Selective para-cyanation of alkoxy- and benzyloxy-substituted benzenes with potassium ferricyanide promoted by copper(II) nitrate and iodine

Article abstract of DOI:10.1002/adsc.201200235

A simple method was developed for selective para-cyanation of alkoxy- and benzyloxy-substituted benzenes with 0.5 equivalents of potassium ferricyanide, 0.8 equivalants of copper(II) nitrate and 0.5 equivalents of iodine in acetonitrile. Among various phenyl carbon-hydrogen bonds, those at the para-position with regard to the alkoxy or benzyloxy groups were selectively cyanated in 20% to 87% yields (23 examples). The present method uses commercially available reagents, and can be performed on a ten gram-scale. Interestingly, methoxybenzene was cyanated in 32% yield in the absence of potassium ferricyanide, which suggests that the nitrile group of a part of the product is possibly from the solvent acetonitrile. Copyright

Full text of DOI:10.1002/adsc.201200235

FULL PAPERS
DOI: 10.1002/adsc.201200235
Selective para-Cyanation of Alkoxy- and Benzyloxy-Substituted
Benzenes with Potassium Ferricyanide Promoted by Copper(II)
Nitrate and Iodine
Yunlai Ren,a Mengjie Yan,a Shuang Zhao,a Jianji Wang,a,* Junying Ma,a
Xinzhe Tian,a and Weiping Yina
a
School of Chemical Engineering & Pharmaceutics, Henan University of Science and Technology, Luoyang Henan 471003,
Peopleꢀs Republic of China
Fax : (+86)-379-6421-0415; e-mail: jwang@mail.haust.edu.cn
Received: March 20, 2012; Published online: July 31, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200235.
Abstract: A simple method was developed for selec- mercially available reagents, and can be performed
tive para-cyanation of alkoxy- and benzyloxy-substi- on a ten gram-scale. Interestingly, methoxybenzene
tuted benzenes with 0.5 equivalents of potassium fer- was cyanated in 32% yield in the absence of potassi-
ricyanide, 0.8 equivalants of copper(II) nitrate and um ferricyanide, which suggests that the nitrile group
0.5 equivalents of iodine in acetonitrile. Among vari- of a part of the product is possibly from the solvent
ous phenyl carbon-hydrogen bonds, those at the acetonitrile.
para-position with regard to the alkoxy or benzyloxy
groups were selectively cyanated in 20% to 87% Keywords: aromatic nitriles; cupric nitrate; cyana-
À
yields (23 examples). The present method uses com- tion; phenyl C H bonds
Introduction
nylpyridines[9] have been reported in the literature.
During the preparation of this manuscript, Chang and
Aromatic nitriles constitute key components of vari- co-workers[10] reported a copper-mediated method for
À
À
ous commercial compounds such as some natural the cyanation of aryl C B and arene C H bonds
products, pharmaceuticals, herbicides and dyes.[1] using ammonium iodide and DMF. Their method suf-
They have also served as the intermediates for many fers from at least two drawbacks: the use of as much
synthetic targets.[2] As a result, much effort has been as 2 equivalents of copper salt and 2 equivalents of
devoted to the development of various effective acetic acid is less attractive for practical applications,
methods for the introduction of a cyanide functionali- and the use of the high-boiling solvent is disadvanta-
ty into aromatic compounds.[3] The traditional way for geous for the separation and purification of the prod-
preparing aromatic nitriles involves the Rosenmund– uct. Moreover, their attention was mainly concentrat-
von Braun reaction[4] where aryl halides are heated ed on the cyanation of aryl C B bonds, and the inves-
with a stoichiometric amount of copper cyanide at tigation on cyanation of C H bonds was deficient
high temperature. Another useful alternative is the (only six electron-rich substrates were investigated).
transition metal-catalyzed cyanation of aryl-X com- We herein report a simple method for selective cyana-
pounds [X=Cl, Br, I, OTf, B(OR)2, SO2Cl, SO2Na tion of phenyl C H bonds at the para-position with
À
À
À
etc.] with KCN, NaCN, Me3SiCN, K4[Fe(CN)6], regard to alkoxy groups using K3[Fe(CN)6] as the cy-
Zn(CN)2, and the combination of NH4HCO3 and anation reagent.
