Pd-Catalyzed cascade reaction for the synthesis of 2-substituted indoles

Article abstract of DOI:10.1055/s-0032-1317320

An efficient cascade methodology toward the synthesis of 2-substituted indoles has been developed. The transformation proceeds via a palladium-catalyzed cross-coupling reaction of o-nitrobenzyl cyanides with boronic acids. The use of Fe as co-catalyst during the course of reaction employs significant enhancement in reaction rates. The developed protocol allows for the unprecedented use of arylboronic acids as coupling partners for constructing 2-substituted indoles.

Full text of DOI:10.1055/s-0032-1317320

LETTER
▌2511
letter
Pd-Catalyzed Cascade Reaction for the Synthesis of 2-Substituted Indoles
Synthesis of 2-Substituted Indoles
Jagannath Jadhav, Vipul Gaikwad, Rajanikant Kurane, Rajashri Salunkhe, Gajanan Rashinkar*
Department of Chemistry, Shivaji University, Kolhapur 416004, M.S., India
Fax +91(231)2692333; E-mail: gsr_chem@unishivaji.ac.in
Received: 22.07.2012; Accepted after revision: 29.08.2012
report herein the transition-metal-catalyzed cascade syn-
Abstract: An efficient cascade methodology toward the synthesis
thesis of 2-substituted indoles by a palladium-catalyzed
cross-coupling reaction of o-nitrobenzyl cyanide by com-
bining Larock’s method, where arylboronic acids are cou-
of 2-substituted indoles has been developed. The transformation
proceeds via a palladium-catalyzed cross-coupling reaction of o-ni-
trobenzyl cyanides with boronic acids. The use of Fe as co-catalyst
during the course of reaction employs significant enhancement in pled to nitrile and generate aryl ketones via the hydrolysis
7
reaction rates. The developed protocol allows for the unprecedented of the intermediate ketimine, followed by in situ ring cy-
use of arylboronic acids as coupling partners for constructing 2-sub-
stituted indoles.
clization by iron-promoted reduction of the nitro group
(
Scheme 1). Our interest in the method stems from the
8
9
Key words: cascade synthesis, 2-substituted indoles, palladium-
catalyzed cross-coupling reaction
Leimgruber–Batcho and Reissert indole synthesis that
depends on the intermediacy of o-nitro aryl ketones. To
the best of our knowledge, this kind of cascade transfor-
mation has not been previously reported.
The indole core is a key structural motif that occurs wide-
ly in natural and unnatural compounds. Indole scaffolds
are found in pigments such as Tyrian purple (1) and also
in compounds having neurological [serotonin (2)] and
psychomimetic [psilocybin (3)] properties (Figure 1). In
view of their prevalence in nature and associated medici-
NH2
O
H
Br
N
HO
N
Br
H
N
H
O
nal properties, these compounds have found widespread
applications in the pharmaceutical industry.1,2 In particu-
Tyrian purple (1)
Serotonin (2)
lar, 2-substituted indoles have been referred as ‘privileged
structures’ for drug development since they possess a
Me
Ms
OH
+
N
Me
O
O
NH
P
3
O–
broad range of biological activities; for example, com-
N
4
HO
pound 4 is a powerful KDR kinase inhibitor. In view of
N
their pharmacological properties and therapeutic efficacy,
a large number of methods have been reported for the con-
struction of an indole ring. The Fischer–Indole synthesis,
Bischler–Napieralski process, and Madelung cyclization
N
H
N
H
Psilocybin (3)
4
are traditional methods to assemble these compounds. For Figure 1
a long time, these reactions were carried out under harsh
conditions, and therefore their use was greatly limited.
