FULL PAPER

DOI: 10.1002/ejoc.200600342

Highly Diastereoselective [3+2] Cyclopenta[b]annulation of Indoles with

2-Arylcyclopropyl Ketones and Diesters

Chelvam Venkatesh,[a] Prabal P. Singh,[a] Hiriyakkanavar Ila,*[a] and

Hiriyakkanavar Junjappa[a]

Dedicated to Prof. Dr. Hartmut Laatsch on the occasion of his 60th birthday

Keywords: [3+2] Cycloaddition / Cyclopenta[b]indoles / Synthetic methods / Diastereoselectivity / Propellanes

A highly diastereoselective Lewis acid (BF3·Et2O or TiCl4) in- clopenta[b]- and cyclohepta[b]indoles affording tetracyclic
duced [3+2] cycloaddition of substituted and unsubstituted propellane type frameworks in modest yields.
indoles with 2-arylcyclopropyl ketones/diesters yielding cy-
clopenta[b]indoles in high yields is reported. This methodol- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ogy has also been extended to tetrahydrocarbazole, cy- Germany, 2006)

Introduction intermediate formed by attack at the 3-position of indole

on cyclopropane diesters. With 3-unsubstituted indoles, the
Cyclopenta[b]indole ring systems occur in a number of product formed was one in which alkylation took place to
indole alkaloids,[1] notably tremorgenic mycotoxins such as yield 2-alkoxycarbonyl-4-(3-indolyl)butanoate.[22,23] Also
paxilline, lolitrems, penitrems, janthitrems, and paspaline[2] with N-unsubstituted indoles, these reactions were compli-
and in monoterpenoid alkaloid yuehchukene[3] which has cated by the formation of N-alkylated products by attack
been shown to exhibit mixed estrogen and antiestrogen, as of the nitrogen atom of indole on a second equivalent of the
well as potent antiimplantation, activities.[4–6] Recently a cy- cyclopropane diester, thus requiring N-protection of indole.
clopenta[b]indole derivative has been identified as a promis- During the course of our continued work on carbocationic
ing prostaglandin D2 (PGD2) receptor antagonist in the al- rearrangements of a range of cyclopropyl ketones,[24] we ex-
leviation of various allergic disorders.[7] Another class of amined the formal [3+2] cycloaddition of the indole 2,3-
naturally occurring cyclopenta[b]indole alkaloids are repre- double bond with few aryl cyclopropyl ketones and ob-
sented by kopsane,[8] possessing an architecturally beautiful served that 1,3-unsubstituted indoles react with 4-meth-
tetracyclic propellane type annulated indole substructure oxyphenyl-substituted cyclopropyl ketones in the presence
exhibiting cholinergic activity.[9,10] Several syntheses of of BF3·Et2O to give substituted cyclopenta[b]indoles in high
yuechukene[11–13] and cyclopenta[b]indole frameworks have yields and with complete diastereoselectivity. We herein de-
been reported in the literature.[14–19] Kerr and co-workers scribe the results of these studies in this paper.
recently described an elegant approach for cyclopenta[b]in-
doles by reaction of 1,3-dimethylindoles with 1,1-cyclopro-
pane diesters in the presence of ytterbium trifluorome- Results and Discussion
thanesulfonate.[20–21] They further elaborated this reaction
for the synthesis of substrates possessing a tetracyclic core The cyclopropyl ketone 2a derived from (4-methoxy-
present in kopsane and related alkaloids by reacting tetra- benzylidene)acetophenone was selected for this model study
hydrocarbazole with cyclopropane diesters. The presence of because of its donor-acceptor character due to the presence
a 3-methyl substituent in the indole ring was necessary for of the cation stabilizing 4-methoxyphenyl group. Initially, a
the success of this cyclopenta[b]annulation to avoid depro- study was undertaken to probe the optimal conditions for
tonation and rearomatization of the putative imminium ion the annulation reaction (Scheme 1). Table 1 illustrates the
results of our studies in which several Lewis acids
[a] Indian Institute of Technology,
[BF3·Et2O, Yb(OTf)3, SnCl4, and TiCl4] were surveyed un-
Kanpur 208016, India der varying conditions. Best results were obtained with
Fax: +91-0512-2597436 or: +91-0512-2590260 BF3·Et2O in nitromethane (entry 5) which gave the cy-
E-mail: hila@[Link]
Supporting information for this article is available on the clopentannulated indole 3a in 92 % yield within 2 h, surpris-
WWW under [Link] or from the author. ingly as a single diastereomer, in contrast with Kerr’s obser-

5378 © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2006, 5378–5386
Diastereoselective [3+2] Cyclopenta[b]annulation of Indoles
FULL PAPER
vation. The structure and stereochemistry of the cy- this reaction by varying the substituents on the indole ring
clopentannulated indole 3a was established with the help of as well as on the aryl group of cyclopropyl ketones with a
spectral and X-ray crystallographic data (Figure 1). En- view to examine the scope of this [3+2] cycloaddition reac-
couraged by these results, we undertook a detailed study of tion. These results are summarized in the Scheme 2 and
Table 2. Thus, 5-bromoindole 1b reacted smoothly with cy-
clopropyl ketone 2a furnishing the cyclopenta[b]indole 3b
in 70 % yield as a single diastereomer (entry 2). The cycliza-
tion was equally facile with N-methylindole and the product
3c was obtained in 83 % yield (entry 3). The presence of a
methyl group either at the 2- or 3-position of the indole
(1d and 1e) did not affect the course of reaction and the
cycloadducts 3d–e were obtained in 80 % and 83 % yields,
respectively, as single diastereomers (entries 4–5). The X-
ray crystallographic studies of 3d also displayed all three
Scheme 1. tertiary and quaternary hydrogens syn to the 2-methyl
group. Similarly, the corresponding 2,3-dimethylindole 1f
Table 1. Formation of cyclopenta[b]indole 3a under the influence also underwent facile reaction with 2a under identical con-
of various Lewis acids. ditions yielding the sterically crowded annulated indole 3f
Entry Lewis acid Solvent Conditions Time [h] Yield [%]
in 93 % yield, having two vicinal quaternary centers adja-
cent to two tertiary centers (entry 6). On the other hand,
1 Yb(OTf)3[a] CH3CN 0 °C to room temp. 36 31(1:1)[b]
2 Yb(OTf)3[a] CH2Cl2 0 °C to room temp. 36 –[d]
the corresponding 1,2,3-trimethylindole 1g failed to react
3 BF3·Et2O CH2Cl2 0 °C to room temp. 5 42 (2:1)[b] with the cyclopropyl ketone 2a under varying conditions,
4 BF3·Et2O CH3CN 0 °C to room temp. 3 48 (1:1)[b] yielding only the indole 1g along with a polymeric product
5 BF3·Et2O CH3NO2 0 °C to room temp. 2 92[c] (entry 7).
6 SnCl4 CH2Cl2 0 °C to room temp. 6 28 (2:1)[b]
Surprisingly the cyclopropyl ketone 2b from (3,4-dimeth-
7 SnCl4 CH3NO2 0 °C to room temp. 6 31 (4:1)[b]
8 TiCl4 CH2Cl2 –78 °C to room temp. 4 70[c] oxybenzylidene)acetophenone failed to yield the cy-
9 TiCl4 CH2Cl2 0 °C to room temp. 5 42 (5:1)[b] clopentannulated product when reacted with indole 1a in
[a] 10 mol-% catalyst. [b] Mixture of diastereomers. [c] Single dia- the presence of BF3·Et2O in nitromethane. The product iso-
stereomer. [d] No reaction. lated from the reaction mixture was characterized as the