DMF as the cyanation sources.[5] In addition, aromatic
nitriles can be synthesized from benzyl halides.[6] In
À
contrast, the direct functionalization of C H bonds is Results and Discussion
more attractive due to the use of readily available
substrates.[7] Very recently, several examples of the At the start of our investigations, the cyanation of
À
direct cyanation of heteroarenes with acidic C H methoxybenzene was chosen as a model reaction to
bonds[8] and the chelation-assisted cyanation of 2-phe- demonstrate the efficiency of various copper salts
Adv. Synth. Catal. 2012, 354, 2301 – 2308
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2301

Yunlai Ren et al.
FULL PAPERS
Table 1. Cyanation of methoxybenzene promoted by copper
salts.[a]
Figure 1. Steric effect of the alkoxy groups.
Entry Ligand
Copper
salt
Isolated
yield [%]
para-selectivity. It is unaccountable for us that among
so many types of copper salts, why only
CuACHTUNRTGNEU(GN NO3)2·3H2O shows high catalytic activity. Similar
1
2
3
4
5
6
7
8
–
–
–
–
–
–
–
–
CuI
CuCl2·2H2O
CuACTHUNGETRNNU(G OAc)2·H2O
CuSO4·5H2O
CuO
~0
~1
~2
~0
~0
~0
~1
phenomena have been reported for the iodination of
[13]
À
phenyl C H bonds.
After identifying a suitable promoter, we optimized
other critical parameters such as additive, solvent,
temperature and so on. The addition of Na2CO3 or
DMEDA significantly decreased the yield of 4-me-
thoxybenzonitrile (Table 1, entries 9 and 13). The re-
action was highly dependent on the type of solvents:
of the screened solvents, only acetonitrile was highly
effective, while the cyanations using N-methylpyrroli-
done, dimethylformamide, ethanol, dimethyl sulfoxide
or toluene were very sluggish. The cyanation reaction
proceeded efficiently with as little as 50 mol%
Cu2O
CuBr2
CuACHTUNGRTNE(NUGN NO3)2·3H2O 85
9[b]
10
11
12
13
14
–
Cu(NO3)2·3H2O 31
ACHTUNGTRENNUNG
DMEDA
DMEDA
DMEDA
DMEDA
CuI
CuCN
CuCl2·2H2O
CuACHTUGNTRENNNUG
~1
4
~1
1,10-phenanthroline CuACHTGNUTRENNUNG
[a]
Reaction conditions: methoxybenzene (0.5 mmol),
K3[Fe(CN)6] (0.25 mmol), ligand (0.3 mmol), copper salt
(0.3 mmol), I2 (0.25 mmol), acetonitrile (2 mL), 1808C,
35 h.
CuACHTUNRTGNE(UNG NO3)2·3H2O. We tried to reduce the promoter
loading to 10 mol%, but it was found that this was
not possible without sacrificing product yield even if
the reaction time was prolonged to 50 h. Sometimes
decreasing the temperature to 1608C or the time to
20 h allowed the cyanation to proceed in high yields,
[b]
1.5 mmol Na2CO3 was additionally used.
under the following conditions: 0.5 mmol methoxy- but the resulting experimental results were less repro-
benzene, 0.5 equiv. K3[Fe(CN)6], 0.6 equiv. copper ducible. This prompted us to perform all the following
salts, 0.5 equiv. I2, 2 mL acetonitrile, 1808C and 35 h. reactions at 1808C for 35 h.
As shown in Table 1, the cyanation using CuI gave
The present procedure is readily applicable to
only a trace amount of cyanation product (Table 1, a multigram-scale preparation of aryl nitriles. For ex-
entry 1). Other copper salts such as CuCl2·2H2O, ample, cyanation of methoxybenzene proceeded effi-
Cu
were also ineffective. Subsequently, we were pleased 4-methoxybenzonitrile in 79% GC yield (Scheme 1).
to find that the Cu(NO3)2·3H2O-mediated cyanation Moreover, the obtained experimental results for the
afforded the desired 4-methoxybenzonitrile in 85% multigram-scale reactions were reproducible.
