Synthetic Studies of cis-3a-Aryloctahydroindole Derivatives by Copper-Catalyzed Cyclization of N-Allyltrichloroacetamides: Facile Construction of Benzylic Quaternary Carbons by Carbon-Carbon Bond-Forming Reactions

Article abstract of DOI:10.1021/jo9912146

Cyclization of N-(2-aryl-2-cyclohexen-1-yl)trichloroacetamides by a copper catalyst was investigated. It is crucially important for successful cyclization under mild conditions that alkoxycarbonyl groups are introduced to the nitrogen atom of the N-allyltrichloroacetamides as well as that CuCl-(bipyridine) is used as the catalyst. Three compounds, N-(2-phenyl-2-cyclohexen-1-yl)-, N-[2-(3,4-dimethoxyphenyl)-2-cyclohexen-1-yl]-, and N-[2-(3,4-methylenedioxyphenyl)-2-cyclohexen-1-yl]-trichloroacetamides, where the Cbz or MeO₂C- group was attached to the nitrogen atom, were instantly converted to the corresponding trichlorinated cis-3a-aryloctahydroindol-2-ones in high yields at room temperature. The reactions offer a facile access to alkaloid skeletons such as mesembrines and crinines; as the simplest examples, total synthesis of (±)-mesembrane and (±)-crinane was accomplished. The effect of alkoxycarbonyl substituents in the amide group was compared with that of the methyl substituent. N-Methyl-N-(2-phenyl-2-cyclohexen-1-yl)trichloroacetamide quickly reacted in the presence of CuCl(bipyridine) catalyst; however, the products were a mixture of complicated materials including a small amount of the desired lactam. The role of the alkoxycarbonyl group was discussed in terms of rate of rotation of the N-C bond in the N-allyltrichloroacetamides; variable-temperature NMR studies and X-ray structure determination of related compounds were carried out as supporting evidence.

Full text of DOI:10.1021/jo9912146

J . Org. Chem. 1999, 64, 9625-9631
9625
Syn th etic Stu d ies of cis-3a -Ar ylocta h yd r oin d ole Der iva tives by
Cop p er -Ca ta lyzed Cycliza tion of N-Allyltr ich lor oa ceta m id es:
F a cile Con str u ction of Ben zylic Qu a ter n a r y Ca r bon s by
Ca r bon -Ca r bon Bon d -F or m in g Rea ction s
Sho-ichi Iwamatsu, Kouki Matsubara, and Hideo Nagashima*
Graduate School of Engineering Sciences and Institute of Advanced Material Study, Kyushu University,
Kasuga, Fukuoka, 816-8580, J apan
Received August 3, 1999
Cyclization of N-(2-aryl-2-cyclohexen-1-yl)trichloroacetamides by a copper catalyst was investigated.
It is crucially important for successful cyclization under mild conditions that alkoxycarbonyl groups
are introduced to the nitrogen atom of the N-allyltrichloroacetamides as well as that CuCl-
(bipyridine) is used as the catalyst. Three compounds, N-(2-phenyl-2-cyclohexen-1-yl)-, N-[2-(3,4-
dimethoxyphenyl)-2-cyclohexen-1-yl]-, and N-[2-(3,4-methylenedioxyphenyl)-2-cyclohexen-1-yl]-
trichloroacetamides, where the Cbz or MeO2C- group was attached to the nitrogen atom, were
instantly converted to the corresponding trichlorinated cis-3a-aryloctahydroindol-2-ones in high
yields at room temperature. The reactions offer a facile access to alkaloid skeletons such as
mesembrines and crinines; as the simplest examples, total synthesis of (()-mesembrane and (()-
crinane was accomplished. The effect of alkoxycarbonyl substituents in the amide group was
compared with that of the methyl substituent. N-Methyl-N-(2-phenyl-2-cyclohexen-1-yl)trichloro-
acetamide quickly reacted in the presence of CuCl(bipyridine) catalyst; however, the products were
a mixture of complicated materials including a small amount of the desired lactam. The role of the
alkoxycarbonyl group was discussed in terms of rate of rotation of the N-C bond in the
N-allyltrichloroacetamides; variable-temperature NMR studies and X-ray structure determination
of related compounds were carried out as supporting evidence.
In tr od u ction
applicability to syntheses of the various pyrrolidinone
skeletons including precursors of alkaloids.6-8 The cis-
3a-aryloctahydroindole nuclei are seen in many naturally
occurring alkaloids and continue to be of interest as
synthetic targets.9 This skeleton has aryl groups at the
junction of the two fused rings. Construction of these ring
systems by carbon-carbon bond-forming reactions at the
position shown in Figure 1 has recently received much
Transition metal catalyzed addition reaction of poly-
halocarbons to alkenes has become an important carbon-
carbon bond-forming reaction in organic synthesis.1,2 The
intramolecular version of this reaction provides a con-
venient method for construction of various ring systems
including skeletons of biologically active compounds.3-5
In particular, cyclization of N-allyltrichloroacetamides
affording R,R,γ-trichlorinated γ-lactams have found wide
(6) (a) Nagashima, H.; Wakamatsu, H.; Itoh, K. J . Chem. Soc., Chem.
Commun. 1984, 652. (b) Nagashima, H.; Wakamatsu, H.; Ozaki, N.;
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H.; Seki, K.; Ozaki, N.; Wakamatsu, H.; Itoh, K.; Tomo, Y.; Tsuji, J .
Ibid. 1990, 55, 985. (e) Nagashima, H.; Ozaki, N.; Seki, K.; Ishii, M.;
Itoh, K. Ibid. 1989, 54, 4497. (f) Iwamatsu, S.; Kondo, H.; Matsubara,
K.; Nagashima, H. Tetrahedron 1999, 55, 1687.
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L.; Ghelfi, F.; Pagnoni, U. M.; Ronzoni, R. Tetrahedron 1997, 53, 14031.
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G. H.; Wongtap, H. Tetrahedron Lett. 1999, 40, 3807. (e) Clark, A. J .;
Filik, R. P.; Thomas, G. H. Tetrahedron Lett. 1999, 40, 4885.
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T.; Nakamura, N.; Ikeda, M. J . Org. Chem. 1993, 58, 2360. (b) Seijas,
J . A.; V-Tato, M. P.; Castedo, L.; Este´vez, R. J .; OÄ nega, M. G.; Ru´ız,
M. Tetrahedron 1992, 48, 1637. (c) Hirai, Y.; Hagiwara, A.; Terada,
T.; Yamazaki, T. Chem. Lett. 1987, 2417. (d) Martin, P.; Steiner, E.;
Streith, J .; Winker, T.; Bellus, D. Tetrahedron 1985, 41, 4057. (e)
Nagashima, H.; Ara, K.; Wakamatsu, H.; Itoh, K. J . Chem. Soc., Chem.
Commun. 1985, 518.
(1) For reviews of the transition metal-catalyzed radical reactions,
see: (a) Iqbal, J .; Bhatia, B.; Nayyer, N. K. Chem Rev. 1994, 94, 519.
