General and Efficient Approaches to Fused [l,2-a]Pyrroles and [1,2-a]Indoles

Article abstract of DOI:10.1021/jo9623191

2-[(Benzotriazol-l-yl)methyl]pyrroles 4a-c, and 15a,b and -indoles 23, prepared as previously reported,1-2 were converted into the corresponding fused [1,2-a]pyrroles 8a-c, and 18a,b and fused [1,2-a]indoles 25, 27 by intramolecular cyclizations; the form

Full text of DOI:10.1021/jo9623191

4148
J . Org. Chem. 1997, 62, 4148-4154
Gen er a l a n d Efficien t Ap p r oa ch es to F u sed [1,2-a ]P yr r oles a n d
[1,2-a ]In d oles
Alan R. Katritzky,* Clara N. Fali, and J ianqing Li
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Received December 11, 1996X
2-[(Benzotriazol-1-yl)methyl]pyrroles 4a -c, and 15a ,b and -indoles 23, prepared as previously
reported,1,2 were converted into the corresponding fused [1,2-a]pyrroles 8a -c, and 18a ,b and fused
[1,2-a]indoles 25, 27 by intramolecular cyclizations; the formations of 25 and 27 involve [3 + 2]
and [3 + 3] annulations. The benzotriazolyl-CH-ring moieties of intermediates 8a ,b, 18a ,b, 25,
and 27 were further elaborated: (i) acylation of 8a and subsequent reduction and elimination
promoted by LiAlH4 to give product 6; (ii) nucleophilic displacements of the benzotriazolyl moiety
with NaCN, NaSPh, and Grignard reagents to afford compounds 9, 11, 12, 20, 29, and 32,
respectively; (iii) base-assisted eliminations of benzotriazole from 8b and 18a to form the
unsaturated fused [1,2-a]pyrroles 10 and 17; (iv) reactions of 18b and 25 with R,â-unsaturated
ketone and aldehyde followed by acid-assisted elimination of the benzotriazolyl group to yield
tricyclic compound 21 and product 31; and (v) Lewis acid promoted dimerization of 27 to form the
fused indolo[3,2-b]carbazole 33.
Ch a r t 1
In tr od u ction
Fused [1,2-a]pyrrole alkaloids, including both 2,3-
dihydro-1H-pyrrolo[1,2-a]pyrrole (I) and 5,6,7,8-tetrahy-
dropyrrolo[1,2-a]pyridine (II) derivatives (Chart 1), are
biologically active and widely distributed in nature.3-5
Consequently, there has been an ongoing interest in the
synthesis of ring systems I and II.6-12 Although numer-
ous synthetic approaches to the fused [1,2-a]pyrroles I
and II have been described, no general route has utilized
precursors of type pyrrolyl-2-CH2X (in which X is both
an electron-withdrawing and a leaving group) to build
the fused ring and, subsequently, to enable further
modification by replacement of the functionality X.
Due to the pharmacological importance of mito-
mycins,13-15 the syntheses of mitomycin skeletons and
mitomycin-like compounds 2,3-dihydro-1H-pyrrolo[1,2-a]-
indole (III) and 1,2,3,4-tetrahydropyrido[1,2-a]indole (IV)
(Chart 1) in the search for new drugs has attracted much
attention. Recent examples for the preparation of such
fused [1,2-a]indoles III include (i) facile intramolecular
radical cyclizations;16-20 (ii) intramolecular cyclization by
photolysis;21,22 (iii) classical intramolecular nucleophilic
substitution;23,24 (iv) intramolecular cycloaddition reaction
by thermolysis of the corresponding tosylhydrazones;25
(v) Dieckmann/ring expansion;26 (iii) a one-pot procedure
via cyclic trialkyl(indol-2-yl)borate;27 (iv) samarium(II)
iodide-promoted intramolecular hydroxyalkylations of
3-formylindoles;28 and (v) C-2 side-chain modification of
X Abstract published in Advance ACS Abstracts, April 1, 1997.
(1) Katritzky, A. R.; Li, J . J . Org. Chem. 1996, 61, 1624.
(2) Katritzky, A. R.; Li, J . Stevens, C. V. J . Org. Chem. 1995, 60,
3401.
(3) Bull, L. B.; Culvenor, C. C. J .; Dick, A. T. The Pyrrolizidine
Alkaloids; North-Holland Publishing Co.: Amsterdam, 1968.
(4) Anderson, W. K.; Corey, P. F. J . Med. Chem. 1977, 20, 812.
(5) Weidner, M. F.; Sigurdsson, S. Th.; Hopkins, P. B. Biochemistry
1990, 29, 9225.
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E.; Antonio, Y.; Franco, F.; Leon, A.; Pe´rez, V.; Salas, R.; Valde´s, D.;
Ackrell, J .; Cho, D.; Gallegra, P.; Halpern, O.; Koehler, R.; Maddox,
M. L.; Muchowski, J . M.; Prince, A.; Tegg, D.; Thurber, T. C.; Van Horn,
A. R.; Wren, D. Can. J . Chem. 1982, 60, 2295.
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Rubio, E. J . Org. Chem. 1996, 61, 2185.
(13) Remers, W. A. The Chemistry of Antitumor Antibiotics; J ohn
Wiley & Sons: New York, 1979.
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Bull. 1993, 41, 854.
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J . Org. Chem. 1994, 59, 2456.
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S0022-3263(96)02319-5 CCC: $14.00 © 1997 American Chemical Society

Fused [1,2-a]Pyrroles and [1,2-a]Indoles
J . Org. Chem., Vol. 62, No. 12, 1997 4149
Sch em e 1
2-methyl-3-alkylindoles via 3-methylthioindoles.29 In
contrast, syntheses of 1,2,3,4-tetrahydropyrido[1,2-a]-
indole (IV) derivatives are less explored. Recent syn-
thetic methods for the construction of ring system IV
mainly involve intramolecular radical cyclization,17-20
classical intramolecular nucleophilic substitution,24 and
the Dieckmann/ring expansion approach.26
Our previous studies demonstrated 2-[(benzotriazol-
1-yl)methyl]pyrroles and -indole to be versatile interme-
diates in the synthesis of pyrrole and indole deriva-
tives.1,2,30 The important feature of 2-(benzotriazol-1-yl)-
methyl side chains attached to electron-rich pyrrole and
indole nuclei is that the benzotriazolyl moiety behaves
as both an anion-stabilizing and a good leaving group,
which allows a wide range of electrophiles and nucleo-
philes to be introduced onto a carbon atom attached to
the 2-position by successive deprotonation, reaction with
an electrophile, and replacement of the benzotriazolyl
group with a nucleophile. Herein, we report our further
investigations on the use of 2-[(benzotriazol-1-yl)methyl]-
pyrroles and -indole for the synthesis of the fused [1,2-
a]pyrroles I and II and -indoles III and IV.
cyclization of the N-functionalized-alkyl-2-[(benzotriazol-
1-yl)methyl]pyrroles 4a -c and 15a ,b (Schemes 1 and 2),
a strategy similar to that reported for the synthesis of
1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids.6
This strategy called for the reaction of 2-hydroxyethyl-
amine and 3-hydroxypropylamine with alkynyloxiranes
3 and 14 which are available in up to 90% yields (based
on GCMS) by treatment of 1-propargylbenzotriazole (1)
with 1 equiv of n-BuLi followed by reaction with an
R-bromo ketone (2 or 13) at -78 °C for 12 h. The
preparation of compounds of type 3 and 14 by this
method seems quite general, and the scope depends on
the availability of R-bromo carbonyl compounds. The
compounds 3a -c and 14a ,b were stable at room tem-
perature but decomposed upon heating above 60 °C. We
found it effective to use alkynyloxiranes 3a -c and 14a ,b,
after aqueous workup, without further purification. They
were refluxed with 2-hydroxyethylamine or 3-hydroxy-
propylamine in i-PrOH for 24-48 h to give the corre-
sponding pyrroles 4a -c and 15a ,b in good yields.
