Directing Group-Assisted Copper(II)-Catalyzed ortho-Carbonylation to Benzamide using 2,2′-Azobisisobutyronitrile (AIBN)

Article abstract of DOI:10.1002/adsc.201600664

An efficient copper-catalyzed regioselective C—H bond carbonylation of benzamides has been developed using 2,2′-azobisisobutyronitrile (AIBN) as traceless cyanating agent. The non-toxic and readily available AIBN was used for the carbonylative cyclization

Full text of DOI:10.1002/adsc.201600664

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DOI: 10.1002/adsc.201600664
Directing Group-Assisted Copper(II)-Catalyzed ortho-Carbonyla-
tion to Benzamide using 2,2’-Azobisisobutyronitrile (AIBN)
Bhuttu Khan,a Afsar Ali Khan,a Ruchir Kant,b and Dipankar Koleya,*
a
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow – 226031, India
E-mail: dkoley@cdri.res.in
b
Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow – 226031, India
Received: July 4, 2016; Revised: September 28, 2016; Published online: && &&, 0000
CDRI Communication No. 9317.
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600664.
Abstract: An efficient copper-catalyzed regioselec-
tive C—H bond carbonylation of benzamides has
been developed using 2,2’-azobisisobutyronitrile
(AIBN) as traceless cyanating agent. The non-toxic
and readily available AIBN was used for the car-
bonylative cyclization of benzamides via copper cat-
alysis. The method is also applicable for the regiose-
lective cyanation of furan, benzofuran, thiophene,
benzothiophene, and pyrrole carboxamide deriva-
tives.
C(sp3)–H functionalizations using second-row transi-
tion metal (Pd,[3] Ru[4] and Rh[4b,5]) catalysts have
been reported over the past decades (Scheme 1).
These include directing group-assisted Ru-catalyzed
C(sp2)–H and C(sp3)–H carbonylation,[4c,e–g,i] Rh-cata-
lyzed arene carbonylation,[5c,f,i,j] Pd-catalyzed carbony-
lation of simple arenes by CO gas under a high pres-
AHCTUNGTRENNUNG
sure,[3b] Pd-catalyzed b-C(sp3)–H carbonylation of N-
arylamides,[3i] carboxylation of electron-rich arenes,[3f]
benzoic acids,[3g] and anilides[3j] under atmospheric
pressure of CO. Chatani et al. first reported[4c] the car-
bonylation to benzamide using a Ru-catalyst. Daugu-
lis et al. first reported[6] a directing group-assisted car-
bonylation of benzamide by CO gas under atmospher-
ic pressure using first-row transition metal (Co, Mn)
catalysts. In the search for an alternative CO source,
Hallberg et al. first reported[2d] Pd-catalyzed amino-
carbonylation of aryl halides using DMF as reagent.
Keywords: 2,2’-azobisisobutyronitrile (AIBN); car-
bonylation; C—H functionalization; copper; cyana-
tion
Transition metal-catalyzed carbonylation reactions Recently, Ge et al. reported[2n] an elegant method for
have found wide application in academic and industri- the aerobic carbonylation to benzamide using DMF
al research. Hydroformylation to alkenes and produc- as carbonyl source. Wu et al. also reported[2l] a Pd(II)-
tion of acetic acid from methanol are very important catalyzed carbonylative cyclization of aniline deriva-
industrial processes that are routinely performed via tive using DMF as the carbonyl source. During the
carbonylation reactions. In addition, syntheses of car- writing of our manuscript, Ge et al. reported[2o] the
boxylic acids, esters, lactones, carbamates, amides
have been achieved from alkenes/alkynes via carbon-
ylation with various nucleophiles.[1] However, in most
of these cases, there are two major drawbacks. Firstly,
prefunctionalized substrates like aryl halides and aryl
triflates are required for arene carbonylation.[1d,e,f]
Most importantly, the highly toxic carbon monoxide
(CO) gas is used for the carbonylation process.[1]
These limitations, therefore, prompted chemists to de-
velop processes that (i) provide carbonylative prod-
ucts directly via C–H bond functionalization without
using prefunctionalized precursors, and (ii) use envi-
ronmentally benign CO-generating reagents.[2] In this
regard, several efficient carbonylative C(sp2)–H and Scheme 1. Direct C–H carbonylation to benzamides.
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copper-promoted carbonylation of C(sp2)–H and al., significant achievements have been realized in the
C(sp3)–H bonds using nitromethane as a carbonyl otherwise inconceivable metal-catalyzed site selective
source.