Our initial studies were aimed at optimization of the reac-
tion conditions employed for the preparation of 2-substi-
tuted indoles. Accordingly, a mixture of o-nitrobenzyl
cyanide and phenylboronic acid was heated in TFA using
Recently, transition-metal-assisted protocols have been
developed for their synthesis. Compared with classical
5
indole synthetic methods, a transition-metal-catalyzed
strategy provides an attractive and mild alternative ap-
proach with the advantage of good functional-group toler-
ance thus providing indoles with greater structural
diversity in excellent yields.
a catalytic amount of DMSO and Pd(OAc) . To our sur-
2
prise, the palladium-catalyzed protocol promoted the gen-
eration of unexpected o-nitrophenyl benzyl ketone
accompanied by a small amount of the desired product
Although many transition-metal-mediated protocols have (path A). As the reduction of the nitro group into the ami-
been developed for the synthesis of substituted indoles, no functionality is a crucial factor for the success of the re-
the development of an efficient route employing easily ac- action, we envisioned that addition of iron metal as co-
cessible building blocks represent an attractive yet diffi- catalyst would selectively allow the formation of the de-
cult synthetic challenge.
sired product due to its ability to carry out the required re-
duction. To our delight, the addition of iron in the same
pot successfully reduced the nitro group that triggered in-
tramolecular cyclization solely furnishing the anticipated
product (path B).
In the framework of our continuous efforts towards effec-
tive synthesis of medicinally relevant compounds, we
6
SYNLETT 2012, 23, 2511–2515
Advanced online publication: 28.09.2012
The generality of this protocol was validated by reaction
of o-nitrobenzyl cyanide with electronically and structur-
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317320; Art ID: ST-2012-B0613-L
Georg Thieme Verlag Stuttgart · New York
©

2
512
J. Jadhav et al.
LETTER
Pd(OAc)2, TFA
+
O
N
NO2
H
path A
1
c
nitroketone
major
desired product
trace
B(OH)2
CN
4
2'
3
3'
9
5
+
2
1'
NO2
o-nitrobenzyl cyanide
4'
6
8
N
H
1b
6'
5'
1a
7
1c
desired product
sole
path B
1
) Pd(OAc)2, TFA
) Fe metal
2
Scheme 1 Cascade synthesis of 2-substituted indoles
ally diverse arylboronic acids under the established condi- entries 12 and 13). To further expand the scope of the
tions. The results are summarized in Table 1. The method, we have assessed the reactivity of various deriv-
corresponding indoles were obtained in moderate to good atives of o-nitrobenzyl cyanide. To our delight, 5-me-
yields for substrates with varying types of substitution on thoxy-2-nitrobenzyl cyanide as well as 5-methyl-2-
the arylboronic acid. A diverse range of functionalities nitrobenzyl cyanide reacted efficiently with phenylboron-
were tolerated by the system. The noteworthy feature is ic acid forming the desired products in good yields (Table
the tolerance of the reaction to the presence of halide sub- 1, entry 15 and 16). On the contrary, 3-nitro-2-pyridyl
stitution on the phenylboronic acid, thus providing in- acetonitrile gave comparatively lower yield (Table 1, en-
doles with a handle for additional synthetic manipulation. try 14).
Extension of this protocol to heteroaromatic arylboronic
On the basis of known metal-catalyzed addition reactions
of organometallic reagents with nitriles, a possible re-
acids would lead to indoles of even greater structural di-
versity, and it was found that pyridine-2-boronic acid and
thiophene 3-boronic acid reacted successfully with o-ni-
trobenzyl cyanide albeit giving the corresponding 2-het-
aryl-substituted indoles in slightly lower yields (Table 1,
7,10
action mechanism is proposed to account for the present
palladium-catalyzed reaction (Scheme 2). Initially, effec-
tive transmetalation of arylboronic acid and the DMSO-
11
coordinated complex A generates aryl palladium species
Pd(OAc)2 + TFA + L
NH
Fe metal
–Ar
–
NH3
N
NO2
ArB(OH)2
H
L2Pd(OCOCF3)2
A
(OH)2BO2CCF3
TFA
E
OCOCF3
L2Pd
ArPd(OCOCF3)L2
Ar–
N
B
D
CN
O2N
Ar–
NO2
(
F3COCO)PdL
+
L = DMSO
N
L
C
L
O2N
Scheme 2 Possible reaction mechanism for the cascade synthesis of 2-substituted indoles
Synlett 2012, 23, 2511–2515
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Substituted Indoles
2513
B, which on coordination with nitrile forms intermediate next catalytic cycle. Finally, intermediate E cyclizes after
C. The 1,2-addition of the coordinated aryl group to the reduction of the nitro group by iron forming the desired
nitrile gives intermediate D. The protonolysis of D affords product.
