Regiochemistry in radical cyclizations (5-endo versus 4-exo) of N-(2-phenylthio- and 2-phenylcyclohex-1-enyl)-α-halo amides

Article abstract of DOI:10.1016/S0040-4020(01)00747-5

Bu₃SnH-mediated radical cyclization of N-(2-phenylthiocyclohex-1-enyl)-α-halo amides was examined. Bromoacetamide 9a having no substituent α to the halogen atom cyclized exclusively in a 4-exo-trig manner, whereas the fully substituted haloamides 9c and 9e gave 5-endo-trig cyclization products. The mono-substituted haloamides 9b and 9d showed an intermediate behavior to give a mixture of 4-exo and 5-endo cyclization products. The results of experiments on the effect of reaction temperature indicated that at a low temperature, i.e. under kinetically controlled conditions, 4-exo-trig cyclization predominated. On the other hand, the 2-phenylcyclohex-1-enyl congeners 22b and 22c gave exclusively 5-endo cyclization products.

Full text of DOI:10.1016/S0040-4020(01)00747-5

TETRAHEDRON
Pergamon
Tetrahedron 57 ,2001) 7629±7637
Regiochemistry in radical cyclizations ꢀ5-endo versus 4-exo) of
N-ꢀ2-phenylthio- and 2-phenylcyclohex-1-enyl)-a-halo amides
Hiroyuki Ishibashi,a,p Kazuya Kodama,a Masahiro Higuchi,a Osamu Muraoka,b Genzoh Tanabeb
and Yoshifumi Takedaa
aFaculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920-0934, Japan
bFaculty of Pharmaceutical Sciences, Kinki University, Kowakae, Higashi-osaka, Osaka 577-0818, Japan
Received 22 June 2001; accepted 19 July 2001
AbstractÐBu3SnH-mediated radical cyclization of N-,2-phenylthiocyclohex-1-enyl)-a-halo amides was examined. Bromoacetamide 9a
having no substituent a to the halogen atom cyclized exclusively in a 4-exo-trig manner, whereas the fully substituted haloamides 9c and 9e
gave 5-endo-trig cyclization products. The mono-substituted haloamides 9b and 9d showed an intermediate behavior to give a mixture of
4-exo and 5-endo cyclization products. The results of experiments on the effect of reaction temperature indicated that at a low temperature,
i.e. under kinetically controlled conditions, 4-exo-trig cyclization predominated. On the other hand, the 2-phenylcyclohex-1-enyl congeners
22b and 22c gave exclusively 5-endo cyclization products. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
concerned with regioselection of radical cyclizations, we
became interested in the modes of cyclization ,5-endo
versus 4-exo) of a series of N-,2-phenylthiocyclohex-1-
enyl)-a-halo amides 9a±e and their 2-phenyl congeners
22a±c. This paper describes the results of our work in this
area3 ,Scheme 1).
Previous studies in our laboratory have revealed that
N-,cyclohex-1-enyl)-a-halo amides 1, upon treatment with
Bu3SnH in the presence of AIBN, undergo radical cycli-
zation in a 5-endo-trig manner to give ®ve-membered
lactams 3 via the intermediate radicals 2.1 a-Halo amides
4 having a phenylthio group at the terminus of their
N-vinylic bond, however, cyclized in a 4-exo-trig manner
to give b-lactams 6.2 Formation of 6 from 4 may be
explained in terms of the high stability of the intermediary
sulfur-substituted radicals 5. As part of our program
2. Results and discussion
2-Phenythio-substituted radical precursors 9a±e were
prepared by condensation of 2-,phenylthio)cyclohexanone
,7) with benzylamine followed by acylation of the resulting
imine 8 with appropriate acyl halides ,Scheme 2).
Treatment of a-bromoacetamide 9a with Bu3SnH in the
presence of AIBN in boiling toluene gave a complex
mixture of products, from which the unexpected product
Scheme 1.
Keywords: radicals and radical reactions; azetidinones; lactams; electron
transfer.
p
Corresponding author. Tel.: 181-76-234-4474; fax: 181-76-234-4476;
e-mail: isibasi@dbs.p.kanazawa-u.ac.jp
Scheme 2.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020,01)00 747-5

7630
H. Ishibashi et al. / Tetrahedron 57 12001) 7629±7637
Scheme 6.
Scheme 3.
³
AIBN in boiling benzene to give b-lactam 12 and g-lactam
13 in 31 and 13% yields, respectively, along with the reduc-
tion product 14 ,40%) ,Scheme 5). On the other hand,
2-bromo-2-methylpropanamide 9c gave only the ®ve-
membered lactams 15 and 16 in 39 and 24% yields, respec-
tively, together with the reduction product 17 ,3%).
10 and simple reduction product 11 were isolated in 16 and
8% yields, respectively ,Scheme 3).
²
The IR spectrum of 10 showed bands at 3420and
1660cm 21, which were clearly indicative of a secondary
amide. The H NMR spectrum of 10 exhibited a signal
1
due to the protons a to the carbonyl group at d 3.40as a
singlet and that due to the benzylic protons at d 4.39 as a
doublet ,Jˆ5.6 Hz). When 9a was treated with Bu3SnD, the
deuterated compound 100 was obtained as a mixture
containing 10 in a ratio of ca. 3:2, together with the deuter-
ated reduction product 110. Formation of 10 from 9a may
therefore be explained as outlined in Scheme 4. Thus, the
carbamoylmethyl radical Ia, formed from 9a, cyclizes in a
4-exo-trig manner to give the sulfur-stabilized radical IIa.
This step is then followed by a ring-opening to give amidyl
radical III. A subsequent 1,5-hydrogen shift gives the allylic
radical IV, which is then trapped by Bu3SnH to give 10. A
partial, direct attack of Bu3SnH on III also gives 10.
The structures of 12, 13, 15 and 16 were deduced from their
spectroscopic evidence. The IR spectrum of 12 showed a
band at 1730cm 21 ascribable to b-lactam, and its 1H NMR
spectrum exhibited three doublets ,Jˆ7.6 Hz) due to methyl
protons at d 1.31, 1.32 and 1.59, respectively, indicating
that compound 12 is a mixture of three diastrereoisomers.
On the other hand, the IR spectrum of 13 showed bands at
1700 and 1670 cm21 and the IR spectrum of 15 showed
bands at 1700 and 1675 cm21, and their 1H NMR spectrum
exhibited a signal due to methyl protons of 13 as a doublet
,Jˆ7.9 Hz) at d 1.27 and that due to two methyl protons of
15 as a singlet at d 1.18. The IR spectrum of 16 showed
1
bands at 1715 and 1675 cm21, and its H NMR spectrum
exhibited signals due to two methyl protons at d 1.00 and
1.26 as a singlet, respectively, and that due to 7a-H as
2-Chloropropanamide 9b was next treated with Bu3SnH±
Scheme 4.
Scheme 5.
³
The reactions of 9b,c in boiling toluene afforded a complex mixture of
products.
²
Another unidenti®ed product was also obtained.

