Indole synthesis by controlled carbolithiation of o-aminostyrenes

Article abstract of DOI:10.1021/jo048723e

An effective synthesis of the functionalized indole ring system has been developed from substituted o-aminostyrene starting material. Our methodology involves a novel cascade reaction sequence of alkyllithium addition to the styrene double bond and subsequent trapping of the intermediate organolithium with a suitable electrophile, followed by an in situ ring closure and dehydration to generate the indole ring. This new reaction sequence allows for the introduction of molecular diversity at all positions on the indole scaffold. The procedure was shown to be successful with a range of both C and N substituents on the o-aminostyrenes. The reaction sequence was tolerant to the reactivity range of alkyllithiums such as tert-, sec-, and n-butyllithium. The electrophiles used were DMF, which generated indole products with C-2 unsubstituted, and nitriles, which incorporated the nitrile substituent at C-2. The o-aminostyrene starting materials were generated by a Pd-catalyzed cross-coupling reaction of a vinyl boronic acid equivalent with the readily available substituted o-bromoanilines.

Full text of DOI:10.1021/jo048723e

Indole Synthesis by Controlled Carbolithiation of o-Aminostyrenes
Albane Kessler, Claire M. Coleman, Patchanee Charoenying,† and Donal F. O’Shea*
Centre for Synthesis and Chemical Biology, Conway Institute, Department of Chemistry,
University College Dublin, Belfield, Dublin 4, Ireland
donal.f.oshea@ucd.ie
Received July 25, 2004
An effective synthesis of the functionalized indole ring system has been developed from substituted
o-aminostyrene starting material. Our methodology involves a novel cascade reaction sequence of
alkyllithium addition to the styrene double bond and subsequent trapping of the intermediate
organolithium with a suitable electrophile, followed by an in situ ring closure and dehydration to
generate the indole ring. This new reaction sequence allows for the introduction of molecular
diversity at all positions on the indole scaffold. The procedure was shown to be successful with a
range of both C and N substituents on the o-aminostyrenes. The reaction sequence was tolerant to
the reactivity range of alkyllithiums such as tert-, sec-, and n-butyllithium. The electrophiles used
were DMF, which generated indole products with C-2 unsubstituted, and nitriles, which incorporated
the nitrile substituent at C-2. The o-aminostyrene starting materials were generated by a Pd-
catalyzed cross-coupling reaction of a vinyl boronic acid equivalent with the readily available
substituted o-bromoanilines.
SCHEME 1. Carbolithiation of Unactivated
Alkenes
Introduction
The synthetic potential of the carbolithiation of un-
activated alkenes lies in the fact that both a new carbon-
carbon bond and organolithium compound are generated
in tandem. The newly generated organolithium species
may then be exploited for further in situ transforma-
tions.1 A drawback of this approach is that it can suffer
in its application as a viable synthetic method due to the
reactivity of the generated organolithium toward the
starting alkene. If the generated organolithium reacts
with a second molecule of the alkene an anionic polym-
erization process could propagate. As such, one of the
earlier demonstrated applications of organolithium reac-
tions was an anionic polymerization of styrene, which
was initiated with n-butyllithium in THF at 20 °C
(Scheme 1).2
The challenge in successfully exploiting the intermedi-
ate organolithium is dependent upon suppressing the
anionic polymerization process in favor of generating a
solution of 2 (Scheme 1). This implies that conditions are
required that will facilitate the initial carbolithiation
process but not favor further carbolithiation by the
intermediate organolithium. This has been accomplished
for the simplest unactivated carbon-carbon double bond
ethene 1a, in which controlled carbolithiation has been
achieved for tert- and sec-butyllithium but not n-butyl-
lithium.3 This can be rationalized by a comparison of the
stability of the starting alkyllithium and the generated
alkyllithium. The rate of carbolithiation is faster for the
more substituted alkyl group; thus, polymerization can
be avoided for tert- and sec-butyllithium which react to
generate primary alkylithiums. In comparison, when a
primary alkyllithium (n-Bu) is used to generate an
intermediate primary alkyllithium this selectivity is lost
and polymerization results.
It was not until recently that the potential for the
controlled organolithium addition to styrene was ex-
ploited. It was demonstrated that by employing diethyl
ether as the reaction solvent and maintaining a low
temperature, polymerization could be avoided and the
generated organolithium product was now available for
further organic transformations.4 Use of this methodology
allows for the addition of alkyl groups to the terminal
carbon of the styrene 1b, followed by trapping of the
generated lithiated intermediate 2 with various electro-
philes providing a viable route to alkyl-substituted aryls
† Current address: Department of Chemistry, King Mongkut’s
Institute of Technology, Ladkrabang, Bangkok 10520, Thailand.
(1) (a) Clayden, J. Organolithiums: Selectivity for Synthesis; Per-
gamon Press: Oxford, U.K., 2002; pp 273-335 (review). (b) Marek, I.
J. Chem. Soc., Perkin Trans. 1 1999, 535 (review).
(3) (a) Bartlett, P. D.; Tauber, S. J.; Weber, W. P. J. Am. Chem.
Soc. 1969, 91, 6362. (b) Bartlett, P. D.; Friedman, S.; Stiles, M. J. Am.
Chem. Soc. 1953, 75, 1771.
(4) (a) Wei, X.; Taylor, R. J. K. J. Chem. Soc., Chem. Commun. 1996,
187. (b) Wei, X.; Johnson, P.; Taylor, R. J. K. J. Chem. Soc., Perkin
Trans. 1 2000, 1109.
(2) Waack, R.; Doran, M. A. J. Org. Chem. 1967, 32, 3395.
10.1021/jo048723e CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/21/2004
7836
J. Org. Chem. 2004, 69, 7836-7846

Indoles from Carbolithiation of o-Aminostyrenes
3 (Scheme 1). Styrene 1b was shown to undergo efficient
carbolithiation from -25 to -78 °C, with the reactivity
of different organolithiums found to be to be tertiary >
secondary > primary > methyl, phenyl. In this case, the
scope of the reaction can be extended to primary alkyl-
lithiums as the generated organolithium is a benzylic-
lithium species, which is less reactive than primary
alkyllithiums.
The carbolithiation of unactivated alkenes has proven
very successful for the synthesis of complex polycyclic
systems. This has typically been achieved by reaction
sequences utilizing an intramolecular carbolithiation
process to generate a variety of carbocycles1a,5 and
heterocycles.6 To date, intermolecular carbolithiation
methodology as a route to ring formation has been much
more limited in its application, with the few reported
examples being applied to the formation of cyclopentanes7
and tetralins.8
FIGURE 1. Sequence of bond formation.
ment of new synthetic methods is of considerable value.10
Routes which would facilitate the introduction of molec-
ular diversity at all positions of the indole ring in one
synthetic operation would have applications for combi-
natorial library formation and act as an entry point into
natural product synthesis. Many recent advances in
indole synthesis have focused on metal-mediated proce-
dures with copper, palladium, tin, titanium, and zirco-
nium being the most prevalent.11
Results and Discussion
Our goal in this work was to exploit an intermolecular
carbolithiation reaction to initiate a controlled cascade
reaction sequence for the generation of indole ring
scaffold. To achieve this, we have expanded the synthetic
utility of the styrene carbolithiation reaction for the
specific case of ortho-substituted aminostyrenes. For
these derivatives it should be possible that upon genera-
tion of the intermediate anion via organolithium addition,
and subsequent reaction with specific electrophiles, a
cascade reaction process could be set up between the
reacted electrophile and the amine components, facilitat-
ing an in situ ring closing and dehydration to generate
indole ring systems (Figure 1).9 In this one-pot process,
the carbon-nitrogen bond would be constructed from the
reaction of the o-amino with the reacted electrophile, the
carbon-carbon bond of the indole ring would be formed
from the reaction of the generated organolithium with
the electrophile, and uniquely, the entire process is
initiated with the formation of an exocyclic carbon-
carbon bond from the carbolithiation step. The formation
of the bonds (ii) and (iii) is not unusual for an indole
synthesis; what is unique is that the process is initiated
by the formation of the exocyclic carbon-carbon bond in
(i), which in the process introduces a further diversity
point into the products (Figure 1).
Synthesis of o-Vinylaniline Starting Materials.
The viability of our reaction sequence was tested using
an array of o-aminostyrenes, substituted on nitrogen with
a tert-butoxycarbonyl (Boc), an ethyl, or a benzyl group.
Our ultimate starting materials were the commercially
available o-bromoanilines 6a-c and 6d-f, which were
prepared according to literature methods (Table 1).12
N-Boc protection of the 2-bromoanilines 6 was first
attempted with 1 equiv of di-tert-butyl dicarbonate
(Boc2O) with a catalytic quantity of DMAP in THF under
reflux (method A, Table 1). This procedure was successful
for the conversion of 6a and 6c into their corresponding
products 7a,c albeit in poor yields of 56 and 40%,
respectively (entries 1 and 5). The poor yields were due
to the formation of the diarylureas 8a and 8c as byprod-
ucts in significant quantities. This side reaction has been
previously observed for other ortho-substituted anilines.13
The omission of the DMAP catalyst and the use of a 2.5
molar excess of Boc2O in THF under reflux was successful
for 6a and 6d leading to 7a and 7d in 83% and 80% yield,
respectively, but the reaction failed for 6e and 6f possibly
due to the presence of electron-withdrawing substituents
on the aromatic ring and/or steric hindrance (method B,
Table 1, entries 2, 6, 8, and 10). To eliminate the urea
formation and overcome the lack of reactivity of some of
the aniline substrates, we carried out reactions using a
2.5-fold excess of Boc2O in the presence of catalytic DMAP
(method C, Table 1).14 This resulted in the formation of
the di-Boc-protected substrates 9, from which the selec-
tive removal of one Boc group using trifluoroacetic acid
in CH2Cl2 could be readily achieved giving the desired
products (7a,b,d,e,f) in high isolated yields (entries 3, 4,
7, 9, and 11).
The key biochemical roles played by the indole ring in
nature ensure that this heterocyclic system maintains
an intense interest from medicinal and synthetic chem-
ists. This privileged biological scaffold continues to be a
common motif for drug targets, and as such, the develop-
(5) See, for example: (a) Bailey, W. F.; Patricia, J. J.; DelGobbo, V.
C.; Jarret, R. M.; Okarma, P. J. J. Org. Chem. 1985, 50, 2000. (b)
Ashby, E. C.; Pham, T. N. J. Org. Chem. 1987, 52, 1291. (c) Bailey, W.
F.; Nurmi, T. T.; Patricia, J. J.; Wang, W. J. Am. Chem. Soc. 1987,
109, 2442. (d) Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K.; Ovaska,
T. V.; Rossi, K.; Thiel, Y.; Wilberg, K. B. J. Am. Chem. Soc. 1991, 113,
5720. (e) Bailey, W. F.; Daskapan, T.; Rampalli, S. J. Org. Chem. 2003,
68, 1334. (f) Wei, X.; Taylor, R. J. K. Tetrahedron Lett. 1997, 38, 6467.
(6) See, for example: Broka, C. A.; Lee, W. J.; Shen, T. J. Org. Chem.
1989, 54, 5044. (b) Broka, C. A.; Shen, T. J. Am. Chem. Soc. 1989,
111, 2981. (c) Coldham, I.; Hufton, R. Tetrahedron 1996, 52, 12541.
