Intramolecular organolithium addition to indol-2(3H)-ones; an approach to the synthesis of pyrrolo[1,2-a]indoles and pyrido[1,2-a]indoles

Article abstract of DOI:10.1039/a909548i

Cyclisation of 3 and 10 by lithium-halogen exchange followed by reduction with lithium aluminium hydride gives pyrrolo[1,2-a]indoles 11 and 13 respectively. Similar treatment of bromides 4a and 4b gives pyrido[1,2-a]indoles 12a and 12b. The Royal Society

Full text of DOI:10.1039/a909548i

View Article Online / Journal Homepage / Table of Contents for this issue
Intramolecular organolithium addition to indol-2(3H)-ones;
an approach to the synthesis of pyrrolo[1,2-a]indoles and
pyrido[1,2-a]indoles
1
Keith Jones*† and John M. D. Storey†
Department of Chemistry, King’s College London, Strand, London, UK WC2R 2LS
Received (in Cambridge, UK) 3rd December 1999, Accepted 12th January 2000
Cyclisation of 3 and 10 by lithium–halogen exchange followed by reduction with lithium aluminium hydride gives
pyrrolo[1,2-a]indoles 11 and 13 respectively. Similar treatment of bromides 4a and 4b gives pyrido[1,2-a]indoles 12a
and 12b.
Introduction
include the cyclisation of a 2-lithioindole by displacement of a
6a
tosylate from an N-alkyl-substituent, cyclisation by N-alkyl-
The tricyclic pyrrolo[1,2-a]indole skeleton has been the target
6b
ation using a suitable 2-substituted indole, dipolar cyclo-
6c
addition chemistry and a variety of cyclisations onto the
-position of indole using radical chemistry from the groups of
2
6d
6e
6f
Ziegler, Moody and Caddick.
Our own contributions to this area have focussed on the use
of oxindoles as key intermediates as first suggested by Raphael
7
and Ravenscroft. Using the electrophilic nature of the carbonyl
8a
8b
group both the intra- and intermolecular addition of
organolithiums has been developed as a method for the syn-
thesis of pyrrolo[1,2-a]indoles. This approach is based firmly on
the pioneering observation by Fowler and co-workers that the
intermolecular addition of organolithiums to lactams followed
by a reductive work-up leads to α-substituted cyclic amines
of considerable activity among synthetic chemists since the
elucidation of the structure of the clinically useful mitomycins
nearly 40 years ago. The many different syntheses of this tri-
1
9
in good yields (Scheme 1). We now wish to report on our
intramolecular approach in detail.
cyclic system can be divided into 3 basic routes. The approach
which led to the first successful synthesis of the mitomycins by
Kishi and co-workers in 1977 involves formation of the B- and
C-rings simultaneously using a transannular cyclisation from
2a
an eight-membered ring precursor. This strategy has also been
2d
2b,c
used by Ban and co-workers and Kosikowski and Mugrage.
A variation on this theme has been used by Danishefsky and co-
workers to create the B- and C-rings in a one-pot procedure
using the sequential formation of these two rings under the
Scheme 1
3
same reaction conditions. An alternative method for the simul-
taneous creation of these two rings was published by Streith
and co-workers and involved the Diels–Alder reaction of
nitrosobenzene with pentadienal and in situ rearrangment
of the initial cycloaddition products.
Formation of the B-ring as the key step has been investigated
Results
In order to explore the generation and cyclisation of organo-
lithiums onto the oxoindole carbonyl, we chose to use 3,3-
dimethyloxoindole carrying a suitable bromoalkyl chain on the
nitrogen from which the organolithium could be derived by
lithium–halogen exchange. The presence of the gem-dimethyl
group adjacent to the carbonyl ensured that deprotonation to
give the enolate was not possible, although the intermolecular
additions reported by Fowler and co-workers contained equally
acidic protons which caused no problems.
ment was a convenient preparation of 3,3-dimethyloxoindole 2.
This was achieved by removal of the N-benzyl group from
4
by a number of groups. Takada et al. used carbene chemistry
5a
to create the indole-2,3 bond. Kametani et al. used the
intramolecular capture of a benzyne intermediate to create
5b
5c
the N-aryl bond. Reinhoudt’s group prepared a number of
pyrrolo[1,2-a]indoles by thermal cyclisation to create the 9, 9a
bond while Rapoport and co-workers reported a photo-
9
The first require-
5d
chemical cyclisation to create ring B. Finally in this area,
Knolker et al. reported the synthesis of pyrrolo[1,2-a]indoles
using the electrophilic nature of iron tricarbonyl cyclohexa-
8b
oxoindole 1, the synthesis of which has been reported
via
5e
radical cyclisation. Exposure of 1 to lithium in liquid ammonia
for 8 minutes led to clean debenzylation in 85% yield with
no problems arising from Birch reduction of the aromatic
ring (Scheme 2). N-Alkylation of 2 was first undertaken with
dienyl complexes to prepare the N-aryl bond.
