Copper-mediated selective aerobic oxidative C3-cyanation of indoles with DMF

Article abstract of DOI:10.1016/j.tetlet.2015.09.044

Under an oxygen atmosphere, the copper-mediated direct C3-cyanation of indole C-H bonds, using cheap and safe DMF as a CN source, took place selectively to produce the corresponding C3-cyanoindoles in good yields. A possible mechanism for this selective cyanation was proposed.

Full text of DOI:10.1016/j.tetlet.2015.09.044

Accepted Manuscript
Copper-Mediated Selective Aerobic Oxidative C3-Cyanation of Indoles with
DMF
Jing Xiao, Qiang Li, Tieqiao Chen, Li-Biao Han
PII:
S0040-4039(15)30086-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.044
TETL 46716
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
27 July 2015
3 September 2015
15 September 2015
Please cite this article as: Xiao, J., Li, Q., Chen, T., Han, L-B., Copper-Mediated Selective Aerobic Oxidative C3-
Cyanation of Indoles with DMF, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.09.044
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Under an oxygen atmosphere, the copper-mediated direct C3-cyanation of indole C-H bonds, using
cheap and safe DMF as a CN source, took place selectively to produce the corresponding C3-
cyanoindoles in good yields. A possible mechanism for this selective cyanation was proposed.
Copper-Mediated Selective Aerobic
Oxidative C3-Cyanation of Indoles with
DMF
Jing Xiao, Qiang Li, Tieqiao Chen, and Li-Biao Han

1
Tetrahedron Letters
Copper-Mediated Selective Aerobic Oxidative C3-Cyanation of Indoles with DMF
Jing Xiao,a Qiang Li,a Tieqiao Chen,a, and Li-Biao Hanb,*
a State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China.
b National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8565, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Under an oxygen atmosphere, the copper-mediated direct C3-cyanation of indole C-H bonds,
using cheap and safe DMF as a CN source, took place selectively to produce the corresponding
C3-cyanoindoles in good yields. A possible mechanism for this selective cyanation was
proposed.
Available online
2015 Elsevier Ltd. All rights reserved.
Keywords:
Indole
C-H Cyanation
Aerobic oxidation
Copper
DMF
Cyanoindoles are synthetically valuable intermediates which
are widely used in synthetic chemistry and industry for the
preparation of pharmaceuticals, agrochemicals, and dyes.1,2 Due
to their importance in modern organic synthesis, many methods
for their preparation have been developed (Scheme 1)3,4,5
Traditional procedures generally depend on metal-catalyzed
cyanation via C-X or C-H bonds functionalization with “CN”
sources bearing a “CN” unit such as metal cyanides (NaCN,
CuCN, etc.) and related cyanide compounds (acetone
cyanohydrin, etc.).3 However, those cyanides are highly toxic and
the preparation of nitriles using these cyanide reagents can cause
serious safety problems. Thus, the development of alternative
green procedures for preparation of cyanoindoles without use of
these toxic cyanides is highly desirable.
efficient copper-mediated direct C3-cyanation of indole C-H
bonds with DMF as the sole CN source using oxygen as an
oxidant, to produce the corresponding C3-cyanoindoles which
are highly useful compounds in organic synthesis, medicinal
chemistry and material science.6
Recently, cyanation of indole C-H bonds via the in situ generation
of CN from non-CN-containing cyanide source is attracting much
attention.3d,3e,4 Combined “CN” sources, in which carbon is derived
from small organic molecules (TMEDA, DMSO and DMF) and
nitrogen is derived from ammonia, have been developed as a non-
CN-containing safe cyanide source.3d For example, Chang4a et al
disclosed efficient Cu-mediated cyanation of indole C-H bonds using
in situ generated CN unit from a combination of NH4I/DMF. The
4c
combination of (NH4)2CO3/TMEDA4b and DMSO/NH4HCO3 can
also be used as good in-situ CN sources for the metal-mediated
cyanation reactions. However, although these combined “CN”
sources serve well for the cyanation reactions, a large excess amount
of ammonia are generally required and these reactions suffer from
poor atom economy. Interestingly, Jiao4d developed Pd, Cu and Fe
co-mediated cyanations of heteroarenes in which DMF was used as
the only “CN” source. Herein, we report a simple and
———
Scheme 1 Cyanation of indole C-H bonds.
As a model reaction, we first tested the cyanation of 1-methyl-
1H-indole (1a) with DMF (Table 1). The cyanation did not take
place at all in the presence of CuI (1 equiv) in DMF (1 mL) under
O2 (entry 1). Remarkably, however, when acetic acid (1.2 equiv)
was additionally added, cyanation underwent selectively at C3
 e-mail: chentieqiao@hnu.edu.cn; libiao-han@aist.go.jp