An initial attempt to transform 4a into fused [1,2-a]-
pyrrole 8a was carried out in onepot: 4a was treated with
1 equiv of LDA, followed by reaction with tosyl chloride
to generate tosylate 5a , which underwent intramolecular
cyclization upon treatment with LDA or n-BuLi to give
8a in fairly low yield. However, the overall yield was
dramatically improved by the isolation of tosylate 5a
using a two-step procedure. Thus, compounds 4a -c or
15a ,b were reacted with tosyl chloride in methylene
chloride in the presence of triethylamine to afford tosyl-
ates 5a -c or 16a ,b in high yields. The intramolecular
cyclizations of 5a -c and 16a ,b via lithiation at the
benzotriazol-1-ylmethyl group and subsequent nucleo-
philic substitution of tosylate gave 1-(benzotriazol-1-yl)-
2,3-dihydro-1H-pyrrolo[1,2-a]pyrroles 8a -c and 8-(ben-
zotriazol-1-yl)-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridines
18a ,b in good yields. Compounds 18a ,b were obtained
Resu lts a n d Discu ssion
Syn th esis of 1-(Ben zotr ia zol-1-yl)-2,3-d ih yd r o-1H-
p yr r olo[1,2-a ]p yr r oles 8a -c, 8-(Ben zotr ia zol-1-yl)-
5,6,7,8-t et r a h yd r op yr r olo[1,2-a ]p yr id in es 18a ,b ,
1-(Ben zotr ia zol-1-yl)-2,3-d ih yd r o-1H-p yr r olo[1,2-a ]-
in d ole (25), a n d 1-(Ben zotr ia zol-1-yl)-1,2,3,4-tetr a h y-
d r op yr id o[1,2-a ]in d ole (27). In our previous paper, we
reported that 2-[(benzotriazol-1-yl)methyl]pyrroles can be
easily obtained by the reaction of alkynyloxiranes, de-
rived from 1-propargylbenzotriazole (1) and R-bromo
ketones 2 or 13, with primary amines.1 To construct the
fused [1,2-a]pyrroles, we examined the intramolecular
(29) Vice, S. F.; Friesen, R. W.; Dmitrienko, G. I. Tetrahedron Lett.
1985, 26, 165.
(30) Katritzky, A. R.; Levell, J . R.; Li, J . Tetrahedron Lett. 1996,
37, 5641.
(31) Kundu, N. G.; Pal, M.; Mahanty, J . S.; Dasgupta, S. K. J . Chem.
Soc., Chem. Commun. 1992, 41.

4150 J . Org. Chem., Vol. 62, No. 12, 1997
Katritzky et al.
Sch em e 2
1
in good purity after aqueous workup, based on H NMR
and GCMS; therefore they were used directly for syn-
thetic manipulation without further purification.
phile to form a fused five- or six-membered ring via [3 +
2] or [3 + 3] annulation given proper choice of the
dielectrophile. Indeed, when dianion 24 was treated with
1 equiv of 1-bromo-2-chloroethane at -78 °C for 3 h,
followed by addition of HMPA as a cosolvent at room
temperature for 12 h, 1-(benzotriazol-1-yl)-2,3-dihydro-
1H-pyrrolo[1,2-a]indole (25) was obtained in high yield.
1-(Benzotriazol-1-yl)-1,2,3,4-tetrahydropyrido[1,2-a]in-
dole (27) was similarly obtained using 1-bromo-3-chlo-
ropropane as the dielectrophile. A reaction pathway
through intermediate 26 and the N-lithium salt of 28 is
supported by the isolation of compound 28 after treat-
2-[(Benzotriazol-1-yl)methyl]indole (23) was readily
prepared from 1-propargylbenzotriazole (1) via a coupling
reaction of the copper salt 22 with o-iodoaniline (Scheme
3). Lithiation of 23 with 2 equiv of n-BuLi in THF at
-30 °C for 30 min generated dianion 24, previously
shown to exhibit interesting reactivity on alkylation.2 An
attempt to synthesize 23 by direct palladium-catalyzed
reaction31 of 1-propargylbenzotriazole (1) with o-iodoa-
niline failed. Dianion 24 should couple with a dielectro-
Sch em e 3

Fused [1,2-a]Pyrroles and [1,2-a]Indoles
J . Org. Chem., Vol. 62, No. 12, 1997 4151
ment of 24 with 1-bromo-3-chloropropane at -78 °C for
3 h. The monoalkylated compound 28 can be trans-
formed into 27 in excellent yield by intramolecular
cyclization in DMSO in the presence of sodium hydride.
Importantly, the cyclizations of 26 and 28 occurred regio-
specifically at the indole nitrogen and no trace of reaction
at indole 3-position was found by 1H NMR or GCMS.
Other functionalized dielectrophiles should enable con-
struction of other functionalized fused ring systems.
Syn th etic Ma n ip u la tion s of th e Ben zotr ia zol-1-
yl Gr ou p Atta ch ed to F u sed [1,2-a ]P yr r oles 8a ,b
a n d 18a ,b a n d [1,2-a ]In d oles 25 a n d 27. The synthetic
versatility of 2-(benzotriazol-1-yl)methyl substituents
attached to pyrroles and indoles, in terms of anion
stabilization and the good leaving ability of the benzotri-
azolyl group, have already been exploited in our previous
work.1,2 Since the reactions at five- and six-membered-
ring carbon atoms are similar to those of open chains,
the reactivity of benzotriazol-1-yl attached methine groups
of the compounds 8a ,b, 18a ,b, 25, and 27 should be
similar to their open chain analogs. In the present study,
we examined the reactivity of 8a ,b; the reactivity of 8c
was presumed to be similar to that of 8a ,b.
and 32, respectively, in good yields. Interestingly, the
reaction of the lithium derivative of compound 25 with
5-methyl-2-phenyl-2-hexenal gave 1,2-addition interme-
diate 30 which upon treatment with p-toluenesulfonic
acid in THF formed the insertion product 31 via a pinacol
type of rearrangement.32 Compound 27 also underwent
zinc bromide-promoted dimerization, followed by dehy-
drogenation on exposure to air, to give the fused indolo-
[3,2-b]carbazole 33 in 50% yield. The novel structure 33
is related to products of interesting biological activity.33
In conclusion, general and efficient syntheses of fused
[1,2-a]pyrroles and -indoles have been described. These
approaches start from readily available starting materi-
als and involve ring synthesis of benzotriazolyl-attached
fused [1,2-a]pyrroles 8a -c and 18a ,b via intramolecular
cyclizations and fused [1,2-a]indoles 25 and 27 via [3 +
2] and [3 + 3] annulations. The intermediates 8a -c,
18a ,b, 25, and 27 were further transformed by alkylation
and replacement of the benzotriazolyl group to provide
a variety of functionalized fused [1,2-a]pyrrole and -indole
derivatives. Moreover, the 3-unsubstituted positions of
pyrrole and indole rings allow further synthetic manipu-
lations.
In the pyrrole systems 8a ,b and 18a ,b, the nucleophilic
substitutions of the benzotriazolyl group with sodium
thiophenolate and Grignard reagents occurred smoothly
to give the products 11, 12a ,b, and 20 in good yields. As
in the open chain analog,1 the reaction of 8b with sodium
cyanide in DMF at 150 °C afforded the “abnormal”
product 9 in 65% yield, in which the cyano group added
to the 5-position of the pyrrole ring. Surprisingly, unlike
the open chain case,1 treatment of 8b and 18a with
sodium malonate in refluxing DMF gave the correspond-
ing elimination products 10 and 17 instead of expected
substitution products. Moreover, use of sodium hydride
and potassium tert-butoxide as bases did not give any
reaction and the starting materials 8b and 18a were
recovered. The partially unsaturated products 10 and
17 were not stable, and they decomposed after several
days at room temperature, upon exposure to air.
