Efficient syntheses of substituted carbazoles and cyclopent[b]indoles from 1-methyl-3-(benzotriazol-1-ylmethyl)indole

Article abstract of DOI:10.1021/jo9604954

1-Methyl-3-(benzotriazol-1-ylmethyl)indole (1) undergoes lithiation and 1,4-addition with a variety of α,β-unsaturated ketones and aldehydes. Subsequent treatment with an acidic resin in refluxing 1,4-dioxane causes intramolecular cyclization followed by aromatization to furnish a wide range of 1,3-di-, 2,3-di-, and 1,2,3-trisubstituted carbazoles 6a-j and 8 in moderate to excellent yields. NMR study is described to discriminate between structures of types 6 and 8 on the basis of ¹H-¹³C long-range correlation. Treatment of 1 with styrenes in the presence of zinc bromide results in formal [3 + 2] cycloaddition to give cyclopent[b]indoles 14a-c in good yields. When 1 is first lithiated and reacts with electrophiles, the resulting alkylation products undergo similar [3 + 2] additions with styrenes to give 1-functionalized cyclopent[b]indoles 15 and 16 with a high degree of stereoselectivity.

Full text of DOI:10.1021/jo9604954

7558
J . Org. Chem. 1996, 61, 7558-7563
Efficien t Syn th eses of Su bstitu ted Ca r ba zoles a n d
Cyclop en t[b]in d oles fr om
1-Meth yl-3-(ben zotr ia zol-1-ylm eth yl)in d ole
Alan R. Katritzky,* Guifen Zhang, Linghong Xie, and Ion Ghiviriga
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Received March 13, 1996X
1-Methyl-3-(benzotriazol-1-ylmethyl)indole (1) undergoes lithiation and 1,4-addition with a variety
of R,â-unsaturated ketones and aldehydes. Subsequent treatment with an acidic resin in refluxing
1,4-dioxane causes intramolecular cyclization followed by aromatization to furnish a wide range of
1,3-di-, 2,3-di-, and 1,2,3-trisubstituted carbazoles 6a -j and 8 in moderate to excellent yields. NMR
study is described to discriminate between structures of types 6 and 8 on the basis of 1H-13C long-
range correlation. Treatment of 1 with styrenes in the presence of zinc bromide results in formal
[3 + 2] cycloaddition to give cyclopent[b]indoles 14a -c in good yields. When 1 is first lithiated
and reacts with electrophiles, the resulting alkylation products undergo similar [3 + 2] additions
with styrenes to give 1-functionalized cyclopent[b]indoles 15 and 16 with a high degree of
stereoselectivity.
In tr od u ction
of appropriate precursors, harsh reaction conditions, or
poor regioselectivity of the cyclization step. Accordingly,
approaches via the [b]-annulation of indole skeletons are
of special importance. The most important methods that
fall into this category include (a) thermal-induced and
photoinduced electrocyclizations of 2,3-divinylindoles,11h
(b) 1,4-additions of indolo-2,3-quinodimethanes11a,e and
of vinylindoles11g with dienophiles, and (c) addition of
R-carbanions at C-2 of indoles with Michael acceptors,
followed by intramolecular cyclization with the ester
group at the indole 3-position.11b,f
Synthetic approaches to substituted carbazoles are of
special interest and contemporary importance1 since the
growing variety of carbazole alkaloids isolated show
antimicrobial,2 antiviral,3 and cytotoxic properties.4 Ma-
jor methods for the preparation of carbazoles include the
following: (i) dehydrogenation of 1,2,3,4-tetrahydrocar-
bazoles which are usually prepared by Fischer indole
syntheses,5 (ii) reductive cyclizations of 2-nitrobiphenyls,6
(iii) thermal,7 photolytic,8 and palladium-promoted9 cy-
clizations of diphenylamines, (iv) iron-mediated oxidative
coupling of 1,3-cyclohexadiene and arylamines,10 and (v)
[b]-annulations of indole skeletons.11 Many methods of
types i-iv are problematic for the synthesis of highly
substituted carbazoles involving multistep preparations
The cyclopent[b]indole structural element occurs in a
large number of indole alkaloids, including the structur-
ally complex tremorgenic mycotoxins12 and the monot-
erpenoid yuehchukene.13 In accordance with the impor-
tance of compounds possessing this skeleton, a number
of methods have been developed for its construction.
However, few approaches are preparatively efficient, the
most useful being the ring closure of unsaturated 3-a-
cylindoles14 and the [3 + 2] addition of indole-2- or
3-methanols with alkenes.15 However, the former re-
quires strongly acidic conditions and the latter frequently
suffers from unsatisfactory yields.
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
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Chakraborty, D. P. Prog. Chem. Org. Nat. Prod. 1987, 52, 159. (b)
Chakraborty, D. P.; Roy, S. Prog. Chem. Org. Nat. Prod. 1991, 57, 71.
(c) Bergman, J .; Pelcman, B. Pure Appl. Chem. 1990, 62, 1967. (d)
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Chem. Commun. 1972, 537.
Our recent work has demonstrated the versatility of
benzotriazolylalkyl-substituted heterocycles for the syn-
thesis of 1,1-bis(heteroaryl)alkanes16 and the utility of
1-methyl-3-(benzotriazol-1-ylmethyl)indole (1) for the
synthesis of a wide range of 3-substituted indoles17 and
(8) Carruthers, W. J . Chem. Soc., Chem. Commun. 1966, 272.
(9) Akermark, B.; Eberson, L.; J onsson, E.; Pettersson, E. J . Org.
Chem. 1975, 40, 1365.
