Electrophilic-induced cyclization reaction of hexahydroindolinone derivatives and its application toward the synthesis of (±)- erysotramidine

Article abstract of DOI:10.1021/jo048647f

A convenient synthesis of variously substituted octahydroindolo[7a,1a]- isoquinolinones has been achieved by an acid-induced cyclization of hexahydroindolinones bearing tethered phenethyl groups. The formation of a single lactam diastereomer is the result

Full text of DOI:10.1021/jo048647f

Electrophilic-Induced Cyclization Reaction of
Hexahydroindolinone Derivatives and Its Application toward the
Synthesis of (()-Erysotramidine
Albert Padwa,* Hyoung Ik Lee, Paitoon Rashatasakhon, and Mickea Rose
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
Received August 4, 2004
A convenient synthesis of variously substituted octahydroindolo[7a,1a]-isoquinolinones has been
achieved by an acid-induced cyclization of hexahydroindolinones bearing tethered phenethyl groups.
The formation of a single lactam diastereomer is the result of the stereoelectronic preference for
axial attack by the aromatic ring onto the initially formed N-acyliminium ion from the least hindered
side. Additional experiments showed that a variety of hexahydroindolinones containing tethered
π-bonds undergo a related acid-induced cyclization reaction. Treatment of the 3-methylbut-3-enyl-
substituted hexahydroindolinone with acid furnished a 3:1 mixture of isomeric octahydropyrido-
[2,1-i]indolinones in near-quantitative yield. Interestingly, cyclization of the closely related 1-(3-
methoxybut-3-enyl)-substituted hexahydroindolin-one afforded a pyrrolo[3,2,1-ij]quinolinone as the
exclusive product. With this system, initial protonation takes place on the more nucleophilic enol
ether π-bond and the resulting carbonium ion undergoes a subsequent cyclization with the enamido
π-bond to give the observed product. The electrophilic promoted cyclizations were extended to include
the related hexahydro[1]pyrindinone and 1H-quinolinone systems. An NBS-promoted intramolecular
electrophilic aromatic substitution reaction of 1-[2-(3,4-dimethoxyphenyl)ethyl]-1,4,5,6-tetrahy-
droindolinone was used to assemble the tetracyclic core of the erythrinone skeleton. The resulting
cyclized product was transformed into (()-erysotramidine in three additional steps.
The hexahydroindolinone nucleus is a structurally
characteristic component found in a wide variety of
alkaloids,1 including the amaryllidaceae,2 aspidosperma,3
erythrina,4 and strychnos5 families. The distinctive struc-
tural feature of these natural products sharing the
hexahydroindolinone framework has attracted much
attention in synthetic organic chemistry.6 Strategies to
prepare this skeleton include [4 + 2]-cycloadditions,7
sigmatropic rearrangements,8 Pummerer-induced cy-
clizations,9 intramolecular condensation of amines onto
carbonyl compounds,10 1,3-dipolar cycloadditions,11 reac-
tions of isocyanates with isocyanides,12 and transition-
metal-mediated cyclization reactions.13 The related
1-azaspirocyclic structure of the erythrina alkaloids has
long been of interest in development of synthetic strate-
(7) (a) Kuehne, M. E.; Matsko, T. H.; Bohnert, J. C.; Motyka, L.;
Oliver-Smith, D. J. Org. Chem. 1981, 46, 2002. (b) Kuehne, M. E.;
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10.1021/jo048647f CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/28/2004
J. Org. Chem. 2004, 69, 8209-8218
8209

Padwa et al.
construction of a wide array of nitrogen-containing
molecules, due to their susceptibility to nucleophilic
attack.25 Of particular importance are the reactions of
cyclic N-acyliminium ions with π-nucleophiles in carbon-
carbon bond-forming processes, with a great deal of
attention given to cyclizations leading to alkaloids and
other nitrogen-containing biologically active compounds.25
These intramolecular R-amidoalkylations proceed ste-
reoselectively26 due to steric control by the substituents
already present in the ring27 or along the chain connect-
ing the π-nucleophiles and the nitrogen atom.28 In this
paper, we detail our observations dealing with the
intramolecular electrophilic aromatic substitution reac-
tion of various hexahydroindolinones which are readily
formed by the condensation of an appropriate amine with
a (1-substituted-2-oxocyclohexyl)acetic acid derivative. To
highlight the method, the above synthetic strategy was
used to assemble (()-erysotramidine (2).29
FIGURE 1.
gies for the efficient formation of their core ring system.14
Erythrina alkaloids are generally classified into two
groups according to their structural features:15 those
whose D-rings are aromatic (e.g., 3-demethoxyerythra-
tidinone (1) and erysotramidine (2)) and the others whose
D-rings possess an unsaturated lactone (e.g., cocculolidine
(3) (Figure 1).16 Many different approaches have been
employed for the synthesis of this class of natural
products. Taking the final step of bond formation into
consideration, the methods for building up the erythrinan
ring system can be loosely classified into seven different
reaction types: (1) C-ring formation with the C-5 qua-
ternary center being constructed by intramolecular cy-
clization;17 (2) C-ring formation by electrophilic substi-
tution;18 (3) A-ring formation by an intramolecular aldol
reaction;19 (4) A-ring formation from a benzoindolizidine
fragment;20 (5) B-ring formation utilizing a C-5 spiro-
isoquinoline system;21 (6) B- and C-ring formation by
intramolecular annulation of dibenzazonine;22 and (7) an
assortment of miscellaneous methods.23
Results and Discussion
The potential of using hexahydroindolinone derivatives
for the synthesis of various erythrina alkaloids prompted
us to first carry out some model studies to probe the
likelihood of this approach for 1-azaspirocyclic ring
assemblage. Our synthesis of the starting bicyclic lactam
substrates follows a methodology similar to that previ-
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On the basis of our earlier work with the erythrina
skeleton,24 we felt that a suitably substituted hexahy-
droindolinone N-acyliminium ion precursor might allow
for a facile entry to the tetracyclic core of erysotramidine
(2). N-Acyliminium ions have historically occupied an
important position as versatile intermediates for the
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8210 J. Org. Chem., Vol. 69, No. 24, 2004

Cyclization Reaction of Hexahydroindolinone Derivatives
SCHEME 1
SCHEME 3
SCHEME 4
SCHEME 2
ously described in the literature.30 Condensation of the
appropriate amine with a (1-substituted-2-oxocyclohexyl)-
acetic acid derivative (i.e., 4) under Dean-Stark condi-
tions in xylene at 160 °C for 1 h afforded the desired
bicyclic lactams in high yield. The resulting aryl lactam
precursors (i.e., 5 and 6) were smoothly converted to the
desired tetracyclic products in essentially quantitative
yield when treated with either trifluoroacetic acid (8) or
trifluoromethanesulfonic acid (9). The formation of a
single lactam diastereomer is the result of the stereo-
electronic preference for axial attack by the aromatic ring
of the N-acyliminium ion (7) from the least hindered side
(Scheme 1).31
A series of additional experiments showed that this
electrophilic-induced cyclization succeeds with a variety
of substrates containing tethered π-bonds. Thus, we were
pleased to find that the analogous furanyl substituted
hexahydroindolinone system 10 also underwent a related
acid-induced cyclization to give the tetracyclic substituted
lactam 11 in 78% yield (Scheme 2). This cyclization is
especially noteworthy considering that none of the previ-
ously reported syntheses of the nonaromatic erythroidine
alkaloids have employed this strategy of assemblage.32
Because all of the previous examples involved aromatic
π-bond cyclizations, we decided to study a hexahydroin-
dolinone system that possesses a simple olefinic tether.
We found that treatment of the 3-methylbut-3-enyl-
substituted lactam 12 with trifluoromethanesulfonic acid
furnished a 3:1-mixture of octahydropyrido[2,1-i]indol-
ones 13 and 14 in near quantitative yield. When the
reaction was carried out in formic acid, the major product
formed corresponded to formate 16 which was obtained
as a 1:1 mixture of diastereomers. Formation of the above
products can be nicely explained in terms of cyclization
of the initially generated N-acyliminium ion onto the
terminal π-bond to give carbocation 15 which subse-
quently reacts with HCO2H to give 16 or else undergoes
loss of a proton to produce 13 and 14 (Scheme 3).
Cationic cyclizations of alkynes have been exploited in
a variety of transformations including polyene cycliza-
tions33 and reactions with N-acyliminium 34 and iminium
ions.35 We found, however, that the annulative ring
cyclization of N-but-3-ynylhexahydroindolinone 17 failed
to give any discernible products. Since we had a sample
of 17 on hand, we converted it to the corresponding vinyl
enol ether 18 by reaction with HgCl2 in methanol. We
then conducted the acid-catalyzed reaction of 18 and
found, somewhat to our surprise, that the cyclization gave
rise to pyrrolo[3,2,1-ij]quinolinone 20 in 48% yield as a
1:1 mixture of diastereomers (Scheme 4). While the acid-
catalyzed cyclization of 18 did not achieve its intended
(30) (a) Ragan, J. A.; Claffey, M. C. Heterocycles 1995, 41, 57. (b)
Ennis, M. D.; Hoffman, R. L.; Ghazal, N. B.; Old, D. W.; Mooney, P. A.
