Palladium-Catalyzed Regioselective Direct Cyanation of Acetanilide Derivatives with K4[Fe(CN)6] by C–H Bond Activation

Article abstract of DOI:10.1002/ejoc.201600618

A practical, versatile, and efficient method for the palladium-catalyzed direct cyanation of readily available acetanilides with K₄[Fe(CN)₆] as a safe cyanating agent through C–H bond activation with excellent C2 regioselectivity was developed. This finding represents a new strategy for the synthesis of N-(2-cyanoaryl)acetamides, which are important structural motifs in natural products and pharmaceuticals.

Full text of DOI:10.1002/ejoc.201600618

DOI: 10.1002/ejoc.201600618
Communication
C–H Activation
Palladium-Catalyzed Regioselective Direct Cyanation of
Acetanilide Derivatives with K4[Fe(CN)6] by C–H Bond Activation
Ebrahim Kianmehr,*[a] Nasser Faghih,[a] Arezoo Tanbakouchian,[a] and
Mohammad Mahdavi[b]
Abstract: A practical, versatile, and efficient method for the oped. This finding represents a new strategy for the synthesis
palladium-catalyzed direct cyanation of readily available acet-
anilides with K4[Fe(CN)6] as a safe cyanating agent through C–
H bond activation with excellent C2 regioselectivity was devel-
of N-(2-cyanoaryl)acetamides, which are important structural
motifs in natural products and pharmaceuticals.
Introduction
cently been published in this area.[7] All of these reports, de-
spite the aforementioned advantages, suffer from prefunction-
alization of the starting material, especially bromination. There-
fore, a more attractive and simple method to synthesize aro-
matic nitriles is required. C–C bond-forming reactions through
transition-metal-catalyzed C–H functionalization is a suitable al-
ternative to achieve this aim.[8]
Aromatic nitriles are omnipresent structural motifs found in
pharmaceutical compounds, natural products, and functional
materials.[1] For instance, bicalutamide was reported as an anti-
androgen and has been used in the treatment of prostate can-
cer,[2] and 2-(acylamino)benzonitriles are important precursors
for the synthesis of quinazolines,[3] which are an important class
of heterocyclic compounds, specifically because of their wide
range of biological activities (Figure 1). Moreover, the nitrile
group serves as an intermediate that can be transformed into
a multitude of other functional groups such as carboxylic acids,
amides, aldehydes, and ketones.[4]
Despite the numerous reports that have emerged for C–C
bond formation through C–H functionalization, cyanation
through direct C–H bond activation to access aromatic nitriles
has rarely been reported (Scheme 1). From a chronological
viewpoint, Yu and co-workers reported the Cu-catalyzed cyan-
ation of 2-arylpyridines with TMSCN or MeNO2 as the CN source
[Scheme 1, Equation (1)].[9] In 2009, the ruthenium-catalyzed
oxidative cyanation of tertiary amines in the presence of so-
dium cyanide and acetic acid for the synthesis of the corre-
sponding α-aminonitriles was developed by Murahashi
[Scheme 1, Equation (2)].[10] The direct cyanation of indoles by
using DMF as the CN source was reported by Jiao in 2011
[Scheme 1, Equation (3)].[11] Cheng and co-workers described
the chelation-assisted palladium-catalyzed ortho-cyanation of
2-arylpyridines by CuCN to provide aromatic nitriles in moder-
ate to good yields [Scheme 1, Equation (4)].[12] Another report
was developed by the same group as a chelation-assisted palla-
dium-catalyzed cascade bromination/cyanation reaction of 2-
arylpyridine and 1-arylpyrazole [Scheme 1, Equation (5)].[13] The
reaction involved the use of K3[Fe(CN)6] as a safe and nontoxic
cyanide reagent. In 2010, Wang and co-workers reported the
direct cyanation of indole derivatives with K4[Fe(CN)6] as the
cyanating agent through Pd-catalyzed C–H bond activation
[Scheme 1, Equation (6)].[14] Finally, our group developed a pal-
ladium-catalyzed one-pot procedure for the regioselective di-
merization and cyanation of indoles through transition-metal-
catalyzed C–H bond activation.[15] In this reaction, we used
K4[Fe(CN)6]·3H2O as the cyanating reagent to introduce a cyano
group selectively into the 3-position of bisindoles in high to
moderate yields. Other agents such as a combination of
NH4HCO3 and DMSO,[16] amine and ammonium,[17] ammonium
Figure 1. Examples of benzonitriles.
The Sandmeyer reaction[5] and the Rosenmund–von Braun
reaction[6] are traditional methods for the synthesis of benzo-
nitriles. Copper(I) cyanide serves as the cyanating source in
both reactions. Harsh conditions (150–250 °C) in the Rosen-
mund–von Braun reaction and the multistep process of the
Sandmeyer reaction have confined their application toward the
preparation of aromatic nitriles. The transition-metal-catalyzed
cyanation of aryl halides was introduced as a mild and direct
route for this transformation, and numerous reports have re-
[a] School of Chemistry, College of Science, University of Tehran,
Tehran, Iran
E-mail: kianmehr@khayam.ut.ac.ir
[b] Drug Design and Development Research Center, Tehran University of
Medical Sciences,
Tehran, Iran
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600618.