Probably the most popular route for the synthesis of the
pyrrolo[1,2-a]indole skeleton is the addition of the C-ring onto
an indole or indole-related system. Examples of this approach
1
,3-dibromopropane using sodium hydride in THF. The N-(3-
bromopropyl)oxoindole 3 was isolated in 97% yield. A similar
reaction using 1,4-dibromobutane as the alkylating agent gave
†
Current Address: School of Applied Chemistry, Kingston University,
Penrhyn Road, Kingston-upon-Thames, Surrey, UK KT1 2EE
DOI: 10.1039/a909548i
J. Chem. Soc., Perkin Trans. 1, 2000, 769–774
769
This journal is © The Royal Society of Chemistry 2000

View Article Online
Scheme 2
the N-(4-bromobutyl)oxoindole 4a in 66% yield. We wished to
explore the formation and cyclisation of a secondary organo-
lithium species and to this end, reaction of 1 with sodium
hydride in THF and 1,4-dibromopentane was carried out lead-
ing to the N-(4-bromopentyl)oxoindole 4b in 54% yield. Our
10
previous use of this reaction to prepare tetrahydrocarbazoles
by organolithium cyclisation from C-3 of the oxoindole had
shown that vinyllithium species were excellent nucleophiles and
moreover gave products with functionality (an alkene) which
could be further exploited. In this case, cyclisation of a suitable
vinyllithium would give rise to a pyrrolo[1,2-a]indole contain-
ing an alkene in the correct position for elaboration into the
aziridine found in the mitomycins.
Reaction of 3,3-dimethyloxoindole 1 with sodium hydride
and commercially available 1,3-dibromopropene gave the vinyl
bromide 5 as approximately a 1:1 mixture of geometric isomers
as determined by NMR spectroscopy. This was confirmed by
separation of the isomers on silica gel, although this turned out
to be difficult to achieve. The starting 1,3-dibromopropene was
an unassigned 55:45 mixture of isomers.
The fact that cyclisation precursor 5 was a mixture of isomers
gave us some cause for concern. The lithium–halogen exchange
reaction is known to occur with retention of configuration at
11
the alkene and the stereochemical interconversion of vinyl-
lithium species is a slow process under the conditions we
planned to use (relatively non-polar solvent and low temper-
12
ature). It was clear that the derived trans-vinyllithium would
be unable to cyclise whilst at the same time, the cis-vinyl brom-
ide is ideally arranged for elimination to an alkyne. To address
both these worries, we decided to synthesise the cis-vinyl iodide
Scheme 3
13
1
0 according to the procedure of Stork and Zhao (Scheme 3).
N-Allylation of methacryloylanilide 6 using sodium hydride in
THF gave the tertiary anilide 7 in 80% yield. As seen in other
examples of this system that we have prepared, the methylene
group adjacent to the nitrogen is diastereotopic with a chemical
shift difference between the two protons of 1 ppm. This effect
is caused by the asymmetry around the aryl carbon–nitrogen
bond. This form of atropisomerism has been discussed previ-
unstable aldehyde 9 in 89% yield. This was swiftly reacted
with the ylide prepared by reaction of iodomethyltriphenyl-
phosphonium bromide with sodium hexamethyldisilazide to
give vinyl iodide 10 as a 4:1 mixture of cis- and trans-isomers
from which the cis-isomer was isolated in 54% yield.
With five cyclisation precursors in hand, attention now
focussed on the generation and cyclisation of the organolithium
species. Initially, we doubted that formation of the pyrrolo-
[1,2-a]indole ring system would be possible using such a cyclis-
ation, as the organolithiums derived from 3, 5 and cis-10 appear
to lack the conformational flexibility to achieve a suitable angle
of approach to the oxoindole carbonyl group. Indeed, an
explorative reaction using the chloro analogue of 3 had given
14
15
ously and has been utilised in asymmetric synthesis. Cyclis-
ation of 7 under standard tin hydride radical conditions, gave
a 3:1 mixture of the desired N-allyloxoindole 8 and the corre-
sponding N-allyl-3-methyldihydroquinolone from which 8
could be isolated in 73% yield by column chromatography. This
remarkable selectivity for cyclisation onto the acryloyl double
bond and not the allyl double bond has been commented
14
8a
upon and is under further investigation in our laboratory.
Ozonolysis of the double bond of 8 followed by decomposition
of the ozonide using dimethyl sulfide gave the somewhat
only minor amounts of cyclised product. Treatment of 3 with
tert-butyllithium in ether at Ϫ78 ЊC followed by warming to
0 ЊC and addition of LiAlH , gave the pyrrolo[1,2-a]indole 11
4
7
70
J. Chem. Soc., Perkin Trans. 1, 2000, 769–774

View Article Online
Scheme 5
methylsilyl iodide were all investigated but in no case were any
identifiable products isolated.
In summary, we have shown that both the pyrrolo[1,2-a]-
indole and the pyrido[1,2-a]indole ring systems can be
synthesised in reasonable to excellent yields using in situ
lithium–halogen exchange and subsequent reductive cyclisation
of the organolithium on to the carbonyl group of oxoindoles.
The exploration of this reaction in systems containing enolis-
able protons represents the next step in this project.