yield and a small amount of 4-methoxy-iodobenzene With the optimized results in hand, we set out to
ACHTUNGTRENNUNG(OAc)2·H2O, CuSO4·5H2O, CuO, Cu2O and CuBr2 ciently on a 10-g scale under our conditions, and gave
AHCTUNGTRENNUNG
(by-product) resulting from iodination of the phenyl evaluate the scope of the present cyanation protocol.
ring. Although the methoxy group is an ortho-para di- In most cases, the obtained isolated yields were signif-
recting group, only a small amount of the ortho-cyan- icantly lower than those from gas chromatography or
ation product was observed. Such an exclusive selec- liquid chromatography under our conditions of sepa-
tivity was also reported in several literature cita- ration and analysis, possibly due to the loss of the
tions[10,11] where the bromination of methoxybenzene product in the course of the chromatographic purifi-
and the cyanation of multi-substituted benzenes were cation. Although our experimental results showed
performed. As described in the literature,[10] the exact that 0.3 equiv. I2 and 0.6 equiv. Cu
ACHTNUTGRNEUNG(NO3)2·3H2O were
reason for this excellent selectivity is not clear at the sufficient for the total conversion of methoxybenzene,
present stage. However, the steric effect seems to be the reactions of some other substrates required using
one of the main reasons: the larger steric hindrance more than 0.6 equiv. CuACTHNUTRGNE(UNG NO3)2·3H2O and more than
of the position ortho to the methoxy group leads to 0.3 equiv. I2 to provide good results. This prompted us
less formation of the ortho-product (note: as shown in to perform all the following reactions using 0.8 equiv.
Figure 1, alkoxy groups have a large steric hin- Cu
ACHTUNGNERT(UNNG NO3)2·3H2O and 0.5 equiv. I2.
drance[12]), and allows the reaction to exhibit a high
2302
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2301 – 2308

Selective para-Cyanation of Alkoxy- and Benzyloxy-Substituted Benzenes with Potassium Ferricyanide
Scheme 1. Cyanation on a 10-g scale.
Cyanation of phenyl rings with one alkoxy group thesized in high yield from 1,2,3-trimethoxybenzene
selectively occurred at the para-position with regard by applying the present procedure (Table 2, entry 23).
to the alkoxy group (Table 2, entries 1–5), and only
To sum up, a variety of alkoxybenzenes was
small amounts of ortho-cyanation products were ob- smoothly converted into the desired products with
served. When benzyl phenyl ethers were employed as low to high yields and 91% to 100% regioselectivities.
the substrates, only phenyl rings bonded to the Although the cyanations of some substrates gave low
oxygen atom were functionalizated (Table 2, en- yields, the obtained para-selectivities were excellent.
tries 6–10) and the cyanation seldom occurred at the For example, the cyanation product shown in Table 2
phenyl side of the benzyloxy moiety, revealing that (entry 19) was obtained in 20% yield and 91% regio-
À
phenyl C H bonds of alkylbenzenes were difficult to selectivity. In most cases, the major side products of
be cleaved under our reaction conditions. Consistent these reactions resulted from iodination of the phenyl
with these results, two alkylbenzenes including tolu- rings, and the main cyanation products were mononi-
À
ene and tert-butylbenzene showed poor reactivities. 4- triles. Among the tested phenyl C H bonds, those at
Chlorobenzyl phenyl ether and 4-fluorobenzyl phenyl the para-position with regard to the alkoxy groups
ether were cyanated in high yields, leaving the fluo- were selectively cyanated. Consistent with these re-
ride and chloride substituents untouched (Table 2, en- sults, methoxybenzene was preferentially reacted over
À
À
tries 7 and 8), which indicates that C F and C Cl all other substrates in the case of competition reac-
bonds are compatible with the reaction conditions, tions between methoxybenzene and several substitut-
and offers an opportunity to further functionalize the ed benzenes such as N,N-dimethylbenzeneamine,
resulting products through substitution reactions of phenol, acetylphenol, toluene, chlorobenzene, sodium
aryl halides.[15]
benzoate and 4-methylanisole (Scheme 2). One can
Among the tested disubstituted benzenes, meta-sub- argue that the alkoxy groups are stronger aromatic
stituted alkoxybenzenes were found to be good sub- activating groups and, therefore,[11a,17] this might be an
strates for the cyanations, even the alkoxybenzene explanation for the ease of cyanation of alkoxyben-
with a deactivating substituent was cyanated in 51% zenes. However, it is unaccountable to us why only al-
yield (Table 2, entry 18). The desired product was ob- koxyphenyl rings among so many types of electron-
tained in low yield in the case of 1,3-dibenzyloxyben- rich phenyl rings showed high reactivities.