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or ammonia and DMF,[18] DMF,[11,19] and acetonitrile[20] have phosphino)-9,9-dimethylxanthene], and PdCl2(cod) (cod = 1,5-
been used as CN sources through C–H bond activation in the cyclooctadiene) were employed, but there was no increase in
last decades.[21] Towards addressing these reports and in con- the yield (Table 1, entries 3 and 4; see also Table S1, entries 2
tinuation of our interest in this area,[22] we wish to report the and 4–8 in the Supporting Information). Solvent screening
palladium-catalyzed regioselective direct cyanation of acet- showed that the role of solvent is crucial for this transformation.
anilides with K4[Fe(CN)6] as a safe and nontoxic cyanation rea-
Table 1. Optimization of the reaction conditions.[a]
gent through C–H bond activation for the first time. This
method is a valuable addition to the repertoire of cyanation
through C–H bond activation and also avoids the use of toxic
cyanide reagents such as CuCN and NaCN.
Entry Catalyst (mol-%)
Oxidant (equiv.)
Solvent Yield [%]
1
2
3
4
5
6
7
8
Pd(OAc)2 (5)
Pd(OAc)2 (10)
PdCl2 (10)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
CuBr2 (2)
Cu(SO4)2·5H2O (2)
Ag2CO3 (2)
PhI(OAc)2 (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (1)
–
DME
DME
DME
DME
DMF
DMSO
NMP
MeCN
DCE
DME
DME
DME
DME
DME
DME
DME
DME
DME
34
79
58
75
0
PdCl2(MeCN)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
–
0
0
56
77
17
76
11
0
9
10
11
12
13
14
15
16
17
18
65[b]
0
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
68
0
Cu(OAc)2·H2O (2)
38[c]
[a] Reaction conditions: A mixture of 1a (0.3 mmol) and 2 (20 mol-%) in
solvent (2.0 mL) was stirred at 130 °C for 24 h. [b] 2 (1.0 equiv.). [c] Performed
at 80 °C.
DMSO, DMF, and N-methylpyrrolidone (NMP) afforded poor
results (Table 1, entries 5–7). Upon conducting the reaction in
MeCN and 1,2-dichloroethane (DCE), 3a was obtained in yields
of 56 and 77 %, respectively (Table 1, entries 8 and 9). 1,2-Di-
methoxyethane (DME) was the best choice for this transforma-
tion (Table 1, entry 2). Screening a range of oxidants revealed
that Cu(OAc)2·H2O performed the best among other oxidants,
including CuBr2, Cu(SO4)2·H2O, Ag2CO3, and PhI(OAc)2 (Table 1,
entries 10–13; Table S1, entries 18–25). We were pleased to find
that the reaction could be performed in the presence of only
20 mol-% of K4[Fe(CN)6]·3H2O (Table 1, entry 2), whereas with
1 equivalent of this cyanation agent, the yield of the reaction
decreased to 65 % (Table 1, entry 14). Notably, no reaction oc-
curred in the absence of a catalyst or an oxidant (Table 1, en-
tries 15 and 17). Upon decreasing the reaction temperature
from 130 to 80 °C, the yield of the reaction decreased from 79
to 38 % (Table 1, entries 2 and 18; Table S1, entries 41–43).
Remarkably, the reaction occurred in the absence of any addi-
tive. Various additives such as Li2CO3, Na2CO3, Et3N, pivalic acid
(PivOH), 2,2′-bipyridine (bipy), and phenanthroline were exam-
ined but no improvement was observed (Table S1, entries 30–
40).
Scheme 1. Literature precedent to cyanation through C–H bond activation.
Results and Discussion
Our initial investigation began with N-(p-tolyl)acetamide (1a)
and potassium hexacyanoferrate(II) trihydrate (2) as the stan-
dard substrates (Table 1). Several catalysts, oxidants, additives,
solvents, and temperatures were examined to optimize the re-
action conditions. The initial trial gave desired product 3a in
34 % yield with 5 mol-% of Pd(OAc)2 as the catalyst (Table 1,
entry 1). Pleasingly, with increasing the amount of the catalyst
to 10 mol-%, the yield was dramatically improved to 79 %
(Table 1, entry 2). Other catalysts such as PdCl2, PdCl2(MeCN)2,
Under the optimal reaction conditions, a broad range of ac-
PdCl2(PPh3)2, PdCl2(Xantphos) [Xantphos = 4,5-bis(diphenyl- etanilide derivatives were successfully subjected to this proto-
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col, and the results are summarized in Table 2. Substituted acet- donating groups such as methyl, ethyl, and methoxy were the
anilides bearing both electron-donating and electron-with- best coupling partners in this transformation with
drawing groups were well tolerated under the standard reac- K4[Fe(CN)6]·3H2O and gave the highest yields. Notably, meta
tion conditions and generated desired products 3 in moderate electron-donating groups on the aryl ring gave products in
to high yields (Table 2). Unfortunately, 2-substituted acet- higher yields than para electron-donating groups (see com-
anilides did not lead to the corresponding products (see com- pounds 3a, 3c, and 3d vs. 3i, 3j, and 3k). Acetanilides with
pounds 3r and 3s). This observation may be explained by the electron-deficient substituents on the aryl ring were compatible
steric effect of the ortho substituent in the metalation step and substrates (see compounds 3e, 3f, 2h, and 3l–n), although the
the formation of a palladacycle.
yields were lower than those with electron-donating groups.
