Synthesis of 2-substituted indoles via Pd/C-catalyzed reaction in water

Article abstract of DOI:10.1055/s-2004-830861

A general and one-pot synthesis of 2-alkyl/aryl substituted indoles via a tandem Pd/C mediated coupling/5-endo-dig cyclization of terminal alkynes (including acetylenic carbinols) with o-iodoanilides in water is reported. The reaction is carried out using PPh₃ and CuI as co-catalysts and 2-aminoethanol as a base. The reaction appears to tolerate a variety of functional groups present in the alkynes and does not require the use of any organic co-solvent.

Full text of DOI:10.1055/s-2004-830861

LETTER
1965
Synthesis of 2-Substituted Indoles via Pd/C-Catalyzed Reaction in Water1
S
M
ynthesis of 2-Substitu
a
ted Indoles
n
via Pd/C-C
a
o
talyzed Reac
j
tion in
i
W
ate
r
t Pal,* Venkataraman Subramanian, Venkateswara Rao Batchu, Indu Dager
Chemistry-Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500049, India
Fax +91(40)23045438; fax +91(40)23045007; E-mail: manojitpal@drreddys.com
Received 7 March 2004
ever, the reaction was carried out in a sealed tube and
appeared to be unsuitable for the preparation of these
compounds in a large scale.
Abstract: A general and one-pot synthesis of 2-alkyl/aryl substitut-
ed indoles via a tandem Pd/C mediated coupling/5-endo-dig cy-
clization of terminal alkynes (including acetylenic carbinols) with
o-iodoanilides in water is reported. The reaction is carried out using
PPh and CuI as co-catalysts and 2-aminoethanol as a base. The re-
action appears to tolerate a variety of functional groups present in
the alkynes and does not require the use of any organic co-solvent.
R2
3
X
1
2
Pd(0) when R , R = H
+
R1
R2
R1
Pd-CuI when R2 = H
N
NHZ
Key words: indoles, Sonogashira coupling/5-endo-dig cyclization,
Z
palladium catalyst, water
X = Br, I; Z = H, Alkyl, COCH3, CO2Et, SO2CH3, SO2Ar, Boc
Scheme 1 Palladium-catalyzed synthesis of indoles
The indole nucleus is a frequently found unit in many nat-
ural products and diverse biologically active molecules.2 Palladium-promoted reactions in aqueous media are a fo-
Interesting pharmacological properties, such as anti- cus of current research1 because water-based synthetic
2,13
3
4
thrombotic,
anticancer,
histamine H3 receptor processes are inherently safer as well as inexpensive (es-
5
antagonism etc. exhibited by the various 2-substituted in- pecially for industrial-scale processes). Therefore, the use
13g
doles have led to a continued interest in the practical syn- of water-soluble catalysts and water-soluble phosphine
thesis of these compounds. Among the classical methods ligands1 has been explored successfully. The use of Pd/
3f
for the synthesis of indole ring, the Fischer indole synthe- C–CuI–PPh
sis, the Batcho–Leimgruber synthesis (from o-nitrotolu- shira coupling has also been reported.
as a catalyst system for efficient Sonoga-
3
14,15
All these Pd-
enes and dimethylformamide acetals), the Gassman catalyzed reactions are usually carried out in an aqueous-
1
3f
synthesis (from N-haloanilines), the reductive cyclization organic media and a co-solvent such as acetonitrile or
of o-nitrobenzylketones and the Madelung cyclization of DME1 is often required. As part of our continuing inter-
5g
16
N-acyl-o-toluidines are often used. However, the intro- est in the utilization of palladium-catalyzed reactions in
duction of an aryl group at the 2-position of an indole ring aqueous media, we have developed a mild and efficient
is usually achieved by de novo indole ring construction6 method for the synthesis of 2-substituted benzo[b]furans
either by Fischer indole synthesis or more popularly by via Pd/C-catalyzed C-C bond formation in water.1 This
17
7a
7
transition metal mediated reactions, especially by palla- prompted us to investigate the feasibility of this method-
8
–10
dium catalyzed protocols.