(c) Zang, D.; Liebeskind, L. S. J. Org. Chem. 1996, 61, 2594. (d) Bailey,
W. F.; Jiang, X.-L. J. Org. Chem. 1996, 61, 2596. (e) Barluenga, J.;
Sanz, R.; Granados, A.; Fan˜ana´s, F. J. J. Am. Chem. Soc. 1998, 120,
4865. (f) Mealy, M. J.; Bailey, W. F. J. Organomet. Chem. 2002, 646,
59 (review).
(10) Gribble, G. W. Comprehensive Heterocyclic Chemistry, 2nd ed.;
Pergamon Press: New York, 1996; Vol. 2, pp 207-257.
(11) For reviews of different approaches, see: Gribble, G. W. J.
Chem. Soc., Perkin Trans. 1 2000, 1045. Sundberg, R. J. Comprehensive
Heterocyclic Chemistry, 2nd ed; Pergamon Press: New York, 1996; Vol.
2, pp 120-206.
(12) (a) Krolski, M. E.; Renaldo, A. F.; Rudisill, D. E.; Stille, J. K.
J. Org. Chem. 1988, 53, 1170. (b) Clark, A. J.; Jones, K. Tetrahedron
1992, 48, 6875. (c) Wright, C.; Schulkind, M.; Jones, K.; Thompson,
M. Tetrahedron Lett. 1987, 28, 6389.
(7) Wei, X.; Taylor, R. J. K. Angew. Chem., Int. Ed. 2000, 39, 409.
(b) Krief, A.; Barbeaux, P. Tetrahedron Lett. 1991, 32, 417.
(8) Wei, X.; Taylor, R. J. K. Tetrahedron Lett. 1997, 38, 6467.
(9) Coleman, C. M.; O’Shea, D. F. J. Am. Chem. Soc. 2003, 125, 4054.
(13) Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65, 6368.
(14) (a) Wensbo, D.; Annby, U.; Gronowitz, S. Tetrahedron 1995,
51, 10323. (b) Darnbrough, S.; Mervic, M.; Condon, S. M.; Burns, C. J.
Synth. Commun. 2001, 31, 3273.
J. Org. Chem, Vol. 69, No. 23, 2004 7837

Kessler et al.
TABLE 1. Preparation of N-Boc-o-bromoanilinesa
TABLE 2. Vinylation of 7a-ia
entry substrate
R1
R2 equiv of 10 product % yieldb
1
2
7a
7a
7b
7c
7d
7d
7e
7f
H
H
Boc
Boc
Boc
1
0.5
1
1
1
0.5
0.5
1
0.5
1
4a
4a
4b
4c
4d
4d
4e
4f
84
90
78
85
80
94
58
57
70
77
78
81
73
3
4-F
4
4-OMe Boc
4-Me
4-Me
5
Boc
Boc
6
7
3-OMe Boc
4,6-diF Boc
4,6-diF Boc
8
9
7f
4f
entry substrate
R1
method 7 (% yield) 8 (% yield)
10
11
12
13
7g
7g
7h
7i
H
Et
Et
Bn
Bn
4g
4g
4h
4i
H
0.5
0.5
0.5
1
2
6a
6a
6a
6b
6c
6d
6d
6e
6e
6f
H
H
H
A
B
C
C
A
B
C
B
C
B
C
7a (56)
7a (83)
7a (82)
7b (86)
7c (40)
7d (80)
7d (84)
7e (0)
8a (17)
H
4-Me
3
4
4-F
a Conditions: Pd(PPh3)4 (5%), K2CO3, DME/H2O, reflux, 20 h.
b Isolated purified yield.
5
4-OMe
4-Me
4-Me
3-OMe
3-OMe
4,6-diF
4,6-diF
8c (26)
6
7
8
three different nitrogen substituents (entries 1, 10, and
12). The steric hindrance from the ortho Boc-, alkyl-, or
benzyl-functionalized anilines did not affect product
outcome except for 7e in which the aryl bromide atom is
particularly hindered with two ortho-substituents (entry
7).
9
7e (76)
7f (0)
7f (88)
10
11
6f
a Method A: 1 equiv of Boc2O, 0.1 equiv of DMAP, THF, reflux,
24 h. Method B: 2.5 equiv of Boc2O, THF, reflux, 24 h. Method
C: (i) 2.5 equiv of Boc2O, 0.1 equiv of DMAP, THF, reflux, 24 h;
(ii) CF3COOH, CH2Cl2, rt, 16 h.
Carbolithiation of Substituted o-Vinylanilines.
Prior to testing the scope of the indole synthesis, a survey
of the carbolithiation reaction between three of the
substituted o-vinylanilines 4a,b,h and a number of
organolithium reagents was undertaken to determine
reaction conditions. The organolithium reagents exam-
ined were tert-butyl-, n-butyl-, methyl-, and phenyl-
lithium, which were chosen to test the scope and limi-
tations of this key step in our reaction sequence. Two sets
of conditions were tested which were chosen to reflect
the differing carbolithiation reactivity of each of the
organolithiums. For the more reactive tert-butyl the
reactions were examined with diethyl ether as solvent
at -78 °C (method A), whereas the remainder were
carried out in diethyl ether, with TMEDA additive at -25
°C (method B). Each carbolithiation reaction was quenched
with 2 M HCl, and the products were isolated, purified,
and characterized (Table 3). Carbolithiation of both
styrenes 4a and 4b with t- or n-BuLi gave the expected
products 11a-c in high yields of 80-85% (entries 1-3).
Attempts to add either methyllithium or phenyllithium
to the styrene double bond of 4a led only to recovery of
the starting material and as such were not investigated
further for the indole synthesis (entries 4 and 5).
Indole Synthesis. We next investigated the indole
synthesis using DMF as the electrophile, which in the
reaction sequence provides the unsubstituted C-2 carbon
of the indole ring. For this study, a series of 1,3,4-, and
1,3,5-, and 1,3,5,7-substituted indoles were prepared
(Table 4). The viability of the reaction sequence was
tested using nine different ortho-N-substituted vinyl-
anilines and three alkyllithiums as a representative
sample. In a typical procedure, the organolithium reagent
was added dropwise over 30 min to a solution of styrene
in dry diethyl ether at -78 °C under an inert nitrogen
Synthesis of the N-ethyl- and N-benzyl-substituted
anilines 7g-i was achieved in a one-pot reductive ami-
nation reaction between 6a or 6d and either acetaldehyde
or benzaldehyde in acceptable yields of 62-84% (Scheme
2).15
SCHEME 2. Preparation of the N-Alkylated
o-Bromoanilines
Suzuki-Miyaura cross-coupling of 7a-i with 2,4,6-
trivinylcyclotriboroxane-pyridine complex 10 proved to
be a very efficient and reliable method for the generation
of the styrenes 4a-i in high yields (Table 2). Compound
10 is bench-stable and acts as a vinylboronic acid
equivalent under the reaction conditions.16 The coupling
reactions were successful using either 1.0 or 0.5 molar
equiv of 10, indicating that 10 has the potential to
provide more than one of the vinyl groups for the reaction
(compare entries 1 and 2; 5 and 6; 10 and 11). The
procedure was tolerant to all the aryl electronic substitu-
ent variants attempted (entries 3, 4, 7, and 9) and to the
(15) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
A.; Shah, R. J. Org. Chem. 1996, 61, 3849.
(16) (a) Kerins, F.; O’Shea, D. F. J. Org. Chem. 2002, 67, 4968. (b)
McKinley, N. F.; O’Shea, D. F. J. Org. Chem. 2004, 69, 5087.
7838 J. Org. Chem., Vol. 69, No. 23, 2004

Indoles from Carbolithiation of o-Aminostyrenes
TABLE 3. Carbolithiation of o-Aminostyrenesa
TABLE 5. Deprotection of
N-tert-Butoxycarbonyl-Substituted Indolesa
entry styrene method R1
R2
R3
product % yieldb
entry
substrate
R1
R3
product
% yieldb
1
2
3
4
5
4a
4b
4b
4a
4a
A
A
B
B
B
H
Boc t-Bu
11a
11b
11c
85
81
80
c
1
2
12a
12b
12c
12d
12e
12f
H
H
H
t-Bu
s-Bu
n-Bu
t-Bu
s-Bu
n-Bu
t-Bu
n-Bu
t-Bu
t-Bu
13a
13b
13c
13d
13e
13f
88
83
97
87
70
90
85
65
67
71
4-F Boc t-Bu
4-F Boc n-Bu
3
H
H
Boc Me
Boc Ph
4
5-F
c
5
5-F
a Conditions A: 2.5 equiv of R3Li, -78 °C, Et2O, 1.5 h.
Conditions B: 4.0 equiv of R3Li, 2 equiv of TMEDA, -78 to -25
°C, Et2O, 2.5 h. b Isolated purified yield. c Recovered starting
material.
6
5-F
7
12g
12h
12i
5-OMe
5-OMe
5-Me
4-OMe
13g
13h
13i
8
9
10
12l
13l
atmosphere. The reaction mixture was then stirred for
another 1 h at -78 °C or, in the case of less reactive
primary alkyllithium, the additive TMEDA was included
and the reaction temperature allowed to warm to -25
°C and maintained for 2 h at this temperature. The
electrophile, DMF, was then added at -78 °C, and after
10 min the reaction was acidified with 2 M HCl.
a Conditions: 12 M HCl, EtOAc, 1-12 h. b Isolated purified
yield.
The mild acidification conditions chosen allowed the
retention of the Boc group on the indole nitrogen, which
could be advantageous for further synthetic transforma-
tion of these products (entries 1-13). The N-ethyl- or
benzyl-substituted substrates 4g-i also yielded their
corresponding nitrogen substituted indoles demonstrat-
ing a complementary direct route to N-alkyl- or benzyl-
indoles (entries 14-18). The reaction was tolerant for the
tested series of tert-, sec-, or n-butyl with each of the
alkyllithiums resulting in good yields with few excep-
tions.
TABLE 4. Synthesis of 1,3,4-, 1,3,5-, and
1,3,5,7-Substituted Indolesa
The deprotection of N-Boc-substituted indoles was
readily accomplished by stirring at room temperature
with 12 M HCl in ethyl acetate, generating 13a-i,l in
excellent yields (Table 5). This deprotection methodology
is complementary with our synthetic approach as it can
be employed as part of the reaction acidification following
the carbolithiation/electrophile reaction sequence. If re-
quired, this allows the N-deprotected indole to be directly
isolated simply by changing the acidification conditions.
This avoids an additional synthetic operation with re-
agents such as aluminum chloride,17 boron tri-
fluoride etherate,18 ceric ammonium nitrate,19 or tetra-
butylammonium fluoride.20
To demonstrate this versatile approach, following
carbolithiation of two examples 4a,b and treatment with
electrophile (DMF) the intermediates were directly con-
verted to deprotected indoles 13a,d by changing the
reaction acidification conditions from 2 M HCl to the 12
M HCl. This resulted in the isolation of the deprotected
indoles 13a and 13d in satisfactory yields (Table 6).
