Synthesis of 3-acylindoles by palladium-catalyzed acylation of free (N-H) indoles with nitriles

Article abstract of DOI:10.1021/ol303440y

An efficient palladium-catalyzed synthesis of 3-acylindoles using free (N-H) indoles and nitriles has been developed. The acylation reaction proceeded well under the Pd(OAc)₂/2,2′-bipyridine system and with d-(+)-camphorsulfonic acid as the additive. A possible mechanism involving carbopalladation of nitriles and subsequent hydrolysis of ketimines is proposed.

Full text of DOI:10.1021/ol303440y

ORGANIC
LETTERS
2013
Vol. 15, No. 4
788–791
Synthesis of 3‑Acylindoles by
Palladium-Catalyzed Acylation of
Free (NꢀH) Indoles with Nitriles
Tao-Shan Jiang and Guan-Wu Wang*
CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical
Sciences at Microscale, and Department of Chemistry, University of Science and
Technology of China, Hefei, Anhui 230026, P. R. China
gwang@ustc.edu.cn
Received December 17, 2012
ABSTRACT
An efficient palladium-catalyzed synthesis of 3-acylindoles using free (NꢀH) indoles and nitriles has been developed. The acylation reaction
proceeded well under the Pd(OAc)2/2,20-bipyridine system and with D-(þ)-camphorsulfonic acid as the additive. A possible mechanism involving
carbopalladation of nitriles and subsequent hydrolysis of ketimines is proposed.
Since indoles exist abundantly in many biologically active
natural products and pharmaceutical compounds,1 their
synthesis and further functionalization are of considerable
importance.2,3 Among many efforts, 3-acylation of indoles
attracts much interest due to their versatile synthetic values
and core structures in many biologically active indole deri-
vatives, such as alkaloids, inhibitors of HIV-1 integrase, and
anticancer and antidiabetic compounds.4 To date, the well-
known synthetic procedures of 3-acylindoles mainly include
FriedelꢀCrafts acylations (Scheme 1, a),5 VilsmeierꢀHaack
type reactions,6 and indole Grignard reactions.7 Other meth-
ods involve nitrilium salts with dialkyl carbenium ions8 and
pyridinium salts.9 As an indole is multiatom and highly
nucleophilic in nature, the most frequently used Friedelꢀ
Crafts acylation requires troublesome N-protection, espe-
cially for indoles bearing an electron-donating group with a
stoichiometric Lewis acid promoter and strict exclusion of
moisture.5 The existing methods often involve uncommonly
used acylated reagents or unbenign reaction conditions.6ꢀ9
Therefore, a novel and operationally simple acylation reac-
tion of indoles is highly desired. Recently, Su and co-workers
reported a convenient and general method for formylation
and acylation of free (NꢀH) indoles via Ru- or Fe-catalyzed
oxidative coupling using anilines as the carbonyl source
(Scheme 1, b).10
(1) Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis II;
Wiley-VCH: Weinheim, 2003.
(2) For recent reviews on Pd-catalyzed indole synthesis and applica-
tions, see: (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (b)
Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215.
(3) For selected recent reviews of indole FriedelꢀCrafts type reac-
tions, see: (a) Poulsen, T. B.; Jøgensen, K. A. Chem. Rev. 2008, 108,
2903. (b) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48,
9608. (c) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38, 2190.
(d) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39,
4449.
(4) (a) Pais, G. C. G.; Zhang, X.; Marchand, C.; Neamati, N.;
Cowansage, K.; Svarovskaia, E. S.; Pathak, V. K.; Tang, Y.; Nicklaus,
M.; Pommier, Y.; Burke, T. R. J. Med. Chem. 2002, 45, 3184. (b)
Barreca, M. L.; Ferro, S.; Rao, A.; Luca, L. D.; Zappala, M.; Monforte,
A.-M.; Debyser, Z.; Witvrouw, M.; Chimirri, A. J. Med. Chem. 2005, 48,
7084. (c) Wu, Y.-S.; Coumar, M. S.; Chang, J.-Y.; Sun, H.-Y.; Kuo,
F.-M.; Kuo, C.-C.; Chen, Y.-J.; Chang, C.-Y.; Hsiao, C.-L.; Liou, J.-P.;
Chen, C.-P.; Yao, H.-T.; Chiang, Y.-K.; Tang, U.-K.; Chen, C.-T.; Chu,
C.-Y.; Wu, S.-Y.; Yeh, T.-K.; Lin, C.-Y.; Hsieh, H.-P. J. Med. Chem.
2009, 52, 4941.
(5) (a) Ketcha, D. M.; Gribble, G. W. J. Org. Chem. 1985, 50, 5451.
(b) Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh, K.; Yoshino,
H. Org. Lett. 2000, 2, 1485. (c) Ottoni, O.; Neder, A. de, V. F.; Dias,
A. K. B.; Cruz, R. P. A.; Aquino, L. B. Org. Lett. 2001, 3, 1005. (d)
Katritzky, A. R.; Suzuki, K.; Singh, S. K.; He, H.-Y. J. Org. Chem. 2003,
68, 5720. (e) Wynne, J. H.; Lloyd, C. T.; Jensen, S. D.; Boson, S.; Stalick,
W. M. Synthesis 2004, 2277. (f) Guchhait, S. K.; Kashyap, M.; Kamble,
H. J. Org. Chem. 2011, 76, 4753.
(6) Sundberg, R. J. The Chemistry of Indoles; Academic Press:
New York, 1970 and references cited therein.
(7) Bergman, J.; Venemalm, L. Tetrahedron Lett. 1987, 28, 3741.
(8) Powers, J. C. J. Org. Chem. 1965, 30, 2534.
(9) Bergman, J.; Backvall, J.-E.; Lindstrom, J.-O. Tetrahedron 1973,
29, 971.
r
10.1021/ol303440y
Published on Web 01/25/2013
2013 American Chemical Society

