Indole cyanation via CH bond activation under catalysis of Ru(III)-exchanged NaY zeolite (RuY) as a recyclable catalyst

Article abstract of DOI:10.1016/j.cclet.2012.06.030

Selective 3-cyanation of indoles was achieved under heterogeneous catalysis of Ru(III)-exchanged NaY zeolite (RuY) as a recyclable catalyst, in combination with K₄[Fe(CN)₆] as a nontoxic, slow cyanide releasing agent. Under the aforementioned conditions, good yields of the desired products were obtained.

Full text of DOI:10.1016/j.cclet.2012.06.030

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 903–906
www.elsevier.com/locate/cclet
Indole cyanation via C–H bond activation under catalysis of
Ru(III)-exchanged NaY zeolite (RuY) as a recyclable catalyst
Alireza Khorshidi
Department of Chemistry, Faculty of Sciences, University of Guilan, P.O. Box: 41335-1914, Rasht, Iran
Received 11 April 2012
Available online 4 July 2012
Abstract
Selective 3-cyanation of indoles was achieved under heterogeneous catalysis of Ru(III)-exchanged NaY zeolite (RuY) as a
recyclable catalyst, in combination with K4[Fe(CN)6] as a nontoxic, slow cyanide releasing agent. Under the aforementioned
conditions, good yields of the desired products were obtained.
# 2012 Alireza Khorshidi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Cyanation; Indole; Zeolite; Heterogeneous; Catalysis
1. Introduction
Indole-containing structures have widespread occurrence in many pharmacologically and biologically active
compounds [1–4]. Aromatic nitriles are also, important building blocks of pharmaceuticals, dyes and agrochemicals
[5]. Cyanation of the aromatic rings, were classically achieved by Rosenmund–von Braun reaction [6] and Sandmeyer
reaction [7], where CuCN was used as cyanide source. In recent years, most attention has been paid to the metal-
catalyzed cyanation of aryl halides or cyanation via C–H bond activation of arens [8–10]. In this context, various –CN
sources have been used such as MCN (M = Cu, K, Na, Zn), K4[Fe(CN)6] [11,12], and more recently, CH3NO2 [13],
(CH3)2NCHO + NH3 [14], DMSO + NH4HCO3 [15], and DMF [16]. Little attention, however, has been paid to the
direct cyanation of indoles through C–H bond activation. Recently, we have been involved in the study of the
chemistry of indoles and ruthenium species as catalyst [17–20]. Limitations associated with recent reports on the direct
cyanation of indoles [15,16,21–24], prompted us to evaluate the catalytic activity of Ru(III)-exchanged NaY zeolite
(RuY), as a catalyst for this reaction. In this contribution, we now describe regioselective 3-cyanation of indoles under
heterogeneous catalysis of Ru(III)-exchanged NaY zeolite (RuY) as a recyclable catalyst, in combination with
K4[Fe(CN)6] as a nontoxic, slow cyanide releasing agent (Scheme 1).
2. Experimental
IR spectra were recorded on a Shimadzu FTIR-8400S spectrometer. 1H NMR and 13C NMR spectra were obtained
on a Bruker DRX-400 (or DRX-100) Avance spectrometer. Chemical shifts were expressed in ppm downfield from
E-mail address: rucatalyst@yahoo.com.
1001-8417/$ – see front matter # 2012 Alireza Khorshidi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.06.030