On the basis of previous reports,[12,13] a possible catalytic
mechanism for this transformation is illustrated in Scheme 2.
Initially, electrophilic palladation occurs preferentially at the or-
tho position of the acetanilide, which leads to the formation
of palladacycle A; this species undergoes transmetalation with
K4[Fe(CN)6]·3H2O to generate intermediate B. Finally, reductive
elimination of B leads to desired product 3 and Pd0, which is
reoxidized to PdII by CuII to complete the catalytic cycle.
Table 2. Palladium-catalyzed regioselective direct 2-cyanation of acet-
anilides.[a]
Scheme 2. Plausible mechanism.
Conclusions
In summary, we developed the first palladium-catalyzed regio-
selective 2-cyanation of acetanilides with K4[Fe(CN)6] as a non-
toxic cyanating agent through C–H bond activation for the syn-
thesis of N-(2-cyanophenyl)acetamide by using Cu(OAc)2·H2O as
the oxidant and DME as a suitable solvent. This transformation
was shown to proceed smoothly and to provide the corre-
sponding products in good to high yields. This method toler-
ates both electron-rich and electron-deficient substrates and
provides a new, simple, and practical route to produce the titled
products, which, in addition to possessing probable pharma-
ceutical properties, serve as important precursors for the syn-
thesis of other biologically active compounds.
[a] Reaction conditions: acetanilide (0.3 mmol), Pd(OAc)2 (10 mol-%),
Cu(OAc)2·H2O (2.0 equiv.), DME (2.0 mL), 130 °C, 24 h.
Acetanilides with halo substituents (e.g., F, Cl) smoothly led
to the corresponding aromatic nitriles in moderate to good
yields. Given that these halogen substituents remained intact
during the reaction, they can bring about a beneficial effect
by enabling additional functionalization at these positions (see
Experimental Section
General Information: Solvents, Cu(OAc)2·H2O, K4[Fe(CN)6], and anil-
ine derivatives were purchased from Merck. Other reagents were
compounds 3e, 3f, 3l, 3m, and 3n). Acetanilides with electron- purchased from commercial distributors and were used without fur-
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ther purification. Acetanilide derivatives[23] and palladium acet-
ate[24] were synthesized according to the literature. Analytical thin-
0.6 mmol), and Pd(OAc)2 (6 mg, 10 mol-%). Purification by column
chromatography (silica gel; n-hexane/EtOAc, 2:1) gave product 3d
layer chromatography (TLC) was performed on precoated silica gel (50 mg, 87 %) as a white solid, m.p. 172–173 °C. IR: ν = 3256, 3080,
˜
60 F254 plates. The products were purified by preparative column 2919, 2846, 2225, 1659, 1524, 1233, 1025, 921, 876, 836, 676 cm–1
.
chromatography on silica gel (0.063–0.200 mm, Merck). 1H NMR and
13C NMR spectra were recorded with a Bruker DRX 500 or a 400
Advance instrument in CDCl3 and [D6]DMSO. Mass spectrometry
was performed with an Agilent 5975C VL MSD (ion source: EI+,
70 eV, 230 °C). IR spectra were obtained with a Bruker Equinox 55.
1H NMR (500 MHz, CDCl3): δ = 8.17 (d, J = 9 Hz, 1 H), 7.48 (br., 1 H),
7.12 (dd, J = 9 & J = 3, 1 H), 7.04 (d, J = 3, 1 H), 3.82 (s, 3 H),
2.23 ppm (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 168.8, 157.4, 133.8,
123.8, 120.6, 116.2, 116, 95.4, 55.7, 24.4 ppm. MS (EI): m/z (%) = 190
(29) [M]+, 148 (100), 133 (96), 105 (13), 77 (7), 52 (8), 43 (45).
C10H10N2O2 (190.20): calcd. C 63.13, H 5.30, N 14.73; found C 63.08,
H 5.31, N 14.68.
General Procedure for the Synthesis of 2-Cyanoacetanilides: A
10 mL microwave vial was charged with the acetanilide derivative
(1 equiv., 0.3 mmol), Cu(OAc)2·H2O (2 equiv.), Pd(OAc)2 (10 mol-%),
K4Fe(CN)6·3H2O (20 mol-%), and DME (2 mL). The vial was then
sealed and immersed in an oil bath, which was preheated at 130 °C,
for 24 h. After this time, the mixture was cooled to room tempera-
ture and then diluted with CH2Cl2 and filtered. The residue was
purified by column chromatography (n-hexane/EtOAc, 2:1) to yield
the desired product.