(b) Kochi, J . K. Organometallic Mechanisms and Catalysts; Academic
Press: New York, 1978.
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B.; Kopping, B.; Go¨bel, T.; Dickhaut, J .; Thoma, G.; Kulicke, K. J .;
Trach, F. Org. React. 1996, 48, 301-586. (b) Giese, B. Radicals in
Organic Synthesis: Formation of Carbon-Carbon Bonds; Pergamon:
New York, 1986. (c) Curran, D. P.; Porter, N. A.; Giese, B. Stereochem-
istry of Radical Reaction; VCH: Weinheim, 1996; pp 23-115. (d)
Curran, D. P. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Perganmon: Oxford, 1991; Vol. 4, p 715.
(3) (a) Nagashima, H.; Wakamatsu, H.; Itoh, K., Tomo, Y.; Tsuji, J .
Tetrahedron Lett. 1983, 23, 2395. (b) Nagashima, H.; Seki, K.; Ozaki,
N.; Wakamatsu, H.; Itoh, K., Tomo, Y.; Tsuji, J . J . Org. Chem. 1990,
55, 985. (c) Takano, S.; Nishizawa, S.; Akiyama, M.; Ogasawara, K.
Synthesis 1984, 949.
(4) (a) Pirrung, F. O. H.; Hiemstra, H.; Speckamp, W. N.; Kaptein,
B.; Schoemaker, H. E. Synthesis 1995, 458. (b) Pirrung, F. O. H.;
Hiemstra, H.; Speckamp, W. N.; Kaptein, B.; Schoemaker, H. E.
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amp, W. N. J . Chem. Soc., Perkin Trans. 2 1992, 1529.
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M. Tetrahedron Lett. 1989, 30, 3915. (c) Lee, G. M.; Parvez, M.;
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K.; Freyer, A. J .; Parvez, M.; Weinreb, S. M. J . Org. Chem. 1986, 51,
5501.
(9) For recent syntheses: (a) Mori, M.; Kuroda, S.; Zhang, C.-S.;
Sato. Y. J . Org. Chem. 1997, 62, 3263. (b) Nishimata, T.; Mori, M. J .
Org. Chem. 1998, 63, 7586. (c) Pearson, W. H.; Lovering, F. E. J . Org.
Chem. 1998, 63, 3607. (d) Denmark, S. E.; Marcin, L. R. J . Org. Chem.
1997, 62, 1675. (e) Rajagopalan, P. Tetrahedron Lett. 1997, 38, 1893.
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Nemoto, H.; Tanabe, T.; Fukumoto, K. J . Org. Chem. 1995, 60, 6785.
10.1021/jo9912146 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/04/1999

9626 J . Org. Chem., Vol. 64, No. 26, 1999
Iwamatsu et al.
Sch em e 2a
F igu r e 1.
Sch em e 1
a
Reagents and conditions: (a) Hg(OAc)2, AcOH, 95 °C, 58%;
(b) KOH, aq MeOH, rt, 98%; (c) pyridine, ClCO2Et, Et2O, rt, 90%;
(d) cat. Pd(OAc)2, PPh3, aq MeNH2, MeCN, 40 °C, then NEt3,
CCl3COCl, Et2O, rt, 80%; (e) (NCO2Et)2, phthalimide, PPh3, THF,
rt, 68%; (f) H2NNH2‚H2O, EtOH, reflux, 79%; (g) NEt3, ClCO2Bn,
Et2O, 0 °C f rt, 87%; (h) n-BuLi, CCl3COCl, THF, -45 °C f rt,
66%.
attention in terms of effective construction of quaternary
carbons by carbon-carbon bond-forming reactions.
In 1985, we reported that copper-mediated radical
cyclization of N-methyl-N-[2-(3,4-dimethoxyphenyl)cy-
clohexen-1-yl]trichloroacetamide was one means of solv-
ing this problem: the reaction proceeded by the catalysis
of CuCl in MeCN at 120-140 °C in a sealed tube. The
resulting bicyclic lactam was transformed to (()-mesem-
brane, a degradation product of mesembrine alkaloid.8e
Although the reaction was accomplished successfully, the
yield of the product was below 50% even with an increase
in the amount of the catalyst to 100%. An analogous
reaction was later reported by Ishibashi and Ikeda, who
stated that RuCl2(PPh3)3-catalyzed cyclization of the
N-methyl-N-(2-arylcyclohexen-1-yl)-R-thiophenyl-R-chlo-
roacetamides at 140 °C;8a however, the yield of the
product was not satisfactory (∼57%) even in the presence
of large amounts of the ruthenium catalyst (∼20 mol %).
In a similar approach, tin-mediated reductive radical
cyclizations were devised by Stork et al.10a and Ishibashi
et al.10b Sterically bulky substituents attached to the
nitrogen atom of the amide group allow efficient cycliza-
tion of N-(2-arylcyclohexen-1-yl)haloamide derivatives
under milder conditions; however, simple reduction of the
halide also occurred as a serious side reaction. In our
initial studies on transition metal-catalyzed cyclization
of N-allyltrichloroacetamides, we found that the reaction
generally occurred at above 100 °C. Our efforts to lower
the reaction temperature allowed the discovery of highly
efficient catalyst systems, a 1:1 mixture of cuprous salts
and bidentate diamine ligand such as 2,2′-bipyridine
(bipy) or N,N,N′,N′-tetramethylethylenediamine (TME-
DA). Another factor in the cyclization at lower temper-
ature is selection of the substituent on the amide
nitrogen; introduction of electron-withdrawing groups
such as Ts, Cbz, and t-Boc resulted in the cyclization
under mild conditions.6a,d As a typical example, cycliza-
tion of N-tosyl-N-allyltrichloroacetamide proceeded at
room temperature with turnover >80. Use of the CuCl-
(bipy) catalyst and introduction of Ts group on the
nitrogen atom provided successful transformation of R,R-
dichlorocarbonyl compounds, which had been difficult to
achieve by a conventional method, under mild conditions.6e
These new findings prompted us to revisit the prob-
lematic cyclization of N-(2-phenyl-2-cyclohexen-1-yl)-
trichloroacetamides, which might be improved by use of
CuCl(bipy) as catalyst and introduction of electron-
withdrawing groups on the nitrogen atom. Herein, we
report that N-alkoxycarbonyl-N-(2-aryl-2-cyclohexen-1-
yl)trichloroacetamides successfully cyclized to give the
corresponding products having cis-3a-aryloctahydroindole
skeletons under mild conditions, and by means of this
reaction, total synthesis of mesembrane and crinane was
accomplished. We also observed that attempted cycliza-
tion of the N-methyl analogue under similar conditions
afforded a mixture of intractable products. The effect of
the N-substituent was discussed in terms of ease of N-C
rotation of the trichloroacetamide; variable-temperature
NMR studies as well as structural analyses of related
N-benzyl- and N-tosyl-N-allyltrichloroacetamides were
also reported as supporting evidence to suggest the
importance of the N-C rotation.
