Iron-mediated cyanation of methoxybenzene, indole, and 2-arylpyridine C-H bonds

Article abstract of DOI:10.1055/s-0031-1289883

An iron-mediated direct cyanation of indole and 2-arylpyridine C-H bonds is described. Notably, trimethoxybenzene reacted smoothly under the procedure, forming a C-CN bond via C-H bond cleavage without chelation assistance. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289883

LETTER
2991
Iron-Mediated Cyanation of Methoxybenzene, Indole, and 2-Arylpyridine
C–H Bonds
a
a
b
a
a
C
G
yanation of Meth
u
oxybenzene,
a
Indole,
a
nd
n
2-Arylpyrid
g
ine C–H
B
o
y
nds ou Zhang, Guanglei Lv, Changduo Pan, Jiang Cheng, Fan Chen*
a
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325000, P. R. of China
Fax +86(577)56998939; E-mail: fanchen@wzu.edu.cn
b
Wenzhou Institute of Industry & Science, Wenzhou 325000, P. R. of China
Received 4 September 2011
simple method to access aromatic nitriles still remains a
highly desirable goal in synthetic chemistry.
Abstract: An iron-mediated direct cyanation of indole and 2-
arylpyridine C–H bonds is described. Notably, trimethoxybenzene
reacted smoothly under the procedure, forming a C–CN bond via As a transition-metal catalyst, iron is highly attractive
C–H bond cleavage without chelation assistance.
19
from both environmental and economic points of view.
Key words: iron, indole, 2-arylpyridine, C–H activation, cyanation Although the iron-catalyzed formation of C–C and C–het-
eroatom bonds has become popular in recent years, iron-
catalyzed C–C bond formation via C–H bond functional-
2
0
ization has been less widely reported. Our interest in the
transition-metal-catalyzed cyanation reaction and C–H
Benzonitriles are of substantial interest in organic chem-
istry as integral ingredients of dyes, herbicides, natural
products, agrochemicals, and pharmaceuticals. In addi-
1
bond functionalization spurred us to test the feasibility of
iron as a catalyst in such transformations.7
b,10,21
Herein,
tion, they are versatile intermediates for further transfor-
2
3
mations in synthetic organic chemistry. Sandmeyer and
Table 1 Selected Results of Screening the Optimal Conditionsa
4
Rosenmund–von Braun reactions are classical methods
OMe
OMe
CN
OMe
for the synthesis of aromatic nitriles. Alternative methods
involve the transition-metal-catalyzed cyanation of aryl
Fe, oxidant
CuCN
5
–7
MeO
MeO
halides or arylboronic acids. However, prefunctional-
ization, such as amination and halogenation, is required
for the aforementioned transformations.
OMe
1a
2a
The direct conversion of C–H bonds into C–C, C–O, C–
N, and C–S bonds is a very powerful methodology for
building complex molecules, and the direct cyanation
through C–H bond cleavage is an attractive method to ob-
tain aromatic nitriles. In 2006, Yu reported a copper-cata-
Yield (%)b
Entry Fe sources
Oxidant
–
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
8
1
2
3
4
5
6
7
8
9
0
FeI2
FeI2
80c
40
35
54
83d
61
55
70
42
<5
24
31
63
44
K S O
2
2
8
FeI2
BQ
lyzed cyanation of the 2-arylpyridine C–H bonds using
9
TMSCN or MeNO as cyanide sources. In 2009, we also
2
FeI2
Cu(OAc)2
demonstrated a chelation-assisted palladium-catalyzed di-
rect cyanation and cascade bromination–cyanation reac-
FeI2
PhI(OAc)2
1
0
tion of arene C–H bonds. Subsequently, Chang
described a palladium-catalyzed cyanation of 2-arylpyri-
dine C–H bonds, using a combination of DMF and ammo-
FeBr3
PhI(OAc)2
FeBr
FeCl ×6H O
PhI(OAc)
2
2
1
1
nia as a new cyanide source. Recently, Daugulis
demonstrated the cyanation of heteroarenes possessing an
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
3
2
1
2
13
14
acidic C–H bond. Very recently, Reddy, Wang,
FeF2
1
5
16
Jiao, and we independently developed the palladium-
catalyzed cyanation of indole C–H bonds. However, a het-
1
Fe(acac)3
FeI2
eroatom was required for such transformations and the cy- 11
anation of simple arenes, even the highly electron-rich
1
2
FeI2
toluene
DMSO
DMF
substrates, such as 1,3,5-trimethoxybenzene, remains a
1
7
great challenge for organic chemists. In 2010, Hartwig
described a cyanation of arenes by C–H borylation fol-
1
3
FeI2
1
8
14
–
lowed by cyanation. Nevertheless, the development of a
a
Reaction conditions: 1a (0.2 mmol), CuCN (0.25 mmol), Fe source
(
30 mol%), oxidant (0.6 equiv), dry solvent (2 mL), 130 °C, 20 h, un-
der air.