Figure 1. Molecular structure of 3a shown at 50 % ellipsoidal probability level.

Scheme 2.

Eur. J. Org. Chem. 2006, 5378–5386 © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim [Link] 5379
FULL PAPER C. Venkatesh, P. P. Singh, H. Ila, H. Junjappa

Table 2. Cyclopentannulation of indoles 1 with cyclopropyl ketones 2. changing the Lewis acid to TiCl4 at lower temperature
(–78 °C), the reaction proceeded smoothly in dichlorometh-
ane yielding the cyclopentannulated adduct 5a in 84 % yield
as single diastereomer (Scheme 2, Table 2, entry 8). Simi-
larly, the corresponding 1-methyl- (1c) and 2,3-dimethylin-
dole (1f) also underwent smooth cycloaddition with the 2-
(3,4-dimethoxyphenyl)cyclopropyl ketone 2b in the pres-
ence of TiCl4/CH2Cl2 catalyst to afford cyclopentaannu-
lated indoles 5c and 5e in 85 % and 83 % yields, respectively,
in a highly stereocontrolled fashion (Table 2, entries 9–10).
Cyclopentannulation of the indole 1a with phenyl 2-phenyl-
cyclopropyl ketone (2c), with lesser cationic stabilization in
comparison with 2a, was investigated next. Thus, the reac-
tion of 1a with 2c in the presence of either BF3·Et2O or
TiCl4 or other Lewis acids [Yb(OTf)3, SnCl4] failed to yield
the corresponding cyclopentannulated indole adduct and
the only product isolated (with either BF3·Et2O or TiCl4)
was found to be the 1,4-diaryl-3,4-dihydrocarbazole 4c
(Scheme 3), whereas with Yb(OTf)3/CH3CN the indole 1a
was recovered unchanged even after prolonged reaction
time (48 h). On the other hand, the corresponding 3-meth-
ylindole 1e underwent smooth cyclopentaannulation with
ketone 2c to give the cycloadduct 6e in 85 % overall yield
as mixture of two diastereomers 6e⬘ and 6e⬘⬘ (2:1) (entry
11, Table 2). Similarly, the corresponding 1-phenyl-2-acetyl-
cyclopropane 2d also reacted with 3-methylindole 1e under
identical conditions to give the diastereomeric mixture of
cycloadducts 7e⬘ and 7e⬘⬘ (3:1) in 70 % overall yield (entry
12, Table 2).

Scheme 3.

Cyclopentaannulation of the indole 1a with 1-(styrenyl)-

2-benzoylcyclopropane 8 was examined next with a view
to probe the effect of the styrenyl group towards cationic
stabilization during the ring opening of the cyclopropyl
ketone 8 in the presence of Lewis acid. Thus, when the in-
dole 1a and phenyl 2-(α-styryl)cyclopropyl ketone (8) were
exposed to BF3·Et2O in nitromethane under standard reac-
[a] Yield of pure isolated product. [b] Reaction conditions: tion conditions, the styrenyl-substituted cycloadduct 9a was
BF3·Et2O, 0 °C to room temp., 2 h. [c] Reaction conditions: TiCl4, formed in 88 % yield as a single diastereomer with the four
CH2Cl2, –78 °C, 2 h. [d] Indole 1g was recovered fully. [e] Pure 6e⬘ cyclopentane hydrogens having syn stereochemistry
was separated in 45 % yield.
(Table 2, entry 13). Similarly, the corresponding 3-methyl-
indole 1e also yielded the styrenyl-substituted cyclopenta-
1,4-diaryl-3,4-dihydrocarbazole 4b (75 %) on the basis of [b]indole 9e in 79 % yield with high stereoselection (Table 2,
spectral and analytical data (Scheme 3). However, on entry 14).

