A novel indole synthesis via conjugate addition of pyrrolidine to o-nitrophenylacetylenes

Article abstract of DOI:10.3987/com-06-s(k)52

A novel indole synthesis reaction by conjugate addition of pyrrolidine to o-nitrophenylacetylenes and subsequent reductive cyclization of o-nitroarylenamines was developed.

Full text of DOI:10.3987/com-06-s(k)52

HETEROCYCLES, Vol. 72, 2007
191
HETEROCYCLES, Vol. 72, 2007, pp. 191 - 197. © The Japan Institute of Heterocyclic Chemistry
Received, 26th December, 2006, Accepted, 1st February, 2007, Published online, 6th February, 2007. COM-06-S(K)52
A NOVEL INDOLE SYNTHESIS VIA CONJUGATE ADDITION OF
PYRROLIDINE TO O-NITROPHENYLACETYLENES†
Hidetoshi Tokuyama,a,b Takaki Makido,a Yuki Han-ya, a and Tohru
Fukuyama*a
aGraduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo,
b
Bunkyo-ku, Tokyo 113-0033, Japan. Graduate School of Pharmaceutical
Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan
E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Abstract – A novel indole synthesis reaction by conjugate addition of pyrrolidine
to o-nitrophenylacetylenes and subsequent reductive cyclization of
o-nitroarylenamines was developed.
The indole skeleton is commonly found in many natural products, and many of them possess significant
biological activities. Therefore, the development of methodologies for indole synthesis has long been a
subject of active research in synthetic organic chemistry.1 While a number of methods have already been
well established, there appear to be few practical procedures available. Among them, the
Leimgruber-Batcho indole synthesis, involving the formation of o-nitrophenyl enamines by heating a
mixture of o-nitrotoluenes and dimethylformamide dimethyl acetal and subsequent reductive cyclization
(Scheme 1), has enjoyed widespread use from laboratory to industry owing to the demonstrated generality
and the high functional group compatibility.2,3 While this protocol is particularly useful for the synthesis
of indoles having substituents on the carbocyclic ring, it is difficult to apply this procedure to the direct
construction of indoles bearing substituents at the 2- and/or 3-positions.4
Me
MeO OMe
CH3
NO2
N
H2, Pd/C
Me2N CH3
Me
R
R
R
DMF
heat
N
H
NO2
Scheme 1 Leimgruber-Batcho indole synthesis.
†This paper is dedicated to Professor Yoshito Kishi on the occasion of his 70th birthday.

192
HETEROCYCLES, Vol. 72, 2007
In the course of our synthetic studies on the antitumor antibiotic FR900482 (1), we have established a
unique transformation of o-nitroarylacetylene (2) to the corresponding ketone (3) (Scheme 2).5 The
unprecedented regioselective addition of pyrrolidine to o-nitroarylacetylene6 (2) gave exclusively the
enamine 4, which was converted to ketone (3) upon acidic hydrolysis. Considering the formation of
enamine intermediate in the Leimgruber-Batcho protocol (Scheme 1), we envisioned that reduction of the
nitro group of the resultant enamines would promote cyclization to give 2-substituted indoles (Scheme 3).
With this idea in mind, we investigated the generality of this conjugate addition reaction and its
application to indole synthesis. Herein we report a novel and efficient synthesis of 2-substituted indoles
via the conjugate addition of secondary amines to o-nitrophenylacetylenes followed by reductive
cyclization.
OCONH2
OH
OH
O
NH
OHC
N
FR-900482 (1)
O
pyrrolidine
benzene
rt, 1 h;
O
N
BnO
O
BnO
BnO
O
O
O
O
OTBS
aq AcOH
rt, 4 h
MeO2C
NO2
MeO2C
NO2
MeO2C
NO2
OTBS
OTBS
2
3
90%
4
Scheme 2 A key transformation in the total synthesis of FR-900482 (1).
R
R'
N
R
R'2N
H3O+
[H]
R'
O
NO2
R
NO2
N
H
R
NO2
[H]
Scheme 3 Proposed indole synthesis via conjugate addition to o-nitroarylacetylene.
Our initial investigation using o-(1-hexynyl)nitrobenzenes (5a) revealed that the reaction rate of the
conjugate addition is highly dependent both on the structure of the amines and on the electron density of
the benzene ring. Cyclic secondary amines such as pyrrolidine, piperidine, and morphorine smoothly
added to the substrate 5a at room temperature (Table 1, entries 1-3). In all cases, good to excellent yields
of the corresponding ketone 6a was obtained after removal of excess amines under reduced pressure and
acidic hydrolysis. In contrast, acyclic secondary amines and primary amines showed poor reactivity, and a
substantial amount of the starting compound 5a was recovered even after a day of reaction. The reaction
was also highly affected by substituents on the aromatic ring (Table 2). In the case of the