SYNLETT 2011, No. 20, pp 2991–2994
Advanced online publication: 11.11.2011
DOI: 10.1055/s-0031-1289883; Art ID: W19311ST
x
x
.x
x
.2
0
1
1
b
Isolated yield.
Under air.
c
d
Reaction time: 8 h.
©
Georg Thieme Verlag Stuttgart · New York

2
992
G. Zhang et al.
LETTER
we report an iron-mediated cyanation of trimethoxyben- ple, 1-methyl-2-phenyl-1H-indole (1i) provided the cya-
zene, indole, and 2-arylpyridine C–H bonds.
nation product 2i in 78% yield. Disappointingly, the free
indole failed to deliver the cyanated product.
We began our investigation by examining the FeI -medi-
2
ated cyanation of 1,3,5-trimethoxybenzene with CuCN as
the model reaction (Table 1). We first focused on the oxi-
dant screening and found that air showed good activity,
producing the cyanation product in 80% yield in 20 hours
Table 2 Iron-Mediated Cyanation of Indolea
H
CN
FeI2 (30 mol%)
R
+
CuCN
R
(
conditions A, Table 1, entry 1). A better yield was ob-
PhI(OAc)2, 130 °C
N
N
tained by using PhI(OAc) as oxidant, and the reaction
time could be shortened to eight hours for 1,3,5-tri-
2
Me
Me
1
2
methoxybenzene (conditions B, Table 1, entry 5). Other Entry
oxidants, such as K S O , benzoquinone (BQ), and
Indole 1
Product 2
Yield (%)b
55
2
2
8
Cu(OAc) were inferior to air and PhI(OAc) . Further
2
2
study revealed that the source of iron had a dramatic effect
1
2d
2e
N
Me
on the reaction, and FeI was the best candidate. The blank
2
experiment confirmed that in the absence of the iron salts,
1
d
e
4
1
4% of the desired product was isolated (Table 1, entry
4). A profound solvent effect was observed, and DMF
2
66
82
N
was found to be superior to other solvents. Moreover, no
product was detected by GC-MS when nontoxic
K [Fe(CN) ] and K [Fe(CN) ] were used as cyanating
Me
1
3
6
4
6
MeO
agents.
3
2f
With the optimized reaction conditions in hand [condi-
tions A: FeI (30 mol%), air, 8 h; conditions B: FeI (30
N
2
2
Me
mol%), PhI(OAc) , 15 h; Table 1], several methoxyben-
2
1f
zenes were tested as outlined in Scheme 1. As expected,
the products were obtained in good yields under both con-
ditions A and B. Notably, the cyanation reaction predom-
inately took place at the 4- and 5-position for 1,3-
dimethoxybenzene and 1,2,4-trimethoxybenzene, respec-
tively. No regioisomeric products were observed by GC-
4
5
6
2g
2h
2i
65
50
78
N
Me
1
g
1
MS and H NMR spectroscopy.