H. Ishibashi et al. / Tetrahedron 57 12001) 7629±7637
Table 1. Formation of 18 and 19 from 9d
7631
Entrya
Hydride
Solvent Temperature ,8C) Yield ,%) 18:19
18 19
1:2.2
1
2
Bu3SnH
Bu3SnH
,Me3Si)3SiH Toluene
,Me3Si)3SiH Benzene
Toluene
Benzene
11018
8043
39
35
32
14
1.2:1
1:1.7
2.1:1
Scheme 7.
3
11019
8029
4b
double doublets ,Jˆ6.3 and 3.0Hz) at d 4.79. However, the
exact stereochemistry of the ring-juncture is unknown
,probably cis).
a
AIBN was used as a radical initiator except for in entry 3 [ACN, azobis-
,cyclohexanecarbonitrile), was used].
35% of 9d was recovered.
b
Formation of 12 from enamide 9b can be explained simply
in terms of an attack of Bu3SnH on the sulfur-substituted
intermediate radical IIb formed by a 4-exo-trig cyclization
of carbamoylmethyl radical Ib ,Scheme 6). On the other
hand, 5-endo-trig cyclization of radical Ib provides radical
Vb, which then undergoes an elimination of benzenethiyl
radical to give 13. A similar sequence of the reactions of
radical Vc, generated from 9c via Ic, gives 15. An attack of
Bu3SnH on the radical center of Vc gives 16.
elimination of benzenethiyl radical to give hexahydro-
indolone VId. An attack of tributyltin radical ,Bu3Snz) on
the chlorine atom of VId followed by a single electron
transfer ,SET) reaction of the resulting radical VIId ,or
VIId0) would give acyliminium ion VIIId. A subsequent
deprotonation gives the observed 19. The SET reaction of
VIId ,or VIId0) probably occurs toward dichloroacetamide
9d, which then produces new carbamoylmethyl radical Id.4
The above results suggest that the size of the substituents
around the radical center strongly affects the mode of cycli-
zation. Thus, radicals Ia ,formed from 9a) and Ib ,formed
from 9b) having no substituent or a small substituent,
cyclizes predominantly in a 4-exo-trig manner, whereas
radical Ic ,formed from 9c) with sterically more-demanding
groups, cyclizes exclusively in a 5-endo-trig manner to give
®ve-membered lactams 15 and 16.
Interestingly, when the reaction of 9d with Bu3SnH±AIBN
was carried out in benzene in place of toluene as a solvent,
an increase in the yield of the 4-exo cyclization product 18
was observed with a decrease in the amount of the 5-endo
cyclization product 19 ,compare entries 1 and 2 in Table 1).
This was also the case for the use of ,Me3Si)3SiH as a
hydride in boiling toluene or benzene ,compare entries 3
and 4 in Table 1). These results suggest that the radical
cyclization of 9d at a low temperature ,in boiling benzene)
occurs preferentially in a 4-exo-trig manner, whereas at
much higher temperature ,in boiling toluene), 5-endo-trig
cyclization predominates. Strong support for this assump-
tion was obtained by the cyclization of trichloroacetamide
9e.
Treatment of dichloroacetamide 9d with Bu3SnH and AIBN
in boiling toluene gave b-lactam 18 and tetrahydroindolone
19 in 18 and 39% yields, respectively, ,Scheme 7). The H
1
NMR spectrum of 18 exhibited a signal due to the proton a
to the sulfur atom at d 3.36 as double doublets ,Jˆ12.5 and
3.6 Hz) and a signal due to the proton a to the chlorine atom
at d 5.13 as a singlet, indicating that it is a single dia-
stereoisomer, though the exact stereochemistry is unknown.
Compound 9e, upon treatment with Bu3SnH±AIBN in
boiling toluene, gave the 5-endo cyclization product 20 as
a sole product in 84% yield ,Scheme 9). On the other hand,
when compound 9e was treated with Bu3SnH at room
temperature using triethylborane as a radical initiator, only
b-lactam 21 was obtained in 35% yield along with the
recovered 9e ,15%) and its partially dechlorinated product
9d ,10%). The IR spectrum of 21 showed two carbonyl
bands at 1790, b-lactam) and 1725 cm21 ,ketone). A similar
reaction of 9e with Bu3SnH±Et3B in boiling toluene,
1
The H NMR spectrum of 19 exhibited signals due to two
ole®nic protons at d 5.51 as double triplets ,Jˆ4.6
and 1.7 Hz, 7-H) and at d 5.81 as a broad singlet ,3-H),
respectively.
Formation of 19 would involve 5-endo-trig cyclization of
radical Id formed from 9d, leading to the intermediate
radical Vd ,Scheme 8). This step is then followed by an
Scheme 8.

7632
H. Ishibashi et al. / Tetrahedron 57 12001) 7629±7637
Scheme 9.
however, gave, again, the 5-endo cyclization product 20 in
51% yield along with the recovered 9e ,24%).§
Compound 20 might arise from the radical intermediate Ve,
formed by 5-endo cyclization of carbamoylmethyl radical Ie
,Scheme 10), by a sequence of reactions similar to that
described above for the formation of 19 from Vd ,Scheme
8). Formation of 21 may be explained as proceeding via
the 4-exo cyclization of radical Ie followed by an attack
of molecular oxygen on the intermediate radical IIe. A
subsequent reduction of the resulting hydroperoxide IX
with Bu3SnH gives ketone 21.
Scheme 11.
group.7 We therefore turned our attention to the behavior of
the reactions of enamide 22a±c having a phenyl group at the
2-position of the N-cyclohex-1-enyl group.
When monobromo enamide 22a was treated with Bu3SnH±
AIBN in boiling benzene, no cyclization product was
detected, and only the simple reduction product 23 was
obtained in 48% yield ,Scheme 11). On the other hand, a
similar reaction of dichloro enamide 22b afforded the
5-endo cyclization product 24 and the reduction product
25 in 63 and 29% yields, respectively.
One possible explanation for the results observed for 9e may
be derived from consideration of the reversibility of 4-exo
cyclization. At a low temperature, i.e. under kinetically
controlled conditions, radical Ie cyclizes predominantly in
a 4-exo-trig manner to give radical IIe. However, at a high
temperature, ring-opening of radical IIe rapidly occurs, and
the resulting radical Ie cyclizes in a 5-endo-trig manner to
give radical Ve.5,6 Subsequent elimination of benzenethiyl
radical from Ve would immediately occur, and hence the
5-endo cyclization of Ie to Ve might be irreversible. This
may also be the case for radical Id generated from 9d
,Scheme 8). The 4-exo cyclization product 18, however,
was formed from 9d in substantial quantity even at a higher
temperature. This is probably because the starting mono-
chloro-substituted radical Id is less stable than the
dichloro-substituted radical Ie, thereby reducing the ability
of ring-opening of IId±Id. This assumption might be
applicable to rationalization for the difference between the
modes of cyclization of the monomethyl substituted halide
9b and dimethyl substituted halide 9c.
Formation of 24 from 22b may involve 5-endo cyclization
of the carbamoylmethyl radical X followed by a SET reac-
tion of the resulting radical XI, yielding the cation XII
,Scheme 12). This step is then followed by deprotonation
and subsequent reductive dechlorination of the resulting
unsaturated lactam 26 with Bu3SnH to give 24.
If the above mechanism for the formation of 24 is correct,
Bu3SnH would work mainly for the dechlorination of 26.
