pylcarbinyl radicals by intramolecular cyclization of alkyl
radicals onto methylenecyclopropanes.4 Herein, we describe
the successful implementation of radical addition-rearrange-
ment chemistry depicted in eq 2.
Gratifyingly, radical rearrangement of 2-methyleneaziri-
dine 4 to 3-methylenepiperidine 6 could be accomplished
using standard tin hydride conditions (Scheme 2). Optimiza-
In designing suitable precursors, we elected to use the
phenylselenide group as the precursor to the alkyl radical
because it is simple to introduce and is an excellent radical
source.5 Furthermore, we anticipated that the PhSe group
would be compatible with the relatively harsh conditions
required for the construction of the methyleneaziridine ring
(vide infra). Our synthetic approach to radical precursor 4
is illustrated in Scheme 1. 3-Amino-propan-1-ol 1 was
Scheme 2a
Scheme 1a
a (a) Bu3SnH, AIBN, benzene, slow addition, reflux; (b) Boc2O,
Et3N.
tion studies established that these reactions were best
performed by slow addition of tri-n-butyltin hydride and
AIBN via syringe pump over 5 h to a dilute solution (final
concentration, 0.015 M) of 4 in benzene.7 In this manner,
3-methylenepiperidine 7 could be isolated in 58% overall
yield after in situ Boc protection of 6 to reduce volatility
and water solubility. We speculate that this reaction proceeds
via aziridinylcarbinyl radical 5, formed by 5-exo-trig cy-
clization of the initially formed alkyl radical, which then
undergoes C-N bond cleavage to relieve the ring strain
associated with the 1-azabicyclo[3.1.0]hexane ring system.
The regioselectivity of the bond fission of 5 parallels findings
made using simple monocyclic systems (cf. eq 1).2
a (a) 2,3-Dibromopropene, K2CO3, THF, reflux; (b) NPSP, Bu3P,
THF, 0 °C; (c) NaNH2 (15 equiv), NH3, 25 min.
alkylated with 2,3-dibromopropene to give alcohol 2, which
was converted into selenide 3 using N-phenylselenophthal-
imide (NPSP) and tri-n-butylphosphine. Final ring closure
to methyleneaziridine 4 was achieved using sodium amide
in liquid ammonia according to the method originally
described by Pollard and Parcell.6 This cyclization was
sufficiently clean that 4 could be fully characterized and used
in the subsequent radical chemistry without further purifica-
tion beyond a simple aqueous workup. Other 2-methylene-
aziridines used in this study (8, 10, 12, 14) were made from
the appropriate amino alcohols and again were used without
purification.
We have used this radical rearrangement sequence to make
several monocyclic and bicyclic systems (Scheme 3). Meth-
yleneaziridines 8 and 10 were readily rearranged to 6-aryl
and 6-alkyl piperidines 9 and 11, respectively, using the same
method. Furthermore, methyleneaziridine 12 rearranged to
Scheme 3a
(3) For a review on the use of aminyl radicals in synthesis, see: Fallis,
A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543-17594.
(4) (a) Destabel, C.; Kilburn, J. D. J. Chem. Soc., Chem. Commun. 1992,
596-598. (b) Pike, K. G.; Destabel, C.; Anson, M.; Kilburn, J. D.
Tetrahedron Lett. 1998, 39, 5877-5880. (c) Penfold, D. J.; Pike, K.; Genge,
A.; Anson, M.; Kitteringham, J.; Kilburn, J. D. Tetrahedron Lett. 2000,
41, 10347-10351 and references therein.
(5) Clive, D. L. J.; Chittatu, G. J.; Farina, V.; Kiel, W. A.; Menchen, S.
M.; Russell, C. G.; Singh, A.; Wong, C. K.; Curtis, N. J. J. Am. Chem.
Soc. 1980, 102, 4438-4447.
(6) (a) Pollard, C. B.; Parcell, R. F. J. Am. Chem. Soc. 1951, 73, 2925-
2927. (b) Bottini, A. T.; Roberts, J. D. J. Am. Chem. Soc. 1957, 79, 1462-
1464. (c) Ince, J.; Ross, T. M.; Shipman, M.; Slawin A. M. Z.; Ennis, D.
S. Tetrahedron 1996, 52, 7037-7044.
(7) Typical Procedure. To a stirred, degassed, refluxing solution of 4
(100 mg, 0.397 mmol) in benzene (21 mL) was added AIBN (27 mg, 0.164
mmol) and tri-n-butytin hydride (147 µL, 0.56 mmol) in benzene (5 mL)
over 5 h by syringe pump. After the addition was complete, the mixture
was refluxed for 1 h and then allowed to cool to room temperature. Di-
tert-butyl dicarbonate (173 mg, 0.79 mmol) and Et3N (110 µL, 0.79 mmol)
were added, and the mixture was stirred overnight. The solvent was removed
in vacuo, and the residue was chromatographed on silica gel (5% EtOAc/
95% petroleum spirit) to give 7 (45 mg, 58%) as a colorless oil: νmax 1685
cm-1; 1H NMR (300 MHz, CDCl3) 4.81 (1H, s), 4.74 (1H, s), 3.86 (2H, s),
3.43 (2H, m), 2.25 (2H, m), 1.61 (2H, m), 1.45 (9H, s); 13C NMR (75
MHz, CDCl3) 154.8, 143.0, 109.7, 79.4, 50.5, 44.1, 32.7, 28.4, 26.7; found
(MH+) 198.1493; C11H20NO2 requires 198.1494.
a (a) Bu3SnH, AIBN, benzene, slow addition, reflux; (b) Boc2O,
Et3N.
2384
Org. Lett., Vol. 3, No. 15, 2001