Rhodium(iii)-catalyzed aromatic C-H cyanation with dimethylmalononitrile as a cyanating agent

Article abstract of DOI:10.1039/c8cc08930b

A rhodium-catalyzed aromatic C-H bond direct cyanation with safe, bench-stable, and commercially available dimethylmalononitrile as the cyanating agent has been successfully developed by using copper oxide as a promotor. Pyridine, quinoline, pyrimidine and pyrazole were used as the directing group in this type of C-H bond direct cyanation reaction.

Full text of DOI:10.1039/c8cc08930b

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Rhodium(III)-catalyzed aromatic C–H cyanation
with dimethylmalononitrile as a cyanating agent†
Cite this:DOI: 10.1039/c8cc08930b
He Li,‡a Sheng Zhang,‡a Xiaoqiang Yu,a Xiujuan Feng,a Yoshinori Yamamotoacd and
ab
Received 12th November 2018,
Accepted 10th December 2018
Ming Bao
*
DOI: 10.1039/c8cc08930b
rsc.li/chemcomm
A rhodium-catalyzed aromatic C–H bond direct cyanation with in the catalytic aromatic C–H bond direct cyanation. Among
safe, bench-stable, and commercially available dimethylmalononitrile them, the non-metallic cyano-group source N-cyano-N-phenyl-p-
as the cyanating agent has been successfully developed by using toluenesulfonamide has been demonstrated to be a user-friendly
copper oxide as a promotor. Pyridine, quinoline, pyrimidine and and efficient cyanating reagent by the Fu’s group and Anbarasan’s
pyrazole were used as the directing group in this type of C–H bond group.15 The use of non-metallic cyano-group sources, namely the
direct cyanation reaction.
organic cyano-group sources, in the catalytic aromatic C–H bond
direct cyanation has attracted considerable attention because the
Aryl nitriles are key structural motifs in a variety of natural poisoning of catalyst can be minimized. However, some organic
products, agrochemicals, pharmaceuticals, dyes, etc.1 In addition, cyanating reagents are highly toxic, are prepared from highly
the nitrile group can be easily transformed to other functional toxic precursors, or require low temperature storage to avoid
groups, such as amino, carboxyl, and acylamino groups, through decomposition.16 Moreover, the frequently used organic cyanating
hydrogenation or hydrolysis.2 Therefore, the development of reagents with high reactivity are expensive and not commercially
convenient and efficient methods for the synthesis of aryl nitriles available in large scale. Therefore, a new organic cyanating reagent
has attracted considerable attention. Over the past decades, many for catalytic aromatic C–H bond direct cyanation is desirable.
methods have been developed for the preparation of aryl nitriles,
Recently, Reeves and co-workers used dimethylmalononitrile
including the Sandmeyer reaction of aryl diazonium salts3 and (DMMN), a commercially available solid with low toxicity, as an
the Rosenmund–von Braun reaction of aryl halides4 with a effective organic cyanating reagent for transnitrilation with both
stoichiometric amount of CuCN, the transition metal-catalyzed Grignard and aryllithium reagents.17 They also succeeded in the
cyanation of aryl halides or pseudohalides with various cyanide use of DMMN as a cyanating reagent for the Rh(I)-catalyzed
sources,5 the reaction of aryl organometallics with electrophilic transnitrilation of arylboronic acids (Scheme 1a).18 Quite recently,
cyanating reagents,6 and the transition metal-catalyzed aromatic Fu’s group reported copper-catalyzed reagent-controlled regio-
C–H bond direct cyanation with appropriate cyano-group sources.7 selective cyanoborylation of vinylarenes using DMMN as the
Among the abovementioned methods, the last one has recently cyano-group source.19 To the best of our knowledge, the use of
attracted considerable attention due to the conciseness of DMMN as a cyanating reagent for the catalytic aromatic C–H
the synthetic procedure. Metallic (e.g., CuCN,8 NaCN,9 KCN,10 bond direct cyanation has not been reported. The reasons may
and K4[Fe(CN)6]11) and non-metallic (e.g., tert-butylisocyanide,12
N-cyanosuccinimide,13 and N-cyano-N-phenyl-p-toluenesulfona-
mide14) cyano-group sources have been successfully employed
a State Key Laboratory of Fine Chemicals, Dalian University of Technology,
Dalian 116023, China. E-mail: mingbao@dlut.edu.cn
b School of Petroleum and Chemical Engineering, Dalian University of Technology,
Panjin 124221, China
c WPI-Advanced Institute for Materials Research, Tohoku University,
Sendai 980-8577, Japan
d Research Organization of Science and Technology, Ritsumeikan University,
Kusatsu, Shiga 525-8577, Japan
† Electronic supplementary information (ESI) available: Experimental details,
analytical data and NMR spectra are provided. See DOI: 10.1039/c8cc08930b
Scheme 1 Synthesis of aryl nitriles with dimethylmalononitrile.
