A novel free-radical ring contraction of a cyclic carbamate

Article abstract of DOI:10.1021/jo0163290

During a study on iodocyclocarbamation reactions of 2-styryl-4-piperidones, a novel ring contraction was observed. Iodocyclocarbamation of 2-styryl-4-piperidone 3 gave the bicyclic carbamate 4. Reduction of 4 under free-radical conditions effected a stereoselective ring contraction to provide oxazolidinone 6. A three-electron-three-center mechanism is proposed.

Full text of DOI:10.1021/jo0163290

1972
J . Org. Chem. 2002, 67, 1972-1973
Sch em e 1
A Novel F r ee-Ra d ica l Rin g Con tr a ction of a
Cyclic Ca r ba m a te
Alfred L. Williams, Teresa Abad Grillo, and
Daniel L. Comins*
Department of Chemistry, North Carolina State University,
Raleigh, North Carolina 27695-8204
daniel_comins@ncsu.edu
Received November 28, 2001
Abstr a ct: During a study on iodocyclocarbamation reac-
tions of 2-styryl-4-piperidones, a novel ring contraction was
observed. Iodocyclocarbamation of 2-styryl-4-piperidone 3
gave the bicyclic carbamate 4. Reduction of 4 under free-
radical conditions effected a stereoselective ring contraction
to provide oxazolidinone 6. A three-electron-three-center
mechanism is proposed.
Sch em e 2
During a study on the iodocyclocarbamation reactions
of 1-acyl-2-alkenyl-1,2,3,6-tetrahydropyridines,1 a related
cyclization of 2-styryl-4-piperidones was examined. The
Grignard reagent 1, prepared from trans-â-bromostyrene,
was added to 4-methoxypyridine and benzyl chlorofor-
mate in THF to provide 2,3-dihydro-4-pyridone 2 in 74%
yield2 (Scheme 1). Conjugate reduction with L-Selectride
(lithium tri-sec-butylborohydride) gave the 4-piperidone
3,1,3 which was subjected to the iodocyclocarbamation
reaction.4 Lithium carbonate and iodine were added to 3
in acetonitrile to give the cyclic carbamate 4 in 71% yield.
The stereochemistry of 4 was determined by 1H NMR (J ab
) 9.6 Hz, J bc ) 4.0 Hz).
This highly regio- and stereoselective cyclization can
be explained through the mechanism depicted in Scheme
2. Due to A(1,3) strain,5 the C-2 styryl group of 3 is axial.
Iodonium ion formation and subsequent attack by the
carbamate carbonyl of the Cbz group leads to the
observed product.
Sch em e 3
It was hoped that bicyclic carbamate 4 would be a
precursor to γ-amino alcohols such as the natural product
sedamine (5) (Scheme 3). To this end, attempts were
made to reductively remove the iodine from 4. When free-
radical conditions were used, either Et3B/Bu3SnH or
AIBN/Bu3SnH, the ring-contracted product 6 resulted in
70% and 65% yields, respectively. The rearrangement
proceeded with complete control of stereochemistry (1H
NMR, COSY, and NOESY). Although it has been re-
ported that halolactones can undergo radical ring con-
tractions,6 this is the first example of a corresponding
carbamate rearrangement. The ring contraction of 4 can
be rationalized as occurring via a three-electron-three-
center mechanism7 as depicted in Scheme 4.
Although this rearrangement presented itself as an
unanticipated event, it has potential value for the ste-
reocontrolled construction of alkaloid building blocks and
â-amino alcohols.
(1) Comins, D. L.; Williams, A. L. Tetrahedron Lett. 2000, 41, 2839.
(2) (a) Comins, D. L.; Brown, J . D. Tetrahedron Lett. 1986, 27, 4549.
(b) Comins, D. L.; J oseph, S. P.; Zhang, Y. Tetrahedron Lett. 1996, 37,
793.
(3) (a) Huang, S.; Comins, D. L. Chem. Commun. 2000, 569. (b)
Comins, D. L.; Hong, H. J . Org. Chem. 1993, 58, 5035 and references
cited therein.
(4) For related iodocyclocarbamation reactions, see: (a) Parker, K.
A.; O’Fee, R. J . Am. Chem. Soc. 1983, 105, 654, and references cited
therein. (b) Kozikowski, A. P.; Park, P.-u. J . Org. Chem. 1990, 55, 4668.
(5) Hoffman, R. W. Chem. Rev. 1989, 89, 1841. J ohnson, F. Chem.
Rev. 1968, 68, 375. Foley, M. A., Comins, D. L. J . Am. Chem. Soc. 1988,
110, 7445 and references cited therein.
Exp er im en ta l Section
All reactions described in this section were performed using
oven-dried glassware under an argon or dry nitrogen atmos-
(6) Crich, D.; Beckwith, A. L. J .; Filzen, G. F.; Longmore, R. W. J .
Am. Chem. Soc. 1996, 118, 7422.
(7) Lacoˆte, E.; Renaud, P. Angew. Chem., Int. Ed. 1998, 37, 2259
and references cited therein.
10.1021/jo0163290 CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/16/2002