J. Org. Chem. 1996, 61, 5813.
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(b) Mondon, A.; Hansen, K. F.; Boehme, K.; Faro, H. P.; Nestler, H. J.;
Vilhuber, H. G.; Bo¨ttcher, K. Chem. Ber. 1970, 103, 615. (c) Mondon,
A.; Nestler, H. J. Chem. Ber. 1979, 112, 1329. (d) Dean, R. T.; Rapoport,
H. A. J. Org. Chem. 1978, 43, 4183.
(32) The â-erythroidine skeleton has been prepared by an oxidative
degradation of the aromatic ring (ring A) in erythrinans as the key
step; see: Isobe, K.; Mohri, K.; Itoh, Y.; Toyokawa, Y.; Takeda, N.;
Taga, J.; Hosoi, S.; Tsuda, Y. Chem. Pharm. Bull. 1992, 40, 2632.
(33) Johnson, W. S.; Ward, C. E.; Boots, S. G.; Gravestock, M. B.;
Markezich, R. L.; McCarry, B. E.; Okorie, D. A.; Parry, R. J. Am. Chem..
Soc. 1981, 103, 88.
(34) Schoemaker, H. E.; Boer-Terpstra, T.; Dijkink, J.; Speckamp,
W. N. Tetrahedron 1980, 36, 143. Boer-Terpstra, T.; Dijkink, J.;
Shoemaker, H. E.; Speckamp, W. N. Tetrahedron Lett. 1977, 939.
(35) Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 1988, 110, 612.
Overman, L. E.; Sharp, M. J. Tetrahedron Lett. 1988, 29, 901.
J. Org. Chem, Vol. 69, No. 24, 2004 8211

Padwa et al.
SCHEME 5
SCHEME 7
SCHEME 8
SCHEME 6
At this point in our studies we became interested in
determining what effect an alkyl substituent on the
enamido π-bond would have on the Lewis acid promoted
reaction. We were specifically interested in determining
what would happen to the N-acyliminium ion (i.e., 34)
derived from the cyclization of 33 since there is no
possibility for proton loss. With this in mind, we treated
the N-(3,3-diethoxypropyl)-7-ethyl-substituted hexahy-
droindolinone 33 with SnCl4 in toluene, and this resulted
in the formation of pyrrolo[3,2,1-ij]quinolinone 35 in 84%
yield as a crystalline solid. The assignment of the
stereochemistry of 35 was unequivocally established by
an X-ray crystallographic study. The stereochemistry of
the final product is the result of axial attack of water
onto the thermodynamically most stable N-acyliminium
ion intermediate (i.e., 34), and this takes place from the
least hindered â-face (Scheme 8).
To further explore the scope and generality of these
electrophilic-promoted cyclizations, we extended our
studies to include the related hexahydro[1]pyrindinone
38 and 1H-quinolinone 39 systems. These compounds
were prepared from the condensation of 2-(3,4-dimethoxy-
phenyl)ethylamine with either 3-(1-methyl-2-oxocyclo-
pentyl) or 3-(1-methyl-2-oxocyclohexyl)propionic acid meth-
yl ester (36 or 37) under Dean-Stark conditions. The
resulting [6,5] and [6,6] lactams (i.e., 38 and 39) were
easily converted to the expected tetracyclic lactams 40
and 41 in 80% yield (Scheme 9). These two additional
examples nicely demonstrate the facility with which the
acid-induced cyclization cascade occurs using a variety
of cyclic enamido lactams.
purpose of providing access to keto-lactam 19 it did
undergo a novel reductive cyclization.
Scheme 5 outlines a working mechanistic hypothesis
to rationalize the formation of 20. We surmise that the
initial protonation takes place with the more nucleophilic
enol ether π-bond and that the resulting carbocation 21
undergoes a subsequent cyclization on the enamido
π-bond to furnish N-acyliminium ion 22. The most
obvious path available to 22 is proton loss thereby
providing 23 as a transient and nondetectable intermedi-
ate. More than likely, under the acidic conditions, 23
suffers loss of methanol and the resulting iminium ion
24 reacts further by a hydride transfer from methanol
to give 20. In support of this proposal, we found that the
yield of 20 could be significantly increased (93%) when
the reaction of 18 was carried out using p-TsOH in the
presence of Et3SiH as the reducing agent.
To provide still additional evidence for the mechanistic
proposal outlined in Scheme 5, we prepared the N-(3,3-
diethoxypropyl)-substituted hexahydroindolinone 25. When
25 was treated with SnCl4/Et3SiH in toluene it reacted
further to furnish pyrrolo[3,2,1-ij]quinolinone 27 in 85%
yield (Scheme 6). The conversion of 25 into 27 undoubt-
edly proceeds via the intermediacy of 26 and this
transformation provides good support for the mechanistic
paradigm presented in Scheme 5.
A somewhat related cyclization reaction was also
observed with the homologous acetal 28. In this case, the
product isolated in 82% yield corresponded to azepino-
[3,2,1-ji]indolone 32. A stepwise sequence of cyclizations
with the eventual generation of intermediate 31 may be
reasonably invoked (i.e., 28 f 29 f 30 f 31). With this
system, loss of a proton from 31 to give 32 is apparently
faster than bimolecular reduction with Et3SiH (Scheme
7). This difference is probably related to the larger ring
size present in 31, which ultimately leads to a less
strained π-bond in the final product. The same product
(i.e., 32) was formed in the absence of Et3SiH.
Encouraged by these results, we decided to apply the
acid-catalyzed cyclization of hexahydroindolinones to the
synthesis of erysotramidine (2) itself. To this end, bicyclic
lactam 44 was prepared in 73% yield by condensation of
3,4-dimethoxyphenethylamine with ketoester 42 in the
presence of TFA (Scheme 10). The formation of the R,â-
unsaturated ene-amide 44 presumably involves initial
generation of the expected hexahydroindolinone 43 fol-
lowed by an acid-catalyzed elimination of the phenyl-
8212 J. Org. Chem., Vol. 69, No. 24, 2004

Cyclization Reaction of Hexahydroindolinone Derivatives
SCHEME 9
SCHEME 10
SCHEME 11
SCHEME 12
N-acyliminium ion intermediate 45. The reaction of 44
with NBS in THF furnished aminal 48 in 77% yield
which, in turn, gave a 5:3 mixture of 46 and 47 when
heated with a trace of p-TsOH in CH3CN. These unan-
ticipated findings can be linked to the polarity of the
solvent and consequently the reactivity of the incipient
N-acyliminium ion 45. The more polar solvent (CH3CN)
stabilizes the N-acyliminium ion and allows the cycliza-
tion to proceed. The other solvents favor deprotonation
(CH2Cl2) or trapping of the cation by some adventitious
water that was present in THF.
Subjection of 46 to DBU in refluxing xylene furnished
the R,â,γ,δ-unsaturated diene-amide 49 in 75% yield.
This product is presumably formed by an initial dehy-
drobromination followed by isomerization of the π-bond
into the thermodynamically most stable position. Ste-
reoselective allylic oxidation with selenium dioxide in the
presence of formic acid gave a 1:1 mixture of formate 50
and alcohol 51 in 60% yield (based on recovered starting
material) as single diastereomers. The stereochemical
outcome of the oxidation involves attack by the oxidant
from the least hindered R-position. Formate 50 was
quantitatively transformed into alcohol 51 by treatment
with acetyl chloride in ethanol.37 Finally, compound 51
was converted into (()-erysotramidine (2) in 91% yield
by O-methylation using KOH/MeI in THF according to
Tsuda’s method (Scheme 12).38
sulfanyl group. With 44 in hand, we attempted to induce
an acid-promoted cyclization but all of our efforts failed
to produce any characterizable products, perhaps as a
consequence of the antiaromatic character of the result-
ing cationic intermediate. Alternatively, the failure of 44
to cyclize might be a consequence of protonation alpha
to the lactam carbonyl group. The resulting cationic
species would be incapable of cyclization.36
We were pleased to discover, however, that bicyclic
lactam 44 underwent an extremely smooth cyclization
to the desired erythrinan skeleton (i.e., 46) in 78% yield
when treated with NBS in acetonitrile. It is of interest
to note that this reaction is markedly dependent on the
nature of the solvent and that acetonitrile is the only
solvent used which favors cyclization (Scheme 11). Thus,
when 44 was subjected to NBS in CH2Cl2, bromoenamide
47 was obtained in 87% yield and its formation can be
attributed to a competitive deprotonation of the presumed
In summary, we have shown that the intramolecular
electrophilic aromatic substitution reaction of hexahy-
(37) Lee, Y. S.; Lee, J. Y.; Kim, D. W.; Park, H. Tetrahedron 1999,
55, 4631.
(38) (a) Ito, K.; Suzuki, F.; Haruna, M. J. Chem. Soc., Chem.
Commun. 1978, 733. (b) Tsuda, Y.; Hosoi, S.; Katagiri, N.; Kaneko,
C.; Sano, T. Chem. Pharm. Bull. 1993, 41, 2087. (c) Hosoi, S.; Nagao,
M.; Tsuda, Y.; Isobe, K.; Sano, T.; Ohta, T. J. Chem. Soc., Perkin Trans.