HETEROCYCLES, Vol. 72, 2007
193
2,4-dinitrophenylacetylene derivative 5b, the desired reaction took place rapidly at room temperature,
even with a reduced amount (5 equiv) of pyrrolidine (entry 1). On the other hand, 2-nitro- and
4-methoxy-2-nitrophenylacetylene derivatives (5a and 5c) were less reactive, and it took from 10 to 36
hours to complete the reaction at 50 °C in acetonitrile. The reaction time could be shortened to several
hours by heating with excess (ca. 20 equivs) pyrrolidine without solvent at 80 °C.
Table 1 Conjugate addition of various amines to o-nitrophenyacetylene.
n-Bu
1. amines (20 equiv)
n-Bu
rt
O
NO2
2. 1 N HCl
rt, 10 min
NO2
5a
6a
Entry
6a (%Yield)
Amines
Time (h)
Recovery of 5a (%)
pyrrolidine
piperidine
1
2
3
4
5
2
8.5
24
24
24
95
83
90
18
37
–
–
morphorine
diethylamine
benzylamine
6
69
56
Table 2. Conjugate addition of pyrrolidine to o-nitrophenylacetylene.
n-Bu
n-Bu
1. pyrrolidine
O
2. 1 N HCl
rt, 10 min
Y
NO2
Solvent Temp (°C)
Time (h) %Yield
X
NO2
Pyrrolidine
(equiv)
Entry
X
1
2
3
5
5
rt
1/60
10
1
NO2 (5b)
MeCN
MeCN
none
88 (6b)
99 (6a)
96 (6a)
87 (6c)
85 (6c)
50
80
50
80
H (5a)
H (5a)
20
4
5
5
36
3
MeO (5c)
MeO (5c)
MeCN
none
20
We then examined the indole formation reaction by reductive cyclization (Scheme 4). Upon
hydrogenation of the ketone 6a over Pd on carbon, the expected indole formation took place smoothly to
give 2-n-butylindole 8a in 79% yield (2 steps from 5a). More conveniently, the indole formation was
carried out by reduction of the crude enamine product 7a.7 For substrates bearing substituents susceptible
to hydrogenation over Pd on carbon, alternative reductive conditions were examined. For example,
reductive dechlorination observed in the case of 5d was completely suppressed by the use of a
combination of Fe and FeCl2 (Scheme 5), leading to the desired 2-butyl-7-chloroindole (8d) in 91% yield.
Reactions of dinitrophenylacetylene derivatives (5e and 5f) provided a complex mixture of byproducts
either by hydrogenation over Pd on carbon or by reduction with a combination of Fe and FeCl2. After