N-(2-Cyano-4-fluorophenyl)acetamide (3e): The general proce-
dure was followed by using 4-fluoroacetanilide (0.3 mmol, 46 mg),
K4[Fe(CN)6]·3H2O (25 mg, 20 mol-%), Cu(OAc)2·H2O (120 mg,
0.6 mmol), and Pd(OAc)2 (6 mg, 10 mol-%). Purification by column
chromatography (silica gel; n-hexane/EtOAc, 2:1) gave product 3e
(33 mg, 63 %) as a white solid, m.p. 152–154 °C. IR: ν = 3255, 3069,
˜
2919, 2850, 2232, 1664, 1526, 1294, 1250, 938, 895, 840, 678 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.32 (q, J = 5 Hz, 1 H), 7.77 (br., 1 H),
7.33–7.27 (m, 2 H), 2.26 ppm (s, 3 H). 13C NMR (125 MHz, CDCl3):
δ = 168.7, 159 (d, J = 201.2 Hz), 137, 124.4 (d, J = 25 Hz), 124, 121.7
(d, J = 21.25 Hz), 118.5 (d, J = 11.25 Hz), 115.3, 103.7, 24.4 ppm. MS
(EI): m/z (%) = 178 (22) [M]+, 161 (20), 136 (100), 109 (29), 82 (17),
57 (16), 43 (93). C9H7FN2O (178.16): calcd. C 60.66, H 3.96, N 15.73;
found C 60.73, H 3.98, N 15.71.
N-(2-Cyano-4-methylphenyl)acetamide (3a): The general proce-
dure was followed by using 4-methylacetanilide (0.3 mmol, 45 mg),
K4[Fe(CN)6]·3H2O (25 mg, 20 mol-%), Cu(OAc)2·H2O (120 mg,
0.6 mmol), and Pd(OAc)2 (6 mg, 10 mol-%). Purification by column
chromatography (silica gel; n-hexane/EtOAc, 2:1) gave product 3a
as a white solid (41 mg, 79 %), m.p. 135–137 °C. IR: ν = 3249, 3031,
˜
2926, 2225, 1659, 1524, 1296, 891, 831, 675 cm–1. 1HNMR (500 MHz,
CDCl3): δ = 8.22 (d, J = 8 Hz, 1 H), 7.60 (br., 1 H), 7.37–7.39 (m, 2 H),
2.33 (s, 3 H), 2.24 ppm (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 168.4,
138.1, 134.9, 134.2, 132.1, 121.5, 116.5, 101.7, 24.5, 20.4 ppm. MS
(EI): m/z (%) = 174 (23) [M]+, 133 (17), 132 (100), 131 (81), 104 (9),
77 (11), 43 (33). C10H10N2O (174.20): calcd. C 68.93, H 5.79, N 16.09;
found C 68.80, H 5.81, N 16.12.
N-(4-Chloro-2-cyanophenyl)acetamide (3f): The general proce-
dure was followed by using 4-chloroacetanilide (0.3 mmol, 51 mg),
K4[Fe(CN)6]·3H2O (25 mg, 20 mol-%), Cu(OAc)2·H2O (120 mg,
0.6 mmol), and Pd(OAc)2 (6 mg, 10 mol-%). Purification by column
chromatography (silica gel; n-hexane/EtOAc, 2:1) gave product 3f
(38 mg, 66 %) as a white solid, m.p. 148–150 °C. IR: ν = 3338, 3066,
˜
2229, 1699, 1585, 1516, 1288, 872, 835, 646 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 8.39 (d, J = 10 Hz, 1 H), 7.68 (br., 1 H), 7.55–7.53 (m, 2
H), 2.27 ppm (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 168.5, 139.2,
134.4, 131.4, 129.2, 122.6, 115.1, 103.5, 24.6 ppm. MS (EI): m/z (%) =
196 (25) [M + 2]+, 194 (31) [M]+, 154 (82), 152 (98), 125 (23), 117
(13), 90 (15), 73 (12), 63 (17), 43 (100). C9H7ClN2O (194.62): calcd. C
55.66, H 3.64, N 14.43; found C 55.75, H 3.66, N 14.39.
N-(2-Cyanophenyl)acetamide (3b): The general procedure was fol-
lowed by using acetanilide (0.3 mmol, 40 mg), K4[Fe(CN)6]·3H2O
(25 mg, 20 mol-%), Cu(OAc)2·H2O (120 mg, 0.6 mmol), and Pd(OAc)2
(6 mg, 10 mol-%). Purification by column chromatography (silica
gel; n-hexane/EtOAc, 2:1) gave product 3b (31 mg, 64 %) as a white
solid, m.p. 129–131 °C. IR: ν = 3320, 3091, 2919, 2230, 1708, 1580,
˜
1525, 1443, 1371, 1291, 751, 636 cm–1
.