Palladium-catalyzed annu- ology in the synthesis of indoles of potential pharmaco-
lation of o-haloanilines with terminal alkynes (under logical interest.5 Herein, we report a straightforward and
Sonogashira reaction conditions) or internal alkynes (un- one-pot Pd/C-catalyzed synthesis of 2-substituted indoles
der Larock’s conditions) has been employed widely due to in water.
,18
the versatile nature of these protocols, increased function-
al group tolerance and improved yields (Scheme 1). De-
spite being quite versatile, the synthesis of 2-substituted
indoles employing terminal alkynes often involves a two-
step process i.e. Sonogashira coupling of o-haloanilines
with terminal alkynes followed by the cyclization of the
resulting 2-alkynylanilines in the presence of various re-
agents (e.g. metal alkoxides, halides or Lewis acids).11
Moreover, cyclization of anilides having an alkynol moi-
ety at the 2-position yielded quinolines/2,3-dihydro-
Our earlier procedure for the synthesis of 2-substituted
benzo[b]furans involves the use of an expensive and
17a
chiral amine base i.e. (S)-prolinol. In the search of an al-
ternative but cheaper amine base for efficient coupling/5-
endo-dig cyclization we were intrigued with the possibil-
ity of using 2-aminoethanol as a suitable replacement. Ac-
cordingly, we examined the reaction of o-iodoanilides 1
with terminal alkynes 2 in the presence of 2-aminoethanol
in water (Table 1). Initially, we chose the reaction of N-
trifluoroacetyl derivatives 1 of 2-iodoanilines (entries 1–
4
(1H)-quinolones rather than indoles.11d Very recently, a
one-pot synthesis of 2-substituted indoles has been report-
3
5
, Table 1) with phenylacetylene 2 to study the coupling/
-endo-dig cyclization in the presence of 10% Pd/C, PPh3
8
a
ed in the presence of Pd(II)-NaY zeolite catalysts. How-
and CuI as catalysts. Except in the case of 4-fluoro deriv-
ative 1c the reaction did not afford good yields of the cor-
responding 2-substituted indoles. Moreover, deprotection
of the trifluoroacetyl group occurred under these reaction
conditions.8 Since the generation of N-protected indoles
SYNLETT 2004, No. 11, pp 1965–1969
0
6
.0
9
.2
0
0
4
Advanced online publication: 06.08.2004
DOI: 10.1055/s-2004-830861; Art ID: D06404ST
a,i
©
Georg Thieme Verlag Stuttgart · New York

1
966
M. Pal et al.
LETTER
would allow us further functionalization of the indole nu- (0.12 equiv), CuI (0.06 equiv) and 2-ethanolamine (3
cleus we therefore, examined the reaction of N-methane- equiv) under nitrogen, 2-substituted indoles 4 were ob-
sulfonyl derivative 1d of 2-iodoanilines with terminal tained.1 The results are summarized in Table 2.
9c
alkynes (entries 4–7, Table 1). The methanesulfonyl
As can be seen from the Table 2, the heteroannulation of
group was found to be stable under the present reaction
acetylenic compounds in a single synthetic operation af-
conditions and the corresponding N-methanesulfonyl in-
forded indoles 4 in good to excellent yields. By the use of
doles 3d–g were isolated in good yields. Using this opti-
this palladium-catalyzed reaction a variety of terminal
acetylenes were reacted with o-iodoanilides (Table 2).