‡ He Li and Sheng Zhang contributed equally to this work.
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be as follows: the chelation of DMMN to metal catalyst may lead the use of CuO (entries 8 and 9). The results obtained from the study
to deactivation of catalyst; the low nucleophilic reactivity of on the effect of rhodium catalyst loading indicate that 5 mol% of
organometallic intermediate generated in situ via C–H activation. [RhCp*(MeCN)3](SbF6)2 is enough to obtain high yield (entry 10 vs.
To solve these issues, we conducted a detailed study. Herein, we entries 7 and 11). The yield of 2a decreases along with the decrease
report the first example of rhodium-catalyzed aromatic C–H bond in CuO loading and temperature (entries 12 and 13). No
direct cyanation with DMMN as the cyanating reagent using reaction was observed when the model reaction was conducted
copper oxide as a promotor to activate DMMN (Scheme 1b).
in the absence of a rhodium catalyst (entry 14). Therefore, the
In our initial studies, the reaction of 2-(p-tolyl)pyridine (1a) subsequent aromatic C–H bond direct cyanation reactions of
with DMMN was chosen as a model to optimize the reaction various substrates with DMMN were conducted in the presence
conditions, and the results are summarized in Table 1. The of [RhCp*(MeCN)3](SbF6)2 (5 mol%) and CuO (4.0 eq.) in HFIP
catalyst was firstly screened in 1,1,1,3,3,3-hexafluoro-2-propanol at 160 1C for 24 h.
(HFIP) at 160 1C (entry 1 vs. Table S1 (ESI†), entries 1–7 in the
The scope and limitation of this type of aromatic C–H bond
ESI†). The desired cyanation product, 5-methyl-2-(pyridin-2-yl)- direct cyanation reaction were determined under the optimal
benzonitrile (2a), was obtained in 38% yield when [RhCp*(MeCN)3]- reaction conditions. Scheme 2 shows the results obtained from
(SbF6)2 was applied (entry 1). This result suggested that the DMMN the reactions of aromatic substrates bearing a simple pyridine
can be used as a cyanating reagent in the aromatic C–H bond direct ring as the directing group. Similarly, the reactions of 2-phenyl-
cyanation, even though the yield is unsatisfactory. The solvent pyridine (1b) and 2-(m-tolyl)pyridine (1c) proceeded also smoothly
was subsequently screened using [RhCp*(MeCN)3](SbF6)2 as the as the reaction of 1a to produce the cyanated products 2b and 2c
catalyst. Among the solvents [HFIP, 2,2,2-trifluoroethanol (TFE), in good yields (79% and 88%, respectively). Products 2d and 2e
chlorobenzene (PhCl), 1,2-dichloroethane (DCE), and 1,4-dioxane], were obtained in moderate yields (58% and 56%, respectively).
HFIP proved to be the best solvent (entry 1 vs. entries 2–5). The These relatively low yields were attributed to the steric hindrance
nucleophilic reactivity of aryl-Rh(III) intermediate is lower than that caused from one or two methyl (Me) groups linked on ortho- or
of aryl-Rh(I) analogue in the reaction with DMMN (Scheme 1). meta-positions of benzene ring. The 2-phenylpyridine substrates
Therefore, a Lewis acid may be required to activate DMMN to 1f–1i bearing an alkyl (Et, nPr, and tBu) or a phenyl (Ph) group on
improve the yield of 2a. Unexpectedly, the use of Cu(OAc)2, a soluble the para-position of benzene ring proceeded with the target
salt in HFIP, leads to the complete inhibition of the target reaction reaction smoothly to give the desired products 2f–2i in satisfactory
(entry 6).20 However, the yield of 2a is dramatically improved to 85% yields (60–68%). Good yields of 2j and 2k (70% and 88%, respec-
by just changing the Lewis acid from Cu(OAc)2 to CuO, an insoluble tively) were obtained in the reactions of 2-phenylpyridine substrates
salt in HFIP (entry 7). The use of other insoluble salt, such as Ag2O 1j and 1k bearing methoxyl (MeO), a stronger electron-donating
and CoO also increase the yield of 2a, but not as better as that with group, on meta- or para-positions of benzene ring. In the case of the
Table 1 Screening of reaction conditionsa
Entry Catalyst
Lewis acid Solvent
HFIP
Yieldb (%)
1
[RhCp*(MeCN)3](SbF6)2 None
38
2
3
4
5
6
7
8
9
[RhCp*(MeCN)3](SbF6)2 None
TFE
20
[RhCp*(MeCN)3](SbF6)2 None
[RhCp*(MeCN)3](SbF6)2 None
[RhCp*(MeCN)3](SbF6)2 None
[RhCp*(MeCN)3](SbF6)2 Cu(OAc)2
[RhCp*(MeCN)3](SbF6)2 CuO
[RhCp*(MeCN)3](SbF6)2 Ag2O
[RhCp*(MeCN)3](SbF6)2 CoO
[RhCp*(MeCN)3](SbF6)2 CuO
[RhCp*(MeCN)3](SbF6)2 CuO
[RhCp*(MeCN)3](SbF6)2 CuO
[RhCp*(MeCN)3](SbF6)2 CuO
PhCl
DCE
16
NRc
Dioxane NRc
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