A proposed reaction sequence for the indole formation
is as follows: the aniline nitrogen is deprotonated upon
the addition of the first equivalent of organolithium, and
a second equivalent carbolithiates the vinyl double bond
leading to a new benzylic lithiated species. This reacts
with the electrophile DMF to give an aldehyde precursor,
entry substrate
R1
R2
R3
indole % yieldb
1
2
4a
4a
4a
4b
4b
4b
4c
4c
4d
4d
4d
4e
4f
H
H
H
Boc t-Bu
Boc s-Bu
Boc n-Bu
Boc t-Bu
Boc s-Bu
Boc n-Bu
Boc t-Bu
Boc n-Bu
Boc t-Bu
Boc s-Bu
Boc n-Bu
Boc t-Bu
12a
12b
12c
12d
12e
12f
75
62
84
70
43
71
77
80
71
74
59
48
34
67
55
27
86
70
3
4
5-F
5
5-F
6
5-F
7
5-OMe
5-OMe
5-Me
5-Me
5-Me
4-OMe
12g
12h
12i
8
9
10
11
12
13
14
15
16
17
18
12j
12k
12l
5,7-di-F Boc t-Bu
12m
12n
12o
12p
12q
12r
4g
4g
4g
4h
4i
H
Et
Et
Et
Bn
Bn
t-Bu
s-Bu
n-Bu
t-Bu
t-Bu
H
H
H
5-Me
a Conditions: (i) R3Li, -78 °C 1.5 h or -25 °C with TMEDA,
2.5 h, Et2O; (ii) DMF, -78 °C, 10 min; (iii) 2 M HCl, THF, 5 h.
b Isolated purified yield.
The reaction sequence was shown to be successful in
generating the indole ring with a wide distribution of
substituents in the 1, 3, 4, 5, and 7 positions (Table 4).
The reaction sequence was tolerant of varying substitu-
ents (Me, OMe, F) in the meta position to the vinyl group
of the aminostyrene substrates 4b-d with the isolated
yields varying from moderate to excellent (Table 4,
entries 4-11). Substitution of a methoxy group ortho to
the vinyl as in 4e gave the 4-methoxy-substituted indole
12l (entry 12), and the 5,7-difluoro substitution pattern
on the indole 12m was also achieved from the corre-
sponding vinylaniline 4f (entry 13).
(17) Bose, D. S.; Lakshminarayana, V. Synthesis 1999, 66.
(18) Evans, E. F.; Lewis, N. J.; Kapfer, I.; Macdonald, G.; Taylor,
R. J. K. Synth. Commun. 1997, 27, 1819.
(19) Hwu, J. R.; Jain, M. L.; Tsay, S.-C.; Hakimelahi, G. H.
Tetrahedron Lett. 1996, 37, 2035.
(20) Routier, S.; Sauge´, L.; Ayerbe, N.; Coudert, G.; Me´rour, J.-Y.
Tetrahedron Lett. 2002, 43, 589.
J. Org. Chem, Vol. 69, No. 23, 2004 7839

Kessler et al.
TABLE 6. Direct Synthesis of N-Unsubstituted Indolesa
TABLE 7. Synthesis of 2,3,5- and 1,2,3,5-Substituted
Indolesa
entry
substrate
R1
R3
product
% yieldb
1
2
4a
4b
H
5-F
t-Bu
t-Bu
13a
13d
75
68
entry substrate
R1
R2
R3
R4
indole % yield
a Conditions: (i) R3Li, -78 °C, 1.5 h, Et2O; (ii) DMF, -78 °C,
1
2
4a
4a
4a
4a
4b
4b
4c
4c
4h
4i
H
H
H
H
H
H
H
H
H
H
H
H
t-Bu Ph
n-Bu C4H3S
t-Bu t-Bu
15a
15b
15c
65
60
67
44
40
54
57
68
36
51
10 min; (iii) 12 M HCl, EtOAc, 5 h. b Isolated purified yield.
3
4
n-Bu COCH3 15d
which after acidification undergoes a ring closure to a
2-hydroxy-2,3-dihydro-2-hydroxyindole 14, which dehy-
drates to generate the final indole products. Using milder
acidification conditions, one derivative of 14 (R1 ) H, R2
) Boc, R3 ) t-Bu) was isolated and characterized (Figure
2).
5
5-F
t-Bu Ph
n-Bu t-Bu
t-Bu Ph
n-Bu Ph
15e
15f
15g
15h
6
5-F
7
5-OMe
5-OMe
H
8
9
Bn t-Bu COCH3 15i
Bn t-Bu Ph 15j
10
5-Me
a Conditions: (i) R3Li, -78 °C or -25 °C with TMEDA, 1.5 h,
Et2O; (ii) R4CN, -25 °C, 2 h; (iii) 12 M HCl, EtOAc, 16 h.
FIGURE 2. Substituted 2-hydroxy-2,3-dihydroindole inter-
mediates.
FIGURE 3. Isolatable reaction intermediates using nitrile
electrophiles.
The use of DMF as an electrophile precludes the direct
introduction of a substituent at the C-2 of the indole ring.
The inclusion of functionality at this position can be
achieved by a change of the electrophile to a substituted
nitrile. Consequently, we repeated our carbolithiation
methods but treated the lithiated intermediates with a
range of substituted nitriles. The reaction of nitriles is
slower than that of DMF, and an efficient reaction was
achieved by stirring at -25 °C for 2 h. Subsequent
treatment of the reaction mixture with 12 M HCl in ethyl
acetate was successful for the direct generation of the
N-unsubstituted 2,3,5-substituted indoles 15a-h in ac-
ceptable yields (Table 7). Incorporation of an indole
N-benzyl substitutient was achieved for the 1,2,3,5-
substituted derivatives 15i and 15j (entries 9 and 10).
The nitrile electrophile methodology was capable of
introducing a range of C-2 substituents, including phenyl,
thiophene, and sterically bulky tert-butyl groups (entries
1, 2, and 3). It was also successful when using 2,2-
diethoxypropionitrile as an electrophile, which in addition
to going through the complex reaction cascade sequence
also underwent a further in situ deprotection of the acetal
protecting group, thereby generating the 2-keto-substi-
tuted indoles 15d and 15i (entries 4 and 9).
bromides and an organolithium addition-cyclization
methodology provides a new entry into the functionalized
indole ring system. The methodology is diversity tolerant,
facilitating the introduction of aryl, hetroaryl, alkyl, keto,
halo, and ether substituents around the indole scaffold.
The use of organolithiation as the key step for the
assembly of cascade reaction sequences to generate other
heterocyclic systems is currently under investigation.
Experimental Section
All reactions were performed under nitrogen atmosphere.
Solvents were distilled and dried according to standard
procedures. t-BuLi was purchased as 1.7 M in pentane, s-BuLi
1.4 M in cyclohexane, and n-BuLi 2.5 M in hexanes. Exact
concentration of organolithiums were determined by titration
in THF with diphenylacetic acid as an indicator prior to use.
All nitriles used were anhydrous. H (300 MHz) and 13C (75
1
MHz) NMR spectra were recorded in CDCl3 (internal Me4Si)
or DMSO-d6. Column chromatography was carried out on silica
gel 60 (230-400 mesh ASTM). Melting points are uncorrected.
3-(2,2-Dimethylpropyl)indolecarboxylic Acid tert-Bu-
tyl Ester 12a. Compound 4a (0.42 g, 1.91 mmol) was dissolved
in dry diethyl ether (25 mL) and cooled to -78 °C under
nitrogen. t-BuLi (4.5 mL, 1.7 M in pentane, 7.6 mmol) was
added dropwise via syringe over 30 min. The orange-red
solution was stirred for a further 1 h at -78 °C. DMF (1.6
mL, 20 mmol) was added and stirring continued for 10 min.
HCl (2 M, 25 mL) was added and the solution warmed to room
temperature. Diethyl ether was evaporated, THF added (25
mL), and the solution stirred at room temperature for 5 h
under nitrogen. The THF was evaporated, the residue ex-
tracted with diethyl ether (2 × 20 mL) and dried over sodium
sulfate, and the solvent evaporated to give a yellow oil. Flash
chromatography eluting with hexane/diethyl ether (7:3) gave
the product as a colorless oil (0.40 g, 75%). 1H NMR (300 MHz,
CDCl3): δ 0.89 (s, 9H), 1.59 (s, 9H), 2.49 (s, 2H), 7.13-7.15
If milder acidification conditions are employed in the
reaction, the intermediate ketones of type 16 can be
isolated indicating a similar reaction pathway as for the
DMF electrophile examples (Figure 3). Isolation of one
intermediate was carried out for the specific case of R1
) 4-F; R2 ) Boc; R3 ) t-Bu; R4 ) Ph).
Conclusion
The combination of a robust vinylation procedure using
the coupling of a vinyl boronic acid equivalent with aryl
7840 J. Org. Chem., Vol. 69, No. 23, 2004

Indoles from Carbolithiation of o-Aminostyrenes
1
(m, 2H), 7.26 (s, 1H), 7.44 (d, J ) 7.0 Hz, 1H), 8.05 (bs, 1H).
13C NMR (75 MHz, CDCl3): δ 27.2, 28.7, 30.9, 37.6, 82.3, 114.0,
117.6, 118.8, 121.1, 122.8, 123.2, 131.1, 134.1, 148.9. IR (NaCl
plate, neat): 2951, 1729 cm-1. EI-MS: m/z 287.3. HRMS
(M)+: 287.1884, C18H25NO2 requires 287.1885. Anal. Calcd for
C18H25NO2: C, 75.22; H, 8.77; N, 4.87. Found: C, 74.95; H,
9.07; N 4.66.
°C. H NMR (300 MHz, CDCl3): δ 0.96 (s, 9H), 1.66 (s, 9H),
2.51 (s, 2H), 6.95-7.05 (m, 1H), 7.16 (d, J ) 9.2 Hz, 1H), 7.36
(s, 1H), 8.10 (bs, 1H). 13C NMR (75 MHz, CDCl3): δ 27.1, 28.6,
30.9, 37.6, 82.5, 104.3 (d, JCF ) 23.6 Hz), 110.5 (d, JCF ) 25.2
Hz), 114.9 (d, JCF ) 9.2 Hz), 117.3 (d, JCF ) 4.6 Hz), 124.7,
130.5, 132.3 (d, JCF ) 9.9 Hz) 148.6, 156.6 (d, JCF ) 238.8 Hz).
IR (KBr disk): 2966,1732 cm-1. EI-MS: m/z 305.4. HRMS
(M)+: 305.1787, C18H24FNO2 requires 305.1791. Anal. Calcd
for C18H24FNO2: C, 70.79; H, 7.92; F, 6.22; N, 4.59. Found:
C, 70.49; H, 7.94; F, 6.48; N, 4.52. (Note: Compound 11b was
also isolated in 13% yield as a reaction byproduct.)
3-(2-Methylbutyl)indole-1-carboxylic Acid tert-Butyl
Ester 12b. Compound 4a (0.43 g, 1.96 mmol) was dissolved
in dry diethyl ether (25 mL) and cooled to -78 °C under
nitrogen. s-BuLi (10 mL, 0.78 M in cyclohexane, 7.8 mmol)
was added dropwise via syringe over 30 min. The orange-red
solution was stirred for a further 1 h at -78 °C. DMF (1.5
mL, 19 mmol) was added and stirring continued for 10 min.