ketimine E and regenerates active Pd(0) species for the
Table 1 Pd-Catalyzed Cascade Reaction for the Synthesis of 2-Substituted Indolesa
B(OH)2
CN
Pd(OAc)2, TFA, DMSO
+
NO2
Fe metal
N
H
a
b
c
Entry
1
Benzyl cyanide (a)
Arylboronic acid (b) Product (c)b
Rfc
Yield (%)d
70
Mp (°C)e
B(OH)2
CN
1
86–187
0.33
12a
(
188–190)
N
H
NO2
B(OH)2
CN
8
4–85
2
3
0.35
0.36
70
72
12d
NO2
(81–83)
N
H
B(OH)2
CN
2
08–210
12d
N
H
(212–214)
NO2
B(OH)2
CN
1
44–145
4
5
0.44
0.41
60
75
[12b
NO2
(146–147)
N
H
MeO
B(OH)2
OMe
CN
80–82
12a
(
82–83)
NO2
N
H
B(OH)2
CN
OMe
231–232
(228–229)
6
0.42
80
12f
NO2
N
H
OMe
B(OH)2
OMe
CN
1
82–184
7
8
9
0.38
0.34
0.32
80
62
60
OMe
12e
NO2
(185–187)
OMe
N
H
OMe
F
B(OH)2
CN
1
25–126
12f
NO2
(127–130)
N
H
F
B(OH)2
CN
F
115–116
(119–122)
12d
N
H
NO2
F
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2511–2515

2
514
J. Jadhav et al.
LETTER
Table 1 Pd-Catalyzed Cascade Reaction for the Synthesis of 2-Substituted Indolesa (continued)
B(OH)2
CN
Pd(OAc)2, TFA, DMSO
+
NO2
Fe metal
N
H
a
b
c
Rfc
Yield (%)d
Mp (°C)e
Entry
Benzyl cyanide (a)
Arylboronic acid (b) Product (c)b
B(OH)2
CN
2
06–207
Cl
Br
1
1
0
1
0.38
65
1
2b
(
203–205)
NO2
N
H
Cl
B(OH)2
CN
210–211
(211–213)
0.44
65
1
2a
2c
NO2
N
H
Br
B(OH)2
N
CN
1
45–146
1
1
1
2
3
4
N
N
H
0.2
40
30
30
1
NO2
(147–148)
B(OH)2
CN
S
1
82–184
0.35
0.3
[12g
NO2
N
H
(186–187)
S
B(OH)2
N
N
CN
2
50–252
12h
12f
12f
(
254–255)
N
H
NO2
B(OH)2
MeO
MeO
CN
NO2
1
62–164
1
5
6
0.5
60
70
(
166–169)
N
H
B(OH)2
CN
NO2
2
15–217
1
0.45
N
(220–221)
H
a
Reaction conditions: o-nitrobenzyl cyanide (4.0 mmol), boronic acid (2.0 mmol.), Pd(OAc) (0.10 mmol), DMSO (0.10 mL), and TFA (5
2
mL) followed by Fe metal powder (10 mol%).
b
c
d
e
1
13
Confirmed by H NMR and C NMR spectroscopy.
Systems: EtOAc–hexane = 2:8 (entries 1–11, 13, 15, and 16), EtOAc–hexane = 4:6 (entry 12), EtOAc–hexane = 1:1 (entry 14).
Isolated yields after column chromatography.
Literature melting points are given in parenthesis.
