Palladium-catalyzed direct cyanation of indoles with K4[Fe(CN) 6]

Article abstract of DOI:10.1021/ol1000439

"Chemical equation presented" Direct cyanation of Indole derivatives has been achieved with nontoxic K₄[Fe(CN)₆] as cyanating agent through Pd-catalyzed C-H bond activation.

Full text of DOI:10.1021/ol1000439

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1052-1055
Palladium-Catalyzed Direct Cyanation of
Indoles with K4[Fe(CN)6]
Guobing Yan,†,‡ Chunxiang Kuang,‡ Yan Zhang,† and Jianbo Wang*,†,‡
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of
Chemistry, Peking UniVersity, Beijing 100871, China, and Department of Chemistry,
Tongji UniVersity, Shanghai 200092, China
wangjb@pku.edu.cn
Received January 8, 2010
ABSTRACT
Direct cyanation of indole derivatives has been achieved with nontoxic K4[Fe(CN)6] as cyanating agent through Pd-catalyzed C-H bond activation.
Aromatic nitriles have found wide applications as pharma-
ceuticals, agrochemicals, dyes, and so on.1 They are also
important intermediates in organic synthesis.2 Traditional
methods for introducing a cyano group into the aromatic ring
are Sandmeyer reaction3 and Rosenmund-von Braun reac-
tion.4 In both cases, copper(I) cyanide is used as cyanating
source. More recently, transition-metal-catalyzed cyanation
of aromatic halide has emerged as a more attractive method
to synthesize aromatic nitriles.5 In contrast to these reactions,
in which either aromatic halides or amines are used as
starting materials, direct cyanation through transition-metal-
catalyzed C-H bond activation is obviously more attractive.
Although transition-metal-catalyzed aromatic C-H bond
activation has witnessed explosive development in recent
years,6 there are only a few reports on cyanation through
direct C-H bond activation. Yu and co-workers in 2006
reported a chelation-assisted Cu-catalyzed cyanation of the
C-H bond using Me3SiCN and MeNO2 as cyanide sources.7
Subsequently, Cheng and co-workers disclosed their study
on Pd-catalyzed direct cyanation with copper(I) cyanide as
cyanating agent.8 The same group recently reported a
cyanation with safe and nontoxic potassium hexacyanofer-
rate(III) (K3[Fe(CN)6]) in a Pd-catalyzed cascade bromina-
tion/cyanation reaction.9 However, to our knowledge, tran-
sition-metal-catalyzed direct cyanation of the aromatic C-H
(5) For selected publications on transition-metal-catalyzed cyanation of
aryl halides in the past three years, see: (a) Ren, Y.; Liu, Z.; Zhao, S.;
Tian, X.; Yin, W.; He, S.; Wang, J. Catal. Commun. 2009, 10, 768. (b)
Ren, Y.; Wang, W.; Zhao, S.; Tian, X.; Wang, J.; Yin, W.; Cheng, L.
Tetrahedron Lett. 2009, 50, 4595. (c) Ren, Y.; Liu, Z.; He, S.; Zhao, S.;
Wang, J.; Niu, R.; Yin, W. Org. Process Res. DeV. 2009, 13, 764. (d)
Velmathi, S.; Leadbeater, N. E. Tetrahedron Lett. 2008, 50, 4693. (e) Buono,
F. G.; Chidambaram, R.; Mueller, R. H.; Waltermire, R. E. Org. Lett. 2008,
10, 5325. (f) Nandurkar, N. S.; Bhanage, B. M. Tetrahedron 2008, 64, 3655.
(g) Ryberg, P. Org. Process Res. DeV. 2008, 12, 540. (h) Schareina, T.;
Zapf, A.; Ma¨gerlein, W.; Mu¨ller, N.; Beller, M. Chem.sEur. J. 2007, 13,
6249. (i) Schareina, T.; Zapf, A.; Magerlein, W.; Muller, N.; Beller, M.
Tetrahedron Lett. 2007, 48, 1087.
† Peking University.
‡ Tongji University.
(1) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical
Substances: Syntheses, Patents, Applications, 4th ed.; Georg Thieme:
Stuttgart, 2001.
(2) (a) Larock, R. C. ComprehensiVe Organic Transformations: A Guide
to Functional Group Preparations; VCH: New York, 1989. (b) Rappoport,
Z. Chemistry of the Cyano Group; John Wiley & Sons: London, 1970; pp
121-312.