We therefore examined a similar reaction using a reduced
amount ,0.5 equiv.) of Bu3SnH in the hope that compound
26 would be produced. These conditions, however, resulted
in recovery of a large amount ,64%) of the starting material
22b, although a small amount of the expected product 26a
,2% yield) was obtained with the formation of 24 ,22%
yield) and 25 ,6% yield). This result indicates that
Bu3SnH is rapidly consumed for reducing chlorides 26.
Carbon radicals are also stabilized by an adjacent phenyl
Scheme 10.
§
Treatment of 9d with Bu3SnH in the presence of Et3B at room tempera-
ture resulted in recovery of the starting material.

H. Ishibashi et al. / Tetrahedron 57 12001) 7629±7637
7633
Scheme 12.
,20%) and its stereoisomer 26b ,7%) and small quantities
of the reduction products 22b and 25 were identi®ed. No
4-exo cyclization product was detected in the reaction
mixture. No formation of the 4-exo cyclization product is
probably because the intermediate radical like IIb ,Scheme
6) is not suf®ciently stabilized by an adjacent phenyl group
due to free rotation of its aromatic p-system. The reason for
the formation of the stereoisomer 26b together with 26a at
room temperature in the presence of Et3B is obscure at the
moment.
In summary, the results described herein suggest that a
4-exo cyclization is essentially a favored process over a
5-endo cyclization for the ring-closure of carbamoylmethyl
radicals, regardless of the nature of the substituent on the
radical center. The product distributions, however, appear to
depend on the relative stability between the initial carba-
moylmethyl radicals and cyclized intermediate radicals.
Figure 1. X-Ray structure of compound 26a.
The structure of 26a was established by X-ray crystallo-
graphic analysis. This compound seems to be an unstable
form because the relative stereochemistry between the
chlorine atom and the angular phenyl group is a cis-relation-
ship. This result can be explained by assuming that the
trans-isomer 26b must be also formed in the course of the
reaction and that reductive dechlorination of 26b with
Bu3SnH occurs much faster than does that of 26a. An Attack
of tributyltin radical on the chlorine atom of the cis-isomer
26a must be retarded by the presence of the adjacent angular
phenyl group, whereas no remarkable steric hindrance is
present in compound 26b ,Fig. 1).
3. Experimental
3.1. General
Melting points are uncorrected. IR spectra were recorded
with a Shimadzu FTIR-8100 spectrophotometer for solu-
tions in CHCl3. 1H NMR spectra were measured on a
JEOL JNM-EX 270spectrometer for solutions in CDCl .
3
d Values quoted are relative to tetramethylsilane. High
resolution mass spectra ,HRMS) were obtained with a
JEOL JMS-SX 102 instrument. Column chromatography
was performed on Silica gel 60PF
under pressure.
,Nacalai Tesque)
The reaction of trichloroacetamide 22c with Bu3SnH±AIBN
in boiling benzene gave the 5-endo cyclization product 26a
in a high yield ,89%) ,Scheme 13). Formation of 26a from
22c can be considered to proceed via a pathway similar to
that described above for 24 from 22b via radical X ,Scheme
12). When Bu3SnH attacks the radical center of XIII so as to
avoid a steric repulsion between the phenyl group at the
3a-position of XIII, this might result in the formation of
the observed 26a.
254
3.2. Preparation of N-benzyl-2-halo-N-ꢀ2-phenylthio-
cyclohex-1-enyl)acetamides 9a±e
3.2.1. N-Benzyl-2-bromo-N-ꢀ2-phenylthiocyclohex-1-enyl)-
acetamide ꢀ9a). A mixture of 2-,phenylthio)cyclohexanone
,7) ,1.53 g, 7.42 mmol), benzylamine ,662 mg, 6.18 mmol)
and a catalytic amount of p-toluenesulfonic acid in toluene
,70mL) was heated under re¯ux with azeotropic removal
of water for 4 h. After the solvent had been evaporated
off, the residue containing the imine 8 was dissolved in
In order to determine the effect of temperature on the mode
of cyclization of 22c, compound 22c was next treated with
Bu3SnH at room temperature using triethylborane as a
radical initiator. These conditions gave a complex mixture
of products, from which 5-endo cyclization product 26a
Et2O ,70mL). DMAP ,79 mg, 0.65 mmol) and Et N
3
,626 mg, 6.19 mmol) were added to the mixture, and then
Scheme 13.

7634
H. Ishibashi et al. / Tetrahedron 57 12001) 7629±7637
bromoacetyl bromide ,1.39 g, 6.88 mmol) was added slowly
to the mixture at 08C. After the mixture was stirred at room
temperature for 15 h, the reaction mixture was washed with
water. The organic phase was dried ,MgSO4) and concen-
trated, and the residue was chromatographed on silica gel
[hexane±AcOEt ,10:1)] to give 9a ,1.74 g, 68%) as an oil:
IR n 1655 cm21; 1H NMR d 1.40±1.66 ,m, 4H), 1.87±2.24
,m, 4H), 3.93 ,d, Jˆ11.4 Hz, 1H, one of COCH2), 4.08 ,d,
Jˆ11.4 Hz, 1H, one of COCH2), 4.50,d, Jˆ14.5 Hz, 1H,
one of NCH2), and 5.05 ,d, Jˆ14.5 Hz, 1H, one of NCH2),
7.19±7.40,m, 1H0 ). HRMS Calcd for C 21H2279BrNOS:
415.0605. Found: 415.0609.
5.09 ,d, Jˆ14.2 Hz, 1H, one of NCH2), 6.41 ,s, 1H, COCH),
7.25±7.40,m, 10H). Anal. Calcd for C 21H21Cl2NOS: C,
62.07; H, 5.21; N, 3.45. Found: C, 62.12; H, 5.18; N, 3.45.
3.2.5. N-Benzyl-2,2,2-trichloro-N-ꢀ2-phenylthiocyclohex-
1-enyl)acetamide ꢀ9e). Using a procedure similar to that
described above for 9a, the crude imine 8, prepared from
2-,phenylthio)cyclohexanone ,2.70g, 13.1 mmol) and
benzylamine ,1.0g, 9.33 mmol), was treated with trichloro-
acetyl chloride ,2.54 g, 14.0mmol) in the presence of
DMAP ,113 mg, 0.93 mmol) and Et3N ,1.42 g, 14.0
mmol). After work-up, the crude material was chromato-
graphed on silica gel [hexane±AcOEt ,5:1)] to give 9e
,1.94 g, 47%), mp 80±818C ,from hexane): IR
n
3.2.2. N-Benzyl-2-chloro-N-ꢀ2-phenylthiocyclohex-1-enyl)-
propanamide ꢀ9b). Using a procedure similar to that
described above for 9a, the crude imine 8, prepared from
2-,phenylthio)cyclohexanone ,1.48 g, 7.17 mmol) and
benzylamine ,846 mg, 7.17 mmol), was treated with
2-chloropropionyl chloride ,1.0g, 7.89 mmol) in the
presence of DMAP ,96 mg, 0.79 mmol) and Et3N
,799 mg, 7.89 mmol). After work-up, the crude material
was chromatographed on silica gel [hexane±AcOEt
,10:1)] to give 9b ,1.56 g, 58%) as a mixture of two
rotamers in a ratio of 5:1, mp 94±958C ,from hexane±
1
1675 cm21; H NMR d 1.30±1.60 ,m, 4H), 1.95±2.1 ,m,
4H), 4.93 ,br d, Jˆ14.4 Hz, 1H, one of NCH2), 5.48 ,br d,
Jˆ14.4 Hz, 1H, one of NCH2), 7.22±7.52 ,m, 10H). Anal.
