A study of vinyl radical cyclization using N-alkenyl-7-bromo-substituted hexahydroindolinones

Article abstract of DOI:10.1021/jo048314i

(Chemical Equation Presented) A new method for the synthesis of the octahydropyrrolo[3,2,1-ij]quinoline ring system that possesses the characteristic skeleton of the aspidosperma family of alkaloids has been developed. The method utilizes an intramolecula

Full text of DOI:10.1021/jo048314i

A Study of Vinyl Radical Cyclization Using
N-Alkenyl-7-bromo-Substituted Hexahydroindolinones
Albert Padwa,* Paitoon Rashatasakhon, Ayse Daut Ozdemir, and Jerremey Willis
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
Received September 22, 2004
A new method for the synthesis of the octahydropyrrolo[3,2,1-ij]quinoline ring system that possesses
the characteristic skeleton of the aspidosperma family of alkaloids has been developed. The method
utilizes an intramolecular Diels-Alder reaction of an amido-substituted furan across a tethered
indole π-bond. To apply this strategy to the synthesis of the indole alkaloid spegazzinidine, it was
necessary to address the problem of assembling the final D-ring of the pentacyclic skeleton. Radical
cyclization of a model N-allyl-7-bromo-3a-methylhexahydroindolinone system was found to
preferentially lead to the 6-endo-trig cyclization product, with the best yield being obtained under
high dilution conditions. The six-membered cyclized product is generated through two reaction
pathways: (a) 6-endo-trig ring closure and (b) rearrangement of an intermediate methylene-
cyclopentyl radical obtained by 5-exo-trig cyclization. A number of related 7-bromo-substituted
hexahydroindolinones containing tethered olefinic groups were prepared and found to undergo
efficient cyclization under both radical and palladium-mediated reaction conditions. Vinyl radical
cyclization with several N-butenyl-substituted systems afforded a mixture of 6-exo and 7-endo
cyclization products. A protocol to introduce an ethyl substituent into the C20-position of the
aspidospermidine skeleton was also developed.
The indole alkaloids feature many indoline-containing
compounds with important biological activity1 including
strychnine2 and the clinically used anticancer agents
vincristine and vinblastine.3,4 These compounds share as
part of their structure, the [6,5,6,5]-ABCE ring system
found in aspidospermidine (1) and spegazzinidine (2). The
presence of the sterically congested C(7) quaternary
carbon center represents a particular challenge toward
the synthesis of this family of natural products.5 The
structures of these alkaloids have long attracted the
attention of the synthetic community and a major focus
of interest has been in finding efficient routes for the
introduction of the B/C cyclic junction, shown in aspido-
spermidine 1.6 Our interest in this area led us to consider
an approach to the ABCE tetracyclic core 4 wherein an
amido-substituted furan undergoes an intramolecular
Diels-Alder reaction across a tethered indole π-bond. In
(1) (a) Sza´ntay, C. Pure Appl. Chem. 1990, 62, 1299. (b) Hibino, S.;
Choshi, T. Nat. Prod. Rep. 2002, 19, 148 and earlier reviews in this
series.
(2) For some leading references, see: Kaburagi, Y.; Tokuyama, H.;
Fukuyama, T. J. Am. Chem. Soc. 2004, 126, 10246.
(3) (a) Kutney, J. P.; Ratcliffe, A. H.; Treasurywala, A. M.; Wunderly,
S. Heterocycles 1975, 3, 639. (b) Vukovic, J.; Goodbody, A. E.; Kutney,
J. P.; Misawa, M. Tetrahedron 1988, 44, 325. (c) Kutney, J. P.; Choi,
L. S. L.; Nakano, J.; Tsukamoto, H.; McHugh, M.; Boulet, C. A.
Heterocycles 1988, 27, 1845.
(4) Kuehne, M. E.; Matson, P. A.; Bornmann, W. G. J. Org. Chem.
1991, 56, 513.
(5) Overman, L. E.; Sworin, M. Recent Advances in the Total
Synthesis of Pentacyclic Aspidosperma Alkaloids. In Alkaloids: Chemi-
cal and Biological Perspectives; Belletier, S. W., Ed.; Wiley-Inter-
science: New York, 1985; Vol. 3, pp 275-307.
(6) (a) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.;
Daeniker, H. U.; Schenker, K. J. Am. Chem. Soc. 1954, 76, 4749. (b)
Wenkert, E. J. Am. Chem. Soc. 1962, 84, 98. (c) Magnus, P.; Gallagher,
T.; Brown, P.; Pappalardo, P. Acc. Chem. Res. 1984, 17, 35. (d) Stork,
G.; Dolfini, J. E. J. Am. Chem. Soc. 1963, 85, 2872. (e) Marino, J. P.;
Rubio, M. B.; Cao, G.; de Dios, A. J. Am. Chem. Soc. 2002, 124, 13398.
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Chem. 1986, 51, 2913. (g) Sumi, S.; Matsumoto, K.; Tokuyama, H.;
Fukuyama, T. Org. Lett. 2003, 5, 1891.
10.1021/jo048314i CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/23/2004
J. Org. Chem. 2005, 70, 519-528
519

Padwa et al.
SCHEME 1
SCHEME 2
earlier reports we showed that the [4+2]-cycloaddition
rearrangement sequence7 was remarkably efficient given
that two aromatic rings were compromised in the reaction
(Scheme 1).8 To apply this strategy to the synthesis of
the alkaloid spegazzinidine (2),9 we needed to address
the problem of assembling the final D-ring of the penta-
cyclic skeleton and to insert the necessary ethyl group.
In this paper, we report an account of our efforts dealing
with the preparation of various octahydropyrrolo[3,2,1-
ij]quinolines from readily available amines and 2-(oxo-
cyclohexyl)acetic acid.10
SCHEME 3
Results and Discussion
The potential of using hexahydroindolinone derivatives
such as 4 for the synthesis of various aspidosperma
alkaloids prompted us to first carry out some model
studies to probe the likelihood of this approach. Our
synthesis of the starting bicyclic lactam substrates fol-
lows a methodology similar to that previously described
in the literature.11 Condensation of the appropriate amine
with 1-methyl-2-(oxocyclohexyl)acetic acid 6 under Dean-
Stark conditions in xylene at 140 °C for 1 h afforded the
desired bicyclic lactam in high yield. Our initial inves-
tigation began with the synthesis of hexahydroindolinone
7, which was readily assembled by heating a sample of
ketoacid 6 with 3-(tert-butyldimethylsilyloxy)propyl-
amine. We reasoned that by converting the OTBS func-
tionality into a better leaving group (i.e., X ) Br or OMs),
it might be possible to induce the modestly activated
enamide π-bond to undergo cyclization to give octahy-
dropyrrolo[3,2,1-ij]quinoline 9.12 However, all of our
attempts to convert the OTBS group present in 7 into
the corresponding hydroxyl group resulted in the forma-
tion of 1-oxa-4a-azabenzo[c]inden-5-one 10 as the exclu-
sive product in 72% isolated yield (Scheme 2). To avoid
this undesired iminium ion cyclization, we first prepared
1,3,3a,4,5,6-hexahydroindol-2-one (NH parent) and treated
it with NaH/DMF followed by a subsequent alkylation
with 1,3-dibromobutane. This sequence of reactions af-
forded bromide 8 in 40% overall yield for the two steps.
Unfortunately, all of our efforts to induce the cyclization
of 8 into 9 failed to produce the desired compound. We
were able, however, to bring about the desired cyclization
by using the more activated N-(3,3-diethoxypropyl)-
substituted hexahydroindolinone 11. When 11 was treated
with SnCl4/Et3SiH in toluene it reacted to furnish pyr-
rolo[3,2,1-ij]quinolinone 15 in 85% yield (Scheme 3). The
conversion of 11 into 15 undoubtedly proceeds via the
intermediacy of N-acyliminium ion 12. The most obvious
path available to 12 is proton loss thereby providing 13
as a transient and nondetectable intermediate. More than
likely, under the Lewis acid conditions, 13 suffers loss
of the ethoxy group and the resulting iminium ion 14
reacts further by a hydride transfer from Et3SiH to give
15. Bromide 8 is insufficiently activated to undergo the
cyclization.
Radical-Mediated Cyclizations
Although we were able to effect the desired hexahy-
droindolinone cyclization (i.e., 11 f 15), this approach
had several drawbacks. The high cost of using 3,3-
diethoxypropylamine and the difficulty associated with
the SnCl4/Et3SiH scale-up were most troublesome. It
occurred to us that we might circumvent these trouble-
some issues if we could carry out a free radical-induced
cyclization reaction using 3-(bromopropyl)hexahydroin-
dolinone 8. The development of free radical cyclization
reactions in total synthesis and in new synthetic meth-
odology has been extensively investigated in recent
years.13 Radical cyclizations of highly reactive aryl and
vinyl radicals onto double and triple bonds have proven
to be very useful for construction of both carbocycles and
heterocycles.14 To investigate whether bromo-substituted
hexahydroindolinones could be used as precursors for
(7) (a) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J. Org.
Chem. 1997, 62, 4088. (b) Padwa, A.; Brodney, M. A.; Dimitroff, M. J.
Org. Chem. 1998, 63, 5304. (c) Padwa, A.; Brodney, M. A.; Satake, K.;
Straub, C. S. J. Org. Chem. 1999, 64, 4617.
(8) Lynch, S. M.; Bur, S. K.; Padwa, A. Org. Lett. 2002, 4, 4643.
(9) Djerassi, C.; Brewer, H. W.; Budzikiewicz, H.; Orazi, O. O.;
Corral, R. A. J. Am. Chem. Soc. 1962, 84, 3480.