1 2000, 1505.
(36) This suggestion was made by one of the reviewers.
J. Org. Chem, Vol. 69, No. 24, 2004 8213

Padwa et al.
g, 0.3 mmol) in 1 mL of trifluoromethanesulfonic acid was
heated in a microwave reactor at 10 W, 60 °C, for 5 min. The
mixture was diluted with ether (20 mL) and neutralized with
a saturated solution of NaHCO3. The organic layer was
separated, dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by flash
chromatography on silica gel using 100% EtOAc as the eluent.
The title compound 9 was obtained as a colorless oil in 88%
droindolinones allows for the rapid construction of the
tetracyclic erythrinane skeleton. The cyclization reaction
is also successful using variously substituted aryl-, fura-
nyl-, and alkenyl-substituted bicyclic lactams under
acidic conditions. The formation of the cyclized product
as a single diastereomer is the result of the stereoelec-
tronic preference for axial attack by the tethered π-bond
onto the initially formed N-acyliminium ion from the
least hindered side. The cyclization method was used to
prepare (()-erysotramidine. We expect that the total
syntheses of other nonaromatic erythroidine alkaloids
will also benefit from this general strategy. These inves-
tigations are currently underway and will be reported
at some future date.
1
yield (0.07 g): IR (neat) 1688, 1488, 1452, and 1307 cm-1; H
NMR (400 MHz, CDCl3) δ 0.69 (s, 3H), 1.55-1.98 (m, 7H), 1.92
(d, 1H, J ) 16.3 Hz), 2.16-2.23 (m, 1H), 2.75 (ddd, 1H, J )
15.9, 4.1, 1.6 Hz), 2.85 (d, 1H, J ) 16.3 Hz), 2.90 (ddd, 1H, J
) 15.9, 12.0, 6.0 Hz), 3.05 (tdd, 1H, J ) 13.0, 4.4, 1.3 Hz),
4.23 (ddd, 1H, J ) 13.0, 6.4, 2.2 Hz), 7.10-7.21 (m, 3H), 7.42-
7.48 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 20.8, 21.3, 26.9,
29.5, 33.4, 34.2, 37.0, 40.4, 42.7, 64.4, 126.0, 126.4, 126.6, 130.0,
134.0, 139.6, 171.5; HRMS calcd for C17H21NO 255.1623, found
255.1616.
Experimental Section
1-(2-Furan-2-ylethyl)-3a-methyl-1,3a,4,5,6-hexahydroin-
dol-2-one (10) was prepared in 65% yield from keto acid 4
and 2-furan-2-yl-ethylamine: IR (thin film) 2860, 1674, 1449,
1072 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.12 (s, 3H), 1.51 (m,
1H), 1.73-1.77 (m, 3H), 2.10-2.23 (m, 4H), 2.87 (t, 2H, J )
7.2 Hz), 3.45 (m, 1H), 3.93 (m, 1H), 4.77 (t, 1H, J ) 3.2 Hz),
6.06 (t, 1H, J ) 2.4 Hz), 6.26 (t, 1H, J ) 2.0 Hz), 7.30 (t, 1H,
J ) 1.2 Hz); 13C NMR (100 MHz, CDCl3) δ 18.5, 22.8, 25.6,
26.1, 34.1, 36.3, 37.9, 46.4, 97.3, 106.5, 110.4, 141.5, 145.4,
152.7, 173.8; HRMS calcd for C15H19NO2 245.1416, found
245.1411.
1,2-Furo[3,2-c]-7a-methyl-3,4,7,7a,8,9,10,11-octahydro-
pyrido[2,1-i]indol-6-one (11). To a solution of 0.31 g (1.3
mmol) of hexahydroindolone 10 in 13 mL of CH2Cl2 was added
trifluoroacetic acid (0.3 mL, 3.8 mmol). The mixture was
stirred at rt for 4 h, and the solvent was removed under
reduced pressure. The crude product was purified by flash
chromatography on silica gel using EtOAc as the eluent. The
title compound 11 was obtained as a colorless oil in 78%
yield: IR (thin film) 2861, 1687, 1452, 1416, 1327 cm-1;1H
NMR (400 MHz, CDCl3) δ 0.72 (s, 3H), 1.47-1.58 (m, 4H),
1.71-1.78 (m, 3H), 1.90 (d, 1H, J ) 16.4 Hz), 2.10 (m, 1H),
2.70 (m, 2H), 2.79 (d, 1H, J ) 16.4 Hz), 3.01 (dddd, 1H, J )
24.4, 11.2, 6.0, 1.6 Hz), 4.38 (ddd, 1H, J ) 12.6, 6.0, 1.6 Hz),
6.38 (d, 1H, J ) 1.6 Hz), 7.30 (d, 1H, J ) 1.6 Hz); 13C NMR
(100 MHz, CDCl3) δ 21.9, 22.1, 23.4, 26.5, 33.7, 33.8, 36.5, 40.2,
42.1, 63.9, 108.5, 119.9, 141.3, 147.8, 172.3; HRMS calcd for
C15H19NO2 245.1416, found 245.1406.
General Procedure for the Preparation of Hexahydro-
indol-2-ones. To a 50 mL round-bottom flask equipped with
a Dean-Stark trap and a reflux condensor was added (1-
methyl-2-oxo-cyclohexyl)acetic acid39 (4) (5.0 mmol) and the
appropriate primary amine (5.5 mmol) in 25 mL of xylene. The
mixture was heated in an oil bath at 160 °C for 1 h during
which time water was collected in the Dean-Stark trap. The
solvent was removed by distillation, and the residue was
purified by flash chromatography on silica gel using 50% ether/
hexane as the eluent.
1-[2-(3,4-Dimethoxyphenyl)ethyl]-3a-methyl-1,3,3a,4,5,6-
hexahydroindol-2-one (5) was prepared in 84% from keto
acid 4 and 3,4-dimethoxyphenethylamine: IR (neat) 1717,
1672, 1514, 1260, 1028 cm-1 1H NMR (400 MHz, CDCl3) δ
;
1.01 (s, 3H), 1.40-1.50 (m, 1H), 1.64-1.78 (m, 3H), 1.98-2.12
(m, 1H), 2.15 (d, 2H, J ) 2.5 Hz), 2.16-2.24 (m, 1H), 2.65-
2.80 (m, 2H), 3.31 (ddd, 1H, J ) 14.3, 8.9, 5.7 Hz), 3.78 (s,
3H), 3.81 (s, 3H), 3.80-3.88 (m, 1H), 4.75 (t, 1H, J ) 3.5 Hz),
6.67-6.75 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 18.4, 22.7,
26.0, 32.4, 33.9, 36.2, 40.4, 46.3, 55.9, 97.2, 111.2, 112.0, 120.8,
131.1, 145.5, 147.6, 148.8, 173.6; HRMS calcd for C19H25NO3
315.1834, found 315.1831.
3a-Methyl-1-phenethyl-1,3,3a,4,5,6-hexahydroindol-2-
one (6) was prepared in 93% from keto acid 4 and phenethy-
lamine: IR (neat) 1718, 1682, 1454, 1407, 1314, 1164 cm-1; 1H
NMR (400 MHz, CDCl3) δ 1.08 (s, 3H), 1.44-1.56 (m, 1H),
1.71-1.81 (m, 3H), 2.02-2.23 (m, 2H), 2.21 (s, 2H), 2.75-2.90
(m, 2H), 3.38 (ddd, 1H, J ) 14.3, 9.2, 5.7 Hz), 3.90 (ddd, 1H,
J ) 13.7, 9.2, 7.3 Hz), 4.79 (t, 1H, J ) 3.5 Hz), 7.16-7.30 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 18.5, 22.8, 26.1, 33.0, 34.1,
36.3, 40.5, 46.4, 97.3, 126.6, 128.6, 129.0, 138.7, 145.7, 173.7;
HRMS calcd for C17H21NO 255.1623, found 255.1622.
11,12-Dimethoxy-4a-methyl-1,2,3,4,4a,5,8,9-octahy-
droindolo[7a,1a]isoquinolin-6-one (8). To a solution of 0.05
g (0.16 mmol) of hexahydroindolone 5 in 3 mL of CH2Cl2 was
added trifluoroacetic acid (0.04 mL, 0.48 mmol). The mixture
was stirred at rt for 4 h, and the solvent was removed under
reduced pressure. The crude product was purified by flash
chromatography to give the title compound 8 as a colorless oil
in 94% yield: IR (neat) 1682, 1515, 1258, 1207, 1093 cm-1;1H
NMR (400 MHz, CDCl3) δ 0.71 (s, 3H), 1.57-1.90 (m, 6H), 1.92
(d, 2H, J ) 16.2 Hz); 2.20 (d, 1H, J ) 13.6 Hz), 2.65 (dd, 1H,
J ) 15.9, 2.9 Hz), 2.82 (t, 1H, J ) 9.5 Hz), 2.86 (t, 1H, J ) 7.3
Hz), 2.99 (ddd, 1H, J ) 13.0, 13.0, 4.1 Hz), 3.84 (s, 3H), 3.86
(s, 3H), 4.24 (ddd, 1H, J ) 13.0, 6.0, 1.6 Hz), 6.59 (s, 1H), 6.94
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.3, 21.5, 26.9, 29.1,
33.7, 34.2, 37.9, 40.5, 42.7, 55.9, 56.3, 64.1, 110.0, 112.2, 126.5,
131.6, 147.0, 147.6, 171.4; HRMS calcd for C19H25NO3 315.1834,
found 315.1840.