Calcd for C21H20Cl3NOS: C, 57.22; H, 4.57; N, 3.18. Found:
C, 57.24; H, 4.55; N, 2.99.
3.3. Radical cyclization of 9a±c
3.3.1. Radical cyclization of 9a with Bu3SnH±AIBN.
General procedure. To a boiling solution of 9a ,289 mg,
0.69 mmol) in toluene ,300 mL) was added dropwise a solu-
tion of Bu3SnH ,222 mg, 0.76 mmol) and AIBN ,37 mg,
0.08 mmol) in toluene ,100 mL) via a syringe during 5 h,
and the mixture was further heated under re¯ux for 3 h.
After evaporation of the solvent, Et2O ,50mL) and 8%
aqueous KF ,20mL) were added to the residue, and the
whole was vigorously stirred at room temperature for 1 h.
The organic layer was separated and the aqueous layer was
further extracted with Et2O. The combined organic phase
was dried ,MgSO4) and concentrated, and the residue was
chromatographed on silica gel [hexane±AcOEt ,10:1)]. The
®rst fraction gave N-benzyl-2-,2-phenylthiocyclohex-1-
enyl)acetamide ,10) ,38 mg, 16%) as an oil: IR n 3420,
1
AcOEt): IR n 1665 cm21; H NMR d 1.40±1.66 ,m, 4H),
1.71 ,d, Jˆ6.4 Hz, 1/6£3H, Me), 1.76 ,d, Jˆ6.4 Hz,
5/6£3H, Me), 1.90±2.08 [m, ,311/6)H], 2.25±2.33 ,m,
5/6H), 4.31 ,d, Jˆ14.2 Hz, 1/6H, one of NCH2), 4.46 ,d,
Jˆ14.2 Hz, 5/6H, one of NCH2), 4.64 ,q, Jˆ6.6 Hz, 1/6H,
COCH), 4.74 ,q, Jˆ6.6 Hz, 5/6H, COCH), 5.09 ,d, Jˆ
14.2 Hz, 5/6H, one of NCH2), 5.36 ,d, Jˆ14.2 Hz, 1/6H,
one of NCH2), 7.18±7.38 ,m, 10H). Anal. Calcd for
C22H24ClNOS: C, 68.46; H, 6.27; N, 3.63. Found: C,
68.52; H, 6.27; N, 3.40.
3.2.3. N-Benzyl-2-bromo-2-methyl-N-ꢀ2-phenylthiocyclo-
hex-1-enyl)propanamide ꢀ9c). Using a procedure similar
to that described above for 9a, the crude imine 8, prepared
from 2-,phenylthio)cyclohexanone ,5.0g, 24.2 mmol)
and benzylamine ,1.6 mg, 15.0mmol), was treated with
2-bromoisobutyryl bromide ,4.48 g, 19.5 mmol) in the
presence of DMAP ,200 mg, 1.64 mmol) and Et3N
,1.66 mg, 16.5 mmol). After work-up, the crude material
was chromatographed on silica gel [hexane±AcOEt
1
1660cm 21; H NMR d 1.54±1.77 ,m, 4H), 2.20,br s,
2H), 2.34 ,br s, 2H), 3.40,s, 2H, COCH ), 4.39 ,d, Jˆ
2
5.6 Hz, 2H, NCH2), 6.00 ,br, 1H, NH), 7.11±7.45 ,m,
10H). HRMS Calcd for C21H23NOS: 337.1501. Found:
337.1501. The second fraction gave N-benzyl-N-,2-
phenylthiocyclohex-1-enyl)acetamide ,11) ,19 mg, 8%) as
1
an oil: IR n 1645 cm21; H NMR d 1.50±1.62 ,m, 4H),
,20:1)] to give 9c ,4.60g, 69%) as an oil: IR
n
1.85±2.20,m, 4H), 2.11 ,s, 3H, COMe), 4.37 ,d, Jˆ
14.4 Hz, 1H, one of NCH2), 5.15 ,d, Jˆ14.4 Hz, 1H, one
of NCH2), 7.16±7.40,m, 1H0). HRMS Calcd for
C21H23NOS: 337.1500. Found: 337.1492.
1
1630cm 21; H NMR d 1.20±1.70 ,m, 4H), 2.0±2.7 ,br,
4H), 2.11 ,s, 6H), 4.11 ,br, 1/2H, one of NCH2), 4.80,br,
1/2H, one of NCH2), 5.62 ,br d, Jˆ14.2 Hz, 1H, one of
NCH2), 7.20±7.50 ,m, 10H). HRMS ,FAB) Calcd for
C23H2779BrNOS [,M1H)1]: 444.0997. Found: 444.0969.
3.3.2. Radical cyclization of 9a with Bu3SnD±ACN.
Following the general procedure, compound 9a ,149 mg,
0.36 mmol) was treated with Bu3SnD ,126 mg, 0.43
mmol) and azobis,cyclohexanecarbonitrile) ,ACN) ,22 mg,
0.09 mmol) in boiling toluene. After work-up, the crude
material was chromatographed on silica gel [hexane±
AcOEt ,4:1)]. The ®rst fraction gave a mixture of N-benzyl-
2-,2-phenylthiocyclohex-1-enyl)acetamide ,10) and its
2-phenylthio-6-deuterocyclohex-1-enyl derivative 100
3.2.4. N-Benzyl-2,2-dichloro-N-ꢀ2-phenylthiocyclohex-1-
enyl)acetamide ꢀ9d). Using a procedure similar to that
described above for 9a, the crude imine 8, prepared from
2-,phenylthio)cyclohexanone ,2.99 g, 14.5 mmol) and
benzylamine ,1.20g, 11.2 mmol), was treated with
dichloroacetyl chloride ,2.15 g, 14.6 mmol) in the presence
of DMAP ,178 mg, 1.46 mmol) and Et3N ,1.48 g,
14.6 mmol). After work-up, the crude material was
chromatographed on silica gel [hexane±AcOEt ,10:1)] to
give 9d ,1.94 g, 47%), mp 81±828C ,from hexane±
1
,16 mg) as an oil. The H NMR spectrum of the mixture
showed a decrese in an integrated intensity of the peak
height of a broad singlet at d 2.34 due to the 6-position of
2-phenylthiocyclohex-1-enyl group of 10, which indicated
the ratio of 10 and 100 to be ca. 2:3. The second fraction
1
AcOEt): IR n 1680cm 21; H NMR d 1.40±1.65 ,m, 4H),
1.85±2.20,m, 4H), 4.51 ,d, Jˆ14.2 Hz, 1H, one of NCH2),

H. Ishibashi et al. / Tetrahedron 57 12001) 7629±7637
7635
gave N-benzyl-2-deutero-N-,2-phenylthiocyclohex-1-enyl)-
acetamide ,110) ,31 mg) as an oil, whose 1H NMR spectrum
indicated that an integrated intensity of the peak height of
the signal due to the acetyl methyl protons of 11 at d 2.11
was reduced to two-thirds.