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G. R. Tetrahedron Lett. 1979, 3565. (b) Kno¨lker, H.-J .; Bauermeister,
M. J . Chem. Soc., Chem. Commun. 1989, 1468. (c) Kno¨lker, H.-J .;
Bauermerster, M. J . Indian Chem. Soc. 1994, 71, 345 and references
cited therein.
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1.
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24, 65. (b) Henry, K. K. J ., J r.; Grieco, P. A. J . Chem. Soc., Chem.
Commun. 1993, 510. (c) Bergman, J .; Venemalm, L. Tetrahedron 1992,
48, 759. (d) Sheu, J .-H.; Chen, Y.-K.; Hong, Y.-L. V. Tetrahedron Lett.
1991, 32, 1045.
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J .; Ila, H.; J unjappa, H. Tetrahedron Lett. 1995, 36, 3385. (b) Moha-
nakrishnan, A. K.; Srinivasan, P. C. Tetrahedron Lett. 1993, 34, 1343.
(c) Bergman, J .; Pelcman, B. Tetrahedron Lett. 1986, 27, 1939. (d)
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31, 1609. (e) Saroja, B.; Srinivasan, P. C. Tetrahedron Lett. 1984, 25,
5429. (f) Mali, R. S.; J agtap, P. G. Tetrahedron Lett. 1992, 33, 1655.
(g) Pindur, U.; Otto, C. Chem. Lett. 1992, 403. (h) Kawasaki, T.;
Sakamoto, M. J . Indian Chem. Soc. 1994, 71, 443 and references cited
therein.
(14) (a) Bergman, J .; Venemalm, L. Tetrahedron Lett. 1987, 28, 3741.
(b) Bergman J .; Venemalm, L.; Gogoll, A. Tetrahedron 1990, 46, 6067.
(15) (a) Harrison, C.-A.; Leineweber, R.; Moody, C. J .; Williams, J .
M. J . Tetrahedron Lett. 1993, 34, 8527. (b) Harrison, C.-A.; Leineweber,
R.; Moody, C. J .; Williams, J . M. J . J . Chem. Soc., Perkin Trans. 1
1995, 1127.
(16) Katritzky, A. R.; Xie, L.; Fan, W.-Q. J . Org. Chem. 1993, 58,
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539.
S0022-3263(96)00495-1 CCC: $12.00 © 1996 American Chemical Society

Syntheses of Substituted Carbazoles and Cyclopent[b]indoles
J . Org. Chem., Vol. 61, No. 21, 1996 7559
Sch em e 1
F igu r e 1. Position numbering and long-range polarization
transfer from protons to carbons in compounds 6a -j and 8,
as seen in the LRHETC spectrum.
Sch em e 2
heterocyclo[b]-fused carbazoles.18 The chemistry of com-
pound 1 has now been further developed to provide facile
and efficient routes to substituted carbazoles and cyclo-
penta[b]indoles.
Resu lts a n d Discu ssion
indole 2-position to give intermediates 4 leading to
products 6, or first at the 3-position to give the corre-
sponding spiro-3H-indolium cations of type 7 (Scheme 2),
followed by the migration of either a or b bond to give in
each case two regioisomers of types 6 and 8. Interest-
ingly, in all cases except 6j, single regioisomers 6a -i
were obtained. The other expected regioisomers of type
8 were not detected, which might imply the direct C2 ring
closure of 5a -i. When R,â-unsaturated aldehyde 2j
(Scheme 2) was used as the substrate, an inseparable
mixture of 6j and 8 was obtained in a ratio of 2:3,
demonstrating the existence of the intermediate 7.
However, the reason for the different behavior of inter-
mediate 5j from 5a -i is not yet clear.
Syn th esis of Su bstitu ted Ca r ba zoles. The requi-
site 1-methyl-3-(benzotriazol-1-ylmethyl)indole (1) was
readily prepared from 1-methylindole and 1-(hydroxy-
methyl)benzotriazole as described in our earlier work.17
Due to the electron-withdrawing ability of the benzo-
triazolyl group,17,19 compound 1 can be easily deproto-
nated at the side-chain CH2 group. Thus, treatment of
1 with n-butyllithium at -78 °C, under argon in THF,
furnished a deep green solution of the lithio derivative
of 1. Reactions of this anion with R,â-unsaturated
ketones or aldehydes, followed by refluxing in 1,4-dioxane
in the presence of an acidic resin (Amberlyst-15), formed
a wide variety of 1,3-di-, 2,3-di-, or 1,2,3-trisubstituted
carbazoles 6a -i in moderate to excellent yields (Scheme
1). These transformations are envisioned to proceed via
1,4-addition of the anion of 1 to R,â-unsaturated carbonyl
compounds to form intermediates 3, which were proto-
nated to ketones 5. Acid-catalyzed cyclization of 5
followed by concurrent elimination of molecules of ben-
zotriazole and water afforded the desired products 6 (for
reviews of benzotriazole as a leaving group see refs 19
and 20).
The structures of 6a -j and 8 are fully supported by
elemental analyses and NMR spectral data (see Experi-
mental Section). Discrimination between structures of
1
types 6 and 8 was made on the basis of H-13C long-
range correlations between the protons/carbons of the
R1-R3 groups and the protons/carbons at the carbazole
ring (see Figure 1 and supporting information). Com-
1
plete H and 13C chemical shift assignments were made
on the basis of the 1H-13C direct (HETCOR) and long
range (LRHETC) correlations. The HETCOR experiment
was run skipping the BIRD module in the pulse sequence,
It is well demonstrated in the literature that the
alkylation of indole at C2 can occur by alkylation at C3
followed by rearrangement.20,21 Accordingly, the ring
closure of ketones 5 could have occurred directly at the
(20) (a) Katritzky, A. R.; Rachwal, S.; Hitchings, G. J . Tetrahedron
1991, 47, 2683. (b) Katritzky, A. R.; Lan, X. Chem. Soc. Rev. 1994,
363. (c) Katritzky, A. R.; Lan, X.; Fan, W.-Q. Synthesis 1994, 445.