[(Scheme_1)TD$FIG]
904
A. Khorshidi / Chinese Chemical Letters 23 (2012) 903–906
Scheme 1. RuY catalyzed direct 3-cyanation of indoles.
tetramethylsilane. Melting points were measured on a Bu¨chi Melting Point B-540 instrument. The BET specific
surface areas were determined by nitrogen adsorption at liquid nitrogen temperature on a Sibata SA-1100 surface area
analyzer. X-ray diffraction measurements were recorded by a D8 Bruker Advanced diffractometer with Cu-Ka
radiation.
The Na-form of Y zeolite was converted into the H-form by repeated ion-exchange with 1 mol/L NH4NO3 solution
and subsequent calcination of the resulting filtered material in air at 550 8C. For the ion exchange with Ru3+ a ‘‘slurry-
filtration-wash’’ cycle [25], was applied using a 0.05 M ruthenium chloride solution in water (15 mL per g of zeolite).
The resulting material then heated overnight at 550 8C.
2-Methylindole (1 mmol, 131 mg), RuY (0.30 g), K4[Fe(CN)6] (1 equiv.), Cu(OAc)2 (3 equiv.), K2CO3 (2 equiv.)
and dry DMF were charged into a two-neck round-bottom flask connected to a condenser under a current of O2. The
flask was then heated in an oil bath at 110 8C for the appropriate time (Table 2). After completion of the reaction (as
indicated by TLC), the mixture was filtered and the catalyst washed thoroughly with ethyl acetate, then filtered and
dried. The filtrate was extracted with ethyl acetate (3 Â 10 mL) and the combined washings and extracts were washed
with water, dried over anhydrous sodium sulfate, and then concentrated in vacuum. The crude product was purified by
preparative TLC (n-hexane/ethyl acetate: 10/3). The filtered catalyst was washed with hot DMF and hot water to
remove inorganic waste and the recovered catalyst was reactivated at 550 8C.
Selected characterization data for 1,2-dimethyl-1H-indole-3-carbonitrile (3g): White solid, mp: 85–88 8C, IR
(KBr, cmÀ1); 740, 1053, 1254, 1410, 1475, 1544, 2204, 2850, 2924. 1H NMR (400 MHz, CDCl3, 25 8C): d 2.56 (s,
3H), 3.67 (s, 3H), 7.21–7.30 (m, 3H), 7.65 (d, 1H, J = 7.1 Hz). 13C NMR (100 MHz, CDCl3, 25 8C): d 11.94, 30.11,
84.79, 109.73, 116.49, 118.88, 121.92, 122.90, 126.95, 136.18, 145.60. Anal. Calcd. for C11H12N2: C, 76.71; H, 7.02;
N, 16.27; found: C, 76.71; H, 7.04; N, 16.27.
3. Results and discussion
First of all, using 2-methylindole as substrate, the reaction conditions were optimized with respect to catalyst-type
and loading, cyanide source, choice of solvent and temperature. The effect of catalyst-type and loading on the yield of
product is summarized in Table 1.
As it is shown, in the absence of catalyst, no formation of the desired product was observed (entry 1). It was also
found, that the presence of O2 (1 atm.) and Cu(OAc)2 (3 equiv.) was necessary to promote the reaction. This may be
Table 1
The effect of catalyst type and loading on the cyanation of 2-methylindole.
a
Entry
Catalyst
Particle
BET surface
area (m2/g)
Pore volume
(cm3/g)
Catalyst loading
(g per mmol of indole)b
Yield (%)
size (mm)
1
2
No catalyst
RuY
RuY
RuY
NaY
NaY
NaY
HY
–
–
628
’’
–
0
0
45
70
71
0
0.5
’’
0.282
0.15
0.30
0.50
0.15
0.30
0.50
0.15
0.30
0.50
3
’’
4
’’
’’
’’
5
’’
635
’’
0.284
6
’’
’’
3
7
’’
’’
’’
3
8
’’
647
’’
0.285
2
9
HY
’’
’’
’’
7
10
HY
’’
’’
6
a
The reaction was carried out according to general experimental procedure.
Ru content was found to be 6.57% by ICP method.
b

[(Scheme_2)TD$FIG]
A. Khorshidi / Chinese Chemical Letters 23 (2012) 903–906
O2
905
K4[Fe(CN)6]
CuI
RuIII
CuII
RuI
RuIIICN
Ru CN
R3
R2
CN
R2
R3
N
R1
R1
N
R2
N
R1
R3
Scheme 2. A plausible mechanistic pathway for the RuY catalyzed 3-cyanation of indoles.
attributed to a second redox cycle, which regenerates Ru(III) species (Scheme 2). In presence of these additives, the
best catalyst was found to be RuY, in an optimum loading of 0.30 g per mmol of 2-methylindole (entry 3). Parent NaY
zeolite and its acidic form (HY) on the other hand, were not as effective as RuY.
Other physico-chemical properties of the zeolites are also, embedded in Table 1. As it is shown, a correlation
between the reaction yield and the particle size, pore size, acidity and BET surface areas of the zeolites could not be
established (entries 2–10). This may decline the Lewis-acid role of the catalyst and strengthen a plausible mechanistic
pathway, based on transmetalation of CNÀ from K4[Fe(CN)6] to Ru(III), electrophilic ruthenation at the C3 position of
indole and then reductive elimination of the product [21]. Reduced Ru(I) species, then undergo oxidation to regenerate
Ru(III) by a second Cu(II)/Cu(I) cycle in the presence of O2 (Scheme 2).
Solvent screening experiments showed that the yields were solvent dependent and the best solvent was found to
be DMF (110 8C). Finally, in order to minimize the formation of homocoupling side products [21], K2CO3 was
used as an additive which resulted in the best conditions. With the optimized conditions in hand (Scheme 1),
various indoles were used and indicated the generality and scope of the reaction. Typical results are shown in
Table 2. Treatment of 2-methylindole (1 mmol, 131 mg) with K4[Fe(CN)6] (1 equiv.) in the presence of Ru(III)-
exchanged NaY zeolite (RuY, 0.30 g, activated at 550 8C for 3 h) at 110 8C for 6 h gave 2-methylindole-3-
carbonitrile in 70% isolated yield (entry 1). Addition of Cu(OAc)2 (3 equiv.) and K2CO3 (2 equiv.) however, was
necessary to promote the reaction and to minimize the formation of uncharacterized side products. The reaction
can be used for cyanation of substituted indoles with either electron donating or electron withdrawing groups
(Table 2, entries 2–8). The same regioselectivity toward cyanation of C3 was observed in each case. In order to
evaluate reusability of the catalyst, the reaction was carried out in presence of the recycled catalyst (see Section 2)
in successive runs. Only 15% loss of efficiency in terms of the product yield was observed after five runs, which
promises minimization of the waste.
Table 2
RuY catalyzed direct 3-cyanation of various indoles with K4[Fe(CN)6].
Entrya
Indole
Product
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
R1 = H, R2 = Me, R3 = H
R1 = Me, R2 = H, R3 = H
R1 = H, R2 = H, R3 = H
R1 = H, R2 = H, R3 = Br
R1 = H, R2 = H, R3 = OMe
R1 = H, R2 = Ph, R3 = H
R1 = Me, R2 = Me, R3 = H
R1 = H, R2 = H, R3 = Cl
2-Methyl-1H-indole-3-carbonitrile 3a
1-Methyl-1H-indole-3-carbonitrile 3b
Indole-3-carbonitrile 3c
6
6
70
71
63
61
66
64
77
63
10
11
8
5-Bromo-1H-indole-3-carbonitrile 3d
5-Methoxy-1H-indole-3-carbonitrile 3e
2-Phenyl-1H-indole-3-carbonitrile 3f
1,2-Dimethyl-1H-indole-3-carbonitrile 3g
5-Chloro-1H-indole-3-carbonitrile 3h
7
4
12
a
All products were characterized by 1H NMR, 13C NMR and IR data.
Isolated yields.
b