mized procedure we synthesized a number of 2-
1
8b,c
substituted 5-methylindoles
4 via palladium-catalyzed
Various substituents (including alkyl, hydroxyl, phenyl
etc.) present in the acetylenic compounds 2 were well tol-
erated during the course of the reaction and yields were
generally good irrespective of the nature of the substitu-
ents present in the acetylenic component (entries 1–8,
heteroannulation with Pd/C–CuI–PPh as catalyst. Thus,
3
8
i,19a
when o-iodoanilide 1e
was treated with 3 equivalents
of terminal alkyne (2, R = alkyl, hydroxyalkyl etc.) in
19b
water in the presence of 10% Pd/C (0.03 equiv), PPh3
Table 1 Pd/C-Catalyzed Synthesis of 2-Substituted Indoles in Aqueous Mediaa
R1
R1
R1
I
10% Pd/C, PPh3, CuI
+
R
R
or
R
2-aminoethanol, H2O, 80 °C
N
N
NHZ
H
Z
1
3
2
b
c
Entry Aryl halide
Alkyne
Time (h) Products 3
Yield (%) of 3
1
Cl
I
Ph
4
Cl
40
2
a
Ph
NHCOCF3
N
H
1
a
3
a
2
3
H C
I
2a
4
Ph
20d
H3C
H3C
Ph
NHCOCF3
+
N
COCF3
NH
1
b
H
3
b 5
3
4
F
I
2a
2a
12
4
F
78
62
Ph
NHCOCF3
N
H
1
c
3
c
Cl
I
Cl
Ph
N
NHSO2CH3
SO2CH3
1
d
3
d
5
6
1d
OH
CH3
12
12
Cl
OH
89
65
CH3
H3C
N
CH3
SO2CH3
2
2
b
c
3
e
1d
1d
CH OH
Cl
2
CH2OH
SO2CH3
N
3
f
7
CH CH OH
12
Cl
60
2
2
CH2CH2OH
2
d
N
SO2CH3
3
g
a
b
c
d
All reactions were carried out by using 1 (1.0 equiv), 2 (3.0 equiv), 1:4:2 ratio of Pd/C:PPh :CuI, 2-aminoethanol (3 equiv) in H O.
Identified by H NMR, C NMR, IR, MS.
Isolated yields.
3
2
1
13
Alkyne 5 was isolated in 35% yield.
Synlett 2004, No. 11, 1965–1969 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Substituted Indoles via Pd/C-Catalyzed Reaction in Water
1967
Table 2). In contrast to the Pd(PPh ) Cl -catalyzed phenyl)methanesulfonamide with phenylacetylene in the
3
2
2
1
1d
reaction the present Pd/C–CuI–PPh mediated coupling presence of Pd–CuI–PPh /KF–Al O yielded N-(o-ethy-
3
3
2
3
of o-iodoanilides with the acetylenic carbinols yielded nylphenyl)methanesulfonamide exclusively instead of the
8
i
the corresponding indole derivatives in good yields (e.g. desired indole. Additional Pd(II) was required to obtain
2
0
entries 6–8, Table 2). It is noteworthy that under the the desired indole derivative in this case.
solvent-free conditions the reaction of N-(2-iodo-
Table 2 Pd/C-Catalyzed Synthesis of 2-Substituted N-Methylsulfonyl Indoles in Aqueous Mediaa
H3C
H3C
I
1
0% Pd/C, PPh3, CuI
R
+
R
N
NH
2-aminoethanol, H2O, 80 °C
SO2CH3
SO2CH3
1e
2
4
b
c
Entry
1
Alkyne
Time (h)
3
Products 4
Yield (%) of 4
Ph
3
H C
70
2a
Ph
N
SO2CH3
4
a
2
3
C(CH ) OH
12
8
H C
OH
85
70
3
2
3
2
b
c
CH3
CH3
SO2CH3
N
4
b
CH OH
2
3
H C
2
CH OH
2
N
SO2CH3
4
c
4
5
6
7
8
CH CH OH
12
48
12
12
12
H C
82
40
78
80
80
2
2
3
2
2
2
2
2
d
e
f
CH2CH2OH
N
SO2CH3
4
d
CH (CH ) CH
2
2 4
3
3
H C
CH (CH ) CH
3
2
2 4
N
SO2CH3
4
e
CH(OH)CH3
3
H C
CH(OH)CH3
N
SO2CH3
4
f
CH(OH)CH CH3
2
3
H C
g
h
2 3
CH(OH)CH CH
N
SO2CH3
4
g
CH(OH)C H5
6
3
H C
CH(OH)C6H5
N
SO2CH3
4
h
a
All reactions were carried out by using 1e (1.0 equiv), 2 (3.0 equiv), 1:4:2 ratio of Pd/C:PPh :CuI, 2-aminoethanol (3 equiv) in H O.
Identified by H NMR, C NMR, IR, MS.
Isolated yields.