(NꢀH) indoles with nitriles catalyzed by a Pd(II) species
may lead to 3-acylindoles (Scheme 1, c).16
Scheme 1. Synthesis of 3-Acylindoles
To prove our working hypothesis, we firstperformed the
reaction of indole 1a (23.4 mg, 0.2 mmol) with 4-methyl-
benzonitrile 2a (2 equiv) in the presence of Pd(OAc)2
(10 mol %), 2,20-bipyridine (12 mol %), and H2O (2 equiv)
in 1 mL of the chosen solvent. To our delight, when HOAc
and DMA wereusedasthesolvent, thedesiredproduct3aa
was obtainedin 20% and 23% yields, respectively(Table1,
entries 1 and 2). Although the reaction in entry 1 gave a
poor yield, 2a was completely consumed due to the hydro-
lysis of nitrile itself. In entry 2, large amounts of 1a and 2a
remained. Then various acids were screened as the additive
to examine their effect on the reaction. Gratifyingly, the
yield was improved to 51% (Table 1, entry 3) when 2 equiv
of MeSO3H was employed. Other acids including pivalic
acid and TFA were not beneficial to the catalytic system
(Table 1, entries 4 and 5). The yield was slightly increased
to 56% when the volume of the solvent was decreased from
1.0 to 0.5 mL (Table 1, entry 6). Further optimizations
(Table 1, entries 7ꢀ10) allowed the use of fewer amounts of
2aand the acid (1.5 equiv of 2a, 1.5 equiv of MeSO3H) with
comparable yields (Table 1, entry 7 vs 6). The influence of
solvent onthereactionefficiencywas alsosignificant;when
N-methylacetamide (NMA) was chosen as the solvent, the
yield was enhanced to 68% (Table 1, entry 11). Further-
more, replacing the additive MeSO3H with D-(þ)-cam-
phorsulfonic acid (D-CSA) provided the desired product in
74% yield (Table 1, entry 12). Much to our pleasure, the
reaction at a larger scale with less catalyst and additive
loading by using 0.4 mmol of 1a, 0.6 mmol of 2a, 5 mol %
of Pd(OAc)2, 6 mol % of 2,20-bipyridine, and 2 equiv of
H2O at120 °C in 1.0 mLofsolvent for 36h furnished3aa in
75% yield, slightly higher than that at the 0.2 mmol scale
(Table 1, entry 13 vs 12). The reaction did not occur in the
absence of a palladium catalyst (Table 1, entry 14).
In the 1970s, transition-metal-catalyzed synthesis of aryl
ketones through the carbopalladation of nitriles and sub-
sequent hydrolysis of ketimine intermediates was first
reported.11 In recent years, this methodology has attracted
much attention from the Larock group,12 the Lu group,13
and others.14 In these reactions, the in situ formed transition
metal complex reacts with a nitrile through carbometalation
to give a nitrile addition product. Protonation of the addi-
tion product affords a ketimine, and subsequent hydrolysis
under acidic conditions provides an aryl ketone (Scheme 2).
Our group recently developed an efficient protocol for
the Pd(II)-catalyzed desulfitative addition reaction of ar-
ylsulfinic acids with nitriles to afford a variety of aryl
Scheme 2. General Process for the Reaction of Palladium
Complex with Nitrile
Withthe optimized reactionconditionsin hand (Table 1,
entry 13), the substrate scope and limitation for the Pd-
catalyzed reaction of indoles with nitriles was explored and
is summarized in Scheme 3. Both electron-withdrawing
and -donating substitutents on the phenyl rings of nitriles
and indoles were suitable for the reaction, giving 3-acylin-
doles in good to excellent yields. For aryl nitriles, the
electron-withdrawing groups on the aromatic ring were
generally preferable to the electron-donating groups
(3afꢀai vs 3aaꢀae). However, the ortho substituted nitrile
did not give the desired product due to the steric hindrance
effect (3ac). Notably, the CꢀBr bond remained intact
during the reaction and product 3ag was obtained in
excellent yield (91%), providing an attractive and useful
handle to introduce new groups for further modification of
indole products. 4-Cyanopyridine was also tolerant and
afforded product 3aj in moderate yield (61%) under a
higher catalyst loading and prolonged reaction time. We
then selected various substituted indoles to react with
ketones.15 The acylation of free (NꢀH) indoles is more
challenging than that of N-substituted indoles. As a con-
tinuous work, we envisioned that the acylation of free
(10) Wu, W.; Su, W. J. Am. Chem. Soc. 2011, 133, 11924.
(11) Garves, K. J. Org. Chem. 1970, 35, 3273.
(12) (a) Larock, R. C.; Tian, Q.; Pletnev, A. A. J. Am. Chem. Soc.
1999, 121, 3238. (b) Pletnev, A. A.; Tian, Q.; Larock, R. C. J. Org. Chem.
2002, 67, 9276. (c) Zhou, C.; Larock, R. C. J. Am. Chem. Soc. 2004, 126,
2302. (d) Zhou, C.; Larock, R. C. J. Org. Chem. 2006, 71, 3551.
(13) (a) Zhao, B.; Lu, X. Tetrahedron Lett. 2006, 47, 6765. (b) Lu, X.;
Zhao, B. Org. Lett. 2006, 8, 5987.
(14) (a) Ueura, K.; Miyamura, S.; Satoh, T.; Miura, M. J. Organo-
met. Chem. 2006, 691, 2821. (b) Shimizu, H.; Murakami, M. Chem.
Commun. 2007, 2855. (c) Lindh, J.; Sjoerg, P. J. R.; Larhed, M. Angew.
Chem., Int. Ed. 2010, 49, 7733. (d) Wong, Y.-C.; Parthasarathy, K.;
Cheng, C.-H. Org. Lett. 2010, 12, 1736. (e) Tsui, G. C.; Glenadel, Q.;
Lau, C.; Lautens, M. Org. Lett. 2011, 13, 208. (f) Behrends, M.;
€
€
Savmarker, J.; Sjoberg, P. J. R.; Larhed, M. ACS Catal. 2011, 1, 1455.
(g) Liu, J.; Zhou, X.; Rao, H.; Xiao, F.; Li, C.-J.; Deng, G.-J. Chem.;
Eur. J. 2011, 17, 7996.
(16) After our work had been finished, a completely independent
report on the palladium-catalyzed addition of indoles to nitriles under
different conditions appeared: Ma, Y.; You, J.; Song, F. Chem.;Eur. J.
2013, 19, 1189.
(15) Miao, T.; Wang, G.-W. Chem. Commun. 2011, 47, 9501.
Org. Lett., Vol. 15, No. 4, 2013
789