Resu lt a n d Discu ssion
Effects of N-Su bstitu en ts in Cycliza tion of N-(2-
P h en yl-2-cycloh exen -1-yl)t r ich lor oa cet a m id e De-
r iva t ives. Trichloroacetamides 7a (N-Me) and 7b (N-
Cbz: carbobenzyloxy) were prepared from commercially
available 1-phenylcyclohexene as outlined in Scheme 2.
Treatment of 1-phenylcyclohexene with Hg(OAc)2 fol-
lowed by hydrolysis of the formed acetate afforded an
allyl alcohol 3,11 which was converted to 4 by reaction
with ClCO2Et. Palladium-catalyzed substitution of the
EtOCO2 group by MeNH moiety followed by trichloro-
acetylation of the resulting amine yielded N-methyl-N-
(2-phenyl-2-cyclohexen-1-yl)trichloroacetamide 7a . The
allyl alcohol 3 was subjected to the Mitsunobu reaction
to afford an allylic amine 5,12 which was transformed to
a N-Cbz derivative 6. Trichloroacetylation of 6 yielded
7b as the N-Cbz analogue of 7a .
The reaction of trichloroacetamide 7a was carried out
in dichloromethane at from room temperature to 40 °C
using a 1:1 mixture of CuCl(bipy) as the catalyst.
Although all of the starting materials disappeared within
1 h, the desired bicyclic γ-lactam 8a was available in less
than 20% yield, and many intractable byproducts were
formed concomitantly (Scheme 3). The yield of 8a was
(10) (a) Stork, G.; Mah, R. Heterocycles 1989, 28, 723. (b) Ishibashi,
H.; So, T. S.; Okochi, K.; Sato, T.; Nakamura, N.; Nakatani, H.; Ikeda,
M. J . Org. Chem. 1991, 56, 95.
(11) Treibs, W.; Weissenfels, M. Chem. Ber. 1960, 93, 1374.
(12) (a) Mitsunobu, O.; Wada, M.; Sano, T. J . Am. Chem. Soc. 1972,
94, 679. (b) Sen, S. E.; Roach, S. L. Synthesis 1995, 756.

Studies of cis-3a-Aryloctahydroindole Derivatives
J . Org. Chem., Vol. 64, No. 26, 1999 9627
Sch em e 3
not improved by changing the reaction temperature (-15
to ∼40 °C) or by increasing amount of the catalysts from
30 to 100 mol %. On the other hand, cyclization of the
N-Cbz analogue 7b proceeded smoothly at room temper-
ature in the presence of 30 mol % of the CuCl(bipy)
catalyst to afford the desired γ-lactam 8b in 83% yield.
The 1H NMR spectra of the crude product showed
exclusive formation of only one diastereomer of 8b and
no detectable byproducts. The stereochemistry of 8b was
elucidated by X-ray crystallography (Figure 2); the
relationship between the angular phenyl group and the
proton was cis, whereas that between the phenyl group
and the chlorine atom in the six-membered ring was
trans. Both the phenyl group and the chlorine atoms
occupy the axial position of the cyclohexane ring.13
Although successful cyclization proceeded with lower
concentration of the catalyst, deactivation of the catalyst
quickly took place. In fact, the yield of 8b was 66% with
recovery of 7b (22%), when the reaction was carried out
in the presence of 10 mol % of the catalyst.
F igu r e 2. The ORTEP representation of the X-ray crystal
structure of lactam 8b.
Sch em e 4
Successful cyclization of 7b prompted us to explore a
more direct synthetic method for N-alkoxycarbonyl-N-
allyltrichloroacetamides. The allyl cyanate-to-isocyanate
rearrangement reported by Ichikawa and Isobe provides
a good method to synthesize 10 from 3 via the [3.3]-
sigmatropic rearrangement.14 Reaction of 3 with 2 equiv
of trichloroacetylisocyanate was followed by hydrolysis
with potassium carbonate in aqueous methanol to give
the carbamate 9 (Scheme 4). Treatment of 9 with
trifluoromethanesulfonic anhydride (Tf2O) and diisopro-
pylethylamine at -78 °C followed by addition of lithium
methoxide afforded the N-allylurethane 10 in 72% yield
from 3. Cyclization of the trichloroacetamide 11 in the
presence of 30 mol % of CuCl(bipy) proceeded smoothly
to give the desired γ-lactam 12 in 88% yield as a single
isomer. To confirm the stereochemistry of angular sub-
stituents of 12, the lactam was subjected to reductive
dechlorination with 4 equiv of tributyltinhydride to give
13 in 79% yield. Deprotection of 13 with 5 equiv tri-
methylsilyliodide (TMSI) in refluxing dichloromethane
afforded the known cis-3a-phenyloctahydroindol-2-one 14
in good yield.15
catalyzed cyclization to total syntheses of mesembrane
and crinane. According to the literature method,16 6-aryl-
3-cylohexen-1-ones 16a and 16b were prepared by the
Diels-Alder reaction of 2-aryl-nitroolefines 15a and 15b,
respectively, with butadiene followed by the Nef reaction
(Scheme 5). The enones 16a and 16b were isomerized to
17a and 17b, respectively, by catalysis of RhCl3 in
ethanol.17 Reduction of the formed enone with LiAlH4
gave the corresponding allyl alcohol 18a or 18b in
moderate yield. N-Allylurethanes 19a and 19b were
synthesized from 18a and 18b, respectively, by way of
the Ichikawa-Isobe rearrangement. Cyclization of the
resulting trichloroacetamides 20a and 20b prepared by
trichloroacetylation of the N-allylurethanes using 30 mol
% CuCl(bipy) resulted in the desired trichlorinated
γ-lactams 21a (78%) and 21b (78%), respectively. The
structure of trichlorinated γ-lactams 21a and 21b was
confirmed by transformation (tin-mediated reductive
dechlorination and deprotection by Me3SiI) to the known
cis-3a-aryloctahydroindol-2-ones 23a and 23b, respec-
tively.18 Synthesis of mesembrane or crinane from 23a
or 23b, respectively, was reported earlier.18
Syn th esis of Mesem br a n e a n d Cr in a n e. Success of
the above experiments encouraged us to apply the copper-
(13) A similar stereochemical outcome was proposed by Ishibashi
et al. in the RuCl2(PPh3)3-catalyzed cyclization of an analogous system,
and the crystal structure unequivocally supported their assignments.
Interestingly, the 3,4-dimethoxyphenyl and 3,4-methylenedioxyphenyl
homologues, 21a and 21b, respectively, exist as a mixture of two
conformers. 1H and 13C NMR spectra of 21a or 21b at -60 °C showed
two sets of signals derived from the conformers. On raising the
temperature to 20 °C, extensive broadening of all of the 1H resonances
were observed, indicating that interconversion of the conformers
occurred at ambient temperature in the NMR time scale. We consider
that both the aryl group and the chlorine atom occupy axial positions
in one conformer of 21a or 21b, whereas those does equatorial positions
in the other conformer.
(14) Ichikawa, Y.; Yamazaki, M.; Isobe, M. J . Chem. Soc., Perkin
Trans. 1 1993, 2429.