Due to the anion-stabilizing ability of the benzotriazolyl
group, the intermediates 8a ,b and 18a ,b can be trans-
formed into various functionalized fused [1,2-a]pyrroles
by sequential lithiation, alkylation, and substitution of
benzotriazolyl groups, as exemplified in the synthesis of
compounds 6 and 21. Compound 8a was acylated by
treatment with n-BuLi, followed by reaction with ethyl
benzoate to form intermediate 7 in 80% yield which was
reacted with LiAlH4 in THF to form the phenylmethyl-
enated fused [1,2-a]pyrrole 6. The reaction pathway
probably involved reductive elimination (by hydride
addition to an immonium cation formed by heterolysis
of the Bt group) of the benzotriazolyl (Bt) group, reduction
of the carbonyl group, and subsequent elimination of
hydroxy group. The structure of the isolated trans-
isomer 6 was confirmed by an NOE spectrum. As with
the open chain analog,30 the lithium derivative of com-
pound 18b reacted with trans-chalcone to give adduct 19
which was refluxed with p-toluenesulfonic acid in THF
to give the tricyclic fused indole 21.
Exp er im en ta l Section
Gen er a l Com m en ts. Melting points were determined on
a hot-stage microscope and are uncorrected. 1H and NOE
NMR spectra were recorded on a 300 MHz spectrometer using
TMS as the internal standard and CDCl3 as the solvent. 13C
NMR spectra were recorded at 75 MHz on the same instru-
ment with the solvent peak (CDCl3) as the reference. HRMS
and elemental analyses (C, H, N) were carried out within the
department.
1-Propargylbenzotriazole (1)34 and 2-(benzotriazol-1-yl)-
methylindole (23)2 were prepared according to previously
reported procedures.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-[(Ben zo-
tr ia zol-1-yl)m eth yl]-p yr r oles 4a -c a n d 15a ,b. To a solu-
tion of 1-propargylbenzotriazole (1) (3.2 g, 20 mmol) in THF
(100 mL) was added a solution of n-BuLi (20 mmol, 12.5 mL,
1.6 M in hexane) at -78 °C; the solution was stirred at this
temperature for 30 min. A solution of the appropriate R-bromo
ketone 2 or 13 (20 mmol) in THF (10 mL) was added, and the
reaction mixture was stirred at -78 °C for 20 h. A saturated
NH4Cl solution (100 mL) was added, and the solution was
extracted with Et2O (200 mL). The organic phase was
separated, washed with a saturated NH4Cl solution (3 × 100
mL), and dried (MgSO4).
After removal of the solvent the residue was dissolved in
i-PrOH, 2-hydroxyethylamine or 3-hydroxypropylamine (40
mmol) was added, and the solution was refluxed for 24 h.
i-PrOH was removed and the residue subjected to column
chromatography or recrystallization to afford the correspond-
ing products 4a -c and 15a ,b.
N-(2-H yd r oxyet h yl)-2-[(b en zot r ia zol-1-yl)m et h yl]-4-
p h en ylp yr r ole (4a ): purified by recrystallization from EtOAc/
hexane (1:3), white microcrystals, yield 65%; mp 142-143 °C;
1H NMR δ 7.98 (d, J ) 8.3 Hz, 1 H), 7.73 (d, J ) 8.3 Hz, 1 H),
7.43-7.48 (m, 3 H), 7.32-7.37 (m, 1 H), 7.24-7.29 (m, 2 H),
7.13 (d, J ) 2.0 Hz, 1 H), 7.06-7.14 (m, 1 H), 6.60 (d, J ) 2.0
Hz, 1 H), 6.00 (s, 2 H), 4.94 (t, J ) 5.2 Hz, 1 H), 4.07 (t, J )
5.4 Hz, 2 H), 3.60 (q, J ) 5.2 Hz, 2 H); 13C NMR δ 145.4, 134.9,
132.2, 128.2, 126.9, 126.4, 124.8, 124.0, 123.5, 122.6, 119.6,
118.9, 110.3, 107.6, 61.3, 48.9, 43.8. Anal. Calcd for
C19H18N4O: C, 71.68; H, 5.70; N, 17.60. Found: C, 72.10; H,
5.68; N, 17.80.
Apparently as compared to the pyrrole analogs 8 and
18, the benzene ring in fused [1,2-a]indole systems 25
and 27 induces less effective cation formation at benzo-
triazolyl-attached carbons in compounds 25 and 27 which
are thus less susceptible to nucleophilic substitution than
8 and 18. Hence, no reactions of 25 and 27 occurred with
sodium thiophenolate and sodium cyanide. However,
Grignard reagents converted 25 and 27 into products 29
N-(2-H yd r oxyet h yl)-2-[(b en zot r ia zol-1-yl)m et h yl]-4-
ter t-bu tylp yr r ole (4b): purified by column chromatography
(32) Katritzky, A. R.; Xie, L.; Toader, D.; Serdyuk, L. J . Am. Chem.
Soc. 1995, 117, 12015.
(33) Gillner, M.; Fernstro¨m, B.; Gustafsson, J .-e`.; Bergman, J .;
Cambillau, C. Chemosphere 1986, 15, 1673.
(34) Katritzky, A. R.; Li, J .; Malhotra, N. Liebigs Ann. Chem. 1992,
843.

4152 J . Org. Chem., Vol. 62, No. 12, 1997
Katritzky et al.
using EtOAc/hexane (1:1) as the eluent, white powder, yield
70%; mp 102-104 °C; H NMR δ 8.00 (d, J ) 8.2 Hz, 1 H),
1H NMR δ 8.02 (d, J ) 8.1 Hz, 1 H), 7.44-7.59 (m, 2 H), 7.20-
7.42 (m, 10 H), 6.44 (s, 1 H), 5.82 (s, 2 H), 4.25 (t, J ) 5.1 Hz,
2 H), 4.03 (t, J ) 5.3 Hz, 2 H), 2.34 (s, 3 H), 2.15 (s, 3 H); 13C
NMR δ 146.2, 144.9, 136.2, 132.5, 131.9, 129.8, 128.3, 127.8,
127.6, 127.4, 127.1, 125.5, 123.9, 123.8, 122.0, 119.8, 111.2,
110.0, 68.3, 44.6, 42.4, 21.4, 11.0. Anal. Calcd for
C27H26N4O3S: N, 11.51. Found: N, 11.09.
1
7.30-7.45 (m, 3 H), 6.51 (d, J ) 2.0 Hz, 1 H), 6.31 (d, J ) 2.0
Hz, 1 H), 5.85 (s, 2 H), 4.00 (t, J ) 5.4 Hz, 2 H), 3.61 (q, J )
5.4, 2 H), 2.28 (t, J ) 5.4 Hz, 1 H), 1.23 (s, 9 H); 13C NMR δ
146.2, 135.1, 132.8, 127.4, 124.1, 124.0, 119.8, 118.4, 110.2,
109.3, 62.6, 48.9, 45.0, 31.7, 30.5. Anal. Calcd for
C17H22N4O: C, 68.43; H, 7.43; N, 18.78. Found: C, 68.49; H,
7.55; N, 18.93.
N -(3-Tosylp r op yl)-2-[(b e n zot r ia zol-1-yl)m e t h yl]-4-
p h en ylp yr r ole (16a ): purified by column chromatography
using EtOAc/hexane (1:1) as the eluent, white powder, yield
N-(2-H yd r oxyet h yl)-2-[(b en zot r ia zol-1-yl)m et h yl]-4-
p h en yl-5-m eth ylp yr r ole (4c): purified by column chroma-
tography using EtOAc/hexane (3:7) as the eluent, white
1
85%; mp 101-102 °C; H NMR δ 8.02 (d, J ) 8.2 Hz, 1 H),
7.76 (d, J ) 8.3 Hz, 2 H), 7.25-7.49 (m, 9 H), 7.18 (t, J ) 7.3
Hz, 1 H), 6.87 (d, J ) 2.0 Hz, 1 H), 6.66 (d, J ) 2.0 Hz, 1 H),
5.81 (s, 2 H), 3.98 (t, J ) 6.9 Hz, 2 H), 3.90 (t, J ) 5.7 Hz, 2
H), 2.41 (s, 3 H), 1.70-1.74 (m, 2 H); 13C NMR δ 146.0, 145.0,
134.8, 132.6, 129.9, 128.7, 127.8, 127.7, 125.8, 125.1, 124.9,
124.4, 124.3, 119.8, 110.1, 109.5, 66.7, 44.7, 42.9, 30.4, 21.6.