(10) Padwa, A.; Rashatasakhon, P.; Daut Ozdemir, A.; Willis, J. Org.
Lett. 2004, 6, 917.
(11) (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.
(12) (a) Wilkens, H. J.; Troxler, F. Helv. Chim. Acta 1975, 58, 1512.
(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. J. Org. Chem. 1978, 43, 4183.
520 J. Org. Chem., Vol. 70, No. 2, 2005

Vinyl Radical Cyclization
SCHEME 4
SCHEME 5
radical cyclization chemistry, we explored the reaction
of 8 with n-Bu3SnH under standard radical-forming
conditions. We found, however, that the initially formed
primary radical failed to cyclize on the enamido π-bond
but instead gave the reduction product 16 in 84% yield
even under very low concentrations of n-Bu3SnH (Scheme
4).
We thought that radical cyclization might be enhanced
by working with the more reactive vinyl radical derived
from a 7-bromo-substituted hexahydroindolinone deriva-
tive. Aza heterocycles of various ring sizes have been
obtained by radical addition to N-vinyl amides (enam-
ides).15 However, the use of related compounds containing
the N-vinyl unit such as enaminones has been less
frequently studied.16 As far as we can tell, there were no
examples in the literature describing an intramolecular
addition of an enamido vinyl radical onto any type of
π-system when we initiated our studies with hexahy-
droindolinone 18 (vide infra). We reasoned that the
selective bromination of the enamido π-bond present in
17 (Scheme 5) should be extremely rapid and efficient
since analogous examples are known.17 We hoped that
generation of a cyclohexenyl radical (i.e., 19) from
bromide 18 would initiate a 6-endo-trig cyclization ulti-
mately leading to 15 after abstraction of hydrogen from
tributyltin hydride (Scheme 5). A model study designed
to test the feasibility of this concept began by the
condensation of allylamine with 1-methyl(2-oxocyclo-
hexyl)acetic acid to give the desired bicyclic lactam 17
in 90% yield. Hexahydroindolinone 17 was subsequently
treated with bromine in CH2Cl2 followed by reaction with
NEt3 to deliver the cyclization precursor 18 in 95% yield.
Exposure of 18 to several radical cyclization conditions
led to various mixtures of the 6-endo and 5-exo-trig
cyclization products 15 and 23, with the best yield and
product ratio obtained by using n-Bu3SnH/AIBN in
refluxing benzene under slow addition conditions.
(13) (a) Neumann, W. P. Synthesis 1987, 665. (b) Curran, D. P.
Synthesis 1988, 417 and 489. (c) Giese, B. Radicals in Organic
Synthesis: Formation of Carbon-Carbon Bonds; Pergamon Press:
Oxford, UK, 1986. (d) Studer, A.; Bossart, M. Tetrahedron 2001, 57,
9649. (e) Aldabbagh, F.; Bowman, W. R. Contemp. Org. Synth. 1997,
4, 261. (f) Curran, D. P. Radical Addition Reactions. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
UK, 1991; Vol. 4, p 715. (g) Radicals in Organic Synthesis; Renaud,
P., Sibi, M. E., Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vols. 1
and 2.
(14) (a) Addition to carbon-carbon double bonds: Togo, H.; Kikuchi,
O. Tetrahedron Lett. 1988, 29, 4133. (b) Dittami, J. P.; Ramanathan,
H. Tetrahedron Lett. 1988, 29, 45. (c) Clark, A. J.; Jones, K. Tetrahe-
dron Lett. 1989, 30, 5485 and references therein. (d) Hart, D. J.; Wu,
S. C. Tetrahedron Lett. 1991, 32, 4099. (e) Clark, A. J.; Jones, K.
Tetrahedron 1992, 48, 6875. (f) Glover, S. A.; Warkentin, J. J. Org.
Chem. 1993, 58, 2115. (g) Clark, A. J.; Davies, D. I.; Jones, K.;
Millbanks, C. J. Chem. Soc., Chem. Commun. 1994, 41. (h) Banik, B.
K.; Subbaraju, G. V.; Manhas, M. S.; Bose, A. K. Tetrahedron Lett.
1996, 37, 1363. (i) Fiumana, A.; Jones, K. Chem. Commun. 1999, 1761.
(j) Jones, K.; Brunton, S. A.; Gosain, R. Tetrahedron Lett. 1999, 40,
8935. (k) Addition to carbon-carbon triple bonds: Brunton, S. A.;
Jones, K. J. Chem. Soc., Perkin Trans. 1 2000, 763. (l) Addition to
carbon-nitrogen double bonds: Booth, S. E.; Jenkins, P. R.; Swain,
C. J.; Sweeney, J. B. J. Chem. Soc., Perkin Trans. 1 1994, 3499. (m)
Takano, S.; Suzuki, M.; Ogasawara, K. Heterocycles 1994, 37, 149. (n)
Gioanola, M.; Leardini, R.; Nanni, D.; Pareschi, P.; Zanardi, G.
Tetrahedron 1995, 51, 2039.
Since their introduction in 1982,18 vinyl radical cy-
clizations have been widely used in organic synthesis,13,19
although preparative sequences incorporating vinyl radi-
cals as part of a heterocyclic array are much less
common.20 Seminal studies by the groups of Beckwith21
and Stork22 have shown that, under tin hydride mediated
reaction conditions, vinyl radical cyclization gives a
mixture of both 5-exo and 6-endo products. The kinetic
work by Beckwith revealed that formation of the six-
membered ring is not solely due to a 6-endo-trig cycliza-
tion but is the result of a rapid rearrangement of the
methylene-cyclopentyl radical, via a reversible 3-exo-trig
cyclization.23 We thought that by keeping the hydride
concentration low, rearrangement of the kinetically
formed radical 20 derived from bromide 18 to the
thermodynamically more stable radical 21 would occur,
(17) (a) Wei, L.-L.; Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas,
C. J.; Hsung, R. P. Tetrahedron 2001, 57, 459. (b) Goffin, E.; Legrand,
Y.; Viehe, H. G. J. Chem. Res., Synop. 1977, 105.
(15) For some recent examples of the use of enamides as radicalo-
philes, see: (a) D’Annibale, A.; Nanni, D.; Trogolo, C.; Umani, F. Org.
Lett. 2000, 2, 401. (b) Davies, D. T.; Kapur, N.; Parsons, A. F.
Tetrahedron Lett. 1999, 40, 8615. (c) Clark, A. J.; Dell, C. P.; Ellard,
J. M.; Hunt, N. A.; McDonagh, J. P. Tetrahedron Lett. 1999, 40, 8619.
(d) Baker, S. R.; Burton, K. I.; Parsons, A. F.; Pons, J.-F.; Wilson, M.
J. Chem. Soc., Perkin Trans. 1 1999, 427. (e) Ishibashi, H.; Inomata,
M.; Ohba, M.; Ikeda, M. Tetrahedron Lett. 1999, 40, 1149. (f) Ishibashi,
H.; Ohata, K.; Niihara, M.; Sato, T.; Ikeda, M. J. Chem. Soc., Perkin
Trans. 1 2000, 547. (g) Ishibashi, H.; Kato, I.; Takeda, Y.; Kogure, M.;
Tamura, O. Chem. Commun. 2000, 1527.
(18) Stork, G.; Baine, N. H. J. Am. Chem. Soc. 1982, 104, 2321.
(19) (a) Giese, B.; Kopping, B.; Go¨bel, T.; Dickhaut, J.; Thoma, G.;
Kulicke, K. J.; Trach, F. Org. React. 1996, 48, 301. (b) Motherwell, W.
B.; Crich, D. Free Radical Reactions in Organic Synthesis; Academic
Press: London, UK, 1992. (c) Jasperse, C. P.; Curran, D. P.; Fevig, T.
L. Chem. Rev. 1991, 91, 1237.
(20) Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P. Tetrahe-
dron 2004, 60, 6239.
(21) Beckwith, A. L. J.; O’Shea, D. M. Tetrahedron Lett. 1986, 27,
4525.
(16) Middleton, D. S.; Simpkins, N. S.; Terrett, N. K. Tetrahedron
Lett. 1989, 30, 3865.
(22) Stork, G.; Mook, R., Jr. Tetrahedron Lett. 1986, 27, 4529.
J. Org. Chem, Vol. 70, No. 2, 2005 521

Padwa et al.
SCHEME 6
SCHEME 7
leading to product 15. Comparison of the strain energies
of 20 and 21, as well as radical stability, supports this
idea. Indeed, when 18 (0.01 M) was treated with tribu-
tyltin hydride and a catalytic amount of AIBN, six-
membered-ring product 15 was the major product formed
in 89% yield. In contrast, when bromide 18 was treated
with n-Bu3SnH at a concentration of 0.1 M, a significant
quantity (20%) of the 5-exo cyclization product 23 (3:1
mixture of diastereomers) was obtained along with the
6-endo cyclization product 15 in a ratio of 1:3, together
with the simple reduction product 17 (19%). These results
clearly indicate that the vinyl radical rearrangement
pathway is responsible, to a considerable extent, for the
regiochemical outcome of the reaction.