N
Me
FeI2 (30 mol%)
1
h
H
+
CuCN
CN
air or PhI(OAc)2, 130 °C
(
OMe)n
(OMe)n
N
1
n = 2, 3
OMe
CN
2
Me
MeO
MeO
1i
O2N
MeO
CN
OMe
MeO
CN
OMe
7
8
2j
30
N
OMe
Me
a
b
2b 60%a
64%b
2c 66%a
1j
2
a 80%
70%b
83%
Scheme 1 Reagents and conditions: a Conditions A: 1 (0.2 mmol),
N
2k
2l
53
64
CuCN (0.25 mmol), FeI (30 mol%), air, dry DMF (2 mL), 130 °C, 8
2
b
h. Conditions B: 1 (0.2 mmol), CuCN (0.25 mmol), FeI (30 mol%),
2
PhI(OAc) (0.6 equiv), dry DMF (2 mL), 130 °C, 15 h; isolated yield.
2
1
k
l
Next, we explored the cyanation protocol for indole deriv-
atives. However, no cyanation products were observed
when N-methylindoles were subjected to conditions A.
Fortunately, cyanation of indoles ran smoothly with ex-
tended time under conditions B, as shown in Table 2.
Generally, the presence of an electron-donating group mol%), PhI(OAc)
would benefit the reaction. Our procedure does not need
9
N
Bn
1
a
Reaction conditions: 1a (0.2 mmol), CuCN (0.25 mmol), FeI (30
2
(0.6 equiv), dry DMF (2 mL), 130 °C, 15 h.
2
b
Isolated yield.
to block the 2-position of the N-methyl indole. For exam-
Synlett 2011, No. 20, 2991–2994 © Thieme Stuttgart · New York

LETTER
Cyanation of Methoxybenzene, Indole, and 2-Arylpyridine C–H Bonds
2993
Table 3 Iron-Mediated Cyanation of 2-Arylpyridinea
delight, cyanation took place under the conditions B. The
results are shown in Table 3. The cyano group was toler-
ated under the standard reaction conditions. Notably, the
chloro group survived under these procedures. The sur-
viving chloro atom could be valuable for further manipu-
lation. When benzo[h]quinoline (1w) was subjected to the
procedure, a 50% yield of the cyanation product was iso-
lated. Evidently, the regioselectivity in the cyanation of
meta-substituted substrates was dominated by steric ef-
fects, and only the less hindered ortho position of the 2-
arylpyridine was cyanated.
FeI2 (30 mol%)
+
CuCN
PhI(OAc)2, 130 °C
R
R
N
N
CN
2
1
Entry
1
2-Arylpyridine 1
Product 2 Yield (%)b
2m
63
71
N
1
1
m
n
In summary, we have developed an efficient iron-mediat-
ed cyanation of methoxybenzene, indole, and 2-arylpyri-
dine C–H bonds. The use of inexpensive iron as the
catalyst as well as the broad substrate scope all contribute
to making this reaction attractive.
2
3
2n
2o
N
80
N
Supporting Information for this article is available online at
1
1
1
o
p
q
http://www.thieme-connect.com/ejournals/toc/synlett.
4
5
2p
2q
64
60
Acknowledgment
N
N
We thank the National Natural Science Foundation of China (No.
2
0972115), the Natural Science Foundation of Zhejiang Province
(Nos. Y4110109 and R4110294), and the Undergraduate Scientific
and Technological Innovation Project of Zhejiang (No.
2010R424064) for financial support.
References and Notes
MeO
6
7
8
9
2r
2s
2t
63
68
57
56
N
(
1) (a) Nagamura, S.; Kobayashi, E.; Gomi, K.; Saito, H.