zene (Table 2, entry 17), probably due to the steric
Interestingly, methoxybenzene was cyanated in
hindrance effect of the benzyloxy group. Surprisingly, 32% yield (Scheme 3) in the absence of K3[Fe(CN)6],
the reaction of 1,3-benzodioxole as an electron-rich which suggests that the nitrile group of a part of prod-
ortho-substituted alkoxybenzene gave the desired uct is possibly from the solvent acetonitrile. Similar
product in poor yield, while another ortho-substituted phenomena were also reported in the literature where
alkoxybenzene (2-butoxytoluene) underwent this aryl iodides were cyanated to form aryl nitriles by
transformation smoothly (Table 2, entry 21). The cy- cyano group transfer from CACTHNUGTRENNUG ACHUTNGTRENNGUN
(sp3) to C(sp2) carbon
anation was difficult to achieve in the absence of atoms.[18]
À
phenyl C H bonds at the para-position with regard to
Subsequently, the cyanation of methoxybenzene
the alkoxy groups. For example, several para-substi- was monitored to gain insight into the reaction path-
tuted alkoxybenzenes such as 4-butoxytoluene, 4-me- way. About 0–53% 4-methoxyiodobenzene was found
thoxytoluene, 1,4-dibenzyloxybenzene and 1,4-dime- to be present throughout the reaction, and the con-
thoxybenzene gave the desired products in poor centration of aryl iodide decreased only towards the
yields. Interestingly, 2,3,4-trimethoxybenzonitrile, end of the cyanation reaction, suggesting that the cy-
a key intermediate used in the manufacture of trime- anation is a stepwise reaction where conversion of
tazidines and some kinase inhibitor drugs,[16] was syn- benzene into iodobenzene is followed by the cyana-
tion of the resulting aryl iodide to yield the desired
Adv. Synth. Catal. 2012, 354, 2301 – 2308
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2303

Yunlai Ren et al.
FULL PAPERS
Table 2. Cyanation of various phenyl rings promoted by CuACTHNUTRGNEUNG
(NO3)2·3H2O.[a]
2304
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2301 – 2308

Selective para-Cyanation of Alkoxy- and Benzyloxy-Substituted Benzenes with Potassium Ferricyanide
Table 2. (Continued)
[a]
Reaction conditions: substituted benzene (0.5 mmol), K3[Fe(CN)6] (0.25 mmol),
CuACTHUNGNRET(UGNN NO3)2·3H2O (0.4 mmol), I2 (0.25 mmol), acetonitrile (2 mL), 1808C, 35 h.
[b]
1
The product was characterized by H NMR and 13C NMR; the regioselectivities
of the reactions occurred at the phenyl rings attached to oxygen atom ranged
from 91% to 100%.[14]
Scheme 2. Several competition reactions between methoxybenzene and some substituted benzenes. Reaction conditions: me-
thoxybenzene (0.25 mmol), another substituted benzene (0.25 mmol), K3[Fe(CN)6] (0.25 mmol), CuACHTUNTRGNEUNG(NO3)2·3H2O (0.3 mmol),
I2 (0.25 mmol), acetonitrile (2 mL), 1808C, 35 h.
product (Scheme 4). Consistent with this assumption, Conclusions
iodination of the methoxyphenyl ring took place
smoothly in the absence of
(Scheme 5, a), and that the Cu(NO3)2·3H2O-promot- the highly regioselective cyanation of electron-rich
ed cyanation of iodobenzene also occurred in the phenyl rings with Cu(NO3)2·3H2O as the promoter.
presence of K3[Fe(CN)6] or acetonitrile (Scheme 5, Among various phenyl C H bonds, those at the para-
a cyanide source In conclusion, we have demonstrated a method for
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
À
b and c).
position with regard to the alkoxy groups were selec-
tively cyanated in 20% to 87% yields. The present cy-
anation proceeded efficiently on a 10-g scale, and is
Adv. Synth. Catal. 2012, 354, 2301 – 2308
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2305

Yunlai Ren et al.