5380 [Link] © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2006, 5378–5386
Diastereoselective [3+2] Cyclopenta[b]annulation of Indoles
FULL PAPER
Next we extended our studies to the cycloaddition of in-
doles with aryl and styrenyl-substituted cyclopropyl diesters
10a–b and 13 (Scheme 4, Table 3). The presence of two elec-
tron-withdrawing substitutents at the acceptor carbon is ex-
pected to facilitate the cationic ring opening of arylcyclo-
propanes in the presence of Lewis acids. Thus, when the
indole 1a was treated with 4-methoxyphenylcyclopropyl di-
ester 10a, in the presence of BF3·Et2O, analysis of the prod-
uct mixture revealed formation of both the diastereomers Scheme 4.
(11a⬘ and 11a⬘⬘) of the cyclopenta[b]indole 11a (2:1) in
overall yield of 86 % (Scheme 4, Table 3, entry 1). Similarly, The success of the cyclopenta[b]annulation of the various
the N-methylindole 1c also afforded the adduct 11c (90 %) substituted indoles, especially 2,3-dimethylindole 1f,
in 1:1 diastereomeric ratio when reacted with cyclopropyl prompted us to extend this reaction to tetrahydrocarbazole
diesters 10a under identical conditions (Scheme 4, Table 3, 15 as a dipolarophile with a view to synthesize propellane
entry 2). On the other hand, cyclopentannulation of 3- type annulation products (Scheme 5). Thus, under opti-
methylindole 1e with either 4-methoxyphenyl or phenyl- mized reaction conditions, the reaction of tetrahydrocarba-
substituted cyclopropyl diesters (10a or 10b) proceeded in zole with cyclopropyl ketone 2a in the presence of BF3·Et2O
highly diastereoselective fashion yielding only dia- in CH2Cl2 afforded a product (58 %) which was charac-
stereomers 11e and 12e in 89 % and 72 % yields, respectively terized as the propellane 16. The product was formed as a
(Table 3, entries 3 and 4). The stereochemical assignment of single diastereomer (Scheme 5) and is in contrast to the re-
the adducts 11e and 12e, having all three contiguous hydro- sults of Kerr with phenylcyclopropyl diester 12e yielding a
gens syn to each other, was established with the help of 1:1 mixture of diastereomers. Attempts to isolate the other
NOESY correlation spectra. The reaction of styrenyl-sub- diastereomer from the reaction mixture were not successful.
stituted cyclopropyl diester 13 with the indole 1a in the The reaction of the corresponding cyclopenta[b]indole 17
presence of either BF3·Et2O or TiCl4 gave only a complex with the 2-arylcyclopropyl ketones 2a and 2c also afforded
mixture of products, whereas use of Yb(OTf)3 in CH3CN the propellane derivatives 18 and 19 as single diastereomers
furnished the cycloadduct 14 in 49 % yield (Table 3, entry in modest yields under similar conditions (Scheme 5). Simi-
5). larly, the propellane synthesis was also extended to cy-

Table 3. Cyclopentannulation of indoles 1 with cyclopropyl diesters 10.

[a] Yields of pure isolated products. [b] Reaction conditions: BF3·Et2O, CH3NO2, 0 °C to room temp., 2 h. [c] 10 mol-% Yb(OTf)3,
CH3CN, room temp., 14 h.

Eur. J. Org. Chem. 2006, 5378–5386 © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim [Link] 5381
FULL PAPER C. Venkatesh, P. P. Singh, H. Ila, H. Junjappa

Scheme 5.

clohepta[b]indole 20 which on reaction with the cyclopropyl Mechanism and Stereochemistry

ketone 2a afforded two products of which the minor one The probable mechanism for this unprecedented [3+2]
(27 %) was characterized as the propellane derivative 19 as annulation of 3-unsubtituted indoles (1a–d) with cyclopro-
a single diastereomer, whereas the structure of the major pyl ketone 2a is shown in the Scheme 6. Apparently the
product (45 %) was established as 22 on the basis of spectral formation of stable zwitterionic intermediates via facile ring
and analytical data (Scheme 5). opening of cyclopropyl ketone is the key factor for this fac-
In the 1H NMR spectra of all newly prepared cy- ile [3+2] cycloaddition of 3-unsubstituted indoles to cy-
clopenta[2,3-b]indoles 3a–f, 5a, 5c, 5f, 6e, 7e, 9a, and 9e, the clopentannulated products 3 via the imminium ion interme-
trans coupling constants (JH1H2⬘⬘, JH2⬘⬘H3) and the gemi- diate 24 in a kinetically controlled process. In the absence
nal coupling constants (JH2⬘H2⬘⬘) are in the range of 12– of the cation stabilizing 4-methoxy group, the ring opening
13 Hz, whereas the three cis coupling constants (JH1H2⬘, of cyclopropyl ketone is slow and the resulting imminium
JH2⬘H3 and JH3H3a) are in the range of 5–6.1 Hz (Fig- ion 24 (Ar = Ph) undergoes slow tautomerization to indole
ure 2). The trans geminal proton (H2⬘⬘) appears as a quartet 25 followed by its BF3·Et2O induced intramolecular cy-
with coupling constants between range of 12–13 Hz in all clocondensation furnishing the 1,4-diaryl-3,4-dihydrocarb-
the 1H NMR spectra of these compounds. On the other azole 4 as the exclusive product.
hand, the cis protons H2⬘ and H3 appear as triplets of dou-
blets with two middle peaks merging (showing five peaks)
with two coupling constants in the range of 5–6.1 Hz (trip-
let) and 12–13 Hz (doublet). The cis coupling constants
JH1H8b and JH3aH8b are in the range of 8.5–10.1 Hz. The
H1 proton appears as a difficult to analyze multiplet in all
the 1H NMR spectra. The same trend is also observed in
the 1H NMR spectra of products 11a, 11c, 11e, 12e, and 14
(JH2⬘⬘H3 and JH2⬘H2⬘⬘ = 13.3–14.6 Hz), 16, 18, 19, and 21.
Average values of coupling constants are reported.

Figure 2. Proton designation for cyclopenta[2,3-b]indole ring. Scheme 6.