The preferential formation of the pyrrolo[3,2,1-ij]-
quinoline ring system from hexahydroindolinone 18
stands in marked contrast with intramolecular aryl
radical cyclization studies with somewhat related N-vinyl
amides. Radical cyclization of N-benzyl enamides such
as 24 has been studied and found to furnish a product
derived from exclusive 5-exo-trig closure (25).24 A similar
reactivity profile was noted in an aryl cyclization reaction
involving indole 26 (Scheme 6). Thus, the primary
product obtained from the tin-induced radical cyclization
of iodide 26 was that derived from a 5-exo-trig spirocy-
clization at C2 of the indole ring.25,26 With these related
systems, radical rearrangement is unlikely to occur as
this would disrupt aromaticity and consequently only the
kinetically derived product from 5-exo-trig cyclization is
observed.
systems is presumably reflective of the slower rate of
addition to the enamido π-bond.24 The successful cycliza-
tion of 28 encouraged us to also apply the reaction to the
simpler 8-bromohexahydro-1H-quinolinone system 32.
Gratifyingly, subjecting a sample of 32 to the standard
radical conditions furnished the cyclized pyrido[3,2,1-jk]-
carbazolonone 33 in 81% yield, thereby demonstrating
the facility of the 5-exo-trig cyclization pathway (Scheme
7).26,27 At this juncture, we decided to extend our studies
toward the homologous N-butenyl-substituted hexahy-
droindolinone 34. A review of the literature revealed,
somewhat surprisingly, that simple 1,6-heptadienyl radi-
cals have not been thoroughly investigated.13 This state
of affairs is most likely attributable to the poorer
prospects for synthetic utility of this higher homologue
of the 1,5-hexadienyl radical. On the basis of using the
parent 6-heptenyl radical as a model,28 the rate of 6-exo-
trig cyclization is expected to be an order of magnitude
slower than the 1,5-hexadienyl cyclization, its ring
closure should be considerably less regioselective, and it
is also possible that a [1,5]-hydrogen atom transfer could
occur to produce a 1-butenylallyl-type radical. A solution
of 34 in benzene was treated with n-Bu3SnH/AlBN at 80
°C for 12 h.
Workup and chromatography led to a 7:2 mixture of
the 6-exo and 7-endo cyclization products.29 The regio-
chemical preference in cyclization of vinyl radicals is
known to parallel that of the alkyl analogues.30 Although
6-exo-trig and 7-endo-trig modes of cyclization are pos-
sible with hexahydroindolinone 34, six-membered-ring
formation predominates (Scheme 8). Interestingly, when
7-bromo-N-(3-bromobut-3-enyl)hexahydroindolinone 37
was reacted with n-Bu3SnH/AlBN under similar condi-
tions, the same two products were formed but in a
strikingly different ratio. With this system, the preferred
route now corresponds to 7-endo-trig cyclization leading
to 36 in 72% yield together with minor quantities of the
6-exo cyclized product 35 (18%). The presence of a
The cyclization method was next extended to the
N-benzyl-substituted hexahydroindolinones 28 and 29.
Exposure of bromo-enamide 28 to n-Bu3SnH under
standard radical forming conditions furnished pyrrolo-
[3,2,1-de]phenanthridinone 30 in 68% yield together with
27% of the reduced hexahydroindolinone 31. In this case,
selective 6-endo cyclization took place on the aromatic
ring. Interestingly, the closely related o-bromobenzyl-
substituted hexahydroindolinone 29 failed to cyclize but
instead gave largely the reduction product 31 in 75%
yield. The different behavior observed with these two
(23) More recently, Crich’s group reported preferential formation
of the 5-exo product when the reaction was conducted in a rapid radical
quenching environment (i.e., PhSeSePh/Bu3SnH), reconfirming that
the five-membered ring closure is the kinetically favored process, see:
Crich, D.; Hwang, J.-T.; Liu, H. Tetrahedron Lett. 1996, 37, 3105.
(24) Navarro-Va´zquez, A.; Garcia, A.; Dominguez, D. J. Org. Chem.
2002, 67, 3213.
(27) The cyclization of 32 to 33 is somewhat related to systems
studied by Ishibashi and co-workers. For leading references, see:
Ishibashi, H.; Ishita, A.; Tamura, O. Tetrahedron Lett. 2002, 43, 473.
(28) (a) Beckwith, A. L. J.; Moad, G. J. Chem. Soc., Chem. Commun.
1974, 472. (b) Chatgilialoglu, C.; Ingold, K. U.; Scaiano, J. C. J. Am.
Chem. Soc. 1981, 103, 7739. (c) Newcomb, M. Tetrahedron 1993, 49,
1151.
(25) (a) Tsuge, O.; Hatta, T.; Tsuchiyama, H. Chem. Lett. 1998, 155.
(b) Flanagan, S. R.; Harrowven, D. C.; Bradley, M. Tetrahedron Lett.
2003, 44, 1795.
(29) Pyrrolo[3.2.1-ij]quinolin-2-one 35 was obtained as
a 2.3:1
mixture of diastereomers.
(30) Beckwith, A. L. J.; Ingold, K. U. In Rearrangement in Ground
and Excited States; de Mayo, P., Ed.; Academic Press: New York, 1980.
(26) (a) Escolano, C.; Jones, K. Tetrahedron Lett. 2000, 41, 8951.
(b) Escolano, C.; Jones, K. Tetrahedron 2002, 58, 1453.
522 J. Org. Chem., Vol. 70, No. 2, 2005

Vinyl Radical Cyclization
SCHEME 8
SCHEME 10
SCHEME 9
product.35 In contrast, radical cyclization mediated by
tributyltin hydride leads to the reduced product.13 Both
processes are generally performed under mild conditions
and tolerate many functional groups. However, our
attempts to induce the cyclization of 7-bromohexahy-
droindolinone 34 to diene 41 under standard experimen-
tal conditions led only to the reduced N-butenyl system
42 (Scheme 10). The structure of 42 was unequivocally
established by comparison with a sample prepared by
treating 1-methyl-2-(oxocyclohexyl)acetic acid (6) with
3-butenyl-1-amine (Scheme 10). A successful synthesis
of diene 41 was eventually carried out by an intramo-
lecular Stille cross-coupling reaction36 of hexahydroin-
dolinone 43. The intramolecular Stille reaction was
performed with PdCl2(PPh3)2 (5 mol %) as catalyst, using
a microwave reactor at 100 °C. To our surprise, the
palladium-catalyzed reaction of 43 gave the seven-
membered cyclized diene 44 as the major product in 48%
yield together with lesser quantities of the six-ring diene
41 (16%). The formation of 44 presumably results from
a preferential 7-endo-trig cyclization, and the regiochemi-
cal outcome is similar to that encountered with the
radical cyclization of dibromide 37 (see Scheme 8).
The reluctance of N-butenylhexahydroindolinone 34 to
undergo a 6-exo-trig Pd(0)-catalyzed carbocyclization led
us to investigate the influence of the size of the N-alkenyl
substituent on the course of the reaction. We found that,
in contrast to 34, the palladium-mediated cyclization of
N-allylhexahydroindolinone 18 in the presence of vinyl
tributyltin under Jeffrey conditions34 led to 1H,4H-
pyrrolo[3,2,1-ij]quinolinone 46 in 68% yield as a 6.5:1
mixture of diastereomers. The formation of 46 can be
explained in terms of a 6-endo-trig cyclization followed
by a subsequent trapping of the initially formed pal-
ladium intermediate 45 with the vinyl tin reagent.
Presumably the 6-endo-trig mode of cyclization is en-
tropically favored over the more demanding 6-exo-trig
process that is required for hexahydroindolinone 34.
The remaining step in our planned approach toward
spegazzinidine (2) (Scheme 1) was to introduce the
3-bromo substituent on the N-but-3-enyl π-bond suf-
ficiently retards the 6-exo-trig cyclization, so that 7-endo
closure now becomes the predominant path. Formation
of azepine[3,2,1-hi]indolone 36 from the initially gener-
ated 7-endo cyclized radical would involve hydrogen atom
abstraction from n-Bu3SnH followed by further reaction
of the resulting secondary bromide with tributyltin
radical in the traditional manner. The isolation of 35 as
the minor product from this reaction is also consistent
with the suggestion that the 6-exo cyclized radical (i.e.,
39) is rapidly quenched by hydrogen abstraction to give
tertiary bromide 40, which is then reduced under the
reaction conditions (Scheme 9). Another possible expla-
nation is that radical 39 ejects the adjacent bromine atom
to give diene 41, which in turn is reduced to 35.31
Although this pathway seems less likely, we decided to
prepare a sample of 41 in order to probe the likelihood
of this possibility. We found (vide infra) that when diene
41 was subjected to the standard n-Bu3SnH/AlBN condi-
tions, it could be recovered unchanged, thereby eliminat-
ing this mechanistic possibility.
Palladium-Mediated Cyclizations
Our first attempt toward the synthesis of diene 41
involved an intramolecular Heck reaction.32 Cyclization
reactions mediated by palladium are often complemen-
tary to those proceeding by radical intermediates.33 They
often occur from the same starting material (i.e., aromatic
or vinyl halides carrying an unsaturated chain) and lead
to cyclized products with different oxidation states.34 The
palladium-mediated reaction delivers the unsaturated
(34) (a) Larock, R. C.; Babu, S. Tetrahedron Lett. 1987, 28, 5291.
(b) Grigg, R.; Sridharan, V.; Stevenson, P.; Sukirthalingam, S.;
Worakun, T. Tetrahedron 1990, 46, 4003. (c) Grigg, R.; Sridharan, V.;
Stevenson, P.; Sukirthalingam, S. Tetrahedron 1989, 45, 3557.
(35) (a) Rawal, V. H.; Michoud, C. Tetrahedron Lett. 1991, 32, 1695.
(b) Rawal, V. H.; Michoud, C.; Monestel, R. F. J. Am. Chem. Soc. 1993,
115, 3030. (c) Rawal, V. H.; Iwasa, S. J. Org. Chem. 1994, 59, 2685.
(36) (a) Marsault, E.; Deslongchamps, P. Org. Lett. 2000, 2, 3317.