194
HETEROCYCLES, Vol. 72, 2007
survey of the reduction conditions, we have found that reaction with Pd on carbon in the presence of 5
equivalents of hydrazine gives the corresponding amino indoles (8e and 8f) in high yields (Scheme 5).8
n-Bu
pyrrolidine
N
n-Bu
H2, Pd/C
1 N HCl
(20 equiv)
n-Bu
NO2
EtOH
rt, 4 h
79% (2 steps)
80 °C
1 h
rt, 10 min
O
N
n-Bu
NO2
NO2
H
ꢀa
5a
7a
8a
H2, Pd/C, EtOH, rt, 4 h, 84%
Scheme 4 Indole formation by reductive cyclization.
n-Bu
1. pyrrolidine (20 equiv)
80 °C, 3 h
2. Fe (10 eq), FeCl2 (1 eq)
EtOH
80 °C, 10 h
Cl
N
H
n-Bu
Cl
NO2
5d
8d 91%
1. pyrrolidine (5 equiv)
MeCN
rt, 1 min
n-Bu
NO2
2. NH2NH2·H2O (5 equiv)
Pd/C
80 °C, 8-10 h
N
H
n-Bu
Y
Y
Y = 4-NO2 (5e)
Y = 6-NO2, 4-Me (5f)
Y = 6-NH2 (8e) 88%
Y = 4-NH2, 6-Me (8f) 91%
Scheme 5 Reaction of substrates bearing chloro and nitro groups.
The generality of the conjugate addition-reductive indole formation sequence was studied using a variety
of substrates which were prepared by Sonogashira-coupling9 between o-nitrophenol triflates and terminal
acetylenes (Table 3). The sequential reactions of substrates bearing n-butyl, tert-butyl, and phenyl groups
at the terminus of the arylacetylenes gave the corresponding 2-substituted indoles in good to excellent
yields (entries 1-3). The protocol was found to be amenable to the synthesis of indole derivatives 8i
having the fully protected aminodiol substituent derived from (S)-serinal, demonstrating the compatibility
of siloxy, carbamate, and acetonide groups with the reaction conditions (entry 4). This protocol is also
effective for the synthesis of indoles bearing substituents on the carbocyclic ring. Thus, in addition to
chloro and amino substituents (Scheme 5), methyl, methoxy, and methoxycarbonyl groups could be
accommmodated on the carbocyclic ring of the indoles. One of the drawbacks of this process is that the
reductive cyclization step of substrates bearing sterically hindered groups at the acetylene terminus is
considerably slower and overall yields are relatively low (entry 4 and 7). We have also found that the
yield of the reaction of this type of substrate was improved by a stepwise protocol via conversion of the
enamine intermediate to the corresponding ketone by acidic treatment, followed by reductive cyclization
with a combination of Fe and FeCl3, leading to the highly substituted indoles in good yield (Scheme 6).

HETEROCYCLES, Vol. 72, 2007
195
Table 3 Indole synthesis with various o-nitrophenylacetylenes.
R
1. pyrrolidine
(excess)
2. H2, Pd/C
EtOH
X
N
H
R
NO2
X
Reduction
Temp (°C) Time (h)
Conjugate Addition
Temp (°C) Time (h)
Substrate
%Yield
84
Product
Entry
n-Bu
1
80
80
80
1
2
1
rt
rt
4
1
N
H
n-Bu
t-Bu
NO2
NO2
NO2
5a
8a
t-Bu
2
3
4
91
99
N
H
5g
8g
Ph
60
10
N
H
Ph
5h
8h
OTBDPS
BocN
O
50
10
60
48
60
O
BocN
N
H
OTBDPS
NO2
NO2
8i
5i
n-Bu
5
6
80
80
3
3
60
60
10
12
97
90
Me
N
H
n-Bu
5j
Me
8j
n-Bu
MeO
N
H
n-Bu
5c
MeO
NO2
8c
OTBDPS
MeO
MeO
BocN
O
7a
50
12
60
48
60
O
BocN
MeO2C
N
H
MeO2C
NO2
5k
OTBDPS
8k
aPyrrolidine (5 equiv) in acetonitrile was used.
In summary, we have developed a novel synthesis of 2-substitituted indoles via enamine formation by
conjugate addition of pyrrolidine to o-nitrophenylacetylene derivatives and subsequent reductive
cyclization. The reaction sequence can easily be conducted on a large scale and proceeds under relatively
mild conditions, which a variety of functionalities including both acid and base labile groups can tolerate.