Bioorg. Med. Chem. 1996, 4, 1379. (b) Kleemann, A.;
Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical
Substances: Syntheses, Patents, Applications, 4th ed.;
Thieme: Stuttgart, 2001. (c) Murdoch, D.; Keam, S. Drugs
1
r
Cl
N
1
s
2
005, 65, 2379. (d) Njar, V. C. O.; Brodie, A. M. H. Drugs
1999, 58, 233.
F
(
2) (a) The Chemistry of the Cyano Group; Rappoport, Z., Ed.;
Wiley: London, 1970. (b) Larock, R. C. Comprehensive
Organic Transformations; Wiley-VCH: New York, 1989,
N
1
t
8
19–995. (c) Ju, Y.; Liu, F.; Li, C. Org. Lett. 2009, 11, 3582.
3) (a) Sandmeyer, T. Ber. Dtsch. Chem. Ges. 1884, 17, 2650.
b) Hodgson, H. H. Chem. Rev. 1947, 40, 251. (c) Galli, C.
NC
2u
(
N
(
1
u
Chem. Rev. 1988, 88, 765. (d) Bohlmann, R. In
Comprehensive Organic Synthesis, Vol. 6; Trost, B. M.;
Fleming, I., Eds.; Pergamon: Oxford, 1991, 203.
4) (a) Friedrich, K.; Wallenfels, K. In The Chemistry of the
Cyano Group; Wiley: New York, 1970, 77–86.
1
0
1
N
2v
59
50
(
(
b) Friedrich, K. In The Chemistry of Functional Groups;
1
1
v
Wiley: New York, 1970, 1345–1390; Suppl. C. (c) Wu, J.;
Beck, B.; Ren, R. Tetrahedron Lett. 2002, 43, 387.
(d) Wang, D.; Kuang, L.; Li, Z.; Ding, K. Synlett 2008, 69.
1
2w
(
5) Review: (a) Anbarasan, P.; Schareina, T.; Beller, M. Chem.
Soc. Rev. 2011, 40, 5409. For selected reports on palladium-
catalyzed cyanation of aryl halides, see: (b) Hatsuda, M.;
Seki, M. Tetrahedron 2005, 61, 9908. (c) Jensen, R. S.;
Gajare, A. S.; Toyota, K.; Yoshifuji, K.; Ozawa, F.
N
w
a
Reaction conditions: 1a (0.2 mmol), CuCN (0.25 mmol), FeI (30
mol%), PhI(OAc) (0.6 equiv), dry DMF (2 mL), 130 °C, 15 h.
Isolated yield.
2
2
b
Tetrahedron Lett. 2005, 46, 8645. (d) Schareina, T.; Zapf,
A.; Beller, M. Chem. Commun. 2004, 1388. (e) Weissman,
S. A.; Zewge, D.; Chen, C. J. Org. Chem. 2005, 70, 1508.
(f) Grossman, O.; Gelman, D. Org. Lett. 2006, 8, 1189.
(g) Mariampillai, B.; Alberico, D.; Bidau, V.; Lautens, M.
J. Am. Chem. Soc. 2006, 128, 14436. (h) Mariampillai, B.;
The scope of this reaction was further demonstrated in the
ortho cyanation of the 2-arylpyridine C–H bond. To our
2
2
Synlett 2011, No. 20, 2991–2994 © Thieme Stuttgart · New York

2
994
G. Zhang et al.
LETTER
Alliot, J.; Li, M.; Lautens, M. J. Am. Chem. Soc. 2007, 129,
(13) Subba Reddy, B.; Begum, V. Z.; Jayasudhan Reddy, Y. J.
Tetrahedron Lett. 2010, 51, 3334.
(14) Yan, G.; Kuang, C.; Zhang, Y.; Wang, J. Org. Lett. 2010, 12,
1052.
1
5372. (i) Littke, A.; Soumeillant, M.; Kaltenbach, R. F.;
Cherney, R. J.; Tarby, C. M.; Kiau, S. Org. Lett. 2007, 9,
711. (j) Yeung, P. Y.; So, C. M.; Lau, C. P.; Kwong, F. Y.
