Rhodium-catalyzed ortho-cyanation of symmetrical azobenzenes with N-cyano-N-phenyl-p-toluenesulfonamide

Article abstract of DOI:10.1039/c4ob01736f

A rhodium-catalyzed ortho-cyanation of symmetrical azobenzenes is described employing N-cyano-N-phenyl-p-toluenesulfonamide as an environmentally friendly cyanide source. The present protocol allows the synthesis of various benzonitrile derivatives in moderate to good yields and tolerates many useful functional groups.

Full text of DOI:10.1039/c4ob01736f

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Rhodium-catalyzed ortho-cyanation of
symmetrical azobenzenes with N-cyano-
N-phenyl-p-toluenesulfonamide†
Cite this: Org. Biomol. Chem., 2014,
12, 8603
Received 13th August 2014,
Jie Han,‡a Changduo Pan,‡b Xuefeng Jia*a and Chengjian Zhu*b
Accepted 15th September 2014
DOI: 10.1039/c4ob01736f
www.rsc.org/obc
A rhodium-catalyzed ortho-cyanation of symmetrical azobenzenes phenylurea with p-toluenesulfonyl chloride.16 However, the
is described employing N-cyano-N-phenyl-p-toluenesulfonamide potential of NCTS as an electrophilic cyanating reagent in the
as an environmentally friendly cyanide source. The present proto- C–H activation process was not evaluated until very
col allows the synthesis of various benzonitrile derivatives in mod- recently.17–20 In 2013, a rhodium-catalyzed cyanation reaction
erate to good yields and tolerates many useful functional groups.
of arenes employing NCTS as an efficient cyanating reagent
was developed by Fu18 and Anbarasan19 independently. Gu
and co-workers also documented ortho-cyanation of arylpho-
sphates with NCTS in the presence of rhodium catalyst and
AgSbF6 in 2014.20 Although many significant advances have
been achieved in this area, there are still few reports on
rhodium-catalyzed cyanation of the C–H bond.
On the other hand, significant developments on azo-group-
directed C–H functionalization of aromatic azo compounds,
such as acylation, alkoxylation, halogenation and amidation,
have been achieved.21 However, the direct ortho-cyanation of
azobenzene was not reported before. Based on the effective-
ness of rhodium catalysis on C–H bond activation22 and our
continuing interest in the C–H functionalization of aromatic
azo compounds,23 we herein describe a rhodium-catalyzed
C–H cyanation of symmetrical azobenzenes with NCTS as the
cyanide source by the chelation effect of the azo group.
Initially, the cyanation of azobenzene (1a) with NCTS (2)
was chosen as a model reaction to screen the reaction con-
ditions. The results are summarized in Table 1. The reaction
of azobenzene (1a) with NCTS (2) was first investigated in the
presence of [RhCp*Cl2]2, AgSbF6 and Cu(OAc)2 in 1,4-dioxane
(entry 1). To our delight, the corresponding product 3a was iso-
lated in 26% yield. After surveying a series of solvents, such as
DCE, toluene, DMSO and THF, DCE was found to be a good
choice of solvent (entries 2–5). The yield of product 3a could
be obviously improved by changing the base to Ag2CO3, AgOAc
and NaOAc. NaOAc was proved to be more efficient for this
transformation. The effects of different additives were also
evaluated. We found that altering the additive to AgBF4 dimin-
ished the reactivity, whereas the use of AgNTf2 increased the
yield of product 3a (entries 9 and 10). The ortho-cyanation reac-
tion of 1a with NCTS (2) was carried out at 120 °C, leading to
the product 3a in 69% yield using the ratio of 1a/2 (1 : 2) and
50 mol% of AgNTf2 (entry 11). Finally, the effect of reaction
The synthesis of aryl nitriles has attracted a great deal of atten-
tion because of the importance of cyano-containing com-
pounds in chemistry and biology. The installation of the CN
group into biologically active molecules may dramatically
modify their properties. The nitrile moiety has also served as a
valuable intermediate and an effective precursor for the syn-
thesis of various functional group compounds such as alde-
hydes, ketones, amines, amidines, amides, carboxylic acids,
and heterocycles.1 Traditionally the synthesis of aryl nitriles
was achieved by the Rosenmund–von Braun reaction,2 the
Sandmeyer reaction,3 and catalytic cyanation of aryl halides.4
Recently, considerable attention has been paid to direct cyana-
tion of C–H bonds with metallic cyano-group sources5 and
“nonmetallic” organic cyano-group sources.6 Representative
examples of “nonmetallic” cyano-group sources include palla-
dium catalyzed and copper mediated direct cyanation of aro-
matic compounds with nitromethane,7 DMF/NH3,8 DMF,9
TMSCN,10 CH3CN,11 isonitrile,12 azobisisobutyronitrile13 and
tosyl cyanide14.
The BF3·OEt2-catalyzed C–H cyanation of heteroarenes such
as pyrroles and indoles was first reported by Wang using
N-cyano-N-phenyl-p-toluenesulfonamide (NCTS) as a new “non-
metallic” cyanating reagent.15 It is noteworthy that NCTS could
be readily and efficiently prepared via treatment of inexpensive
aSchool of Chemical and Material Science, Shanxi Normal University, Linfen
041004, China
bState Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical
Engineering, Nanjing University, Nanjing 210093, China. E-mail: jxfliu@163.com,
cjzhu@nju.edu.cn
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data for all new compounds. See DOI: 10.1039/