196
HETEROCYCLES, Vol. 72, 2007
1. pyrrolidine
(5 equiv)
acetonitrile
50 °C, 12 h
Fe
OTBDPS
(30 equiv)
FeCl2
(3 equiv)
MeO
OTBDPS
MeO
MeO
O
O
BocN
BocN
O
BocN
O
NO2
MeO2C
MeO2C
N
2. CSA (2 equiv)
THF-H2O (1/1)
80 °C, 6 h
EtOH
80 °C, 24 h
93%
MeO2C
NO2
H
OTBDPS
6k
8k
5k
90 %
Scheme 6 Stepwise protocol via conversion of enamine to ketone.
This is advantageous over the other representative 2-substituted indole synthesis from phenylacetylene
derivatives, such as 5-exo-dig type cyclizations of o-alkenylanilines,10 which require strong basic
conditions11 or heating conditions in the presence of stoichiometric amounts of Cu(I)12 or the relatively
valuable Pd(II) catalysts.13 Thus, this protocol would effectively serve as a mild and practical method to
form 2-subsituted indoles from o-nitrophenylacetylene derivatives.
ꢀ
ACKNOWLEDGEMENTS
The authors thank the Ministry of Education, Sports, Culture, and Science, Japan for partial financial
support of this work. Y. H. is a recipient of the JSPS pre-doctoral fellowship.
ꢀ
REFERENCES AND NOTES
1. For recent representative reviews, see: (a) J. A. Joule, ‘Indole and Its Derivatives, in Science of
Synthesis: Houben-Weyl Methods of Molecular Transformations,’ Category 2, Vol. 10, Chapter
10.13, ed. by E. J. Thomas, Georg Thieme Verlag, Stuttgart, 2000. (b) R. J. Sundberg, ‘Indoles, Best
Synthetic Methods,’ ed. by A. R. Katritzky, E. Meth-Cohn, and C. W. Rees, Academic Press,
London, 1996. (c) ‘Comprehensive Heterocyclic Chemistry II,’ ed. by A. R. Katritzky, C. W. Rees,
and E. F. V. Scriven, Vol. 2, Chapters 2.01-2.04, ‘Pyrroles and their Benzo Derivatives’ Pergamon,
Elsevier Science Ltd., Oxford, 1996. (d) G. W. Gribble, J. Chem. Soc., Perkin Trans. 1, 2000, 1045.
(e) G. Battistuzzi, S. Cacchi, and G. Fabrizi, Eur. J. Org. Chem., 2002, 2671. (f) H. Tokuyama and T.
Fukuyama, Chem. Rec., 2002, 2, 37. (g) Y. Kobayashi and T. Fukuyama, J. Heterocycl. Chem., 1998,
35, 1043.
2. For a review, see: R. D. Clark and D. B. Repke, Heterocycles, 1984, 22, 195.
3. A. D. Batcho and W. Leimgruber, Org. Synth., Coll. Vol. VII, 1990, 34.
4. A modification of the Leimgruber-Batcho protocol to synthesize 2- or 3-substituted indoles, see: (a)
E. E. Garcia and R. I. Fryer, J. Heterocycl. Chem., 1974, 11, 219. (b) U. Hengartner, A. D. Batcho,
J. F. Blount, W. Leimgruber, M. E. Barscheid, and J. W. Scott, J. Chem. Soc., Chem. Commun.,
1987, 1176. (c) W. Haefliger and H. Knecht, Tetrahedron Lett., 1984, 25, 285.

