Efficient synthesis of aromatic nitriles via cyanation of aryl bromides and K4[Fe(CN)6] catalyzed by a palladium(II) complex

Article abstract of DOI:10.2174/1570178611310030013

Cyanation of aryl bromides and K₄[Fe(CN)₆] were carried out in the presence of catalytic amounts of {[(PhCH₂O) ₂P(CH₃)₂CHNCH(CH₃)₂] ₂PdCl₂} (PdCl₂L₂) in DMF and a variety of Aromatic nitriles were obtained in good yields under aerobic conditions.

Full text of DOI:10.2174/1570178611310030013

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Letters in Organic Chemistry, 2013, 10, 213-215
213
Efficient Synthesis of Aromatic Nitriles via Cyanation of Aryl Bromides
and K4[Fe(CN)6] Catalyzed by a Palladium(II) Complex
Mengping Guo*, Junying Ge, Zhiyong Zhu and Xiaochun Wu
Institute of Coordination Catalysis, Engineering Center of Jiangxi University for Lithium Energy, Key Laboratory of
Jiangxi University for Applied Chemistry and Chemical Biology, Yichun University, Yichun 336000, China
Received September 19, 2012: Revised November 20, 2012: Accepted February 12, 2013
Abstract: Cyanation of aryl bromides and K4[Fe(CN)6] were carried out in the presence of catalytic amounts of
{[(PhCH2O)2P(CH3)2CHNCH(CH3)2]2PdCl2} (PdCl2L2) in DMF and a variety of Aromatic nitriles were obtained in good
yields under aerobic conditions.
Keywords: Aromatic nitriles, cyanation, palladium(II) complex, synthesis.
INTRODUCTION
air- and moisture- stable dichlorobis(dibenzyl diisopropyl-
phosphoramidite)palladium {[(PhCH2O)2P(CH3)2CHNCH
(CH3)2]2PdCl2} (PdCl2L2) containing electron-rich, sterically
bulky phosphane (L) (Fig. 1) that exhibited promising cata-
lytic activity in Suzuki cross-coupling reactions at room
temperature in aqueous media under ambient atmosphere
[19]. Here, we would like to report our research on cyanation
of aryl bromides with K4[Fe(CN)6] catalyzed by dichloro-
bis(dibenzyl diisopropylphosphoramidite)palladium under
aerobic conditions.
Aromatic nitriles are a key building blocks in a variety of
pharmaceuticals, agrochemicals, natural products, and pig-
ments and dyes [1-4]. Since Beller and co-workers described
the first palladium-catalyzed cyanation of aryl halides with
K4[Fe(CN)6] for the preparation of aromatic nitriles in 2004
[5, 6], K4[Fe(CN)6] as a cyanide source is particularly in-
triguing because all six CN are available for reaction and it is
inexpensive, easily handled, and nontoxic [7-8]. Conse-
quently, significant research effort has been focused on the
N
P
O
N
O
P
N
P
O
Pd
O
O
O
Cl Cl
L
PdCl2L2
Fig. (1).
preparation and use of catalysts capable of activating this
reaction. To date, some auxiliary ligands and palladium cata-
lysts, such as ligand-free palladium salts [6, 7], palladacycles
[9, 10], phosphine ligands [5, 11-15], and microwave-
promoted reaction [16-18], have been developed in order to
enable the cyanation reaction to be performed under mild
reaction conditions, with a good substrate scope. Recently,
we reported the synthesis and characterization of a new
RESULTS AND DISCUSSION
In initial experiments, the cyanation of 4–bromoaceto-
phenone, which generally showed a high reactivity with
K4[Fe(CN)6], was selected as the prototype. Application of
the Beller’s reaction conditions [7] in DMF with Na2CO3
gave an 83 % assay yield at 130 °C. We further investigated
the influence of the base in the same reaction, examining
.
Et3N, NaF, NaOAc.3H2O, K3PO4 3H2O, NaOH. As shown in
Table 1, an investigation of the influence of the base sug-
gested that NaF (Table 1, entry 2) was the reagent of choice.
*Address correspondence to this author at the Institute of Coordination
Catalysis, Engineering Center of Jiangxi University for Lithium Energy,
Key Laboratory of Jiangxi University for Applied Chemistry and Chemical
Biology, Yichun University, Yichun 336000, China; Tel: +86 0795
3200535; Fax: +86 0795 3200535. E-mail: guomengping65@163.com
Treatment of p-bromoacetophenone (1 mmol) with
K4[Fe(CN)6] (0.22 mmol) in DMF (4 ml) at 130 °C for 16 h
in the presence of PdCl2L2 (0.03 mmol) and NaF (2 mmol)
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214 Letters in Organic Chemistry, 2013, Vol. 10, No. 3
Guo et al.
Table 1. Effects of Different Bases on the Cyanation.a
Entry
Base
Yieldb (%)
1
2
3
4
5
6
Et3N
NaF
94%
97%
80%
82%
84%
64%
NaOAc.3H2O
Na2CO3
.
K3PO4 3H2O
NaOH
aCarried out with 1 mmol of 4-bromoacetophenone, 0.22 mmol of K4[Fe(CN)6] and 0.03 mmol of PdCl2L2 in 4 ml of DMF for 16 h, 130 0C.
bIsolated yield was based on the aryl bromide.
Table 2. Cyanation of Aryl Bromides with K4[Fe(CN)6] Catalyzed by PdCl2L2.a
Entry
Arylbromide
Product
Yieldb (%)
Br
CN
H3C(O)C
H3C(O)C
H3C
1
97
1a
2a
Br
CN
H3C
2
1b
2b
90 [11]
46 [9]
90 [9]
95
Br
CN
H3CO
H3CO
1c
2c
3
4
5
6
7
Br
CN
1d
2d
O
O
Br
CN
1e
2e
Br
CN
1f
2f
94 [11]
90 [11]
Br
CN
CH3
CH3
1g
2g
aCarried out with 1 mmol of aryl bromide, 0.22 mmol of K4[Fe(CN)6], 0.03 mmol of PdCl2L2 and 2 mmol of NaF in 4 ml of DMF for 16 h, 130 0C.
bIsolated yield was based on the aryl bromide.
cReaction time is 24 h.
afforded p-acetylbenzonitrile in 97 % yield. This result
prompted us to study various substituted bromobenzene
(Scheme 1), Typical results are tabulated in Table 2. Effi-
cient transformation of electron deficient (entries 1, 5) and
electron neutral (entries 2, 4, 6-7) aryl bromides was ob-
served and a variety of substituted benzonitriles were ob-
tained in good yields. Interestingly, our catalyst does not
require the co-assistance of amine ligands (TMEDA, DBU,
etc.) and troublesome solvents (NMP, DMAC, etc.) [20],
This is consistent with Gelman’s report [12]. Furthermore,
since Pd black formation was not observed in the course of
the reaction suggests that our catalytic system is perfectly
stable to air. Electron-rich aryl bromides were generally less
reactive and led to incomplete reaction even at longer reac-
tion times (entry 3).