(21) (a) J oule, J . A. Heterocyclic Chemistry; Chapman & Hall:
London, U.K.; 1995. (b) Biswas, K. M.; J ackson, A. H. Tetrahedron
1969, 25, 227. (c) Hamel, P.; Preville, P. J . Org. Chem. 1996, 61, 1573.
(18) Katritzky, A. R.; Xie, L. J . Org. Chem. 1995, 60, 3707.
(19) Katritzky, A. R.; Yang, Z.; Cundy, D. J . Aldrichimica Acta 1994,
27, 31.

7560 J . Org. Chem., Vol. 61, No. 21, 1996
Katritzky et al.
thus preserving the 1H-1H couplings in the f1 dimen-
sion.22 The LRHETC experiments employed the pulse
sequence proposed by Krishnamurthy23 which suppresses
Sch em e 3
1
the direct H-13C couplings. The polarization transfers
from protons to carbons as seen in the LRHETC experi-
ment are represented by arrows in Figure 1 and sup-
porting information. The chemical shift assignments are
briefly presented below for one typical compound.
Two quaternary carbons, 8a and 9a, correlate at long
range with the protons of the methyl group in position
9. The carbon in position 8a also displayed long-range
correlations with the protons in positions 5 (doublet) and
1
7 (triplet). The H and 13C chemical shifts for positions
6, 8, and 4b were assigned on the basis of their mutual
long-range couplings and proton multiplicity in the
HETCOR spectrum. Carbon 4a was recognized on the
basis of its chemical shift similar to that of 4b and on
the basis of polarization transfer from proton 5. Proton
4 was identified on the basis of long-range correlations
with carbons 9a, 4a, and 4b; the long-range correlation
of H-4 with carbon 2 allowed the assignment of C-2. The
chemical shift assignments made as described above are
presented in Tables 1 (1H) and 2 (13C) (supporting
information). The chemical shift assignments for groups
R1-R3 and carbons 1 and 3 are presented in Figure 2
(supporting information), together with the long-range
proton to carbon polarization transfers (over two or three
bonds) which allowed discrimination between structures
6 and 8.
In summary, a general, facile route to substituted
carbazoles has been developed starting from readily
available 1-methyl-3-(benzotriazol-1-ylmethyl)indole (1).
An attractive feature of this approach is that by ap-
propriate choice of the R,â-unsaturated ketones and
aldehydes, a wide range of 1,3-di-, 2,3-di-, and 1,2,3-
trisubstituted carbazoles becomes readily accessible. This
route will complement the literature methods via the
[b]-annulation of indole skeletons (a)-(c) already dis-
cribed. Thus, route (a) via 1,6-π-electrocyclization of 2,3-
divinylindoles is versatile in view of the substituents
incorporated into the carbazole nuclei and has been
successfully used in the synthesis of many carbazole
alkaloids. However, the preparation of the appropriately
substituted 2,3-divinylindole precursors is often a mul-
tistep operation. Approaches (b) and (c) normally pro-
duce carbazoles substituted with electron-withdrawing
substituents, especially CN and CO2R groups. Thus, our
general synthetic route to other types of substituted
carbazoles from readily available starting materials
should be of significant utility.
Syn th esis of Cyclop en t[b]in d oles. Our earlier work
demonstrated that (benzotriazolylmethyl)indoles revers-
ibly ionize to yield the benzotriazolate anion and the
corresponding indolylmethyl cations in the presence of
Lewis acids or upon heating.16-18 Due to such ionization,
the benzotriazole auxiliary group can be displaced by
various nucleophiles. Following a similar protocol, it
seems possible that alkenes could function as nucleo-
philes to induce formal [2 + 3] cycloadditions with the
(benzotriazolylmethyl)indoles 1 and 9. This indeed proved
to be the case, and we now report that the reaction
provides a simple route to a range of cyclopent[b]indoles
14-16.
Thus, treatment of compound 1 with zinc bromide
followed by the addition of the appropriate styrene
afforded cyclopent[b]indoles 14a -c in 61-72% yields
(Scheme 3) via the addition of cation 10 to styrenes and
subsequent ring closure of the intermediate benzylic
cations 12. While reactions of 1 with â-unsubstituted
styrenes were successful, the use of â-substituted sty-
renes (e.g. â-methylstyrene) provided no detectable cy-
clopent[b]indoles. This observation contrasts the results
seen in the cycloadditions of benzylic cations with sty-
renes, where a â-substituent is necessary for successful
cycloaddition by slowing down styrene polymerization.24
Thus, our method extends and complements Moody’s
[2 + 3] cycloadditions of indole-3-methanols with â-sub-
stituted styrenes.15
Since compound 1 can be readily lithiated and alky-
lated (vide supra), this strategy was successfully extended
to the facile synthesis of 1-functionalized cyclopent[b]-
indoles from intermediates 9. Accordingly, treatment of
1 with 1.2 equiv of n-butyllithium (-78 °C, THF) followed
by the addition of appropriate electrophiles (methyl iodide
for 15a + 16a and 15b + 16b, cyclohexanone for 15c +
16c, and pentanone for 15d + 16d ) gave the correspond-
ing alkylation products 9. After workup, the crude
(22) Bax, A. J . Magn. Reson. 1983, 53, 517.
(23) Krishnamurthy, V. V.; Nunlist, R. J . Magn. Reson. 1988, 80,
280.
(24) Angle, S. R.; Arnaiz, D. O. J . Org. Chem. 1992, 57, 5937.