3a-Methyl-1-(3-methylbut-3-enyl)-1,3,3a,4,5,6-hexahy-
droindol-2-one (12) was prepared in 81% yield from keto acid
4 and 3-methylbut-3-enylamine: IR (neat) 1717, 1679, 1619,
1
1454, 1406, 1318 cm-1; H NMR (400 MHz, CDCl3) δ 1.14 (s,
3H), 1.44-1.56 (m, 1H), 1.70-1.81 (m, 3H), 1.75 (s, 3H), 2.02-
2.14 (m, 1H), 2.17-2.27 (m, 3H), 2.21 (s, 2H), 3.22 (dt, 1H, J
) 13.7, 6.7 Hz), 3.80 (dt, 1H, J ) 13.7, 8.3 Hz), 4.68 (s, 1H),
4.74 (s, 1H), 4.76 (t, 1H, J ) 3.5 Hz); 13C NMR (100 MHz,
CDCl3) δ 18.6, 22.4, 22.9, 26.3, 34.1, 34.7, 36.3, 37.4, 46.5, 97.1,
112.3, 142.7, 145.7, 173.8; HRMS calcd for C14H21NO 219.1623,
found 219.1620.
2,7a-Dimethyl-3,4,7,7a,8,9,10,11-octahydropyrido[2,1-
i]indol-6-one (13). A solution of hexahydroindolone 12 (0.2
g, 0.9 mmol) in 1 mL of trifluoromethanesulfonic acid was
stirred at rt for 2 h. The mixture was diluted with ice-water
(20 mL) and neutralized with a saturated solution of NaHCO3.
After extraction with ether, the organic layer was combined,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatog-
raphy on silica gel using 50% ether in hexane as the eluent to
give a 3:1 mixture of lactams 13 and 14. Compound 13 was
obtained pure in 75% yield (0.14 g) as a white solid: mp 77-
4a-Methyl-1,2,3,4,4a,5,8,9-octahydroindolo[7a,1a]iso-
quinolin-6-one (9). A solution of hexahydroindolone 6 (0.08
1
79 °C; IR (KBr) 1688, 1452, 1422, 1307 cm-1; H NMR (400
MHz, CDCl3) δ 0.78 (s, 3H), 1.15-1.42 (m, 4H), 1.52-1.65 (m,
3H), 1.68 (s, 3H), 1.77 (d, 1H, J ) 16.0 Hz), 1.83 (dd, 1H, J )
16.8, 4.8 Hz), 1.91 (dq, 1H, J ) 13.0, 2.8 Hz), 2.02-2.14 (m,
(39) Asselin, A. A.; Humber, L. G.; Dobson, T. A.; Komlossy, J.;
Martel, R. R. J. Med. Chem. 1976, 19, 787.
8214 J. Org. Chem., Vol. 69, No. 24, 2004

Cyclization Reaction of Hexahydroindolinone Derivatives
1H), 2.63 (d, 1H, J ) 16.0 Hz), 2.80 (dddd, 1H, J ) 13.0, 11.8,
4.8, 1.3 Hz), 4.03 (ddd, 1H, J ) 13.0, 6.7, 0.6 Hz), 5.49 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 22.0, 22.2, 23.9, 25.7, 29.2, 33.4,
33.6, 36.0, 40.3, 42.4, 62.6, 121.7, 132.3, 172.0; HRMS calcd
for C14H21NO 219.1623, found 219.1631.
2,7a-Dimethyl-1,4,7,7a,8,9,10,11-octahydropyrido[2,1-
i]indol-6-one (14) was obtained from the chromatographic
separation in 25% yield (0.05 g) as a white solid: mp 49-52
°C; IR (KBr) 1697, 1669, 1438, 1394 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.06 (s, 3H), 1.20-1.59 (m, 8H), 1.64 (s, 3H), 1.78-
1.86 (m,1H), 2.12 (s, 2H), 2.16-2.26 (m, 1H), 3.19-3.28 (m,
1H), 4.26-4.35 (m, 1H), 5.29 (brs, 1H); 13C NMR (100 MHz,
CDCl3) δ 20.1, 21.9, 22.2, 24.1, 29.2, 36.0, 36.4, 37.9, 38.2, 45.1,
61.6, 117.1, 131.8, 175.1; HRMS calcd for C14H21NO 219.1623,
found 219.1631.
Formic Acid 2,7a-Dimethyl-6-oxodecahydropyrido-
[2,1-i]indol-2-yl Ester (16). A solution of hexahydroindolone
12 (0.1 g, 0.46 mmol) in 2 mL of anhydrous formic acid was
stirred at rt for 5 h. The mixture was diluted with water (20
mL) and neutralized with a saturated solution of NaHCO3.
After extraction with ether, the organic layer was combined,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatog-
raphy on silica gel using ether as the eluent. A 1:1 mixture of
the two diastereomers of 16 was obtained as the major product
in 58% yield. The minor product (15%) was identified as 2,-
7a-dimethyl-3,4,7,7a,8,9,10,11-octahydropyrido[2,1-i]indol-6-
one (13).
6,9a-Dimethyl-5,6,7,8,9,9a-hexahydro-1H,4H-pyrrolo-
[3,2,1-ij]quinolin-2-one (20). To a solution of the above enol
ether 18 (0.12 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0 °C was slowly
added trifluoroacetic acid (0.12 mL, 1.5 mmol). The mixture
was allowed to warm to rt, stirred for 2 h, and concentrated
under reduced pressure. The crude product was purified by
flash chromatography using 50% ether in hexane as the eluent.
The title compound was obtained as a 1:1 mixture of diaster-
eomers: IR (neat) 1728, 1690, 1404, 1365, 1312 cm-1;1H NMR
(400 MHz, CDCl3) δ 0.92 and 0.96 (d, 3H, J ) 7.1 Hz), 1.08-
1.10 (s, 3H), 1.34-1.50 (m, 2H), 1.63-1.75 (m, 3H), 1.77-2.08
(m, 3H), 2.12-2.21 (m, 3H), 3.14 (td, 1H, J ) 13.8, 3.8 Hz)
and 3.25 (ddd, 1H, J ) 12.4, 8.1, 4.3 Hz), 3.60 (ddd, 1H, J )
12.4, 8.1, 4.8 Hz) and 3.72 (dt, 1H, J ) 12.9, 4.8 Hz); 13C NMR
(100 MHz, CDCl3) δ 17.9, 18.7, 18.8, 19.9, 24.1, 24.9, 25.8, 28.8,
29.5, 29.8, 30.0, 33.9, 34.0, 35.1, 35.2, 35.4, 36.9, 46.8, 47.2,
110.8, 111.3, 137.9, 138.1, 172.7, 172.9; HRMS calcd for C13H19-
NO 205.1467, found 205.1474.
1-(3,3-Diethoxypropyl)-3a-methyl-1,3,3a,4,5,6-hexahy-
droindol-2-one (25) was prepared in 76% yield from keto acid
4 and 3,3-diethoxypropylamine: IR (neat) 1722, 1680, 1408,
1
1129, 1061 cm-1; H NMR (400 MHz, CDCl3) δ 1.16 (t, 3H, J
) 7.0 Hz), 1.17 (t, 3H, J ) 7.0 Hz), 1.21 (s, 3H), 1.43-1.55 (m,
1H), 1.66-1.90 (m, 5H), 2.06 (dtd, 1H, J ) 17.8, 8.6, 3.5 Hz),
2.12-2.20 (m, 1H), 2.19 (s, 2H), 3.21 (ddd, 1H, J ) 14.0, 8.3,
5.7 Hz), 3.38-3.50 (m, 2H), 3.55-3.72 (m, 3H), 4.45 (t, 1H, J
) 5.7 Hz), 4.77 (t, 1H, J ) 3.5 Hz); 13C NMR (100 MHz, CDCl3)
δ 15.5, 18.5, 22.8, 26.1, 31.4, 34.0, 35.4, 36.3, 46.4, 61.6, 61.8,
97.3, 101.3, 145.7, 173.7; HRMS calcd for C16H27NO3 281.1991,
found 281.1986.