Efficient Synthesis of Aromatic Nitriles via Cyanation
Letters in Organic Chemistry, 2013, Vol. 10, No. 3 215
Br
[2]
[3]
[4]
Harris, T.M.; Harris, C.M.; Oster, T.A.; Brown, L.E.T.; Lee, J.Y.C.
Biomimetic syntheses of pretetramides. 2. A synthetic route based
on a preformed D ring. J. Am. Chem. Soc., 1988, 110(20), 6180-
6186.
Srivastava, R.R.; Collibee, S.E. Application of polymer-supported
triphenyl phosphine in the palladium-catalyzed cyanation reaction
under microwave conditions. Tetrahedron Lett., 2004, 45(48),
8895-8897.
Knight, V.K.; Berman, M.H.; Häggblom, M.M. Biotransformation
of 3,5-dibromo-4-hydroxybenzonitrile under denitrifying, Fe(III)-
reducing, sulfidogenic, and methanogenic conditions. Environ.
Toxicol. Chem., 2003, 22(3), 540-544.
Schareina, T.; Zapf, A.; Beller, M. Potassium hexacyanoferrate(II)-
a new cyanating agent for the palladium-catalyzed cyanation of
aryl halides. Chem. Commun., 2004, 12, 1388-1389.
Schareina, T.; Zapf, A.; Beller, M. Improving palladium-catalyzed
cyanation of aryl halides: development of a stste-of-the-art meth-
odology using potassium hexacyanoferrate(II) as cyanating agent.
J. Organomet. Chem., 2004, 689(24), 4576-4583.
Weissman, S.A.; Zewge, D.; Chen, C. Ligand-free palladium-
catalyzed cyanation of aryl halides. J. Org. Chem., 2005, 70(4),
1508-1510.
Hou, J.T. Potassium Hexacyanoferrate(II). Synlett, 2010, 20, 3115-
3116.
Cheng, Y.N.; Duan, Z.; Li, T.; Wu, Y.J. Palladium-catalyzed cy-
anation of aryl bromides with potassium hexacyanoferrate(II). Lett.
Org. Chem., 2007, 4, 352-356.
Cheng, Y.N.; Duan, Z.; Li, T.; Wu, Y.J. Cyanation of aryl chlorides
with potassium hexacyanoferrate(II) catalyzed by cyclopalladated
ferrocenylimine tricyclohexylphosphine complexes. Synlett, 2007,
4, 543-546.
CN
3 mol% PdCl2L2
K4[Fe(CN)6]
+
NaF, DMF, 130 °C
R
R
1
2
Scheme 1. Cyanation of aryl bromides.
EXPERIMENTAL SECTION
Typical Procedure for the Synthesis of Aromatic nitriles
[5]
[6]
The complex {[(PhCH2O)2P(CH3)2CHNCH(CH3)2]2
PdCl2} (PdCl2L2) was prepared according to the literature
procedure[19]. A mixture of aryl bromide (1.0 mmol),
K4[Fe(CN)6] (0.22 mmol), NaF (2.0 mmol), DMF (4 ml) and
0
catalyst PdCl2L2 (3 %) was stirred at 130 C under air. The
[7]
reaction mixture was stirred for 16 h, and then quenched
with water. The mixture was diluted with ethyl acetate. The
organic layer was separated and the aqueous layer was ex-
tracted with ethyl acetate (3 ꢀ10 ml). The combined organic
phase was dried with MgSO4, filtered, solvent was removed
on a rotary evaporator, and the product was isolated by thin
layer chromatography. The purified products were identified
[8]
[9]
by H NMR, 13C NMR spectroscopy and melting points by
1
[10]
comparison with those reported in the literatures [9, 11].
1
Spectral data for the aromatic nitriles: 2a: H NMR (400
MHz, CDCl3): ꢁ 2.66 (s, 3H), 7.78 (d, J=8.8Hz, 2H), 8.05 (d,
J=8Hz, 2H). 13C NMR (400 MHz, CDCl3): ꢁ 26.7, 116.4,