HCl (2 M, 25 mL) was added and the solution warmed to room
temperature. The diethyl ether was evaporated, THF added
(25 mL), and the solution stirred at room temperature for 5 h
under nitrogen. The THF was evaporated, the residue ex-
tracted with diethyl ether (2 × 20 mL) and dried over sodium
sulfate, and the solvent evaporated to give a yellow oil. Flash
chromatography eluting with hexane/diethyl ether (4:1) gave
the product as a colorless oil (0.32 g, 62%). 1H NMR (300 MHz,
CDCl3): δ 0.90-0.95 (m, 6H), 1.15-1.29 (m, 1H), 1.40-1.54
(m, 1H), 1.66 (s, 9H), 1.71-1.82 (m, 1H), 2.43 (dd, J ) 8.05,
14.3 Hz, 1H), 2.68 (dd, J ) 6.0, 14.3 Hz, 1H), 7.18-7.33 (m,
3H), 7.50 (d, J ) 7.0 Hz, 1H), 8.10 (bs, 1H). 13C NMR (75 MHz,
CDCl3): δ 11.8, 19.7, 28.5, 29.8, 32.5, 35.1, 83.5, 115.4, 119.5,
120.4, 122.4, 123.3, 124.4, 131.5, 136.1, 150.2. IR (NaCl plate,
neat): 2956, 1736 cm-1. EI-MS: m/z 287.2. HRMS: (M + Na)+
310.1780, C18H25NO2Na requires 310.1783. Anal. Calcd for
C18H25NO2: C, 75.22; H, 8.77; N, 4.87. Found: C, 74.97; H,
8.67; N, 4.80.
5-Fluoro-3-(2-methylbutyl)indole-1-carboxylic Acid tert-
Butyl Ester 12e. Compound 4b (0.40 g, 1.69 mmol) was
dissolved in dry diethyl ether (25 mL) and cooled to -78 °C
under nitrogen. s-BuLi (6.2 mL, 1.2 M in cyclohexane, 7.4
mmol) was added dropwise via syringe over 30 min. The
orange solution was stirred for a further 1 h at -78 °C. DMF
(1.5 mL, 20 mmol) was added and stirring continued for 10
min. HCl (2 M, 25 mL) was added, and the solution was
warmed to room temperature. The diethyl ether was evapo-
rated, THF added (25 mL), and the solution stirred at room
temperature for 5 h under nitrogen. The THF was evaporated,
the residue extracted with diethyl ether (3 × 30 mL) and dried
over sodium sulfate, and the solvent evaporated to give a
yellow liquid. Flash chromatography on silica gel eluting with
hexane/diethyl ether (4:1) gave the product as colorless oil (0.24
g, 43%). 1H NMR (300 MHz, CDCl3): δ 0.90-0.96 (m, 6H),
1.14-1.26 (m, 1H), 1.39-1.52 (m, 1H), 1.66 (s, 9H), 1.69-1.87
(m, 1H), 2.40 (dd, J ) 8.05, 14.4 Hz, 1H), 2.64 (dd, J ) 6.1,
14.4 Hz, 1H), 6.97-7.04 (m, 1H), 7.15 (d, J ) 8.9 Hz, 1H), 7.36
(s, 1H), 8.05 (bs, 1H). 13C NMR (75 MHz, CDCl3): δ 11.8, 19.6,
28.4, 29.7, 32.4, 35.1, 83.7, 105.0 (d, JCF ) 23.6 Hz), 111.9 (d,
JCF ) 25.3 Hz), 116.3 (d, JCF ) 9.2 Hz), 120.1 (d, J ) 4.0 Hz),
124.8, 132.0, 132.3 (d, J ) 9.7 Hz), 149.8, 159.3 (d, J ) 238.7
Hz). IR (NaCl plate, neat): 2968, 1741 cm-1. EI-MS: m/z 305.3.
HRMS (M + Na)+: 328.1696, C18H25NO2Na requires 328.1689.
Anal. Calcd for C18H24NO2: C, 70.79; H, 7.92; F, 6.22; N, 4.59.
Found: C, 71.04; H, 7.97; F, 6.62; N, 4.34.
3-Pentylindole-1-carboxylic Acid tert-Butyl Ester 12c.
Compound 4a (0.39 g, 1.77 mmol) and TMEDA (0.5 mL, 3.2
mmol) were dissolved in dry diethyl ether (25 mL) and cooled
to -78 °C under nitrogen. n-BuLi (3.5 mL, 2.0 M in pentane,
7.0 mmol) was added dropwise via syringe over 30 min. The
temperature was warmed to -25 °C with stirring for 2 h
during which time an orange-red color developed. The solution
was cooled to -78 °C, DMF (1.4 mL, 18 mmol) was added, and
stirring was continued for 10 min. HCl (2 M, 25 mL) was added
and the solution warmed to room temperature. The diethyl
ether was evaporated, THF added (20 mL), and the solution
stirred at room temperature for 5 h under nitrogen. The THF
was evaporated, the residue extracted with diethyl ether (4 ×
20 mL) and dried over sodium sulfate, and the solvent
evaporated to give a pale yellow oil. Flash chromatography
eluting with hexane/diethyl ether (4:1) gave the product as a
colorless oil (0.42 g, 84%). 1H NMR (300 MHz, CDCl3): δ 0.95-
1.00 (m, 3H), 1.42-1.47 (m, 4H), 1.72 (s, 9H), 1.74-1.79 (m,
2H), 2.72 (t, J ) 7.8 Hz, 2H), 7.28-7.41 (m, 3H), 7.57 (d, J )
6.8 Hz, 1H), 8.16 (bs, 1H). 13C NMR (75 MHz, CDCl3): δ 14.3,
22.8, 25.2, 28.5, 29.2, 32.0, 83.4, 115.5, 119.3, 121.8, 122.5,
5-Fluoro-3-pentylindole-1-carboxylic Acid tert-Butyl
Ester 12f. Compound 4b (0.41 g, 1.73 mmol) and TMEDA (0.5
mL, 3.2 mmol) were dissolved in dry diethyl ether (20 mL)
and cooled to -78 °C under nitrogen. n-BuLi (3.8 mL, 1.8 M
in pentane, 6.8 mmol) was added dropwise via syringe over
30 min. The temperature was warmed to -25 °C with stirring
for 2 h during which time a red color developed. The solution
was cooled -78 °C, DMF (1.4 mL, 18 mmol) was added, and
stirring was continued for 10 min. HCl (2 M, 25 mL) was added
and the solution warmed to room temperature. The diethyl
ether was evaporated, THF added (25 mL), and the solution
stirred at room temperature for 5 h. The THF was evaporated,
the residue extracted with diethyl ether (3 × 50 mL) and dried
over sodium sulfate, and the solvent evaporated to give a
yellow solid. Flash chromatography eluting with hexane/
diethyl ether (95:5) gave the product as a pale yellow solid
124.1, 124.4, 131.2, 135.9, 150.2. IR (NaCl plate, neat) cm-1
:
2957, 1731. EI-MS: m/z 287.2. HRMS (M)+: 287.1881, C18H25-
NFO2 requires 287.1885. Anal. Calcd for C18H25NFO2: C,
75.22; H, 8.77; N, 4.87. Found C, 75.55; H, 8.98; N, 4.63.
(0.37 g, 71%). Mp: 40-41 °C. H NMR (300 MHz, CDCl3): δ
1
0.89-0.94 (m, 3H), 1.35-1.39 (m, 4H), 1.66 (s, 9H), 1.70-1.73
(m, 2H), 2.60 (t, J ) 7.7 Hz, 2H), 6.97-7.04 (m, 1H), 7.15 (d,
J ) 8.9 Hz, 1H), 7.36 (s, 1H), 8.05 (bs, 1H). 13C NMR (75 MHz,
CDCl3): δ 14.2, 22.7, 25.0, 28.4, 29.0, 31.9, 83.7, 104.9 (d, JCF
) 23.7 Hz), 111.9 (d, JCF ) 25.2 Hz), 116.4 (d, JCF ) 9.2 Hz),
121.5 (d, JCF ) 4.6 Hz), 124.0, 132.1 (d, JCF ) 9.1 Hz), 149.9,
3-(2,2-Dimethylpropyl)-5-fluoroindole-1-carboxylic Acid
tert-Butyl Ester 12d. Compound 4b (0.40 g, 1.69 mmol) was
dissolved in dry diethyl ether (25 mL) and cooled to -78 °C
under nitrogen. t-BuLi (6.7 mL, 1.0 M in pentane, 6.7 mmol)
was added dropwise via syringe over 30 min. The orange-red
solution was stirred for a further 1 h. DMF (1.3 mL, 17 mmol)
was added and stirring continued for 10 min. HCl (2 M, 25
mL) was added and the solution warmed to room temperature.
The diethyl ether was evaporated, THF added (25 mL), and
the solution stirred at room temperature for 5 h under
nitrogen. The THF was evaporated, the residue extracted with
diethyl ether (3 × 30 mL) and dried over sodium sulfate, and
the solvent evaporated to give a yellow solid. Purification by
chromatography eluting with hexane/diethyl ether (95:5) gave
the product as a pale yellow solid (0.36 g, 70%). Mp: 70-71
157.8 (d, JCF ) 239.5 Hz). IR (KBr disk): 2929, 1726 cm-1
.
EI-MS: m/z 305.3. HRMS (M)+: 305.1786, C18H24FNO2 re-
quires 305.1791. Anal. Calcd for C18H24FNO2: C, 70.79; H,
7.92; F, 6.22; N, 4.59. Found: C, 70.74; H, 7.88; F, 6.39; N,
4.60.
3-(2,2-Dimethylpropyl)-5-methoxyindole-1-carboxyl-
ic Acid tert-Butyl Ester 12g. Compound 4c (0.4 g, 1.6 mmol)
was dissolved in dry diethyl ether (25 mL) and cooled to -78
°C under nitrogen. t-BuLi (6.3 mL, 1.0 M in pentane, 6.3 mmol)
was added dropwise via syringe over 30 min. The red solution
was stirred for a further 1 h at -78 °C. DMF (1.3 mL, 17 mmol)
J. Org. Chem, Vol. 69, No. 23, 2004 7841

Kessler et al.
was added and stirring continued for 10 min. HCl (2 M, 25
mL) was added and the solution warmed to room temperature.
The diethyl ether was evaporated, THF added (20 mL), and
the solution stirred at room temperature for 5 h under
nitrogen. The THF was evaporated, the residue extracted with
diethyl ether (3 × 50 mL) and dried over sodium sulfate, and
the solvent evaporated to give a brown oil. Flash chromatog-
raphy eluting with hexane/diethyl ether (95:5) gave the
product as a colorless oil (0.39 g, 77%). 1H NMR (300 MHz,
CDCl3): δ 0.97 (s, 9H), 1.66 (s, 9H), 2.53 (s, 2H), 3.85 (s, 3H),
6.87-6.98 (m, 2H) 7.31 (s, 1H), 8.05 (bs, 1H). 13C NMR (75
MHz, CDCl3): δ 28.5, 29.9, 32.2, 38.9, 55.9, 83.4, 103.2, 112.4,
115.9, 118.6, 125.2, 130.1, 133.2, 150.1, 155.8. IR (NaCl plate,
neat): 2945, 1735 cm-1. EI-MS: m/z 317.2. HRMS (M)+:
317.1993, C19H27NO3 requires 317.1990. Anal. Calcd for C19H27-
NO3: C, 71.89; H, 8.57; N, 4.41. Found C, 72.0; H, 8.57; N,
4.35.