(15) (a) Olah, G. A.; Narang, S. C. Tetrahedron 1982, 38, 2225. (b)
Kozmin, S. A.; Rawal, V. H. J . Am. Chem. Soc. 1998, 120, 13523.
(16) Wildman, W. C.; Wildman, R. B. J . Org. Chem. 1952, 17, 581.
(17) Grieco, P. A.; Nishizawa, M.; Marinovic. N.; Ehmann, W. J . J .
Am. Chem. Soc. 1976, 98, 7102.

9628 J . Org. Chem., Vol. 64, No. 26, 1999
Iwamatsu et al.
Sch em e 5
F igu r e 3.
cyclization, which occurred from the anti-rotamer, was
facilitated by introduction of bulky substituents on the
nitrogen atom.10,22 Since the syn/anti equilibrium is
influenced by the steric nature of the group attached to
the nitrogen atom, the bulky substituent played an
important role in decreasing the percentage of the syn
rotamer leading to simple reduction of the N-allylhalo-
amides.
As model experiments to clarify the effect of CO-N
rotation on the fate of the cyclization in our copper-
catalyzed system, we carried out variable-temperature
NMR studies on N-benzyl- and N-tosyltrichloroacet-
amides 24a and 24b (Figure 3). The benzyl group is
representative of electron-donating groups, whereas the
tosyl group is that of electron-withdrawing groups. As
1
shown in Figure 4, H NMR of 24a showed two sets of
independent signals derived from the two rotamers at
lower than 233 K. Above 233 K, the signals began to
broaden, and they coalesced at 308 K. At 343 K, syn-
anti interconversion was fast in the NMR time scale,
leading to the appearance of only one set of sharp signals.
This NMR observation is in accord with the CO-N
rotational barrier of 15 kcal/mol reported for N,N-
dimethyltrichloroacetamide. On the other hand, 24b
showed only one set of signals even below at -50 °C,
which suggested that amide rotational barrier of the 24b
was much lower than that of 24a . X-ray structural
analyses of 24a and 24b also supported the dependence
of rotational barrier on the electronic nature of the N
substituent.23
As mentioned above, the ORTEP view of the bicyclic
lactam 8b suggest a possibly congested transition state
for cyclization as illustrated in Scheme 6. Steric repulsion
between the phenyl group bound to the CdC bond and
the dichloromethyl radical species makes access of the
radical species to the CdC bond difficult. Consideration
of molecular models suggested the sterically most favor-
Th e Role of th e Electr on -With d r a w in g Gr ou p of
N-Allyltr ich lor oa ceta m id es in th e Cycliza tion . As
reported, the use of the CuCl(bipy) catalyst apparently
facilitates activation of a carbon-chlorine bond of N-
allyltrichloroacetamides compared with the conventional
catalysts CuCl in acetonitrile and RuCl2(PPh3)3. This is
in accord with the fact that treatment of 7a or 7b with
the CuCl(bipy) catalyst resulted in disappearance of the
starting trichloroacetamide within 1 h at room temper-
ature. It is important that smooth cyclization of 7b
proceeded to give 8b in high yield; this is in sharp
contrast to the result that the reaction of 7a competed
with serious side reactions to give a mixture of products.
How can we explain this difference?
An interesting observation was reported by Curran and
co-workers in the radical cyclization of N-allyl R-poly-
haloamides:19 syn-anti rotamer population and its rota-
tional energy barrier are important in the fate of the
reaction because the rotational energy barriers of amide
C-N bonds (16-22 kcal/mol)20 are generally higher than
5-exo cyclization (<10 kcal/mol).19 They found that atom-
transfer cyclization of N-allyl-N-methyliodoacetamide
was much more efficient at 80 °C than at 25 °C and
proposed that this beneficial effect of temperature arises
because an increase in the rate of rotation of the OC-N
bond in the intermediate radicals begins to convert syn
radicals (which cannot cyclize) to anti radicals (which can
cyclize). Recently, Newcomb et al. reported supporting
evidence using laser flash photolysis kinetic studies of
OC-N bond rotation.21 Stork and Ishibashi also claimed
the importance of the OC-N rotation in the tin-mediated
reductive radical cyclization of N-allylhaloamides; the
(22) Sato, T.; Wada, Y.; Nishimoto, M.; Ishibashi, H.; Ikeda, M. J .
Chem. Soc., Perkin Trans. 1 1989, 879. See also ref 10.
(23) We carried out crystallographic analysis of 24a and 24b. The
molecular structure of 24a showed that very effective resonance
stabilization provided that six atoms, C2, C1, O1, N1, C3, and C6, lie
on the same plane in the molecular structure of 24a . The C-O distance
is substantially longer than the usual CdO distances, whereas the
N-CO bond length is shorter than normal N-C single bond distances
(N-CO; 1.35 Å (1), CdO.; 1.24 Å (1)). Thus, the N-CO bond of 24a
has a considerable double-bond character like A. Since X-ray analysis
of 24b did not converge well (R ) 7.7%), precise comparison of the
structure of 24b with that of 24a is difficult. However, it is noteworthy
that the molecular structure suggested a single bond character of
N-CO bond (N-CO; 1.375 Å (4), CdO.; 1.195 Å (1)). Five atoms, C1,
N1, C3, S1, and O3, lie on the same plane, which makes an angle of
13° with a plane consisting of C2, C1, and O1. We consider that the
resonance structure shown as B is responsible for facile rotation of
the CO-N bond in 24b.
(18) (a) For compound 23a : Oh-ishi, T.; Kugita, H. Chem. Pharm.
Bull. 1970, 18, 291. (b) For compound 23b: Keck, G. E.; Webb, R. R.,
II. J . Am. Chem. Soc. 1981, 103, 3173.
(19) Curran, D. P.; Tamine, J . J . Org. Chem. 1991, 56, 2746.
(20) (a) Stewart, W. E.; Siddall, T. H., III. Chem. Rev. 1970, 70, 517.
(b) Gansow, O. A.; Killough, J .; Burke, A. R. J . Am. Chem. Soc. 1971,
93, 4297.
(21) Musa, O. M.; Horner, J . H.; Newcomb, M. J . Org. Chem. 1999,
64, 1022.

Studies of cis-3a-Aryloctahydroindole Derivatives
J . Org. Chem., Vol. 64, No. 26, 1999 9629
trichloroacetyl moiety and facilitate abstraction of a
chlorine atom by the Cu(I) complex via the electron
transfer. Usually, this chlorine abstraction is reversible,
and hence, cyclization of the N-alkyl analogues afforded
the product in good yields, though high population of the
undesired rotamer makes the reaction slower. A signifi-
cant difference in the product yield between the reaction
of 7a and 7b is attributable to the existence of the side
reactions, namely those from I or II. To suppress these
reactions, it is important to facilitate the formation of
III by lowering the N-CO rotational barrier through
introduction of the electron-withdrawing substituents.