In summary, we have developed a straightforward method mL) were placed. The flask was stirred and heated at the 90 °C for
2
4 h. After disappearance of substrate (monitored by TLC) Fe metal
for the synthesis of 2-arylindoles directly by coupling of
arylboronic acids with o-nitrobenzyl cyanides through a
palladium-catalyzed cascade reaction. We believe that
this protocol represents an important contribution towards
powder (10 mol%) was added, and the resulted mixture was again
stirred for additional 2 h at 90 °C. The reaction mixture was neutral-
ized with sat. NaHCO solution and then extracted with EtOAc. The
combined organic layers were washed with brine, dried over
3
developing one of the more direct and benign synthesis of Na SO , and concentrated. The residue was purified by column
2
4
the ubiquitous indole substructure, and continued im- chromatography (EtOAc–hexane = 20:80 v/v) to give the desired
product.
provements to the described reaction should engender the
process as a viable alternative to more traditional synthe-
ses of indoles.
Compound 1c
1
2a
Pale yellow solid; mp 186–187 °C (lit. 188–190 °C); Rf = 0.33
1
(
n-hexane–EtOAc = 8:2). H NMR (300 MHz, CDCl ): δ = 8.33 (br
3
Typical Procedure for the Synthesis of 2-Substituted Indoles
To a 25 mL flask, o-nitrobenzyl cyanide (4.0 mmol), boronic acid
s, 1 H), 7.68–7.64 (m, 3 H), 7.47–7.44 (m, 2 H), 7.41 (m, 1 H), 7.34
(m, 1 H), 7.21 (m, 1 H), 7.14 (m, 1 H), 6.85 (dd, J = 1.0, 2.2 Hz, 1
(
2.0 mmol), Pd(OAc) (0.10 mmol), DMSO (0.10 mL), and TFA (5
2
Synlett 2012, 23, 2511–2515
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Substituted Indoles
2515
H). 13C NMR (75 MHz, CDCl ): δ = 137.8 (C8), 136.8 (C1′), 132.3 References
3
(
1
C4′), 129.2 (C3′), 129.0 (C9), 127.7 (C2′), 125.1 (C2), 122.3 (C6),
20.7 (C5), 120.3 (C7), 110.9 (C4), 100.0 (C3).
(
(
1) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
2) Denmark, S. E.; Baird, J. D.; Regens, C. S. J. Org. Chem.
2008, 73, 1440.
Compound 2c
White solid; mp 84–85 °C (lit. 81–83 °C);
EtOAc = 8:2). H NMR (300 MHz, CDCl ): δ = 8.13 (br s, 1 H),
7
H), 7.27–7.41 (m, 3 H), 7.21 (t, J = 7.4 Hz, 1 H), 7.14 (d, J = 7.4 Hz,
1
1
(
1
1
2d
Rf = 0.35 (n-hexane–
(3) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873.
(4) (a) Fraley, M. E.; Hoffman, W. F.; Arrington, K. L.;
Hungate, R. W.; Hartman, G. D.; McFall, R. C.; Coll, K. E.;
Rickert, K.; Thomas, K. A.; McGaughey, G. B. Curr. Med.
Chem. 2004, 11, 709. (b) Fang, Y. Q.; Karisch, R.; Lautens,
M. J. Org. Chem. 2007, 72, 1341. (c) Palimkar, S. S.; More,
V. S.; Harish Kumar, P.; Srinivasan, K. V. Tetrahedron
2007, 63, 12786.
1
3
.65 (d, J = 7.6 Hz, 1 H), 7.48–7.66 (m, 1 H), 7.46 (d, J = 4.0 Hz, 1
1
3
H), 6.62 (s, 1 H), 2.50 (s, 3 H). C NMR (75 MHz; CDCl ): δ =
3
37.4 (C2′), 136.1(C8), 136.0 (C1′), 132.6 (C4′), 131.0 (C9), 128.9
C3′), 128.8 (C5′), 127.9 (C6′), 126.0 (C2), 122.0 (C6), 120.5 (C5),
20.0 (C7), 110.7 (C4), 102.9 (C3), 21.1 (CH3).
(
5) For reviews of different approaches, see: (a) Taber, D. F.;
Tirunahari, P. K. Tetrahedron 2011, 67, 7195. (b) Patil, S.
A.; Patil, R.; Miller, D. D. Curr. Med. Chem. 2011, 18, 615.