FULL PAPERS
Scheme 3. Cyanation in the absence of K3[Fe(CN)6].
Scheme 4. Proposed pathways of the cyanation.
Scheme 5. Investigation of the pathway of the cyanation.
a stepwise reaction where conversion of benzenes tetramethylsilane. Gas chromatographic analyses were per-
formed on a Varian CP-3800 instrument with an FID detec-
tor and a CP-WAX 57CB FS capillary chromatographic
column (25 mꢂ0.32 mm).
into iodobenzenes is followed by the cyanation of the
resulting iodobenzenes to yield the desired products.
Investigations on overcoming the major drawbacks
(such as high reaction temperature and high promoter
loading) of the present method are underway in our
laboratory.
General Procedure for Electron-Rich Phenyl Rings
After 0.5 mmol phenyl methyl ether, 0.25 mmol
K3[Fe(CN)6],
0.25 mmol
I2,
0.4 mmol
Cu(NO3)2·3H2O and 2 mL acetonitrile had been added into
AHCTUNGTRENNUNG
a dried 40-mL tube, the reaction tube was sealed with
a septum and placed in a constant-temperature oil bath set
at 180(Æ5)oC to perform the reaction for 35 h. Once the re-
action time was reached, the mixture was mixture cooled to
room temperature. The cyanation product was purified by
column chromatography, and identified by 1H NMR and
13C NMR.
Experimental Section
For the quality and suppliers of the reagents see Table S1 in
the Supporting Information. All benzyl phenyl ethers were
obtained from the reactions between the corresponding sub-
stituted benzyl chloride and substituted phenol. Other
chemicals were commercially available and were used with-
out further purification. 1H NMR and 13C NMR spectra
were recorded on a Bruker 400 MHz instrument with chemi-
cal shifts reported in ppm relative to the internal standard
1
4-Methoxybenzonitrile: H NMR (400 MHz, CDCl3): d=
7.58 (d, J=8.0 Hz, 2H), 6.94 (d, J=8.0 Hz, 2H), 3.85 (s,
3H); 13C NMR (100 MHz, CDCl3): d=163.0, 134.1, 119.4,
114.9, 104.1, 55.7.
2306
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2301 – 2308

Selective para-Cyanation of Alkoxy- and Benzyloxy-Substituted Benzenes with Potassium Ferricyanide
4-Butoxybenzonitrile: 1H NMR (400 MHz, CDCl3): d=
7.56 (d, J=8.0 Hz, 2H), 6.93 (d, J=8.0 Hz, 2H), 4.00 (t, J=
8.0 Hz, 2H), 1.75–1.82 (m, 2H), 1.47–1.52 (m, 2H), 0.98 (t,
J=8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=162.5,
134.0, 119.3, 115.2, 103.6, 68.1, 31.0, 19.2, 13.8.
tallics 2012, 31, 729; c) A. V. Ushkov, V. V. Grushin, J.
Am. Chem. Soc. 2011, 133, 10999; d) P. Y. Yeung, C. M.
So, C. P. Lau, F. Y. Kwong, Org. Lett. 2011, 13, 648;
e) H. Yu, R. N. Richey, W. D. Miller, J. Xu, S. A. May,
J. Org. Chem. 2011, 76, 665; f) P. Y. Yeung, C. M. So,
C. P. Lau, F. Y. Kwong, Org. Lett. 2011, 13, 648–651;
g) C. DeBlase, N. E. Leadbeater, Tetrahedron 2010, 66,
1098; h) Y. L. Ren, W. Wang, S. Zhao, X. Z. Tian, J. J.