The title compound 16 showed the following spectral
1
properties: IR (neat) 1721, 1687, 1445, 1411, 1135 cm-1; H
9a-Methyl-5,6,7,8,9,9a-hexahydro-1H,4H-pyrrolo[3,2,1-
ij]quinolin-2-one (27). To a solution of the above acetal 25
(1.0 mmol) in 10 mL of anhydrous toluene cooled in an ethylene
glycol-CO2 bath were added Et3SiH (0.16 mL, 1.0 mmol) and
SnCl4 (0.12 mL, 1.0 mmol). The solution was allowed to warm
to rt, stirred for 1 h, and then quenched by the addition of 10
mL of water. The mixture was extracted with ether, and the
combined organic phase was dried over MgSO4, filtered, and
concentrated. The crude product was purified by flash chro-
matography on silica gel using 50% ether/hexane as the eluent
to give 27 in 85% yield: IR (neat) 1691, 1676, 1456, 1409, and
1366 cm-1;1H NMR (400 MHz, CDCl3) δ 1.15 (s, 3H), 1.40-
1.51 (m, 1H), 1.60-2.09 (m, 9H), 2.22 (dd, 2H, J ) 20, 15.9
Hz), 3.19 (ddd, 1H, J ) 13.0, 9.5, 3.2 Hz), and 3.77 (dt, 1H, J
) 13.0, 5.1 Hz); 13C NMR (100 MHz, CDCl3) δ 18.9, 21.6, 25.5,
25.7, 27.0, 34.2, 35.3, 38.8, 47.2, 106.8, 138.8, 173.1. Anal.
Calcd for C12H17NO: C, 75.35; H, 8.96; N, 7.32. Found: C,
75.10; H, 9.00; N, 7.20.
1-(4,4-Diethoxybutyl)-3a-methyl-1,3,3a,4,5,6-hexahy-
droindol-2-one (28) was prepared in 75% from keto acid 4
and 4,4-diethoxybutylamine: IR (neat) 1720, 1677, 1401, 1127,
1063 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.15 (s, 3H), 1.18 (t,
6H, J ) 7.0 Hz), 1.45-1.82 (m, 8H), 2.08 (dtd, 1H, J ) 17.8,
8.6, 3.5 Hz), 2.16-2.22 (m, 1H), 2.22 (s, 2H), 3.14-3.24 (m,
1H), 3.46 (dq, 2H, J ) 9.5, 7.3 Hz), 3.56-3.67 (m, 3H), 4.47 (t,
1H, J ) 5.1 Hz), 4.77 (t, 1H, J ) 3.5 Hz); 13C NMR (100 MHz,
CDCl3) δ 15.5, 18.5, 22.2, 22.8, 26.3, 31.1, 34.1, 36.3, 39.0, 46.5,
61.2, 61.5, 97.2, 102.6, 145.8, 173.9; HRMS calcd for C17H29-
NO3 295.2147, found 295.2144.
NMR (400 MHz, CDCl3) δ 0.99 and 1.00 (s, 3H), 1.25-1.50
(m, 5H), 1.52 and 1.69 (s, 3H), 1.53-1.61 (m, 2H), 1.70-1.77
(m, 1H), 1.82-1.90 (m, 2H), 1.95 and 2.09 (d, 2H, J ) 14.8
Hz), 2.12 and 2.45 (dd, 1H, J ) 14.8, 1.4 Hz), 2.36 (m, 1H),
2.82 (dt, J ) 14.3, 7.1 Hz) and 2.90 (ddd, J ) 13.8, 13.8, 1.9
Hz) (1H), 3.90 (ddd, J ) 13.8, 5.2, 1.9 Hz) and 3.94 (dt, J )
14., 5.2 Hz) (1H), 7.88 and 8.00 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 21.5, 21.6, 21.7, 21.8, 23.2, 23.5, 26.2, 28.0, 30.2, 32.7,
33.1, 34.3, 34.5, 35.1, 35.3, 35.7, 36.2, 39.1, 39.2, 39.7, 43.4,
43.6, 62.3, 81.5. 82.4, 160.2, 160.8, 174.7; HRMS calcd for
C15H23NO3 265.1678, found 265.1685.
1-But-3-ynyl-3a-methyl-1,3,3a,4,5,6-hexahydroindol-2-
one (17) was prepared in 67% yield from (1-methyl-2-oxocy-
clohexyl)acetic acid (4) and but-3-ynylamine: IR (neat) 1720,
1678, 1405, 1314, 1169 cm-1 1H NMR (400 MHz, CDCl3) δ
;
1.14 (s, 3H), 1.42-1.53 (m, 1H), 1.68-1.80 (m, 3H), 1.92 (t,
1H, J ) 2.1 Hz), 2.00-2.19 (m, 2H), 2.20 (s, 2H), 2.33-2.43
(m, 2H), 3.30 (ddd, 1H, J ) 13.9, 7.6, 6.0 Hz), 3.80 (dt, 1H, J
) 15.9, 7.6 Hz), 4.77 (t, 1H, J ) 3.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 16.7, 18.5, 22.7, 26.2, 33.9, 36.4, 37.8, 46.3, 70.0, 81.0,
97.4, 145.2, 173.8; HRMS calcd for C13H17NO 203.1310, found
203.1308.
1-(3-Methoxybut-3-enyl)-3a-methyl-1,3,3a,4,5,6-hexahy-
droindol-2-one (18). To a solution of the above but-3-
ynylhexahydroindolone 17 (0.37 g, 1.8 mmol) and NEt3 (0.4
mL, 2.7 mmol) in anhydrous methanol (10 mL) was added
HgCl2 (0.37 g, 1.4 mmol). The suspension was stirred vigor-
ously under reflux for 4 h. The solvent was removed under
reduced pressure, and the residue was diluted with ether. The
precipitate that formed was removed by filtration, and the
filtrate was concentrated under reduced pressure. The crude
oil was purified by flash chromatography on silica gel using
50% of ether in hexane with 3% NEt3 as the eluent. The title
compound 18 was obtained as a colorless oil in 63% yield (0.27
g): IR (neat) 1724, 1677, 1403, 1314, 1083 cm-1; 1H NMR (400
MHz, CDCl3) δ 1.14 (s, 3H), 1.45-1.55 (m, 1H), 1.70-1.80 (m,
3H), 2.01-2.13 (m, 1H), 2.15-2.35 (m, 3H), 2.21 (s, 2H), 3.30
(ddd, 1H, J ) 14.0, 7.4, 6.4 Hz), 3.48 (s, 3H), 3.78 (dt, 1H, J )
14.0, 7.4 Hz), 3.86 (s, 2H), 4.78 (t, 1H, J ) 3.5 Hz); 13C NMR
(100 MHz, CDCl3) δ 18.6, 22.8, 26.3, 32.6, 34.1, 36.3, 37.3, 46.5,
54.9, 82.5, 97.0, 145.7, 161.0, 173.8; HRMS calcd for C14H21-
NO2 235.1572, found 235.1568.
10a-Methyl-4,5,8,9,10,10a-hexahydro-1H-azepino[3,2,1-
hi]indol-2-one (32). To a solution of the above acetal 28 (1.0
mmol) in 10 mL of anhydrous toluene cooled in an ethylene
glycol-CO2 bath were added Et3SiH (0.16 mL, 1.0 mmol) and
SnCl4 (0.12 mL, 1.0 mmol). The solution was allowed to warm
to rt, stirred for 1 h, and then quenched by the addition of 10
mL of water. The mixture was extracted with ether, and the
combined organic phase was dried over MgSO4, filtered, and
concentrated. The crude product was purified by flash chro-
matography on silica gel using 50% ether/hexane as the eluent
to give 32 in 82% yield: IR (neat) 1716, 1662, 1615, 1363, 1173
cm-1 1H NMR (400 MHz, CDCl3) δ 1.14 (s, 3H), 1.41-1.52
;
(m, 1H), 1.69-1.82 (m, 3H), 2.10-2.33 (m, 3H), 2.25 (d, 2H, J
J. Org. Chem, Vol. 69, No. 24, 2004 8215

Padwa et al.
) 1.9 Hz), 2.47 (dddd, 1H, J ) 16.8, 7.0, 5.4, 1.3 Hz), 2.93 (dd,
1H, J ) 13.0, 9.5 Hz), 4.26 (ddd, 1H, J ) 13.0, 5.4, 2.9 Hz),
5.56 (dd, 1H, J ) 11.4, 1.9 Hz), 5.71 (ddd, 1H, J ) 11.4, 7.6,
4.1 Hz); 13C NMR (100 MHz, CDCl3) δ 18.7, 26.1, 29.3, 30.2,
33.6, 37.7, 41.0, 46.7, 108.4, 128.5, 129.3, 143.9, 173.4; HRMS
calcd for C13H17NO 203.1310, found 203.1312.
tube were placed 3-(1-methyl-2-oxocyclohexyl)propionic acid
methyl ester (37) (1.0 mmol), 2-(3,4-dimethoxyphenyl)ethy-
lamine (3.0 mmol), and xylene (1.0 mL). The reaction vessel
was heated in a microwave reactor at 150 W at 160 °C for 5 h.
The reaction mixture was allowed to cool to rt, and the crude
product was purified by flash silica gel chromatography using
a 50% ether in hexane mixture as the eluent. The title
compound 39 was obtained in 67% yield as a colorless oil: IR
(neat) 1663, 1636, 1514, 1261, 1233, 1158, 1028 cm-1;1H NMR
(400 MHz, CDCl3) δ 1.03 (s, 3H), 1.37-1.47 (m, 1H), 1.52-
1.70 (m, 5H), 2.05-2.16 (m, 1H), 2.17-2.27 (m, 1H), 2.46-
2.60 (m, 2H), 2.68 (ddd, 1H, J ) 13.3, 9.5, 7.3 Hz), 2.81 (ddd,
1H, J ) 13.3, 9.5, 7.3 Hz), 3.80-3.88 (m, 2H), 3.83 (s, 3H),
3.86 (s, 3H), 5.13 (dd, 1H, J ) 5.1, 2.5 Hz), 6.73-6.79 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 17.9, 22.9, 24.9, 29.3, 32.5, 33.1,
34.2, 38.2, 45.1, 56.0, 105.0, 111.3, 112.1, 120.7, 130.9, 142.1,
147.6, 148.9, 168.5; HRMS calcd for C20H27NO3 329.1991, found
329.1988.