Con clu sion
Cyclization of N-alkoxycarbonyl-N-(2-aryl-2-cyclohexen-
1-yl)trichloroacetamides converted to the corresponding
trichlorinated cis-3a-aryloctahydroindol-2-ones at room
temperature in the presence of CuCl(bipy) catalyst.
Introduction of alkoxycarbonyl groups is considered to
play an important role in lowering the N-CO rotational
barrier, leading to the preferable production of the radical
intermediates suitable for the cyclization.24 The reactions
are proved to offer a facile access to alkaloid skeletons
such as mesembrines and crinines. Asymmetric synthesis
of these alkaloids is now under study by preparing chiral
allylic amine derivatives via the Ichikawa-Isobe reac-
tion. Since chirality transfer reaction can generally be
achieved by [3.3]sigmatropic rearrangement, we antici-
pate the chiral N-allyltrichloroacetamides can be syn-
thesized from the chiral allylic alcohols such as 18a and
18b.
F igu r e 4. Variable-temperature 1H NMR spectra of N-
allyltrichloroacetamides 24a (left) and 24b (right) in toluene-
d8 solution.
Sch em e 6
Exp er im en ta l Section
Gen er a l Meth od s. All manipulations were performed
under an argon atmosphere unless otherwise noted. Cuprous
chloride (CuCl) was prepared from CuCl2 hydrate25 and stored
under a dry argon atmosphere. Purification of 2,2′-bipyridine
was made by sublimation. Solvents were distilled under an
inert atmosphere from CaH2 (CH2Cl2, MeCN), sodium/ben-
zophenone (THF, toluene), or magnesium tunings (EtOH). The
solvent used for the cyclization was degassed by three freeze-
pump-thaw cycles just before use. 2-Phenyl-2-cyclohexen-1-
ol (3)11 and 6-aryl-3-cyclohexen-1-ones (16a ) and (16b) were
prepared by the procedure in the literature.15 Transformation
of 3, 16a , and 16b to the corresponding N-substituted 2-aryl-
2-cyclohexenylamines was described in the Supporting Infor-
mation. Column chromatography was carried out using silica
gel (Merck No. 1.07734.9025 or Wakogel FC-40). Thin-layer
chromatography was carried out with silica gel 60 F254 (Merck).
N -Me t h yl-N -(2-p h e n yl-2-cycloh e xe n -1-yl)t r ich lor o-
a ceta m id e (7a ). To a solution of N-methyl-N-(2-phenyl-2-
cyclohexen-1-yl)amine (661 mg, 3.5 mmol) in Et2O (12 mL) was
added triethylamine (1.28 mL, 7.1 mmol) at room temperature.
Trichloroacetyl chloride (800 µL, 7.1 mmol) was then added
at 0 °C, and the mixture was stirred at room temperature for
3 h. The resulting mixture was treated with 2 N HCl, stirred
for an additional 10 min, and extracted with Et2O. The
combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated. The residue was purified
by chromatography (silica gel, eluent: 10% Et2O/hexane) to
give 7a (1.09 g, 80% from 4) as a colorless oil: 1H NMR (CDCl3)
7.31-7.18 (m, 5H), 6.30 (m, 1H), 5.78 (m, 1H), 2.89 (s, 3H),
2.32-2.21 (m, 2H), 2.14-2.07 (m, 1H), 1.91-1.83 (m, 1H),
able conformer of the intermediate radical species to be
I as shown in Scheme 6. Rotation of the N-C(cyclohexane
ring) bond causes the dichloroacetyl moiety to be close
to the carbon-carbon double bond; however, rotamer II
should preferentially exist over III, which is suitable for
the cyclization. In the case of 7a , the small N-methyl
group produces a high population of I. Furthermore, the
high energy barrier of N-CO rotation resulted in a low
population of III compared with II. This low population
of III makes the cyclization difficult, and the existence
of other reaction pathways from I or II led to production
of a mixture of products. In contrast, alkoxycarbonyl
group in 7b is sterically more bulky than the methyl
group in 7a ; this leads to decrease in the population of I
and an increase in the population of II and III. More
importantly, flexible C-N bond rotation of 7b facilitates
the formation of III from II, resulting in efficient produc-
tion of the bicyclic lactams. There may be other reaction
pathways from I or II to a mixture of products; however,
free rotation of N-C and N-CO bonds producing III
predominantly occurs to result in high-yield formation
of the cyclization product.
As reported previously, the cyclization of N-allyl-
trichloroacetamides is facilitated by introduction of elec-
tron-withdrawing substituents. This is presumably due
to the fact that these substituents lower the LUMO of
(24) The importance of the electron-withdrawing group on the
nitrogen atom has recently reported by Giese et al. in the photocy-
clization of o-aminophenyl ketones: Seiler, M.; Schumacher, A.;
Lindemann, U.; Barbosa, F.; Giese B. Synlett 1999, 1588.
(25) Keller, R. N.; Wycoff, H. D. Inorg. Synth. 1946, 2, 1.

9630 J . Org. Chem., Vol. 64, No. 26, 1999
Iwamatsu et al.
1.83-1.74 (m, 2H); 13C NMR (CDCl3) 160.50, 139.38, 137.21,
131.83, 128.39, 127.20, 125.48, 93.52, 55.08, 32.72, 26.37,
25.62, 20.88; IR (CH2Cl2) 1668 cm-1; FAB-MS m/z 336 (MH+
eluent: 30% Et2O/hexane) to give the lactam 21a (241 mg,
78%) as a colorless solid.
3,3,4-Tr ich lor o-1-m eth yl-3a -p h en yl-2,3,3a ,4,5,6,7,7a -oc-
ta h yd r oin d ol-2-on e (8a ): colorless solid; 20% yield; mp 210-
211 °C (Et2O/hexane); 1H NMR (CDCl3) 7.95 (d, J ) 8 Hz, 1H),
7.51-7.46 (m, 1H), 7.45-7.39 (m, 2H), 7.34-7.29 (m, 1H), 4.90
(m, 1H), 4.51 (m, 1H), 3.00 (s, 3H), 2.39-2.31 (m, 1H), 2.17-
2.09 (m, 1H), 2.04-1.94 (m, 1H), 1.89-1.82 (m, 1H), 1.60-
1.47 (m, 2H); 13C NMR (CDCl3) 166.70, 136.56, 129.27, 128.72,
128.51, 127.66, 126.72, 90.88, 62.16, 57.12, 55.46, 30.11, 27.47,
22.09, 14.84; IR (CH2Cl2) 1729 cm-1; FAB-MS m/z 336 (MH+
+ 4), 334 (MH+ + 2), 332 (MH+). Anal. Calcd for C15H16
-
NOCl3: C, 54.16; H, 4.85; N, 4.21. Found: C, 54.13; H, 4.89;
N, 4.07.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-(Alk oxy-
car bon yl)-N-(2-ar yl-2-cycloh exen -1-yl)tr ich lor oacetam ides
7b, 11, 20a , a n d 20b. In a typical example, to a solution of 10
(278 mg, 1.20 mmol) and 2,2′-bipy (trace, as indicator) in 12
mL of THF was added dropwise a hexane solution of n-BuLi
(1.54 M, 840 µL) at -45 °C. The mixture was stirred at the
same temperature for 10 min and at 0 °C for 10 min.