NCH2), 5.31 ,d, Jˆ14.5 Hz, 1H, one of NCH2), 7.25±7.45
,m, 10H). HRMS Calcd for C23H27NOS: 365.1813. Found:
365.1792. The third fraction gave 1-benzyl-1,3,4,5,6,7-
hexahydro-3,3-dimethylindol-2-one ,15)8 ,36 mg, 39%) as
1
an oil: IR n 1700, 1675 cm21; H NMR d 1.18 ,s, 6H,
2£Me), 1.60±1.70 ,m, 4H), 1.90±2.10 ,m, 4H), 4.63 ,s,
2H, NCH2), 7.15±7.40,m, 5H). HRMS Calcd for
C17H21NO: 255.1623. Found: 255.1623.
3.3.3. Radical cyclization of 9b with Bu3SnH±AIBN.
Following the general procedure, compound 9b ,150mg,
0.39 mmol) was treated with Bu3SnH ,125 mg,
0.43 mmol) and AIBN ,20 mg, 0.12 mmol) in boiling ben-
zene. After work-up, the crude material was chromato-
graphed on silica gel [hexane±AcOEt ,4:1)]. The ®rst
fraction gave N-benzyl-N-,2-phenylthiocyclohex-1-enyl)-
3.4. Radical cyclization of 9d
3.4.1. Entry 1 in Table 1. Following the general procedure,
compound 9d ,300 mg, 0.74 mmol) was treated with
Bu3SnH ,236 mg, 0.81 mmol) and AIBN ,40 mg,
0.24 mmol) in boiling toluene. After work-up, the crude
material was chromatographed on silica gel [hexane±
AcOEt ,10:1)]. The ®rst fraction gave 1-benzyl-3-chloro-
5-phenylthio-1-azaspiro[3.5]nonan-2-one ,18) ,50mg,
18%) as a single stereoisomer, mp 110.5±111.58C ,from
propanamide ,14) ,55 mg, 40%): IR n 1645 cm21 1H
;
NMR d 1.21 ,t, Jˆ7.4 Hz, 3H), 1.40±1.64 ,m, 4H), 1.83±
2.05 ,m, 4H), 2.16±2.32 ,m, 1H, one of COCH2), 2.36±2.52
,m, 1H, one of COCH2), 4.35 ,d, Jˆ14.3 Hz, 1H, one of
NCH2), 5.20,d, Jˆ14.3 Hz, 1H, one of NCH2), 7.20±7.40
,m, 10H). HRMS Calcd for C22H25NOS: 351.1657. Found:
351.1653. The second fraction gave 1-benzyl-1,3,4,5,6,7-
hexahydro-3-methylindol-2-one ,13) ,12 mg, 13%) as an
1
hexane±AcOEt): IR n 1760cm 21; H NMR d 1.10±1.30
,m, 2H), 1.35±1.62 ,m, 3H), 1.68±1.80,m, 1H), 1.85±1.96
,m, 1H), 2.15±2.30,m, 1H), 3.22 ,d, Jˆ15.7 Hz, 1H, one of
NCH2), 3.36 ,dd, Jˆ12.5, 3.6 Hz, 1H, 5-H), 4.22 ,d,
Jˆ15.7 Hz, 1H, one of NCH2), 5.13 ,s, 1H, 3-H), 7.10±
7.55 ,m, 10H). Anal. Calcd for C21H22ClNOS: C, 67.82;
H, 5.96; N, 3.77. Found: C, 68.09; H, 6.00; N, 3.73. The
second fraction gave 1-benzyl-1,4,5,6-tetrahydro-2H-indol-
2-one ,19)5 ,65 mg, 39%), mp 92±92.58C ,from hexane±
1
oil: IR n 1700, 1670 cm21; H NMR d 1.27 ,d, Jˆ7.9 Hz,
3H, Me), 1.60±1.75 ,m, 4H), 1.90±2.15 ,m, 4H), 2.83±2.98
,m, 1H, 3-H), 4.62 ,s, 2H, NCH2), 7.15±7.40,m, 5H).
HRMS Calcd for C16H19NO: 241.1466. Found: 241.1464.
The third fraction gave one isomer of 1-benzyl-3-methyl-5-
phenylthio-1-azaspiro[3.5]nonan-2-one ,12) ,20mg, 15%)
1
as an oil: IR n 1730cm 21; H NMR d 1.10±1.80 ,m, 7H),
1
AcOEt) ,lit.5 mp 948C): IR n 1680cm 21; H NMR d 1.79
1.32 ,d, Jˆ7.6 Hz, 3H, Me), 2.10±2.20 ,m, 1H), 3.29 ,dd,
Jˆ11.9, 3.6 Hz, 1H, 5-H), 3.44 ,q, Jˆ7.6 Hz, 1H, 3-H), 3.46
,d, Jˆ15.7 Hz, 1H, one of NCH2), 4.33 ,d, Jˆ15.7 Hz, 1H,
one of NCH2), 7.20±7.45 ,m, 10H). HRMS Calcd for
C22H25NOS: 351.1657. Found: 351.1657. The fourth frac-
tion gave a ca. 1:1 mixture of two stereoisomers of 12
,quintet, Jˆ6.2 Hz, 2H, 5-H), 2.26 ,q, Jˆ5.5 Hz, 2H, 6-H),
2.63 ,td, Jˆ6.4, 1.7 Hz, 2H, 4-H), 4.76 ,s, 2H, NCH2), 5.51
,td, Jˆ4.6, 1.7 Hz, 1H, 7-H), 5.81 ,br s, 1H, 3-H), 7.15±7.35
,m, 5H).
,23 mg, 16%) as an oil: IR n 1730cm 21 1H NMR d
;
3.4.2. Entry 2 in Table 1. Following the general procedure,
compound 9d ,153 mg, 0.38 mmol) was treated with
Bu3SnH ,131 mg, 0.45 mmol) and AIBN ,8 mg,
0.05 mmol) in boiling benzene. After work-up, the crude
material was chromatographed on silica gel [hexane±
AcOEt ,10:1)]. The ®rst fraction gave 18 ,60mg, 43%).
The second fraction gave 19 ,30mg, 35%).
1.10±1.90 ,m, 7H), 1.31 ,d, Jˆ7.6 Hz, 1/2£3H), 1.59 ,d,
Jˆ7.6 Hz, 1/2£3H), 2.10±2.25 ,m, 1H), 3.02 ,q, Jˆ7.6 Hz,
1/2H, 3-H), 3.08 ,q, Jˆ7.6 Hz, 1/2H, 3-H), 3.32 ,dd,
Jˆ12.2, 4.0Hz, 1/2H, 5-H), 3.38±3.43 ,m, 1/2H, 5-H),
3.66 ,d, Jˆ15.5 Hz, 1/2H, one of NH2), 4.50,d,
Jˆ15.5 Hz, 1/2H, one of NH2), 4.65 ,d, Jˆ15.5 Hz, 1/2H,
one of NH2), 4.81 ,d, Jˆ15.5 Hz, 1/2H, one of NH2), 7.10±
7.50,m, 10H). HRMS Calcd for C 22H25NOS: 351.1657.
Found: 351.1659.