Table 1. Optimization of Reaction Conditionsa
Scheme 3. Palladium-Catalyzed Acylation of Indoles with
Nitrilesa
2a
additive
(equiv)
solvent
(mL)
temp
yield
(%)
entry
(equiv)
(°C)
1
2
none
HOAc (1)
DMA (1)
120
120
120
120
120
120
120
120
120
100
120
120
120
120
20
23
51
27
trace
56
55
50
48
33
68
74
75
nr
2
2
none
3
2
MsOH (2)
PivOH (2)
TFA (2)
DMA (1)
4
2
DMA (1)
5
2
DMA (1)
6
2
MsOH (2)
MsOH (1.5)
MsOH (1.5)
MsOH (1.2)
MsOH (1.5)
MsOH (1.5)
D-CSA (1.5)
D-CSA (1.5)
D-CSA (1.5)
DMA (0.5)
DMA (0.5)
DMA (0.5)
DMA (0.5)
DMA (0.5)
NMA (0.5)
NMA (0.5)
NMA (1.0)
NMA (0.5)
7
1.5
1.2
1.5
1.5
1.5
1.5
1.5
1.5
8
9
10
11
12
13b
14c
a Unless otherwise specified, all reactions were carried out using 1a
(0.2 mmol), Pd(OAc)2 (10 mol %), 2,20-bipyridine (12 mol %), and H2O
(0.4 mmol) for 24 h. b Reaction conditions: 0.4 mmol scale, 5 mol % of
Pd(OAc)2, 6 mol % of 2,20-bipyridine, and 2 equiv of H2O in 1.0 mL of
solvent for 36 h. c The reaction was carried out without Pd(OAc)2.
D-CSA: D-(þ)-camphorsulfonic acid. DMA: N,N-dimethylacetamide.
NMA: N-methylacetamide.
4-chlorobenzonitrile; the corresponding products 3bfꢀef
were obtained in 73ꢀ86% yields. For the reactions with
2-methylindole and 6-fluoroindole, a longer reaction time
was required to give satisfactory yields of 3bf and 3ef. We
finally examined the reaction of indoles with alkyl nitriles.
Phenylacetonitrile is known to smoothly react with other
types of substrates.12,14a,14c,14e,14f,15 Nevertheless, no de-
sired product (3ak) was detected in our catalytic system.
Interestingly, when 4-phenylbutanenitrile was used, prod-
uct 3al could be generated in 50% yield. To our pleasure,
replacing the nitriles with 1 mL of acetonitrile allowed the
reaction to proceed very well and provided 3-acylindoles
3amꢀem in 76ꢀ95% yields under our optimized condi-
tions. The yields for indoles bearing electron-rich groups
were higher than those with electron-deficient groups.
Even the sterically hindered 2-phenyl-1H-indole could
undergo acylation well, and 3fm was obtained in 92%
yield. When cyanoacetic acid or ethyl cyanoacetate was
used, the same product 3am was formed via a decarbox-
ylative process.
a Reaction conditions: 1 (0.4 mmol), 2 (0.6 mmol) and Pd(OAc)2
(5 mol %), 2,20-bipyridine (6 mol %), D-CSA (0.6 mmol), H2O (0.8 mmol)
b
in NMA (1.0 mL) at 120 °C for 36 h. Pd(OAc)2 (10 mol %), 2,20-
bipyridine(12mol %). c The reactiontimewas48 h. d 1 mLofCH3CN was
e
f
used. 5.0 equiv of 2-cyanoacetic acid was used. 5.0 equiv of ethyl
2-cyanoacetate was used.
Based on the previous literature14c,f,g,15 and particularly
the electronspray ionization mass spectrometry (ESI/MS)
study14c,f on similar reactions, a plausible mechanism to
rationalize the acylation reaction is shown in Scheme 4. In
the presence of a strong Brønsted acid, the free (NꢀH)
indoles can easily form the iminium salt by protonation of
the carbonꢀcarbon double bond.17 Then the reaction
pathway involves the following key steps: (1) palladation
at C3 of an indole with [(bpy)Pd(OAc)2] A gives an active
(17) (a) Hinman, R. L.; Shull, E. R. J. Org. Chem. 1961, 26, 2339. (b)
Chen, C.-B.; Wang, X.-F.; Cao, Y.-J.; Cheng, H.-G.; Xiao, W.-J. J. Org.
Chem. 2009, 74, 3532. (c) Wang, D.-S.; Chen, Q.-A.; Li, W.; Yu, C.-B.;
Zhou, Y.-G.; Zhang, X. J. Am. Chem. Soc. 2010, 132, 8909.
790
Org. Lett., Vol. 15, No. 4, 2013