Trichloroacetyl chloride (145 µL, 1.30 mmol) was added to the
solution, and the mixture was stirred for 1 h at room temper-
ature. The reaction mixture was quenched with a saturated
aqueous solution of NH4Cl and extracted with Et2O. The
combined organic layers were washed with a 1 N NaOH
aqueous solution and brine successively, dried over MgSO4,
filtered, and concentrated. The residue was purified by chro-
matography (silica gel, eluent: 12% Et2O/hexane) to give the
trichloroacetamide 11 (392 mg, 87%) as a colorless solid.
N-(Ben zyloxycar bon yl)-N-(2-ph en yl-2-cycloh exen -1-yl)-
tr ich lor oa ceta m id e (7b): colorless solid; 66% yield; mp 71-
73 °C; 1H NMR (CDCl3) 7.35-7.31 (m, 3H), 7.28-7.17 (m, 7H),
6.09 (m, 1H), 5.54 (m, 1H), 5.15 (br, 1H), 5.01 (d, J ) 12 Hz,
1H), 2.32-2.05 (m, 4H), 1.96-1.88 (m, 1H), 1.78-1.65 (m, 1H);
13C NMR (CDCl3) 165.49, 152.98, 138.91, 136.21, 133.72,
130.59, 128.99, 128.77, 128.46, 128.21, 127.17, 126.43, 93.01,
+ 4), 334 (MH+ + 2), 332 (MH+). Anal. Calcd for C15H16
-
NOCl3: C, 54.16; H, 4.85; N 4.21. Found: C, 54.26; H, 4.90; N
4.17.
1-(Ben zyloxyca r bon yl)-3,3,4-t r ich lor o-3a -p h en yl-2,3,-
3a ,4,5,6,7,7a -octa h yd r oin d ol-2-on e (8b): colorless solid; 83%
yield; mp 210.5-212 °C (CH2Cl2/cyclohexane); 1H NMR (CDCl3)
7.91 (br, 1H), 7.51-7.32 (m, 9H), 5.46 (d, J ) 13 Hz, 1H), 5.36
(d, J ) 13 Hz, 1H), 5.02 (m, 1H), 4.98 (m, 1H), 2.92 (m, 1H),
2.09-1.94 (m, 2H), 1.87 (m, 1H), 1.55-1.45 (m, 2H); 13C NMR
(CDCl3, -30 °C) 165.29, 151.27, 134.96, 134.47, 129.24, 128.98,
128.72, 128.58, 128.28, 127.50, 127.42, 126.40, 89.42, 68.94,
62.08, 55.21, 54.79, 29.97, 21.57, 14.29; IR (CH2Cl2) 1802, 1777,
1734 cm-1; FAB-MS m/z 456 (MH+ + 4), 454 (MH+ + 2), 452
(MH+). Anal. Calcd for C22H20NO3Cl3: C, 58.36; H, 4.45; N,
3.09. Found: C, 58.42; H, 4.52; N, 3.05.
3,3,4-Tr ich lor o-1-(m et h oxyca r b on yl)-3a -p h en yl-2,3,-
3a ,4,5,6,7,7a -octa h yd r oin d ol-2-on e (12): colorless solid; 88%
yield; mp 150.5-152.5 °C (Et2O/hexane); 1H NMR (CDCl3) 7.92
(m, 1H), 7.56-7.33 (m, 4H), 5.03 (m, 1H), 4.99 (m, 1H), 3.98
(s, 3H), 2.93 (m, 1H), 2.14-1.95 (m, 2H), 1.94-1.83 (m, 1H),
1.59-1.45 (m, 2H); 13C NMR (CDCl3) 165.04, 152.19, 135.45,
129.32, 129.02, 128.75, 127.68, 126.63, 89.68, 62.16, 55.40,
55.09, 54.40, 30.17, 22.04, 14.53; IR (CH2Cl2) 1804, 1776, 1739
cm-1; FAB-MS m/z 380 (MH+ + 4), 378 (MH+ + 2), 376 (MH+);
FAB-HRMS calcd for C16H16NO3Cl3 + H 376.0274, found
376.0274.
69.53, 58.31, 27.96, 25.29, 21.30; IR (CH2Cl2) 1753, 1707 cm-1
;
FAB-MS m/z 456 (MH+ + 4), 454 (MH+ + 2), 452 (MH+); FAB-
HRMS calcd for C22H20NO3Cl3 + H 452.0587, found 452.0603.
N-(Meth oxyca r bon yl)-N-(2-p h en yl-2-cycloh exen -1-yl)-
tr ich lor oa ceta m id e (11): colorless solid; 87% yield; mp 93-
95 °C (Et2O/hexane); 1H NMR (CDCl3) 7.34-7.17 (m, 5H), 6.13
(m, 1H), 5.52 (m, 1H), 3.70 (s, 3H), 2.38-2.08 (m, 4H), 2.00-
1.90 (m, 1H), 1.80-1.66 (m, 1H); 13C NMR (CDCl3) 165.42,
153.68, 138.91, 136.06, 130.81, 128.24, 127.24, 126.56, 93.14,
3,3,4-Tr ich lor o-1-(m eth oxyca r bon yl)-3a -(3,4-d im eth ox-
yph en yl)-2,3,3a,4,5,6,7,7a-octah ydr oin dol-2-on e (21a): col-
58.26, 53.77, 27.92, 25.36, 21.32; IR (CH2Cl2) 1759, 1709 cm-1
;
FAB-MS m/z 380 (MH+ + 4), 378 (MH+ + 2), 376 (MH+). Anal.
Calcd for C16H16NO3Cl3: C, 51.02; H, 4.28; N, 3.72. Found: C,
51.37; H, 4.45; N, 3.70.
orless solid; 78% yield; mp 194-196 °C (CH2Cl2/hexane); H
1
NMR (CDCl3) 7.51-7.35 (m, 1H), 7.01-6.78 (m, 2H), 4.97-
4.89 (m, 2H), 3.98 (s, 3H), 3.94 (brs, 3H), 3.92 (s, 3H), 3.02-
2.85 (m, 1H), 2.16-1.94 (m, 2H), 1.93-1.83 (m, 1H), 1.68-
1.46 (m, 2H); 13C NMR (CDCl3, -60 °C) 165.60, 165.55, 152.03,
151.91, 148.52, 148.38, 148.34, 147.86, 126.96, 126.83, 120.14,
119.18, 110.77, 109.79, 109.66, 108.22, 89.81, 89.66, 62.30,
62.18, 55.95, 55.91, 55.87, 55.74, 55.39, 55.32, 55.04, 54.97,
54.33, 54.25, 29.84, 29.79, 21.73, 21.50, 14.35, 14.29; IR (CH2-
Cl2) 1804, 1777, 1738 cm-1; FAB-MS m/z 440 (MH+ + 4), 438
(MH+ + 2), 436 (MH+); FAB-HRMS calcd for C18H20NO5Cl3 +
H 436.0485, found 436.0479.