3.4.3. Entry 3 in Table 1. Following the general procedure,
compound 9d ,147 mg, 0.36 mmol) was treated with
,Me3Si)3SiH ,131 mg, 0.45 mmol) and azobis,cyclohexane-
carbonitrile) ,ACN) ,30mg, 0.12 mmol) in boiling toluene.
After work-up, the crude material was chromatographed on
silica gel [hexane±AcOEt ,10:1)]. The ®rst fraction gave 18
,26 mg, 19%). The second fraction gave 19 ,26 mg, 32%).
3.3.4. Radical cyclization of 9c with Bu3SnH±AIBN.
Following the general procedure, compound 9c ,186 mg,
0.42 mmol) was treated with Bu3SnH ,134 mg,
0.46 mmol) and AIBN ,20 mg, 0.12 mmol) in boiling ben-
zene. After work-up, the crude material was chromato-
graphed on silica gel [hexane±AcOEt ,10:1)]. The ®rst
3.4.4. Entry 4 in Table 1. Following the general procedure,
compound 9d ,150mg, 0.37 mmol) was treated with
,Me3Si)3SiH ,99 mg, 0.40 mmol) and AIBN ,20 mg,
0.12 mmol) in boiling benzene. After work-up, the crude
material was chromatographed on silica gel [hexane±
AcOEt ,10:1)]. The ®rst fraction gave the recovered 9d
,43 mg, 35%). The second fraction gave 18 ,40mg, 29%).
The third fraction gave 19 ,12 mg, 14%).
fraction
gave
1-benzyl-octahydro-3,3-dimethyl-3a-
,phenylthio)indol-2-one ,16) 836 mg, 24%) as an oil: IR n
1715, 1675 cm21; 1H NMR d 1.00 ,s, 3H, one of Me), 1.26
,s, 3H, one of Me), 1.40±2.10,m, 7H), 2.35±2.50,m, 1H),
4.56, 4.65 ,AB q, Jˆ15.2 Hz, 2H, NCH2), 4.79 ,dd, Jˆ6.3,
3.0Hz, 1H, 7a-H), 7.15±7.35 ,m, 10H). HRMS Calcd for
C23H27NOS: 365.1813. Found: 365.1815. The second frac-
tion N-benzyl-2-methyl-N-,2-phenylthiocyclohex-1-enyl)-
propanamide ,17) ,5 mg, 3%) as an oil: IR n 1650cm 21
;
3.5. Radical cyclization of 9e
1H NMR d 1.17 ,d, Jˆ6.6 Hz, 3H, one of Me), 1.25 ,d,
Jˆ6.6 Hz, 3H, one of Me), 1.45±2.15 ,m, 8H), 2.76 ,septet,
Jˆ6.6 Hz, 1H, COCH), 4.26 ,d, Jˆ14.5 Hz, 1H, one of
3.5.1. Radical cyclization of 9e with Bu3SnH and AIBN
in boiling toluene. Following the general procedure,

7636
H. Ishibashi et al. / Tetrahedron 57 12001) 7629±7637
compound 9e ,200 mg, 0.45 mmol) was treated with
Bu3SnH ,173 mg, 0.6 mmol) and AIBN ,23 mg,
0.14 mmol) in boiling toluene. After work-up, the crude
material was chromatographed on silica gel [hexane±
AcOEt ,10:1)] to give 1-benzyl-3-chloro-1,4,5,6-tetra-
hydro-2H-indol-2-one ,20)4a,8 ,99 mg, 84%) as an oil: IR
described above for 9a, 2-phenylcyclohexanone ,871 mg,
5.00 mmol) was condensed with benzylamine ,540 mg,
5.00 mmol), and the resulting imine was treated with
dichloroacetyl chloride ,0.93 g, 6.39 mmol) in the presence
of Et3N ,1.52 g, 15.0mmol) in toluene. After work-up, the
crude material was chromatographed on silica gel [hexane±
AcOEt ,20:1)] to give 22b ,1.06 g, 57%): mp 101±1038C
1
n 1700 cm21; H NMR d 1.81 ,quintet, Jˆ6.3 Hz, 2H,
1
5-H), 2.28 ,q, Jˆ5.5 Hz, 2H, 6-H), 2.62 ,t, Jˆ6.6 Hz, 2H,
,hexane±AcOEt): IR n 1680cm 21; H NMR ,270MHz) d
4-H), 4.80,s, 2H, NCH ), 5.58 ,t, Jˆ4.6 Hz, 1H, 7-H),
1.60±2.50 ,m, 8H), 3.74 ,d, Jˆ14.5 Hz, 1H, one of NCH2),
5.14 ,d, Jˆ14.5 Hz, 1H, one of NCH2), 6.45 ,s, 1H, CHCl2),
7.09±7.37 ,m, 10H). Anal. Calcd for C21H21Cl2NO: C,
67.39; H, 5.65; N, 3.74. Found: C, 67.54; H, 5.79; N, 3.73.
2
7.20±7.25 ,m, 5H). HRMS Calcd for C15H1435ClNO:
259.0764. Found: 259.0758.
3.5.2. Radical cyclization of 9e with Bu3SnH and Et3B at
room temperature in toluene. To a solution of 9e ,104 mg,
0.24 mmol) and Bu3SnH ,76 mg, 0.26 mmol) in toluene
,15 mL) was added Et3B ,1 M solution in hexane)
,0.03 mL, 0.03 mmol) at 08C, and the mixture was stirred
at room temperature for 3 h. Stirring was continued for
about 2 days with occasional addition of Et3B. After usual
work-up, the crude material was chromatographed on silica
gel [hexane±AcOEt ,10:1)]. The ®rst fraction gave the
recovered 9e ,16 mg, 15%). The second fraction gave 9d
,10mg, 10%), whose spectrospopic data were identical with
those described above. The third fraction gave 1-benzyl-3,3-
dichloro-1-azaspiro[3.5]nonane-2,5-dione ,21) ,26 mg,
3.6.3. N-Benzyl-2,2,2-trichloro-N-ꢀ2-phenylcyclohex-1-
enyl)acetamide ꢀ22c). Using a procedure similar to that
described above for 9a, 2-phenylcyclohexanone ,871 mg,
5.00 mmol) was condensed with benzylamine ,540 mg,
5.00 mmol), and the resulting imine was treated with
trichloroacetyl chloride ,1.00 g, 5.50 mmol)in the presence
of Et3N ,1.52 g, 15.0mmol) in toluene. After work-up, the
crude material was chromatographed on silica gel [hexane±
AcOEt ,20:1)] to give 22c ,1.59 g, 78%): mp 108±1098C
1
,hexane±AcOEt): IR n 1670cm 21; H NMR ,270MHz) d
1.07±2.48 ,m, 8H), 3.56 ,d, Jˆ14.2 Hz, 1H, one of NCH2),
5.17 ,d, Jˆ14.2 Hz, 1H, one of NCH2), 7.21±7.41 ,m, 10H).
Anal. Calcd for C21H20Cl3NO: C, 61.71; H, 4.93; N, 3.43.
Found: C, 61.81; H, 4.98; N, 3.49.