(6) For recent reviews: (a) Dick, A. R.; Sanford, M. S. Tetrahedron
2006, 62, 2439. (b) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006,
4, 4041. (c) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q.;
Lazareva, A. Synlett 2006, 3382. (d) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett
2008, 949.
(3) (a) Sandmeyer, T. Ber. Dtsch. Chem. Ges. 1884, 17, 1633. (b)
Hodgson, H. H. Chem. ReV. 1947, 40, 251. (c) Galli, C. Chem. ReV. 1988,
88, 765. (d) Merkushev, E. B. Synthesis 1988, 923. (e) Bohlmann, R. In
ComprehensiVe Organic Synthesis; Trost, B. M., ; Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 6, 203.
(7) Chen, X.; Hao, X. S.; Goodhue, C. E.; Yu, J. Q. J. Am. Chem. Soc.
2006, 128, 6790.
(4) (a) Rosenmund, K. W.; Struck, E. Ber. Dtsch. Chem. Ges. 1919, 2,
1749. (b) Lindley, J. Tetrahedron 1984, 40, 1433.
(8) Jia, X.; Yang, D.; Zhang, S.; Cheng, J. Org. Lett. 2009, 11, 4716.
10.1021/ol1000439  2010 American Chemical Society
Published on Web 02/08/2010

bond without chelation assistance is not known in the
literature.10 On the other hand, indoles represent an important
class of aromatic compounds frequently encountered in
natural products and pharmaceuticals.11 Transition-metal-
catalyzed selective and controllable C-H functionalization
of indoles has been extensively studied in recent years.12,13
Herein we report a Pd-catalyzed cyanation of indoles through
C-H bond activation. The reaction uses safe and nontoxic
K4[Fe(CN)6] as cyanating agent14 and selectively introduces
a cyano group into the 3-position of indoles with high
efficiency.
On the outset of this investigation, we used N-methylindole
1a as model substrate with K4[Fe(CN)6] to screen suitable
reaction conditions. In order to ensure sufficient solubility
of K4[Fe(CN)6], dipolar aprotic solvents such as DMF,
DMSO, N,N-dimethyl acetamide (DMA), and 1-methyl-2-
pyrrolidinone (NMP) were examined. C3 cyanation took
place in the presence of Pd(OAc)2 (10%) with Cu(OAc)2 (3
equiv) and O2 (1 atm) as oxidant in DMSO at 130 °C.
However, the homocoupling of 1a predominated under such
conditions, giving product 3a (Table 1, entry 1).15 To our
delight, we found that addition of potassium acetate (KOAc)
in above system could dramatically suppress the homocou-
pling (entry 2). Further optimization showed that reactions
in the other three solvents (DMF, DMA, NMP) gave almost
exclusively C3 cyanation product 2a, but the reactions took
Table 1. Optimization of Pd-Catalyzed Cyanation of 1a with
K4[Fe(CN)6]a
time yield
entry
solvent
DMSO
DMSO
DMF
DMA
NMP
base
additive
(h)
(%)b 2a/3ac
1
2
3
4
5
6
-
-
5
3
24
36
48
3
78
85
66
51
44
78
1:3
3:1
21:1
21:1
20:1
3:1
KOAc
KOAc
KOAc
KOAc
-
-
-
-
-
DMF/DMSO KOAc
(10:1)
7
8
9
10
11
12
DMF
DMF
DMF
DMF
DMF
DMF
CsOAc
NaOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
-
-
4
36
12
36
36
36
24
24
71
50
76
56
38
30
73
0
11:1
32:1
11:1
8:1
11:1
8:1
nBu4NCl
nBu4NBr
BnEt3NCl
3-NO2Py
-
13d DMF
18:1
-
14e
DMF
-
a Unless otherwise noted, the reaction conditions are as follows:
N-methylindole 1a (0.45 mmol), K4[Fe(CN)6] (0.5 equiv), Pd(OAc)2 (0.1
equiv), Cu(OAc)2 (3.0 equiv), base (2.0 equiv), additive (1.0 equiv) in
anhydrous solvent (5 mL), 130 °C, with O2 balloon. b Isolated yield. c Ratio
(9) Jia, X. F.; Yang, D. P.; Wang, W. H.; Luo, F.; Cheng, J. J. Org.
Chem. 2009, 74, 9470.
determined by H NMR. d The reaction was carried out at 150 °C. e The
1
(10) For cyanation of the C-H bond under non-metal-catalyzed condi-
tions, see: (a) Tamura, Y.; Kawasaki, T.; Adachi, M.; Tanio, M.; Kita, Y.