(0.5 mL, 6.4 mmol) was added and stirring continued for 10
min. HCl (2 M, 8.0 mL) was added and the solution warmed
to room temperature. The diethyl ether was evaporated, THF
added (8.0 mL), and the solution stirred at room temperature
for 5 h under nitrogen. The THF was evaporated, the residue
extracted with diethyl ether (2 × 10 mL) and dried over sodium
sulfate, and the solvent evaporated to give a yellow oil. Flash
chromatography eluting with hexane/diethyl ether (4:1) gave
the product as a colorless oil (143 mg, 74%). 1H NMR (300
MHz, CDCl3): δ 0.86-0.96 (m, 6H), 1.14-1.32 (m, 1H), 1.40-
1.52 (m, 1H), 1.66 (s, 9H), 1.70-1.79 (m, 1H), 2.41 (dd, J )
6.0 Hz, 13.3 Hz, 1H), 2.44 (s, 3H), 2.65 (dd, J ) 6.0 Hz, 14.3
Hz, 1H), 7.11 (d, J ) 8.5 Hz, 1H), 7.28 (s, 2H), 7.96 (d, J ) 6.0
Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 11.8, 19.6, 21.6, 28.5,
29.8, 32.5, 35.0, 83.4, 115.1, 119.4, 120.1, 123.3, 125.7, 131.8,
136.0, 160.3. IR (NaCl plates): 2962, 1730 cm-1. EI-MS: m/z
301.3. HRMS (M + H)+: 302.2119, C19H28NO2 requires
302.2120. Anal. Calcd for C19H27NO2: C, 75.71; H, 9.03; N,
4.65. Found: C, 75.71; H, 9.00; N, 4.57.
5-Methoxy-3-pentylindole-1-carboxylic Acid tert-Butyl
Ester 12h. Compound 4c (0.40 g, 1.60 mmol) and TMEDA
(0.5 mL, 3.2 mmol) were dissolved in dry diethyl ether (25 mL)
and cooled to -78 °C under nitrogen. n-BuLi (3.3 mL, 2.0 M
in pentane, 6.6 mmol) was added dropwise via syringe over
30 min. The temperature was warmed to -25 °C with stirring
for 2 h during which time a red color developed. The solution
was cooled to -78 °C, DMF (1.5 mL, 20 mmol) was added, and
stirring was continued for 10 min. HCl (2 M, 25 mL) was added
and the solution warmed to room temperature. The diethyl
ether was evaporated, THF added (25 mL), and the solution
stirred at room temperature under nitrogen for 5 h. The THF
was evaporated, the residue extracted with diethyl ether (2 ×
30 mL) and dried over sodium sulfate, and the solvent
evaporated. Flash chromatography eluting with hexane/diethyl
ether (9:1) to give the product as a white solid (0.40 g, 80%).
Mp: 54-55 °C. 1H NMR (300 MHz, DMSO-d6): δ 0.88 (t, J )
7.0 Hz, 3H), 1.24-1.37 (m, 4H), 1.61 (s, 9H), 1.62-1.68 (m,
2H), 2.62 (t, J ) 7.3 Hz, 2H), 3.80 (s, 3H), 6.93 (dd, J ) 2.5,
8.9 Hz, 1H), 7.06 (d, J ) 2.5 Hz, 1H), 7.38 (s, 1H), 7.90 (d, J
) 8.9 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 14.2, 22.7, 25.1,
28.5, 29.0, 32.0, 56.0, 83.2, 102.3, 112.6, 116.1, 118.6, 125.3,
5-Methyl-3-pentylindole-1-carboxylic Acid tert-Butyl
Ester 12k. Compound 4d (150 mg, 0.64 mmol) and TMEDA
(0.2 mL, 1.3 mmol) were dissolved in dry diethyl ether (8.0
mL) and cooled to -78 °C under nitrogen. n-BuLi (1.4 mL,
1.9 M in pentane, 2.6 mmol) was added dropwise via syringe
over 30 min. The temperature was warmed to -25 °C with
stirring for 2 h during which time an orange color developed.
The solution was cooled to -78 °C, DMF (0.5 mL, 6.4 mmol)
was added, and stirring was continued for 10 min. HCl (2 M,
8.0 mL) was added and the solution warmed to room temper-
ature. The diethyl ether was evaporated, THF added (8.0 mL),
and the solution stirred at room temperature for 5 h under
nitrogen. The THF was evaporated, the residue extracted with
diethyl ether (4 × 10 mL) and dried over sodium sulfate, and
the solvent evaporated to give a pale yellow oil. Flash chro-
matography eluting with hexane/diethyl ether (9:1) gave the
1
product as a colorless oil (114 mg, 59%). H NMR (300 MHz,
CDCl3): δ 0.90 (t, 3H), 1.23-1.41 (m, 6H), 1.65 (s, 9H), 2.44
(s, 3H), 2.63 (t, J ) 7.5 Hz, 2H), 7.11 (d, J ) 8.5 Hz, 1H), 7.29
(s, 2H), 7.96 (d, J ) 7.0 Hz, 1H). 13C NMR (75 MHz, CDCl3):
14.1, 21.4, 22.6, 24.9, 28.3, 29.0, 31.8, 83.1, 114.9, 119.0, 121.3,
122.3, 125.5, 131.1, 131.7, 133.8, 150.0. IR (NaCl plates): 2929,
1730 cm-1. EI-MS: m/z 301.3. HRMS (M + H)+: 302.2121,
C19H28NO2 requires 302.2120. Anal. Calcd for C19H27NO2: C,
75.71; H, 9.03; N, 4.65. Found: C, 75.32; H, 9.13; N, 4.50.
130.1, 133.2, 150.1, 155.9. IR (KBr disk): 2998, 1721 cm-1
.
EI-MS: m/z 317.3. HRMS (M + H)+: 318.2080, C19H28NO3
requires 318.2069. Anal. Calcd for C19H27NO3: C, 71.89; H,
8.57; N, 4.41. Found C, 71.94; H, 8.60; N, 4.33.
5-Methyl-3-(2,2-dimethyl-propyl)-indole-1-carboxylic
acid tert-butyl ester 12i: Compound 4d (150 mg, 0.64 mmol)
was dissolved in dry diethyl ether (8.0 mL) and cooled to -78
°C under nitrogen. t-BuLi (1.0 mL, 1.6M in pentane, 1.6 mmol)
was added dropwise via syringe over 30 min. The red solution
was stirred for a further 1 h at -78 °C. DMF (0.5 mL, 6.4
mmol) was added and stirring continued for 10 min. 2M HCl
(8.0 mL) was added and the solution warmed to room tem-
perature. The diethyl ether was evaporated, THF added (8.0
mL) and the solution stirred at room temperature for 5 h under
nitrogen. The THF was evaporated, the residue extracted with
diethyl ether (2 × 10 mL) and dried over sodium sulfate, and
the solvent evaporated to give a yellow oil. Flash chromatog-
raphy eluting with hexane/diethyl ether (4:1) gave the product
as a colorless oil which crystallize on standing (136 mg, 71%).
4-Methoxy-3-(2,2-dimethylpropyl)indole-1-carboxyl-
ic Acid tert-Butyl Ester 12l. Compound 4e (98 mg, 0.39
mmol) was dissolved in dry diethyl ether (6.2 mL) and cooled
to -78 °C under nitrogen. t-BuLi (0.6 mL, 1.8 M in cyclohex-
ane, 1.0 mmol) was added dropwise via syringe over 30 min.
The orange solution was stirred for a further 1 h at -78 °C.
DMF (0.3 mL, 3.9 mmol) was added and stirring continued
for 10 min. HCl (2 M, 6.2 mL) was added and the solution
warmed to room temperature. The diethyl ether was evapo-
rated, THF added (6.2 mL), and the solution stirred at room
temperature for 5 h under nitrogen. The THF was evaporated,
the residue extracted with diethyl ether (2 × 10 mL) and dried
over sodium sulfate, and the solvent evaporated to give a
yellow oil. Flash chromatography eluting with hexane/diethyl
ether (4:1) gave the product as a colorless oil which crystallize
on standing (60 mg, 48%). Mp: 74-76 °C. 1H NMR (300 MHz,
CDCl3): δ 0.93 (s, 9H), 1.66 (s, 9H), 2.79 (s, 2H), 3.89 (s, 9H),
6.63 (d, J ) 8.0 Hz, 1H), 7.15-7.21 (m, 2H), 7.74 (d, J ) 8.3
Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 28.3, 29.4, 31.9, 38.9,
54.9, 83.3, 103.3, 108.2, 118.6, 121.2, 123.1, 124.6, 136.7, 149.9,
154.5. IR (NaCl plates): 2951, 1734 cm-1. ES+-MS: m/z 318.2.
HRMS (M + H)+: 318.2068, C19H28NO3 requires 318.2069.
Anal. Calcd for C19H27NO3: C, 71.89; H, 8.57; N, 4.41. Found:
C, 71.71; H, 8.62; N, 4.30.
1
Mp: 59-61 °C. H NMR (300 MHz, CDCl3): δ 0.90 (s, 9H),
1.59 (s, 9H), 2.36 (s, 3H), 2.46 (s, 2H), 7.01 (d, J ) 8.5 Hz,
1H), 7.22 (s, 2H), 7.96 (d, J ) 6.0 Hz, 1H). 13C NMR (75 MHz,
CDCl3): δ 21.7, 28.5, 30.0, 32.2, 38.8, 83.4, 114.9, 118.6, 119.9,
124.5, 125.4, 131.8, 132.6, 133.5, 150.1. IR (KBr disk): 2948,
1724 cm-1. EI-MS: m/z 301.3. HRMS (M + H)+: 302.2127,
C19H28NO2 requires 302.2120. Anal. Calcd for C19H27NO2: C,
75.71; H, 9.03; N, 4.65. Found: C, 75.45; H, 8.82; N, 4.75.
5-Methyl-3-(2-methylbutyl)indole-1-carboxylic Acid tert-
Butyl Ester 12j. Compound 4d (150 mg, 0.64 mmol) was
dissolved in dry diethyl ether (8.0 mL) and cooled to -78 °C
under nitrogen. s-BuLi (2.0 mL, 1.3 M in cyclohexane, 2.6
mmol) was added dropwise via syringe over 30 min. The
orange solution was stirred for a further 1 h at -78 °C. DMF
5,7-Difluoro-3-(2,2-dimethylpropyl)indole-1-carbox-
ylic Acid tert-Butyl Ester 12m. Compound 4f (127 mg, 0.5
mmol) was dissolved in dry diethyl ether (6.2 mL) and cooled
to -78 °C under nitrogen. t-BuLi (0.9 mL, 1.4 M in cyclohex-
7842 J. Org. Chem., Vol. 69, No. 23, 2004

Indoles from Carbolithiation of o-Aminostyrenes
ane, 1.2 mmol) was added dropwise via syringe over 15 min.
The orange solution was stirred for a further 1 h at -78 °C.
DMF (0.4 mL, 5.2 mmol) was added and stirring continued
for 10 min. HCl (2 M, 6.2 mL) was added and the solution
warmed to room temperature. The diethyl ether was evapo-
rated, THF added (6.2 mL), and the solution stirred at room
temperature for 60 h under nitrogen. The THF was evapo-
rated, the residue extracted with diethyl ether (2 × 10 mL)
and dried over sodium sulfate, and the solvent evaporated to
give a yellow oil. Flash chromatography eluting with hexane/
diethyl ether (4:1) gave the product as a pale yellow oil (55
mg, 34%). 1H NMR (300 MHz, CDCl3): δ 1.02 (s, 9H), 1.71 (s,
9H), 2.56 (s, 2H), 6.80-6.85 (m, 1H), 7.03 (dd, J ) 2.4, 8.4 Hz,
1H), 7.49 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 28.0, 29.6,
32.0, 38.5, 84.2, 100.4 (dd, JCF ) 26.4, 28.7 Hz), 101.2 (dd, JCF
warmed to -25 °C with stirring for 2 h during which time a
yellow-orange color developed. The solution was cooled to -78
°C, DMF (0.5 mL, 6.4 mmol) was added, and stirring continued
for 10 min. HCl (2 M, 8.5 mL) was added and the solution
warmed to room temperature. The diethyl ether was evapo-
rated, THF added (8.5 mL), and the solution stirred at room
temperature for 5 h under nitrogen. The THF was evaporated,
the residue extracted with diethyl ether (3 × 15 mL) and dried
over sodium sulfate, and the solvent evaporated to give a pale
yellow oil. Flash chromatography eluting with hexane/diethyl
ether (4:1) gave the product as a colorless oil (39 mg, 27%). 1H
NMR (300 MHz, CDCl3): δ 0.88-0.93 (m, 3H), 1.35-1.40 (m,
4H), 1.43 (t, J ) 7.2 Hz, 3H), 1.70 (m, 2H), 2.73 (t, J ) 7.6 Hz,
2H), 4.12 (q, J ) 7.2 Hz, 2H), 6.88 (s, 1H), 7.07 (m, 1H), 7.18
(m, 1H), 7.30 (d, J ) 8.1 Hz), 7.59 (d, J ) 7.9 Hz, 1H). 13C
NMR (75 MHz, CDCl3): δ 14.3, 15.7, 22.8, 25.4, 30.3, 32.2,
40.9, 109.3, 116.0, 118.6, 119.4, 121.4, 124.3, 128.5, 136.2. IR
(NaCl plates): 2926 cm-1. EI-MS: m/z 215.4. HRMS (M +
H)+: 216.1757, C15H22N requires 216.1752.