Anal. Calcd for C27H26N4O3S: C, 66.65; H, 5.39; N, 11.51.
Found: C, 66.66; H, 5.56; N, 11.63.
1
powder, yield 40%; mp 171-173 °C; H NMR δ 8.05 (d, J )
8.3 Hz, 1 H), 7.59 (d, J ) 8.3 Hz, 1 H), 7.33-7.46 (m, 6 H),
7.21-7.27 (m, 1 H), 6.51 (s, 1 H), 5.97 (s, 2 H), 4.14 (t, J ) 5.8
Hz, 2 H), 3.64 (q, J ) 5.6 Hz, 2 H), 2.32 (s, 3 H), 1.95 (t, J )
5.7 Hz, 1 H); 13C NMR δ 145.6, 136.3, 132.3, 127.8, 127.4,
126.7, 126.5, 124.7, 123.9, 123.4, 120.9, 119.1, 109.9, 109.7,
61.1, 10.6. Anal. Calcd for C20H20N4O: C, 72.27; H, 6.06; N,
16.85. Found: C, 72.23; H, 6.14; N, 16.87.
N-(3-Tosylp r op yl)-2-[(ben zotr ia zol-1-yl)m eth yl]-4-ter t-
bu tylp yr r ole (16b): purified by column chromatography
using EtOAc/hexane (3:7) as the eluent, white powder, yield
70%; mp 83-85 °C; 1H NMR δ 8.02 (d, J ) 8.2 Hz, 1 H), 7.78
(d, J ) 8.1 Hz, 2 H), 7.33-7.42 (m, 5 H), 6.37 (d, J ) 1.7 Hz,
1 H), 6.23 (d, J ) 1.7 Hz, 1 H), 5.74 (s, 2 H), 3.87-3.91 (m, 4
H), 2.45 (s, 3 H), 1.65-1.69 (m, 2 H), 1.21 (s, 9 H); 13C NMR δ
146.3, 144.9, 135.2, 132.7, 129.9, 128.9, 127.9, 127.4, 123.9,
123.6, 119.9, 118.2, 110.1, 109.5, 67.0, 44.8, 42.6, 31.6, 30.5,
30.4, 21.6. Anal. Calcd for C25H30N4O3S: C, 64.35; H, 6.48;
N, 12.01. Found: C, 64.36; H, 6.42; N, 12.68.
Gen er a l P r oced u r e for th e P r ep a r a tion of F u sed [1,2-
a ]P yr r oles 8a -c a n d 18a ,b. To a solution of tosylate 5 or
16 (10 mmol) in THF (80 mL) was added a solution of n-BuLi
(10 mmol, 6.25 mL, 1.6 M in hexane) at -78 °C. The reaction
mixture was stirred and allowed to warm to room temperature
overnight. The reaction was quenched with saturated NH4Cl
solution (50 mL), extracted with EtOAc, washed with brine (3
× 50 mL), and dried (MgSO4). The solvent was removed to
give the crude product which was purified by column chroma-
tography to give the corresponding compounds 5a -c. The
crude products 18a -c were used directly for the synthesis of
compounds 17, 20 and 21 without further purification, and
the yields were determined by GCMS (Scheme 2).
N-(3-Hyd r oxyp r op yl)-2-[(ben zotr ia zol-1-yl)m eth yl]-4-
p h en ylp yr r ole (15a ): purified by column chromatography
using EtOAc/hexane (3:7) as the eluent, yellow oil, yield 60%;
1H NMR δ 8.02 (d, J ) 8.1 Hz, 1 H), 7.47-7.53 (m, 3 H), 7.30-
7.40 (m, 4 H), 7.19 (t, J ) 8.7 Hz, 1 H), 7.01 (s, 1 H), 6.64 (d,
J ) 1.7 Hz, 1 H), 5.87 (s, 2 H), 4.09 (t, J ) 6.8 Hz, 2 H), 3.56
(t, J ) 5.5 Hz, 2 H), 3.10 (s, 1 H), 1.70-1.75 (m, 2 H); 13C
NMR δ 145.0, 135.0, 132.6, 128.5, 127.4, 125.5, 125.4, 124.7,
124.0, 123.9, 119.6, 110.1, 108.6, 58.6, 44.6, 43.3, 33.7. Anal.
Calcd for C20H20N4O: C, 72.27; H, 6.06; N, 16.85. Found: C,
72.00; H, 6.12; N, 16.92.
N-(3-Hyd r oxyp r op yl)-2-[(ben zotr ia zol-1-yl)m eth yl]-4-
ter t-bu tylp yr r ole (15b): purified by column chromatography
using EtOAc/hexane (3:7) as the eluent, white powder, yield
75%; mp 83-85 °C; 1H NMR δ 8.01 (d, J ) 8.2 Hz, 1 H), 7.31-
7.46 (m, 3 H), 6.48 (s, 1 H), 6.29 (d, J ) 1.7 Hz, 1 H), 5.83 (s,
2 H), 3.98 (t, J ) 7.2 Hz, 2 H), 3.55 (t, J ) 5.9 Hz, 2 H), 2.43
(brs, 1 H), 1.64-1.69 (m, 2 H), 1.23 (s, 9 H); 13C NMR δ 146.2,
135.0, 132.8, 127.3, 124.0, 123.7, 119.7, 117.9, 110.3, 108.9,
59.2, 45.0, 43.2, 33.9, 31.7, 30.5. Anal. Calcd for C18H24N4O:
C, 69.20; H, 7.74; N, 17.93. Found: C, 69.57; H, 7.76; N, 17.90.
Gen er a l P r oced u r e for th e P r ep a r a tion of Tosyla tes
5a -c a n d 16a ,b. To a solution of compound 4 or 15 (10 mmol)
in CH2Cl2 (60 mL) was added triethylamine (15 mL). Tolu-
enesulfonic acid chloride (5.87 g, 30 mmol) was added in
portions over a period of 1 h, and the reaction mixture was
stirred at room temperature overnight. The reaction solution
was washed with a 2 N HCl solution (50 mL), followed by a
10% NaHCO3 solution (50 mL) and water (3 × 50 mL). The
organic layer was separated and dried (MgSO4) and the solvent
removed to give the product 5a -c or 16a ,b.
N-(2-Tosyleth yl)-2-[(ben zotr ia zol-1-yl)m eth yl]-4-p h en -
ylp yr r ole (5a ): purified by recrystallization from EtOAc/
hexane (1:1), white powder, yield 98%; mp 121-122 °C; 1H
NMR δ 8.03 (d, J ) 8.1 Hz, 1 H), 7.51 (d, J ) 8.3 Hz, 3 H),
7.46-7.33 (m, 6 H), 7.21 (t, J ) 7.2 Hz, 1 H), 7.09 (d, J ) 8.5
Hz, 2 H), 6.81 (d, J ) 1.9 Hz, 1 H), 6.59 (d, J ) 1.9 Hz, 1 H),
5.78 (s, 2 H), 4.20 (t, J ) 4.7 Hz, 2 H), 4.01 (t, J ) 4.7 Hz, 2
H), 2.25 (s, 3 H); 13C NMR δ 146.2, 144.9, 134.6, 132.4, 131.8,
129.7, 128.6, 127.5, 125.8, 125.7, 124.7, 124.5, 124.0, 119.8,
119.7, 109.9, 109.2, 69.0, 45.4, 44.2, 21.4. Anal. Calcd for
C26H24N4O3S: C, 66.08; H, 5.12; N, 11.86. Found: C, 66.08;
H, 5.08; N, 11.86.