3
2
b
c
1
13
Synlett 2004, No. 11, 1965–1969 © Thieme Stuttgart · New York

1
968
M. Pal et al.
LETTER
Mechanistically, the reaction may proceed via in situ gen-
M.; Spencer, J. R.; Sprengeler, P. A.; Tario, J.; Verner, E.;
Wang, J. Bioorg. Med. Chem. Lett. 2002, 12, 2019.
(5) Chai, W.; Breitenbucher, J. G.; Kwok, A.; Li, X.; Wong, V.;
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eration of a Pd(0) complex e.g. L Pd(0) according to the
2
2
1a
typical Sonogashira pathway. However, the question
arises as to whether palladium remains on the support or
dissolves before the catalytically active species is formed.
13, 1767.
2
1b,c
Recent studies
have shown that a minor portion of the
(
6) For a recent review on indole ring synthesis, see: Gribble, G.
bound palladium (Pd/C) released into the solution is the
actual catalytic species in such coupling reactions and Pd/
C therefore serves as the source of the palladium. This
also indicates that the catalytic cycle works in solution
rather than on the surface and the active species is a dis-
W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
(7) For Cu-mediated process, see: (a) Cacchi, S.; Fabrizi, G.;
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2
1d
solved Pd–PPh complex. In the present case a 2-ami-
3
Sakamoto, T. Tetrahedron Lett. 2002, 43, 1277.
no-ethanol-stabilized Pd(0)-complex perhaps catalyzes
the reaction in aqueous media. Recent work by Amatore
and Jutand provides strong evidence in support of the spe-
cific role played by halide ions to generate an anionic spe-
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–
22a–22c
cies such as [L Pd(0)Cl] .
In the present case, this
2
anionic species is generated in situ from Pd/C and PPh in
3
the presence of CuI and presumably the 2-aminoethanol
stabilized anionic species (A) facilitates the reaction in
aqueous media due to its interaction with water molecules
89. (f) Fagnola, M. C.; Candiani, I.; Visentin, G.; Cabri, W.;
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(
A).
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1
6c
2-Alkynylanilide thus obtained then undergoes
7
–10
(i) Kabalka, G. W.; Wang, L.; Pagni, R. M. Tetrahedron
transition metal promoted cyclization
substituted indole.
to yield the 2-
2001, 57, 8017.
(
9) (a) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 1551.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem.
In conclusion, we have described a palladium on carbon
mediated practical synthesis of 2-alkyl/aryl substituted in-
doles in water in the presence of 2-aminoethanol. The
present methodology is simple to perform, efficient and
does not involve the use of expensive reagents or cata-
lysts. Since water-based syntheses are safer and inexpen-
sive, the described methodology will permit easy access
to 2-substituted indoles not only for laboratory use but
also for large-scale production. Some of the indoles syn-
thesized were converted to compounds of potential bio-
1
998, 63, 7652. (c) Zhang, H.-C.; Brumfield, K. K.;
Maryanoff, B. E. Tetrahedron Lett. 1997, 38, 2439.
d) Chen, C. Y.; Lieberman, D. R.; Larsen, R. D.; Reamer,
(
R. A.; Verhoven, T. R.; Reider, P. J.; Cottrell, I. F.;
Houghton, P. G. Tetrahedron Lett. 1994, 35, 6981.
(e) Jeschke, T.; Wensbo, D.; Annby, U.; Gronowitz, S.;
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R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(
10) For Pd-mediated coupling reactions of haloindoles; see:
a) Liu, Y.; Gribble, G. W. Tetrahedron Lett. 2000, 41,
717. (b) Zhang, H.-C.; Ye, H.; White, K. B.; Maryanoff, B.
(
8
2
3
logical significance.
Further application of this
E. Tetrahedron Lett. 2001, 42, 4751.
methodology for the generation of biologically interesting
indole-based chemical libraries is under investigation.
(
11) (a) Sakamoto, T.; Kondo, Y.; Iwashita, S.; Nagano, T.;
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(b) Amjad, M.; Knight, D. W. Tetrahedron Lett. 2004, 45,
5
39. (c) Mackman, R. L.; Katz, B. A.; Breitenbucher, J. G.;
Acknowledgment
Hui, H. C.; Verner, E.; Luong, C.; Liu, L.; Sprengeler, P. A.
