Cren et al.
SCHEME 8. Carboazidation of 2,2-Disubstituted
Methylenecyclohexanes 3k-n
clohexanes is possible when the substrate is properly designed.
A high level of equatorial attack can only be obtained with very
bulky substituents at position 2. Axial attack is the preferred
reaction pathway for cyclohexyl radicals, and excellent stereo-
selectivities can be obtained by introducing an axial substituent
at position 2. In this case, a second equatorial substituent at
position 2 may be tolerated without a large detrimental effect
on the diastereoselectivity. Application of these results for the
stereoselective synthesis of naturally occurring alkaloids is
underway and will be reported in due course.
Experimental Section
General Procedure for the Radical Carboazidation of Alk-
enes. To a mixture of the olefin (2.0 equiv), ethyl 2-iodoacetate or
ethyl 2-ethoxythiocarbonylsulfanylethanoate (1.0 equiv), and 3-py-
ridinesulfonyl azide (3.0 equiv) in benzene (4 mL/mmol) were
added hexabutyldistannane (1.5 equiv) and di-tert-butylhyponitrite
(0.1 equiv). The reaction mixture was stirred at 70-80 °C for 90
min. The solvent was then removed under reduced pressure and
the yellow residue purified by flash chromatography (FC). The
1
diastereomeric ratio was determined by integration of the H and/
or 13C NMR signals.
Ethyl 3-(1-Azido-4-tert-butylcyclohexyl)propanoate (4a). Pre-
pared according to the general procedure from olefin 3a and ethyl
2-iodoacetate. FC (silica gel containing 10% KF, cyclohexane/t-
BuOMe 98:2) gave 4a (262 mg, 0.93 mmol, 93%, dr 84:16) as a
colorless liquid.
with a moderate stereoselectivity. This selectivity could be
increased by introducing a tert-butyl group at postion 4. Indeed,
carboazidation of 3n affords 4n with excellent stereocontrol
(trans/cis 97:3). By comparison with 3m, the carboazidation
of 3n represents a case of matched asymmetric induction.
Unfortunately, the diastereomeric methylenecyclohexane could
not be synthesized, and the level of stereoselectivity for the
expected mismatched case could not be determined. The relative
stereochemistry of azides 4k and 4n was determined after
conversion into the γ-lactams 5k and 5n by X-ray crystal
structure analysis (Scheme 8).
The preferential axial selectivity leading to the formation of
cis-4k is rationalized by transition-state model VI (Figure 3)
closely related to III (Figure 2). For 4l and 4m, the observed
stereoselectivities depend on the conformation equilibrium of
the radical intermediate and the axial/equatorial selectivity for
each radical conformer. The higher selectivity for 4m may
results from dipole-dipole interactions between the sulfonyl
azide and the ester group. The good level of stereocontrol for
the formation of 4n is explained by model VII where selectivity
of the axial attack is reinforced by the presence of an anti ester
group.
Mixture of diastereoisomers: 1H NMR (300 MHz, CDCl3) δ 4.15
(q, J ) 7.1 Hz, 2H), 2.50-2.28 (m, 2H), 1.95-0.77 (m, 11H),
1.27 (t, J ) 7.1 Hz, 3H), 0.86 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 173.5 (minor), 173.3 (major), 63.2 (minor), 63.1 (major), 60.6
(major + minor), 47.6 (major), 47.5 (minor), 36.2 (major), 34.7
(2C, minor), 35.0 (2C, major), 32.5 (major), 32.3 (minor), 29.1
(minor), 28.9 (major), 28.7 (minor), 27.6 (3C, major + minor),
23.6 (2C, minor), 22.9 (2C, major), 14.3 (major + minor); IR (ATR)
ν 2943, 2867, 2095, 1734, 1254, 1181 cm-1; MS (EI) m/z 239 (11),
193 (14), 180 (13), 152 (15), 136 (20), 110 (13), 96 (22), 69 (17),
57 (100), 41 (34); HRMS (EI) calcd for C15H27O2 ([M - N3]+)
239.2011, found 239.2001. Anal. Calcd for C15H27N3O2: C, 64.03;
H, 9.67; N, 14.93; O, 11.37. Found: C, 64.00; H, 9.61; N, 14.90;
O, 11.37.
Acknowledgment. We thank the Swiss National Science
Foundation (Project No. 200020-112250) and the University of
Bern for financial support. We are grateful to Dr. Erich Nyfeler
for the synthesis and the carboazidation reaction of 3c.
Supporting Information Available: Experimental proce-
dures and characterization data of compounds 3a-n, 4b-n,
5a,e,j-n and copies of 1H and 13C NMR spectra of compounds
3b,f-h,l-n, 4a-n, 5a,e,j-n. X-ray crystallographic data for
5j, 5k, and 5n. This material is available free of charge via the
Conclusions
This study of the model system has shown that control of
the selectivity of the carboazidation reaction of methylenecy-
JO900088X
2946 J. Org. Chem. Vol. 74, No. 8, 2009