) 4.2, 23.1 Hz), 118.5 (dd, JCF ) 1.9, 4.6 Hz), 118.6 (d, JCF
)
2.0 Hz), 128.2, 136.4 (dd, JCF ) 4.9, 10.4 Hz), 148.9, 149.5 (dd,
JCF ) 13.5, 255.4 Hz), 158.6 (dd, JCF ) 10.3, 241.0 Hz). IR
(NaCl plates): 1737 cm-1. ES+-MS: m/z 324.0. HRMS (M +
H)+: 324.1773, C18H24FNO2 requires 324.1175.
1-Benzyl-3-(2,2-dimethylpropyl)-1H-indole 12q. Com-
pound 4h (129 mg, 0.61 mmol) was dissolved in dry diethyl
ether (6.2 mL) and cooled to -78 °C under nitrogen. t-BuLi
(1.0 mL, 1.5 M in cyclohexane, 1.5 mmol) was added dropwise
via syringe over 30 min. The orange solution was stirred for a
further 1 h at -78 °C. DMF (0.5 mL, 6.4 mmol) was added
and stirring continued for 10 min. HCl (2 M, 6.2 mL) was
added and the solution warmed to room temperature. The
diethyl ether was evaporated, THF added (6.2 mL), and the
solution stirred at room temperature for 5 h under nitrogen.
The THF was evaporated, the residue extracted with diethyl
ether (3 × 15 mL) and dried over sodium sulfate, and the
solvent evaporated to give a yellow oil. Flash chromatography
eluting with hexane/diethyl ether (9:1) gave the product as a
white solid. Mp: 96-99 °C (148 mg, 86%). 1H NMR (300 MHz,
CDCl3): δ 0.96 (s, 9H), 2.63 (s, 2H), 5.30 (s, 2H), 6.89 (s, 1H),
7.06-7.15 (m, 4H), 7.22-7.37 (m, 4H), 7.61 (d, J ) 7.2 Hz,
1H). 13C NMR (75 MHz, CDCl3): δ 29.8, 32.2, 39.1, 49.8, 109.4,
113.4, 118.8, 119.9, 121.3, 126.7, 127.4, 127.5, 128.8, 129.6,
136.3, 138.2. IR (KBr disk): 2954 cm-1. EI-MS: m/z 277.4.
ES+-MS: m/z 278.4. HRMS (M + H)+: 278.1913, C21H24N
requires 278.1909. Anal. Calcd for C20H23N: C, 86.59; H, 8.36;
N, 5.05. Found: C, 86.37; H, 8.54; N, 4.99.
3-(2,2-Dimethylpropyl)-1-ethyl-1H-indole 12n. Com-
pound 4g (147 mg, 1.00 mmol) was dissolved in dry diethyl
ether (12.5 mL) and cooled to -78 °C under nitrogen. t-BuLi
(1.7 mL, 1.5 M in cyclohexane, 2.5 mmol) was added dropwise
via syringe over 30 min. The orange solution was stirred for a
further 1 h at -78 °C. DMF (0.8 mL, 10.0 mmol) was added
and stirring continued for 10 min. HCl (2 M, 12.5 mL) was
added and the solution warmed to room temperature. The
diethyl ether was evaporated, THF added (12.5 mL), and the
solution stirred at room temperature for 5 h under nitrogen.
The THF was evaporated, the residue extracted with diethyl
ether (3 × 20 mL) and dried over sodium sulfate, and the
solvent evaporated to give a yellow oil. Flash chromatography
eluting with hexane/diethyl ether (9:1) gave the product as a
colorless oil (145 mg, 67%). 1H NMR (300 MHz, CDCl3): δ 0.95
(s, 9H), 1.44 (t, J ) 7.2 Hz, 3H), 2.62 (s, 2H), 4.14 (q, J ) 7.2
Hz, 2H), 6.87 (s, 1H), 7.07 (t, J ) 8.0 Hz, 1H), 7.17 (t, J ) 8.0
Hz, 1H), 7.30 (d, J ) 8.0 Hz, 1H), 7.58 (d, J ) 8.0 Hz, 1H). 13
C
NMR (75 MHz, CDCl3): δ 15.7, 29.9, 32.4, 39.3, 40.9, 109.2,
112.9, 118.6, 120.1, 121.1, 126.4, 129.8, 135.9. IR (NaCl
plates): 2949 cm-1. EI-MS: m/z 215.3. HRMS (M + H)+:
216.1754, C15H22N requires 216.1752. Anal. Calcd for
C15H21N: C, 83.67; H, 9.83; N, 6.50. Found: C, 82.90; H, 9.77;
N, 6.35.
1-Benzyl-3-(2,2-dimethylpropyl)-5-methyl-1H-indole 12r.
Compound 4i (100 mg, 0.45 mmol) was dissolved in dry diethyl
ether (5.6 mL) and cooled to -78 °C under nitrogen. t-BuLi
(0.7 mL, 1.6 M in cyclohexane, 1.1 mmol) was added dropwise
via syringe over 30 min. The orange solution was stirred for a
further 1 h at -78 °C. DMF (0.4 mL, 5.1 mmol) was added
and stirring continued for 10 min. HCl (2 M, 5.6 mL) was
added and the solution warmed to room temperature. The
diethyl ether was evaporated, THF added (5.6 mL), and the
solution stirred at room temperature for 5 h under nitrogen.
The THF was evaporated, the residue extracted with diethyl
ether (3 × 10 mL) and dried over sodium sulfate, and the
solvent evaporated to give a yellow oil. Flash chromatography
eluting with hexane/diethyl ether (9:1) gave the product as a
1-Ethyl-3-(2-methylbutyl)-1H-indole 12o. Compound 4g
(100 mg, 0.68 mmol) was dissolved in dry diethyl ether (8.5
mL) and cooled to -78 °C under nitrogen. s-BuLi (1.4 mL, 1.2
M in cyclohexane, 1.7 mmol) was added dropwise via syringe
over 30 min. The orange solution was stirred for a further 1 h
at -78 °C. DMF (0.5 mL, 6.4 mmol) was added and stirring
continued for 10 min. HCl (2 M, 8.5 mL) was added and the
solution warmed to room temperature. The diethyl ether was
evaporated, THF added (8.5 mL), and the solution stirred at
room temperature for 5 h under nitrogen. The THF was
evaporated, the residue extracted with diethyl ether (3 × 15
mL) and dried over sodium sulfate, and the solvent evaporated
to give a yellow oil. Flash chromatography eluting with hexane/
diethyl ether (9:1) gave the product as a colorless oil (80 mg,
55%). 1H NMR (300 MHz, CDCl3): δ 0.86-0.95 (m, 6H), 1.14-
1.32 (m, 1H), 1.40-1.54 (m, 1H), 1.43 (t, J ) 7.1 Hz, 3H), 1.67-
1.79 (m, 1H), 2.51 (dd, J ) 7.7, 14.2 Hz, 1H), 2.75 (dd, J )
6.1, 14.2 Hz, 1H), 4.12 (q, J ) 7.1 Hz, 2H), 6.86 (s, 1H), 7.07
(m, 1H), 7.18 (m, 1H), 7.30 (d, J ) 8.2 Hz, 1H), 7.58 (d, J )
7.9 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 11.9, 15.7, 19.7,
29.7, 32.7, 36.0, 40.9, 109.3, 114.6, 118.6, 119.6, 121.3, 125.2,
128.8, 136.2. IR (NaCl plates): 2959 cm-1. EI-MS: m/z 215.4.
HRMS (M + H)+: 216.1762, C15H22N requires 216.1752.
1
pale yellow oil (90 mg, 70%). H NMR (300 MHz, CDCl3): δ
0.96 (s, 9H), 2.44 (s, 3H), 2.60 (s, 2H), 5.26 (s, 2H), 6.85 (s,
1H), 6.95 (d, J ) 8.4 Hz, 1H), 7.05-7.12 (m, 3H), 7.20-7.30
(m, 3H), 7.38 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 21.6, 29.8,
32.1, 39.1, 49.9, 109.1, 112.8, 119.6, 122.9, 126.6, 127.4, 127.5,
127.9, 128.7, 129.8, 134.7, 138.1. IR (NaCl plates): 2948 cm-1
.
EI-MS: m/z 291.5. ES+-MS: 291.9. HRMS (M + H)+: 292.2065,
C21H26N requires 292.2065. Anal. Calcd for C21H25N: C, 86.55;
H, 8.65; N, 4.81. Found: C, 86.09; H, 8.53; N, 4.59.
3-(2,2-Dimethylpropyl)-2-phenyl-1H-indole 15a. Com-
pound 4a (0.50 g, 2.3 mmol) was dissolved in diethyl ether
(25 mL) and cooled to -78 °C under nitrogen. t-BuLi (6.3 mL,
1.44 M in hexane, 9.12 mmol) was added dropwise via syringe
over 30 min. The orange-red solution was stirred for a further
1 h at -78 °C. Benzonitrile (2.3 mL, 23 mmol) was added and
the solution warmed to -25 °C with stirring continued for 2
1-Ethyl-3-pentyl-1H-indole 12p. Compound 4g (100 mg,
0.68 mmol) and TMEDA (0.2 mL, 1.3 mmol) were dissolved in
dry diethyl ether (8.5 mL) and cooled to -78 °C under nitrogen.
n-BuLi (1.3 mL, 2.1 M in pentane, 2.7 mmol) was added
dropwise via syringe over 30 min. The temperature was
J. Org. Chem, Vol. 69, No. 23, 2004 7843

Kessler et al.
h. The reaction was cooled to -78 °C, 2 M HCl (25 mL) added,
and the solution warmed to room temperature. The reaction
mixture was extracted with ethyl acetate (3 × 30 mL), the
organic layer dried over sodium sulfate, and the solvent
evaporated. The residue was dissolved in a solution of ethyl
acetate (8.4 mL)/12 M HCl (3.6 mL) and stirred at room
temperature for 16 h under nitrogen. The reaction mixture
was extracted with ethyl acetate (3 × 20 mL), washed with
sodium hydrogen carbonate (1 M, 2 × 50 mL), and dried over
sodium sulfate and the solvent evaporated. Flash chromatog-
raphy on silica eluting with a gradient of hexane/diethyl ether
(9:1 to 3:7) gave the product as a white solid (0.39 g, 65%).