Tetrahedron Lett. 1977, 18, 4417. (b) Yoshida, K. Chem. Commun. 1978,
1108. (c) Smaliy, R. V.; Chaikovskaya, A. A.; Pinchuk, A. M.; Tolmachev,
A. A. Synthesis 2002, 2416.
reaction was carried out in the absence of Pd(OAc)2.
(11) For comprehensive reviews, see: (a) Crich, D.; Banerjee, A. Acc.
Chem. Res. 2007, 40, 151. (b) Humphrey, G. R.; Kuethe, J. T. Chem. ReV.
2006, 106, 2875. (c) Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873.
(12) For reviews, see: (a) Bandini, M.; Eichholzer, A. Angew. Chem.,
Int. Ed. 2009, 48, 9608. (b) Joucla, L.; Djakovitch, L. AdV. Synth. Catal.
longer with slightly decreased yields (entries 3-5). Reaction
with a mixed solvent of DMSO and DMF improved the yield,
but the ratio of 2a to 3a dropped significantly (entry 6).
Switch of KOAc to NaOAc or CsOAc could not significantly
increase the yields (entries 7 and 8). Adding additional
additives such as n-Bu4NCl, n-Bu4NBr, BnEt3NCl, or 3-ni-
tropyridine also failed to improve the reaction (entries 8-12).
The yield of the reaction and the ratio of 2a to 3a were
slightly improved by increasing reaction temperature (entry
13). Finally, a control experiment demonstrated that no
product 2a could be detected when the reaction was carried
out in the absence of Pd(OAc)2.
Under the optimized conditions, the substrate scope of this
reaction was investigated (Table 2).16 It was observed that
the reaction was significantly affected by electronic effects
of the substituents on the indole substrates. The reaction of
N-methylindole with electron-donating substituent on the
benzene ring of indole substrtates proceeded efficiently
(entries 2 and 3). On the contrary, for 5-nitro-N-methylindole,
2009, 351, 673
.
(13) For recent selected publications, see: (a) Brand, J. P.; Charpentier,
J.; Waser, J. Angew. Chem., Int. Ed. 2009, DOI: 10.1002/anie.200905419.
(b) Mutule, I.; Suna, E.; Olofsson, K.; Pelcman, B. J. Org. Chem. 2009,
74, 7195. (c) Yang, S. D.; Sun, C. L.; Fang, Z.; Li, B. J.; Li, Y. Z.; Shi,
Z. J. Angew. Chem., Int. Ed. 2008, 47, 1473. (d) Phipps, R. J.; Grimster,
N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172. (e) Lebrasseur, N.;
Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926. (f) Zhao, J. l.; Zhang, Y. H.;
Cheng, K. J. Org. Chem. 2008, 73, 7428. (g) Bellina, F.; Benelli, F.; Rossi,
R. J. Org. Chem. 2008, 73, 5529. (h) Potavathri, S.; Dumas, A. S.; Dwight,
T. A.; Naumiec, G. R.; Hammann, J. M.; DeBoef, B. Tetrahedron Lett.
2008, 49, 4050. (i) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (j)
Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129,
12072. (k) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef,
B. Org. Lett. 2007, 9, 3137. (l) Zhang, Z. Q.; Hu, Z. Z.; Yu, Z. X.; Lei, P.;
Chi, H. J.; Wang, Y.; He, R. Tetrahedron Lett. 2007, 48, 2415. (m) Wang,
X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72, 1476. (n) Nakao,
Y.; Kanyiva, K. S.; Oda, S.; Hiyama, T. J. Am. Chem. Soc. 2006, 128,
8146. (o) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am.
Chem. Soc. 2006, 128, 4972. (p) Bressy, C.; Alberico, D.; Lautens, M. J. Am.
Chem. Soc. 2005, 127, 13148. (q) Wang, X.; Lane, B. S.; Sames, D. J. Am.
Chem. Soc. 2005, 127, 4996. (r) Lane, B. S.; Brown, M. A.; Sames, D.
J. Am. Chem. Soc. 2005, 127, 8050. (s) Grimster, N. P.; Gauntlett, C.;
Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125. (t)
Capito, E.; Brown, J. M.; Ricci, A. Chem. Commun. 2005, 1854. (u) Lane,
B. S.; Sames, D. Org. Lett. 2004, 6, 2897. (v) Ma, S. M.; Yu, S. C.
Tetrahedron Lett. 2004, 45, 8419.