J. Med. Chem. 2001, 44, 3856. (d) Kundu, N. G.; Mahanty,
J. S.; Das, P.; Das, B. Tetrahedron Lett. 1993, 34, 1625.
The authors sincerely thank Dr. A. Venkateswarlu, Dr. R. Rajago-
palan and Prof. J. Iqbal for their encouragement and the analytical
group for spectroscopic support.
(
e) For palladium mediated cyclization of 2-alkynylanilines
see: Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem.
Soc. 2000, 122, 5662.
(
(
12) (a) Leadbeater, N. E.; Marco, M.; Tominack, B. J. Org. Lett.
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Synlett 2004, No. 11, 1965–1969 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Substituted Indoles via Pd/C-Catalyzed Reaction in Water
1969
1
990, 112, 4324. (h) Dibowski, H.; Schmidtchen, F. P.
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(
(
14) De la Rosa, M. A.; Velarde, E.; Guzman, A. Synth. Commun.
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1
1990, 20, 2059.
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CDCl ): d = 7.98 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 2.5 Hz, 1
3
H), 7.43–7.38 (m, 5 H), 7.19 (d, J = 8.4 Hz, 1 H), 6.65 (s, 1
H), 2.69 (s, 3 H, SO CH ), 2.46 (s, 3 H, CH ). MS (CI):
2
3
3
1
571. (c) Heidenreich, R. G.; Köhler, K.; Krauter, J. G. E.;
m/z = 286 (100) [M + 1]. IR (neat): 1586.1, 1462.5, 1361.1
–
1 13
Pietsch, J. Synlett 2002, 1118. (d) Felpin, F.-X.; Vo-Thanh,
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3
134.20, 131.99, 130.55, 129.96 (2 C), 128.68, 127.60 (2 C),
126.39, 120.88, 115.50, 112.98, 38.91 (SO CH ), 21.18
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2
3
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(CH ). HPLC: 97.3% [Symmetry Shield RP18 (250 × 4.6
3
mm), 0.01 M KH PO :MeCN, 1 mL/min 225 nm, retention
2
4
time 13.7 min]. Elemental analysis found C, 67.39; H, 5.35;
N, 4.89; C H NO S requires C, 67.34; H, 5.30; N. 4.91%.
1
6
15
2
Compound 4g: light brown solid; yield 80%; mp 78–80 °C
1
(hexane). H NMR (200 MHz, CDCl ): d = 7.89 (d, J = 8.7
3
(
16) (a) Pal, M.; Parasuraman, K.; Subramanian, V.; Dakarapu,
R.; Yeleswarapu, K. R. Tetrahedron Lett. 2004, 45, 2305.
Hz, 1 H), 7.34 (s, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 6.62 (s, 1
H), 5.02 (d, J = 7.9 Hz, 1 H), 3.09 (s, 3 H), 2.94 (d, J = 5.9
(
2
b) Pal, M.; Parasuraman, K.; Yeleswarapu, K. R. Org. Lett.
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Hz, D O exchangeable, OH), 2.43 (s, 3 H), 2.07–1.97 (m, 2
2
+
H), 1.09 (t, J = 7.3 Hz, 3 H). MS (CI): m/z = 250 (100) [M
–
1 13
– OH]. IR (neat): 3540.1, 1462.4, 1358.0, 1159.6 cm .
C
(
NMR (50 MHz, CDCl ): d = 143.42, 135.06, 133.29, 129.16,
3
Synlett 2002, 1976. (e) Pal, M.; Kundu, N. G. J. Chem. Soc.,
Perkin Trans. 1 1996, 449.
126.19, 121.01, 113.67, 108.36, 67.76 (CHOH), 40.12
(SO CH ), 28.59 (CH ), 20.98 (CH ), 10.53 (CH ). HPLC:
2
3
2
3
3
(
(
17) (a) Pal, M.; Subramanian, V.; Yeleswarapu, K. R.
Tetrahedron Lett. 2003, 44, 8221. (b) Kundu, N. G.; Pal, M.