1
35%) as an oil: IR n 1790, 1725 cm21; H NMR d 1.40±
1.90,m, 4H), 2.00±2.15 ,m, 2H), 2.55±2.80,m, 2H, 6-H 2),
4.21 ,d, Jˆ15.5 Hz, 1H, one of NCH2), 4.97 ,d, Jˆ15.5 Hz,
1H, one of NCH2), 7.15±7.45 ,m, 5H). HRMS Calcd for
C15H1535Cl2NO2: 311.0479. Found: 311.0458.
3.7. Radical cyclization of 22a±c
3.7.1. Radical cyclization of 22a. Following the general
procedure, compound 22a ,192 mg, 0.50 mmol) was treated
with Bu3SnH ,189 mg, 0.65 mmol) and AIBN ,24.6 mg,
0.15 mmol) during 2 h in boiling benzene. After work-up,
the crude material was chromatographed on silica gel
[hexane±AcOEt ,5:1)] to give N-benzyl-N-,2-phenylcyclo-
hex-1-enyl)acetamide ,23) ,73.8 mg, 48%) as an oil: IR n
1630cm 21; 1H NMR ,270MHz) d 1.50±1.72 ,m, 6H), 2.11
,s, 3H, COMe), 2.36±2.41 ,m, 2H), 3.52 ,d, Jˆ14.2 Hz, 1H,
one of NCH2), 5.11 ,d, Jˆ14.2 Hz, 1H, one of NCH2), 7.10±
7.33 ,m, 10H). Anal. Calcd for C21H23NO: C, 82.59; H,
7.59; N, 4.59. Found: C, 82.34; H, 7.74; N, 4.58.
3.5.3. Radical cyclization of 9e with Bu3SnH and Et3B in
boiling toluene. To a boiling solution of 9e ,100 mg,
0.23 mmol) and Bu3SnH ,73 mg, 0.25 mmol) in toluene
,15 mL) was added Et3B ,1 M solution in hexane)
,0.13 mL, 0.13 mmol), and the mixture was heated under
re¯ux for 10min. After work-up, the crude material was
chromatographed on silica gel [hexane±AcOEt ,10:1)].
The ®rst fraction gave the recovered 9e ,24 mg, 24%).
The second fraction gave 20 ,30mg, 51%), whose spectro-
spopic data were identical with those obtained above.
3.6. Preparation of N-benzyl-2-halo-N-ꢀ2-phenylcyclo-
hex-1-enyl)acetamides 22a±c
3.7.2. Radical cyclization of 22b. Following the general
procedure, compound 22b ,187 mg, 0.50 mmol) was treated
with Bu3SnH ,189 mg, 0.65 mmol) and AIBN ,24.6 mg,
0.15 mmol) during 2 h in boiling benzene. After work-up,
the crude material was chromatographed on silica gel
[hexane±AcOEt ,8:1)]. The ®rst fraction gave N-benzyl-2-
chloro-N-,2-phenylcyclohex-1-enyl)acetamide ,25) ,48.5 mg,
3.6.1. N-Benzyl-2-bromo-N-ꢀ2-phenylcyclohex-1-enyl)-
acetamide ꢀ22a). Using a procedure similar to that
described above for 9a, 2-phenylcyclohexanone ,871 mg,
5.00 mmol) was condenced with benzylamine ,540 mg,
5.00 mmol), and the resulting imine was treated with
bromoacetyl bromide ,1.11 g, 5.50mmol) in the presence
of Et3N ,1.52 g, 15.0mmol) in toluene. After work-up, the
crude material was chromatographed on silica gel [hexane±
AcOEt ,10:1)] to give 22a ,452 mg, 24%) as an oil: IR n
1645 cm21; 1H NMR ,270MHz) d 1.50±2.50 ,m, 8H), 3.71
,d, Jˆ11.2 Hz, 1H, one of COCH2), 3.76 ,d, Jˆ14.5 Hz, 1H,
one of NCH2), 4.08 ,d, Jˆ11.2 Hz, 1H, one of COCH2),
5.16 ,d, Jˆ14.5 Hz, 1H, one of NCH2), 7.06±7.38 ,m,
10H). Anal. Calcd for C21H22BrNO: C, 65.63; H, 5.77; N,
3.64. Found: C, 65.53; H, 5.82; N, 3.79.
29%) as an oil: IR ,CHCl3) n 1660cm 21 1H NMR
;
,270MHz) d 1.59±2.43 ,m, 8H), 3.77 ,d, Jˆ14.5 Hz, 1H,
one of NCH2), 3.94 ,d, Jˆ12.9 Hz, 1H, one of COCH2),
4.17 ,d, Jˆ12.9 Hz, 1H, one of COCH2), 5.15 ,d, Jˆ
14.5 Hz, 1H, one of NCH2), 7.05±7.35 ,m, 10H). Anal.
Calcd for C21H22ClNO: C, 74.22; H, 6.52; N, 4.12. Found:
C, 73.87; H, 6.57; N, 4.19. The second fraction gave
1-benzyl-1,3,3a,4,5,6-hexahydro-3a-phenylindol-2-one
1
,24) ,94.9 mg, 63%) as an oil: IR n 1715, 1680cm 21; H
NMR ,270MHz) d 0.96±1.15 ,m, 1H), 1.45±1.57 ,m, 1H),
1.75±1.90,m, 1H), 2.06±2.13 ,m, 2H), 2.24 ,dt, Jˆ12.2,
3.6 Hz, 1H), 2.73 ,d, Jˆ16.0Hz, 1H, one of COCH 2), 2.86
,d, Jˆ16.0Hz, 1H, one of COCH 2), 4.41 ,d, Jˆ15.2 Hz, 1H,
3.6.2. N-Benzyl-2,2-dichloro-N-ꢀ2-phenylcyclohex-1-enyl)-
acetamide ꢀ22b). Using a procedure similar to that

H. Ishibashi et al. / Tetrahedron 57 12001) 7629±7637
7637
Ê 3
Vˆ1738.2,6) A ,
one of NCH2), 4.93 ,d, Jˆ15.2 Hz, 1H, one of NCH2), 5.14
,t, Jˆ3.6 Hz, 7-H), 7.14±7.34 ,m, 10H). HRMS Calcd for
C21H21NO: 303.1623. Found: 303.1626.
bˆ91.42,2)8,
Zˆ4,
m,MoKa)ˆ
2.26 cm21, F,000)ˆ712, Dcˆ1.291 g cm23, crystal dimen-
sions: 0.10£0.14£0.20 mm. A total of 4473 re¯ections
,4307 unique) were collected using the v-2u scan technique
to a maximum 2u value of 558, and 1393 re¯ections with
l.3s,l) were used in the structure determination. Final R
and Rw values were 0.041 and 0.043, respectively. The
maximum and minimum peaks in the difference map were
3.7.3. Radical cyclization of 22b with 0.5 equiv. of
Bu3SnH. Following the general procedure, compound 22b
,187 mg, 0.50 mmol) was treated with Bu3SnH ,75.6 mg,
0.26 mmol) and AIBN ,8.2 mg, 0.05 mmol) during 2 h in
boiling benzene. After work-up, the crude material was
chromatographed on silica gel [hexane±AcOEt ,20:1!
8:1!5:1)]. The ®rst fraction gave 22b ,120mg, 64%).