1H NMR (500 MHz, CDCl3):
N-[2-Cyano-4-(trifluoromethyl)phenyl]acetamide (3g): The gen-
eral procedure was followed by using 4-(trifluoromethyl)acetanilide
(0.3 mmol, 61 mg), K4[Fe(CN)6]·3H2O (25 mg, 20 mol-%),
Cu(OAc)2·H2O (120 mg, 0.6 mmol), and Pd(OAc)2 (6 mg, 10 mol-%).
Purification by column chromatography (silica gel; n-hexane/EtOAc,
2:1) gave product 3g (29 mg, 43 %) as an off-white solid, m.p. 169–
δ = 8.40 (d, J = 8.5 Hz, 1 H), 7.65 (br., 1 H), 7.60 (m, 2 H), 7.17 (t, J =
8 Hz, 1 H), 2.26 ppm (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 169,
140.5, 134.1, 132.2, 124.1, 121.3, 116.3, 101.3, 24.7 ppm. MS (EI): m/z
(%) = 160 (40) [M]+, 119 (25), 118 (100), 91 (40), 90 (19), 64 (17), 43
(90). C9H8N2O (160.17): calcd. C 67.47, H 5.04, N 17.50; found C
67.61, H 5.02, N 17.56.
171 °C. IR: ν = 3338, 2920, 2852, 2233, 1696, 1590, 1535, 1328, 1297,
˜
1109, 1073, 854, 733, 673 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.66
(d, J = 9 Hz, 1 H), 7.84–7.81 (m, 3 H), 2.31 ppm (s, 3 H). 13C NMR
(100 MHz, [D6]DMSO): δ = 169.5, 144.3, 131.2 (q, J = 3 Hz), 130.9 (q,
J = 3 Hz), 125.9 (q, J = 33 Hz), 125.4, 125 (q, J = 270 Hz), 116, 106.8,
23.8 ppm. MS (EI): m/z (%) = 228 (57) [M]+, 187 (42), 186 (100), 167
(81), 161 (38), 136 (37), 108 (12), 88 (22), 69 (15), 57 (16), 43 (93).
C10H7F3N2O (228.17): calcd. C 52.62, H 3.09, N 12.28; found C 52.68,
H 3.07, N 12.32.
N-(2-Cyano-4-ethylphenyl)acetamide (3c): The general procedure
was followed by using 4-ethylacetanilide (0.3 mmol, 49 mg),
K4[Fe(CN)6]·3H2O (25 mg, 20 mol-%), Cu(OAc)2·H2O (120 mg,
0.6 mmol), and Pd(OAc)2 (6 mg, 10 mol-%). Purification by column
chromatography (silica gel; n-hexane/EtOAc, 2:1) gave product 3c
(47 mg, 84 %) as a white solid, m.p. 114–115 °C. IR: ν = 3279, 2964,
˜
2921, 2230, 1662, 1497, 1362, 1263, 842, 815, 694 cm–1
.
1H NMR
(500 MHz, CDCl3): δ = 8.23 (d, J = 8.5, 1 H) 7.66 (br., 1 H) 7.40 (m, 2
H), 2.65 (q, J = 7.5 Hz, 2 H) 2.25 (s, 3 H), 1.23 ppm (t, J = 7.5 Hz, 3
H). 13C NMR (125 MHz, CDCl3): δ = 168.5, 140.5, 138.2, 133.8, 131,
121.7, 116.6, 102.1, 27.3, 24.5, 15 ppm. MS (EI): m/z (%) = 188 (40)
[M]+, 147 (21), 146 (100), 132 (39), 131 (97), 116 (12), 104 (14), 91
(17), 77 (22), 57 (15), 43 (94). C11H12N2O (188.23): calcd. C 70.18, H
6.43, N 14.89; found C 70.33, H 6.46, N 14.92.
N-(2-Cyano-4-nitrophenyl)acetamide (3h): The general procedure
was followed by using 4-nitroacetanilide (0.3 mmol, 54 mg),
K4[Fe(CN)6]·3H2O (25 mg, 20 mol-%), Cu(OAc)2·H2O (120 mg,
0.6 mmol), and Pd(OAc)2 (6 mg, 10 mol-%). Purification by column
chromatography (silica gel; n-hexane/EtOAc, 2:1) gave product 3h
(31 mg, 51 %) as a yellow solid, m.p. 183–185 °C. IR: ν = 3293, 3141,
˜
N-(2-Cyano-4-methoxyphenyl)acetamide (3d): The general pro-
cedure was followed by using 4-methoxyacetanilide (0.3 mmol,
2920, 2240, 1712, 1582, 1546, 1503, 1342, 825, 778, 743, 677 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.77 (d, J = 9 Hz, 1 H), 8.48 (d, J =
50 mg), K4[Fe(CN)6]·3H2O (25 mg, 20 mol-%), Cu(OAc)2·H2O (120 mg, 2.5 Hz, 1 H), 8.44 (dd, J = 9.5 Hz & J = 2.5 Hz, 1 H), 7.93 (br., 1 H),
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2.34 ppm (s, 3 H). 13C NMR (100 MHz, [D6]DMSO): δ = 169.7, 146.3,
143.4, 129.7, 129.2, 124.6, 115.5, 105.8, 24.1 ppm. MS (EI): m/z (%) =
205 (21) [M]+, 164 (11), 163 (93), 133 (31), 117 (16), 105 (8), 90 (20),
63 (11), 43 (100). C9H7N3O3 (205.17): calcd. C 52.67, H 3.44, N 20.49;
found C 52.74, H 3.42, N 20.53.