Syntheses of Substituted Carbazoles and Cyclopent[b]indoles
J . Org. Chem., Vol. 61, No. 21, 1996 7561
signals (1.34 ppm in 15b and 1.32 ppm in 16b) enhanced
the doublet at 7.50 ppm. Since the signal at 7.50 ppm
was assigned to position 8 on the basis of its multiplicity
and chemical shift, this again supports the assigned
regiochemistry. Other notable enhancements upon the
irradiation of the doublet methyl signals were for the
methylene protons at 2.13 ppm in 15b and 2.17 ppm in
16b. For compound 15b, irradiations of the methyl
groups in positions 1 and 3 induced positive NOEs on
the same methylene proton (2.13 ppm), demonstrating
the cis relationship of these groups. In compound 16b,
irradiations of the methyl groups in positions 1 and 3
produced positive NOEs on different methylene protons
(2.17 and 2.71 ppm, respectively); thus these methyl
groups are trans.
When compared with the analogous method previously
developed by Moody,15 our approach takes advantage of
the ready introduction of functionality into the 1-position
of cyclopent[b]indoles due to the anion-stabilizing ability
of the benzotriazolyl group. The readily available start-
ing material, high stereoselectivity, convenient one-pot
procedure, and reasonable yields combine to make our
methodology attractive for the synthesis of substituted
cyclopent[b]indoles.
F igu r e 3. Position numbering NOE effects in compounds 15b
and 16b.
Con clu sion
1-Methyl-3-(benzotriazol-1-ylmethyl)indole (1) has been
shown to be a useful and efficient reagent for the
construction of substituted carbazoles and cyclopent[b]-
indoles. The convenient and versatile approaches pre-
sented in this paper should find utility in the synthesis
of related natural products.
compounds 9 reacted with styrenes via intermediates 11
and 13 in the presence of zinc bromide to furnish in each
case a mixture of diastereoisomeric cyclopent[b]indoles
(15 and 16) in good yields with the trans isomer 15
largely predominant (19:1 for 15a /16a , 30:1 for 15b/16b,
15:1 for 15c/16c, and 18:1 for 15d /16d , based on the GC-
MS and NMR analyses of the crude reaction mixtures).
Compounds 14-16 are new, and their structures were
confirmed by elemental analyses and NMR spectral data
(Experimental Section).
J ust as for the cyclization of compounds 5 in the
synthesis of carbazoles described above, ring closure of
the benzylic cations (12 and 13) could occur either directly
at the indole 2-position or first at the 3-position to give
the corresponding 4-membered spiroindolenine interme-
diates, followed by the migration of one of the two alkyl
groups. 3,3-Disubstituted indolenines have proved to be
intermediates to cyclopent[b]indoles in some cases,25 but
this mechanism seems unlikely in the present examples
since a second regioisomer would be expected and none
was detected.
The regiochemistry and cis-trans stereochemistry of
products 15 and 16 were clarified by NOE difference
spectroscopy as exemplified by the study on 15b and 16b.
A 2:1 mixture of 15b and 16b, obtained by column
chromatography, showed singlet methyl signals at 3.32
ppm in 15b and 3.16 ppm in 16b, assigned to the NCH3
in position 4 (Figure 3) on the basis of their chemical
shifts. Irradiation of the methyl signal at 1.79 ppm
(singlet, thus geminal to the phenyl substituent) in 15b
enhanced the signal at 3.32 ppm, confirming the regio-
chemistry given in Scheme 3. Similarly, irradiation of
the singlet at 1.64 ppm in 16b enhanced the signal at
3.16 ppm. Additional positive NOEs upon these irradia-
tions were found for the ortho protons of the 3-phenyl
(7.05 ppm in 15b and 7.27 ppm in 16b) and for one of
the methylene protons (2.13 ppm in 15b and 2.71 ppm
in 16b). Simultaneous irradiation of the doublet methyl
Exp er im en ta l Section
Gen er a l. Melting points were determined with a hot-stage
apparatus and are uncorrected. NMR spectra were taken in
1
CDCl3 with tetramethylsilane as the internal standard for H
(300 MHz) or solvent as the internal standard for 13C (75 MHz).
Tetrahydrofuran was distilled under nitrogen immediately
prior to use from sodium/benzophenone. All reactions with
air-sensitive compounds were carried out under an argon
atmosphere. Column chromatography was conducted with
silica gel 230-400 mesh. 1-Methyl-3-(benzotriazol-1-ylmeth-
yl)indole (1) was prepared according to our previously reported
procedure.17
Gen er a l P r oced u r e for th e P r ep a r a tion of Su bstitu ted
Ca r ba zoles 6a -j a n d 8. To a solution of 1-methyl-3-
(benzotriazol-1-ylmethyl)indole (1) (1.05 g, 4 mmol) in THF
(75 mL) at -78 °C under argon was added n-BuLi (1.7 mL,
2.5 M in hexane, 4.4 mmol). After 1 h, the appropriate R,â-
unsaturated aldehyde or ketone in THF (10 mL) was added.
The reaction mixture was stirred at -78 °C for an additional
3 h and then allowed to warm to room temperature overnight.
After the THF was distilled off under argon, 1,4-dioxane (70
mL) and amberlyst-15 (15 g) were added. The mixture was
refluxed under argon for 14 h. The Amberlyst-15 was filtered
off and 1,4-dioxane evaporated. The residue was dissolved in
CH2Cl2 (60 mL), and the solution was washed with aqueous
sodium hydroxide (2 N, 30 mL) and water (20 mL). The
aqueous layer was extracted with diethyl ether (2 × 30 mL).