(b) Bru¨ckner, S.; Abraham, E.; Klotz, P.; Suffert, J. Org. Lett. 2002, 4,
3391. (c) Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem. 1990,
55, 1857.
(31) Still another possibility is the occurrence of a 1,2-bromo group
migration followed by quenching the tertiary radical and eventual
reduction of the resulting primary bromide.
(32) Heck, R. F. Vinyl Substitution with Organopalladium Inter-
mediates. In Comprehensive Organic Synthesis; Trost, B., Ed.; Perga-
mon Press: Oxford, UK, 1991; Vol. 4, p 842.
(33) Berteina, S.; De Mesmaeker, A. Synlett 1998, 1227.
J. Org. Chem, Vol. 70, No. 2, 2005 523

Padwa et al.
SCHEME 11
SCHEME 12
point, we decided to stop further work with the model
system as we assumed that we would eventually be able
to convert the dichloromethyl group into an ethyl sub-
stituent (perhaps via the corresponding aldehyde).
In summary, a new strategy for the synthesis of indole
alkaloid derivatives has been developed that should be
amenable to the preparation of certain aspidosperma
alkaloids such as spegazzinidine. This approach involves
an intramolecular Diels-Alder reaction between an
N-allyl-substituted amidofuran moiety tethered onto an
indole component to deliver a cycloadduct in which the
ABCE tetracyclic core of aspidospermidine is rapidly
assembled. Radical cyclization of a model N-allyl-7-
bromo-3a-methylhexahydroindolinone preferentially led
to the 6-endo-trig cyclization product, with the best yield
being obtained under high dilution conditions. The six-
membered cyclized product is generated through two
reaction pathways: (a) 6-endo-trig ring closure and (b)
rearrangement of an intermediate methylenecyclopentyl
radical obtained by 5-exo-trig cyclization. We have also
developed a protocol to introduce an ethyl substituent
into the C20-position of the aspidospermidine skeleton.
The present methodology should be useful for the con-
struction of other heterocyclic ring systems. Further work
on these cyclizations and the synthesis of spegazzinidine
and its analogues is currently underway and will be
reported in due course.
Experimental Section
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in flame-dried glassware under
an atmosphere of dry argon. The microwave reactor and
reaction vessels were purchased from CEM Corporation. All
solids were recrystallized from ethyl acetate/hexane for ana-
lytical data.
General Procedure for the Preparation of Hexahy-
droindol-2-ones. In a 35 mL reaction tube were placed (1-
methyl-2-oxocyclohexyl)acetic acid (6)40 (2.0 mmol), the appro-
priate amine (2.2 mmol), and xylene (5 mL). The tube was
sealed and then heated in an oil bath at 160 °C for 1 h. An
alternative procedure involved heating the mixture in a
microwave reactor at 160 °C for 10 min at 100 W. The reaction
mixture was allowed to cool to room temperature, the solvent
was removed, and the residue was purified by flash silica gel
chromatography, using a 50% ether/hexane mixture as the
eluent.
1-[3-(tert-Butyldimethylsilanyloxy)propyl]-3a-methyl-
1,3,3a,4,5,6-hexahydroindol-2-one (7). To a solution of
1-amino-3-propanol (8.4 mL, 110 mmol) and TBDMSCl (18.2
g, 120 mmol) in CH2Cl2 (200 mL) was added NEt3 (23 mL,
165 mmol). The cloudy mixture was vigorously stirred at room
temperature for 12 h. The resulting clear solution was washed
with water and the organic layer was dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
oil was purified by distillation (bp 65-70 °C at 3.5 mm) to
give 3-(tert-butyldimethylsilanoxy)propylamine in 97% yield.41
A mixture of the above amine (1.0 g, 5.3 mmol) and
(1-methyl-2-oxocyclohexyl)acetic acid (6) (0.75 g, 4.4 mmol) in
xylene (4 mL) was heated in a sealed tube at 180 °C for 2 h.
After being cooled to room temperature, the mixture was
concentrated under reduced pressure and the residue was
subjected to silica gel column chromatography, using a 30%
necessary ethyl group at the C20-position with the correct
stereochemistry starting from enamide 5. Since there
were several concerns that we had about this approach,
we decided to carry out some model studies using
octahydropyrrolo[3,2,1-ij]quinoline 15 (Scheme 12). We
found that addition of dichlorocarbene to 15 proceeded
uneventfully and gave the expected amido-dichlorocyclo-
propane 47 as a single diastereomer.37 The stereochem-
istry of the carbene addition was found to proceed from
the least hindered position cis to the methyl group. This
was established by the procurement of an X-ray crystal
structure of monochloride 48 that was, in turn, obtained
from the zinc-acetic acid induced reduction of 47. To
complete the model study, we needed to reduce the
lactam carbonyl group and regioselectively open the
cyclopropane ring. This was accomplished by first con-
verting the amido group in 47 to the corresponding
thioamide with use of Lawesson’s reagent,38 which pro-
vided 49 in 94% yield. Treatment of 49 with methyl
iodide/NaBH4 gave 6a-dichloromethyl-9a-methyldecahy-
dropyrrolo[3,2,1-ij]quinoline 52 in 56% yield. The ex-
clusive formation of 52 from this reaction can be ration-
alized by assuming that the initially formed tricyclic
amine 50 is sufficiently nucleophilic to induce preferen-
tial cleavage of the cyclopropane bond, which leads to the
most stable zwitterionic intermediate (i.e., 51).39 Further
reduction of iminium ion 51 with NaBH4 gives 52. At this
(37) (a) Wentrup, C. Adv. Heterocycl. Chem. 1981, 28, 231. (b) Conia,
J.; Blanco, L. In Current Trends in Organic Synthesis; Nozaki, H., Ed.;
Pergamon: Oxford, UK, 1983; p 331. (c) Nelson, D. J. Tetrahedron Lett.
1999, 40, 5823.
(38) Scheibye, S.; Pedersen, B. S.; Lawesson, S. O. Bull. Soc. Chim.
Belg. 1978, 87, 229.
(39) Lee, J.; Sun, J. U.; Blackstock S. C.; Cha, J. K. J. Am. Chem.
Soc. 1997, 119, 10241.
(40) Asselin, A. A.; Humber, L. G.; Dobson, T. A.; Komlossy, J.;
Martel, R. R. J. Med. Chem. 1976, 19, 787.
(41) Prabhakaran, P. C.; Gould, S. J.; Orr, G. R.; Coward, J. K. J.
Am. Chem. Soc. 1988, 110, 5779.
524 J. Org. Chem., Vol. 70, No. 2, 2005

Vinyl Radical Cyclization
Et2O in hexane mixture as the eluent, to give (1.3 g, 93%) of
the titled compound 7 as a colorless oil; IR (neat) 1709, 1690,
1464, 1348, and 1316 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.01
(s, 3H), 0.02 (s, 3H), 0.86 (s, 9H), 1.14 (s, 3H), 1.49 (ddd, 1H,
J ) 11.9, 11.9, and 5.7 Hz), 1.65-1.80 (m, 5H), 2.03-2.11 (m,
1H), 2.14-2.22 (m, 1H), 2.20 (s, 2H), 3.27 (ddd, 1H, J ) 13.8,
8.1, and 5.7 Hz), 3.58 (t, 2H, J ) 6.2 Hz), 3.64 (ddd, 1H, J )
14.3, 8.1, and 6.7 Hz), 4.81 (t, 1H, J ) 3.8 Hz); 13C NMR (100
MHz, CDCl3) δ -5.2, 18.4, 18.5, 22.7, 26.0, 26.2, 30.3, 34.0,
36.3, 36.3, 46.6, 60.7, 97.2, 145.9, and 173.8; HRMS calcd for
C18H33NO2Si 323.2281, found 323.2289.
SnCl4 (0.12 mL, 1.0 mmol). The solution was allowed to warm
to room temperature, 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, flitered, and concentrated. The crude product was
purified by flash chromatography on silica gel, using 50%
ether/hexane as the eluent, to give 15 in 85% yield; IR (neat)
1
1691, 1676, 1456, 1409, and 1366 cm-1; H 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 and 15.9 Hz), 3.19 (ddd, 1H, J ) 13.0,
9.5, and 3.2 Hz), and 3.77 (dt, 1H, J ) 13.0 and 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, and 173.1. Anal. Calcd for C12H17-
NO: C, 75.35; H, 8.96; N, 7.32. Found: C, 75.10; H, 9.00; N,
7.20.
1-(3-Bromopropyl)-3a-methyl-1,3,3a,4,5,6-hexahydroin-
dol-2-one (8). To a solution of keto acid 6 (1.0 g, 5.9 mmol) in
benzene (15 mL) was added oxalyl chloride (1.5 mL, 17.6 mmol)
and the mixture was stirred at room temperature for 2 h. The
solvent was removed under reduced pressure and the residue
was dissolved in THF (15 mL) and cooled in an ice bath. A
30% aqueous solution of NH4OH (10 mL) was slowly added.
The reaction mixture was stirred at 0 °C for 2 h and was then
partitioned between EtOAc and water. The organic layer was
separated and the aqueous phase was extracted with EtOAc.
The combined organic phase was dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was
taken up in CH2Cl2 (15 mL) and p-TsOH (0.05 g) was added.