Scheme 4
in 47% yield after column chromatography (Scheme 4). This
illustrates the advantages of the alkyl bromides over the alkyl
chlorides for the generation of organolithiums by lithium–
16
halogen exchange. The pyrido[1,2-a]indole system is little
17
studied and we believed that the cyclisation of the organo-
lithiums derived from 4a and 4b should be easier than that
derived from 3 owing to the greater flexibility available in the
chain. Treatment of 4a under the same conditions (t-BuLi, then
Experimental
1
H NMR spectra were recorded on a Bruker AM360 or AM250
spectrometer at 360 and 250 MHz respectively using CDCl as
3
LiAlH ) gave the tricycle 12a in 95% yield seemingly indicating
4
solvent with SiMe as an internal standard, unless otherwise
4
that this analysis is correct (Scheme 4). Similar reaction of 4b
was less successful giving pyrido[1,2-a]indole 12b in 64% yield
as a 3:1 mixture of diastereoisomers (Scheme 4). There was
some evidence in the NMR spectrum of the crude product that
alkene formation occurred by elimination of HBr from the
secondary bromide 4b. The major diastereoisomer of 12b was
assigned the cis-methyl–10a-H stereochemistry on account of a
J1-H/10a-H value of 10.3 Hz.
Reaction of the vinyl bromide 5 (as a mixture of stereo-
isomers) under the cyclisation conditions gave a mixture of
products in which the desired tricycle 13 could be tentatively
identified along with alkyne arising from HBr elimination.
Turning to the vinyl iodide 10 instead, cyclisation gave the
pyrrolo[1,2-a]indole 13 in 60% yield (Scheme 4). This improve-
ment in the reaction of the iodide almost certainly arises from
the two factors discussed above, namely the improved lithium–
halogen exchange for the iodide and the generation of the cis-
organolithium exclusively.
stated. J-values are given in Hz. IR spectra were recorded on a
Perkin–Elmer 983G infrared spectrometer, using Nujol mulls
or carbon tetrachloride solutions unless otherwise stated. All
Ϫ1
values in cm . Mass spectral data were recorded on a JEOL
AX505W with complement data system. Samples were ionised
electronically at 70 eV with typical accelerating voltage of 6 kV.
Melting points were determined using a Kofler hot plate
apparatus and are uncorrected. All column chromatography
was carried out using the flash chromatography technique,
using Merck 60 (230–400 mesh) silica gel. Analytical TLC was
carried out on Merck plastic backed TLC plates, coated with
silica gel 60 F-254. Plates were visualised using ultraviolet light,
unless otherwise stated. Eluting solvent systems are stated
where appropriate. All dry reactions were performed in an inert
argon atmosphere using a vacuum–argon manifold for the
exclusion of water. Stirring was by internal magnetic bead. All
syringes, needles and glassware were pre-dried at 110 ЊC and
cooled in an anhydrous atmosphere before use. Diethyl ether,
THF, and toluene were pre-dried over Na wire and refluxed
over Na under Ar with benzophenone as an indicator in the
reaction vessel. Dichloromethane was refluxed under Ar, over
Finally, we carried out a series of experiments to trap the
intermediate hydroxymethylamine using methylating and
silylating agents. The course of the reaction is outlined in
Scheme 5 based mainly on the observation that the intermedi-
ate hydroxymethylamine can be isolated in the hexahydro-
CaH and distilled directly into the reaction vessel.
2
10
carbazole synthesis if the LiAlH step is omitted. The first
4
3
,3-Dimethylindol-2(3H)-one 2
step involves the addition of the organolithium to the lactam
carbonyl to give the O-lithiated hydroxymethylamine. On addi-
A solution of lithium metal (0.138 g, 19.7 mmol) in dry ammo-
nia (100 ml) at Ϫ78 ЊC was treated with N-phenylmethyl-3,3-
dimethylindol-2(3H)-one 1 (3.24 g, 12.9 mmol) in THF (50 ml).
The mixture was stirred for 8 minutes then rapidly quenched
with methanol (40 ml) and warmed to room temperature whilst
blowing off ammonia with a stream of nitrogen. Solvent was
removed at reduced pressure and the resultant residue was dis-
solved in diethyl ether (100 ml). The ether solution was washed
with water (3 × 50 ml), dried with magnesium sulfate and the
solvent was removed at reduced pressure to give a yellow oil.
The crude product was purified by column chromatography on
tion of LiAlH , we believe that transmetallation occurs to give
4
the aluminate complex which readily eliminates the oxygen to
give an iminium ion. The iminium ion is then rapidly reduced
by the LiAlH . Addition of a methylating agent after the initial
4
cyclisation and omission of the reductive step should allow
introduction of the C-9a methoxy group characteristic of the
mitomycins. The cyclisation of 3 was carried out as before
by treatment with t-BuLi followed by warming to 0 ЊC and
addition of an appropriate electrophile. The addition of methyl
iodide, methyl triflate, water, trimethylsilyl chloride and tri-
J. Chem. Soc., Perkin Trans. 1, 2000, 769–774
771

View Article Online
silica using petroleum (40–60 ЊC)–ethyl acetate (4:1) as eluent
to give the 3,3-dimethyloxoindole 2 (1.76 g, 85%) as a white
crystalline solid, mp 161 ЊC (Found: C, 74.48; H, 6.97; N, 8.47.