the nitrile forms ketimine complex D; (4) protonation of
thecomplex D toaffordthefreeketimine E andsubsequent
hydrolysis lead to 3-acylindole. In this catalytic system, the
strong Brønsted acid D-CSA plays important roles: it may
activate indole to form the iminium salt as well as promote
the formation of cationic palladium complex B and the
hydrolysis of ketimine E.
Scheme 4. Possible Reaction Mechanism for the Formation of
3-Acylindoles
In conclusion, we have successfully developed an effi-
cient strategy for the palladium(II)-catalyzed addition
reaction of free (NꢀH) indoles with nitriles to afford a
variety of 3-acylindoles in good to excellent yields. In the
present protocol, the challenging acylation of free (NꢀH)
indoles is accomplished in the presence of D-(þ)-camphor-
sulfonic acid and 2,20-bipyridine, broadening the scope of
indole reactions.
Acknowledgment. We are grateful for financial support
from the NSFC (91021004), National Basic Research
Program of China (2011CB921402), and Key Project of
Science and Technology of the Department of Education,
Anhui Province, China (KJ2010ZD05).
Supporting Information Available. Detailed experimen-
tal procedures including spectroscopic and analytical
data. This material is available free of charge via the
Internet at http://pubs.acs.org.
cationic palladium complex B; (2) coordination of the
nitrile generates intermediate C; (3) carbopalladation of
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
791