2
Tetrahedron Letters
corresponding cyano compounds (2n-2s). Furthermore, 2t was
position to give 3-cyano-1-methylindole 2a in 56% yield (entry
also obtained in a moderate yield under similar conditions.
However, the reaction became sluggish when N-phenylindoles
were employed as the substrates. Thus, N-phenylindole and N-
anisylindole only afforded the desired products 2u and 2v in 25%
and 28% isolated yields, respectively. Finally, it was found that
unprotected indoles such as 1H-indole did not undergo similar
cyanation under similar reaction conditions. It was noted that
possible regio-isomeric products could not be detected from the
reactions.
2). Further screening on the additive acid showed that the
stronger acid trifluoroacetic acid (TFA) performed the best
compared to acetic acid and diphenylphosphinic acid to produce
74% yield of 2a (entries 2-4).7 The yields of the product did not
increase when less (0.6 equiv) or more (2.0 equiv) TFA was used
(entries 5 and 6). As expected, under air, the reaction also
proceeded albeit the yield of the product decreased (entry 7). As
shown in entries 8 and 9, both oxygen and CuI were essential for
the present cyanation. A further screening on the copper salts
revealed that other coppers such as CuCl (entry 10), Cu(OAc)2
(entry 11), Cu(O2CCF3)2 (entry 12), Cu2O (entry 13) and even
metallic copper (entry 14), all could produce 2a, with CuI (entry
4) being the most efficient copper reagent.
In order to clarify the origin of the “CN” unit in this cyanation
reaction, a series of control experiments were conducted (Table
3). There is no doubt that the nitrogen atom N comes from DMF.
As to the origin of the carbon atom, however, it could come from
either the formyl C(O)H or the methyl group. As shown in Table
3, although DMF gave 2a in a high yield (run 4), we found that
both formamide (run 1) and acetamide (run 2) could only
Table 1. Selective cyanation of 1-methyl-1H-indole with
DMF.a
produce
a trace amount of 2a. Interestingly, with N-
methylformamide, 20% yield of 2a was obtained. Very
surprisingly, when N, N-dimethylacetamide (DMAC) was used,
2a was hardly detected, 3-formylindole 3a was formed in 42%
yield instead (entry 5). As described below, 3a could be
transformed to 2a in the copper/DMF system under oxygen (vide
infra), thus, it is reasonable to conclude that the carbon of CN
should predominantly come from the methyl group rather than
the formyl group.
entry
1
[Cu]
additive
yield( %)b
CuI
none
0
2
CuI
AcOH
56
52
74
65
48
31
0
3
CuI
Ph2P(O)OH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
Table 2 CuI-mediated selective C3-cyanation of indoles with DMF a,b
4
CuI
5 c
6 d
7 e
8 f
9
CuI
CuI
CuI
CuI
none
0
10
11
12
13
14
CuCl
Cu(OAc)2
Cu(O2CCF3)2
Cu2O
Cu powder
22
18
21
29
56
a Conditions: 1-methyl-1H-indole (0.2 mmol), [Cu] (0.2 mmol), acid (0.24
mmol), DMF (1 mL), 25 mL sealed glass tube, O2 (1 atm), 130 oC, 36 h,
recharging oxygen after 12 h.
b GC yield.
c 0.6 equiv TFA was used.
d 2 equiv TFA was used. e Under air. f Under N2.
With the optimized reaction conditions in hand, we next
investigated the scope of this copper-mediated cyanation
reaction. As shown in Table 2, N-methylindole 1a could produce
2a in 72% isolated yield. Indoles with a methyl group on either
5-position or 7-position, all gave the corresponding 3-
cyanoindoles in good yields (2b and 2c). Similar to these methyl
substituted indoles, an electron-donating group exemplified by a
methoxy substituted indole also produced the corresponding
product 2d in 63% yield. However, electron-withdrawing groups
such as fluoro (2e) and methoxycarbonyl (2f) gave low yields
under similar reaction conditions, which was consistent with an
electrophilic substitution process. Similarly, the bulky N-
isopropyl indoles and N-butyl indoles also proceeded smoothly to
give the corresponding 3-cyanoindoles in high yields (2g-2l). It is
noted that an ally group remained intact in the current system
(2m). Finally, a variety of N-benzylindoles were employed as
substrates in the reaction system to give moderate yields of the
a
Conditions: indoles 1 (0.2 mmol), TFA (0.24 mmol), CuI (0.2
o
mmol), DMF (1 mL), 25 mL sealed glass tube, O2 (1 atm), 130 C,
36 h, recharging oxygen after 12 h. For data about compounds 2n, 2o,
2q-2t and 2v, see supporting information.
b Isolated yield.
c 150 oC, 96 h.
d 130 oC, 96 h.
To further clarify the reaction process, a reaction profile was
obtained for the cyanation of 1-methyl-1H-indole 1a under the
optical reaction conditions (Fig. 1). It was noted that iodinated