(29.5 mg, 1.02 mmol) in THF (15 ml) at 0 ЊC was treated with
3,3-dimethylindol-2(3H)-one 2 (0.15 g, 0.93 mmol) in THF
(5 ml) followed by 1,3-dibromoprop-1-ene (205 mg, 1.02
mmol). The reaction was warmed to room temperature and
stirred for 6 hours. Water (2 ml) was then added and the solvent
removed at reduced pressure. The organic residue was dissolved
in ether (100 ml), washed with water (3 × 25 ml) and dried
with magnesium sulfate. The crude product was purified by
chromatography on silica using petroleum (40–60 ЊC)–ethyl
acetate (5:1) as eluent to give vinyl bromide 5 (191 mg, 73%) as
a clear oil. After iterative chromatography it was possible to
C H NO requires C, 74.50; H, 6.87; N, 8.68%); ν
(CCl )/
10
Ϫ1
11
max
4
cm 3445, 3185, 1705, 1617; δH (360 MHz), 1.41 (6H, s,
C(3)Me), 6.97 (1H, dd, J 8, 1.1, H-7), 7.05 (1H, dt, J 8, 1.1,
H-5), 7.18 (1H, dd, J 8, 1.1, H-4), 7.19 (1H, dt, J 8, 1.1, H-6),
9
.34 (1H, br s, N-H); m/z (EI) 161 (70%), 146 (100).
N-(3-Bromopropyl)-3,3-dimethylindol-2(3H)-one 3
general method 1)
(
Ϫ1
separate cis- and trans-isomers. νmax (neat)/cm 3193, 2969,
Sodium hydride (80 %w/w, 19.6 mg, 0.68 mmol) was prewashed
with petroleum ether (3 × 5 ml) and the washings discarded. A
solution of 3,3-dimethylindol-2(3H)-one 2 (100 mg, 0.62
mmol) in THF (5 ml) was added and when hydrogen evolution
ceased 1,3-dibromopropane (150 mg, 0.74 mmol) was added as
a solution in THF (5 ml). The reaction was stirred at room
temperature for 12 hours, whereupon the solvent was removed
at reduced pressure. The residue was diluted with ether (20 ml),
the ethereal solution was washed with water (3 × 10 ml), dried
and concentrated at reduced pressure. The crude product was
purified by column chromatography on silica using petroleum
spirit (40–60 ЊC)–ethyl acetate (10:1) as eluent to give N-(3-
2
4
927, 1722; δH (360 MHz), (cis-isomer) 1.39 (6H, s, C-(3)Me),
.53 (2H, dd, J 6.2, 1.7, H-1Ј), 6.10 (1H, m, H-2Ј), 6.43 (1H, dt,
J 7.1, 1.7, H-3Ј), 6.89 (1H, dd, J 7.7, 1.2, H-7), 7.07 (1H, td,
J 7.7, 1.2, H-5), 7.24 (2H, m, H-6, H-4); (trans-isomer) 1.38
(
6H, s, C-(3)Me), 4.30 (2H, dd, J 5.4, 0.8, H-1Ј), 6.25 (1H, m,
H-2Ј), 6.31 (1H, dt, J 13.7, 0.8, H-3Ј), 6.82 (1H, dd, J 7.7, 0.9,
H-7), 7.07 (1H, td, J 7.7, 0.9, H-5), 7.25 (2H, m, H-6, H-4); m/z
ϩ
(
EI) (Found: M , 281.0231/279.0261. C H NOBr requires:
13
14
ϩ
ϩ
M , 281.0235/279.0255) 281/279 (M , 30%), 202 (10), 163 (20),
6 (100).
5
N-(2-Bromophenyl)-N-(prop-2-enyl)-2-methylpropenamide 7
bromopropyl)oxoindole 3 (0.17 g, 97%) as a pale yellow oil. ν
max
Ϫ1
(neat)/cm 3045, 2966–2925, 1712, 1610; δH (360 MHz), 1.35
6H, s, C(3)Me), 2.24 (2H, quintet, J 6.5, H-2Ј), 3.42 (2H, t,
According to the general method 1, a suspension of NaH (80 %
w/w) (14 mg, 0.48 mmol) in THF (5 ml) was treated with N-(2-
bromophenyl)-2-methylpropenamide 6 (100 mg, 0.44 mmol) in
THF (5 ml) followed by allyl bromide (80.2 mg, 0.66 mmol).
The reaction was stirred at room temperature for 12 hours,
diluted with ether, washed with water (3 × 10 ml) and dried
with magnesium sulfate. The crude product was purified by
column chromatography on silica using petroleum spirit
(
J 6.5, H-1Ј), 3.85 (2H, t, J 6.5, H-3Ј), 6.93 (1H, dd, J 7.8, 0.9,
H-7), 7.05 (1H, td, J 7.8, 0.9, H-5), 7.20 (1H, dd, J 7.8, 0.9,
H-4), 7.25 (1H, dt, J 7.8, 0.9, H-6); m/z (EI) (Found:
ϩ
ϩ
M , 281.0422/283.0403. C H NOBr requires: M , 281.0415/
13
16
2
83.0396) 281/283 (10%), 202 (40), 163 (30), 83 (100).