The mixture was heated at reflux for 6 h and the solvent was
subsequently removed under reduced pressure. The crude
product was purified by flash silica gel chromatography to give
3a-methyl-1,3,3a,4,5,6-hexahydroindol-2-one as a white solid
in 58% yield; mp 103-105 °C; IR (KBr) 1717, 1679, 1458, 1356,
1-Allyl-7-bromo-3a-methyl-1,3,3a,4,5,6-hexahydroindol-
2-one (18). A solution of the above enamide 17 (0.6 g) in CH2-
Cl2 (25 mL) was cooled in an ice bath. Bromine (0.13 mL) was
slowly added via a syringe and the colorless mixture was
stirred for 5 min at 0 °C. Triethylamine (1.1 mL) was added
in one portion and the mixture was allowed to warm to room
temperature, stirred for 10 min, and washed with water. The
organic phase was separated, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was
purified by flash silica gel chromatography, using a 30% Et2O/
hexane mixture as the eluent. The titled compound 18 was
obtained as a colorless oil in 96% yield; IR (neat) 1725, 1670,
1328, 1175, and 1083 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.16
(s, 3H), 1.54-1.65 (m, 1H), 1.73-1.93 (m, 3H), 2.23 (d, 1H, J
) 15.6 Hz), 2.33 (d, 1H, J ) 15.9 Hz), 2.57 (dd, 2H, J ) 8.6
and 4.4 Hz), 4.48 (dd, 1H, J ) 15.6 and 6.4 Hz), 4.55 (ddt, 1H,
J ) 15.6, 5.4, and 1.6 Hz), 5.17 (dd, 1H, J ) 10.4 and 1.3 Hz),
5.25 (dd, 1H, J ) 17.2 and 1.6 Hz), and 5.74-5.85 (m, 1H);
13C NMR (CDCl3, 100 MHz) δ 20.6, 25.5, 33.7, 35.9, 42.3, 43.8,
46.3, 96.9, 117.8, 133.0, 142.0, and 174.7; HRMS calcd for
C12H16BrNO 269.0416, found 269.0427.
5,8a-Dimethyl-4,5,6,7,8,8a-hexahydro-1H-pyrrolo[3,2,1-
hi]indol-2-one (23). To a solution of the above bromo-enamide
18 (0.2 g, 0.7 mmol) in benzene (70 mL) was added n-Bu3SnH
(0.4 mL, 1.1 mmol) and AIBN (0.012 g, 0.07 mmol). The
mixture was heated at reflux for 12 h and then the solvent
was removed under reduced pressure. The crude reaction
mixture was purified by flash chromatography on silica gel.
The major product 15 isolated from the reaction in 71% yield
was identified as 9a-methyl-5,6,7,8,9,9a-hexahydro-1H,4H-
pyrrolo[3,2,1-ij]quinolin-2-one (15). The minor product 23 was
a colorless oil that was isolated in 21% yield and consisted of
a 3:1 mixture of diastereomers; IR (CHCl3) 1678, 1447, 1419,
and 1055 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.19 (s, 3H), 1.30
(d, 3H, J ) 7.2 Hz), 1.47-1.60 (m, 5H), 1.62-1.86 (m, 2H),
2.09 (d, 1H, J ) 16.0 Hz), 2.74 (d, 1H, J ) 16.0 Hz), 2.91 (dd,
1H, J ) 12.0 and 2.0 Hz), and 3.73 (dd, 1H, J ) 12.0 and 8.4
Hz); 13C NMR (CDCl3, 300 MHz) δ 19.6, 20.6, 21.9, 29.8, 37.6,
41.7, 42.1, 48.9, 49.2, 99.5, 145.0, and 169.0; HRMS calcd for
C12H17NO 191.1310, found 191.1308.
1320, and 1167 cm-1 1H NMR (400 MHz, CDCl3) δ 1.19 (s,
;
3H), 1.46-1.54 (m, 1H), 1.67-1.80 (m, 3H), 2.00-2.13 (m, 2H),
2.15 (d, 1H, J ) 15.7 Hz), 2.25 (d, 1H, J ) 15.7 Hz), 4.80 (t,
1H, J ) 3.3 Hz), and 8.28 (br s, 1H); 13C NMR (100 MHz,
CDCl3) δ 18.5, 22.8, 25.8, 34.0, 38.0, 46.7, 99.2, 143.5, and
177.0.
A solution containing 0.1 g (0.66 mmol) of the above
compound in DMF (6.0 mL) was cooled in an ice bath and NaH
(60%, 0.05 g, 1.3 mmol) was added in one portion. The reaction
mixture was stirred at room temperature for 30 min and then
1,3-dibromopropane (0.1 mL, 1.0 mmol) was added dropwise.
The solution was stirred for 4 h at room temperature and was
then quenched with water. The mixture was extracted with
ether and the combined organic phase was washed with brine,
dried over MgSO4, flitered, and concentrated under reduced
pressure. The crude product was purified by flash chromatog-
raphy on silica gel to give 1-(3-bromopropyl)-3a-methyl-1,3,-
3a,4,5,6-hexahydroindol-2-one (8) as a colorless oil in 67%
yield; IR (neat) 1718, 1677, 1404, 1317, and 1241 cm-1 1H
;
NMR (CDCl3, 400 MHz) δ 1.14 (s, 3H), 1.46-1.53 (m, 1H),
1.71-1.80 (m, 3H), 2.03-2.11 (m, 3H), 2.19 (dd, 1H, J ) 8.1
and 3.8 Hz), 2.22 (s, 2H), 3.31 (dd, 1H, J ) 13.8 and 6.7 Hz),
3.34 (t, 2H, J ) 6.7 Hz), 3.71 (dt, 1H, J ) 13.8 and 7.1 Hz),
and 4.82 (t, 1H, J ) 3.3 Hz); 13C NMR (CDCl3, 100 MHz) δ
18.5, 22.8, 26.3, 30.4, 30.7, 34.0, 36.4, 38.0, 46.3, 97.5, 145.7,
and 174.1; HRMS calcd for C12H18BrNO 271.0572, found
271.0581.
1-Benzyl-7-bromo-3a-methyl-1,3,3a,4,5,6-hexahydroin-
dol-2-one (28). A sample of 1-benzyl-3a-methyl-1,3,3a,4,5,6-
hexahydroindol-2-one (31) was prepared in 76% yield from (1-
methyl-2-oxocyclohexyl)acetic acid (6) and benzylamine: 1H
NMR (CDCl3, 400 MHz) δ 1.16 (s, 3H), 1.50-1.57 (m, 1H),
1.68-1.74 (m, 2H), 1.80 (dt, 1H, J ) 12.4 and 3.3 Hz), 1.98-
2.06 (m, 1H), 2.08-2.15 (m, 1H), 2.33 (s, 2H), 4.38 (d, 1H, J )
15.7 Hz), 4.71 (t, 1H, J ) 3.8 Hz), 4.82 (d, 1H, J ) 15.7 Hz),
and 7.19-7.31 (m, 5H). The spectral data of this compound
are identical with those reported in the literature.42
A solution of enamide 31 (0.5 g) in CH2Cl2 (20 mL) was
cooled in an ice bath. Bromine (0.13 mL) was slowly added
via a syringe and the colorless mixture was stirred for 5 min
at 0 °C. Triethylamine (1.0 mL) was added in one portion and
1-(3,3-Diethoxypropyl)-3a-methyl-1,3,3a,4,5,6-hexahy-
droindol-2-one (11) was prepared in 76% yield from keto acid
6 and 3,3-diethoxypropylamine; IR (neat) 1722, 1680, 1408,
1129, and 1061 cm-1 1H 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,
and 3.5 Hz), 2.12-2.20 (m, 1H), 2.19 (s, 2H), 3.21 (ddd, 1H, J
) 14.0, 8.3, and 5.7 Hz), 3.38-3.50 (m, 2H), 3.55-3.72 (m, 3H),
4.45 (t, 1H, J ) 5.7 Hz), and 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, and 173.7; HRMS calcd for
C16H27NO3 281.1991, found 281.1986.
9a-Methyl-5,6,7,8,9,9a-hexahydro-1H,4H-pyrrolo[3,2,1-
ij]quinolin-2-one (15). To a solution of the above acetal 11
(1.0 mmol) in 10 mL of anhydrous toluene cooled in an ethylene
glycol-CO2 bath was added Et3SiH (0.16 mL, 1.0 mmol) and
(42) Cassayre, J.; Quiclet-Sire, B.; Saunier, J.-B.; Zard, S. Z.
Tetrahedron 1998, 54, 1029.
J. Org. Chem, Vol. 70, No. 2, 2005 525

Padwa et al.
the mixture was allowed to warm to room temperature, stirred
for 10 min, and washed with water. The organic phase was
separated, dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by flash
silica gel chromatography, using a 30% Et2O/hexane mixture
as the eluent. The titled compound 28 was obtained as a white
solid in 88% yield: mp 99-100 °C; IR (KBr) 1725, 1677, 1395,
39.9, 116.5, 125.4, 128.5, 140.8, 142.0, and 171.0. Anal. Calcd
for C16H18BrNO: C, 60.01; H, 5.67; N, 4.37. Found: C, 60.21;
H, 5.68; N, 4.41.