1
Org. Lett. 2011, 13, 648. (k) Yu, H.; Richey, R. N.; Miller,
W. D.; Xu, J.; May, S. A. J. Org. Chem. 2011, 76, 665.
(15) Ding, S. T.; Jiao, N. J. Am. Chem. Soc. 2011, 133, 12374.
(16) Ren, X.; Chen, J.; Chen, F.; Cheng, J. Chem. Commun. 2011,
47, 6725.
(l) Yeung, P. Y.; Tsang, C. P.; Kwong, F. Y. Tetrahedron
Lett. 2011, in press; DOI: 10.1016/j.tetlet.2011.09.088.
(17) Wang reported the Pd-catalyzed cyanation of
trimethoxybenzene, providing the product in 35% yield; see
ref. 14.
(18) Liskey, C. W.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc.
2010, 132, 11389.
(
6) For selected reports on copper-catalyzed or copper-mediated
cyanation of aryl halides, see: (a) Zanon, J.; Klapars, A.;
Buchwald, S. J. Am. Chem. Soc. 2003, 125, 2890.
(
b) Cristau, H.-J.; Ouali, A.; Spindler, J.-F.; Taillefer, M.
Chem. Eur. J. 2005, 11, 2483. (c) Schareina, T.; Zapf, A.;
Beller, M. Tetrahedron Lett. 2005, 46, 2585. (d) Schareina,
T.; Zapf, A.; Mägerlein, W.; Müller, N.; Beller, M. Chem.
Eur. J. 2007, 13, 6249. (e) Schareina, T.; Zapf, A.;
(19) (a) Bolm, C.; Legros, J.; Paih, J. L.; Zani, L. Chem. Rev.
2004, 104, 6217. (b) Correa, A.; Mancheńo, O. G.; Bolm, C.
Chem. Soc. Rev. 2008, 37, 1108. (c) Enthaler, S.; Junge, K.;
Beller, M. Angew. Chem. Int. Ed. 2008, 47, 3317.
(d) Sherry, B. D.; Fürstner, A. Acc. Chem. Res. 2008, 41,
1500. (e) Sarhan, A. A. O.; Bolm, C. Chem. Soc. Rev. 2009,
38, 2730. (f) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev.
2011, 111, 1293.
Mägerlein, W.; Müller, N.; Beller, M. Synlett 2007, 555.
(
f) Ren, Y.; Wang, W.; Zhao, S.; Tian, X.; Wang, J.; Yin, W.;
Cheng, L. Tetrahedron Lett. 2009, 50, 4595. (g) Zhang, G.;
Ren, X.; Chen, J.; Hu, M.; Cheng, J. Org. Lett. 2011, 13,
5
004.
(20) (a) Vallée, F.; Mousseau, J. J.; Charette, A. B. J. Am. Chem.
Soc. 2010, 132, 1514. (b) Li, Y.-Z.; Li, B.-J.; Lu, X.-Y.; Lin,
S.; Shi, Z.-J. Angew. Chem. Int. Ed. 2009, 48, 3817.
(c) Song, C. X.; Cai, G. X.; Farrell, T. R.; Jiang, Z. P.; Li, H.;
Gan, L. B.; Shi, Z.-J. Chem. Commun. 2009, 6002. (d) Li,
Z.; Cao, L.; Li, C.-J. Angew. Chem. Int. Ed. 2007, 46, 6505.
(e) Li, Z.; Yu, R.; Li, H. Angew. Chem. Int. Ed. 2008, 47,
7497. (f) Zhang, Y.; Li, C.-J. Eur. J. Org. Chem. 2007,
4654. (g) Wen, J.; Zhang, J.; Chen, S.-Y.; Li, J.; Yu, X.-Q.
