ol990720e CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/08/1999

Table 1. Radical Cyclizations of Oxime Olefins Using 2,6-Dimethylbenzenesulfinyl Chloridea,b
the possibility that the Hudson reaction might provide a
synthetically useful source of such radicals for intramolecular
cyclizations onto olefins.
For our initial exploratory work in this area, 2-allylcyclo-
hexanone oxime (5) was chosen as the substrate. Treatment
of this compound with p-toluenesulfinyl chloride8 as de-
scribed by Hudson indeed led to some of the desired bicyclic
sulfone imine 8a, but only in low yield (Scheme 2).9 In the
presence of diphenyl diselenide as a trapping agent, a
similarly poor yield of selenide cyclization product 8b was
produced. It appeared most likely that recombination of the
diradical 6 to the corresponding N-sulfonylimine was re-
sponsible for the low yields of the desired cyclization
products. Although we could in fact detect by TLC what
we believed to be the N-tosylimine derived from oxime 5, it
was too hydrolytically unstable to be isolated.
We thus reasoned that if we could suppress recombination
of diradical 6, it should be possible to intercept the iminyl
radical more efficiently to produce the requisite bicyclic
radical 7.
Two different strategies toward solving this problem have
been explored which are based upon the sulfinyl chloride
reagent. Therefore, reagents that lead to unstable sulfonyl
radicals (i.e. radicals which can rapidly lose SO210) and
preclude recombination (cf. entries c-e, Scheme 2) were
investigated, and/or more hindered sulfinyl chlorides were
utilized to slow the recombination step by steric effects (cf.
entries e-g, Scheme 2).
Scheme 2
Thus, replacing p-toluenesulfinyl chloride with the benzyl
derivative led to a significantly improved yield of the bicyclic
seleno imine (cf. 8c). It was found that benzyl phenyl
selenide was also produced in this reaction in about 24%
(8) Kurzer, F. Organic Syntheses; Wiley: New York; Collect. Vol. IV,
1967; p 937.
(9) In all cases, cyclization products 8 were ∼3:2 mixtures of stereo-
isomers which were not separated.
(10) See: Bertrand, M. P. Org. Prep. Proc. Int. 1994, 26, 257, and
references cited.
638
Org. Lett., Vol. 1, No. 4, 1999

yield based on oxime, thereby supporting the presumption
that loss of sulfur dioxide is of significance. Similarly, tert-
butylsulfinyl chloride11 gave an even higher yield of cy-
clization product along with some tert-butyl phenyl selenide
(∼14%). This latter system may work by a combination of
the loss of SO2 from the intermediate tert-butylsulfonyl
radical and steric effects. It might be noted that in the cases
involving alkylsulfinyl chlorides, only 1 equiv could be used
since excess reagent destroys the imine product.
Noteworthy is the fact that 1,4-cyclohexadiene can be used
as a source of a hydrogen atom, thus avoiding the use of
toxic tributylstannane, along with the usual problems as-
sociated with removal of tin residues.
It is important to note that the reaction conditions
employed here are exceptionally mild compared to many of
the other current methods for the production and cyclization
of iminyl radicals. In addition, radical traps can be used
which lead to more highly functionalized products than those
produced by tin hydride-induced processes. Thus, we have
proven that it is possible to easily incorporate an oxygen-,
selenium-, or sulfur-based substituent in the termination step.
Indeed, one of the appealing features of this chemistry is
the range of synthetically useful postcyclization manipula-
tions that are potentially available from the various product
imines.
In conclusion, we have demonstrated the utility of the
Hudson reaction for the generation and cyclization of iminyl
radicals generated at room temperature from olefinic oximes
and 2,6-dimethylbenzenesulfinyl chloride. Further variations
and synthetic applications of this new methodology will be
reported in due course.
With hindered arylsulfinyl chlorides, the best yield of 8
(61%) was obtained using 2,6-dimethylbenzenesulfinyl chlo-
ride, which was easily synthesized in two steps from the
corresponding commercially available aryl Grignard reagent
(see Supporting Information).12 It is also possible to use this
arylsulfinyl chloride in excess in order to improve the yields
of cyclization products. With the hindered triisopropyl-
benzenesulfinyl derivative, the yield of cyclization product
8 was low, probably reflecting the difficulty in the initial
O-sulfinylation of the oxime. Therefore, 2,6-dimethylben-
zenesulfinyl chloride was used for all further investigations.
Using this sulfinylating reagent, a variety of ketoximes
and aldoximes were successfully cyclized to afford the
desired imines in yields ranging from 49 to 75% (Table 1).
To demonstrate the functional group versatility of the
methodology, four different radical traps were explored in
these reactions, including diphenyl diselenide, TEMPO,
diphenyl disulfide, and 1,4-cyclohexadiene. It is noteworthy
that the use of a less reactive radical scavenger must be
compensated for by increasing its concentration (from 0.06
M with TEMPO (ktermination ≈ 109 M-1 s-1)13 to 2.9 M with
cyclohexadiene (ktermination ≈ 6 × 104 M-1 s-1)14).15 If the
concentration of the less efficient trapping agents is not
increased, a variety of unidentified side products are pro-
duced.
Acknowledgment. We are grateful to the National
Institutes of Health (CA-34303) for generous financial
support of this research. We also thank the Ministry of
Foreign Affairs (France) for a Lavoisier Postdoctoral Fel-
lowship to D.S.
Supporting Information Available: Experimental details
and spectral data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL990720E
(11) Richey, H. G., Jr.; Farkas, J., Jr. J. Org. Chem. 1987, 52, 479.
(12) 2,6-Dimethylbenzenesulfinyl chloride has been synthesized previ-
ously by a less convenient procedure: Cevasco, G.; Novi, M.; Petrillo, G.;
Thea, S. Gazz. Chim. Ital. 1990, 120, 131.
(13) Rate constants are at room temperature: Claridge, R. F. C., Ed.
Landolt Bo´rnstein, New Series II, Vol. 18-A; Springer-Verlag: Berlin, 1994;
p 57.
(14) Claridge, R. F. C., Ed. Landolt Bo´rnstein, New Series II, Vol. 18-
A; Springer-Verlag: Berlin, 1994; p 4.
(15) For the rate constants of radical trapping with diphenyl diselenide
and diphenyl disulfide, see: Newcomb, M. Tetrahedron 1993, 49, 1151.
Org. Lett., Vol. 1, No. 4, 1999
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