The combined organic solution was dried (MgSO4) and solvent
evaporated. The residue was purified by column chromatog-
raphy (silica gel) to give the pure product.
1,3-Dip h en yl-9-m eth ylca r ba zole (6a ). Hexane/ethyl ac-
etate (7:1) was used as the eluent to give 6a in 83% yield as a
colorless solid, mp 126-127 °C: 1H NMR δ 8.23 (d, J ) 1.9
Hz, 1H), 8.08-8.05 (d, J ) 6.7 Hz, 1H), 7.66-7.63 (m, 2H),
7.47-7.43 (m, 3H), 7.40-7.32 (m, 6H), 7.24-7.14 (m, 3H), 3.27
(s, 3H); 13C NMR δ 142.6, 141.7, 140.3, 137.9, 132.1, 130.1,
128.7, 128.0, 127.9, 127.4, 127.3, 126.5, 126.2, 126.1, 124.6,
(25) Ganesan, A.; Heathcock, C. H. Tetrahedron Lett. 1993, 34, 439.

7562 J . Org. Chem., Vol. 61, No. 21, 1996
Katritzky et al.
123.0, 120.1, 119.0, 117.7, 109.3, 32.7. Anal. Calcd for
C25H19N: C, 90.06; H, 5.74; N, 4.20. Found: C, 89.67; H, 5.54;
N, 4.09.
133.6, 133.5, 129.8, 128.0, 126.4, 125.3, 122.9, 121.4, 120.9,
120.0, 118.8, 109.5, 108.4, 29.0, 21.7. Anal. Calcd for
C20H17N: C, 88.52; H, 6.31; N, 5.16. Found: C, 88.18; H, 6.31;
N, 5.02.
1,9-Dim eth yl-3-p h en ylca r ba zole (6b). Hexane/ethyl ac-
etate (6:1) was used as the eluent to give 6b in 80% yield as
colorless needles, mp 170-171 °C: 1H NMR δ 8.04 (d, J ) 1.4
Hz, 1H), 8.00 (d, J ) 7.6 Hz, 1H), 7.61 (d, J ) 7.4 Hz, 2H),
7.38-7.30 (m, 4H), 7.25-7.20(m, 2H), 7.15-7.10 (m, 1H), 3.89
(s, 3H), 2.72 (s, 3H); 13C NMR δ 142.0, 141.9, 139.2, 132.4,
128.7, 128.2, 127.1, 126.3, 125.7, 124.1, 123.1, 120.5, 120.0,
119.0, 116.5, 108.6, 32.1, 20.3. Anal. Calcd for C20H17N: C,
88.52; H, 6.31; N, 5.16. Found: C, 88.89; H, 6.45; N, 5.07.
1-(2-P h en ylvin yl)-3-p h en yl-9-m et h ylca r b a zole (6c).
Hexane/methylene chloride (6:1) was used as the eluent to give
6c in 66% yield as a white solid, mp 174-175 °C: 1H NMR δ
8.19 (d, J ) 1.8 Hz, 1H), 8.07 (d, J ) 7.8 Hz, 1H), 7.80 (d, J )
15.9 Hz, 1H), 7.73-7.70 (m, 3H), 7.52-7.22 (m, 11H), 6.99 (d,
J ) 15.9 Hz, 1H), 3.95 (s, 3H); 13C NMR δ 142.3, 141.7, 138.1,
137.5, 132.6, 131.4, 128.8, 127.7, 127.2, 126.5, 126.4, 126.2,
126.0, 124.8, 124.6, 123.0, 120.1, 119.3, 118.1, 108.8, 33.0.
Anal. Calcd for C27H21N: C, 90.22; H, 5.89; N, 3.90. Found:
C, 90.27; H, 5.96; N, 3.58.
2-P h en yl-3-(2-m eth ylpr opyl)-9-m eth ylcar bazole (6j) an d
2-(2-Meth ylp r op yl)-3-p h en yl-9-m eth ylca r ba zole (8). Hex-
ane/ethyl acetate (6:1) was used as the eluent to give an
inseparable mixture of 6j and 8 in 67% total yield in a ratio of
2:3 as a colorless oil (signals for minor isomer are quoted in
brackets): 1H NMR δ 7.89 [7.97] (d, J ) 7.7 Hz, 1H), 7.80 [7.83]
(s, 1H), 7.34-7.17 (m, 7H), 7.12-6.98 (m, 2H), 3.65 [3.59] (s,
3H), 2.58 [2.54] (d, J ) 7.3 Hz, 2H), 1.66-1.23 (m, 1H), 0.66
[0.65] (d, J ) 6.6 Hz, 6H); 13C NMR δ 143.2 [143.3], 141.4
[141.5], 140.5 [139.4], 137.5, 134.0, 130.1 [129.7], 127.9, 126.3
[126.6], 125.4 [125.5], 122.9 [122.6], 121.6 [121.2], 120.7
[121.9], 120.0 [120.2], 118.8 [118.7], 109.2 [109.8], 108.3, 43.3
[42.5], 30.0 [30.1], 29.0 [28.9], 22.5 [22.4]. Anal. Calcd for
C23H23N: C, 88.14; H, 7.40; N, 4.47. Found: C, 88.36; H, 7.50;
N, 4.38.