3a-Methyl-1,2,3,3a,4,5-hexahydropyrido[3,2,1-jk]carba-
zol-6-one (33). To a solution of the above bromo-enamide 32
(0.5 g, 1.6 mmol) in benzene (30 mL) was added n-Bu3SnH
(0.84 mL, 3.1 mmol) and AIBN (0.05 g, 0.31 mmol). The
mixture was heated at reflux for 12 h and the solvent was were
removed under reduced pressure. The crude product was
purified by flash silica gel chromatography, using a 30% Et2O/
hexane mixture as the eluent. The title compound 33 was
obtained as a white solid in 81% yield; mp 98-100 °C; IR (KBr)
1330, and 1021 cm-1 1H NMR (CDCl3, 400 MHz) δ 0.95 (s,
;
3H), 1.56-1.63 (m, 1H), 1.17-1.83 (m, 3H), 2.26 (d, 1H, J )
15.7 Hz), 2.37 (d, 1H, J ) 15.7 Hz), 2.50-2.61 (m, 2H), 5.12-
5.18 (m, 2H), and 7.22-7.33 (m, 5H); 13C NMR (CDCl3, 100
MHz) δ 20.5, 25.0, 33.7, 36.0, 42.3, 44.5, 46.2, 97.4, 127.4,
128.1, 128.5, 137.5, 141.7, and 175.0. Anal. Calcd for C16H18-
BrNO: C, 60.01; H, 5.67; N, 4.37. Found: C, 60.17; H, 5.79;
N, 4.43.
3a-Methyl-2,3,3a,4-tetrahydro-1H,7H-pyrrolo[3,2,1-de]-
phenanthridin-5-one (30). To a solution of bromo-enamide
28 (0.2 g) in benzene (35 mL) was added n-Bu3SnH (0.4 mL)
and AIBN (0.012 g). The mixture was heated at reflux for 12
h and then the solvent was removed under reduced pressure.
The crude reaction mixture was purified by flash chromatog-
raphy on silica gel. The major product 30 isolated from the
above free radical cyclization reaction was obtained in 68%
yield as a white solid; mp 104-106 °C; IR (KBr) 2930, 1714,
1677, 1360, and 1323 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.22
(s, 3H), 1.47 (dt, 1H, J ) 12.4 Hz), 1.80-1.96 (m, 3H), 2.17-
2.31 (m, 3H), 2.39-2.45 (m, 1H), 4.46 (d, 1H, J ) 16.4 Hz),
5.17 (d, 1H, J ) 16.4 Hz), 6.98-7.08 (m, 3H), 7.14 (t, 1H, J )
7.6 Hz); 13C NMR (75 MHz, CDCl3) δ 18.7, 21.9, 25.7, 33.6,
36.6, 42.7, 46.1, 105.8, 120.9, 126.1, 126.2, 127.6, 127.6, 132.2,
142.3, and 172.9; HRMS calcd for C16H17NO 239.1310, found
239.1300.
1
1695, 1633, 1453, 1373, and 1191 cm-1; H NMR (400 MHz,
CDCl3) δ 1.31 (s, 3H), 1.53 (td, 1H, J ) 12.9 and 3.8 Hz), 1.79
(td, 1H, J ) 13.3 and 4.8 Hz), 1.84 (dt, 1H, J ) 12.9 and 3.3
Hz), 1.88 (ddd, 1H, J ) 12.9, 5.7, and 1.4 Hz), 1.99-2.10 (m,
2H), 2.52 (ddd, 1H, J ) 16.7, 10.9, and 7.1 Hz), 2.70-2.73 (m,
1H), 2.73-2.76 (m, 1H), 2.99 (ddd, 1H, J ) 18.1, 13.8, and 5.7
Hz), 7.22-7.30 (m, 2H), 7.37 (d, 1H, J ) 7.6 Hz), and 8.40 (d,
1H, J ) 8.1 Hz); 13C NMR (100 MHz, CDCl3) δ 18.8, 20.0, 23.9,
30.6, 31.3, 35.7, 37.1, 113.6, 116.3, 117.0, 123.8, 124.1, 130.1,
135.2, 140.1, and 168.8. Anal. Calcd for C16H17NO: C, 80.30;
H, 7.16; N, 5.85. Found: C, 80.31; H, 7.19; N, 5.84.
7-Bromo-1-but-3-enyl-3a-methyl-1,3,3a,4,5,6-hexahy-
droindol-2-one (34). A solution of the above hexahydroindol-
2-one (0.6 g) in CH2Cl2 (25 mL) was cooled in an ice bath.
Bromine (0.12 mL) was slowly added via a syringe and the
colorless mixture was stirred for 5 min at 0 °C. Triethylamine
(1.1 mL) was added in one portion and the mixture was
allowed to warm to room temperature, stirred for 10 min, and
washed with water. The organic phase was separated, dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude product was purified by flash silica gel
chromatography, using a 30% Et2O/hexane mixture as the
eluent. The titled compound 34 was obtained as a colorless
oil in 82% yield: IR (neat) 1727, 1668, 1360, 1328, and 1298
cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.12 (s, 3H), 1.56 (td, 1H,
J ) 12.9 and 3.3 Hz), 1.72-1.89 (m, 3H), 2.18 (d, 1H, J ) 15.7
Hz), 2.18-2.24 (m, 1H), 2.27 (d, 1H, J ) 15.2 Hz), 2.33-2.40
(m, 1H), 2.55 (dd, 2H, J ) 9.1 and 4.8 Hz), 3.89 (ddd, 1H, J )
13.8, 9.1, and 5.2 Hz), 3.96 (ddd, 1H, J ) 13.8, 9.1, and 7.6
Hz), 5.00 (d, 1H, J ) 10.0 Hz), 5.07 (dd, 1H, J ) 17.1 and 1.9
Hz), and 5.75 (qt, 1H, J ) 10.0 and 6.7 Hz); 13C NMR (CDCl3,
100 MHz) δ 20.6, 25.9, 32.5, 33.6, 35.9, 40.3, 42.1, 46.2, 96.5,
117.1,134.9, 141.9, and 174.6; HRMS calcd for C13H18BrNO
283.0572, found 283.0581.
4a-Methyl-1-phenyl-3,4,4a,5,6,7-hexahydro-1H-quino-
lin-2-one. A mixture of 3-(1-methyl-2-oxocyclohexyl)propionic
acid methyl ester43 (0.5 g, 2.51 mmol) and aniline (0.7 mL, 7.6
mmol) was heated in a sealed tube at 190 °C for 20 h. The
reaction mixture was allowed to cool to room temperature and
was subjected to silica gel chromatography, using a 50% Et2O/
hexane mixture as the eluent. The title compound was
obtained as a white solid in 74% yield; mp 141-143 °C; IR
1
(KBr) 1665, 1640, 1450, 1391, 1353, and 1209 cm-1; H NMR
(400 MHz, CDCl3) δ 1.29 (s, 3H), 1.46-1.53 (m, 1H), 1.60-
1.66 (m, 2H), 1.68-1.74 (m, 2H), 1.79 (td, 1H, J ) 12.9 and
7.1 Hz), 1.90-2.01 (m, 2H), 2.68 (ddd, 1H, J ) 18.6, 7.1, and
1.9 Hz), 2.74 (ddd, 1H, J ) 19.0, 12.9, and 7.1 Hz), 4.38 (dd,
1H, J ) 5.2, and 3.3 Hz), 7.08 (d, 2H, J ) 7.6 Hz), 7.31 (t, 1H,
J ) 7.6 Hz), and 7.42 (t, 2H, J ) 7.6 Hz); 13C NMR (100 MHz,
CDCl3) δ 17.9, 22.9, 24.5, 29.5, 32.4, 34.3, 37.9, 108.4, 127.5,
128.8, 129.4, 140.2, 145.1, and 168.7. Anal. Calcd for C16H19-
NO: C, 79.63; H, 7.94; N, 5.80. Found: C, 79.74; H, 7.94; N,
5.83.
6,9a-Dimethyl-5,6,7,8,9,9a-hexahydro-1H,4H-pyrrolo-
[3,2,1-ij]quinolin-2-one (35). To a solution of the above
bromo-enamide 34 (0.5 g) in benzene (30 mL) was added n-Bu3-
SnH (0.8 mL) and AIBN (0.05 g). The mixture was heated at
reflux for 12 h and the solvent was removed under reduced
pressure. The crude product was purified by flash silica gel
chromatography, using a 30% Et2O/hexane mixture as the
eluent. The major product (71%) obtained from the reaction
was identified as 1H,4H-pyrrolo[3,2,1-ij]quinolin-2-one (35)
and was isolated as a 2.3:1 mixture of diastereomers: IR (neat)
8-Bromo-4a-methyl-1-phenyl-3,4,4a,5,6,7-hexahydro-
1H-quinolin-2-one (32). A solution of the above hexahydro-
1H-quinolin-2-one (0.63 g, 2.6 mmol) in CH2Cl2 (25 mL) was
cooled in an ice bath. Bromine (0.13 mL, 2.6 mmol) was slowly
added via a syringe and the colorless mixture was stirred for
5 min at 0 °C. Triethylamine (1.1 mL, 7.8 mmol) was added
in one portion and the mixture was allowed to warm to room
temperature, stirred for 10 min, and washed with water. The
organic phase was separated, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was
purified by flash silica gel chromatography, using a 30% Et2O/
hexane mixture as the eluent. The bromo-enamide was
obtained as a white solid in 90% yield; mp 118-119 °C; IR
1
1728, 1690, 1404, 1365, and 1312 cm-1; H 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 and 3.8 Hz) and 3.25
(ddd, 1H, J ) 12.4, 8.1, and 4.3 Hz), 3.60 (ddd, 1H, J ) 12.4,
8.1, and 4.8 Hz) and 3.72 (dt, 1H, J ) 12.9 and 4.8); 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, and 172.9; HRMS calcd for
C13H19NO 205.1467, found 205.1474.