N-(4-Bromobutyl)-3,3-dimethylindol-2(3H)-one 4a
(
40–60 ЊC)–ethyl acetate (5:1) as eluent to give the tertiary
Ϫ1
anilide 7 (82 mg, 80%) as a pale yellow oil. νmax (neat)/cm
According to general method 1, a suspension of NaH (80 %
w/w) (19.6 mg, 0.68 mmol) in THF (10 ml) at 0 ЊC was treated
with 3,3-dimethylindol-2(3H)-one 2 (100 mg, 0.62 mmol) in
THF (3 ml), followed by 1,4-dibromobutane (161 mg, 0.74
mmol). The reaction was heated at 40 ЊC for 12 hours, cooled,
and diluted with ether (30 ml). The crude product was purified
by chromatography on silica using petroleum spirit (40–60 ЊC)–
3
078, 1670, 1640; δH (360 MHz), 1.83 (3H, s, C(3)Me), 3.82
(
(
1H, dd, J 14.6, 7.4, H1Љ), 4.80 (1H, dd, J 14.6, 4.7, H1Љ), 4.98
1H, s, H-4), 5.00 (1H, s, H-4), 5.07 (1H, dd, J 17.0, 1.3, H3Љ-
cis), 5.11 (1H, dd, J 8.0, 1.3, H3Љ-trans), 5.91 (1H, m, H2Љ), 7.16
(
(
(
1H, td, J 7.6, 1.6, H-4Ј), 7.18 (1H, dd, J 7.6, 1.6, H-6Ј), 7.30
1H, td, J 7.6, 1.0, H5Ј), 7.67 (1H, dd, J 7.6, 1.0, H-3Ј); m/z (EI)
Found: M , 279.0252/281.0248. C H NOBr requires: M ,
ϩ
ϩ
13
14
ethyl acetate (6:1) as eluent to give N-(4-bromobutyl)oxoindole
ϩ
Ϫ1
279.0259/281.0238) 279/281 (M , 20%), 210 (60), 49 (100).
4
a (122 mg, 66%) as a clear viscous oil. νmax (CCl )/cm 3000–
4
2
800, 1711, 1610; δH (360 MHz), 1.37 (6H, s, C(3)Me), 1.78
N-(Prop-2-enyl)-3,3-dimethylindol-2(3H)-one 8
(
(
2H, quintet, J 6.8, H-2Ј), 2.24 (2H, quintet, J 6.8, H-3Ј), 3.39
2H, t, J 6.8, H-1Ј), 3.90 (2H, t, J 6.8, H-4Ј), 7.00 (1H, td, J 7.0,
N-(2-Bromophenyl)-N-(prop-2-enyl)-2-methylpropenamide
7
0
.8, H-5), 7.18 (1H, dd, J 7.0, 0.8, H-7), 7.23 (2H, m, H-6, H-4);
(
92.1 mg, 0.32 mmol) was added to tributyltin hydride (105 mg,
ϩ
ϩ
m/z (EI) (Found: M , 295.0563. C H NOBr requires: M ,
2
14
18
0
.36 mmol) and a catalytic amount of AIBN in de-gassed tolu-
95.0572) 296 (20%), 216 (40).
ene (50 ml). The reaction was heated to 110 ЊC for 1 hour,
cooled, diluted with ether and washed with ammonia solution
N-(4-Bromopentyl)-3,3-dimethylindol-2(3H)-one 4b
(
20%) (5 × 20 ml). After drying and removal of solvents at
reduced pressure the crude product was purified by chromato-
graphy on silica using petroleum spirit (40–60 ЊC)–ethyl acetate
According to general method 1 a suspension of NaH (80 %w/w)
(
3
(
19.6 mg, 0.68 mmol) in THF (5 ml) at 0 ЊC was treated with
,3-dimethylindol-2(3H)-one 2 (100 mg, 0.68 mmol) in THF
5 ml) followed by 1,4-dibromopentane. The reaction was
(
5:1) as eluent to give the N-allyloxoindole 8 and N-allyl-3-
methylquinol-4(2H)-one as a 3:1 mixture (64.8 mg, 98%)
as a clear oil. Iterative chromatography resulted in the isolation
heated at reflux overnight and the crude product was purified
by chromatography on silica using petroleum spirit (40–60 ЊC)–
of pure N-(prop-2-enyl)-3,3-dimethylindol-2(3H)-one 8. ν
max
Ϫ1
(
neat)/cm 3056, 1713, 1610; δH (360 MHz), 1.38 (6H, s,
C(3)Me), 4.34 (2H, dt, J 5.2, 1.6, H-1Ј), 5.21 (2H, m, H-3Ј), 5.84
1H, m, H-2Ј), 6.82 (1H, d, J 7.4, H-7), 7.04 (1H, t, J 7.4, H-5),
ethyl acetate (5:1) as eluent to give N-(4-bromopentyl)-
Ϫ1
oxoindole 4b (114 mg, 54%) as a colourless oil. νmax (CCl )/cm
4
(
7
3
1
045, 2966–2925, 1710; δH (360 MHz), 1.37 (6H, s, C(3)Me),
.69 (3H, d, J 6.6, H-5Ј), 1.83 (3H, m, H-2Ј,H-3Ј), 1.94 (1H, m,
ϩ
.21 (2H, m, H-4, H-6); m/z (EI) (Found: M , 201.1155.
ϩ
ϩ
C H NO requires: M , 201.1153) 201 (M , 100%), 186 (90),
H-3Ј), 3.74 (2H, m, H-1Ј), 4.19 (1H, m, H-4Ј), 6.88 (1H, dd,
J 7.7, 0.8, H-7), 7.06 (1H, dt, J 7.7, 0.8, H-5), 7.25 (2H, m, H-4,
13 15
1
71 (60), 130 (90).