Wang, W. P. Yin, L. Cheng, Tetrahedron Lett. 2009, 50,
4595–4597; i) O. Yabe, H. Mizufune, T. Ikemoto, Synlett
2009, 1291; j) S. Velmathi, N. E. Leadbeater, Tetrahe-
dron Lett. 2008, 49, 4693; k) A. W. Franz, L. N. Popa,
T. J. J. Mꢄller, Tetrahedron Lett. 2008, 49, 3300; l) P.
Ryberg, Org. Process Res. Dev. 2008, 12, 540; m) C. R.
Reddy, P. P . Madhavi, A. S. Reddy, Tetrahedron Lett.
2007, 48, 7169; n) T. Schareina, A. Zapf, M. Beller, J.
Organomet. Chem. 2004, 689, 4576; o) T. Schareina, A.
Zapf, M. Beller, Chem. Commun. 2004, 1388; p) G. Y.
Zhang, L. L. Zhang, M. L. Hu, J. Cheng, Adv. Synth.
Catal. 2011, 353, 291; q) C. W. Liskey, X. Liao, J. F.
Hartwig, J. Am. Chem. Soc. 2010, 132, 11389; r) P. An-
barasan, H. Neumann, M. Beller, Angew. Chem. 2011,
123, 539; Angew. Chem. Int. Ed. 2011, 50, 519; s) G. Y.
Zhang, X. Y. Ren, J. B. Chen, M. L. Hu, J. Cheng, Org.
Lett. 2011, 13, 5004; t) J. B. Chen, Y. Sun, B. Liu, D. F.
Liu, J. Cheng, Chem. Commun. 2012, 48, 449; u) A. V.
Ushkov, V. V. Grushin, J. Am. Chem. Soc. 2011, 133,
10999. For a recent review, see v) P. Anbarasan, T.
Schareina, M. Beller, Chem. Soc. Rev. 2011, 40, 5049.
[6] W. Zhou, J. J. Xu, L. R. Zhang, N. Jiao, Org. Lett. 2010,
12, 2888.
4-Benzyloxybenzonitrile: 1H NMR (400 MHz, CDCl3):
d=7.58 (d, J=8.0 Hz, 2H), 7.35–7.41 (m, 5H), 7.01 (d, J=
8.0 Hz, 2H), 5.11 (s, 2H); 13C NMR (100 MHz, CDCl3): d=
162.1, 135.8, 134.1, 128.9, 128.5, 127.6, 119.3, 115.7, 104.3,
70.4.
4-(4-Chlorobenzyloxy)-benzonitrile: 1H NMR (400 MHz,
CDCl3): d=7.50–7.55 (m, 2H), 7.34–7.38 (m, 4H), 6.98 (d,
J=8.0 Hz, 2H), 5.05 (s, 2H); 13C NMR (100 MHz, CDCl3):
d=161.6, 134.2, 134.1, 133.9, 128.81, 128.77, 119.0, 115.5,
104.3, 69.3.
4-(4-tert-Butylbenzyloxy)-benzonitrile:
1H NMR
(400 MHz, CDCl3): d=7.56 (d, J=8.0 Hz, 2H), 7.42 (d, J=
8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.00 (d, J=8.0 Hz,
2H), 5.06 (s, 2H), 1.32 (s, 9H); 13C NMR (100 MHz,
CDCl3): d=162.2, 151.6, 134.1, 132.7, 127.5, 125.8, 119.3,
115.6, 104.2, 70.3, 34.7, 31.4.
2-Chloro-4-(4-Fluorobenzyloxy)-benzonitrile:
1H NMR
(400 MHz, CDCl3): d=7.56 (d, J=8.0 Hz, 1H), 7.37–7.40
(m, 2H), 7.07–7.11 (m, 3H), 6.92 (d, J=8.0 Hz, 1H), 5.06 (s,
2H); 13C NMR (100 MHz, CDCl3): d=164.1, 162.3, 161.6,
138.4, 135.1, 131.0, 131.0, 129.7, 129.6, 116.5, 116.4, 116.0,
115.8, 114.2, 105.4, 70.1.
3,5-Dimethyl-4-ethoxybenzonitrile: 1H NMR (400 MHz,
CDCl3): d=7.31 (s, 1H), 7.27 (s, 1H), 3.85–3.90 (m, 2H),
2.32 (s, 3H), 2.29 (s, 3H), 1.43 (t, J=8.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=160.1, 132.83, 132.76, 119.3, 107.2,
68.4, 16.4, 15.8.