Compound 3c
1
2d
Yellow solid; mp 208–210 °C (lit. 212–214 °C); Rf = 0.36 (n-
1
hexane–EtOAc = 8:2). H NMR (300 MHz, CDCl ): δ = 8.29 (br s,
3
(
(
c) Cacchi, S.; Fabrizi, G. Org. Biomol. Chem. 2011, 9, 641.
d) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215.
1
H), 7.63 (m, 1 H), 7.58–7.56 (m, 2 H), 7.40 (m, 1H), 7.27–7.25
(
m, 2 H), 7.19 (m, 1 H), 7.13 (m, 1 H), 6.80 (dd, J = 0.9, 2.1 Hz, 1
1
3
(6) (a) Rashinkar, G. S.; Salunkhe, R. S. J. Mol. Catal. A: Chem.
010, 316, 146. (b) Kamble, S.; Kumbhar, A.; Rashinkar,
G.; Barge, M.; Salunkhe, R. Ultrason. Sonochem. 2012, 19,
12.
H), 2.41 (s, 3 H). C NMR (75 MHz, CDCl ): δ = 138.0 (C4′), 137.6
3
2
(
1
(
C8), 136.6 (C1′), 129.7 (C3′), 129.5 (C5′), 129.3 (C9), 125.0 (C2′),
25.0 (C6′), 122.1 (C6), 120.5 (C5), 120.2 (C7), 110.8 (C4), 99.4
C3), 21.2 (CH3).
8
(
7) (a) Zhou, C. X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126,
2302. (b) Zhou, C. X.; Larock, R. C. J. Org. Chem. 2006, 71,
3551.
Compound 7c
Pale yellow solid; mp 182–184 °C (lit. 185–187 °C); Rf = 0.38
1
2e
1
(
n-hexane–EtOAc = 8:2). H NMR (300 MHz, CDCl ): δ = 7.50 (m,
3
(8) Siu, J.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem.
004, 2, 160; and references cited therein.
1
7
3
1
H), 7.39 (d, J = 2.1 Hz, 1 H), 7.37–7.35 (m, 2 H), 7.06 (m, 1 H),
.01–6.96 (m, 2 H), 6.70 (d, J = 0.8 Hz, 1 H), 3.93 (s, 3 H), 3.88 (s,
2
(9) Katayama, S.; Ae, N.; Nagata, R. J. Org. Chem. 2001, 66,
H). 13C NMR (75 MHz, CDCl ): δ = 150.9 (C5′), 150.2 (C4′),
3
3474; and references cited therein.
39.6 (C8), 138.9 (C9), 130.9 (C1′), 127.8 (C2), 122.5 (C6), 121.0
(
10) (a) Larock, R. C.; Tian, Q.; Pletnev, A. A. J. Am. Chem. Soc.
999, 121, 3238. (b) Pletnev, A. A.; Larock, R. C.
(C2′), 120.5 (C5), 119.2 (C7), 113.4 (C6′), 112.0 (C3′), 110.4 (C4),
1
9
9.0 (C3), 56.7 (OCH ), 56.6 (OCH ).
3 3
Tetrahedron Lett. 2002, 43, 2133. (c) Pletnev, A. A.; Tian,
Q.; Larock, R. C. J. Org. Chem. 2002, 67, 9276. (d) Zhao,
L.; Lu, X. Angew. Chem. Int. Ed. 2002, 41, 4343. (e) Zhao,
B.; Lu, X. Tetrahedron Lett. 2006, 47, 6765. (f) Zhao, B.;
Lu, X. Org. Lett. 2006, 8, 5987. (g) Ueura, K.; Miyamura,
S.; Satoh, T.; Miyaura, M. J. Organomet. Chem. 2000, 595,
Compound 10c
1
2b
Light brown solid; mp 206–207 °C (lit. 203–205 °C); Rf = 0.38
1
(
n-hexane–EtOAc = 8:2). H NMR (300 MHz, CDCl ): δ = 8.28 (br
3
s, 1 H), 7.63 (d, J = 7.9 Hz, 1 H), 7.60–7.57 (m, 2 H), 7.43–7.40 (m,
1
3
3
H), 7.22 (m, 1 H), 7.14 (m, 1 H), 6.82 (m, 1 H). C NMR (75
31. (h) Shimizu, H.; Murakami, Y. C. Chem. Commun.