N-(2-Tosylet h yl)-2-[(b en zot r ia zol-1-yl)m et h yl]-4-ter t-
bu tylp yr r ole (5b): purified by recrystallization from EtOAc/
hexane (1:1), white needles, yield 98%; mp 96-98 °C; 1H NMR
δ 8.03 (d, J ) 8.2 Hz, 1 H), 7.61 (d, J ) 8.3 Hz, 2 H), 7.33-
7.44 (m, 3 H), 7.26 (d, J ) 8.1 Hz, 2 H), 6.41 (d, J ) 2.0 Hz, 1
H), 6.28 (d, J ) 2.0 Hz, 1 H), 5.74 (s, 2 H), 4.16 (t, J ) 5.3 Hz,
2 H), 3.96 (t, J ) 5.3 Hz, 2 H), 2.43 (s, 3 H), 1.22 (s, 9 H); 13C
NMR δ 146.3, 144.6, 135.4, 132.6, 132.4, 129.8, 127.7, 127.4,
124.0, 123.9, 119.9, 118.6, 110.0, 109.6, 69.1, 45.3, 44.6, 31.6,
30.4, 21.6. Anal. Calcd for C24H28N4O3S: C, 63.69; H, 6.24;
N, 12.38. Found: C, 63.69; H, 6.24; N, 12.38.
1-(Ben zotr ia zol-1-yl)-6-p h en yl-2,3-d ih yd r o-1H-p yr r oli-
zin e (8a ): purified by column chromatography using EtOAc/
1
hexane (1:2) as the eluent, yellow oil, yield 75%; H NMR δ
8.02-8.08 (m, 1 H), 7.48 (d, J )7.2 Hz, 2 H), 7.30-7.34 (m, 4
H), 7.15-7.19 (m, 2 H), 6.65-6.69 (m, 1 H), 6.55 (dd, J ) 8.0
and 2.7 Hz, 1 H), 6.33 (s, 1 H), 4.26-4.35 (m, 1 H), 4.15-4.22
(m, 1 H), 3.20-3.32 (m, 1 H), 2.78-2.87 (m, 1 H); 13C NMR δ
146.4, 135.7, 132.8, 131.7, 130.7, 128.6, 127.4, 125.7, 124.9,
123.8, 119.9, 112.3, 109.7, 100.8, 56.5, 45.4, 36.3. Anal. Calcd
for C19H17N4O: C, 75.72; H, 5.69; N, 18.59. Found: C, 75.38;
H, 5.31; N, 18.41.
1-(Ben zotr ia zol-1-yl)-6-ter t-bu tyl-2,3-d ih yd r o-1H-p yr -
r olo[1,2-a ]p yr r ole (8b): purified by column chromatography
using EtOAc/hexane (1:2) as the eluent, yellow oil, yield 90%;
1H NMR δ 8.02-8.06 (m, 1 H), 7.27-7.35 (m, 2 H), 6.68 (d, J
) 1.4 Hz, 1 H), 6.50-6.53 (m, 1 H), 6.34-6.39 (m, 1 H), 5.98
(d, J ) 1.4 Hz, 1 H), 4.09-4.23 (m, 2 H), 3.18-3.31 (m, 1 H),
2.71-2.80 (m, 1 H),1.25 (s, 9 H); 13C NMR δ 146.3, 142.4, 131.8,
131.3, 127.2, 123.7, 119.9, 110.8, 110.0, 100.9, 56.9, 45.2, 36.7,
31.9, 31.1. Anal. Calcd for C17H20N4: C, 72.83; H, 7.19; N,
19.98. Found: C, 72.55; H, 7.44; N, 20.31.
1-(Ben zot r ia zol-1-yl)-5-m et h yl-6-p h en yl-2,3-d ih yd r o-
1H-p yr r olo[1,2-a ]p yr r ole (8c): purified by column chroma-
tography using EtOAc/hexane (1:2) as the eluent, yellow oil,
yield 70%; 1H NMR δ 8.03-8.06 (m, 1 H), 7.28-7.41 (m, 6 H),
7.16-7.22 (m, 1 H), 6.81-6.85 (m, 1 H), 6.50 (dd, J ) 8.0 Hz
and 2.7 Hz, 1 H), 6.17 (s, 1 H), 4.06-4.25 (m, 2 H), 3.18-3.38
(m, 1 H), 2.85-2.95 (m, 1 H), 2.46 (s, 3 H); 13C NMR δ 146.3,
136.9, 131.7, 129.5, 128.2, 127.3, 127.2, 126.4, 125.2, 123.7,
121.4, 119.8, 109.8, 102.2, 56.6, 43.4, 35.9, 11.2. Anal. Calcd
for C17H20N4: C, 76.41; H, 5.77; N, 17.82. Found: C, 76.18;
H, 6.00; N, 17.59.
N-(2-Tosyleth yl)-2-[(ben zotr ia zol-1-yl)m eth yl]-4-p h en -
yl-5-m eth ylp yr r ole (5c): purified by recrystallization from
EtOAc/hexane (1:1), white powder, yield 60%; mp 128-130 °C;
P r ep a r a tion of 1-(Ben zotr ia zol-1-yl)-1-(p h en ylca r bon -
yl)-6-p h en yl-2,3-d ih yd r o-1H -p yr r olo[1,2-a ]p yr r ole (7).

Fused [1,2-a]Pyrroles and [1,2-a]Indoles
J . Org. Chem., Vol. 62, No. 12, 1997 4153
To a solution of compound 8a (0.97 g, 3.2 mmol) in THF (80
mL) was added a solution of n-BuLi (2 mL, 3.2 mmol, 1.6 M
in hexane) at -78 °C. After 30 min, ethyl benzoate (0.48 g,
3.2 mmol) was added and the reaction mixture was allowed
to warm to room temperature overnight. The reaction was
quenched with saturated NH4Cl solution (100 mL), extracted
with EtOAc (100 mL), and dried (MgSO4). The solvent was
removed and the product isolated as yellow needles (1.03 g,
80% yield) by column chromatography using EtOAc/hexane
(1:2) as the eluent: mp 175-178 °C; 1H NMR δ 8.05-8.08 (m,
1 H), 7.67 (d, J ) 8.6 Hz, 2 H), 7.44-7.47 (m, 3 H), 7.29-7.38
(m, 6 H), 7.15-7.21 (m, 2 H), 6.62-6.67 (m, 1 H), 6.48 (s, 1
H), 4.24-4.32 (m, 1 H), 4.10-4.20 (m, 1 H), 2.91-2.99 (m, 1
H); 13C NMR δ 190.0, 146.4, 135.3, 133.8, 133.4, 131.9, 130.6,
130.4, 129.6, 128.7, 128.5, 128.1, 126.1, 125.2, 124.3, 120.4,
113.9, 110.6, 105.1, 74.2, 45.1, 41.0. Anal. Calcd for
C26H20N4O: C, 77.21; H, 4.98; N, 13.85. Found: C, 77.27; H,
5.00; N, 13.65.
P r ep a r a tion of 1-(P h en ylm eth ylen e)-6-p h en yl-2,3-d i-
h yd r o-1H-p yr r olo[1,2-a ]p yr r ole (6). To a solution of LiAlH4
(0.087 g, 2.3 mmol) in THF (30 mL) was added a solution of
compound 7 (0.45 g, 1.1 mmol) at room temperature, and the
reaction mixture was refluxed for 4 h. After cooling, EtOAc
(50 mL) and water (50 mL) were added. The organic layer
was separated, washed with water (3 × 50 mL), and dried
(MgSO4). The solvent was evaporated off, and the solid residue
was washed with diethyl ether to give the product 6 (0.12 g,
40% yield) as white powder: mp 188-189 °C; 1H NMR δ 7.53
(d, J ) 7.7 Hz, 2 H), 7.31-7.37 (m, 6 H), 7.17-7.23 (m, 2 H),
7.03 (s, 1 H), 6.74 (d, J ) 1.9 Hz, 1 H), 6.56 (s, 1 H), 4.16 (t, J
) 6.3 Hz, 2 H), 3.45 (t, J ) 6.3 Hz, 2 H); 13C NMR δ 140.1,
138.1, 136.1, 131.6, 128.6, 128.5, 128.0, 126.0, 125.6, 125.1,
117.3, 113.0, 111.2, 96.1, 45.5, 33.2. Anal. Calcd for
C20H17N: C, 88.52; H, 6.32; N, 5.16. Found: C, 88.74; H, 6.42;
N, 5.25.