108 (20), 82 (10), 57 (11), 43 (99). C9H7FN2O (178.16): calcd. C 60.66,
H 3.96, N 15.73; found C 60.63, H 3.98, N 15.67.
N-(5-Chloro-2-cyanophenyl)acetamide (3m): The general proce-
dure was followed by using 3-chloroacetanilide (0.3 mmol, 51 mg),
K4[Fe(CN)6]·3H2O (25 mg, 20 mol-%), Cu(OAc)2·H2O (120 mg,
0.6 mmol), and Pd(OAc)2 (6 mg, 10 mol-%). Purification by column
chromatography (silica gel; n-hexane/EtOAc, 2:1) gave product 3m
N-(2-Cyano-5-methylphenyl)acetamide (3i): The general proce-
dure was followed by using 3-methylacetanilide (0.3 mmol, 45 mg),
K4[Fe(CN)6]·3H2O (25 mg, 20 mol-%), Cu(OAc)2·H2O (120 mg,
0.6 mmol), and Pd(OAc)2 (6 mg, 10 mol-%). Purification by column
chromatography (silica gel; n-hexane/EtOAc, 2:1) gave product 3i
(37 mg, 65 %) as a white solid, m.p. 178–180 °C. IR: ν = 3327, 3120,
˜
2224, 1698, 1567, 1518, 1407, 1251, 887, 822, 773, 657 cm–1
.
1H
NMR (500 MHz, CDCl3): δ = 8.54 (d, J = 1.5 Hz, 1 H), 7.64 (br., 1 H),
7.50 (d, J = 8.5, 1 H), 7.16 (dd, J = 8 & J = 2, 1 H), 2.27 ppm (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 168.4, 140.9, 140.8, 132.8, 124.4,
121.2, 115.7, 100.7, 24.7 ppm. MS (EI): m/z (%) = 194 (19) [M]+, 153
(73), 152 (24), 151 (100), 124 (17), 88 (9), 63 (15). C9H7ClN2O (194.62):
calcd. C 55.66, H 3.64, N 14.43; found C 55.55, H 3.62, N 14.38.
(46 mg, 87 %) as a white solid, m.p. 136–138 °C. IR: ν = 3232, 3058,
˜
3006, 2918, 2815, 2223, 1664, 1569, 1536, 1422, 1289, 1032, 890,
818, 710 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.21 (s, 1 H), 7.62 (br.,
1 H), 7.46 (d, J = 7.5 Hz, 1 H), 6.98 (d, J = 8 Hz, 1 H), 2.41 (s, 3 H),
2.25 ppm (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 168.5, 145.6, 140.3,
131.9, 125.1, 121.8, 116.6, 102.8, 24.7, 22.2 ppm. MS (EI): m/z (%) =
175 (13) [M + 1]+, 174 (11) [M]+, 133 (12), 132 (100), 131 (55), 104
(40), 89 (12), 77 (37), 51 (10). C10H10N2O (174.20): calcd. C 68.93, H
5.79, N 16.09; found C 68.85, H 5.82, N 16.04.
N-(4,5-Dichloro-2-cyanophenyl)acetamide (3n): The general pro-
cedure was followed by using 3,4-dichloroacetanilide (0.3 mmol,
61 mg), K4[Fe(CN)6]·3H2O (25 mg, 20 mol-%), Cu(OAc)2·H2O (120 mg,
0.6 mmol), and Pd(OAc)2 (6 mg, 10 mol-%). Purification by column
chromatography (silica gel; n-hexane/EtOAc, 2:1) gave product 3n
N-(2-Cyano-5-ethylphenyl)acetamide (3j): The general procedure
was followed by using 3-ethylacetanilide (0.3 mmol, 49 mg),
K4[Fe(CN)6]·3H2O (25 mg, 20 mol-%), Cu(OAc)2·H2O (120 mg,
0.6 mmol), and Pd(OAc)2 (6 mg, 10 mol-%). Purification by column
chromatography (silica gel; n-hexane/EtOAc, 2:1) gave product 3j
(35 mg, 52 %) as a white solid, m.p. 196–198 °C. IR: ν = 3238, 2917,
˜
2850, 2232, 1670, 1563, 1509, 1368, 1278, 907, 871, 820, 665 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.66 (s, 1 H), 7.68 (br., 1 H), 7.64 (s,
1 H), 2.27 ppm (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 168.4, 139.4,
135.1, 132.7, 127.7, 122.9, 114.6, 100.3, 24.7 ppm. MS (EI): m/z (%) =
230 (3) [M + 2]+, 228 (7) [M]+, 190 (10), 188 (57), 186 (83), 136 (12),
88 (7), 57 (12), 43 (100). C9H6Cl2N2O (229.06): calcd. C 47.37, H 2.65,
N 12.28; found C 47.48, H 2.64, N 12.32.