Angew. Chem. Int. Ed. 2008, 47, 8897. (h) Norinder, J.;
Matsumoto, A.; Yoshikai, N.; Nakamura, E. J. Am. Chem.
Soc. 2008, 130, 5858. (i) Liu, W.; Cao, H.; Lei, A. Angew.
Chem. Int. Ed. 2010, 49, 2004. (j) Nakamura, E.; Yoshikai,
N. J. Org. Chem. 2010, 75, 6061. (k) Jones, W. D.; Foster,
G. P.; Putinas, J. M. J. Am. Chem. Soc. 1987, 109, 5047.
(l) Qin, C.; Jiao, N. J. Am. Chem. Soc. 2010, 132, 15893.
(21) (a) Wang, W.; Pan, C.; Chen, F.; Cheng, J. Chem. Commun.
2011, 47, 3978. (b) Jia, X.; Zhang, S.; Wang, W.; Luo, F.;
Cheng, J. Org. Lett. 2009, 11, 3120. (c) Ye, Z.; Wang, W.;
Luo, F.; Zhang, S.; Cheng, J. Org. Lett. 2009, 11, 3974.
(d) Wang, W.; Luo, F.; Zhang, S.; Cheng, J. J. Org. Chem.
2010, 75, 2415. (e) Zhang, S.; Qian, P.; Zhang, M.; Hu, M.;
Cheng, J. J. Org. Chem. 2010, 75, 6732. (f) Zhang, S.; Luo,
F.; Wang, W.; Jia, X.; Hu, M.; Cheng, J. Tetrahedron Lett.
2010, 51, 33172.
(
(
7) For the cyanation of organoboron, see ref. 18 and:
(
(
a) Zhang, Z. H.; Liebeskind, L. S. Org. Lett. 2006, 8, 4331.
b) Zhang, G.; Zhang, L.; Hu, M.; Cheng, J. Adv. Synth.
Catal. 2011, 353, 291. (c) Anbarasan, P.; Neumann, H.;
Beller, M. Angew. Chem. Int. Ed. 2011, 50, 519.
8) For selected reviews on C–H functionalization, please see:
(
1
a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110,
147. (b) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q.
Angew. Chem. Int. Ed. 2009, 48, 5094. (c) Yeung, C. S.;
Dong, V. M. Chem. Rev. 2011, 111, 1215. For selected
reports on C–H functionalization, please see: (d) Lu, Y.;
Leow, D.; Wang, X.; Engle, K. M.; Yu, J.-Q. Chem. Sci.
2
011, 2, 967. (e) Li, B.-J.; Shi, Z.-J. Chem. Sci. 2011, 2,
488. (f) Tang, B.-X.; Song, R.-J.; Wu, C.-Y.; Liu, Y.; Zhou,
M.-B.; Wei, W.-T.; Deng, G.-B.; Yin, D.-L.; Li, J.-H. J. Am.
Chem. Soc. 2010, 132, 8900. (g) Wang, G.-W.; Yuan, T.-T.;
Li, D.-D. Angew. Chem. Int. Ed. 2011, 50, 1380. (h) Kwak,
J.; Kim, M.; Chang, S. J. Am. Chem. Soc. 2011, 133, 3780.
9) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am.
Chem. Soc. 2006, 128, 6790.
(
(
10) (a) Jia, X.; Yang, D.; Zhang, S.; Cheng, J. Org. Lett. 2009,
11, 4716. (b) Jia, X.; Yang, D.; Wang, W.; Luo, F.; Cheng,
J. J. Org. Chem. 2009, 74, 9470.
(
(
11) Kim, J.; Chang, S. J. Am. Chem. Soc. 2010, 132, 10272.
12) Do, H.-Q.; Daugulis, O. Org. Lett. 2010, 12, 2517.
2
(22) For the transition-metal-catalyzed 2-aryl pyridine sp C–H
cyanation, please see ref. 9–11.
Synlett 2011, No. 20, 2991–2994 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.