ϩ
H-6); m/z (EI) (Found: M , 309.0731/311.0711. C H NOBr
1
5
20
ϩ
ϩ
requires: M , 309.0729/311.0709) 311/309 (M , 81%), 230 (70),
46 (100).
N-(2-Formylmethyl)-3,3-dimethylindol-2(3H)-one 9
1
N-(Prop-2-enyl)-3,3-dimethylindol-2(3H)-one 8 (40 mg, 0.19
mmol) in dichloromethane (50 ml) at Ϫ78 ЊC was treated with
a steady stream of ozone until a blue colouration persisted.
Dimethyl sulfide (14.8 mg, 0.24 mmol) was then added to the
N-(3-Bromoprop-2-enyl)-3,3-dimethylindol-2(3H)-one 5
According to general method 1 a suspension of NaH (80 %w/w)
7
72
J. Chem. Soc., Perkin Trans. 1, 2000, 769–774

View Article Online
solution which was warmed to room temperature while stirring
over 1.5 hours. The reaction was stirred at room temperature
for 1 hour then solvent was removed at reduced pressure. Purifi-
cation by chromatography on silica using petroleum spirit (40–
mmol). The crude product was purified by chromatography on
silica using petroleum spirit (40–60 ЊC)–ethyl acetate (20:1) as
eluent to give the tricycle 12a (36.2 mg, 95%) as a pale yellow
Ϫ1
oil. νmax (neat)/cm 2937, 2865 1606, 1481; δ (360 MHz; C D ;
H
6
6
6
0 ЊC)–EtOAc (6:1) as eluent gave the aldehyde 9 as a white
Me Si) 1.01 (6H, s, C(3)Me), 1.00–1.75 (6H, m, H-1, H-2,
4
crystalline solid which proved to be unstable (34 mg, 89%), mp
H-3), 2.26 (1H, m, H-4), 2.46 (1H, dd, J 10.3, 2.0, H-4),
3.38 (1H, dd, J 10.3, 1.2, H-10a), 6.44 (1H, dd, J 7.7, 1.0, H-6),
6.82 (1H, td, J 7.7, 1.0, H-8), 7.06 (1H, dd, J 7.7, 1.0, H-9), 7.13
Ϫ1
7
1
0
9
5 ЊC. νmax (neat)/cm 3100–2900, 1725, 1700; δH (360 MHz),
.43 (6H, s, C(3)Me), 4.52 (2H, s, H-1Ј), 6.65 (1H, dd, J 8.0,
.9, H-7), 7.09 (1H, td, J 8.0, 0.9, H-5), 7.25 (2H, m, H-6, H-4),
ϩ
(1H, td, J 7.7, 1.0, H-7); m/z (EI) (Found: M , 201.1523.
ϩ
ϩ
ϩ
.67 (1H, s, H-2Ј); m/z (EA) (Found: M , 203.0945. C H NO
C H N requires: M , 201.1517) 201 (M , 40%), 186 (100), 171
12
13
2
14 19
ϩ
requires: M , 203.0946) 203 (30%), 174 (65), 161 (15), 146
100).
(15).
(
1
,2,3,4,10,10a-Hexahydro-1,10,10-trimethylpyrido[1,2-a]indole
N-(3-Iodoprop-2-enyl)-3,3-dimethylindol-2(3H)-one 10
12b
Sodium hexamethyldisilazide (1 M solution in THF) (0.25 ml,
According to general method 2, a stirred solution of N-(5-
bromopentyl)-3,3-dimethylindol-2(3H)-one 4b (100 mg, 0.323
mmol) in ether (10 ml) at Ϫ78 ЊC was treated with tert-
0
.25 mmol) was added to a stirred suspension of iodomethyl-
triphenylphosphonium iodide (134 mg, 0.25 mmol) in THF
10 ml) at room temperature. After 1 minute the solution was
(
butyllithium (1.7 M, 0.39 ml, 0.663 mmol), followed by LiAlH
4
cooled to Ϫ60 ЊC and HMPA (0.073 ml, 0.4 mmol) was added,
followed by cooling the mixture to Ϫ78 ЊC. The reaction was
stirred at this temperature for 5 minutes whereupon a solution
of N-(formylmethyl)-3,3-dimethylindol-2(3H)-one 9 (43 mg,
(1 M solution in ether, 0.32 ml, 0.323 mmol). The crude product
was purified by chromatography on silica using petroleum spirit
(40–60 ЊC)–ethyl acetate (40:1) as eluent to give the tricycle 12b
(44.4 mg, 64%) as a pale yellow oil which rapidly darkened on
Ϫ1
0
.21 mmol) in THF (5 ml) was slowly added. The reaction was
standing in air. νmax (neat)/cm 3045, 2950; δ (360 MHz; C D ;
H 6 6
allowed to slowly warm to room temperature over 1 hour and
diluted with ether (100 ml). The ethereal solution was washed
with water (3 × 10 ml), dried with magnesium sulfate and the
solvents removed at reduced pressure. The crude product was
purified by column chromatography using petroleum spirit (40–
Me Si) 0.81 (3H, d, J 6.4, C(1)Me), 1.08 (3H, s, C(10)Me), 1.10–
4
1.60 (4H, m, H-2, H-3), 1.31 (3H, s, C(10)Me), 2.21 (2H, m,
H-4), 3.30–3.50 (1H, m, H-10a), 6.42 (1H, d, J 7.7, H-9), 6.83
(1H, t, J 7.7, H-7), 6.87 (1H, d, J 7.7, H-6), 6.99 (1H, t, J 7.7,
ϩ
ϩ
H-8); m/z (EI) (Found: M , 215.1684. C15
H
21N requires: M ,
6
0 ЊC)–ethyl acetate (6:1) as eluent to give the cis-vinyl iodide 10
215.1674) 215 (60%), 200 (100), 144 (50).