1
(KBr) 1696, 1679, 1632, 1491, 1453, and 1294 cm-1; H NMR
(400 MHz, CDCl3) δ 1.39 (s, 3H), 1.67-1.90 (m, 6H), 2.45-
2.49 (m, 2H), 2.52-2.58 (m, 1H), 2.61 (ddd, 1H, J ) 18.1, 9.5,
and 6.2 Hz), 7.15 (t, 1H, J ) 7.1 Hz), and 7.31-7.39 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 20.9, 26.9, 32.0, 35.1, 37.2, 37.6,
10a-Methyl-4,5,6,7,8,9,10,10a-octahydro-1H-azepino-
[3,2,1-hi]indol-2-one (36). The minor fraction isolated from
the chromatographic separation in 21% yield was a colorless
oil and was assigned as 36 on the basis of its spectral
properties; IR (neat) 1718, 1680, 1392, 1359, and 1302 cm-1
;
(43) House, H. O.; Roelofs, W. L.; Trost, B. M. J. Org. Chem. 1966,
31, 646.
1H NMR (400 MHz, CDCl3) δ 1.08 (s, 3H), 1.39-1.52 (m, 3H),
526 J. Org. Chem., Vol. 70, No. 2, 2005

Vinyl Radical Cyclization
1.66-1.76 (m, 3H), 1.82-1.88 (m, 2H), 1.99-2.15 (m, 4H), 2.16
(d, 1H, J ) 15.7 Hz), 2.25 (d, 1H, J ) 15.7 Hz), 2.76 (t, 1H, J
) 11.9 Hz), and 4.36 (m,1H); 13C NMR (100 MHz, CDCl3) δ
19.1, 25.5, 27.1, 28.3, 31.2, 34.0, 34.3, 38.7, 43.6, 47.0, 114.3,
140.9, and 174.3; HRMS calcd for C13H19NO 205.1467, found
205.1469.
tion vessel was placed a 0.07 g (0.16 mmol) sample of 43,
PdCl2(PPh3)2 (5.0 mg, 7.1 µmol), Bu3NBr (0.06 g, 0.19 mmol),
and DMF (1.0 mL). The vessel was sealed and heated at 100
°C for 20 min. The mixture was allowed to cool to room
temperature and was transferred into a separatory funnel.
Water (5 mL) and Et2O (25 mL) were added and the organic
phase was collected, dried over MgSO4, filtered, and concen-
trated under reduced pressure. Flash chromatography of the
cruder residue on silica gel, using a 30% Et2O/hexane mixture
as the eluent, gave 41 as the minor product in 16% yield; IR
1-(3-Bromobut-3-enyl)-3a-methyl-1,3,3a,4,5,6-hexahy-
droindol-2-one was prepared in 80% yield from (1-methyl-
2-oxocyclohexyl)acetic acid (6) and 3-bromo-3-butenyl-1-
1
amine: IR (neat) 1720, 1677, 1402, 1317, and 1173 cm-1; H
1
(neat) 1717, 1663, 1414, 1349, and 1186 cm-1; H NMR (400
NMR (CDCl3, 400 MHz) δ 1.14 (s, 3H), 1.45-1.56 (m, 1H),
1.70-1.83 (m, 3H), 2.00-2.15 (m, 1H), 2.20-2.28 (m, 1H), 2.22
(s, 2H), 2.58-2.71 (m, 2H), 3.36 (dt, 1H, J ) 14.0 and 6.4 Hz),
3.86 (dt, 1H, J ) 14.0 and 7.3 Hz), 4.84 (t, 1H, J ) 3.2 Hz),
5.43 (s, 1H), and 5.63 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ
18.5, 22.8, 26.3, 34.0, 36.4, 37.7, 38.7, 46.4, 97.5, 118.9, 130.5,
145.4, and 174.9; HRMS calcd for C13H18BrNO 283.0572, found
283.0586.
MHz, CDCl3) δ 1.20 (s, 3H), 1.51 (td, 1H, J ) 12.4 and 4.3
Hz), 1.75-1.90 (m, 3H), 2.08-2.16 (m, 1H), 2.25-2.35 (m, 1H),
2.30 (s, 2H), 2.42-2.52 (m, 2H), 3.37 (ddd, 1H, J ) 13.3, 7.6,
and 4.8 Hz), 3.75 (dt, 1H, J ) 11.9 and 5.7 Hz), 4.67 (s, 1H),
and 4.75 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 18.6, 22.2, 25.9,
30.0, 33.7, 36.0, 38.9, 47.0, 106.0, 107.6, 139.2, 143.6, and
173.1; HRMS calcd for C13H17NO 203.1310, found 203.1312.
10a-Methyl-4,5,8,9,10,10a-hexahydro-1H-azepino[3,2,1-
hi]indol-2-one (44) was isolated from the column as the major
product in 48% yield; IR (neat) 1716, 1662, 1615, 1363, and
7-Bromo-1-(3-bromobut-3-enyl)-3a-methyl-1,3,3a,4,5,6-
hexahydroindol-2-one (37). A solution of the above hexahy-
droindol-2-one (0.5 g) in CH2Cl2 (20 mL) was cooled in an ice
bath. Bromine (0.13 mL) was slowly added via a syringe and
the colorless mixture was stirred for 5 min at 0 °C. Triethyl-
amine (1.0 mL) was added in one portion and the mixture was
allowed to warm to room temperature, stirred for 10 min, and
washed with water. The organic phase was separated, dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude product was purified by flash silica gel
chromatography, using a 30% Et2O/hexane mixture as the
eluent. The titled compound 37 was obtained in 88% yield as
a colorless oil: IR (neat) 1724, 1669, 1326, 1297, and 1173
1
1173 cm-1; H 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 ) 1.9 Hz), 2.47 (dddd, 1H, J ) 16.8, 7.0, 5.4, and 1.3
Hz), 2.93 (dd, 1H, J ) 13.0 and 9.5 Hz), 4.26 (ddd, 1H, J )
13.0, 5.4, and 2.9 Hz), 5.56 (dd, 1H, J ) 11.4 and 1.9 Hz), and
5.71 (ddd, 1H, J ) 11.4, 7.6, and, 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, and 173.4; HRMS calcd for C13H17NO
203.1310, found 203.1316.
9a-Methyl-5-vinyl-5,6,7,8,9,9a-hexahydro-1H,4H-pyrrolo-
[3,2,1-ij]quinolin-2-one (46). A mixture of bromo-hexahy-
droindolinone 18 (0.2 g, 0.74 mmol), vinyl-tributyltin (0.3 mL,
1.1 mmol), PdCl2(PPh3)2 (0.025 g, 0.04 mmol), and Bu4NBr
(0.29 g, 0.9 mmol) in DMF (3.0 mL) was heated at 100 °C for
6 h. The mixture was diluted with Et2O and washed with
water. The organic phase was separated, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
product was purified by flash chromatography on silica gel,
using a 50% Et2O/hexane mixture as the eluent. The title
compound 46 was obtained as a 6.5:1 mixture of diastereomers
cm-1 1H NMR (CDCl3, 400 MHz) δ 1.15 (s, 3H), 1.58 (ddd,
;
1H, J ) 19.1, 14.6, and 4.8 Hz), 1.73-1.90 (m, 3H), 2.22 (d,
1H, J ) 15.9 Hz), 2.30 (d, 1H, J ) 15.9 Hz), 2.55-2.60 (m,
2H), 2.63 (ddd, 1H, J ) 14.9, 8.3, and 6.7 Hz), 2.79 (ddd, 1H,
J ) 14.0, 9.2, and 4.8 Hz), 4.03 (ddd, 1H, J ) 14.0, 8.9, and
4.8 Hz), 4.17 (ddd, 1H, J ) 14.0, 8.9, and 6.7 Hz), 5.47 (d, 1H,
J ) 1.6 Hz), and 5.68 (d,1H, J ) 1.6 Hz); 13C NMR (CDCl3,
100 MHz) δ 20.6, 25.8, 33.7, 36.0, 39.7, 40.0, 42.2, 46.3, 97.0,
118.7, 130.2, 141.9, and 174.7; HRMS calcd for C13H17Br2NO
360.9678, found 360.9692.
The n-Bu3SnH/AIBN-induced radical reaction of dibromo-
hexahydroindolinone 37 afforded a mixture of the 6-exo (35)
(18%) and 7-endo (36) (72%) cyclized products which were
separated by silica gel chromatography and compared to those
obtained from 7-bromohexahydroindolinone 34.
1
in 68% yield; IR (neat) 1719, 1679, 1404, and 1314 cm-1; H
NMR (400 MHz, CDCl3) δ 1.14 and 1.16 (s, 3H), 1.36-1.52
(m, 1H), 1.56-2.00 (m, 7H), 2.04-2.28 (m, 4H), 2.44-2.56 (m,
1H), 3.02 (dd, 1H, J ) 13.0 and 5.1 Hz), 3.83 (dt, 1H, J ) 13.0
and 4.1 Hz), 4.87-5.08 (m, 2H), and 5.67 (ddd, 1H, J ) 17.2,
10.2, and 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 13.8, 17.5,
18.8, 22.0, 25.5, 25.9, 26.0, 26.6, 27.0, 34.0, 34.1, 35.0, 35.4,
39.1, 40.0, 46.7, 46.8, 49.0, 106.3, 107.1, 115.2, 135.9, 139.7,
140.0, and 172.8; HRMS calcd for C14H19NO 217.1467, found
217.1474.