(16) Typical procedure for cyanation of indoles. Under O2 balloon or
open air, a reaction tube was charged with indoles (0.45 mmol), K4[Fe(CN)6]
(0.5 equiv), Pd(OAc)2 (10 mol %), Cu(OAc)2 (3 equiv), and dry DMF or
DMSO (5 mL). In the reaction with 1a-h, KOAc (2.0 equiv) was added.
The mixture was kept stirring at 130 or 150 °C for 2-36 h. After completion
of the reaction, the solution was extracted with ethyl acetate (3 × 10 mL),
then combined solution washed with H2O and brine, and dried over MgSO4.
Removal of the solvent under reduced pressure gave a crude product
which was purified on silica gel (petroleum ether/EtOAc) to afford the
products.
(14) For the first use of K4[Fe(CN)6] in Pd-catalyzed cyanation of aryl
halides, see: (a) Schareina, T.; Zapf, A.; Beller, M. Chem Commun. 2004,
1388. For a recent example, see: (b) DeBlase, C.; Leadbeater, N. E.
Tetrahedron 2010, 66, 1098.
(15) Liang, Z. J.; Zhao, J. L.; Zhang, Y. H. J. Org. Chem. 2010, 75,
170.
Org. Lett., Vol. 12, No. 5, 2010
1053

Table 2. Pd-Catalyzed Direct C-H Bond Cyanation of Indoles
1a-h with K4[Fe(CN)6]a
Table 3. Optimization of Pd-Catalyzed Cyanation of 4a with
K4[Fe(CN)6]a
Pd(OAc)2 Cu(OAc)2
entry solvent (mol %)
(equiv)
T (°C) t (h) yield (%)b
1
2
3
4
5
6
7
8
DMF
DMA
10
10
10
10
10
10
5
3
3
3
2
1
0
3
3
3
3
3
3
3
3
130
130
130
130
130
130
130
130
110
80
24
24
5
76
58
95
81
51
18
69
0
67
trace
92
67
86
78
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
6
entry
indole 1a-h
time (h) yield (2, %)b 2/3c
24
48
6
24
36
72
5
36
5
5
1
2
3
4
5
6
7
8
R1 ) Me, R2 ) H
24
12
12
48
24
24
24
24
73
74
81
trace
48
50
56
trace
18:1
>19:1
>19:1
-
>19:1
10:1
15:1
-
R1 ) Me, R2 ) Me
R1 ) Me, R2 ) OMe
R1 ) Me, R2 ) NO2
R1 ) Ph, R2 ) H
0
9
10
10
10
10
10
10
10
11c
12d
R1 ) p-MeOC6H4, R2 ) H
R1 ) Bn, R2 ) H
130
130
130
130
R1 ) H, R2 ) Me
13c e DMSO
,
14c f DMSO
,
a Reaction conditions: indoles 1a-h (0.45 mmol), K4[Fe(CN)6] (0.5
equiv), Pd(OAc)2 (0.1 equiv), Cu(OAc)2 (3.0 equiv), KOAc (2.0 equiv),
dry DMF (5 mL), 150 °C, under O2 balloon. b Isolated yield. c Ratio
a Unless otherwise noted, the reaction conditions are as follows: solvent
(5 mL), 4a (0.3 mmol), K4[Fe(CN)6] (0.5 equiv), under oxygen. b Isolated
yield. c Reaction was carried out under open air. d Reaction was carried
out under nitrogen. e K4[Fe(CN)6] (0.4 equiv). f K4[Fe(CN)6] (0.3 equiv).
1
determined by H NMR.
only a trace amount of the desired product could be detected
(entry 4). The substituent on the nitrogen showed marginal
effect on the reaction (entries 5-7), but reaction with an
indole substrate bearing no N-substituent provided trace
desired cyanation product (entry 8).
it would be desirable that all six cyanide anions in
K4[Fe(CN)6] were transferred into the product. This was
indeed possible, but the yields decreased gradually with the
decrease of K4[Fe(CN)6] (entries 13 and 14).
Since the only byproduct in this Pd-catalyzed cyanation
is homocoupling of indole at the C2 and C3 positions, we
then decided to examine the indole substrates with a
substituent at the C2 position. Thus, 1,2-dimethyl-1H-indole
4a was employed as a model substrate to screen suitable
reaction conditions for this type of indole substrate (Table
3). The cyanation product 5a was isolated in moderate to
good yields in the presence of 10% Pd(OAc)2 as catalyst
and Cu(OAc)2 (3.0 equiv)/O2 as oxidant in three different
solvents (DMF, DMA, and DMSO) at 130 °C (Table 3,
entries 1-3). The results indicated that DMSO was a better
reaction media than DMF and DMA, and in contrast to the
reaction of 1a, KOAc was not required for reaction of 4a.