Gen er a l P r oced u r e for th e P r ep a r a tion of Cyclop en t-
[b]in d oles 14a -c. To a solution of 1-methyl-3-(benzotriazol-
1-ylmethyl)indole (1) (0.78 g, 3 mmol) in CH2
Cl2 (60 mL) at 0
1,3-Dip h en yl-2-cya n o-9-m eth ylca r ba zole (6d ). Hexane/
ethyl acetate (7:1) was used as the eluent to give 6d in 45%
yield as a colorless solid, mp 160-161 °C: 1H NMR δ 8.17 (s,
1H), 8.13 (d, J ) 7.9 Hz, 1H), 7.70-7.67 (m, 2H), 7.57-7.42
(m, 9H), 7.36-7.27 (m, 2H), 3.26 (s, 3H); 13C NMR δ 143.5,
139.6, 136.9, 136.3, 130.4, 130.3, 129.4, 128.9, 128.5, 128.4,
127.9, 126.8, 121.7, 120.9, 120.6, 120.1, 118.4, 109.5, 109.3,
32.1. Anal. Calcd for C26H18N2: C, 87.12; H, 5.06; N, 7.82.
Found: C, 87.46; H, 5.22; N, 7.89.
1-Meth yl-2-(eth oxyca r bon yl)-3-p h en yl-9-m eth ylca r ba -
zole (6e). Hexane/ethyl acetate (7:1) was used as the eluent
to give a solid, which was recrystallized from ethyl acetate and
hexane to give 6e in 38% yield as a colorless solid, mp 168-
169 °C: 1H NMR δ 8.03 (d, J ) 7.9 Hz, 1H), 7.92 (s, 1H), 7.51-
7.44 (m, 3H), 7.43-7.30 (m, 4H), 7.25-7.19 (m, 1H), 4.11 (s,
3H), 4.08 (q, J ) 7.2 Hz, 2H), 2.85 (s, 3H), 0.97 (t, J ) 7.2 Hz,
3H); 13C NMR δ 170.5, 142.9, 141.9, 138.9, 132.7, 131.8, 128.9,
128.1, 126.8, 126.4, 124.2, 122.5, 120.3, 119.4, 119.3, 117.9,
108.9, 61.1, 33.0, 16.8, 13.7. Anal. Calcd for C23H21NO2: C,
80.44; H, 6.16; N, 4.08. Found: C, 80.11; H, 6.08; N, 4.00.
1,9-Dim eth yl-2-(eth oxycar bon yl)-3-pr opylcar bazole (6f).
Hexane/ethyl acetate (7:1) was used as the eluent to give 6f
in 36% yield as a colorless solid, mp 111-112 °C: 1H NMR δ
7.98 (d, J ) 7.8 Hz, 1H), 7.72 (s, 1H), 7.42-7.37 (m, 1H), 7.23-
7.13 (m, 2H), 4.45 (q, J ) 7.1 Hz, 2H), 3.88 (s, 3H), 2.70 (t, J
) 7.6 Hz, 2H), 2.67 (s, 3H), 1.76-1.68 (m, 2H), 1.41 (t, J ) 7.1
Hz, 3H), 1.00 (t, J ) 7.6 Hz, 3H); 13C NMR δ 170.9, 142.6,
137.9, 133.3, 129.9, 125.9, 124.1, 122.2, 120.0, 118.9, 118.3,
116.9, 108.6, 60.9, 35.9, 32.6, 24.9, 16.6, 14.2, 14.1. Anal. Calcd
for C20H23NO2: C, 77.64; H, 7.49; N, 4.53. Found: C, 77.69;
H, 7.75; N, 4.45.
2-P h en yl-3,9-d im eth ylca r ba zole (6g). Hexane/methyl-
ene chloride (6:1) was used as the eluent to give 6g in 62%
yield as a colorless solid, mp 135-136 °C: 1H NMR δ 8.00 (d,
J ) 7.7 Hz, 1H), 7.88 (s, 1H), 7.40-7.33 (m, 5H), 7.32-7.25
(m, 2H), 7.16 (s, 1H), 7.12 (d, J ) 8.1 Hz, 1H), 3.69 (s, 3H),
2.34 (s, 3H); 13C NMR δ 143.1, 141.5, 140.2, 139.6, 129.5, 128.0,
126.7, 126.0, 125.5, 122.5, 122.0, 121.3, 120.2, 118.7, 109.6,
108.3, 29.0, 20.7. Anal. Calcd for C20H17N: C, 88.52; H, 6.31;
N, 5.16. Found: C, 88.52; H, 6.54; N, 5.10.
2-P h en yl-3-eth yl-9-m eth ylca r ba zole (6h ). Hexane/me-
thylene chloride (6:1) was used as the eluent to give 6h in 60%
yield as a colorless solid, mp 76-77 °C: 1H NMR δ 8.08 (d, J
) 7.7 Hz, 1H), 7.99 (s, 1H), 7.45-7.29 (m, 7H), 7.23-7.18 (m,
2H), 3.71 (s, 3H), 2.75 (q, J ) 7.5 Hz, 2H), 1.17 (t, J ) 7.5 Hz,
3H); 13C NMR δ 143.1, 141.5, 140.0, 139.4, 132.6, 129.6, 128.0,
126.7, 125.5, 122.6, 122.2, 120.2, 119.7, 118.7, 109.8, 108.3,
29.0, 26.4, 16.3. Anal. Calcd for C21H19N: C, 88.38; H, 6.71;
N, 4.91. Found: C, 88.38; H, 6.61; N, 4.71.
°C under nitrogen was added zinc bromide (1.35 g, 6 mmol).
After 1 h, the appropriate styrene (3.15 mmol) in CH2Cl2 (3
mL) was added. The reaction mixture was stirred at 0 °C for
an additional 3 h. After the zinc bromide was filtered off,
aqueous sodium hydroxide (1 N, 20 mL) was added. The
aqueous layer was extracted with diethyl ether (3 × 30 mL).
The combined organic solution was dried (MgSO4) and solvent
evaporated. The residue was purified by column chromatog-
raphy (silica gel, hexane/methylene chloride ) 1:1) to give the
pure product.