The second fraction gave 25 ,9.5 mg, 6%). The third
fraction gave ,3Rp,3aSp)-1-benzyl-3-chloro-1,3,3a,4,5,6-
hexahydro-3a-phenylindol-2-one ,26a) ,4.2 mg, 2%): mp
Ê 23
0.15 and 20.19 e A , respectively. Crystallographic data
have been deposited at the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK
and copies can be obtained on request, free of charge, by
quoting the publication and the deposition number 167494.
178±1808C ,from AcOEt); IR n 1730, 1685 cm21 1H
;
Acknowledgements
NMR ,270MHz) d 1.07±1.23 ,m, 1H, one of 5-H), 1.58±
1.67 ,m, 1H, one of 5-H), 1.77 ,td, Jˆ13.4, 3.3 Hz, 1H, one
of 6-H), 2.04±2.12 ,m, 2H, 4-H), 2.68 ,dt, Jˆ13.4, 3.3 Hz,
1H, one of 6-H), 4.62 ,d, Jˆ14.7 Hz, 1H, one of NCH2),
4.65 ,s, 1H, CHCl), 4.91 ,d, Jˆ14.7 Hz, 1H, one of NCH2),
5.27 ,t, Jˆ3.3 Hz, 1H, 7-H), 6.98±7.42 ,m. 10H). Anal.
Calcd for C21H20ClNO: C, 74.66; H, 5.97; N, 4.15. Found:
C, 74.41; H, 5.96; N, 4.13. The fourth fraction gave the
starting material 24 ,32.9 mg, 22%).
This work was supported by a Grant-in-Aid for Scienti®c
Research from the Ministry of Education, Science, Sports
and Culture of Japan and Hoh-ansha Foundation ,Japan).
References
1. ,a) Sato, T.; Nakamura, N.; Ikeda, K.; Okada, M.; Ishibashi, H.;
Ikeda, M. J. Chem. Soc., Perkin Trans. 1 1992, 2399±2407.
,b) Ishibashi, H.; Fuke, Y.; Yamashita, T.; Ikeda, M.
Tetrahedron: Asymmetry 1996, 7, 2531±2538. ,c) Ikeda, M.;
Hamada, M.; Yamashita, T.; Matsui, K.; Sato, T.; Ishibashi, H.
J. Chem. Soc., Perkin Trans. 1 1999, 1949±1956. ,d) Ishibashi,
H.; Matsukida, H.; Toyao, A.; Tamura, O.; Takeda, Y. Synlett
2000, 1497±1499.
3.7.4. Radical cyclization of 22c in boiling benzene in the
presence of AIBN. Following the general procedure,
compound 22c ,204 mg, 0.50 mmol) was treated with
Bu3SnH ,189 mg, 0.65 mmol) and AIBN ,24.6 mg,
0.15 mmol) during 2 h in boiling benzene. After work-up,
the crude material was chromatographed on silica gel
[hexane±AcOEt ,8:1)] to give 26a ,151 mg, 89%).
2. ,a) Ishibashi, H.; Kameoka, C.; Iriyama, H.; Kodama, K.; Sato,
T.; Ikeda, M. J. Org. Chem. 1995, 60, 1276±1284. ,b) Ishibashi,
H.; Kodama, K.; Kameoka, C.; Kawanami, H.; Ikeda, M.
Tetrahedron 1996, 52, 13867±13880. ,c) Ishibashi, H.;
Kameoka, C.; Kodama, K.; Kawanami, H.; Hamada, M.;
Ikeda, M. Tetrahedron 1997, 53, 6911±6922.
3.7.5. Radical cyclization of 22c in toluene at room
temparature in the presence of Et3B. Accoring to a pro-
cedure similar to that described above for Section 3.5.2, a
mixture of compound 22c ,167 mg, 0.41 mmol) and
Bu3SnH ,179 mg, 0.62 mmol) in toluene ,15 mL) was
treated with occasional addition of Et3B ,1 M solution in
hexane) ,total 0.56 mL, 0.56 mmol) at room temperature
for 43 h. After usual work-up, the crude material was
chromatographed on silica gel. The ®rst fraction gave
22b ,28 mg, 18%). The second fraction gave ,3Sp,3aSp)-1-
benzyl-3-chloro-1,3,3a,4,5,6-hexahydro-3a-phenylindol-2-
3. For a preliminary communication, see: Ishibashi, H.; Higuchi,
M.; Ohba, M.; Ikeda, M. Tetrahedron Lett. 1998, 39, 75±78.
4. Recently, an analogous discussion has been made for nickel
powder-mediated or CuCl-mediated 5-endo-trig radical
cyclization of N-,cyclohex-1-enyl)trichloroacetamides. See:
,a) Cassayre, J.; Quiclet-Sire, B.; Saunier, J.-B.; Zard, S. Z.
Tetrahedron 1998, 54, 1029±1040. ,b) Davies, D. T.; Kapur,
N.; Parsons, A. F. Tetrahedron Lett. 1999, 40, 8615±8618.
,c) Cassayre, J.; Dauge, D.; Zard, S. Z. Synlett 2000, 471±474.
5. A similar result has been reported for the radical cyclizations of
2-halo-N-,3,4-dihydro-2-naphthyl)acetamides. See: Ikeda, M.;
Ohtani, S.; Yamamoto, T.; Sato, T.; Ishibashi, H. J. Chem. Soc.,
Perkin Trans. 1 1998, 1763±1768.
1
one ,26b) ,9 mg, 7%): IR n 1725, 1680cm 21; H NMR
,270MHz) d 1.02±1.23 ,m, 1H, one of 5-H), 1.52±1.62
,m, 1H, one of 5-H), 2.01±2.15 ,m, 3H), 2.28±2.39 ,m,
1H), 4.61 ,s, 1H, CHCl), 4.65 ,d, Jˆ15.2 Hz, 1H, one of
NCH2), 4.81 ,d, Jˆ15.2 Hz, 1H, one of NCH2), 5.34 ,t,
Jˆ3.6 Hz, 1H, 7-H), 7.00±7.38 ,m. 10H). HRMS Calcd
for C21H2035ClNO: 337.1233. Found: 337.1242. The third
fraction gave 25 as a mixture of an unidenti®ed product
,total 6 mg). The fourth fraction gave 26a ,27 mg, 20%).
The ®fth fraction gave an unidenti®ed product ,27 mg): IR n
6. For the effects of temperature on 5-exo and 6-endo radical
cyclizations, see: Shuto, S.; Kanazaki, M.; Ichikawa, S.;
Matsuda, A. J. Org. Chem. 1997, 62, 5676±5677.
7. Radical cyclizations of halo amides and related compounds
having a phenyl group at the terminus of their N-vinylic
bonds gave mixtures of 4-exo and 5-endo cyclization products.
See: Sato, T.; Chono, N.; Ishibashi, H.; Ikeda, M. J. Chem. Soc.,
Perkin Trans. 1 1995, 1115±1120and Ref. 2a.
1730, 1680 cm21
.
3.8. Crystal data for compound 26a
8. Clark, A. J.; Dell, C. P.; Ellard, J. M.; Hunt, N. A.; McDonagh,
J. P. Tetrahedron Lett. 1999, 40, 8619±8623.
C21H20ClNO, Mˆ337.85, monoclinic ,from AcOEt), space
Ê
group P21/c, aˆ14.183,2), bˆ7.403,2), cˆ16.561,3) A,