P r ep a r a tion of 5-Cya n o-6-ter t-bu tyl-2,3-d ih yd r o-1H-
p yr r olo[1,2-a ]p yr r ole (9). A solution of 8b (0.60 g, 2.14
mmol) and NaCN (0.51 g, 10 mmol) in DMF (30 mL) was
refluxed for 12 h. After cooling, Et2O (50 mL) and water (50
mL) were added and the organic phase was separated, washed
with NaOH solution (2 N, 2 × 50 mL), and dried (MgSO4).
After removal of the solvent under reduce pressure, the residue
was purified by column chromatography using CH2Cl2/hexane
(1:4) as the eluent to give product 9 as a yellow oil (0.62 g,
65%): 1H NMR δ 5.79 (s, 1 H), 3.88-3.96 (m, 2 H), 2.73-2.91
(m, 2 H), 2.50 (t, J ) 7.4 Hz, 2 H), 1.34 (s, 9 H); 13C NMR δ
151.0, 141.6, 115.7, 99.5, 46.4, 32.0, 31.0, 31.8, 26.6; HRMS
calcd for C12H16N2 118.1313 (M+), found 118.1321.
Gen er a l P r oced u r e for th e P r ep a r a tion of 6-ter t-
Bu tyl-3H-p yr r olo[1,2-a ]p yr r ole (10) a n d 2-P h en yl-5,6-
d ih yd r op yr r olo[1,2-a ]p yr id in e (17). To a solution of di-
ethyl malonate (0.34 g, 2 mmol) in DMF was added sodium
hydride (0.08 g, 2 mmol) at room temperature. After the
solution was stirred for 30 min, compound 8b or 18a (1 mmol)
in DMF (5 mL) was added and the reaction mixture was
refluxed for 12-24 h. After cooling, Et2O (50 mL) and water
(50 mL) were added and the organic phase was separated,
washed with water (3 × 30 mL), and dried (MgSO4). The
solvent was removed under reduced pressure, and the residue
was separated by column chromatography using CH2Cl2/
hexane (1:4) to afford the corresponding 10 or 17.
mL) was refluxed for 24 h. After cooling, water (50 mL) and
Et2O (100 mL) were added and the organic phase was
separated, washed with water (3 x 50 mL), and dried (MgSO4).
The solvent was removed under reduced pressure, and the
residue was separated by column chromatography using CH2-
Cl2/hexane (1:4) as the eluent to give the product 11 as a yellow
oil (0.33 g, 60% yield): 1H NMR δ 7.50 (d, J ) 8.2 Hz, 1 H),
7.34-7.40 (m, 2 H), 7.22-7.33 (m, 2 H), 6.39 (d, J ) 1.5 Hz, 1
H), 5.83 (d, J ) 1.5 Hz, 1 H), 4.69 (dd, J ) 7.5 and 2.9 Hz, 1
H), 3.82-3.94 (m, 2 H), 2.85-2.97 (m, 1 H), 2.47-2.56 (m, 1
H), 1.23 (s, 9 H); 13C NMR δ 141.1, 135.4, 135.3, 131.9, 128.8,
127.0, 109.7, 98.9, 44.9, 44.4, 36.5, 31.9, 31.1. Anal. Calcd
for C17H21NS: N, 5.16. Found: N, 5.47.
Gen er a l P r oced u r e for th e Nu cleop h ilic Su bstitu tion
of 8a a n d 18a w ith Gr ign a r d Rea gen ts. To a solution of
8a or 18a (2 mmol) in toluene (30 mL) under argon was added
a solution of an appropriate Grignard reagent (Schemes 1 and
2) (4 mmol) in Et2O, and the reaction mixture was refluxed
for 1 h. The solvent was removed under reduced pressure,
and the residue was extracted with Et2O (2 × 50 mL). The
combined Et2O solution was washed with water (2 × 50 mL)
and dried (MgSO4). After removal of the solvent, the residue
was purified by column chromatography using CH2Cl2/hexane
(1:4) as the eluent to give the corresponding product 12a ,b or
20.
1,6-Diph en yl-2,3-dih ydr o-1H-pyr r olo[1,2-a ]pyr r ole (12a):
yellow oil, 85% yield; 1H NMR δ 7.50 (d, J ) 7.1 Hz, 2 H),
7.20-7.38 (m, 7 H), 7.14 (t, J ) 7.4 Hz, 1 H), 6.99 (s, 1 H),
6.14 (d, J ) 1.0 Hz, 1 H), 4.40 (t, J ) 7.7 Hz, 1 H), 4.11-4.16
(m, 1 H), 3.95-4.10 (m, 1 H), 2.91-2.97 (m, 1 H), 2.39-2.45
(m, 1 H); 13C NMR δ 143.4, 140.4, 136.5, 129.4, 128.6, 128.5,
127.4, 126.7, 125.2, 124.9, 110.7, 98.4, 45.9, 43.6, 38.6; HRMS
calcd for C19H17N 259.1361 (M+), found 259.1358.
1-Met h yl-6-p h en yl-2,3-d ih yd r o-1H -p yr r olo[1,2-a ]p yr -
1
r ole (12b): yellow oil, 90% yield; H NMR δ 7.51 (d, J ) 7.1
Hz, 2 H), 7.32 (t, J ) 7.7 Hz, 2 H), 7.14 (t, J ) 7.4 Hz, 1 H),
6.88 (d, J ) 1.5 Hz, 1 H), 6.14 (d, J ) 1.2 Hz, 1 H), 4.00-4.06
(m, 1 H), 3.86-3.98 (m, 1 H), 3.21-3.34 (m, 1 H), 2.57-2.71
(m, 1 H), 2.00-2.12 (m, 1 H), 1.34 (d, J ) 6.9 Hz, 3 H); 13C
NMR δ 143.3, 136.4, 128.9, 128.4, 125.0, 124.9, 110.2, 96.2,
45.9, 36.7, 32.2, 19.7; HRMS calcd for C14H15N 197.1205 (M+),
found 197.1267.
2-P h en yl-8-ben zyl-5,6,7,8-tetr a h yd r op yr r olo[1,2-a ]p yr -
1
id in e (20): yellow oil, 80% yield; H NMR δ 7.48 (d, J ) 7.1
Hz, 2 H), 7.09-7.36 (m, 8 H), 6.80 (d, J ) 1.7 Hz, 1 H), 6.26
(d, J ) 1.7 Hz, 1 H), 3.81-3.97 (m, 2 H), 3.30 (dd, J ) 13.5
and 5.0 Hz, 1 H), 3.04-3.07 (m, 1 H), 2.68 (dd, J ) 13.5 and
9.8 Hz, 1 H), 1.94-2.00 (m, 1 H), 1.74-1.85 (m, 2 H), 1.34-
1.39 (m, 1 H); 13C NMR δ 140.0, 136.1, 134.5, 129.2, 128.4,
128.3, 126.1, 125.1, 124.9, 124.2, 115.6, 102.0, 45.4, 41.8, 36.1,
26.7, 22.5; HRMS calcd for C21H21N 288.1752 (M+), found
288.1745.