3-(4-Meth ylp h en yl)-4-m eth yl-1,2,3,4-tetr a h yd r ocyclo-
p en t[b]in d ole (14a ): colorless solid; yield 61%; mp 108-109
1
°C; H NMR δ 7.49 (d, J ) 6.8 Hz, 1H), 7.18-7.01 (m, 5H),
7.00-6.94 (m, 2H), 4.31 (dd, J ) 7.4 and 5.1 Hz, 1H), 3.28 (s,
3H), 3.04-2.95 (m, 2H), 2.87-2.82 (m, 1H), 2.39-2.30 (m, 1H),
2.28 (s, 3H); 13C NMR δ 147.2, 141.7, 141.6, 135.9, 129.3, 127.2,
124.0, 120.3, 119.0, 118.8, 118.7, 109.4, 44.3, 40.8, 30.4, 23.9,
21.0. Anal. Calcd for C19H19N: C, 87.31; H, 7.33; N, 5.36.
Found: C, 87.32; H, 7.41; N, 5.30.
3,4-Dim eth yl-3-p h en yl-1,2,3,4-tetr a h yd r ocyclop en t[b]-
1
in d ole (14b): colorless plates; yield 64%; mp 66-67 °C; H
NMR δ 7.51 (d, J ) 6.9 Hz, 1H), 7.29-7.04 (m, 8H), 3.30 (s,
3H), 2.88 (t, J ) 6.9 Hz, 2H), 2.73-2.55 (m, 2H), 1.76 (s, 3H);
13C NMR δ 150.2, 148.0, 141.7, 128.4, 126.1, 124.0, 120.4,
119.0, 118.9, 117.7, 109.3, 50.2, 47.3, 30.1, 25.2, 22.9. Anal.
Calcd for C19H19N: C, 87.31; H, 7.33; N, 5.36. Found: C, 86.94;
H, 7.51; N, 5.41.
3,3-Dip h en yl-4-m eth yl-1,2,3,4-tetr a h yd r ocyclop en t[b]-
1
in d ole (14c): colorless solid; yield 72%; mp 157-158 °C; H
NMR δ 7.52 (d, J ) 7.0 Hz, 1H), 7.30-7.08 (m, 13H), 3.24 (t,
J ) 6.4 Hz, 2H), 3.21 (s, 3H), 2.93 (t, J ) 6.4 Hz, 2H); 13C
NMR δ 148.7, 146.2, 141.8, 128.4, 128.1, 126.3, 124.0, 120.6,
119.2, 119.1, 118.6, 109.5, 57.8, 52.4, 30.6, 23.5. Anal. Calcd
for C24H21N: C, 89.13; H, 6.54; N, 4.33. Found: C, 88.80; H,
6.57; N, 4.30.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1-Su bsti-
tu ted Cyclop en t[b]in d oles 15a -d a n d 16a -d . To a solu-
tion of 1-methyl-3-(benzotriazol-1-ylmethyl)indole (1) (0.79 g,
3 mmol) in THF (75 mL) at -78 °C under argon was added
n-BuLi (1.3 mL, 2.5 M in hexane, 3.3 mmol). After 1 h, the
appropriate electrophile (methyl iodide for 15a , 16a , 15b, and
16b; cyclohexanone for 15c and 16d ; 3-pentanone for 15d and
16d ) in THF (10 mL) was added. The reaction mixture was
stirred at -78 °C for additional 3 h and then allowed to warm
to room temperature overnight. Water (50 mL) was added,
and the aqueous layer was extracted with diethyl ether (2 ×
30 mL). The combined organic solution was dried (MgSO4)
and solvent evaporated to give the corresponding crude
compound 9, which was dissolved in CH2Cl2 (60 mL). To this
solution at 0 °C under nitrogen was added zinc bromide (1.35
g, 6 mmol). After 1 h, the appropriate styrene (3.15 mmol) in
CH2Cl2 (3 mL) was added. The reaction mixture was stirred
at 0 °C for additional 3 h and at room temperature for 2 days.
After the zinc bromide was filtered off, aqueous sodium
2,9-Dim eth yl-3-p h en ylca r ba zole (6i). Hexane/methylene
chloride (6:1) was used as the eluent to give 6i in 31% yield
as a colorless solid, mp 115-115.5 °C: 1H NMR δ 8.02 (d, J )
7.7 Hz, 1H), 7.94 (s, 1H), 7.46-7.33 (m, 7H), 7.24-7.17 (m,
2H), 3.79 (s, 3H), 2.46 (s, 3H); 13C NMR δ 142.7, 141.3, 140.6,

Syntheses of Substituted Carbazoles and Cyclopent[b]indoles
J . Org. Chem., Vol. 61, No. 21, 1996 7563
hydroxide (1 N, 20 mL) was added. The aqueous layer was
extracted with diethyl ether (3 × 30 mL). The combined
organic solution was dried (MgSO4) and solvent evaporated.
The residue was purified by column chromatography (silica
gel) to give the pure product.
yield as a single isomer, as a colorless solid (GCMS analysis of
the crude mixture indicated that 15c and 16c were formed in
a ratio of 15:1). Analysis sample was obtained by further
recrystallization in ethyl acetate and hexane, mp 244-245
°C: 1H NMR δ 7.69 (d, J ) 7.9 Hz, 1H), 7.58-7.55 (m, 2H),
7.39-7.32 (m, 2H), 7.29-7.21 (m, 3H), 7.15-7.10 (m, 1H), 6.80
(s, 1H), 3.78-3.68 (m, 1H), 3.73 (s, 3H), 2.70 (t, J ) 12.7 Hz,
1H), 2.52 (dd, J ) 12.1 and 6.9 Hz, 1H), 1.90-1.81 (m, 2H),
1.79-1.68 (m, 2H), 1.65-1.56 (m, 2H), 1.61 (s, 3H), 1.46-1.37
(m, 2H), 0.93-0.78 (m, 2H); 13C NMR δ 151.2, 136.9, 128.3,
127.9, 126.9, 126.0, 124.6, 121.5, 119.7, 118.8, 112.3, 109.2,
84.4, 81.5, 46.4, 45.1, 39.0, 32.7, 32.6, 32.3, 25.7, 23.5, 22.1.