MHz, CDCl ): δ = 136.9 (C4′), 136.7 (C8), 133.4 (C9), 130.9 (C1′),
3
1
29.2 (C3′), 129.1 (C2′), 126.3 (C2′), 122.7 (C6), 120.7 (C5), 120.5
2007, 2855. (i) Wong, Y.-C.; Parthasarathy, K.; Cheng,
C.-H. Org. Lett. 2010, 12, 1736.
(
C7), 110.9 (C4), 100.4 (C3).
(
11) The complex (DMSO) Pd(O CCF ) has been well
2
2
3 2
Compound 14c
Yellow solid; mp 250–252 °C (lit. 254–255 °C);
hexane–EtOAc = 6:4). H NMR (300 MHz, DMSO-d ): δ = 11.56
characterized, see: Bancroft, D. P.; Cotton, F. A.;
Verbruggen, M. Acta Crystallogr., Sect. C: Cryst. Struct.
Commun. 1989, 45, 1289.
1
2h
Rf = 0.38 (n-
1
6
(
7
br s, 1 H), 8.72 (dd, J = 4.6, 1.3 Hz, 1 H), 8.53–8.31 (m, 2 H), 7.97–
.91 (m, 1 H), 7.88–7.85 (m, 1 H), 7.55–7.46 (m, 1 H), 7.41–7.34
(
12) (a) Kraus, G. A.; Guo, H. Org. Lett. 2008, 10, 3061.
(
3
b) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5,
843. (c) Sakai, N.; Annaka, K.; Fujita, A.; Sato, A.;
1
3
(
1
(
1
m, 1 H), 6.92–6.87 (m, 2 H). C NMR (75 MHz, DMSO-d ): δ =
6
46.7 (C5), 142.6 (C7), 140.8 (C8), 131.3 (C1′), 129.8 (C3′), 129.0
C5′), 128.2 (C4′), 125.3 (C2), 122 (C6), 117.0 (C2′), 116.5 (C6′),
00.1 (C3).
Konakahara, T. J. Org. Chem. 2008, 73, 4160. (d) Yamane,
Y.; Liu, X.; Hamasaki, A.; Ishida, T.; Haruta, M.;
Yokoyama, T.; Tokunaga, M. Org. Lett. 2009, 11, 5162.
(
e) Slätt, J.; Bergman, J. Tetrahedron 2002, 58, 9187.
Compound 15c
1
2f
(f) Zhao, J.; Zhang, Y.; Cheng, K. J. Org. Chem. 2008, 73,
7428. (g) Tsuchimoto, T.; Matsubayashi, H.; Kaneko, M.;
Nagase, Y.; Miyamura, T.; Shirakawa, E. J. Am. Chem. Soc.
2008, 130, 15823. (h) Koradin, C.; Dohle, W.; Rodriguez, A.
L.; Schmid, B.; Knochel, P. Tetrahedron 2003, 59, 1571.
White solid; mp 162–164 °C (lit. 166–169 °C); Rf = 0.5 (n-hex-
1
ane–EtOAc = 8:2). H NMR (300 MHz, CDCl ): δ = 8.55 (br s, 1
H), 7.65 (d, 2 H, J = 7.6 Hz), 7.52 (t, 2 H, J = 7.6 Hz), 7.25–7.36 (m,
3
2
H), 7.11 (d, J = 2.4 Hz, 1 H), 6.88 (dd, J = 8.8, 2.4 Hz, 1 H), 6.77
1
3
(
d, J = 1.9 Hz, 1 H), 3.88 (s, 3 H). C NMR (75 MHz, CDCl ): δ =
3
1
(
9
55.4 (C5), 138.5 (C8), 132.3 (C1′), 132.0 (C9), 129.7 (C3′), 129.0
C5′), 127.6 (C4′), 125.0 (C2′), 112.6 (C7), 111.6 (C6), 102.2 (C4),
9.8 (C3), 55.8 (OCH3).
©
Georg Thieme Verlag Stuttgart · New York
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