P r ep a r a tion of F u sed In d ole 21. To a solution of
compound 18b (0.80 g, 2.7 mmol) in THF (100 mL) was added
a solution of n-BuLi (1.69 mL, 1.6 M in hexane) at -78 °C
and the reaction mixture was stirred at this temperature for
30 min. A solution of trans-chalcone ((0.60 g, 2.7 mmol) in
THF (10 mL) was added, and the reaction mixture was stirred
and allowed to warm to room temperature overnight. The
reaction was quenched with saturated NH4Cl solution (100
mL) and EtOAc (100 mL) added. The organic phase was
separated, washed with water (3 × 100 mL), and dried
(MgSO4). The solvent was removed under reduced pressure
to give the crude oily product 19 which was dissolved in THF
(100 mL). To the solution of 19 was added p-toluenesulfonic
acid monohydrate (0.19 g, 1 mmol), and the reaction mixture
was refluxed for 3 h. After cooling, EtOAc (100 mL) and water
(100 mL) were added, and the organic layer was separated,
washed with water (3 × 300 mL), and dried (MgSO4). After
removal of the solvent, the residue was subjected to column
chromatography using CH2Cl2/hexane (1:4) as the eluent to
give compound 21 as white powder (0.49 g, 65%); mp 150-
151 °C; 1H NMR δ 7.26-7.49 (m, 10 H), 6.97 (s, 1 H), 6.84 (s,
1 H), 4.12 (t, J ) 5.6 Hz, 2 H), 3.03 (t, J ) 6.0 Hz, 2H), 2.14-
2.17 (m, 2 H), 1.08 (s, 9 H); 13C NMR δ 145.4, 141.0, 135.5,
133.9, 131.4, 130.7, 129.6, 127.9, 127.2, 126.8, 126.3, 126.1,
6-ter t-Bu tyl-3H-p yr r olo[1,2-a ]p yr r ole (10): yellow oil,
1
56% yield; H NMR δ 6.87 (s, 1 H), 6.22 (d, J ) 8.9 Hz, 2 H),
5.79 (s, 1 H), 4.43 (s, 2 H), 1.21 (s, 9 H); 13C NMR δ 153.3,
141.7, 116.1, 114.9, 111.2, 95.9, 50.9, 32.9, 30.1; HRMS calcd
for C11H15N 161.1205 (M+), found 161.1205.
2-P h en yl-5,6-d ih yd r op yr r olo[1,2-a ]p yr id in e (17): yel-
low oil, 68% yield; 1H NMR δ 7.49 (d, J ) 7.1 Hz, 2 H), 7.31 (t,
J ) 7.6 Hz, 2 H), 7.15 (t, J ) 7.3 Hz, 1 H), 6.86 (d, J ) 1.6 Hz,
1 H), 6.45 (d, J ) 9.8 Hz, 1 H), 6.31 (d, J ) 1.6 Hz, 1 H), 5.71-
5.77 (m, 1 H), 3.97 (t, J ) 7.2 Hz, 2 H), 2.48-2.55 (m, 2 H);
13C NMR δ 135.8, 130.2, 128.6, 125.3, 124.9, 122.4, 120.1,
119.5, 117.8, 103.7, 43.8, 24.4; HRMS calcd for C14H13
N
195.1048 (M+), found 195.1075.
P r ep a r a tion of 1-(p h en ylth io)-6-ter t-bu tyl-2,3-d ih yd r o-
1H-p yr r olo[1,2-a ]p yr r ole (11). A solution of 8b (0.50 g, 2
mmol) and sodium thiophenolate (0.66g, 5 mmol) in DMF (50

4154 J . Org. Chem., Vol. 62, No. 12, 1997
Katritzky et al.
124.6, 1222.1, 117.9, 44.1, 32.1, 31.2, 24.2, 22.4. Anal. Calcd
for C27H27N: N, 3.83. Found: N 3.63.
added a solution of Grignard reagent (Scheme 1) (5 mmol) in
Et2O (10 mL), and the reaction was refluxed for the time
indicated in Scheme 3. The solvent was removed under
reduced pressure, and the residue was extracted with Et2O (2
× 50 mL). The combined organic solution was washed with
water (3 × 50 mL) and dried (MgSO4). After removal of the
solvent, the residue was separated by column chromatography
using Et2O/hexane (1:1) as the eluent to give the corresponding
product 29 or 32.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1-(Ben zo-
tr ia zol-1-yl)-2,3-d ih yd r o-1H-p yr r olo[1,2-a ]in d ole (25) a n d
1-[(Ben zot r ia zol-1-yl)m et h yl]-1,2,3,4-t et r a h yd r op yr id o-
[1,2-a ]in d ole (27). On e-P ot Meth od . To a solution of
2-[(benzotriazol-1-yl)methyl]indole (23) (5 mmol) in THF (50
mL) was added a solution of n-BuLi (6.25 mL, 10 mmol, 1.6 M
in hexane) at -78 °C. The temperature was allowed to warm
to -30 °C, and the reaction mixture was stirred at this
temperature for 30 min. After being cooled to -78 °C, a
solution of 1-chloro-2-bromoethane or 1-chloro-3-bromopropane
(5 mmol) in THF (5 mL) was added and the reaction mixture
stirred at -78 °C for a further 3 h. HMPA (2 mL) was added,
and the reaction solution was allowed to warm to room
temperature and stirred overnight. Water (100 mL) and
EtOAc (100 mL) were poured into the reaction mixture, and
the organic phase was separated, washed with water (3 × 100
mL), and dried (MgSO4). After removal of the solvent, the
crystalline residue was recrystallized from EtOAc/hexane (1:
3) to afford the corresponding 25 or 27.
1-Meth yl-2,3-dih ydr o-1H-pyr r olo[1,2-a ]in dole (29): white
1
needles, 70% yield; mp 49-50 °C; H NMR δ 7.57 (d, J ) 7.1
Hz, 1 H), 7.24 (d, J ) 7.7 Hz, 1 H), 7.04-7.20 (m, 2 H), 6.16
(s, 1 H), 4.07-4.15 (m, 1 H), 3.92-4.01 (m, 2 H), 3.35-3.42
(m, 1 H), 2.71-2.81 (m, 1 H), 2.12-2.22 (m, 1 H), 1.39 (d, J )
6.9 Hz, 3 H); 13C NMR δ 149.6, 133.0, 132.5, 120.4, 120.2,
119.0, 109.3, 91.4, 43.1, 36.9, 32.1, 19.5. Anal. Calcd for
C12H13N: N, 8.18. Found: N, 7.94.
1-P h en yl-1,2,3,4-tetr ah ydr opyr ido[1,2-a ]in dole (32): yel-
low oil, 58% yield; 1H NMR δ 7.46 (d, J ) 7.8 Hz, 1 H), 7.21-
7.33 (m, 6 H), 7.16 (t, J ) 7.7 Hz, 1 H), 7.06 (t, J ) 8.0 Hz, 1
H), 5.92 (s, 1 H), 4.17-4.25 (m, 2 H), 3.94-4.03 (m, 1 H), 2.18-
2.23 (m, 2 H), 1.91-2.16 (m, 2 H); 13C NMR δ 144.4, 140.4,
136.3, 128.3, 128.1, 126.6, 120.5, 119.9, 119.7, 108.8, 99.5, 42.4,
42.3, 30.8, 22.2. Anal. Calcd for C18H17N: C, 87.40; H, 6.93;
N, 5.67. Found: C, 87.14; H, 7.35; N, 5.32.
1-(Ben zotr ia zol-1-yl)-2,3-d ih yd r o-1H-p yr r olo[1,2-a ]in -
1
d ole (25): white plates, 82% yield; mp 164-165 °C; H NMR
δ 8.02 (d, J ) 6.9 Hz, 1 H), 7.56 (d, J ) 8.0 Hz, 1 H), 7.37 (d,
J ) 8.2 Hz, 1 H), 7.21-7.31 (m, 4 H), 7.12 (t, J ) 7.6 Hz, 1 H),
6.82 (d, J ) 6.7 Hz, 1 H), 6.62 (dd, J ) 8.3 Hz, 1 H), 6.28 (s,
1 H), 4.38-4.46 (m, 1 H), 4.18-4.26 (m, 1 H), 3.21-3.34 (m, 1
H), 2.94-3.04 (m, 1 H); 13C NMR δ 146.4, 138.6, 132.6, 132.5,
131.5, 127.3, 123.9, 121.9, 121.6, 120.0, 110.0, 109.7, 95.6, 56.0,
42.7, 35.8. Anal. Calcd for C17H14N4: C, 74.42; H, 5.15; N,
20.43. Found: C, 74.50; H, 5.20; N, 20.51.
P r ep a r a t ion of 1-(tr a n s-5-Met h yl-2-p h en yl-1-oxo-2-
h exen yl)-2,3-d ih yd r o-1H-p yr r olo[1,2-a ]in d ole (31). To a
stirred solution of compound 25 (0.82 g, 3 mmol) in THF (100
mL) was added a solution of n-BuLi (1.88 mL, 3 mmol) at -78
°C. After 30 min, a solution of 5-methyl-2-phenyl-2-hexenal
(0.56 g, 3 mmol) in THF (10 mL) was added and the reaction
mixture was allowed to warm to room temperature overnight.