Mp: 94-95 °C. 1H NMR (300 MHz, CDCl3): δ 0.74 (s, 9H),
2.86 (s, 2H), 7.07-7.17 (m, 2H), 7.24-7.33 (m, 2H), 7.37-7.42
(m, 2H), 7.48-7.52 (m, 2H), 7.60-7.65 (m, 1H), 7.83 (bs, 1H).
13C NMR (75 MHz, CDCl3): δ 30.3, 34.5, 37.6, 110.9, 111.6,
119.6, 120.6, 122.1, 127.8, 129.0, 129.1, 130.8, 135.1, 135.9,
136.2. IR (KBr disk): 3396 cm-1. EI-MS: m/z 263.3. HRMS
(M)+: 263.1670, C19H21N requires 263.1673. Anal. Calcd for
C19H21N: C, 86.65; H, 8.04; N, 5.32. Found C, 86.36; H, 8.14;
N, 5.27.
(m, 2H), 7.08-7.10 (m, 1H), 7.46-7.50 (m, 1H), 7.83 (bs, 1H).
13C NMR (75 MHz, CDCl3): δ 31.5, 31.8, 33.6, 34.1, 37.7, 109.2,
109.9, 118.6, 120.7, 121.1, 130.9, 134.8, 142.6. IR (KBr disk):
3147, 2960 cm-1. EI-MS: m/z 243.2. HRMS (M)+: 243.1982,
C17H25N requires 243.1986. Anal. Calcd for C17H25N: C, 83.89;
H, 10.35; N, 5.75. Found: C, 83.51; H, 10.15; N, 5.42. (Note:
2,3-dialkylsubstituted indoles are prone to oxidative ring
opening of the five-membered ring in the presence of air.)
1-(3-Pentyl-1H-indol-2-yl)ethanone 15d. Compound 4a
(0.40 g, 1.8 mmol) and TMEDA (0.5 mL, 3.3 mmol) were
dissolved in dry diethyl ether (25 mL) and cooled to -78 °C
under nitrogen. n-BuLi (3.7 mL, 2.0 M in pentane, 7.4 mmol)
was added dropwise over 30 min. The temperature was
warmed to -25 °C with stirring for 2 h during which time an
orange-red color developed. The mixture was cooled to -78
°C, 2,2-diethoxypropionitrile (2.8 mL, 18 mmol) added, the
temperature raised to -25 °C, and stirring continued for 2 h.
The reaction was cooled to -78 °C, saturated NH4Cl (25 mL)
added, and the solution warmed to room temperature for 1 h.
The reaction mixture was extracted with ethyl acetate (3 ×
10 mL), the organic layer dried over sodium sulfate, and the
solvent evaporated. The residue was dissolved in a solution of
ethyl acetate (8.4 mL)/12 M HCl (3.6 mL) and stirred at room
temperature for 16 h under nitrogen. The reaction mixture
was extracted with ethyl acetate (3 × 20 mL), washed with
sodium hydrogen carbonate (1 M, 2 × 50 mL), and dried over
sodium sulfate and the solvent evaporated. Flash chromatog-
raphy eluting with hexane/diethyl ether (2:1) gave the product
as a white solid (0.182 g, 44%). Mp: 77-78 °C. 1H NMR (300
MHz, CDCl3): δ 0.9 (t, J ) 7.1 Hz, 3H), 1.25-1.47 (m, 4H),
1.66-1.76 (m, 2H), 2.65 (s, 3H), 3.09 (t, J ) 8.0 Hz, 2H), 7.10-
7.15 (m, 1H), 7.30-7.37 (m, 2H), 7.70 (d, J ) 8.1 Hz, 1H), 8.91
(bs, 1H). 13C NMR (75 MHz, CDCl3): δ 14.2, 22.7, 25.7, 28.5,
31.7, 32.3, 112.0, 120.2, 121.6, 124.5, 126.6, 129.1, 132.2, 136.3,
190.6. IR (KBr disk): 3332, 2951, 1637 cm-1. EI-MS: m/z
229.3. HRMS (M)+: 229.1465, C15H19NO requires 229.1466.
Anal. Calcd for C15H19NO: C, 78.56; H, 8.35; N, 6.11. Found:
C, 78.44; H, 8.35; N, 6.10.
3-Pentyl-2-thiophene-2-yl-1H-indole 15b. Compound 4a
(0.40 g, 1.8 mmol) and TMEDA (0.54 mL, 3.6 mmol) were
dissolved in dry diethyl ether (25 mL) and cooled to -78 °C
under nitrogen. n-BuLi (3.1 mL, 2.35 M in hexane, 7.2 mmol)
was added dropwise via syringe over 30 min. The temperature
was warmed to -25 °C with stirring for 2 h during which time
a red-orange solution developed. The mixture was cooled to
-78 °C, 2-thiophenecarbonitrile (1.68 mL, 18.0 mmol) added,
the temperature raised to -25 °C, and stirring continued for
2 h. The solution developed a deep red-brown color and a black
solid precipitated. The reaction was cooled to -78 °C, 2 M HCl
(25 mL) added, and the solution warmed to room temperature.
The solution was filtered to remove the black solid, the filtrate
extracted with ethyl acetate (3 × 30 mL), the organic layer
dried over sodium sulfate, and the solvent evaporated. The
residue was dissolved in a solution of ethyl acetate (8.4 mL)/
12 M HCl (3.6 mL) and stirred at room temperature for 16 h
under nitrogen. The reaction mixture was extracted with ethyl
acetate (3 × 20 mL), washed with sodium hydrogen carbonate
(1 M, 2 × 50 mL), and dried over sodium sulfate and the
solvent evaporated. Flash chromatography eluting with a
gradient of hexane/diethyl ether (9:1 to 7:3) gave the product
3-(2,2-Dimethylpropyl)-5-fluoro-2-phenyl-1H-indole 15e.
Compound 4b (0.42 g, 1.8 mmol) was dissolved in dry diethyl
ether (25 mL) and cooled to -78 °C under nitrogen. t-BuLi
(6.4 mL, 1.1 M in hexane, 7.0 mmol) was added dropwise via
syringe over 30 min. The orange-red solution was stirred for
a further 1 h at -78 °C. Benzonitrile (1.8 mL, 18 mmol) was
added and the solution warmed to -25 °C with stirring
continued for 2 h. The reaction was cooled to -78 °C, 2 M HCl
(25 mL) added, and the solution warmed to room temperature.
The reaction mixture was extracted with ethyl acetate (3 ×
30 mL), the organic layer dried over sodium sulfate, and the
solvent evaporated. The residue was dissolved in a solution of
ethyl acetate (8.4 mL)/12 M HCl (3.6 mL) and stirred at room
temperature for 16 h under nitrogen. The reaction mixture
was extracted with ethyl acetate (3 × 20 mL), washed with
sodium hydrogen carbonate (1 M, 2 × 50 mL), and dried over
sodium sulfate and the solvent evaporated. Flash chromatog-
raphy on silica eluting with hexane/ethyl acetate (19:1) gave
the product as a pale yellow solid (0.2 g, 40%). Mp: 100-101
°C. 1H NMR (300 MHz, CDCl3): δ 0.73 (s, 9H), 2.8 (s, 2H),
6.86-6.92 (m, 1H), 7.18-7.36 (m, 2H), 7.39-7.52 (m, 5H), 7.9
(bs, 1H). 13C NMR (75 MHz, CDCl3): δ 30.1, 34.4, 37.6, 105.3
1
as a yellow oil (0.29 g, 60%). H NMR (300 MHz, CDCl3): δ
0.88 (t, J ) 7.1 Hz, 3H), 1.31-1.44 (m, 4H), 1.54-1.75 (m, 2H),
2.92 (t, J ) 7.8 Hz, 2H), 7.07-7.17 (m, 4H), 7.18-7.31 (m, 2H),
7.59 (m, 1H), 7.95 (bs, 1H). 13C NMR (75 MHz, CDCl3): δ 14.4,
22.9, 25.1, 30.7, 32.4, 110.9, 115.4, 119.5, 119.9, 122.9, 124.4,
125.2, 127.8, 128.2, 129.6, 135.4, 136.2. IR (NaCl plate, neat):
3055, 2987 cm-1. EI-MS: m/z 269.2. HRMS (M)+: 269.1223,
C17H19NS requires 269.1238.
2-tert-Butyl-3-(2,2-dimethylpropyl)-1H-indole 15c. Com-
pound 4a (0.40 g, 1.8 mmol) was dissolved in dry diethyl ether
(25 mL) and cooled to -78 °C under nitrogen. t-BuLi (5.8 mL,
1.3 M in pentane, 7.5 mmol) was added dropwise via syringe
over 30 min. The orange-red solution was stirred for a further
1 h at -78 °C. Trimethylacetonitrile (2 mL, 18 mmol) was
added and the solution warmed to -25 °C with stirring
continued for 2 h. The reaction was cooled to -78 °C, 2 M HCl
(25 mL) added, and the solution warmed to room temperature.
The reaction mixture was extracted with ethyl acetate (3 ×
30 mL), the organic layer dried over sodium sulfate, and the
solvent evaporated. The residue was dissolved in a solution of
solution of ethyl acetate (8.4 mL)/12 M HCl (3.6 mL) and
stirred at room temperature for 16 h under nitrogen. The
reaction mixture was extracted with ethyl acetate (3 × 20 mL),
washed with sodium hydrogen carbonate (1 M, 2 × 50 mL),
and dried over sodium sulfate and the solvent evaporated.
Flash chromatography on silica eluting with a gradient of
hexane/diethyl ether (95:5 to 1:1) gave the product as a white
solid (0.29 g, 67%). Mp: 61-62 °C. 1H NMR (300 MHz,
CDCl3): δ 0.92 (s, 9H), 1.34 (s, 9H), 2.87 (s, 2H), 6.92-6.99
(d, JCF ) 23.6 Hz), 110.2, (d, JCF ) 25.9 Hz), 111.4 (d, JCF
)
9.9 Hz), 111.8 (d, JCF ) 4.5 Hz), 128.0, 128.9, 129.0, 131.2 (d,
JCF ) 9.9 Hz), 132.3, 134.6, 138.0, 158.1 (d, JCF ) 233.4 Hz).
IR (KBr disk): 3429, 2960 cm-1. EI-MS: m/z 281.3. HRMS
(M)+: 281.1577, C19H20FN requires 281.1579. Anal. Calcd for
C19H20FN: C, 81.11; H, 7.16; F, 6.75; N, 4.98. Found: C, 81.0;
H, 7.45; F, 6.48; N, 4.90. (Note: Compound 11b was also
isolated in 10% yield as a reaction byproduct.)