5382 [Link] © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2006, 5378–5386
Diastereoselective [3+2] Cyclopenta[b]annulation of Indoles
FULL PAPER
Another noteworthy feature of this [3+2] cycloannulation ence. Melting points are uncorrected. Chromatographic purifica-
is the remarkable stereoselectivity which deserves comment. tion was conducted by column chromatography using 100–200
In all the cyclopentaannulation reactions of the indoles 1a– mesh silica gel obtained from Acme Synthetic Chemicals. DMF
g and methoxyaryl-(or α-styryl-)cyclopropyl ketones 2a–b, and DMSO were distilled from CaH2 and stored with molecular
sieves. THF was distilled from sodium/benzophenone prior to use.
only one diastereomer was obtained which has a trans rela-
NaH (as 60 % suspension in oil), SnCl4, BF3·Et2O (50 % solution
tionship between its angular substitutents (H or Me) and in Et2O), TiCl4, Yb(OTf)3, and nitromethane (AR grade) were pur-
the substituents (Ar or ArCO) on the newly formed cyclo- chased from standard firms and used directly. The cyclopropyl
pentane ring which are in an endo relationship with the bent ketones 2a, 2b, 2c, 2d, 8, and diesters 10a, 10b, and 13 were pre-
ring system. The possible conformations for the transition pared according to the literature procedure[25] in nearly quantitative
states for the intramolecular cyclization of imminium ion yields. Single-crystal X-ray crystallographic data on 3a and 3d were
intermediate 24 are shown in Figure 3. For the Z enolate collected at 100 K on a Bruker SMART APEX CCD dif-
the possible transition states are 24A and 24C whereas fractometer with graphite-monochromated Mo-Kα (λ = 0.71073 A)
structures 24B and 24D represent possible transition states radiation using the ω–θ scan technique. The hydrogen atoms were
for the E enolate. Apparently the conformations 24C and fixed in their ideal positions and refined as a riding model except
for the hydrogen atom of the chiral center, which was located from
24D, which will yield trans products, are of higher energy
the difference Fourier map and refined isotropically. See Support-
than 24A and 24B because of pseudodiaxial interactions ing Information for more details on X-ray crystal data and molecu-
shown in Figure 3. Therefore, all cis products 3 are formed lar structure of 3a and 3d.
through cyclization of intermediates 24A or 24B with mini-
mal pseudodiaxial interactions. General Procedure for the Cycloaddition of Cyclopropyl Ketones 2a,
2b, 2c, 2d, and 8 or Diesters 10a, 10b, and 13 to Indoles 1a–g, 15,
17, and 20 in the Presence of BF3·Et2O as a Lewis Acid: A solution
of the Lewis acid (3.0 mmol) in dry solvent (nitromethane or
CH2Cl2 or CH3CN) (5 mL) was added dropwise at 0 °C to a stirred
solution of the cyclopropyl ketone (2a, 2b, 2c, 2d, or 8 or diesters
10a, 10b, or 13) (2.0 mmol) and the appropriate indole (1a–g, 15,
17, or 20) (2.0 mmol) in respective solvent (10 mL). After the com-
plete addition, the reaction mixture was stirred at room temp. for
1–4 h (monitored by TLC). It was then diluted with an ice-cold
saturated NaHCO3 solution (10 mL), and extracted by CHCl3
(2 × 25 mL), washed with water (1 × 25 mL), followed by brine
(25 mL) and dried with anhydrous Na2SO4. The solvent was evapo-
rated under reduced pressure to afford the cyclopentannulated in-
doles 3a–f, 6, 7, 9a, 9e, 11a, 11c, 11e, 12e, and 14, and dihydro-
carbazoles 4b and 4c, or propellanes 16, 18, 19, and 21 which were
purified by column chromatography using silica gel and hexane/
EtOAc as eluent.
(1R*,3S*,3aR*,8bS*)-[1-(4-Methoxyphenyl)-1,2,3,3a,4,8b-hexahy-
Figure 3. Possible conformations for the formation of cyclo- drocyclopenta[b]indol-3-yl]phenylmethanone (3a): Yield 92 %
penta[2,3-b]indoles. (0.67 g); colorless crystals; m.p. 174–175 °C; Rf 0.66 (3:1 hexanes/
EtOAc). IR (KBr): ν̃ = 3367, 1676, 1602, 1512, 1463, 1362, 1258,
1178, 1034, 749 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.08 (td,
J = 12.80, 5.8 Hz, 1 H, H2⬘), 2.47 (q, J = 12.80 Hz, 1 H, H2⬘⬘), 3.62
Conclusion (m, 1 H, H1), 3.78 (s, 3 H, OCH3), 3.93 (td, J = 12.80, 5.8 Hz, 1
H, H3), 4.12 (t, J = 9.6 Hz, 1 H, H8b), 4.94 (dd, J = 9.6, 5.8 Hz, 1
In summary, we have demonstrated an unusual [3+2] cy- H, H3a), 5.79 (d, J = 7.3 Hz, 1 H, ArH), 6.28 (t, J = 7.3 Hz, 1 H,
cloannulation of 1,3-unsubstituted/substituted indoles with ArH), 6.42 (d, J = 7.8 Hz, 1 H, ArH), 6.77 (d, J = 8.5 Hz, 2 H,
aryl-(or α-styryl-)cyclopropyl ketones under BF3·Et2O (or ArH), 6.85 (t, J = 7.5 Hz, 1 H, ArH), 6.96 (d, J = 8.5 Hz, 2 H,
TiCl4) induced reaction conditions yielding cyclopentannul- ArH), 7.51 (t, J = 7.0 Hz, 2 H, ArH), 7.59 (t, J = 7.3 Hz, 1 H,
ated indolines in high yields and in a highly stereocontrolled ArH), 8.04 (dd, J = 8.0 Hz, 1.2 Hz, 2 H, ArH) ppm. 13C NMR
fashion as single diastereomers. The reaction has also been (100 MHz, CDCl3): δ = 30.9, 48.8, 52.5, 54.4, 55.2, 65.2, 108.6,
extended to tetrahydrocarbazole, cyclopenta[b]- and cy- 113.2, 117.6, 126.6, 127.5, 127.6, 128.2, 128.8, 129.7, 131.5, 133.1,
137.2, 151.4, 158.2, 199.5 ppm. MS: m/z (%) = 369 (100) [M+].
clohepta[b]indoles affording tetracyclic propellane type an-
C25H23NO2 (369.46): calcd. C 81.27, H 6.27, N 3.79 %; found C
nulated substructures present in kopsane type alkaloids. 81.11, H 6.09, N 3.54 %.
Further work to study the detailed mechanism and the
scope of this annulation methodology are in progress. (1R*,3S*,3aR*,8bS*)-[(4-Methoxyphenyl)-3a-methyl-1,2,3,3a,4,8b-
hexahydrocyclopenta[b]indol-3-yl]phenylmethanone (3d): Yield 80 %
(0.61 g); colorless crystals; m.p. 170–171 °C; Rf 0.5 (6:1 hexanes/
Experimental Section EtOAc). IR (KBr): ν̃ = 3393, 1676, 1603, 1512, 1463, 1232, 1177,
1031, 828, 752, 707 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.50
General: 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra (s, 3 H, CH3), 2.17 (td, J = 12.5, 5.4 Hz, 1 H, H2⬘), 2.42 (q, J =
were recorded in CDCl3 and TMS was used as an internal refer- 12.5 Hz, 1 H, H2⬘⬘), 3.54 (d, J = 9.8 Hz, 1 H, H8b), 3.67 (m, 1 H,