1H NMR
(400 MHz,
[7] a) K. Okamoto, M. Watanabe, M. Murai, R. Hatano,
K. Ohe, Chem. Commun. 2012, 48, 3127; b) W. Zhou,
L. R. Zhang, N. Jiao, Angew. Chem. 2009, 121, 7228;
Angew. Chem. Int. Ed. 2009, 48, 7094; c) L. Ilies, M.
Kobayashi, A. Matsumoto, N. Yoshikai, E. Nakamura,
Adv. Synth. Catal. 2012, 354, 593; d) P. Wang, H. H.
Rao, R. M. Hua, C. J. Li, Org. Lett. 2012, 14, 902–905;
e) H. Richter, S. Beckendorf, O. G. MancheÇo, Adv.
Synth. Catal. 2011, 353, 295; f) C. A. Correia, C. J. Li,
Adv. Synth. Catal. 2010, 352, 1446; g) R. Zhu, S. L.
Buchwald, Angew. Chem. 2012, 124, 1962; Angew.
Chem. Int. Ed. 2012, 51, 1926; h) K. B. Cho, Y. N. Push-
kar, W. Nam, J. Am. Chem. Soc. 2011, 133, 20088; i) M.
Mewald, J. A. Schiffner, M. Oestreich, Angew. Chem.
2012, 124, 1797; Angew. Chem. Int. Ed. 2012, 51, 1763;
j) L. Ackermann, Angew. Chem. 2011, 123, 3926;
Angew. Chem. Int. Ed. 2011, 50, 3842; k) F. W. Patur-
eau, F. Glorius, Angew. Chem. 2011, 123, 2021; Angew.
Chem. Int. Ed. 2011, 50, 1977; l) G. S. Kumar, C. U. Ma-
heswari, R. A. Kumar, M. L. Kantam, R. Reddy,
Angew. Chem. 2011, 123, 11952; Angew. Chem. Int. Ed.
2011, 50, 11748; m) K. D. Hesp, R. G. Bergman, J. A.
Ellman, J. Am. Chem. Soc. 2011, 133, 11430; n) A. E.
Wendlandt, A. M. Suess, S. S. Stahl, Angew. Chem.
2011, 123, 11256; Angew. Chem. Int. Ed. 2011, 50,
11062.
2,3,4-Trimethoxybenzonitrile:
CDCl3): d=7.28 (d, J=8.0 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H),
4.06 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=158.1, 155.9, 141.9, 128.9, 116.7, 107.6, 99.1, 61.8,
61.2, 56.4.
Acknowledgements
The financial supports from the National Natural Science
Foundation of China (Grant No. 21002023) and the National
Basic Research Program of China (973 Program, Grant No.
2011CB211702) are greatly acknowledged.
References
[1] R. C. Larock, in: Comprehensive Organic Transforma-
tions, VCH, New York, 1989, p 819.
[2] Z. Rappoport, in: Chemistry of the Cyano Group; John
Wiley & Sons, London, 1970, p 121.
[3] T. Schareina, A. Zapf, W. Mꢃgerlein, N. Mꢄller, M.
Beller, Chem. Eur. J. 2007, 13, 6249.
[4] a) T. Sandmeyer, Ber. Dtsch. Chem. Ges. 1884, 17,
1633; b) H. H. Hodgson, Chem. Rev. 1947, 40, 251;
c) C. Galli, Chem. Rev. 1988, 88, 765.
[8] a) G. B. Yan, C. X. Kuang, Y. Zhang, J. B. Wang, Org.
Lett. 2010, 12, 1052; b) H. Q. Do, O. Daugulis, Org.
Lett. 2010, 12, 2517; c) X. Y. Ren, J. B. Chen, F. Chen,
J. Cheng, Chem. Commun. 2011, 47, 6725; d) Y. Yang,
[5] a) D. N. Sawant, Y. S. Wagh, P. J. Tambade, K. D.
Bhatte, B. M. Bhanage, Adv. Synth. Catal. 2011, 353,
ˇ
ˇ
ˇ
ˇ
781; b) J. Schulz, I. Cꢅsarovꢆ, P. Stepnicka, Organome-
Adv. Synth. Catal. 2012, 354, 2301 – 2308
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2307

Yunlai Ren et al.