C–H functionalization processes utilizing 8-aminoqui-
Our interest[7] in heterocycles and C–H functionali- noline as bidentate directing group. In this regard,
zation led us to investigate the possibility of an alter- copper (a cheap and greener first-row transition
native carbonylation strategy. We argued that if di- metal) in conjunction with 8-aminoquinoline has been
rected ortho-cyanation to benzamide could be ach- found to be very effective[10] in the functionalization
ieved, the newly formed ortho-cyanobenzamide deriv- of various types of C–H bonds. On the other hand,
ative could undergo in situ intramolecular cyclization Han et al.[8f] and others[11] described that the readily
followed by hydrolysis to furnish the phthalimide de- available and less toxic 2,2’-azobisisobutyronitrile
rivative. Although there are a number of reports that (AIBN) could be used as a source of CN radical for
describe[8] both direct cyanation and directing group- C–H cyanation employing a copper catalyst. Inspired
assisted cyanation of arene C–H bonds using non- by these results, we report the directing group-assisted
metallic cyano group sources, there is only one report copper-catalyzed traceless cyanation to benzamide
of cyanation to benzamide using Ru catalyst[8j] and, to using AIBN to furnish phthalimide derivatives.
the best of our knowledge, a first-row transition
We began our investigation for the carbonylation of
metal-catalyzed cyanation to benzamide has not been N-(quinolin-8-yl)benzamide (1a) in acetonitrile using
reported. Since the seminal report[9] by Daugulis et 0.2 equiv. of Cu(OAc)2 and 1.1 equiv. of AIBN under
Table 1. Screening of the carbonylation conditions.[a]
Entry
Catalyst
Reagent (equiv)
Solvent
Oxidant
Yield[b] [%]
1[c]
2[c]
3
4
5
6
7
8
9
10
11
12
13
14[d]
15
16
17[e]
18[f]
19
20
21[g]
22[h]
23[h]
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(acac)2
Cu(OMe)2
Cu(NO3)2·xH2O
Cu(NO3)2·xH2O
Cu(NO3)2·xH2O
Cu(NO3)2·xH2O
Cu(NO3)2·xH2O
Cu(NO3)2·xH2O
Cu(NO3)2·xH2O
Cu(NO3)2·xH2O
Cu(NO3)2·xH2O
Cu(NO3)2·xH2O
Cu(NO3)2·xH2O
Cu(NO3)2·xH2O
Cu(Tc)
AIBN (1.1)
AIBN (1.1)
AIBN (1.1)
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
DMF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
–
–
–
–
–
–
–
–
NR
19
28
NR
25
trace
42
NR
NR
NF
49
55
60
59
87
96
NR
trace
trace
35
45
trace
78
AIBN (1.1)
AIBN (1.1)
AIBN (1.1)
AIBN (1.1)
AIBN (1.1)
AIBN (1.1)
AIBN (1.1)
AIBN (1.1)
AIBN (1.1)
AIBN (1.1)
AIBN (2.0)
AIBN (2.5)
AIBN (2.5)
AIBN (2.5)
AIBN (2.5)
AIBN (2.5)
AIBN (2.5)
AIBN (2.5)
AIBN (2.5)
–
TBAI
AgNO3
Ag2CO3
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
–
Cu(Tc)
Cu(Tc)
Cu(Tc)
Cu(NO3)2·xH2O
AgOAc
AgOAc
–
–
[a]
Reaction conditions: the reactions were run on 1a (0.2 mmol, 1 equiv.), MeCN (2 mL), catalyst (0.2 equiv.), oxidant
(0.8 equiv.), AIBN, O2 atmosphere, 1308C.
Isolated yields after column chromatography.
Temperature 808C.
4ꢁ molecular sieves (50 mg) used.
Reaction was run under an N2 atmosphere.
Reaction was run in the presence of 1.5 equiv. of TEMPO.
Oxidant (2.0 equiv.).
[b]
[c]
[d]
[e]
[f]
[g]
[h]
Catalyst (1.0 equiv.).
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atmospheric oxygen. No isolable product was ob- stituted derivatives, carbonylation occurred regiose-
tained at 808C (Table 1, entry 1). When the reaction lectively at the less hindered ortho position. Almost
was run under an oxygen atmosphere, 2a was isolated quantitative yields were obtained for naphthalene and
in 19% yield (Table 1, entry 2). An unsatisfactory in- phenylbenzene derivatives (2g–2i). In the case of 2-
crease in the yield (28%) was realized at an elevated naphthoic acid carboxamide, a regioselective carbony-
temperature (1308C). The reaction did not furnish lation occurred and 2g was obtained in 98% yield.
any product at all in the absence of AIBN (Table 1, Halogen functional groups were also tolerated
entry 4). We then screened various copper-based cata- (fluoro, chloro, bromo) and provided the phthalimide
lysts and 2a was isolated in 42% yield on treatment derivatives in good yields (2k–2m). Unfortunately,
with Cu(NO3)2·xH2O (Table 1, entries 5–7). We then substrates containing highly electron-withdrawing
tested different solvents and found that only acetoni- functional groups (cyano and nitro) did not furnish
trile promotes the desired carbonylation (Table 1, en- the product. Formation of the carbonylated product
tries 7–9). Addition of an external oxidant helped to was unambiguously confirmed by the X-ray crystallo-
obtain an improved yield (Table 1, entries 10–13) and graphic structure of 2a (see Table 2).[12]
it turned out that AgOAc was optimal, providing 2a
We were next intrigued by the possibility of carbon-
in 60% yield. Molecular sieves had no effect to im- ylation to the heteroarene substrates. Under the de-
prove the yield (Table 1, entry 14). When 2.0 equiv. of veloped protocol, only the cyanated derivatives were
the source of the cyanide radical was used, an 87% isolated, presumably because of the ring strain for
yield was obtained (Table 1, entry 15). Finally, which the cyano derivative could not furnish the car-
2.5 equiv. of AIBN delivered an excellent yield (96%) bonylated product (Table 3). Nevertheless, this con-
of 2a (Table 1, entry 16).