8,9-Dimethoxy-13a-methyl-1,2,5,6,11,12,13,13a-octahy-
drocyclopenta[2,3]pyrido-[2,1-a]isoquinolin-3-one (40).
To a solution of 0.05 g (0.16 mmol) of hexahydro[1]pyrindin-
2-one 38 in 1.0 mL of CH2Cl2 was added trifluoroacetic acid
(0.1 mL). The mixture was stirred at rt for 16 h, and the
solvent was removed under reduced pressure. The crude
product was purified by flash chromatography to give 40 as a
white solid in 80% yield (0.04 g): mp 118-120 °C; IR (neat)
1633, 1516, 1407, 1258, 1217 cm-1; 1H NMR (400 MHz, CDCl3)
δ 0.78 (s, 3H), 1.47 (dt, 1H, J ) 12.9, 3.3 Hz), 1.93-2.18 (m,
4H), 2.20-2.35 (m, 2H), 2.37-2.52 (m, 4H), 2.66 (ddd, 1H, J
) 14.3, 12.4, 1.9 Hz), 2.88 (ddd, 1H, J ) 16.2, 12.4, 4.3 Hz),
3.83 (s, 6H), 4.87 (dd, 1H, J ) 11.9, 3.8 Hz), 6.55 (s, 1H), 6.80
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.8, 21.5, 29.1, 29.9,
34.1, 39.9, 42.0, 42.5, 44.5, 55.9, 56.2, 73.7, 110.5, 111.8, 129.0,
133.6, 147.1, 147.3, 168.9. Anal. Calcd for C19H25NO3: C, 72.35;
H, 7.99; N, 4.44. Found: C, 72.31; H, 8.04; N, 4.35.
1-(3,3-Diethoxypropyl)-7-ethyl-3a-methyl-1,3,3a,4,5,6-
hexahydroindol-2-one (33). A mixture of 1-(3,3-diethoxypro-
pyl)-3a-methyl-7-vinyl-1,3,3a,4,5,6-hexahydroindol-2-one40 (0.35
g, 1.14 mmol) and 10% of palladium on charcoal (0.05 g) in
absolute ethanol (10 mL) was stirred at rt in a flask equipped
with a balloon of hydrogen gas. After being stirred for 20 h,
the mixture was filtered through a pad of Celite, and the
solvent was removed under reduced pressure. The crude
product was purified by flash chromatography on silica gel
using a 50% ether /hexane mixture as the eluent. The title
compound 33 was obtained in 83% yield (0.29 g) as a colorless
oil: IR (neat) 1714, 1676, 1371, 1133, 1061 cm-1; 1H NMR (400
MHz, CDCl3) δ 0.98 (t, 3H, J ) 7.6 Hz), 1.05 (s, 3H) 1.18 (t,
3H, J ) 7.0 Hz), 1.19 (t, 3H, J ) 7.0 Hz), 1.36-1.48 (m, 1H),
1.60-2.16 (m, 8H), 2.12 (d, 1H, J ) 15.6 Hz), 2.20 (d, 1H, J )
15.6 Hz), 3.32-3.55 (m, 4H), 3.59-3.72 (m, 2H), 3.99 (ddd, 1H,
J ) 14.0, 10.2, 6.0 Hz), 4.51 (t, 1H, J ) 5.7 Hz); 13C NMR (100
MHz, CDCl3) δ 13.3, 15.5, 18.8, 24.7, 25.5, 29.3, 32.2, 34.6,
38.5, 39.1, 47.0, 61.7, 62.4, 101.5, 115.5, 137.8, 175.4; HRMS
calcd for C18H31NO3 309.2304, found 309.2312.
6-Ethoxy-6a-ethyl-9b-hydroxy-9a-methyloctahydropy-
rrolo[3,2,1-ij]quinolin-2-one (35). To a solution of the above
acetal 33 (0.29 g, 0.94 mmol) in 10 mL of anhydrous toluene
cooled in an ethylene glycol-CO2 bath was added SnCl4 (0.11
mL, 0.94 mmol). The solution was allowed to warm to rt,
stirred for 2 h, and then quenched by the addition of 10 mL of
water. The mixture was extracted with ether, and the com-
bined organic phases were dried over MgSO4, filtered, and
concentrated. The crude product was purified by flash chro-
matography on silica gel using 50% ether/hexane as the eluent.
The title compound 35 was obtained as a white solid in 84%
yield (0.22 g): mp 131-133 °C; IR (KBr) 1690, 1454, 1398,
7,8-Dimethoxy-13a-methyl-1,4,5,10,11,12,13,13a-octahy-
dro-2H-3a-azabenzo[d]phenanthren-3-one (41). To a solu-
tion of hexahydro-1H-quinolinone 39 (0.2 g, 0.6 mmol) in 6.0
mL of CH2Cl2 was added several drops of trifluoromethane-
sulfonic acid, and the mixture was stirred at rt for 2 h. The
mixture was diluted with ice-water (20 mL) and neutralized
with a saturated solution of NaHCO3. After extraction with
ether, the organic layer was dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was
purified by flash chromatography on silica gel using ether as
the eluent to give 41 in 80% yield (0.16 g) as a white solid:
1
1098, 1067 cm-1; H NMR (400 MHz, CDCl3) δ 0.76 (t, 3H, J
) 7.1 Hz), 1.08 (s, 3H), 1.22 (t, 3H, J ) 6.7 Hz), 1.30 (dddd,
1H, J ) 14.8, 14.8, 7.6, 1.9 Hz), 1.39 (dt, 1H, J ) 8.6, 13.3
Hz), 1.54 (dt, 1H, J ) 13.8, 3.8 Hz), 1.57-1.72 (m, 4H), 1.75-
1.88 (m, 3H), 1.89-1.99 (m, 1H), 2.26 (d, 1H, J ) 16.9 Hz),
2.32 (d, 1H, J ) 16.9 Hz), 3.16 (ddd, 1H, J ) 13.3, 13.3, 4.8
Hz), 3.36 (ddt, 1H, J ) 9.1, 7.1, 7.1 Hz), 3.49 (t, 1H, J ) 2.9
Hz), 3.67 (ddt, 1H, J ) 9.1, 7.1, 7.1 Hz), 3.94 (dd, 1H, J )
13.3, 6.2 Hz), 6.56 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 7.7,
15.5, 17.4, 19.9, 22.4, 26.0, 26.6, 31.5, 33.5, 38.9, 44.4, 48.9,
66.7, 78.8, 92.8, 171.6. Anal. Calcd for C16H27NO3: C, 68.29;
H, 9.67; N, 4.98. Found: C, 68.57; H, 9.77; N, 4.96.
mp 143-144 °C; IR (KBr) 1631, 1514, 1409, 1258, 1218 cm-1
;
1H NMR (400 MHz, CDCl3) δ 0.62 (s, 3H), 1.14-1.20 (m, 1H),
1.57 (d, 1H, J ) 14.8 Hz), 1.68-1.82 (m, 3H), 1.88-2.00 (m,
2H), 2.22-2.38 (m, 2H), 2.42-2.56 (m, 4H), 2.80-2.90 (m, 2H),
3.84 (s, 3H), 3.85 (s, 3H), 4.85-4.92 (m, 1H), 6.57 (s, 1H), 7.35
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 19.7, 21.9, 23.6, 28.6,
30.0, 30.1, 35.8, 36.1, 37.0, 38.4, 55.6, 56.3, 65.8, 112.1, 112.3,
130.1, 132.4, 145.8, 147.1, 168.4. Anal. Calcd for C20H27NO3:
C, 72.92; H, 8.26; N, 4.25. Found: C, 72.70; H, 8.24; N, 4.26.
The structure of 35 was unequivocally established by an
X-ray crystallographic study.
1-[2-(3,4-Dimethoxyphenyl)ethyl]-4a-methyl-1,3,4,4a,5,6-
hexahydro[1]pyrindin-2-one (38) was prepared in 41%
yield from 3-(1-methyl-2-oxocyclopentyl)propionic acid methyl
ester (36) and 2-(3,4-dimethoxyphenyl)ethylamine: IR (neat)
1664, 1631, 1514, 1261, 1235, 1029 cm-1;1H NMR (400 MHz,
CDCl3) δ 1.04 (s, 3H), 1.60-1.70 (m, 2H), 1.73-1.86 (m, 2H),
2.27 (ddd, 1H, J ) 15.6, 8.9, 3.2 Hz), 2.41-2.64 (m, 3H), 2.75
(t, 2H, J ) 8.6 Hz), 3.66 (dt, 1H, J ) 13.3, 7.9 Hz), 3.83 (s,
3H), 3.85 (s, 3H), 3.90 (dt, 1H, J ) 13.3, 7.9 Hz), 4.78 (t, 1H,
J ) 2.2 Hz), 6.69-6.79 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
21.1, 28.4, 29.7, 32.8, 33.1, 39.6, 42.7, 45.1, 56.0, 101.7, 111.3,
112.2, 120.9, 131.7, 147.3, 147.7, 149.0, 168.7; HRMS calcd
for C19H25NO3 315.1834, found 315.1842.