2-tert-Butyl-5-fluoro-3-pentyl-1H-indole 15f. Compound
4b (0.50 g, 2.1 mmol) and TMEDA (0.6 mL, 4.2 mmol) were
dissolved in dry diethyl ether (30 mL) and cooled to -78 °C
under nitrogen. n-BuLi (3.6 mL, 2.3 M in hexane, 8.3 mmol)
7844 J. Org. Chem., Vol. 69, No. 23, 2004

Indoles from Carbolithiation of o-Aminostyrenes
was added dropwise via syringe over 30 min. The temperature
was warmed to -25 °C with stirring for 2 h during which time
an orange-red color developed. The mixture was cooled to -78
°C, trimethylacetonitrile (2.3 mL, 21 mmol) added, the tem-
perature raised to -25 °C, and stirring continued for 2 h. The
reaction was cooled to -78 °C, 2 M HCl (25 mL) added, and
the solution warmed to room temperature. The reaction
mixture was extracted with ethyl acetate (3 × 30 mL) and
dried, the organic layer dried over sodium sulfate, and the
solvent evaporated. The residue was dissolved in a solution of
ethyl acetate (8.4 mL)/12 M HCl (3.6 mL) and stirred at room
temperature for 16 h under nitrogen. The reaction mixture
was extracted with ethyl acetate (3 × 20 mL), washed with
sodium hydrogen carbonate (1 M, 2 × 50 mL), and dried over
sodium sulfate and the solvent evaporated. Flash chromatog-
raphy on silica eluting with hexane/diethyl ether (4:1) gave
the product as a colorless oil (0.29 g, 54%). 1H NMR (300 MHz,
CDCl3): δ 0.92 (t, J ) 7.0 Hz, 3H), 1.37-1.43 (m, 4H), 1.44 (s,
9H), 1.57-1.67 (m, 2H), 2.77 (t, J ) 8.0 Hz, 2H), 6.79-6.86
(m, 1H), 7.10-7.22 (m, 2H), 7.67 (bs, 1H). 13C NMR (75 MHz,
CDCl3): δ 14.3, 22.8, 25.8, 30.7, 31.3, 32.7, 33.2, 103.3 (d, JCF
) 23.6 Hz), 109.1 (d, JCF ) 25.9 Hz), 111.0 (d, JCF ) 9.8 Hz),
111.9 (d, JCF ) 4.5 Hz), 130.6 (d, JCF ) 9.9 Hz), 143.2, 143.5,
158.3 (d, JCF ) 233.2 Hz). IR (NaCl plate, neat): 3477, 2958
cm-1. EI-MS m/z: 261.3. HRMS (M + H)+: 262.1927, C17H25-
FN requires 262.1971. (Note: 2,3-dialkyl-substituted indoles
are prone to oxidative ring opening of the five-membered ring
in the presence of air.)
3-(2,2-Dimethylpropyl)-5-methoxy-2-phenyl-1H-in-
dole 15g. Compound 4c (0.5 g, 2.0 mmol) was dissolved in
dry diethyl ether (30 mL) and cooled to -78 °C under nitrogen.
t-BuLi (7.2 mL, 1.2 M in pentane, 8.6 mmol) was added
dropwise via syringe over 30 min. The orange-red solution was
stirred for a further 1 h at -78 °C. Benzonitrile (2 mL, 20
mmol) was added and the solution warmed to -25 °C with
stirring continued for 2 h. The reaction was cooled to -78 °C,
2 M HCl (25 mL) added, and the solution warmed to room
temperature. The reaction mixture was extracted with ethyl
acetate (3 × 30 mL), the organic layer dried over sodium
sulfate, and the solvent evaporated. The residue was dissolved
in a solution of ethyl acetate (8.4 mL)/12 M HCl (3.6 mL) and
stirred at room temperature for 16 h under nitrogen. The
reaction mixture was washed with sodium hydrogen carbonate
(1 M, 2 × 50 mL), extracted with ethyl acetate (3 × 20 mL),
and dried over sodium sulfate and the solvent evaporated.
Flash chromatography on silica eluting with hexane/diethyl
ether (4:1) gave the product as a yellow solid (0.33 g, 57%).
Mp: 116-117 °C. 1H NMR (300 MHz, CDCl3): δ 0.75 (s, 9H),
2.85 (s, 2H), 3.87 (s, 3H), 6.85 (d, J ) 8.6 Hz, 1H), 7.07 (d, J
) 2.3 Hz, 1H), 7.22 (d, J ) 8.2 Hz, 1H), 7.33-7.36 (1H, m),
7.40-7.45 (m, 2H), 7.54 (m, 2H), 7.88 (bs, 1H). 13C NMR (75
MHz, CDCl3): δ 30.2, 34.3, 37.5, 56.2, 102.7, 111.4, 111.5,
112.0, 127.7, 128.8, 128.9, 131.1, 131.2, 135.8, 137.8, 154.0.
IR (KBr disk): 3424, 2954 cm-1. EI-MS m/z: 293.4. HRMS:
(M + H)+ 294.1851, C20H24NO requires 294.1858. Anal. Calcd
for C20H23NO: 81.87; H, 7.90; N, 4.77. Found: C, 81.48; H,
7.89; N, 4.62.
reaction mixture was extracted with ethyl acetate (3 × 20 mL),
washed with sodium hydrogen carbonate (1 M, 2 × 50 mL),
and dried over sodium sulfate and the solvent evaporated.
Flash chromatography on silica eluting with hexane/diethyl
ether (4:1) gave the product as a white solid (0.32 g, 68%).
Mp: 65-66 °C. 1H NMR (300 MHz, CDCl3): δ 0.88 (t, J ) 7.3
Hz, 3H), 1.30-1.41 (m, 4H), 1.66-1.74 (m, 2H), 2.83 (t, J )
8.0 Hz, 2H), 3.89 (s, 3H), 6.86 (dd, J ) 2.4, 8.8 Hz, 1H), 7.07
(d, J ) 2.4 Hz, 1H), 7.24-7.56 (m, 6H,), 7.85 (bs, 1H). 13C NMR
(75 MHz, DMSO-d6): δ 14.6, 22.6, 24.7, 30.8, 32.1, 56.1, 101.1,
112.1, 112.5, 112.7, 127.7, 128.2, 129.3, 129.7, 131.9, 134.0,
135.2, 153.8. IR (KBr disk): 3383, 2957 cm-1. EI-MS: m/z
293.3. HRMS (M)+: 293.1773, C20H23NO requires 293.1779.
1-Benzyl-3-(2,2-dimethylpropyl)-2-acetyl-1H-indole 15i.
Compound 4h (67 mg, 0.32 mmol) was dissolved in dry diethyl
ether (4.0 mL) and cooled to -78 °C under nitrogen. t-BuLi
(0.5 mL, 1.7 M in hexanes, 0.8 mmol) was added dropwise over
30 min. The yellow-orange solution was stirred for a further
1 h at -78 °C. 2,2-Ethoxypropionitrile (0.5 mL, 3.2 mmol) was
added, the temperature raised to -25 °C, and stirring contin-
ued for 2 h. The reaction mixture was cooled to -78 °C, 2 M
HCl (4.0 mL) added, and the solution warmed to room
temperature. The reaction mixture was extracted with ethyl
acetate (3 × 10 mL), the organic layer dried over sodium
sulfate, and the solvent evaporated. The residue was dissolved
in a solution of ethyl acetate (1.4 mL)/12 M HCl (0.6 mL) and
stirred at room temperature for 16 h under nitrogen. The
reaction mixture was extracted with ethyl acetate (3 × 10 mL),
washed with 1 M sodium hydrogen carbonate (2 × 20 mL),
and dried over sodium sulfate and the solvent evaporated.
Flash chromatography eluting with cyclohexane/diethyl ether
(9:1) gave the product as a yellow oil, (37 mg, 36%). Mp: 78-
80 °C. 1H NMR (300 MHz, CDCl3): δ 0.94 (s, 9H), 2.51 (s, 3H),
3.03 (s, 2H), 5.60 (s, 2H), 6.91-6.94 (m, 2H), 7.10-7.33 (m,
6H), 7.69-7.72 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 30.1,
31.1, 33.9, 38.3, 47.9, 110.5, 120.0, 120.2, 122.1, 125.2, 126.2,
127.1, 128.3, 128.5, 138.2, 138.5, 195.5. IR (KBr disk): 2963,
1660 cm-1. ES+-MS: m/z 320. HRMS (M + H)+: 320.2022,
C22H26NO requires 320.2014.
1-Benzyl-3-(2,2-dimethylpropyl)-5-methyl-2-phenyl-1H-
indole 15j. Compound 4i (85 mg, 0.38 mmol) was dissolved
in dry diethyl ether (4.1 mL) and cooled to -78 °C under
nitrogen. t-BuLi (0.6 mL, 1.7 M in hexanes, 1.0 mmol) was
added dropwise over 30 min. The yellow-orange solution was
stirred for a further 1 h at -78 °C. Benzonitrile (0.4 mL, 4.0
mmol) was added, the temperature raised to -25 °C, and
stirring continued for 2 h. The reaction mixture was cooled to
-78 °C, 2 M HCl (4.1 mL) added, and the solution warmed to
room temperature. The reaction mixture was extracted with
ethyl acetate (3 × 10 mL), the organic layer dried over sodium
sulfate, and the solvent evaporated. The residue was dissolved
in a solution of ethyl acetate (1.4 mL)/12 M HCl (0.6 mL) and
stirred at room temperature for 16 h. The reaction mixture
was extracted with ethyl acetate (3 × 10 mL), washed with 1
M sodium hydrogen carbonate (2 × 10 mL), and dried over
sodium sulfate and the solvent evaporated. Flash chromatog-
raphy eluting with cyclohexane/diethyl ether (9:1) gave the
product as a yellow oil (71 mg, 51%). 1H NMR (300 MHz,
DMSO-d6): δ 0.67 (s, 9H), 2.38 (s, 3H), 2.67 (s, 2H), 5.24 (s,
2H), 6.76 (m, Hz, 2H), 6.91 (m, 1H), 7.14-7.20 (m, 4H), 7.33-
7.45 (m, 6H). 13C NMR (75 MHz, CDCl3): δ 30.2, 33.8, 37.8,
47.4, 109.7, 111.3, 120.1, 123.0, 126.0, 129.9, 127.8, 128.3,
128.4, 128.5, 129.7, 131.2, 133.1, 134.8, 138.7, 139.5. IR (NaCl
plates): 2948 cm-1. ES+-MS: m/z 368.2. HRMS (M + H)+:
368.2387, C27H30N requires 368.2378.
5-Methoxy-3-pentyl-2-phenyl-1H-indole 15h. Compound
4c (0.4 g, 1.6 mmol) and TMEDA (0.5 mL, 3.3 mmol) were
dissolved in dry diethyl ether (25 mL) and cooled to -78 °C
under nitrogen. n-BuLi (4.4 mL, 1.5 M, 6.6 mmol) was added
dropwise via syringe over 30 min. The red solution was stirred
for a further 1 h at -78 °C. Anhydrous benzonitrile (1.6 mL,
16 mmol) was added and the solution warmed to -25 °C with
stirring continued for 2 h. The reaction was cooled to -78 °C,
2 M HCl (25 mL) added, and the solution warmed to room
temperature. The reaction mixture was extracted with ethyl
acetate (3 × 30 mL), the organic layer dried over sodium
sulfate, and the solvent evaporated. The residue was dissolved
in a solution of ethyl acetate (8.4 mL)/12 M HCl (3.6 mL) and
stirred at room temperature for 16 h under nitrogen. The
Acknowledgment. This work was supported in part
by Enterprise Ireland and the Centre for Synthesis and
Chemical Biology, UCD. We thank D. Rai of the CSCB
Mass Spectrometry Centre for analysis.
J. Org. Chem, Vol. 69, No. 23, 2004 7845

Kessler et al.
12a-r, and 15a-j. This material is available free of charge
Supporting Information Available: Literature refer-
ences for known compounds. Experimental procedures and
characterization data for 4c-i, 7a-i, 11a-c, 13a-i, 13l, 14,
and 16. 1H and 13C NMR spectra for new compounds 4d-i,
via the Internet at http://pubs.acs.org.
JO048723E
7846 J. Org. Chem., Vol. 69, No. 23, 2004