Notes
J . Org. Chem., Vol. 67, No. 6, 2002 1973
Sch em e 4
phere. THF, toluene, and diethyl ether were dried by distillation
from sodium/benzophenone. Other reagents and solvents were
stored over molecular sieves under argon and used directly.
Radial PLC was done using a model 7924T Chromatotron
(Harrison Research, Palo Alto, CA) using thin layers of silica
gel-gypsum. Elemental analyses were performed by Atlantic
Microlabs, Norcross, GA.
1-(Ben zyloxyca r bon yl)-2-(2′-tr a n s-p h en yleth en yl)-2,3-d i-
h yd r o-4-p yr id on e (2). Magnesium turnings (0.75 g, 41.26
mmol) were mechanically stirred at rt overnight under argon,
and then 8 mL of anhydrous THF was added to the flask. Neat
trans-â-bromo-1-styrene (1.51 mL, 8.25 mmol) was added drop-
wise at rt. The mixture was stirred for 2 h at rt.
g, 9.05 mmol) and anhydrous iodine (0.97 g, 3.80 mmol). The
reaction mixture was stirred overnight at rt. Saturated aqueous
Na2CO3 (10 mL) was added and the solution was allowed to
warm to rt. The aqueous layer was extracted with diethyl ether.
The combined organic extracts were washed with 10% NaHSO3
and brine and were dried over anhydrous K2CO3. The solution
was filtered through Celite and concentrated in vacuo to give
the crude product. Purification by radial PLC (silica gel, 5-50%
EtOAc/hexanes) and recrystallization from CHCl3/hexane gave
473 mg (71%) of compound 4 as a yellow solid: mp 177-8 °C;
IR (KBr) 2848, 1754, 1707, 1684 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 7.41-7.26 (m, 5 H), 5.14 (d, 1 H, J ) 9.6 Hz), 4.75 (dd,
1 H, J ) 4.0 and 9.6 Hz), 4.24 (ddd, 1 H, J ) 1.6, 7.2 and 13.6
Hz), 4.05 (dt, 1 H, J ) 4.0 and 11.6 Hz), 3.20 (td, 1 H, J ) 4.4
and 13.2 Hz), 2.85 (dd, 1 H, J ) 4.0 and 14.0 Hz), 2.59-2.42 (m,
3 H); 13C NMR (75 MHz, CDCl3) δ 203.9, 155.2, 138.4, 129.3,
129.2, 128.3, 82.1, 59.9, 47.2, 40.5, 39.8, 32.6; HRMS calcd for
[C14H14INO3 + H] 372.0097 [(M + H)+], found 372.0092.
To a solution of 4-methoxypyridine (0.75 g, 6.88 mmol) in 100
mL of anhydrous THF at -23 °C was added dropwise benzyl
chloroformate (1.03 mL, 7.22 mmol). The reaction mixture was
stirred at -23 °C for 1.5 h. The previously prepared Grignard
reagent was transferred dropwise via a double-tipped stainless
steel needle to the flask containing the N-acylpyridinium salt,
and the mixture was stirred at -23 °C for 2 h. Saturated
aqueous oxalic acid (30 mL) was added. The reaction mixture
was warmed to rt and stirred for 2 h. The aqueous layer was
extracted with diethyl ether. The combined ether extracts were
washed with saturated aqueous Na2CO3 and brine and were
dried over anhydrous K2CO3. Filtration through Celite and
concentration in vacuo gave the crude product. Purification by
radial PLC (silica gel, 5-20% EtOAc/hexanes) yielded 1.70 g
(74%) of 2 as a white solid: mp 107-8 °C; IR (KBr) 2964, 2895,
1726, 1670 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.83 (d, 1 H, J )
8.2 Hz), 7.39-7.27 (m, 10 H), 6.50 (d, 1 H, J ) 15.5 Hz), 6.21
(dd, 1 H, J ) 6.7 and 18.0 Hz), 5.41-5.24 (m, 4 H), 2.97 (dd, 1
H, J ) 6.9 and 16.6 Hz), 2.63 (d, 1 H, J ) 16.6 Hz); 13C NMR
(75 MHz, CDCl3) δ 192.4, 152.7, 141.8, 135.9, 135.1, 133.3, 128.9,
128.8, 128.7, 128.4, 126.8, 123.8, 107.7, 69.4, 55.1, 40.7. Anal.
Calcd for C21H19NO3: C, 75.66; H, 5.74; N, 4.20. Found; C, 75.73;
H, 5.78; N, 4.18.
1-(Ben zyloxyca r bon yl)-2-(2′-tr a n s-p h en yleth en yl)-4-p i-