The reaction was quenched with saturated NH4Cl solution (100
mL) and extracted with EtOAc (100 mL). The organic phase
was separated, washed with water (3 × 100 mL), and dried
over magnesium sulfate. The solvent was removed under
reduced pressure, and the residue was dissolved in THF (50
mL). To this THF solution was added p-toluenesulfonic acid
monohydrate (0.57 g, 3 mmol), and the resulting reaction
mixture was refluxed for 24 h. After cooling, EtOAc (50 mL)
and water (50 mL) were added, and the organic layer was
separated, washed with water (3 × 50 mL), and dried (MgSO4).
The solvent was removed to give an oily residue which was
subjected to column chromatography using EtOAc/hexane (1:
4) as the eluent to afford the product 31 as a white solid (0.54
g, 52% yield): mp 146-148 °C; 1H NMR δ 7.54 (d, J ) 7.8 Hz,
1 H), 7.29-7.40 (m, 3 H), 7.23 (d, J ) 8.1 Hz, 1 H), 7.03-7.16
(m, 5 H), 6.18 (s, 1 H), 4.83 (dd, J ) 8.2 and 4.4 Hz, 1 H),
4.17-4.26 (m, 1 H), 4.04-4.11 (m, 1 H), 3.07-3.15 (m, 1 H),
2.63-2.69 (m,1 H), 2.12 (t, J )7.1 Hz, 2 H), 1.81-1.90 (m, 1
H), 0.96 (d, J ) 6.6 Hz, 6 H); 13C NMR δ 196.8, 144.5, 143.0,
141.7, 135.8, 132.9, 132.6, 129.7, 128.2, 127.5, 121.0, 120.7,
119.4, 109.6, 94.3, 44.9, 43.4, 38.9, 30.8, 28.6, 22.6, 22.5. Anal.
Calcd for C24H25NO: N, 4.08. Found: N, 3.97.
P r ep a r a tion of F u sed In d olo[3,2-b]ca r ba zole 33. To a
solution of compound 27 (1.16 g, 4.03 mmol) in CH2Cl2 (30 mL)
was added ZnBr2 (1.00 g, 4.4 mmol), and the reaction mixture
stirred at room temperature for 12 h. The reaction solution
was filtered. The filtrate was washed with water (3 × 50 mL)
and dried (MgSO4). After evaporation of the solvent, the
product was separated by column chromatography using CH2-
Cl2/hexane (1:4) as the eluent to afford product 32 as yellow
powder (0.67 g, 50% yield): 1H NMR δ 8.24 (d, J ) 7.7 Hz, 2
H), 7.40-7.49 (m, 4 H), 7.20-7.28 (m, 2 H), 4.33 (t, J ) 5.2
Hz, 4 H), 3.64 (t, J ) 5.4 Hz, 4 H), 2.50-2.54 (m, 4 H); 13C
NMR δ 124.8, 122.4, 117.6, 113.8, 40.9, 23.3, 22.6 (other
quaternary carbon signals were not observed due to the poor
solubility of the sample in organic solvents); HRMS calcd for
C24H20N2 336.1627 (M+), found 336.1627.
1-[(Ben zotr iazol-1-yl)m eth yl]-1,2,3,4-tetr ah ydr opyr ido-
[1,2-a ]in d ole (27): white needles, 92% yield; mp 161-163 °C;
1H NMR δ 8.08 (d, J ) 8.5 Hz, 1 H), 7.50 (d, J ) 7.8 Hz, 1 H),
7.42 (d, J ) 8.1 Hz, 1 H), 7.25-7.34 (m, 3 H), 7.13 (t, J ) 7.9
Hz, 1 H), 6.89 (d, J ) 8.4 Hz, 1 H), 6.53 (t, J ) 7.2 Hz, 1 H),
6.09 (s, 1 H), 4.35-4.17 (m, 2 H), 2.48-2.60 (m, 2 H), 2.21-
2.41 (m, 2 H); 13C NMR δ 146.4, 136.4, 132.2, 132.1, 127.7,
127.2, 123.8, 122.0, 120.9, 120.4, 120.2, 110.7, 109.4, 100.8,
55.1, 42.1, 28.8, 21.3. Anal. Calcd for C18H16N4: C, 74.98; H,
5.59; N, 19.43. Found: C, 74.92; H, 5.57; N, 19.45.
Tw o Step Meth od . To a solution of compound 23 (2.5 g,
10.1 mmol) in THF (150 mL) was added a solution of n-BuLi
(12.63 mL, 20.2 mmol, 1.6 M in hexane) at -78 °C, and the
temperature was raised to -30 °C. The reaction mixture was
stirred at this temperature for 30 min and cooled to -78 °C.
A solution of 1-chloro-3-bromopropane (1.60 g, 10.1 mmol) in
THF (10 mL) was added, and the mixture was stirred for 3 h
at -78 °C. The reaction was quenched with saturated NH4Cl
solution and extracted with EtOAc (100 mL), and the organic
phase was separated, washed with water (3 × 100 mL), and
dried (MgSO4). After removal of the solvent, the crystalline
residue was recrystallized from EtOAc/hexane (1:4) to give the
product 28 as white needles (3.02 g, 92% yield): mp 136-138
°C; 1H NMR δ 9.36 (s, 1 H), 7.84 (d, J ) 8.4 Hz, 1 H), 7.66 (d,
J ) 7.7 Hz, 1 H), 7.31-7.40 (m, 3 H), 7.11-7.28 (m, 3 H), 6.76
(s, 1 H), 6.23 (t, J ) 7.8 Hz, 1 H), 3.53-3.63 (m, 2 H), 2.76-
2.85 (m, 2 H), 1.84-1.94 (m, 1 H), 1.69-1.76 (m, 1 H); 13C NMR
δ 146.0,136.9, 134.3, 132.1, 127.7, 127.5, 124.3, 122.8, 120.8,
120.2, 119.7, 111.4, 109.9, 101.8, 57.6, 44.0, 31.1, 29.1. Anal.
Calcd for C18H17ClN4: C, 66.56; H, 5.28; N, 17.25. Found: C,
66.22; H, 5.36; N, 17.20.
To a solution of compound 28 (1.62 g, 5 mmol) in DMSO
(20 mL) was added sodium hydride (0.15 g, 5 mmol, 80% in
dispersion in mineral oil) at room temperature, and the
reaction mixture was stirred at this temperature for 12 h.
EtOAc (50 mL) and water (50 mL) were added, and the organic
phase was separated, washed with water (3 × 50 mL), and
dried (MgSO4). The solvent was removed under reduced
pressure to give the crystalline residue which was recrystal-
lized from EtOAc/hexane (1:3) to afford product 27 (1.30 g, 90%
yield).
Gen er a l P r oced u r e for th e Rea ction of 1-(Ben zotr ia -
zol-1-yl)-2,3-d ih yd r o-1H -p yr r olo[1,2-a ]in d ole (25) a n d
1-[(Ben zot r ia zol-1-yl)m et h yl]-1,2,3,4-t et r a h yd r op yr id o-
[1,2-a ]in d ole (27) w ith Gr ign a r d Rea gen ts. To a solution
of 25 or 27 (2.5 mmol) in toluene (30 mL) under argon was
Su p p or tin g In for m a tion Ava ila ble: HRMS and NMR
spectra of compounds 9, 10, 12a , 12b, 17, 20, and 33 (14
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.
J O9623191