117.9, 128.7, 132.5, 139.9, 196.5. 2e: 1H NMR (400 MHz,
CDCl3): ꢁ 7.49-7.89 (m, 9H). 13C NMR (400 MHz, CDCl3):
ꢁ 115.7, 117.9, 128.4, 130.2, 130.8, 131.6, 132.6, 137.2,
141.2, 195.6.
[11]
[12]
[13]
[14]
Grossman, O.; Gelman, D. Novel trans-spanned palladium com-
plexes as efficient catalysts in mild and amine-free cyanation of
aryl bromides under air. Org. Lett. 2006, 8(6), 1189-.1191.
Schareina, T.; Zapf, A.; Mägerlein, W.; Mûller, N.; Beller, M. A
new palladium catalyst system for the cyanation of aryl chlorides
with K4[Fe(CN)6]. Tetrahedron Lett., 2007, 48(7), 1087-1090.
Pui, Y.Y.; Chau, M.S.; Chak, P.L.; Fuk, Y.K. A mild and efficient
palladium-catalyzed cyanation of aryl chlorides with K4[Fe(CN)6].
Org. Lett. 2011, 13(4), 648-651.
CONCLUSION
Gerber, R.; Oberholzer, M.; Frech, C.M. Cyanation of aryl bro-
mides with K4[Fe(CN)6] catalyzed by Dichloro[bis{1-
In conclusion, we have reported a simple and practical
method for the cyanation of aryl bromides with K4[Fe(CN)6]
catalyzed by dichlorobis(dibenzyl diisopropylphosphoramid-
ite)palladium complex under relatively mild reaction condi-
tions.
(dicyclohexylphospharyl) piperidine}] palladium,
a molecular
source of nanoparticles, and the reactions involved in the catalyst-
deactivation processes. Chemistry-A Eur. J. 2012, 18(10), 2978-
2986.
[15]
Zhang, D.Y.; Sun, H.F.; Zhang, L.; Zhou, Y.; Li, C.P.; Jiang, H.L.;
Chen, K.X.; Liu, H. An expedient Pd/DBU mediated cyanation of
aryl/heteroaryl bromides with K4[Fe(CN)6]. Chem. Commun., 2012,
48(23), 2909-2911.
Li, I.H.; Pan, Z.L.; Duan, X.H.; Liang, Y.M. An environmentally
benign procedure for the synthesis of aryl and arylvinyl nitriles as-
sisted by microwave in ionic liquid. Synlett, 2006, 13, 2094-2098.
Velmathi, S.; Leadheate, N.E. Palladium-catalyzed cyanation of
aryl halides using K4[Fe(CN)6] as cyanide source, water as solvent,
and microwave heating. Tetrahedron Lett., 2008, 49(32), 4693-
4694.
Chen, G.; Weng, J.; Zheng, Z.C.; Zhu, X.H.; Cai, Y.Y.; Cai, J.W.;
Wan, Y.Q. Pd/C-catalyzed cyanation of aryl halides in aqueous
PEG. Eur. J. Org. Chem., 2008, 2008(20), 3524-3528.
Guo, M.P.; Zhang, Q.C. An inexpensive and highly stable palla-
dium(II) complex for room temperature Suzuki coupling reactions
under ambient atmosphere. Tetrahedron Lett., 2009, 50(17), 1965-
1968.
Sundermeier, M.; Zapf, A.; Mutyala, S.; Baumann, W.; Sans, J.;
Weiss, S.; Beller, M. Progress in the palladium-catalyzed cyanation
of aryl chlorides. Chem. Eur. J., 2003, 9(8), 1828-1836.
CONFLICT OF INTEREST
[16]
[17]
The author(s) confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
The authors thank the Natural Science Foundation of
China (No. 21063015) for financial support. We thank Mr.
Linxi Shi for his excellent analytical support.
[18]
[19]
REFERENCES
[1]
Liu, K.C.; Howe, R.K. 3’-arylspiro[isobenzofuran-1(3H), 5’(4’H)-
isoxazol] -3- ones and their conversion to 2-(3-arylisoxazol-5-yl)
benzoates. J. Org. Chem., 1983, 48(24), 4590-4592.
[20]