We then attempted to reduce the catalyst and oxidant loading,
but under such conditions the yields decreased and the
reaction took longer (entries 4-7). We also found that
reaction temperature significantly affected the reaction. Only
trace quantities of the desired product could be detected at
80 °C, and the main byproduct was 1,2-dimethyl-1H-indol-
3-yl acetate (entry 10). We speculate that this may be
attributed to the difficulty of cyanide transfer from
K4[Fe(CN)6] when reaction temperature was below 120 °C.
Interestingly, comparable yield could be obtained by carrying
out the reaction under air instead of O2 (entry 11). However,
when the reaction was carried out under N2, only 67% of
the desired product was isolated and the reaction took much
longer. Finally, as in the case of cyanation of aryl halides,5
A series of 2-substituted indoles 4a-q were then subjected
to the optimized reaction conditions, and the results are
summarized in Figure 1.16 We observed that the reaction
was sensitive to the electronic nature of N-substituents of
the indole substrates. Both N-alkyl- and N-arylindoles were
smoothly converted to the 3-cyanoindoles under the standard
conditions (5a,d,g-n). The reaction also worked with indoles
without N-substituent (5b,c,e,f), whereas the indoles with
N-acetyl, N-phenylsulfonyl, or N-Boc substituents were
inactive under the same conditions (5o-q). The substituents
on the C2 position of indoles also affect the reaction (5f-j).
Electron-withdrawing groups, such as an ester group, com-
pletely deactivated the indole substrate (5h). However, the
electronic nature of substituents on the benzene ring of the
indoles had relatively less effect on the cyanation (5c-e).
A plausible mechanism for the cyanation of indoles is
proposed in Scheme 1. First, the cyanide anion is transmeta-
lated from K4[Fe(CN)6] to palladium to form Pd(II) species
A, which undergoes electrophilic palladation at the C3
position of the indole to afford intermediate B. Reductive
elimination occurs from intermediate B to give the product
along with a Pd(0) species, which was oxidized to Pd(II) by
Cu(II) and/or air to complete the catalytic cycle. A general
problem of metal-catalyzed cyanation is the deactivation of
the metal catalyst due to the formation of stable cyanide
complexes. Thus, controlling of the concentration of cyanide
ion is crucial for this type of reaction.5e,14 We attribute the
1054
Org. Lett., Vol. 12, No. 5, 2010

Scheme 1. Mechanistic Rationale
Encouraged by the success of direct cyanation of indoles,
we next attempted to explore the cyanation of other aromatic
systems under the same reaction conditions. Thus, electron-
rich arenes, including pyrrole, benzofuran, benzo[b]-
thiophene, benzo[d]thiazole, and benzo[d]oxazole, were
subjected to identical reaction conditions, but only a trace
amount of the cyanation products could be identified in all
cases. However, the reaction with electron-rich 1,3,5-
trimethoxybenzene afforded the expected product in 35%
yield (eq 1).
In summary, we have reported the first selective cyanation
of indoles through a Pd-catalyzed direct C-H bond func-
tionalization reaction. Current efforts are directed toward the
extension of the Pd-catalyzed cyanation to other electron-
rich arenes.
Figure 1. Pd-catalyzed direct C-H bond cyanation of indole 4a-q
with K4[Fe(CN)6]. Reaction conditions: indoles 4a-q (0.45 mmol),
K4[Fe(CN)6] (0.5 equiv), Pd(OAc)2 (10 mol %), Cu(OAc)2 (3
equiv), DMSO (5 mL), 130 °C, under air. bIsolated yield and
reaction time in parentheses.
Acknowledgment. The project is supported by NSFC and
973 Program (No. 2009CB825300).
success of this Pd-catalyzed cyanation to the slow liberation
of cyanide anion from K4[Fe(CN)6]. As a comparison, we
also carried out the cyanation with Me3SiCN or Zn(CN)2 as
cyanide sources under otherwise identical conditions. Only
trace amount of cyanation product could be obtained in both
cases.
Supporting Information Available: Experiment proce-
dure, characterization data, 1H and 13C NMR spectra for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL1000439
Org. Lett., Vol. 12, No. 5, 2010
1055