NRc
85
43
60
87
10d
11e
12f
13g
14
70
73
67
None
CuO
NRc
a
Reaction conditions: 2-(p-tolyl)pyridine (1a, 0.2 mmol, 33.8 mg),
Scheme 2 Rhodium-catalyzed aromatic C–H bond cyanation of 2-aryl-
pyridines with dimethylmalononitrile.a,b a Reaction conditions: 2-arylpyridine
derivatives (1, 0.2 mmol), dimethylmalononitrile (DMMN, 0.4 mmol, 37.6 mg),
[RhCp*(MeCN)3](SbF6)2 (5 mol%, 8.3 mg), CuO (0.8 mmol, 63.6 mg) in HFIP
(1.0 mL) at 160 1C for 24 h. b Isolated yield. c An isomer 2-methoxy-6-
(pyridin-2-yl)benzonitrile (2j0) was isorated in 12% yield. d The reaction was
performed for 36 h.
dimethylmalononitrile (DMMN, 0.4 mmol, 37.6 mg), catalyst (10 mol%)
b
and Lewis acid (4.0 eq.) in solvent (1.0 mL) at 160 1C for 24 h. Determined
by 1H NMR analysis of the crude reaction mixture using dibromomethane
c
as an internal standard. No reaction was observed, and starting
d
materials were recovered. [RhCp*(MeCN)3](SbF6)2 (5 mol%) was used.
e
g
f
[RhCp*(MeCN)3](SbF6)2 (2.5 mol%) was used. CuO (3.0 eq.) was used.
The reaction was performed at 130 1C.
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reaction of 1j, an isomer, 2-methoxy-6-(pyridin-2-yl)benzonitrile (2j0),
was also separated in 12% yield; this result was considered that due
to the chelation effect of nitrogen and oxygen atoms to rhodium
catalyst. However, moderate yields (43–59%) of 2l–2n were achieved
when the substrates 1l–1n bearing an electron-withdrawing group
(COOMe, CF3 or Cl) on para-position of benzene ring. These
results clearly indicated that this type of cyanation reaction
was influenced by the electron density of benzene ring. The
naphthalene ring-containing substrate 1o was finally examined,
and the corresponding cyanated product 2o was obtained in
46% yield.
Scheme 4 Synthesis of Angiotensin II Antagonist from product 4g.
and pyrazole were successfully used as the directing group in
the further investigation on the catalytic aromatic C–H bond
direct cyanation reaction. The desired products 4i–4l were
obtained in moderate yields (45–59%).
To prove the practicality of the present method, a deprotection
reaction of product 4g was performed in the presence of tetra-
butylammonium fluoride (TBAF) (Scheme 4). The product 2-[5-
(hydroxymethyl)pyridin-2-yl]benzonitrile (5) having a free hydroxyl
group was obtained in 93% yield, which was previously used
as a key intermediate for the development of Angiotensin II
Antagonist.21
Scheme 3 shows the results obtained from the reactions of
aromatic substrates bearing a substituted pyridine ring or other
nitrogen heterocycle as the directing group. Moderate to satis-
factory yields (57–78%) of products 4a–4d were obtained from
the reactions of substrates 3a–3d bearing a methyl group on the
pyridine ring; these results suggested that the methyl group did
not influence on the reactivity of substrate even when linked on
different positions. Reactions of substrates 3e–3g having a
t
substituent (CF3, Br or CH2OSiMe2 Bu) linked on the 5-position
of pyridine ring proceeded smoothly to offer the products 4e–4g
in 80%, 45%, and 67% yields, respectively. These aforementioned
results indicated that the electron property of substituent linked
on pyridine ring did not exert a significant influence on the
Control experiments were conducted to gain insight into the
mechanism of the cyanation reaction (Scheme 5). The aromatic
C–H bond direct cyanation reaction of 1b with DMMN also
proceeded smoothly in the presence of a well-defined rhodium(III)
complex and AgSbF6 to produce the desired product 2b in 64%
yield (eqn (1)). The rhodium(III) complex 6 would react with
AgSbF6 in situ to generate a cationic rhodium(III) complex, which
was considered to be the catalytic species. The desired product 2b
was still obtained in 76% yield even though the C–H bond
cyanation reaction of 1b was performed in the presence of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), a radical scavenger
(eqn (2)). This result indicates that a radical process is not
involved in the target reaction. The deuterium kinetic isotope
effect was investigated by conducting an intermolecular competition
reaction between 1b and 1b-d5; a 1:1 ratio of 2b to 2b-d4 demon-
strated that the cleavage of the aromatic C–H bond in 1b is not
involved in the rate-determining step (eqn (3)). A 15 : 1 ratio of 2a
to 2m was observed in the intermolecular reaction between 1b and
1m (eqn (4)), indicating electron-rich arenes to be preferentially
converted.