(2-Oxo-1-phenylthiocyclohexyl)acetic Acid Ethyl Es-
ter (42). To a solution containing 2.1 g (10.2 mmol) of
2-phenythiocyclohexanone41 in 30 mL of THF was added 0.45
g (11.2 mmol) of NaH at 0 °C. The reaction mixture was
allowed to warm to room temperature and was stirred for 1
h. The resulting mixture was added to 1.87 g (11.2 mmol) of
ethyl bromoacetate at room temperature. The solution was
stirred for 8 h at 25 °C and was quenched by the addition of
water. The mixture was extracted with EtOAc, and the
combined organic layers were dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. Purification
of the residue by silica gel column chromatography provided
2.4 g (82%) of keto ester 42 as a colorless oil: IR (neat) 2937,
1-[2-(3,4-Dimethoxyphenyl)ethyl]-4a-methyl-3,4,4a,5,6,7-
hexahydro-1H-quinolin-2-one (39). In a 10 mL reaction
1
(40) Hexahydroindolinone 33 was prepared by the selective bromi-
nation of 28 followed by a palladium-catalyzed cross-coupling reaction
with vinyl tributyltin and a subsequent catalytic hydrogenation of the
vinyl group. Details of the procedure are described in the Supporting
Information.
1733, 1701 cm-1; H NMR (CDCl3, 400 MHz) δ 1.21 (t, 3H, J
(41) Coates, R. M.; Pigott, H. D.; Ollinger, J. Tetrahedron Lett. 1974,
15, 3955.
8216 J. Org. Chem., Vol. 69, No. 24, 2004

Cyclization Reaction of Hexahydroindolinone Derivatives
) 7.2 Hz), 1.72-1.89 (m, 2H), 2.05-2.21 (m, 3H), 2.40 (ddd,
1H, J ) 13.3, 4.0, 2.4 Hz), 2.47 (d, 1H, J ) 16.8 Hz), 2.48-
2.59 (m, 1H), 2.86 (d, 1H, J ) 16.8 Hz), 3.21 (ddd, 1H, J )
15.3, 13.6, 6.0 Hz), 4.07 (dq, 2H, J ) 7.2, 2.8 Hz), 7.29-7.40
(m, 5H); 13C NMR (CDCl3, 100 MHz) δ 14.1, 21.3. 26.0, 36.3,
37.3, 40.7, 58.0, 60.4, 129.0, 129.4, 129.9, 136.9, 170.7, 204.8;
HRMS calcd for C16H20O3SLi (M + Li+) 299.1293, found
299.1289.
25 °C and was then quenched by the addition of water. The
mixture was extracted with EtOAc, and the combined organic
layers were dried over anhydrous MgSO4, filtered, and con-
centrated under reduced pressure. Purification of the residue
by silica gel column chromatography provided 0.59 g (77%) of
aminal 48 as a white solid: mp 81-82 °C; IR (neat) 3251, 2946,
1681, 1514 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.59 (brs, 1H),
1.76-1.92 (m, 2H), 1.98 (d, 1H, J ) 13.6 Hz), 2.18-2.36 (m,
2H), 2.59 (d, 1H, J ) 13.6 Hz), 2.55-2.95 (m, 1H), 3.11 (ddd,
2H, J ) 8.8, 6.0, 3.2 Hz), 3.85 (s, 3H), 3.86 (s, 3H), 3.83-3.87
(m, 1H), 4.50 (t, 1H, J ) 2.8 Hz), 5.81 (d, 1H, J ) 1.6 Hz),
6.74 (d, 1H, J ) 1.6 Hz), 6.75 (dd, 1H, J ) 8.0, 1.6 Hz), 6.81
(d, 1H, J ) 8.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 21.8, 25.2,
29.7, 34.2, 40.7, 54.7, 55.8, 89.7, 111.3, 112.1, 120.3, 120.6,
132.0, 147.5, 148.8, 158.3, 170.6; HRMS calcd for C18H22BrNO4-
Li (M + Li+) 402.0892, found 402.0910.
11,12-Dimethoxy-1,2,8,9-tetrahydroindolo[7a,1a]iso-
quinolin-6-one (49). To a solution containing 1.0 g (2.8 mmol)
of 46 in 10 mL of xylene was added 3 mL of DBU at 25 °C.
The reaction mixture was heated at reflux for 48 h with
stirring. After cooling, water was added and the mixture was
extracted with EtOAc. The combined organic layers were dried
over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. Purification of the residue by silica gel
column chromatography provided 0.62 g (75%) of the R,â,γ,δ-
unsaturated diene-amide 49 as a clear oil: IR (neat) 2929,
1687, 1513 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.84 (dt, 1H, J
) 12.0, 5.6 Hz), 2.14-2.26 (m, 1H), 2.32 (dd, 1H, J ) 12.0, 4.6
Hz), 2.41 (dt, 1H, J ) 19.2, 5.6 Hz), 2.97 (t, 2H, J ) 6.8 Hz),
3.55 (dt, 1H, J ) 12.8, 6.8 Hz), 3.76 (s, 3H), 3.84 (s, 3H), 4.03
(dt, 1H, J ) 12.8, 6.8 Hz), 5.88 (s, 1H), 6.28 (ddd, 1H, J ) 9.6,
5.6, 2.0 Hz), 6.69 (s, 1H), 6.81 (dd, 1H, J ) 9.6, 2.8 Hz), 7.00
(s, 1H); 13C NMR (CDCl3, 100 MHz) δ 24.5, 27.1, 34.9, 37.0,
55.8, 55.9, 64.6, 108.5, 112.0, 118.7, 123.9, 126.2, 128.5, 136.1,
146.8, 148.1, 158.0; HRMS calcd for C18H19rNO3Li (M + Li+)
304.1525, found 304.1516.
1-[2-(3,4-Dimethoxyphenyl)ethyl]-1,4,5,6-tetrahydroin-
dol-2-one (44). To a solution containing 2.3 g (7.9 mmol) of
42 in 16 mL of toluene at room temperature was added 2.1 g
(11.8 mmol) of 3,4-dimethoxyphenethylamine. The reaction
mixture was heated at reflux for 3 h and then cooled to room
temperature. To the resulting mixture was added 1.35 g (11.8
mmol) of trifluoroacetic acid at 25 °C, and the solution was
heated at reflux for an additional 48 h. After cooling, 30 mL
of water was added to the reaction mixture. The mixture was
extracted with EtOAc, and the combined organic layers were
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. Purification of the residue by silica gel
column chromatography provided 1.7 g (73%) of ene-amide 44
as a yellow pale oil: IR (neat) 2832, 1689, 1515 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.79 (m, 2H), 2.28 (dt, 2H, J ) 5.6, 4.8
Hz), 2.60 (dt, 2H, J ) 6.8, 1.6 Hz), 2.80 (t, 2H, J ) 7.6 Hz),
3.73 (t, 2H, J ) 7.6 Hz), 3.85 (s, 6H), 5.47 (dt, 1H, J ) 4.8, 1.6
Hz), 5.74 (d, 1H, J ) 1.6 Hz), 6.69 (d, 1H, J ) 1.6 Hz), 6.74
(dd, 1H, J ) 8.4, 1.6 Hz), 6.79 (d, 1H, J ) 8.4 Hz); 13C NMR
(CDCl3, 100 MHz) δ 23.4, 24.2, 24.5, 34.7, 40.6, 55.77, 55.83,
110.0, 111.1, 112.0, 115.6, 120.6, 131.4, 139.7, 147.1, 147.5,
148.7, 170.1; HRMS calcd for C18H21NO3Li (M + Li+) 306.1681,
found 306.1673.