Eur. J. Org. Chem. 2006, 5378–5386 © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim [Link] 5383
FULL PAPER C. Venkatesh, P. P. Singh, H. Ila, H. Junjappa

H1), 3.74 (s, 3 H, OCH3), 3.83 (dd, J = 12.5, 5.4 Hz, 1 H, H3), 4.86 133.1, 137.1, 137.3, 151.2, 199.4 ppm. MS: m/z (%) = 365 (100)
(br. s, 1 H, NH), 5.89 (d, J = 7.3 Hz, 1 H, ArH), 6.26 (dt, J = 7.4, [M+]. C26H23NO (365.47): calcd. C 85.45, H 6.34, N 3.83 %; found
1.0 Hz, 1 H, ArH), 6.51 (d, J = 7.5 Hz, 1 H, ArH), 6.76 (d, J = C 85.61, H 6.12, N 4.11 %.
8.6 Hz, 2 H, ArH), 6.83 (d, J = 8.6 Hz, 2 H, ArH), 6.90 (dt, J =
4-(3,4-Dimethoxyphenyl)-1-phenyl-4,9-dihydro-3H-carbazole (4b):
7.7, 1.0 Hz, 1 H, ArH), 7.47 (t, J = 7.2 Hz, 2 H, ArH), 7.56 (t, J
Yield 75 % (0.57 g); colorless crystals; m.p. 177–178 °C; Rf 0.39 (6:1
= 7.3 Hz, 1 H, ArH), 7.96 (dd, J = 8.4, 1.1 Hz, 2 H, ArH) ppm.
13
hexanes/EtOAc). IR (KBr): ν̃ = 3338, 1593, 1512, 1458, 1247, 1133,
C NMR (100 MHz, CDCl3): δ = 27.7, 35.7, 49.1, 55.1, 57.0, 59.4,
1025, 759 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.75 (ddd, J =
72.3, 108.0, 113.0, 116.9, 126.7, 126.9, 127.5, 128.3, 128.5, 129.6,
17.1, 10.2, 4.5 Hz, 1 H, H3), 2.95 (ddd, J = 17.1, 8.2, 4.5 Hz, 1 H,
131.7, 133.0, 138.2, 150.9, 158.0, 201.2 ppm. MS: m/z (%) = 383
H3), 3.77 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 4.37 (dd, J = 10.2,
(22) [M+], (100) [263]. C26H25NO2 (383.48): calcd. C 81.43, H 6.57,
8.2 Hz, 1 H, H4), 5.97 (t, J = 4.5 Hz, 1 H, =CH), 6.80 (d, J =
N 3.65 %; found C 81.31, H 6.34, N 3.42 %.
8.3 Hz, 1 H, ArH), 6.88–6.95 (m, 4 H, ArH), 7.06 (dt, J = 7.1,
(1R*,3S*,3aS*,8bS*)-[(4-Methoxyphenyl)-8b-methyl-1,2,3,3a,4,8b- 2.4 Hz, 1 H, ArH), 7.19–7.26 (m, 1 H, ArH), 7.38–7.61 (m, 5 H,
hexahydrocyclopenta[b]indol-3-yl]phenylmethanone (3e): Yield 83 % ArH), 7.98 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ
(0.63 g); colorless crystals; m.p. 141–142 °C; Rf 0.60 (6:1 hexanes/ = 35.2, 38.5, 55.7, 55.8, 110.9, 111.1, 112.8, 119.5, 119.7, 119.9,
EtOAc). IR (KBr): ν̃ = 3369, 2957, 1674, 1600, 1512, 1461, 1358, 121.6, 124.8, 126.6, 127.4, 127.8, 128.9, 129.2, 132.6, 133.2, 135.8,
1301, 1248, 1185, 1029, 822, 744, 703 cm–1. 1H NMR (400 MHz, 137.6, 138.1, 147.5, 148.8 ppm. MS: m/z (%) = 381 (40) [M + ].
CDCl3): δ = 1.55 (s, 3 H, CH3), 2.05 (td, J = 12.8, 5.6 Hz, 1 H, C26H23NO2 (381.47): calcd. C 81.86, H 6.08, N 3.67 %; found C
H2⬘), 2.54 (q, J = 12.8 Hz, 1 H, H2⬘⬘), 3.19 (dd, J = 12.8, 5.6 Hz, 1 81.97, H 5.83, N 3.42 %.
H, H1), 3.77 (s, 3 H, OCH3), 3.94 (td, J = 12.8, 5.6 Hz, 1 H, H3), Diethyl (1S*,3aR*,8bS*)-1-(4-methoxyphenyl)-8b-methyl-1,3a,4,8b-
4.47 (d, J = 5.6 Hz, 1 H, H3a), 5.68 (d, J = 7.3 Hz, 1 H, ArH), 6.29 tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxylate (11e): Yield