906
A. Khorshidi / Chinese Chemical Letters 23 (2012) 903–906
4. Conclusions
In conclusion, we have developed a more convenient method for 3-cyanation of indoles. The present protocol has
several advantages such as milder reaction conditions, higher yields, lower reaction times and reusability of the
catalyst.
Acknowledgments
Partial support of this study by the Research Council of University of Guilan is gratefully acknowledged.
References
[1] M. Bandini, A. Eichholzer, Angew. Chem. Int. Ed. 48 (2009) 9608.
[2] R.J. Sundberg, The Chemistry of Indoles, Academic Press, New York, USA, 1996.
[3] J.Y. Sun, H.X. Lou, H. Xu, S.J. Dai, K. Liu, Chin. Chem. Lett. 18 (2007) 1084.
[4] J. Yang, J. Zhang, T.T. Chen, D.M. Sun, J. Li, X.F. Wu, Chin. Chem. Lett. 22 (2011) 1391.
[5] A. Kleemann, J. Engel, B. Kutscher, D. Reichert, Pharmaceutical Substances: Synthesis, Patents, Applications, 4th ed., Thieme, Stuttgart,
Germany, 2001.
[6] K.W. Rosenmund, E. Struck, Ber. Dtsch. Chem. Ges. 2 (1919) 1749.
[7] T. Sandmeyer, Ber. Dtsch. Chem. Ges. 17 (1884) 1633.
[8] G.A. Ellis, T.M. Romney-Alexander, Chem. Rev. 87 (1987) 779.
[9] V.V. Grushin, H. Alper, Chem. Rev. 94 (1994) 1047.
[10] T. Schareina, A. Zapf, M. Beller, Chem. Commun. (2004) 1388.
[11] X.F. Jia, D.P. Yang, W.H. Wang, F. Luo, J.J. Cheng, Org. Chem. 74 (2009) 9470.
[12] C. DeBlase, N.E. Leadbeater, Tetrahedron 66 (2010) 1098.
[13] X. Chen, X.S. Hao, C.E. Goodhue, J.Q. Yu, J. Am. Chem. Soc. 128 (2006) 6790.
[14] J. Kim, S.J. Chang, J. Am. Chem. Soc. 132 (2010) 10272.
[15] X. Ren, J. Chen, F. Chen, J. Cheng, Chem. Commun. 47 (2011) 6725.
[16] S. Ding, N.J. Jiao, J. Am. Chem. Soc. 133 (2011) 12374.
[17] A. Khorshidi, Ultrason. Sonochem. 19 (2012) 570.
[18] A. Khorshidi, K. Tabatabaeian, J. Mol. Catal. A: Chem. 344 (2011) 128.
[19] K. Tabatabaeian, M. Mamaghani, N.O. Mahmoodi, A. Khorshidi, Can. J. Chem. 87 (2009) 1213.
[20] K. Tabatabaeian, M. Mamaghani, N.O. Mahmoodi, A. Khorshidi, Synth. Commun. 40 (2010) 1677.
[21] G. Yan, C. Kuang, Y. Zhang, J. Wang, Org. Lett. 12 (2010) 1052.
[22] Y. Yang, Y. Zhang, J. Wang, Org. Lett. 13 (2011) 5608.
[23] B.V. Subba Reddy, Z. Begum, Y. Jayasudhan Reddy, J.S. Yadav, Tetrahedron Lett. 51 (2010) 3334.
[24] E. Kianmehr, M. Ghanbari, N. Faghih, F. Rominger, Tetrahedron Lett. 53 (2012) 11900.
[25] J.M. Kim, J.H. Kwak, S. Jun, R. Ryoo, J. Phys. Chem. 99 (1995) 16742.