J. Chem. Soc., Chem. Commun. 1993, 86. (c) Kundu, N. G.;
Pal, M.; Mahanty, J. S.; Dasgupta, S. K. J. Chem. Soc.,
Chem. Commun. 1992, 41.
18) (a) Radl, S.; Hezky, P.; Urbankova, J.; Vachal, P.; Krejci, I.
Collect. Czech. Chem. Commun. 2000, 65, 280. (b) For
biological activities of 5-methylindoles, see: Dai, J.; Sun, B.;
Zhang, A.; Lin, K.; Wang, L. Bull. Environ. Contam.
Toxicol. 1998, 61, 591. (c) Kon-Ya, K.; Shimidzu, N.; Miki,
W.; Endo, M. Biosci. Biotechnol. Biochem. 1994, 58, 2178.
99.3% [Inertsil ODS 3V (250 × 4.6 mm), 0.01 M KH PO in
2
4
MeCN, 1 mL/min, 220 nm, retention time 16.6 min].
Elemental analysis found C, 58.38; H, 6.40; N, 5.27;
C H NO S requires C, 58.40; H, 6.41; N. 5.24%.
1
3
17
3
(20) Although the methanesulfonyl group of iodoarene 1e was
tolerated under the present reaction conditions this group
was removed efficiently from 4 using tetrabutylammonium
fluoride in THF at elevated temperature to afford the
corresponding indoles in good yields, see: Yasuhara, A.;
Sakamoto, T. Tetrahedron Lett. 1998, 39, 595.
(21) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467. (b) Novak, Z.; Szabo, A.; Repasi, J.;
Kotschy, A. J. Org. Chem. 2003, 68, 3327. (c) Mori, Y.;
Seki, M. J. Org. Chem. 2003, 68, 1571. (d) De la Rosa, M.
A.; Velarde, E.; Guzman, A. Synth. Commun. 1990, 20,
2059.
(
d) For our recent synthesis of indole derivatives, see: Pal,
M.; Dakarapu, R.; Padakanti, S. J. Org. Chem. 2004, 69,
913.
2
(
19) (a) o-Iodoanilides were prepared according to the procedure
described in the literature, see: Xiao, W.-J.; Alper, H. J. Org.
Chem. 1999, 64, 9646. (b) All the terminal alkynes used are
commercially available. (c) General Procedure for the
Preparation of 2-Substituted Indoles(4): A mixture of 1e
(22) (a) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314.
(b) Amatore, C.; Jutand, A.; Khalil, F.; M’Barki, M. A.;
Mottier, L. Organometallics 1993, 12, 3168. (c) The
anionic species generated from Pd(PPh ) Cl is thought to be
(
1.60 mmol), 10% Pd/C (51 mg, 0.05 mmol), PPh (50 mg,
3
3
2
2
0
.19 mmol), CuI (18 mg, 0.09 mmol) and 2-aminoethanol
the key intermediate and participates as active palladium
species in these cross-coupling reactions, see: Grosshenny,
V.; Romero, F. M.; Ziessel, R. J. Org. Chem. 1997, 62,
1491. (d) Amatore, C.; Jutand, A. J. Am. Chem. Soc. 1993,
115, 9531.
(
4.83 mmol) in H O (8 mL) was stirred at 25 °C for 1 h under
2
nitrogen. The acetylenic compound 2 (4.00–5.00 mmol) was
added slowly to the mixture with stirring. The reaction
mixture was then stirred at 80 °C for the time indicated in
Table 1. The mixture was cooled to r.t., diluted with EtOAc
(23) Indole 4h was converted to the corresponding ketone using
MnO in CH Cl according to the procedure described in the
(
120 mL) and filtered through celite. The filtrate was
2
2
2
1
8a
collected, washed with cold H O (2 × 75 mL), dried over
Na SO , filtered and concentrated under vacuum. The
literature. These ketones are of interest as analgesics.
2
See: Jiang, J.; Gribble, G. W. Synth. Commun. 2002, 32,
2
4
residue thus obtained was purified by column
2035.
Synlett 2004, No. 11, 1965–1969 © Thieme Stuttgart · New York