firms our hypothesis of C–H cyanation followed by
With the optimized conditions in hand, the scope hydrolysis to yield carbonylated products. To our de-
and limitations of our traceless cyanation protocol light, various heteroarenes possessing diverse substitu-
was investigated as shown in Table 2. To our delight, ents yielded the cyano derivatives in excellent yields.
arenes containing electron-donating (methyl, ethyl, Furan-2-carboxamide furnished the regioselective
tert-butyl, methoxy) as well as electron-withdrawing cyano derivative 4a in 91% yield. Alkyl- (4b) and
(trifluoromethoxy, trufluoromethyl) substituents pro- aryl- (4c and 4d) substituted furan-carboxamides also
vided the corresponding phthalimide derivatives in furnished the corresponding cyano derivatives in ex-
very good to excellent yields. Alkyl-substituted arenes cellent yields. Cyanated benzofuran-carboxamide de-
provided phthalimide derivatives in excellent yields rivative 4e was also obtained in 88% yield. Pyrrole
(2b–2f). The substitution pattern did not affect the and pyrazole derivatives also furnished the cyanated
yield of the product (2b–2d). In the case of meta-sub- products in excellent yields (4f and 4g). Pharmaceuti-
Table 2. Carbonylation to arene carboxamides.[a]
[a]
Reaction conditions: the reactions were run on 1a–o (0.2 mmol), yields mentioned are after column chromatography.
Isolated yield when conducted with 4.0 mmol scale reaction (brsm=based on recovered starting materials).
[b]
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Table 3. Cyanation to heteroarene carboxamides.[a]
[a]
Reaction conditions: the reactions were run on 3a–k (0.2 mmol), yields mentioned are after column chromatography.
cally relevant heteroarene substrates like thiophene-
(4h), 5-methylthiophene- (4i) and benzothiophene-
carboxamides (4j) yielded the 3-cyano derivatives in
excellent yields. Finally, a highly substituted furan de-
rivative was also cyanated using our protocol to fur-
nish 4k in 48% yield.
To better understand the mechanism of this cyana-
tion process several control experiments were per-
formed. Under a nitrogen atmosphere no product was
isolated, implicating the importance of oxygen
(Table 1, entry 17). The formation of only a trace
amount of 2a in the presence of 1.5 equiv. of TEMPO
suggested that the reaction is likely to proceed via
a radical pathway (entry 18). Han et al. demonstra-
ted[8f] that under thermal conditions Cu(II) is reduced
Scheme 2. Plausible mechanistic pathway.
to Cu(I) by AIBN and Cu(I) is the real catalytically with 1a to form doubly N,N-chelated intermediate A.
active species. Therefore, we conducted the reaction In the subsequent step, C–H cupration of the benzene
using Cu(I). It was realized that Cu(I) does not cata- ring furnishes the cyclometallated intermediate B
lyze the reaction (Table 1, entries 19, 22) and There- which further reacts with cyanide radical to provide
fore, contrary to the hypothesis of Han et al., we may aryl-Cu(III) intermediate C. Reductive elimination
postulate that Cu(II) is the real catalytic species in furnishes cyano derivative D which upon intramolecu-
our protocol. This is further understood in light of the lar cyclization and hydrolysis provides the phthali-
fact that Cu(I) delivers the product when AgOAc is mide derivative 2a. AgOAc regenerates Cu(II) by oxi-
used as an additive (entries 20 and 21). This could dizing Cu(I).[13,14]
possibly be attributed to the oxidation of Cu(I) to
To demonstrate the synthetic usefulness of the de-
Cu(II). However, besides its expected oxidant nature, veloped method, the reaction was carried out on
some other possible roles of AgOAc cannot be ruled gram scale, and the product 4h was obtained in 86%
out.[13] We believe that before AIBN reduces Cu(II), yield (Scheme 3). For further exploitation of the de-
the bidentate, chelating ligand 8-amidoquinoline veloped C–H cyanation process, 4h was converted to
moiety stabilizes Cu(II), thereby inhibiting its reduc- ketone (5h), tetrazole (6h) and carboxamide (7h) de-
tion. Further study is under process to unravel the rivatves. The cyano product 4i also furnished the tet-
detail mechanistic pathway.
razole derivative 6i in excellent yield.
Thus, on the basis of our mechanistic study and the
In summary, we have developed a strategy that ena-
reported literature on the copper-catalyzed[10] 8-ami- bles C–H carbonylation of benzamide derivatives
noquinoline-assisted C–H functionalization of arenes through traceless cynataion using AIBN as the source
it appears that involvement of an aryl-Cu(III) species of cyano radical and 8-aminoquinolyl moiety as di-
is rational and a plausible reaction mechanism is pro- recting group. The process is highly regioselective and
posed as shown in Scheme 2. First Cu(II) coordinates compatible with diverse functional groups. The pro-
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