(50 mg, 88 %) as a white solid, m.p. 90–92 °C. IR: ν = 3254, 2966,
˜
2225, 1665, 1532, 1424, 1370, 881, 835, 690 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 8.20 (s, 1 H), 7.79 (br., 1 H), 7.46–7.48 (d, J = 7.5 Hz, 1
H), 7.01–6.69 (d, J = 8 Hz, 1 H), 2.67–2.71 (q, J = 7.5, 2 H), 2.25 (s, 3
H), 1.25–1.22 ppm (t, J = 7.5 Hz,3 H). 13C NMR (125 MHz, CDCl3):
δ = 168.6, 151.6, 140.5, 132.1, 123.9, 121, 116.7, 99.3, 29.3, 24.5,
14.8 ppm. MS (EI): m/z (%) = 189 (37) [M + 1]+, 188 (40) [M]+, 147
(34), 146 (100), 131 (67), 118 (10), 104 (11), 91 (10), 77 (10), 43 (95).
C11H12N2O (188.23): calcd. C 70.18, H 6.43, N 14.89; found C 70.37,
H 6.40, N 14.91.
N-(6-Cyanobenzo[d][1,3]dioxol-5-yl)acetamide (3o): The general
procedure was followed by using 3,4-(methylenedioxy)acetanilide
(0.3 mmol, 54 mg), K4[Fe(CN)6]·3H2O (25 mg, 20 mol-%),
Cu(OAc)2·H2O (120 mg, 0.6 mmol), and Pd(OAc)2 (6 mg, 10 mol-%).
Purification by column chromatography (silica gel; n-hexane/EtOAc,
2:1) gave product 3o (43 mg, 70 %) as a pink solid, m.p. 190–193 °C.
IR: ν = 3324, 3138, 2920, 2218, 1710, 1538, 1488, 1279, 1231, 1034,
˜
N-(2-Cyano-5-methoxyphenyl)acetamide (3k): The general proce-
dure was followed by using 3-methoxyacetanilide (0.3 mmol,
50 mg), K4[Fe(CN)6]·3H2O (25 mg, 20 mol-%), Cu(OAc)2·H2O (120 mg,
0.6 mmol), and Pd(OAc)2 (6 mg, 10 mol-%). Purification by column
chromatography (silica gel; n-hexane/EtOAc, 2:1) gave product 3k
923, 880, 854, 816, 734, 661 cm–1
.
1H NMR (500 MHz, CDCl3): δ =
7.89 (s, 1 H), 7.56 (br., 1 H), 6.91–6.90 (d, J = 2, 1 H), 6.05 ppm (s, 2
H). 13C NMR (125 MHz, CDCl3): δ = 169, 149.4, 145.7, 137.8, 116.6,
109.6, 103.4, 102.5, 95.3, 24.5 ppm. MS (EI): m/z (%) = 204 (23) [M]+,
179 (19), 163 (28), 162 (100), 149 (18), 137 (27), 121 (31), 107 (40),
106 (59), 104 (20), 77 (24), 52 (21), 43 (97). C10H8N2O3 (204.18): calcd.
C 58.81, H 3.95, N 13.72; found C 58.88, H 3.95, N 13.74.
(50 mg, 88 %) as an off-white solid, m.p. 144–146 °C. IR: ν = 3343,
˜
3121, 2922, 2215, 1697, 1536, 1430, 1240, 1035, 867, 812, 690,
633 cm–1 1H NMR (500 MHz, CDCl3): δ = 8.00 (s, 1 H), 7.69 (br., 1
.
H), 7.46 (d, J = 8.5 Hz, 1 H), 6.68 (m, 2 H), 3.84 (s, 3 H), 2.26 ppm (s,
3 H). 13C NMR (125 MHz, CDCl3): δ = 168.8, 164, 142.3, 133.3, 116.8,
111.1, 106, 93.3, 55.6, 24.7 ppm. MS (EI): m/z (%) = 191 (10) [M +
1]+, 190 (66) [M]+, 165 (8), 149 (29), 148 (100), 147 (17), 120 (15),
119 (64), 118 (55), 105 (20), 91 (15), 77 (17), 65 (12), 52 (7), 43 (86).
C10H10N2O2 (190.20): calcd. C 63.13, H 5.30, N 14.73; found C 63.03,
H 5.28, N 14.77.
N-(2-Cyano-4,5-dimethoxyphenyl)acetamide (3p): The general
procedure was followed by using 3,4-dimethoxyacetanilide
(0.3 mmol, 58 mg), K4[Fe(CN)6]·3H2O (25 mg, 20 mol-%),
Cu(OAc)2·H2O (120 mg, 0.6 mmol), and Pd(OAc)2 (6 mg, 10 mol-%).