1-Bromo-11,12-dimethoxy-1,2,3,4,8,9-hexahydroindolo-
[7a,1a]isoquinolin-6-one (46). To a solution containing 1.2
g (4.0 mmol) of 44 in 400 mL of acetonitrile was added 0.78 g
(4.4 mmol) of NBS at 25 °C. The reaction mixture was stirred
for 3 h at 25 °C, and the solvent was removed under reduced
pressure. The mixture was quenched by the addition of water
and extracted with EtOAc, and the combined organic layers
were dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. Purification of the residue by silica
gel column chromatography provided 1.18 g (78%) of the
cyclized product 46 as a white solid: mp 133-135 °C; IR (neat)
Formic Acid 11,12-Dimethoxy-6-oxo-2,6,8,9-tetrahy-
dro-1H-indolo[7a,1a]isoquinolin-2-yl Ester (50). To a solu-
tion containing 0.55 g (1.8 mmol) of 49 in 7 mL of 1,4-dioxane
at room temperature was added 2.0 g (18.5 mmol) of selenium
dioxide and 0.85 g (18.5 mmol) of formic acid. The reaction
mixture was heated at reflux for 7 days with stirring. After
cooling, 15 mL of a 10% NaOH solution was added, and the
mixture was extracted with CHCl3. The combined organic
layers were dried over anhydrous MgSO4, filtered, and con-
centrated under reduced pressure. Purification of the residue
by column chromatography provided 0.09 g (14%) of formate
1
2934, 1686, 1509 cm-1; H NMR (CDCl3, 400 MHz) δ 1.96-
2.27 (m, 4H), 2.80-2.92 (m, 1H), 3.01 (t, 2H, J ) 7.2 Hz), 2.94-
3.08 (m, 1H), 3.56 (dt, 1H, J ) 12.4, 7.2 Hz), 3.87 (s, 3H), 3.82-
3.92 (m, 1H), 4.68 (brs, 1H), 3.88 (s, 3H), 6.10 (d, 1H, J ) 1.6
Hz), 6.75 (s, 1H), 7.00 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ
21.4, 27.4, 28.8, 29.2, 36.2, 55.9, 56.4, 59.7, 68.2, 110.1, 112.5,
124.8, 127.6, 128.1, 146.9, 148.8, 157.5, 169.5; HRMS calcd
for C18H21BrNO3Li (M + H+) 378.0705, found 378.0703.
50 as a yellow pale oil: IR (neat) 2933, 1720, 1686, 1512 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.87 (dd, 1H, J ) 11.2, 10.4 Hz),
2.84 (dd, 1H, J ) 11.2, 5.2 Hz), 2.93-3.103 (m, 2H), 3.58 (dt,
1H, J ) 12.8, 6.4 Hz), 3.77 (s, 3H), 3.85 (s, 3H), 4.00 (dt, 1H,
J ) 12.8, 7.6 Hz), 5.44-5.52 (m, 1H), 6.08 (s, 1H), 6.17 (d, 1H,
J ) 10.0 Hz), 6.71 (s, 1H), 6.80 (s, 1H), 6.99 (dd, 1H, J ) 10.0,
2.4 Hz), 8.02 (d, 1H, J ) 1.2 Hz); 13C NMR (CDCl3, 100 MHz)
δ 27.0, 37.3, 41.1, 55.9, 56.1, 65.9, 68.1, 107.8, 112.4, 121.3,
125.6, 126.5, 127.8, 133.5, 147.2, 148.7, 155.9, 159.9, 170.6;
HRMS calcd for C19H19NO5 (M+) 341.1263, found 341.1263.
7-Bromo-1-[2-(3,4-dimethoxyphenyl)ethyl]-1,4,5,6-tet-
rahydroindol-2-one (47). To a solution containing 0.6 g (1.9
mmol) of 44 in 20 mL of CH2Cl2 was added 0.38 g (2.1 mmol)
of NBS. The reaction mixture was stirred for 1 h at 25 °C and
was quenched by the addition of water. The mixture was
extracted with CH2Cl2, and the combined organic layers were
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. Purification of the residue by silica gel
column chromatography provided 0.64 g (87%) of the bromi-
nated ene-amide 47 as tan solid: mp 122-124 °C; IR (neat)
Another fraction isolated from the column contained 0.09 g
(15%) of 2-hydroxy-11,12-dimethoxy-1,2,8,9-tetrahydroindolo-
[7a,1a]isoquinolin-6-one (51) which was isolated as a tan
2937, 1704, 1509, 1028 cm-1
;
1H NMR (CDCl3, 400 MHz) δ
solid: mp 230-232 °C; IR (KBR) 3419, 2927, 1680, 1510 cm-1
;
1.90 (quint, 2H, J ) 6.4 Hz), 2.62 (dt, 2H, J ) 6.4, 1.6 Hz),
2.81 (t, 2H, J ) 6.4 Hz), 2.85 (ddd, 2H, J ) 8.0, 5.6, 2.0 Hz),
3.85 (s, 3H), 3.87 (s, 3H), 4.16 (ddd, 2H, J ) 8.0, 5.6, 2.0 Hz),
5.74 (s, 1H), 6.77-6.84 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ
35.5, 37.7, 41.7, 55.73, 55.75, 107.6, 111.0, 112.0, 115.2, 120.7,
131.0, 136.9, 147.4, 148.7, 148.8, 170.8; HRMS calcd for C18H20-
BrNO3Li (M + Li+) 384.0787, found 384.0798.
7-Bromo-1-[2-(3,4-dimethoxyphenyl)ethyl]-7a-hydroxy-
1,4,5,6,7,7a-hexahydroindol-2-one (48). To a solution con-
taining 0.58 g (1.9 mmol) of 44 in 20 mL of THF was added
0.38 g (2.1 mmol) of NBS. The mixture was stirred for 1 h at
1H NMR (CDCl3, 400 MHz) δ 1.70 (dd, 1H, J ) 11.6, 10.0 Hz),
2.11 (brs, 1H), 2.81 (dd, 1H, J ) 11.6, 4.8 Hz), 2.90-3.12 (m,
2H), 3.60 (ddd, 1H, J ) 12.8, 6.8, 5.2 Hz), 3.75 (s, 3H), 3.85 (s,
3H), 3.91-4.02 (m, 1H), 4.30 (brs, 1H), 6.02 (s, 1H), 6.30 (d,
1H, J ) 10.0 Hz), 6.71 (s, 1H), 6.79 (s, 1H), 6.87 (dd, 1H, J )
10.0, 2.4 Hz); 13C NMR (CDCl3, 100 MHz) δ 27.0, 37.4, 45.0,
55.9, 56.1, 66.4, 66.6, 108.0, 112.2, 120.1, 123.5, 126.4, 128.4,
139.4, 147.0, 148.5, 157.3, 171.0; HRMS calcd for C18H19NO4
(M+) 313.1314, found 313.1305.
Alcohol 51 could also be obtained from the solvolysis of
formate 50. To a solution of 50 (0.002 g, 0.064 mmol) in EtOH
J. Org. Chem, Vol. 69, No. 24, 2004 8217

Padwa et al.
(3 mL) was added 0.1 mL of acetyl chloride at 25 °C. The
reaction mixture was stirred for 1 h at room temperature.
Removal of the solvent under reduced pressure afforded 0.002
g (100%) of 51 as the exclusive product.
Acknowledgment. We thank the National Insti-
tutes of Health (GM 59384) for generous support of this
work. We also thank our colleague, Dr. Kenneth Hard-
castle, for his assistance with the X-ray crystallographic
studies together with Grant Nos.NSF CHE-9974864 and
NIH S10-RR13673 and the University Research Com-
mittee of Emory University for funds to acquire a
microwave reactor.
(()-Erysotramidine (2). To a mixture containing 0.09 g
(0.27 mmol) of 51 in 7 mL of THF and 4 mL of methyl iodide
was added 0.18 g (3.2 mmol) of NaOH and 0.17 g (0.8 mmol)
of tetraethylammonium bromide. The reaction mixture was
stirred for 36 h at room temperature. The solution was poured
into ice-water, and the resulting mixture was extracted with
CHCl3. The combined organic layers were dried over anhy-
drous MgSO4, filtered, and concentrated under reduced pres-
sure. Purification of the residue by preparative TLC provided
0.08 g (91%) of (()-erysotramidine 2 as a colorless oil:42 IR
Supporting Information Available: Spectroscopic and
experimental procedures for 7-bromo-1-(3,3-diethoxypropyl)-
3a-methyl-1,3,3a,4,5,6-hexahydroindol-2-one and 1-(3,3-di-
ethoxypropyl)-3a-methyl-7-vinyl-1,3,3a,4,5,6-hexahydroindol-
2-one. 1H and 13C NMR spectra for new compounds lacking
elemental analyses together with an ORTEP drawing for
structure 35. The authors have deposited atomic coordinates
for this structure with the Cambridge Crystallographic Data
Centre. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
(neat) 2930, 1666, 1518 cm-1; H NMR (CDCl3, 400 MHz) δ
1.71 (dd, 1H, J ) 11.6, 10.4 Hz), 2.80 (dd, 1H, J ) 11.6, 4.4
Hz), 2.90-3.24 (m, 2H), 3.34 (s, 3H), 3.61 (ddd, 1H, J ) 12.8,
7.2, 6.0 Hz), 3.76 (s, 3H), 3.86 (s, 3H), 3.82-3.88 (m, 1H), 4.00
(ddd, 1H, J ) 12.8, 8.4, 7.2 Hz), 6.02 (s, 1H), 6.33 (d, 1H, J )
10.0 Hz), 6.72 (s, 1H), 6.80 (s, 1H), 6.90 (dd, 1H, J ) 10.0, 2.0
Hz); 13C NMR (CDCl3, 100 MHz) δ 27.0, 37.2, 41.3, 55.8, 56.0,
56.3, 66.3, 74.8, 108.1, 120.2, 124.1, 126.5, 128.6, 136.2, 146.9,
148.5, 157.0, 170.8; HRMS calcd for C19H21NO4Li (M + Li+)
334.1631, found 334.1633.
JO048647F
(42) Toda, J.; Niimura, Y.; Takeda, K.; Sano, T.; Tsuda, Y. Chem.
Pharm. Bull. 1998, 46, 906.
8218 J. Org. Chem., Vol. 69, No. 24, 2004