Anal. Calcd for C25H29N: C, 83.52; H, 8.13; N, 3.90. Found:
C, 83.39; H, 8.28; N, 3.81.
1,4-Dim eth yl-3-(4-m eth ylp h en yl)-1,2,3,4-tetr a h yd r ocy-
clop en t[b]in d ole (15a a n d 16a ). Hexane/methylene chloride
(6:1) was used as the eluent to give 15a and 16a in 42% yield
as a mixture of two diastereoisomers in a ratio of 11:1 as a
colorless oil (GCMS analysis of the crude mixture indicated
that they were formed in a ratio of 19:1) (signals for minor
isomer are quoted in brackets): 1H NMR δ 7.56 (d, J ) 7.4
Hz, 1H), 7.21-7.02 (m, 5H), 6.99-6.95 (m, 2H), 4.41 (t, J )
6.6 Hz, 1H), 3.57-3.51 (m, 1H), 3.35 [3.26] (s, 3H), 2.56 (t, J
) 6.3 Hz, 2H), 2.29 [2.31] (s, 3H), 1.38 [1.43] (d, J ) 6.6 [6.8]
Hz, 3H); 13C NMR δ 146.4, 141.6, 141.5, 135.9, 129.3, 127.1,
123.7, 123.5, 120.3, 118.9, 118.5, 109.5, 50.1, 43.7, 32.4, 30.3,
21.5, 21.0. Anal. Calcd for C20H21N: C, 87.23; H, 7.69; N, 5.09.
Found: C, 87.49; H, 7.79; N, 5.06.
1,3,4-Tr im eth yl-3-p h en yl-1,2,3,4-tetr a h yd r ocyclop en t-
[b]in d ole (15b a n d 16b). Hexane/methylene chloride (6:1)
was used as the eluent to give 15b and 16b in 50% yield as a
mixture of two diastereoisomers in a ratio of 2:1 (GCMS
analysis of the crude mixture indicated that they were formed
in a ratio of 30:1) as a colorless solid; mp 85-86 °C (signals
for minor isomer are quoted in brackets): 1H NMR δ 7.50 (d,
J ) 8.2 Hz, 1H), 7.26-7.00 (m, 8H), 3.42-3.25 (m, 1H), 3.33
[3.16] (s, 3H), 2.79 [2.71] (dd, J ) 12.8 and 7.5 Hz, 1H), 2.13
[2.17] (dd, J ) 12.8 and 6.0 Hz, 1H), 1.79 [1.64] (s, 3H), 1.34
[1.32] (d, J ) 6.8 [5.5] Hz, 3H); 13C NMR δ 149.0 [149.5], 148.1
[148.4], 141.7, 128.4, 126.3 [126.1], 126.0 [125.8], 123.7 [123.8],
122.9 [122.3], 120.4 [120.3], 119.0 [118.9], 118.7 [118.6], 109.5
[109.4], 59.4 [59.9], 47.4 [47.3], 31.6 [31.8], 30.2 [30.1], 27.4
[24.8], 21.7 [21.6]. Anal. Calcd for C20H21N: C, 87.23; H, 7.69;
N, 5.09. Found: C, 87.40; H, 7.88; N, 5.04.
1-(3-H yd r oxyp en t -3-yl)-3-(4-m et h ylp h en yl)-4-m et h yl-
1,2,3,4-tetr a h yd r ocyclop en t[b]in d ole (15d a n d 16d ). Hex-
ane/ethyl acetate (2:1) was used as the eluent to give 15d in
50% yield as a single isomer, as a colorless oil (GCMS analysis
of the crude mixture indicated that 15d and 16d were formed
in a ratio of 18:1): 1H NMR δ 7.63 (d, J ) 7.7 Hz, 1H), 7.32 (d,
J ) 8.0 Hz, 2H), 7.25-7.07 (m, 5H), 6.80 (s, 1H), 5.04 (dd, J )
10.7 and 5.2, 1H), 3.93 (dd, J ) 12.7 and 6.2 Hz, 1H), 3.64 (s,
3H), 2.51-2.45 (m, 1H), 2.35-2.27 (m, 1H), 2.33 (s, 3H), 1.99-
1.92 (m, 1H), 1.71-1.58 (m, 2H), 1.20-1.13 (m, 4H), 0.79 (t, J
) 7.4 Hz, 3H); 13C NMR δ 140.6, 136.8, 136.5, 128.9, 128.1,
126.8, 125.7, 121.4, 119.2, 118.9, 112.8, 109.1, 86.1, 79.6, 42.6,
42.5, 32.5, 30.4, 28.8, 21.0, 8.1, 7.9; HRMS calcd for C24H29
-
NO 348.2327 (M + 1), found 348.2331.
1
Su p p or tin g In for m a tion Ava ila ble: Detailed H and 13C
chemical shift assignments for compounds 6a -j and 8 (Figure
2, Tables 1 and 2) (4 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
1-(1-Hydr oxycycloh exyl)-3,4-Dim eth yl-3-ph en yl-1,2,3,4-
tetr a h yd r ocyclop en t[b]in d ole (15c a n d 16c). Hexane/
ethyl acetate (2:1) was used as the eluent to give 15c in 66%
J O9604954