3
indole 4a was generated nearly quantitatively within 30 minutes.
The cyanided product 2a then gradually appeared with the
concomitant disappearance of 4a. In addition to 2a, another
product, 3-formylindole 3a was also formed in 5% GC yield after
1 h and increased to 23% yield after 8 h. As shown in Figure 1,
both 4a and 3a decreased as time went on, while the yield of 2a
kept increasing, and finally reached a maximum at 36 h in 74%
GC yield. In addition, two control experiments were performed.
Under similar reaction conditions, benzylamine could be
oxidized to produce the corresponding benzylnitrile in 44% GC
yield (eq 1).8 Interestingly, in the present CuI/CF3COOH system,
the reaction of 3-formylindole 3a with equivalent methylamine
also proceeded smoothly and the 2a was given in 41% GC yield
in 2 h (eq 2).
On the basis of these experiments described above and
literatures, we proposed a possible mechanism for the cyanation
of indole C-H bonds (Scheme 3). It was assumed that the C-H
bond of the indole was selectively activated in presence of CuI
and O2 to form the intermediate 4’,5 which underwent reductive
elimination to give iodinated indole 4. Species 4’ subsequently
reacted with 59 from DMF to form intermediate 6,10 followed by
decarbonylation to produce secondary amine 6’.11 In the absence
of Cu/O2, secondary amine 6’ was oxidized and converted to
iminium ion 7 and 7’. The hydrolysis of iminium ion 7’ afforded
3-formylindole 3 and methylamine,12 while hydrolysis of 7 gave
primary amine 8. Primary amine 8 is further oxidized to produce
the cyano product 2.8 It should be noted that the resulting 3-
formylindole 3 and methylamine could undergo condensation
regenerating iminium ion 7’, which could be isomerized to
iminium ion 7 and further converted to the cyano product 2.13
Table 3 Cyanation of 1-methyl-1H-indole with amides a
a Conditions: a mixture of 1a (0.2 mmol), CuI (0.2 mmol), TFA (0.24 mmol)
in 1 mL amide was heated at 130 oC for 36 h in a 25 mL sealed glass tube
under 1 atm O2, recharging oxygen after 12 h. b GC yields.
Scheme 3 Possible mechanisms for the copper-mediated
cyanation reaction with DMF.
In summary, we have developed a copper-mediated
aerobic oxidative cyanation of indole C-H bonds at the C3
position, using cheap and safe DMF as the sole CN source.
Control experiments indicate that both carbon and nitrogen
are derived from DMF, in which the carbon comes from the
methyl group. Further mechanistic studies also elucidate the
reaction process of the current copper mediated cyanation of
indoles with DMF. This protocol not only provides a simple
and safe access to the potentially medicinally valuable C3-
cyanoindoles in good yields but also offers in-depth
understanding of the chemistry of DMF for cyanation.
Acknowledgments
Partial financial supports from NSFC (21373080, 21403062),
HNNSF 2015JJ3039, the Fundamental Research Funds for the
Central Universities (Hunan University) are gratefully
acknowledged.
Fig.1 Reaction profile for cyanation of 1a mediated by CuI
conditions.
Scheme 2 control experiments
.

4
Tetrahedron Letters
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