Ϫ1
(
36.7 mg, 54%) as a clear oil. νmax (neat)/cm 3200–3000, 1654,
5
1
6
56; δH (360 MHz), 1.38 (6H, s, C(3)Me), 4.43 (2H, dd, J 6.0,
.9, H-1Ј), 6.24 (1H, m, H-2Ј), 6.53 (1H, dt, J 10.7, 1.9, H-3Ј),
9,9a-Dihydro-9,9-dimethyl-3H-pyrrolo[1,2-a]indole 13
According to general method 2 a solution of N-(3-iodoprop-2-
enyl)-3,3-dimethylindol-2(3H)-one 10 (33.6 mg, 0.10 mmol) in
ether (10 ml) was treated with tert-butyllithium (1.7 M, 0.14
.86 (1H, dd, J 7.8, 0.9, H-7), 7.07 (1H, td, J 7.8, 0.9, H-5), 7.25
ϩ
(
2H, m, H-6, H-4); m/z (EI) (Found: M , 327.0137. C H NOI
13
14
ϩ
requires: M , 327.0120) 327 (20%), 200 (100).
ml, 0.22 mmol) followed by LiAlH (1 M solution in ether, 0.15
4
ml, 0.15 mmol). The crude product was purified by chromato-
graphy using petroleum spirit (40–60 ЊC)–ethyl acetate (10:1) as
9
,9-Dimethyl-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indole 11
(
general method 2)
eluent to give the tricycle 13 (11 mg, 59%) as a clear oil. ν
max
Ϫ1
(
(
neat)/cm 3200–3000, 1650; δ (360 MHz; C D ; Me Si) 1.35
3H, s, C(3)Me), 1.51 (3H, s, C(3)Me), 3.71 (1H, dd, J 7.0, 1.2,
A solution of N-(3-bromopropyl)-3,3-dimethylindol-2(3H)-one
(67 mg, 0.24 mmol) in ether (10 ml) at Ϫ78 ЊC was treated
H 6 6 4
3
H-9a), 5.10 (2H, m, H-3), 6.02 (1H, m, H-2), 6.35 (1H, m, H-1),
with tert-butyllithium (1.7 M, 0.31 ml, 0.53 mmol). The reac-
tion was maintained at Ϫ78 ЊC for 1 hour then slowly warmed
to 0 ЊC and stirred for a further hour. LiAlH (1 M solution
in ether, 0.32 ml, 0.32 mmol) was then added and the reaction
heated at reflux overnight. After cooling to room temperature
the reaction was cautiously quenched with NaOH (2 M,
6
7
.95 (1H, d, J 8.1, H-5), 7.10 (1H, m, H-7), 7.25 (1H, m, H-6),
ϩ
.30 (1H, m, H-8); m/z (EI) (Found: M , 185.1208. C H N
13 15
4
ϩ
ϩ
requires: M , 185.1204) 185 (M , 100%).
Acknowledgements
2
ml), followed by rapid stirring with a saturated solution of
Rochelle’s salt (10 ml) for one hour. The organic phase was
separated and the aqueous phase extracted with ether (3 × 10
ml). The combined organic extracts were dried with magnesium
sulfate, the solvent was removed at reduced pressure, and the
crude product was purified by chromatography on silica using
petroleum spirit (40–60 ЊC)–ethyl acetate (20:1) as eluent to
give the tricycle 11 (21 mg, 47%) as a pale yellow oil. ν (CCl )/
We would like to acknowledge financial support from Conoco
in the form of a studentship (J. M. D. S.) and the U.L.I.R.S.
NMR service for spectra. We are grateful to one of the referees
for a suggestion concerning the mechanism of the reaction
shown in Scheme 5.
max
4
References
Ϫ1
cm 3229, 2957–2870; δH (360 MHz; C D ; Me Si) 0.85–0.98
6
6
4
(
1
(
2H, m, H-2), 1.13 (3H, s, C(3)Me), 1.24 (3H, s, C(3)Me), 1.35–
.56 (2H, m, H-1), 2.95 (1H, dt, J 10.5, 8.4, H-3), 3.15–3.30
2H, m, H-3, H-9a), 6.53 (1H, dd, J 7.6, 0.9, H-5), 6.84 (1H, td,
J 7.6, 0.9, H-7), 6.94 (1H, dd, J 7.6, 0.9, H-8), 7.13 (1H, td,
1 D. V. Lefemine, M. Dann, F. Barbatschi, W. K. Hausmann,
V. Zbinovsky, P. Monnikendam, J. Adam and N. Bohonos, J. Am.
Chem. Soc., 1962, 84, 3184; J. S. Webb, D. B. Cosulich, J. H. Mowat,
J. B. Patrick, R. W. Broschard, W. E. Meyer, R. P. Williams,
C. F. Wolf, W. Fulmor, C. Pidacks and J. E. Lancaster, J. Am. Chem.
Soc., 1962, 84, 3185 and 3187.