(t, J = 7.3 Hz, 1 H, ArH), 6.43 (d, J = 7.8 Hz, 1 H, ArH), 6.75 (d, 89 % (0.75 g); colorless viscous liquid; Rf 0.35 (9:1 hexanes/EtOAc).
J = 8.56 Hz, 2 H, ArH), 6.86 (t, J = 5.6 Hz, 1 H, ArH), 6.90 (d, J IR (neat): ν̃ = 3468, 2363, 1726, 1597, 1516, 1351, 1263, 669 cm–1.
= 8.5 Hz, 2 H, ArH), 7.51 (t, J = 7.4 Hz, 2 H, ArH), 7.59 (t, J = 1
H NMR (400 MHz, CDCl3): δ = 1.19 (t, J = 7.4 Hz, 3 H, CH3),
7.3 Hz, 1 H, ArH), 8.04 (d, J = 7.8 Hz, 2 H, ArH) ppm. 13C NMR 1.23 (t, J = 7.4 Hz, 3 H, CH3), 1.47 (s, 3 H, CH3), 2.22 (dd, J =
(100 MHz, CDCl 3 ): δ = 28.4, 32.5, 52.8, 55.1, 56.4, 57.8, 72.6, 13.6, 5.1 Hz, 1 H, H2⬘), 2.57 (dd, J = 14.5, 13.1 Hz, 1 H, H2⬘⬘), 3.03
108.3, 112.9, 117.4, 125.6, 127.3, 128.1, 128.8, 129.8, 131.3, 131.7, (dd, J = 14.5, 5.1 Hz, 1 H, H1), 3.70 (s, 3 H, OCH3), 3.91 (br. s, 1
133.0, 137.2, 150.8, 158.3, 199.6 ppm. MS: m/z (%) = 383 (100) H, NH), 4.06–4.28 (m, 4 H, 2 × CH2), 4.64 (s, 1 H, H3a), 5.53 (d, J
[M+]. C26H25NO2 (383.48): calcd. C 81.43, H 6.57, N 3.65 %; found = 7.5 Hz, 1 H, ArH), 6.24 (t, J = 7.4 Hz, 1 H, ArH), 6.41 (d, J =
C 81.62, H 6.31, N 3.79 %. 7.5 Hz, 1 H, ArH), 6.69 (d, J = 8.5 Hz, 2 H, ArH), 6.81 (d, J =
(1R*,3S*,3aS*,8bS*)-[(4-Methoxyphenyl)-3a,8b-dimethyl- 8.5 Hz, 2 H, ArH), 6.82 (t, J = 7.8 Hz, 1 H, ArH) ppm. 13C NMR
1,2,3,3a,4,8b-hexahydrocyclopenta[b]indol-3-yl]phenylmethanone (100 MHz, CDCl3): δ = 14.0, 14.1, 27.8, 36.3, 53.3, 55.1, 57.5, 61.2,
(3f): Yield 93 % (0.73 g); yellow viscous oil; Rf 0.72 (19:1 hexanes/ 61.5, 65.8, 73.3, 108.6, 112.9, 117.7, 126.0, 127.4, 129.8, 130.4,
EtOAc). IR (CH 2Cl2 ): ν̃ = 3397, 2965, 2834, 2361, 1676, 1607, 132.0, 150.4, 158.4, 169.1, 170.9 ppm. MS: m/z (%) = 423 (100)
1512, 1485, 1464, 1446, 1379, 1319, 1247, 1179, 1110, 1035, 829, [M+]. C25H29NO5 (423.50): calcd. C 70.90, H 6.90, N 3.31 %; found
742 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.30 (s, 3 H, CH3), C 70.73, H 7.13, N 3.11 %.
1.34 (s, 3 H, CH3), 2.07 (td, J = 12.5, 5.6 Hz, 1 H, H2⬘), 2.35 (q, J (1S*,3S*,4aR*,9aR*)-3-[4-Methoxyphenyl]-1,2,3,4,9-pentahydro-
= 12.5 Hz, 1 H, H2⬘⬘), 3.06 (dd, J = 12.5, 5.6 Hz, 1 H, H1), 3.65 (s, 4a,9a-propanocarbazole Derivative 16: Yield 58 % (0.49 g); viscous
3 H, OCH3), 3.70 (dd, J = 12.5, 5.6 Hz, 1 H, H3), 4.43 (br. s, 1 H, liquid; Rf 0.75 (6:1 hexanes/EtOAc). IR (neat): ν̃ = 3446, 2921,
NH), 5.74 (d, J = 7.1 Hz, 1 H, ArH), 6.18 (t, J = 7.3 Hz, 1 H, 2851, 2365, 1597, 1352, 1251, 1032, 669 cm–1. 1H NMR (400 MHz,
ArH), 6.43 (d, J = 7.8 Hz, 1 H, ArH), 6.58 (d, J = 8.7 Hz, 2 H, CDCl3): δ = 1.11–1.25 (m, 2 H, CH2), 1.33–1.37 (m, 2 H, CH2),
ArH), 6.66 (d, J = 8.7 Hz, 2 H, ArH), 6.81 (t, J = 7.3 Hz, 1 H, 1.60–1.65 (m, 1 H, CH), 1.70–1.76 (m, 1 H, CH), 1.81–1.90 (m, 1