t
reactivity of substrate. Br and CH2OSiMe2 Bu linked to the
pyridine ring were notably maintained in the structures of
products 4f and 4g, suggesting that further manipulation may
produce more useful compounds. As expected, 4h was obtained
in good yield (84%) from the reaction of substrate 3h having a
methyl, which is an electron-donating group, on the benzene
ring. Other nitrogen heterocycles such as quinoline, pyrimidine,
On the basis of our experimental outcomes and previous
reports,22 a catalytic cycle is proposed to account for the present
Scheme 3 Rhodium-catalyzed C–H bond cyanation of arenes having
various directing groups with dimethylmalononitrile.a,b a Reaction conditions:
2-arylpyridine derivatives (3, 0.2 mmol), dimethylmalononitrile (DMMN,
0.4 mmol, 37.6 mg), [RhCp*(MeCN)3](SbF6)2 (5 mol%, 8.3 mg), CuO
(0.8 mmol, 63.6 mg) in HFIP (1.0 mL) at 160 1C for 24 h. bIsolated products.
c10 mol% of [RhCp*(MeCN)3](SbF6)2 was used. dPhCl (1 mL) was used as
solvent.
Scheme 5 Control experiments.
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Notes and references
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Chem. Ges., 1884, 17, 1633.
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Scheme 6 Proposed mechanism for the Rh-catalyzed aromatic C–H
bond cyanation.
catalytic C–H bond cyanation reaction (Scheme 6). The catalytic
cycle starts from [Cp*Rh(III)]2+, which is generated in situ from
the precatalyst [RhCp*(MeCN)3](SbF6)2. Coordination of the
nitrogen atom of 1b to rhodium catalyst species and subsequent
ortho C–H bond activation would generate a cationic five-membered
rhodacyclic intermediate A. Then, the insertion of CRN moiety in
DMMN activated by CuO into the Rh–C bond would produce the
intermediate B, which would subsequently undergo C–C(N) bond
cleavage to afford product 2b and generate intermediate C.
Protodemetalation of C would proceed to generate isopropylnitrile
and regenerate catalytic species [Cp*Rh(III)]2+. The formation of
isopropylnitrile was detected by gas chromatography–mass
spectrometry.
15 (a) T.-J. Gong, B. Xiao, W.-M. Cheng, W. Su, J. Xu, Z.-J. Liu, L. Liu and Y. Fu,
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I. Volchkov, C. A. Busacca, A. R. Howell and C. H. Senanayake, J. Org.
Chem., 2017, 82, 4993.
In summary, we developed a rhodium-catalyzed aromatic
C–H bond direct cyanation by using safe, bench-stable, and
commercially available DMMN as a cyanating reagent for the
synthesis of aryl nitriles. The cyanation reaction of 2-phenylpyridine
and its derivatives with DMMN proceeded smoothly in the presence
of rhodium(III) complex and copper oxide as the catalyst and
promotor, respectively, to produce the corresponding aryl nitriles
in moderate to good yields. Synthetically useful functional
t
groups, namely, MeO(O)C, Cl, Br, and CH2OSiMe2 Bu, remained
intact during the C–H bond direct cyanation. Further studies on
the extensive use of the DMMN as a cyanating reagent for C–H
bond direct cyanation are ongoing.
We thank the National Natural Science Foundation of China
(No. 21573032 and 21602026) and the China Postdoctoral
Science Foundation (No. 2016M590226) for financial support
of this work.
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cyano group in DMMN would take place to generate a 1,3-diiminium-
copper complex. Thus, the target reaction was completely inhibited.
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Conflicts of interest
22 (a) M. Chaitanya, D. Yadagiri and P. Anbarasan, Org. Lett., 2013,
15, 4960; (b) Y. Park, K. T. Park, J. G. Kim and S. Chang, J. Am. Chem.
Soc., 2015, 137, 4534.
There are no conflicts to declare.
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