2 (a) T. Fukuyama, F. Nakatsubo, A. J. Cocuzza and Y. Kishi,
Tetrahedron Lett., 1977, 18, 4295; (b) T. Ohnuma, Y. Sekine and
Y. Ban, Tetrahedron Lett., 1979, 20, 2533 and 2537; (c) S. Nakajima,
K. Yoshida, M. Mori, Y. Ban and M Shibasaki, J. Chem. Soc.,
Chem. Commun., 1990, 468; (d) A. P. Kosikowski and B. B.
Mugrage, J. Chem. Soc., Chem. Commun., 1988, 198.
ϩ
J 7.6, 0.9, H-6); m/z (EI) (Found: M , 187.1360. C H N
requires M , 187.1361) 187 (65%), 172 (100), 144 (70).
13
17
ϩ
1
1
0,10-Dimethyl-1,2,3,4,10,10a-hexahydropyrido[1,2-a]indole
2a
According to general method 2, N-(4-bromobutyl)-3,3-
dimethylindol-2(3H)-one 4a (56 mg, 0.19 mmol) in ether (10
ml) was treated with tert-butyllithium (1.7 M, 0.23 ml, 0.39
3
J. W. Benbow, K. F. McClure and S. J. Danishefsky, J. Am. Chem.
Soc., 1993, 115, 12305.
A. Defoin, G. Geffroy, D. Le-Noun, D. Spileers and J. Streith,
Helv. Chim. Acta, 1989, 72, 1199.
4
mmol) followed by LiAlH (1 M solution in ether, 0.2 ml, 0.20
4
J. Chem. Soc., Perkin Trans. 1, 2000, 769–774
773

View Article Online
5
6
(a) T. Takada, Y. Kosugi and M. Akiba, Tetrahedron Lett., 1974, 14,
283; (b) T. Kametani, Y. Kigawa, H. Nemoto, M. Ihara and
K. Fukumoto, J. Chem. Soc., Perkin Trans. 1, 1980, 1607; (c) W. C.
Dijksman, W. Verboom, R. J. M. Egberink and D. N. Reinhoudt,
J. Org. Chem., 1985, 50, 3791; (d) K. J. Shaw, J. R. Luly and
H. Rapoport, J. Org. Chem., 1985, 50, 4515; (e) H. J. Knolker, A. A.
El-Ahl and G. Weingartner, Synlett, 1994, 194.
9 Y. C. Huang, M. Chu and F. W. Fowler, J. Org. Chem., 1985, 50,
3
3885.
10 C. McCarthy and K. Jones, J. Chem. Soc., Chem. Commun., 1989,
1717.
11 D. Seyferth and L. G. Vaughan, J. Am. Chem. Soc., 1964, 86, 883.
12 D. Y. Curtin and W. J. Koehl, J. Am. Chem. Soc., 1962, 84, 1967.
13 G. Stork and K. Zhao, Tetrahedron Lett., 1989, 30, 2173.
14 K. Jones and J. M. D. Storey, J. Chem. Soc., Chem. Commun., 1992,
1766; D. P. Curran and N. C. DeMello, J. Chem. Soc., Chem.
Commun., 1993, 1314.
(a) O. Asano, S. Nakatsuka and T. Goto, Heterocycles, 1987, 26,
1
207; (b) P. A. Wender and C. B. Cooper, Tetrahedron, 1986,
4
2, 2985; (c) C. W. G. Fishwick, A. D. Jones, M. B. Mitchell and
C. Szanty, Tetrahedron Lett., 1988, 29, 5325; P. J. Bhuyan, R. C.
Boruah and J. S. Sandhu, Tetrahedron Lett., 1989, 30, 1421;
15 D. P. Curran, H. Y. Qi, S. J. Geib and N. C. DeMello, J. Am. Chem.
Soc., 1994, 116, 3131.
16 W. F. Bailey and E. R. Punzalan, J. Org. Chem., 1990, 55, 5404.
17 L. Strekowski and K. Van Aken, in Comprehensive Heterocyclic
Chemistry II, ed. A. R. Katritzky, C. W. Rees and E. F. V. Scriven,
Pergamon, Oxford, UK, 1996, vol. 8, pp. 1065–1089.
(
d) F. E. Ziegler and M. Y. Berlin, Tetrahedron Lett., 1998, 39, 2455;
e) C. J. Moody and C. L. Norton, J. Chem. Soc., Perkin Trans. 1,
(
1
997, 2639; ( f ) S. Caddick, C. L. Shering and S. N. Wadman,
Tetrahedron Lett., 1997, 38, 6249.
R. A. Raphael and P. Ravenscroft, J. Chem. Soc., Perkin Trans. 1,
7
8
1
988, 1823.
(a) J. M. D. Storey, C. McCarthy and K. Jones, J. Chem. Soc., Chem.
Commun., 1991, 892; (b) K. Jones and J. M. D. Storey, Tetrahedron,
1
993, 49, 4901.
Paper a909548i
7
74
J. Chem. Soc., Perkin Trans. 1, 2000, 769–774