ArH), 7.39 (t, J = 7.6 Hz, 2 H, ArH), 7.48 (t, J = 7.3 Hz, 1 H, H, CH), 2.08–2.13 (m, 2 H, cyclohexane CH and H2⬘), 2.36 (q, J
ArH), 7.90 (dd, J = 8.5, 1.5 Hz, 2 H, ArH) ppm. 13 C NMR = 12.6 Hz, 1 H, H2⬘⬘), 3.14 (dd, J = 12.6, 5.9 Hz, 1 H, H1), 3.67 (s,
(100 MHz, CDCl 3 ): δ = 23.3, 35.6, 55.1, 55.6, 58.3, 58.9, 74.3, 3 H, OCH3), 3.86 (dd, J = 12.6, 5.2 Hz, 1 H, H3), 4.23 (br. s, 1 H,
107.6, 112.8, 116.8, 125.3, 127.5, 128.2, 128.5, 129.7, 130.0, 131.4, NH), 5.72 (d, J = 7.5 Hz, 1 H, ArH), 6.17 (t, J = 7.4 Hz, 1 H,
131.9, 133.0, 138.1, 149.5, 158.2, 201.5 ppm. MS: m/z (%) = 397 ArH), 6.42 (d, J = 7.5 Hz, 1 H, ArH), 6.59 (d, J = 8.5 Hz, 2 H,
(100) [M+]. C27H27NO2 (397.20): calcd. C 81.58, H 6.85, N 3.52 %; ArH), 6.73 (d, J = 8.5 Hz, 2 H, ArH), 6.80 (t, J = 7.5 Hz, 1 H,
found C 81.70, H 6.72, N 3.62 %. ArH), 7.41 (t, J = 7.4 Hz, 2 H, ArH), 7.50 (t, J = 7.0 Hz, 1 H,
ArH), 7.91 (d, J = 8.3 Hz, 2 H, ArH) ppm. 13C NMR (100 MHz,
(1S*,3S*,3aR*,8bS*)-Phenyl-(1-styryl-1,2,3,3a,4,8b-hexahydro-
CDCl3): δ = 17.8, 18.9, 32.7, 33.4, 34.8, 54.1, 55.1, 57.5, 59.4, 74.0,
cyclopenta[b]indol-3-yl)methanone (9a): Yield 88 % (0.64 g); color-
107.6, 112.8, 116.8, 125.2, 127.3, 128.2, 128.6, 129.6, 130.0, 132.1,
less solid; m.p. 150–151 °C; Rf 0.40 (9:1 hexanes/EtOAc). IR (KBr):
133.0, 138.3, 151.2, 158.1, 201.7 ppm. MS: m/z (%) = 423 (100)
ν̃ = 3368, 3027, 2926, 2374, 1679, 1599, 1482, 1364, 1322, 1251,
[M+]. C29H29NO2 (423.55): calcd. C 82.24, H 6.90, N 3.31 %; found
1150, 968, 745, 691 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.96
C 82.53, H 6.71, N 3.51 %.
(td, J = 12.5, 5.7 Hz, 1 H, H2⬘), 2.11 (q, J = 12.5 Hz, 1 H, H2⬘⬘),
3.06–3.11 (m, 1 H, H1), 3.82 (td, J = 12.5, 5.7 Hz, 1 H, H3), 4.02 (1S*,3S*,3aR*,8bR*)-1-Phenyl-1,2,3,4-tetrahydro-3a,8b-propanocy-
(t, J = 8.5 Hz, 1 H, H8b), 4.87 (dd, J = 8.5, 5.7 Hz, 1 H, H3a), 5.96 clopenta[b]indole Derivative 19: Yield 25 % (0.18 g); colorless crys-
(dd, J = 15.9, 9.0 Hz, 1 H, =CH), 6.42 (d, J = 15.9 Hz, 1 H, =CH), tals; m.p. 180–183 °C; Rf 0.61 (19:1 hexanes/EtOAc). IR (KBr): ν̃
6.44 (d, J = 7.5 Hz, 1 H, ArH), 6.55 (t, J = 7.3 Hz, 1 H, ArH), = 3355, 3058, 2941, 2363, 1662, 1598, 1484, 1457, 1401, 1319, 1254,
6.89–6.94 (m, 2 H, ArH), 7.12–7.25 (m, 5 H, ArH), 7.42–7.54 (m, 1207, 1159, 1015, 746, 707 cm–1. 1H NMR (400 MHz, CDCl3): δ =
3 H, ArH), 7.96 (d, J = 8.1 Hz, 2 H, ArH) ppm. 13 C NMR 1.08–1.26 (m, 3 H, CH2, CH), 1.50–1.56 (m, 1 H, CH), 1.62–1.69
(100 MHz, CDCl3): δ = 32.9, 47.5, 51.8, 54.2, 65.6, 109.2, 118.0, (m, 2 H, CH2), 1.91 (td, J = 13.0, 5.0 Hz, 1 H, H2⬘), 2.64 (q, J =
126.1, 126.5, 127.0, 127.5, 127.8, 128.2, 128.5, 128.8, 130.3, 131.0, 13.0 Hz, 1 H, H2⬘⬘), 3.32 (dd, J = 13.0, 5.0 Hz, 1 H, H1), 3.97 (dd,