FULL PAPERS
Y. Zhang, J. B. Wang, Org. Lett. 2011, 13, 5608; e) S. T.
Ding, N. Jiao, J. Am. Chem. Soc. 2011, 133, 12374.
[9] a) J. Kim, S. Chang, J. Am. Chem. Soc. 2010, 132,
10272; b) X. F. Jia, D. P. Yang, S. H. Zhang, J. Cheng,
Org. Lett. 2009, 11, 4716; c) X. Chen, X. S. Hao, C. E.
Goodhue, J. Q. Yu, J. Am. Chem. Soc. 2006, 128, 6790.
[10] J. Kim, J. Choi, K. Shin, S. Chang, J. Am. Chem. Soc.
2012, 134, 2528.
[11] a) S. R. K. Pingali, M. Madhav, B. S. Jursic, Tetrahedron
Lett. 2010, 51, 1383; b) P. K. Chhattise, A. V. Ramaswa-
my, S. B. Waghmode, Tetrahedron Lett. 2008, 49, 189.
[12] Y. Hirokawa, T. Higashimura, K. Matsuzaki, T. Kawa-
mura, T. Uryu, J. Polym. Sci. Polym. Chem. Ed. 1979,
17, 3923.
[13] a) S. Wan, S. R. Wang, W. J. Lu, J. Org. Chem. 2006, 71,
4349; b) V. M. Alexander, B. M. Khadilkar, S. D.
Samant, Synlett 2003, 12, 1895.
[14] The regioselectivities were respectively 98% (entry 1),
98% (entry 2), ~100% (entry 3), 96% (entry 4), ~100%
(entry 5), 93% (entry 6), 96% (entry 7), 97% (entry 8),
91% (entry 9), 91% (entry 10), 94% (entry 11), 92%
(entry 12), 95% (entry 13), 92% (entry 14), 94%
(entry 15), 91% (entry 16), – (entry 17), – (entry 18),
91% (entry 19), 92% (entry 20),
(entry 22), 94% (entry 23).
– (entry 21), –
[15] a) A. S. K. Hashmi, C. Lothschꢄtz, R. Dçpp, M. Acker-
mann, J. D. B. Becker, M. Rudolph, C. Scholz, F. Ro-
minger, Adv. Synth. Catal. 2012, 354, 133; b) T. Scharei-
na, R. Jackstell, T. Schulz, A. Zapf, A. Cottꢇ, M. Gotta,
M. Beller, Adv. Synth. Catal. 2009, 351, 643; c) V.
Farina, Adv. Synth. Catal. 2004, 346, 1553; d) T. Truong,
O. Daugulis, Org. Lett. 2011, 13, 4172; e) A. Ziadi, R.
Martin, Org. Lett. 2012, 14, 1266; f) G. A. Molande, L.
Iannazzo, J. Org. Chem. 2011, 76, 9182; g) G. A. Mo-
lander, S. L. J. Trice, S. D. Dreher, J. Am. Chem. Soc.
2010, 132, 17701; h) C. L. Sun, H. Li, D. G. Yu, M. Yu,
X. Zhou, X. Y. Lu, K. Huang, S. F. Zheng, B. J. Li, Z. J.
Shi, Nat. Chem. 2010, 2, 1044.
[16] a) A. Maiti, P. V. N. Reddy, M. Sturdy, L. Marler, S. D.
Pegan, A. D. Mesecar, J. M. Pezzuto, M. Cushman, J.
Med. Chem. 2009, 52, 1873; b) T. Asano, T. Yoshikawa,
T. Usui, H. Yamamoto, Y. Yamamoto, Y. Ueharac, H.
Nakamura, Bioorg. Med. Chem. 2004, 12, 3529.
[17] C. Y. Zhou, J. Li, S. Peddibhotla, D. Romo, Org. Lett.
2010, 12, 2014.
[18] Z. Q. Jiang, Q. Huang, S. Chen, L. Long, X. G. Zhou,
Adv. Synth. Catal. 2012, 354, 589.
2308
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2301 – 2308