Purification by column chromatography (silica gel; n-hexane/EtOAc,
2:1) gave product 3p (60 mg, 91 %) as an off-white solid, m.p. 185–
186 °C. IR: ν = 3334, 2922, 2852, 2213, 1692, 1519, 1253, 1222, 860,
˜
756 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.06 (s, 1 H), 7.57 (br., 1
N-(2-Cyano-5-fluorophenyl)acetamide (3l): The general proce-
dure was followed by using 3-fluoroacetanilide (0.3 mmol, 46 mg),
K4[Fe(CN)6]·3H2O (25 mg, 20 mol-%), Cu(OAc)2·H2O (120 mg,
0.6 mmol), and Pd(OAc)2 (6 mg, 10 mol-%). Purification by column
chromatography (silica gel; n-hexane/EtOAc, 2:1) gave product 3l
H), 6.96 (s, 1 H), 3.97 (s, 3 H), 3.9 (s, 3 H), 2.28 ppm (s, 3 H). 13C NMR
(100 MHz, CDCl3): δ = 168.9, 153.5, 145.4, 136.4, 116.9, 112.7, 105.3,
92.6, 56.2, 24.6 ppm. MS (EI): m/z (%) = 220 (33) [M]+, 178 (89), 163
(93), 135 (37), 57 (42), 43 (100). C11H12N2O3 (220.22): calcd. C 59.98,
H 5.50, N 12.73; found C 59.94, H 5.51, N 12.67.
(32 mg, 61 %) as a white solid, m.p. 160–162 °C. IR: ν = 3259, 3068,
˜
2920, 2231, 1665, 1525, 1245, 1141, 936, 896, 838, 675 cm–1
.
1H N-(2-Cyano-4,5-dimethylphenyl)acetamide (3q): The general pro-
NMR (500 MHz, CDCl3): δ = 8.37–8.35 (m, 1 H), 7.55 (br., 1 H), 7.33–
cedure was followed by using 3,4-dimethylacetanilide (0.3 mmol,
7.27 (m, 2 H), 2.26 ppm (s, 3 H). 13C NMR (100 MHz, [D6]DMSO): δ = 49 mg), K4[Fe(CN)6]·3H2O (25 mg, 20 mol-%), Cu(OAc)2·H2O (120 mg,
169.2, 160 (d, J = 244 Hz), 137.5 (d, J = 3 Hz), 128.4 (d, J = 8 Hz), 0.6 mmol), and Pd(OAc)2 (6 mg, 10 mol-%). Purification by column
121.8 (d, J = 22 Hz), 120.1 (d, J = 26), 116.2 (d, J = 2), 109.2 (d, J =
chromatography (silica gel; n-hexane/EtOAc, 2:1) gave product 3q
10), 23.4 ppm. MS (EI): m/z (%) = 178 (23) [M]+, 136 (100), 109 (19),
(50 mg, 89 %) as an orange solid, m.p. 175–177 °C. IR: ν = 3227,
˜
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Communication
3041, 2922, 2221, 1666, 1526, 1290, 888, 711 cm–1 1H NMR
.
N. Pham, A. Lazareva, Synlett 2006, 3382; f) K. Kawasumi, K. Mochida, T.
Kajino, Y. Segawa, K. Itami, Org. Lett. 2012, 14, 418; g) R. Rossi, F. Bellina,
M. Lessi, C. Manzini, Adv. Synth. Catal. 2014, 356, 17; h) Y. H. Zhang, B. F.
Shi, J. Q. Yu, J. Am. Chem. Soc. 2009, 131, 5072; i) W. Liu, Y. Li, B. Xu, C.
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(400 MHz, CDCl3): δ = 8.12 (s, 1 H), 7.66 (br., 1 H), 7.33 (s, 1 H), 2.35
(s, 3 H), 2.26 (s, 3 H), 2.24 ppm (s, 3 H). 13C NMR (100 MHz, CDCl3):
δ = 168.6, 144.2, 138.2, 133.3, 132.4, 122.8, 116.8, 99.4, 24.6, 20.6,
19 ppm. MS (EI): m/z (%) = 189 (16) [M + 1]+, 188 (20) [M]+, 146
(100), 145 (50), 131 (42), 91 (14), 57 (26), 43 (79). C11H12N2O (188.23):
calcd. C 70.18, H 6.43, N 14.89; found C 70.35, H 6.44, N 14.86.
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Acknowledgments
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We gratefully acknowledge financial support from the Research
Council of the University of Tehran.
Keywords: Homogeneous catalysis · Palladium · C–C
coupling · C–H activation · Cyanation
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Received: May 19, 2016
Published Online: ■
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Communication
C–H Activation
E. Kianmehr,* N. Faghih,
A. Tanbakouchian, M. Mahdavi ..... 1–7
Palladium-Catalyzed Regioselective
Direct Cyanation of Acetanilide De-
rivatives with K4[Fe(CN)6] by C–H
Bond Activation
The palladium-catalyzed highly regio- aid of K4[Fe(CN)6] as the cyano-group
selective cyanation of acetanilides source. A series of 2-cyanoacetanilides
through C–H bond activation is devel- are obtained in moderate to good
oped. The reaction proceeds with the yields; DME = 1,2-dimethoxyethane.
DOI: 10.1002/ejoc.201600618
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