5384 [Link] © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2006, 5378–5386
Diastereoselective [3+2] Cyclopenta[b]annulation of Indoles
FULL PAPER
J = 13.0, 5.0 Hz, 1 H, H3), 6.54 (d, J = 7.8 Hz, 1 H, ArH), 6.67 (t, Supporting Information (see also the footnote on the first page of
J = 7.3 Hz, 1 H, ArH), 6.94 (d, J = 7.5 Hz, 1 H, ArH), 7.00 (dt, J this article): 1H and 13C NMR spectroscopic data for all new com-
= 7.1, 1.0 Hz, 1 H, ArH), 7.23 (t, J = 7.1 Hz, 1 H, ArH), 7.31 (t, pounds 3b, 3c, 5c, 5f, 4c, 6e⬘, 7e⬘, 7e⬘⬘, 9e⬘, 11a⬘, 11a⬘⬘, 11c⬘, 11c⬘⬘,
J = 7.4 Hz, 2 H, ArH), 7.39 (d, J = 7.3 Hz, 2 H, ArH), 7.46 (t, J 12e, 14, 18, and 22, and X-ray crystal structure data for compounds
= 7.5 Hz, 2 H, ArH), 7.54 (t, J = 7.4 Hz, 1 H, ArH), 8.11 (d, J = 3a and 3d are available.
7.8 Hz, 2 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.1,
31.6, 36.8, 38.5, 52.4, 59.0, 69.1, 82.6, 108.9, 119.0, 124.0, 126.7,
127.8, 128.0, 128.3, 128.6, 128.91, 128.95, 133.1, 135.9, 137.8,
Acknowledgments
139.9, 201.3 ppm. MS: m/z (%) = 379 (100) [M + ]. C 27 H 25 NO Financial assistance under CSIR project is acknowledged.
(379.49): calcd. C 85.45, H 6.64, N 3.69 %; found C 85.21, H 6.91,
N 3.92 %.
[1] Review: P. S. Steyn, R. Vleggaar, Fortschr. Chem. Org. Naturst.
(1S*,3S*,5aR*,10bR*)-1-(4-Methoxyphenyl)-1,2,3,4,5,6-hexahydro- 1985, 48, 1.
5a,10b-propanocyclohepta[b]indole Derivative 21: Yield 27 % [2] a) A. B. Smith III, R. Mewshaw, J. Am. Chem. Soc. 1985, 107,
(0.23 g); colorless solid; m.p. 142–144 °C; Rf 0.67 (9:1 hexanes/ 1769; b) R. E. Mewshaw, M. D. Taylor, A. B. Smith III, J. Org.
EtOAc). IR (KBr): ν̃ = 3413, 2930, 2854, 2363, 1676, 1604, 1512, Chem. 1989, 54, 3449; c) A. B. Smith III, T. L. Leenay, J. Am.
Chem. Soc. 1989, 111, 5761.
1486, 1448, 1363, 1248, 1222, 1179, 1035, 831, 742, 703 cm–1. 1H
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NMR (400 MHz, CDCl3): δ = 0.98–1.08 (m, 2 H, CH2), 1.10–1.31 Chem. Soc., Chem. Commun. 1985, 47.
(m, 3 H, CH2, CH), 1.40–1.55 (m, 2 H, CH2), 1.78 (t, J = 14.4 Hz, [4] Y. C. Kong, K.-H. Ng, K.-H. Wat, A. Wong, I. F. Saxena, K.-
1 H, CH), 1.90–1.96 (m, 2 H, H2⬘ and CH), 2.11 (dd, J = 14.4, F. Cheng, P. P. But, H.-T. Chang, Planta Med. 1985, 44, 304.
7.1 Hz, 1 H, CH), 2.30 (q, J = 12.9 Hz, 1 H, H2⬘⬘), 3.03 (dd, J = [5] a) D. C. C. Wong, W. P. Fong, S. S. Lee, Y. C. Kong, K. F.
12.9, 5.1 Hz, 1 H, H1), 3.66 (s, 3 H, OCH3), 3.77 (dd, J = 12.9, Cheng, G. Stone, Eur. J. Pharmacol. 1998, 362, 87; b) K. F.
4.6 Hz, 1 H, H3), 4.65 (br. s, 1 H, NH), 5.45 (d, J = 7.3 Hz, 1 H, Cheng, T. T. Wong, K. P. Chan, Y. C. Kong, Eur. J. Med. Chem.
ArH), 6.14 (t, J = 7.3 Hz, 1 H, ArH), 6.47 (d, J = 7.6 Hz, 1 H, 1992, 27, 121.
ArH), 6.61 (br. s, 4 H, ArH), 6.84 (t, J = 7.5 Hz, 1 H, ArH), 7.37 [6] T. W. Leung, G. Cheng, C. H. Chui, S. K. Ho, F. Y. Lau, J. K.
Tjong, T. C. Poon, J. C. Tang, W. C. Tse, K. F. Cheng, K. C.
(t, J = 7.4 Hz, 2 H, ArH), 7.47 (t, J = 8.3 Hz, 1 H, ArH), 7.87 (d,
Kong, Chemotherapy 2000, 46, 62.
J = 7.3 Hz, 2 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = [7] K. R. Campos, M. Journet, S. Lee, E. J. J. Grabowski, R. D.
23.4, 25.1, 29.6, 31.2, 35.1, 36.4, 40.2, 55.1, 56.1, 58.7, 64.7, 106.6, Tillyer, J. Org. Chem. 2005, 70, 268.
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138.3, 151.0, 158.2, 202.2 ppm. MS: m/z (%) = 437 (100) [M+]. [9] a) P. Magnus, T. Gallagher, P. Brown, C. Huffman, J. Am.
C30H31NO2 (437.57): calcd. C 82.35, H 7.14, N 3.20 %; found C Chem. Soc. 1984, 106, 2105; b) T. Gallagher, P. Magnus, J. Am.
82.12, H 7.32, N 3.47 %. Chem. Soc. 1983, 105, 2086.
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at –78 °C to a stirred solution of 2b (0.50 g, 1.77 mmol) and appro- 625–623.
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water (1 × 25 mL), followed by brine (25 mL) and dried with anhy- Heterocycles 1995, 41, 1385.
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to afford cyclopentannulated indoles 5a, 5c, and 5f, which were F. Cheng, T.-T. Wong, K.-P. Chan, Eur. J. Med. Chem. 1991,
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hydrocyclopenta[b]indol-3-yl]phenylmethanone (5a): Yield 84 % 3339.
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EtOAc). IR (KBr): ν̃ = 3337, 1659, 1597, 1515, 1460, 1328, 1249, Bergman, L. Venemalm, A. Gogoll, Tetrahedron 1990, 46,
1144, 1028, 756 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.21 (q, J 6067; d) J. Bergman, L. Venemalm, Tetrahedron Lett. 1988, 29,
= 12.2 Hz, 1 H, H2⬘⬘), 2.31 (td, J = 12.2, 6.1 Hz, 1 H, H2⬘), 3.24 2993; e) J. Bergman, L. Venemalm, Pure Appl. Chem. 1994, 66,
(m, 1 H, H1), 3.85 (t, J = 10.1 Hz, 1 H, H8b), 3.89 (s, 6 H, 2331.
2 × OCH3), 4.02 (td, J = 12.2, 6.1 Hz, 1 H, H3), 4.80 (dd, J = 10.1, [18] M. Ishikura, K. Imaizumi, N. Katagiri, Heterocycles 2000, 53,
6.1 Hz, 1 H, H3a), 6.63–6.68 (m, 2 H, ArH), 6.84–6.87 (m, 4 H, 553.
ArH), 7.06 (t, J = 7.56 Hz, 1 H, ArH), 7.51 (t, J = 7.3 Hz, 2 H, [19] C. A. Harrison, R. Leineweber, C. J. Moody, J. M. J. Williams,
ArH), 7.60 (t, J = 7.3 Hz, 1 H, ArH), 8.06 (dd, J = 8.3, 1.2 Hz, 2 Tetrahedron Lett. 1993, 34, 8527.
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H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 39.8, 53.9, 55.6,
[21] D. B. England, T. D. O. Kuss, R. G. Keddy, M. A. Kerr, J. Org.
55.9, 56.0, 56.9, 66.8, 109.8, 110.5, 111.3, 118.8, 119.6, 124.3, 127.9, Chem. 2001, 66, 4704.
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C 78.17, H 6.31, N 3.51 %; found C 78.30, H 6.12, N 3.69 %. Chem. 2002, 80, 992.

Eur. J. Org. Chem. 2006, 5378–5386 © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim [Link] 5385
FULL PAPER C. Venkatesh, P. P. Singh, H. Ila, H. Junjappa

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5386 [Link] © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2006, 5378–5386