p er id on e (3). L-Selectride (1.50 mL, 1.50 mmol, 1 M in THF)
was added dropwise to a -78 °C solution of dihydropyridone 2
(0.50 g, 1.50 mmol) in 10 mL of anhydrous THF. The resulting
mixture was stirred at -78 °C for 1 h and then poured into 10
mL of saturated aqueous Na2CO3 at 0 °C. The mixture was
allowed to warm to rt, and the aqueous layer was extracted with
diethyl ether (3 × 10 mL). The combined organic extracts were
washed with brine, dried over anhydrous K2CO3, filtered through
Celite, and concentrated in vacuo to give the crude product.
Purification by radial PLC (silica gel, 5-30% EtOAc/hexanes)
gave 430 mg (85%) of piperidone 3 as a clear oil: IR (neat) 2966,
2919, 1689, 1595 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.40-7.21
(m, 10 H), 6.48 (d,1 H, J ) 15.5 Hz), 6.12 (dd, 1 H, J ) 6.7 and
18.0 Hz), 5.40 (b s, 1 H), 5.21 (s, 2 H), 4.29 (m, 1 H), 3.43 (m, 1
H), 2.83-2.30 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 207.0, 155.5,
136.5, 136.2, 133.0, 128.8, 128.6, 128.4, 128.3, 127.3, 126.8, 68.0,
53.5, 44.4, 40.7, 39.6. Anal. Calcd for C21H21NO3: C, 75.20; H,
6.31; N, 4.18. Found; C, 75.21; H, 6.37; N, 4.17.
6-Aza -8-oxa -9-ben zylbicyclo[4.3.0]n on a n e-3,7-d ion e (6).
To a stirred cloudy solution of compound 4 (0.075 g, 0.202 mmol)
in 5 mL of toluene at rt were added tributyltin hydride (0.12
mL, 0.446 mmol) and Et3B (0.02 mL, 0.02 mmol, 1.0 M in
hexane). The reaction mixture was stirred for 30 min and then
diluted with EtOAc (7 mL). Saturated aqueous KF (1 mL) and
anhydrous KF (0.5 g) were added, and the mixture was stirred
for 30 min at rt. The mixture was filtered, and the filtrate was
washed with brine, dried over anhydrous MgSO4, and concen-
trated in vacuo. The crude product was purified by radial PLC
(silica gel, 5-30% EtOAc/hexanes) to give 34.6 mg (70%) of 6 as
a white solid: mp 139-40 °C; IR (KBr) 2923, 1755, 1717 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.35-7.19 (m, 5 H), 4.41 (ddd, 1
H, J ) 5.2, 7.6 and 11.2 Hz), 4.19 (ddd, 1 H, J ) 1.6, 7.6 and
13.4 Hz), 3.68 (dt, 1 H, J ) 4.8 and 11.2 Hz), 3.21 (dd, 1 H, J )
5.6 and 13.8 Hz), 3.12 (td, 1 H, J ) 4.4 and 11.6 Hz), 2.91 (dd,
1 H, J ) 7.6 and 13.8 Hz), 2.58-2.46 (m, 1 H), 2.40-2.36 (m, 1
H), 2.30 (dd, 1 H, J ) 11.6 and 14.0 Hz), 2.19 (ddd, 1 H, J ) 1.6,
4.4 and 14.0 Hz); 13C NMR (75 MHz, CDCl3) δ 204.3, 159.0,
134.3, 129.2, 128.9, 127.5, 80.3, 58.4, 45.9, 40.1, 39.7; HRMS
calcd for C14H15NO3 245.1052 (M+), found 245.1061.
Ack n ow led gm en t. We express appreciation to the
National Institutes of Health (Grant GM 34442) for
financial support of this research. A.L.W. also thanks
the NIH for a Minority Graduate Research Assistant-
ship. We thank the Spanish Government (Ministerio de
Educacio´n, Cultura y Deportes) for fellowship support
to T.A.G. NMR and mass spectra were obtained at
NCSU instrumentation laboratories, which were estab-
lished by grants from the North Carolina Biotechnology
Center and the National Science Foundation (Grants
CHE-9509532 and CHE-0078253).
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for 4 and 6. This material is available free of
charge via the Internet at http://pubs.acs.org.
(4R*,5S*,6S*)-1-Aza -5-iod o-3-oxa -4-p h en ylbicyclo[4.4.0]-
d eca n e-2,8-d ion e (4). To a flask covered with aluminum foil,
a solution of piperidone 3 (0.61 g, 1.81 mmol) in 17 mL of
anhydrous acetonitrile at rt was added along with Li2CO3 (0.67
J O0163290