HETEROCYCLES, Vol. 72, 2007
197
5. (a) M. Suzuki, M. Kambe, H. Tokuyama, and T. Fukuyama, Angew. Chem. Int. Ed., 2002, 41, 4686.
(b) M. Suzuki, M. Kambe, H. Tokuyama, and T. Fukuyama, J. Org. Chem., 2004, 69, 2831.
6. For a similar reaction, see: I. D. Ivanchikova, R. N. Myasnikova, and M. S. Shvartsberg, Russian
Chemical Bulletin (Translation of Izvestiya Akademii Nauk, Seriya Khmicheskaya) 1998, 47, 1975.
7. A typical procedure for the conversion of o-nitrophenylacetylene derivatives to indoles by
catalytic
hydrogenation.
Preparation
of
2-n-butyl-1H-indole.
A
solution
of
1-hex-1-ynyl-2-nitrobenzene 5a (4.30 g, 21.2 mmol) in pyrrolidine (35.0 mL, 423 mmol) was stirred
at 80 °C for 1 h. After removal of pyrrolidine on a rotary evaporator, the residue was dissolved in
EtOH (42 mL), to which was added 10% Pd/C (23 mg, 2.1 mmol). After stirring for 4 h under a
hydrogen atmosphere at rt, the reaction mixture was filtered through a pad of Celite, and
concentrated. The residue was purified by flash column chromatography on silica gel (20% EtOAc
in hexane) to afford 2-butyl-1H-indoles 8a (3.43 g, 84%); IR (film, cm-1) 3400, 3056, 2956, 2930,
2871, 2300, 2342, 1877, 1768, 1617, 1584, 1551, 1458 1415, 1341, 1286, 1232, 1150, 1013, 926,
845; 1H NMR (400 MHz, CDC13) ꢀ 0.93 (t, J = 7.3 Hz, 3H), 1.36 (m, 2H), 1.63 (m, 2H), 2.63 (t, J =
7.6 Hz, 2H), 6.19 (s, 1H), 7.03-7.11 (m, 2H), 7.17 (d, J= 9.0Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.54
13
(br, IH); C NMR (100 MHz, CDC13) ꢀ 13.8, 22.3, 27.8, 31.2, 99.3, 110.3, 119.5, 119.6, 120.8,
128.8, 135.7 140.0; HRMS calcd for C12H15N 173.1204, found 173.1204; Anal. Calcd for C12H15N: C,
83.19; H, 8.73 N, 8.08. Found: C, 83.47; H, 8.97; N, 8.02.
8. A modification of the Leimgruber-Batcho protocol for the synthesis of 5-nitroindole, see: A.
Kasahara, T. Izumi, T. Kikuchi, and L. Xiao-ping, J. Heterocycl. Chem., 1987, 24, 1555.
9. K. Sonogashira, ‘Coupling reactions between sp2 and sp carbon centers,’ in Comp. Org. Synth., vol.
3, 521, ed. by B. M. Trost and I. Fleming, Pergamon, Oxford, 1991.
10. A review, see: Ref. 1e.
11. (a) T. Sakamoto, Y. Kondo, and H. Yamanaka, Chem. Pharm. Bull., 1986, 34, 2362. (b) A. N.
Tischler and T. J. Lanza, Tetrahedron Lett., 1986, 27, 1653. (c) T. Sakamoto, Y. Kondo, S. Iwashita,
and H. Yamanaka, Chem. Pharm. Bull., 1987, 35, 1823. (d) Y. Kondo, S. Kojima, and T. Sakamoto,
J. Org. Chem., 1997, 62, 6507.
12. (a) C. E. Castro, E. J. Gaughan, and D. C. Owsley, J. Org. Chem., 1966, 31, 4071. (b) J. Fujiwara, Y.
Fukutani, H. Sano, K. Maruoka, and H. Yamamoto, J. Am. Chem. Soc., 1983, 105, 7177.
13. (a) E. C. Taylor, A. H. Katz, and H. Salgado-Zamora, Tetrahedron Lett., 1985, 26, 5963. (b) D. E.
Rudisill and J. K. Stille, J. Org. Chem., 1989, 54, 5856. (c) K. Iritani, S. Matsubara, and K. Utimoto,
Tetrahedron Lett., 1988, 29, 1799.