7-Bromo-3a-methyl-1-(3-trimethylstannanylbut-3-enyl)-
1,3,3a,4,5,6-hexahydroindol-2-one (43). In a microwave
reaction vessel was placed dibromo-hexahydroindolinine 37
(0.1 g, 0.28 mmol), PdCl2(PPh3)2 (0.01 g, 0.014 mmol), hexa-
methylditin (0.14 g, 0.41 mmol), and degassed 1,4-dioxane (1.0
mL). The vessel was sealed and the mixture was stirred at
room temperature for 5 min until a homogeneous solution was
obtained. The vessel was then placed in the microwave reactor
and was heated at 150 W at 140 °C for 10 min. The mixture
was allowed to cool to room temperature and was transferred
into a round-bottom flask. The solvent was removed under
reduced pressure and the residue was purified by flash
chromatography on silica gel, using a 8% Et2O/hexane mixture
as the eluent. The title compound 43 was obtained as a
colorless oil in 69% yield; IR (neat) 1720, 1667, 1294, and 772
9a-Methyl-6a,9b-dichlorocyclopropyloctahydropyrrolo-
[3,2,1-ij]quinolin-2-one (47). To a solution of 9a-methyl-
5,6,7,8,9,9a-hexahydro-1H,4H-pyrrolo[3,2,1-ij]quinolin-2-one (15)
(2.1 g, 11.1 mmol) and Bu4NBr (0.5 g) in CHCl3 (150 mL) was
added 50 mL of a 50% aqueous solution of NaOH dropwise.
The mixture was vigorously stirred for 4 h and diluted with
water, the organic layer was separated and extracted with
Et2O, and the combined organic phase was dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
product was purified by flash chromatography on silica gel,
using a 50% Et2O-hexane mixture as the eluent. The major
product formed 47 was obtained as a white solid in 70% yield;
mp 136-138 °C; IR (KBr) 1709, 1690, 1464, 1348, and 1316
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.15 (s, 9H), 1.13 (s, 3H),
1.52-1.60 (m, 1H), 1.72-1.90 (m, 3H), 2.18 (d, 1H, J ) 15.7
Hz), 2.28 (d, 1H, J ) 15.7 Hz), 2.35 (ddd, 1H, J ) 13.3, 10.5,
and 6.2 Hz), 2.53-2.62 (m, 3H), 3.84 (ddd, 1H, J ) 13.8, 9.1,
and 3.3 Hz), 3.92 (ddd, 1H, J ) 13.8, 11.0, and 6.2 Hz), 5.21
(s, 1H), and 5.74 (s, 1H); 13C NMR (100 MHz, CDCl3) δ -9.1,
20.7, 25.8, 33.7, 36.0, 38.8, 41.2, 42.2, 46.3, 96.6, 127.1, 142.2,
151.5, and 174.6; HRMS calcd for C16H26BrNOSn 445.0220,
found 445.0216.
1
cm-1; H NMR (400 MHz, CDCl3) δ 1.18-1.36 (m, 2H), 1.46
(s, 3H), 1.44-1.48 (m, 2H), 1.49-1.54 (m, 1H), 1.55-1.64 (m,
1H), 1.85 (ddd, 1H, J ) 14.8, 5.2, and 2.9 Hz), 2.05 (m, 2H),
2.33 (dd, 1H, J ) 17.2 and 1.0 Hz), 2.42 (d, 1H, J ) 17.2 Hz),
2.43 (ddd, 1H, J ) 14.8, 14.8, and 6.2 Hz), 3.22 (ddd, 1H, J )
13.3, 13.3, and 1.9 Hz), and 4.06 (ddd, 1H, J ) 13.3, 4.3, and
1.9 Hz); 13C NMR (100 MHz, CDCl3) δ 19.6, 21.6, 25.6, 25.9,
29.8, 30.9, 32.6, 34.4, 39.8, 47.1, 53.6, 74.4, and 177.3. Anal.
9a-Methyl-6-methylene-5,6,7,8,9,9a-hexahydro-1H,4H-
pyrrolo[3,2,1-ij]quinolin-2-one (41). In a microwave reac-
J. Org. Chem, Vol. 70, No. 2, 2005 527

Padwa et al.
Calcd for C13H17Cl2NO: C, 56.95; H, 6.25; N, 5.11. Found: C,
57.00; H, 6.18; N, 5.05.
g, 0.7 mmol) and methyl iodide (0.2 mL, 3.5 mmol) in THF
(6.0 mL) was stirred at room temperature overnight. The
yellow mixture was concentrated under reduced pressure and
the resulting residue was dissolved in MeOH (6.0 mL) at 0
°C. To this solution was added NaBH4 (0.05 g, 1.4 mmol) in
one portion and the mixture was stirred for 2 h at 0 °C. The
reaction mixture was quenched with water and extracted with
Et2O, and 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 a
30% Et2O/hexane mixture as the eluent. The major product
52 was obtained as a colorless oil in 56% yield; IR (neat) 2938,
2796, 1448, 1183, and 750 cm-1; 1H NMR (400 MHz, CDCl3) δ
1.12 (s, 3H), 1.20-1.25 (m, 1H), 1.38-1.73 (m, 10H), 1.85-
1.90 (m, 1H), 2.00 (ddd, 1H, J ) 13.3, 13.3, and 5.2 Hz), 2.11
(ddd, 1H, J ) 10.5, 9.1, and 6.7 Hz), 2.90 (d, 1H, J ) 10.5 Hz),
9a-Methyl-6a-chlorocyclopropyloctahydropyrrolo[3,2,1-
ij]quinolin-2-one (48). A mixture of the above dichlorocy-
clopropyloctahydropyrrolo[3,2,1-ij]quinoline 47 (0.15 g, 0.55
mmol) and zinc powder (0.2 g) in acetic acid (5.0 mL) was
heated at reflux for 6 h. The reaction mixture was allowed to
cool to room temperature and was diluted with 20 mL of
EtOAc. The organic layer was washed with 1.0 N NaOH, dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude residue was purified by flash silica gel
chromatography, using a 50% Et2O in hexane mixture as the
eluent. Recrystallization of the major chromatographic fraction
from hexanes-EtOAc afforded 0.06 g (46%) of 48 as a crystal-
line solid, which was suitable for X-ray analysis; mp 114-116
°C; IR (KBr) 1706, 1689, 1464, 1345, and 1315 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.18-1.36 (m, 2H), 1.45 (s, 3H), 1.45-
1.82 (m, 7H), 1.90-2.00 (m, 1H), 2.12 (dd, 1H, J ) 17.2 and
1.0 Hz), 2.48 (d, 1H, J ) 17.2 Hz), 2.75-2.85 (m, 1H), 3.70 (s,
1H), and 3.88-3.99 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
18.5, 19.6, 22.0, 25.1, 25.7, 27.8, 33.6, 34.0, 35.8, 40.2, 45.6,
49.8, and 174.4; HRMS calcd for C13H18ClNO 239.1077, found
239.1068.
9a-Methyl-6a,9b-dichlorocyclopropyloctahydropyrrolo-
[3,2,1-ij]quinolin-2-thione (49). To a solution of lactam 47
(0.6 g, 2.2 mmol) in THF (20 mL) was added Lawesson’s
reagent (1.0 g, 2.6 mmol) and the mixture was stirred at room
temperature overnight. The solvent was removed under re-
duced pressure and the crude product was purified by flash
chromatography on silica gel, using a 30% Et2O-hexane
mixture as the eluent. Thioamide 49 was obtained as a white
solid in 94% yield; mp 155-156 °C; IR (KBr) 1465, 1445, 1312,
1178, 1137, and 1013 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.32-
1.44 (m, 4H), 1.38 (s, 3H), 1.56-1.63 (m, 2H), 1.81 (ddd, 1H,
J ) 14.8, 5.2, and 2.9 Hz), 1.98 (ddd, 1H, J ) 14.8, 12.4, and
5.2 Hz), 2.01 (dd, 1H, J ) 14.8 and 6.7 Hz), 2.46 (ddd, 1H, J
) 15.2, 13.3, and 6.7 Hz), 2.84 (d, 1H, J ) 17.6 Hz), 2.95 (dd,
1H, J ) 17.6 and 1.4 Hz), 3.59-3.68 (m, 1H), and 4.90 (ddd,
1H, J ) 13.3, 5.2, and 2.4 Hz); 13C NMR (100 MHz, CDCl3) δ
19.1, 21.5, 24.9, 28.6, 28.9, 32.0, 36.7, 44.8, 58.8, 59.5, 73.7,
and 205.5. Anal. Calcd for C13H17Cl2NS: C, 53.79; H, 5.90; N,
4.83. Found: C, 53.93; H, 5.96; N, 4.77.
3.02 (ddd, 1H, J ) 13.3, 9.1, and 4.3 Hz), and 6.36 (s, 1H); 13
C
NMR (100 MHz, CDCl3) δ 18.8, 21.6, 25.0, 26.9, 27.4, 35.4,
39.1, 40.1, 44.4, 52.0, 53.2, 70.5, and 81.1; HRMS calcd for
C13H21NCl2 261.1051, found 261.1060.
Acknowledgment. This research was supported by
the National Science Foundation (grant CHE-0132651).
We also thank our colleague, Dr. Kenneth Hardcastle,
for his assistance with the X-ray crystallographic studies
of compound 48 together with grants NSF CHE-
9974864 and NIH S10-RR13673 and the University
Research Committee of Emory University for funds to
acquire a microwave reactor. A.D.O. thanks Istanbul
Technical University for a Visiting Scholarship.
Supporting Information Available: Spectroscopic and
experimental procedures for compounds 10, 16, 17, 29, and
42; 1H and 13C NMR spectra for new compounds lacking
elemental analyses; and an ORTEP drawing for structure 48.
This material is available free of charge via the Internet at
http://pubs.acs.org. The authors have deposited atomic coor-
dinates for this structure with the Cambridge Crystallographic
Data Centre.
6a-Dichloromethyl-9a-methyldecahydropyrrolo[3,2,1-
ij]quinoline (52). A solution of the above thioamide 49 (0.2
JO048314I
528 J. Org. Chem., Vol. 70, No. 2, 2005