N-(Met h oxyca r b on yl)-N-[2-(3,4-d im et h oxyp h en yl)-2-
cycloh exen -1-yl]tr ich lor oa ceta m id e (20a ): colorless solid;
1
74% yield; mp 126-128 °C; H NMR (CDCl3) 6.86-6.82 (m,
2H), 6.77 (d, J ) 9 Hz, 1H), 6.09 (m, 1H), 5.50 (m, 1H), 3.85
(s, 3H), 3.84 (s, 3H), 3.68 (brs, 3H), 2.37-2.16 (m, 3H), 2.15-
2.05 (m, 1H), 2.00-1.90 (m, 1H), 1.79-1.66 (m, 1H); 13C NMR
(CDCl3) 165.28, 153.64, 148.47, 148.28, 135.49, 131.82, 129.86,
118.94, 110.91, 109.67, 93.21, 58.32, 55.89, 55.69, 53.72, 28.04,
25.25, 21.28; IR (CH2Cl2) 1759, 1708 cm-1; FAB-MS m/z 439
(M+ + 4), 437 (M+ + 2), 435 (M+), 217; FAB-HRMS calcd for
3,3,4-Tr ich lor o-1-(m et h oxyca r b on yl)-3a -(3,4-m et h yl-
en ed ioxyp h en yl)-2,3,3a ,4,5,6,7,7a -octa h yd r oin d ol-2-on e
(21b): colorless solid; 78% yield; mp 217-219 °C (CH2Cl2/
C
18H20NO5Cl3 435.0407, found 435.0400.
N-(Meth oxycar bon yl)-N-[2-(3,4-m eth ylen edioxyph en yl)-
1
2-cycloh exen -1-yl]tr ich lor oa ceta m id e (20b): colorless oil;
hexane); H NMR (CDCl3) 7.45-7.33 (m, 1H), 6.95-6.77 (m,
1
76% yield; H NMR (CDCl3) 6.77 (d, J ) 2 Hz, 1H), 6.74 (dd,
2H), 6.04 (s, 2H), 4.98-4.79 (m, 2H), 3.98 (s, 3H), 2.99-2.79
(m, 1H), 2.12-1.79 (m, 4H), 1.65-1.45 (m, 2H); 13C NMR
(CDCl3, -60 °C) 165.50, 151.76, 148.02, 147.68, 147.35, 128.23,
128.09, 121.30, 120.32, 108.84, 108.15, 107.90, 106.66, 101.68,
101.59, 89.69, 89.35, 62.29, 62.07, 55.43, 54.88, 54.37, 54.19,
29.74, 29.65, 21.27, 14.23, 14.19; IR (CH2Cl2) 1806, 1778, 1738
cm-1; FAB-MS m/z 424 (MH+ + 4), 422 (MH+ + 2), 420 (MH+);
FAB-HRMS calcd for C17H16NO5Cl3 + H, 420.0172, found
420.0168.
J ) 8, 2 Hz, 1H), 6.70 (d, J ) 8 Hz, 1H), 6.04 (m, 1H), 5.91 (d,
J ) 1 Hz, 1H), 5.90 (d, J ) 1 Hz, 1H), 5.42 (m, 1H), 3.73 (brs,
3H), 2.36-2.04 (m, 4H), 1.99-1.88 (m, 1H), 1.79-1.64 (m, 1H);
13C NMR (CDCl3) 165.38, 153.63, 147.45, 146.74, 135.48,
133.13, 130.11, 120.02, 108.04, 107.39. 100.83, 93.16, 58.38,
53.79, 27.90, 25.27, 21.22; IR (CH2Cl2) 1760, 1709 cm-1; FAB-
MS m/z 423 (M+ + 4), 421 (M+ + 2), 419 (M+), 200; HRMS
calcd for C17H16NO5Cl3 419.0094. found 419.0096.
Gen er a l P r oced u r e for th e Cu Cl(bip y)-Ca ta lyzed Cy-
cliza tion of Tr ich lor oa ceta m id es 7a ,b, 11, a n d 20a ,b. In
a typical example, CuCl (20.8 mg, 0.21 mmol) and 20a (308
mg, 0.71 mmol) were measured into a 20 mL flask. The
atmosphere was replaced carefully by argon and degassed
dichloromethane (3 mL) was added. Then, a solution of 2,2′-
bipyridine (32.8 mg in 1 mL of CH2Cl2, 0.21 mmol) was added,
and the mixture was stirred at room temperature for 1 h. The
resulting mixture was transferred to the head of a short pad
of silica gel and eluted with Et2O. The eluent was concentrated,
and the residue was purified by chromatography (silica gel,
Gen er a l P r oced u r e for th e Tin -m ed ia ted Dech lor in a -
tion of γ-La cta m s 12 a n d 21a ,b. In a typical example, to a
solution of 12 (126 mg, 0.335 mmol) and AIBN (22 mg, 0.134
mmol) in 10 mL of toluene was added tributyltin hydride (370
µL, 1.38 mmol), and the mixture was heated under reflux for
3 h. After being cooled to room temperature, the solvent was
removed under reduced pressure. The residue was purified by
chromatography (silica gel, eluent: 30% EtOAc/hexane) to give
13 (72 mg, 79%) as a colorless solid.
1-(Meth oxycar bon yl)-3a-ph en yl-2,3,3a,4,5,6,7,7a-octah y-
d r oin d ol-2-on e (13): mp 99-100.5 °C; 1H NMR (CDCl3)

Studies of cis-3a-Aryloctahydroindole Derivatives
J . Org. Chem., Vol. 64, No. 26, 1999 9631
7.30-7.23 (m, 4H), 7.20-7.13 (m, 1H), 4.44 (dd, J ) 10, 6 Hz,
1H), 3.73 (s, 3H), 2.94 (d, J ) 17 Hz, 1H), 2.66 (d, J ) 17 Hz,
1H), 2.38-2.28 (m, 1H), 1.97-1.87 (m, 1H), 1.79-1.57 (m, 3H),
1.49-1.21 (m, 3H); 13C NMR (CDCl3) 172.32, 151.95, 145.55,
128.71, 126.83, 125.57, 61.53, 53.37, 43.12, 41.36, 35.54, 28.52,
22.37, 21.88; IR (CH2Cl2) 1784, 1752, 1722 cm-1; EI-MS m/z
273 (M+); HRMS calcd for C16H19NO3 273.1365, found 273.1365.