c4ob01736f
‡Han and Pan contributed equally.
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Table 1 Screening for optimal reaction conditionsa
Table 2 Substrate scope for direct C–H cyanation of substituted azo
compounds with NCTSa,b,c
Entry
Additive
Base
Solvent
T (°C)
Yieldc (%)
1
2
3
4
5
6
7
8
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgBF4
AgNTf2
AgNTf2
AgNTf2
AgNTf2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Ag2CO3
AgOAc
NaOAc
NaOAc
NaOAc
NaOAc
1,4-Dioxane
DCE
Toluene
DMSO
THF
DCE
DCE
DCE
DCE
DCE
DCE
120
120
120
120
120
120
120
120
120
120
120
130
110
26
31
0
0
0
38
46
55
9
0
60
10
11b
12b
13b
69
NaOAc
NaOAc
DCE
DCE
75 (68)d
60
a Reaction conditions: 1a (0.15 mmol), 2 (1 equiv.), [Cp*RhCl2]2 (5 mol%),
base (1 equiv.) and additive (20 mol%) in solvent (1.0 mL) at 120 °C for
24 h. b Reaction conditions: 1a (0.15 mmol), 2 (2 equiv.), [Cp*RhCl2]2
(5 mol%), AgNTf2 (50 mol%) and NaOAc (1 equiv.) in DCE at indicated
temperature for 24 h. c Isolated yield. d The cyanation reaction was
performed on a 1 mmol scale.
temperature on the reaction was investigated. Higher reaction
temperature could further improve the efficiency of this trans-
formation, but a lower yield of product 3a was obtained when
the reaction proceeded at 110 °C (entries 12 and 13). It should
be noted that the cyanation reaction of 1a with NCTS (2) could
be carried out to give 3a in 68% yield on a 1 mmol scale
without the lack of activity.
a Reaction conditions: 1 (0.15 mmol), 2 (1.5 equiv.), [Cp*RhCl2]2 (5 mol%),
AgNTf2 (50 mol%) and NaOAc (1 equiv.) in DCE (1 mL) at 130 °C for 24 h.
b Isolated yield. c AgNTf2 (100 mol%) was used.
Having established the optimal conditions for rhodium-
catalyzed ortho-cyanation of azobenzene, we then extended the
reaction with a variety of substrates to evaluate the scope of
this protocol. As shown in Table 2, a series of azobenzene
derivatives 1 were found to participate in the reaction,
affording the corresponding aryl nitriles 3 in a satisfactory yield.
For example, the para-substituted substrates with methyl, ethyl
or isopropyl underwent this reaction to furnish the corres-
ponding products (73% for 3b; 61% for 3c; 67% for 3d,
respectively). Azobenzene with a methoxy or ethoxy group
gave the cyanated products 3e and 3f in 72% and 73% yields,
respectively, but the substrate with a trifluoromethoxy group
afforded the product 3g in 39% yield. Further studies showed
the presence of a halogen atom such as fluoro, chloro
or bromo was unfavorable to this cyanation reaction. Only
when 100 mol% AgNTf2 was used under optimized conditions,
could the cyanated products 3h and 3i be isolated in moderate
yield (55% for 3h and 67% for 3i). In these cases, the starting
materials were recovered after the reaction finished. These
results indicated that the direct cyanation of aromatic azo
compounds possessing electron-donating groups was more
effective than those with electron-withdrawing groups. The
electronic effect of substituents on this cyanation reaction was
further extended to other substrates. The meta-substituted
(Me, OMe) azobenzene reacted with NCTS (2) smoothly to give
cyanated products 3k and 3l in 85% and 60% yields, while the
meta-bromo-substituted azobenzene provided the corres-
ponding product 3m in 40% yield. Compared with p-methyl-
substituted azobenzene 1b, 2,4-dimethyl-substituted azo-
benzene 1n was treated with NCTS (2) to provide the corres-
ponding product 3n in 41% yield, which was due to the steric
hindrance effect from methyl at the ortho position of azo-
benzene. The ortho-substituted substrates could also be cya-
nated in our cyanation methodology and led to the desired
products 3o–q in lower yields (48% for 3o; 32% for 3p; 30% for
3q, respectively), albeit with the use of 100 mol% AgNTf2.
Scheme 1 The H/D exchange experiment of 1a.
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of Higher Education of China (20120091110010) was also
acknowledged.
Notes and references
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(Scheme 1). When D2O was subjected to the reaction mixture,
a remarkable H/D exchange of the recovering substrate [D]n-1a
was observed. This demonstrated that the cyanation reaction
was typical of the rhodium-catalyzed C–H bond activation
process.
On the basis of the above result and previous related
studies,18–20 a possible mechanism for the newly developed
cyanation protocol is proposed, as shown in Scheme 2. First,
treatment of a rhodium precursor with AgNTf2 and NaOAc
generates the reactive cationic rhodium(III) species A, which
reacted with azobenzene (1a) to obtain the cyclic rhodium
species B with a vacant coordination site. Then coordination
of NCTS (2) with rhodium species B provides intermediate C,
followed by insertion of the CN group into the C–RhIII bond
generating D. Subsequent rearrangement of D leads to the cya-
nated product (3a) and reactive rhodium species E. Finally,
active rhodium species A participates in the next catalytic cycle
after the ligand exchange.
In conclusion, we have developed a useful synthetic method
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groups could be directly cyanated to provide important aro-
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