1-(Met h oxyca r b on yl)-3a -(3,4-d im et h oxyp h en yl)-2,3,-
3a ,4,5,6,7,7a -octa h yd r oin d ol-2-on e (22a ): colorless oil; 97%
yield; 1H NMR (CDCl3) 6.89 (dd, J ) 8, 2 Hz, 1H), 6.84 (d, J )
2 Hz, 1H), 6.81 (d, J ) 8 Hz, 1H), 4.45 (dd, J ) 10, 6 Hz, 1H),
3.88 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H), 3.00 (d, J ) 17 Hz, 1H),
2.70 (d, J ) 17 Hz, 1H), 2.45-2.35 (m, 1H), 2.03-1.93 (m, 1H),
1.84-1.66 (m, 3H), 1.55-1.30 (m, 3H); 13C NMR (CDCl3)
172.46, 152.13, 149.07, 147.96, 138.21, 117.79, 111.15, 109.43,
61.96, 55.95, 55.88, 53.48, 43.01, 41.62, 35.66, 28.68, 22.52,
21.01; IR (CH2Cl2) 1784, 1746, 1721 cm-1; EI-MS m/z 333 (M+);
HRMS calcd for C18H23NO5 333.1576, found 333.1575.
NMR (CDCl3) 176.83, 144.55, 128.47, 126.51, 126.39, 56.76,
48.41, 45.34, 35.09, 26.62, 21.15, 19.89; IR (CH2Cl2) 3425, 1698
cm-1; EI-MS m/z 215 (M+); HRMS calcd for C14H17NO 215.1310,
found 215.1310.
cis-3a -(3,4-Dim eth oxyp h en yl)-2,3,3a ,4,5,6,7,7a -octa h y-
d r oin d ol-2-on e (23a ): pale yellow solid; 91% yield; mp 144-
1
146 °C (lit.18a 149-151 °C); H NMR (CDCl3) 6.89 (dd, J ) 8,
2 Hz, 1H), 6.84 (d, J ) 8 Hz, 1H), 6.83 (d, J ) 2 Hz, 1H), 6.18
(br, 1H), 4.22 (t, J ) 3 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 2.59
(d, J ) 16 Hz, 1H), 2.45 (d, J ) 16 Hz, 1H), 2.01-1.93 (m,
1H), 1.91-1.76 (m, 3H), 1.61-1.46 (m, 3H), 1.30-1.17 (m, 1H);
13C NMR/DEPT (CDCl3) 176.29 (C), 148.88 (C), 147.59 (C),
137.02 (C), 118.67 (CH), 110.85 (CH), 110.25 (CH), 56.85 (CH),
56.00 (CH3), 55.87 (CH3), 48.49 (CH2), 45.03 (C), 34.86 (CH2),
26.73 (CH2), 21.27 (CH2), 19.91 (CH2); IR (CH2Cl2) 3425, 1699
cm-1; EI-MS m/z 275 (M+); HRMS calcd for C16H21NO3
275.1521, found 275.1518.
cis-3a -(3,4-Meth ylen ed ioxyp h en yl)-2,3,3a ,4,5,6,7,7a -oc-
ta h yd r oin d ol-2-on e (23b): slightly yellow solid; 92% yield;
mp 145-147 °C (lit.18b 142-144 °C); 1H NMR (CDCl3) 6.81 (m,
1H), 6.78 (m, 2H), 5.96 (s, 2H), 5.90 (br, 1H), 4.16 (t, J ) 3
Hz, 1H), 2.54 (d, J ) 16 Hz, 1H), 2.42 (d, J ) 16 Hz, 1H),
1-(Meth oxyca r bon yl)-3a -(3,4-m eth ylen ed ioxyp h en yl)-
2,3,3a ,4,5,6,7,7a -octa h yd r oin d ol-2-on e (22b): colorless solid;
1
87% yield; mp 121-123 °C; H NMR (CDCl3) 6.84 (d, J ) 2
Hz, 1H), 6.79 (dd, J ) 8, 2 Hz, 1H), 6.75 (d, J ) 8 Hz, 1H),
5.95 (s, 2H), 4.41 (dd, J ) 10, 6 Hz, 1H), 3.82 (s, 3H), 2.98 (d,
J ) 17 Hz, 1H), 2.65 (d, J ) 17 Hz, 1H), 2.44-2.34 (m, 1H),
1.95-1.77 (m, 4H), 1.61-1.45 (m, 3H), 1.29-1.14 (m, 1H); 13
C
NMR/DEPT (CDCl3) 176.40 (C), 147.84 (C), 145.87 (C), 138.49
(C), 119.47 (CH), 107.96 (CH), 107.34 (CH), 101.06 (CH2), 56.78
(CH), 48.60 (CH2), 45.21 (C), 35.14 (CH2), 26.55 (CH2), 21.13
(CH2), 19.89 (CH2); IR (CH2Cl2) 3425, 1701 cm-1; EI-MS m/z
259 (M+); Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61; N,
5.40. Found: C, 69.37; H, 6.63; N, 5.39.
2.00-1.90 (m, 1H), 1.82-1.65 (m, 3H), 1.53-1.28 (m, 3H); 13
C
NMR (CDCl3) 172.32, 152.08, 148.18, 146.40, 139.69, 118.67,
108.15, 106.63, 101.18, 62.01, 53.49, 43.23, 41.64, 35.84, 28.66,
22.48, 22.02; IR (CH2Cl2) 1784, 1746, 1721 cm-1; EI-MS m/z
317 (M+); HRMS calcd for C17H19NO5 317.1263, found 317.1261.
Gen er a l P r oced u r e for th e TMSI-Med ia ted Dep r otec-
tion of th e γ-La cta m s 13 a n d 22a ,b. In a typical example,
to a solution of 13 (242 mg, 0.89 mmol) in dichloromethane (8
mL) was added iodotrimethylsilane (630 µL, 4.4 mmol), and
the mixture was heated under reflux for 2 h. After the mixture
was cooled to room temperature, MeOH (0.5 mL) was added,
and after concentration, Et2O (40 mL) and a 1 N aqueous HCl
solution (20 mL) were added. The organic layer was separated,
and the aqueous layer was neutralized with a 4 N aqueous
NaOH solution at 0 °C and extracted with dichloromethane
(30 mL × 3). The combined organic layers were dried over Na2-
SO4, filtered, and concentrated to give 14 (192 mg, 100%) as a
yellow oil.
Ack n ow led gm en t. This work was supported by
Grants-in-Aid for Scientific Research (Nos. 08245222,
0923129, 10125230, 10450343) from the Ministry of
Education, Science, Sports, and Culture or J apan So-
ciety for the Promotion of Science, J apan.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails including those for the preparation of 2-aryl-2-cyclohexyl-
amine derivatives. Crystallographic data and ORTEP draw-
ings for 8b, 24a , and 24b and copies of 1H and 13C NMR
spectra of all compounds lacking elemental analysis (4, 5, 7b,
12-14, 17a , 20a ,b-22a ,b, 23a ). This material is available free
of charge via the Internet at http://pubs.acs.org.
3a -P h en yl-2,3,3a ,4,5,6,7,7a -octa h yd r oin d ol-2-on e (14):
1H NMR (CDCl3) 7.39-7.22 (m, 5H), 5.84 (br, 1H), 4.24 (t, J
) 3 Hz, 1H), 2.59 (d, J ) 16 Hz, 1H), 2.49 (d, J ) 16 Hz, 1H),
2.04-1.80 (m, 4H), 1.62-1.46 (m, 3H), 1.29-1.14 (m, 1H); 13
C
J O9912146