CN-Dimeric ortho-palladated complex catalyzed cyanation of aryl halides under microwave irradiation

Article abstract of DOI:10.1007/s13738-014-0408-8

The catalytic activity of dimeric [Pd{C₆H₂(CH ₂CH₂NH₂)-(OMe)₂,2,3}(m-Br)] ₂ complex was investigated in the synthesis of benzonitriles under microwave irradiation conditions. The substituted benzonitriles were produced from various aryl halides in excellent yields and short reaction times using a catalytic amount of this complex as efficient, stable and air- and moisture-tolerant catalyst, and K₄[Fe(CN)₆] as a green cyanide source in DMF at 130 °C.

Full text of DOI:10.1007/s13738-014-0408-8

J IRAN CHEM SOC
DOI 10.1007/s13738-014-0408-8
ORIGINAL PAPER
CN-Dimeric ortho-palladated complex catalyzed cyanation of aryl
halides under microwave irradiation
•
Abdol Reza Hajipour Fatemeh Rafiee
Received: 17 September 2013 / Accepted: 3 January 2014
Ó Iranian Chemical Society 2014
Abstract The
catalytic
activity
of
dimeric
contain thiazoles, triazoles, tetrazoles, oxadiazoles, etc. [1–
4]. The substituted benzonitriles constitute the key com-
ponents of different commercial compounds, including
dyes, herbicides, agrochemicals, pesticides, natural pro-
ducts and pigments and so on [5–9]. Therefore, develop-
ment of efficient and practical methods for the synthesis of
benzonitriles is an attractive subject in organic synthesis.
One of the most convenient methods for the synthesis of
aryl nitriles is the Rosenmund–von Braun reaction using
stoichiometric amounts of CuCN [10]. However, the harsh
reaction conditions and the use of stoichiometric amounts
of copper(I) cyanide leads to the production of equimolar
amounts of heavy metal wastes, especially in the case of
industrial large-scale synthesis, which is a major drawback
of these methods [11, 12]. A refined method for the prep-
aration of benzonitriles is the transition metal-mediated
cyanation of aryl halides using inorganic or organic cya-
nide sources, such as alkali cyanides [13], Zn(CN)2 [14],
CuCN [15], TMSCN [16], and acetone cyanohydrins [17].
The toxicity of alkali cyanides, the sensitivity of Me3SiCN
to moisture, the release of HCN and production of heavy
metal waste, in the case of Zn(CN)2, significantly limit the
applications of these reagents. The palladium-catalyzed
cyanation of aryl halides using K4[Fe(CN)6] as an inex-
pensive, non-toxic and efficient source of cyanide is a
useful and powerful method to obtain substituted benzo-
nitriles [18–23].
[Pd{C6H2(CH2CH2NH2)–(OMe)2,2,3}(m-Br)]2 complex
was investigated in the synthesis of benzonitriles under
microwave irradiation conditions. The substituted benzo-
nitriles were produced from various aryl halides in excel-
lent yields and short reaction times using a catalytic
amount of this complex as efficient, stable and air- and
moisture-tolerant catalyst, and K4[Fe(CN)6] as a green
cyanide source in DMF at 130 °C.
Keywords ortho-palladated complex ꢀ Palladium
catalyst ꢀ Cyanation reaction ꢀ K4[Fe(CN)6]
Introduction
The cyanide functional group serves as an important
intermediate for many of possible transformations into
other functional groups such as carboxylic acids and their
derivatives, aldehydes, amines, amidines, and heterocycles
A. R. Hajipour (&)
Department of Chemistry, Pharmaceutical Research Laboratory,
Isfahan University of Technology, 84156 Isfahan, Islamic
Republic of Iran
e-mail: haji@cc.iut.ac.ir
The use of microwave irradiation in homogeneous
transition metal-catalyzed reactions leads to the reduction
of the reaction times, producing high yields and higher
selectivity, the decrease of discarded by-products from
thermal-side reactions and increased lifetime of the catalyst
[24]. Microwave methodology has been reported as a
simple, fast and efficient process for palladium-catalyzed
cyanation of aryl halides [25–28].
A. R. Hajipour
Department of Neuroscience, Medical School, University of
Wisconsin, 1300 University Avenue, Madison, WI 53706-1532,
USA
F. Rafiee
Department of Chemistry, Faculty of Science, Alzahra
University, Vanak, Tehran, Iran
123

J IRAN CHEM SOC
Experimental
(s, 3H), 13C-NMR (100 MHz, ppm, CDCl3): d = 162.8,
133.9, 119.1, 114.7, 103.8, 55.5, FT-IR (KBr, cm-1): m
2221.
General
4-Cyanobenzonitrile (Table 2, entry 5): M.p.
222–224 °C, 1H-NMR (400 MHz, ppm, CDCl3, TMS):
d = 7.8 (s, 4H), 13C-NMR (100 MHz, ppm, CDCl3):
d = 116.9, 116.8, 132.7, FT-IR (KBr, cm-1): m 2221.
Phenanthrene-9-carbonitrile (Table 2, entry 13):
90–92 °C, 1H-NMR (400 MHz, ppm, CDCl3, TMS):
d = 8.70 (t, 2H, J = 8.4 Hz), 8.30 (d, 1H, J = 8.4 Hz),
8.26 (s, 1H), 7.95 (d, 1H, J = 8 Hz), 7.78–7.84 (m, 3H),
7.72 (t, 1H, J = 7.6 Hz), FT-IR (KBr, cm-1): m 2224.
All melting points were taken on a Gallenkamp melting
apparatus. 1H-NMR spectra were recorded using 400 MHz
in CDCl3 solutions at room temperature (TMS was used as
an internal standard) on a Bruker, Avance 500 instrument
(Rheinstetten, Germany) and Varian 400 NMR. FT-IR
spectra were recorded on a spectrophotometer (Jasco-680,
Japan). Spectra of solids were carried out using KBr pel-
lets. Vibrational transition frequencies were reported in a
wave number (cm-1). We used the Milestone microwave
(Microwave Labstation, MLS GmbH- ATC-FO 300) for
synthesis. Furthermore, we used GC (BEIFIN 3420 Gas
Chromatograph equipped a Varian CP SIL 5CB column—
30 m, 0.32 mm, 0.25 lm) for examination of reaction
completion and yields. Palladium chloride, aryl halides and
all chemicals were purchased from Merck and Aldrich and
were used as received.
Results and discussion
In continuation of our recent investigations on the synthesis
and application of the palladacycle catalysts [29–36], we
now wish to report the extension of dimeric
[Pd{C6H2(CH2CH2NH2)–(OMe)2,2,3}(m-Br)]2 homoge-
neous complex, as a thermally stable and oxygen insensi-
tive catalyst for conversion of various aryl halides to aryl
nitriles under microwave irradiation.
General procedure for cyanation reaction of aryl halides
with K4[Fe(CN)6] under microwave irradiation
In order to optimize the reaction conditions, we chose
the reaction of 9-bromophenanthrene with K4[Fe(CN)6] in
various solvents and bases using various catalyst concen-
trations (Table 1) under microwave irradiation. The mon-
itoring system for reaction times, temperature, pressure,
and power in microwave reactor allows for an excellent
control of reaction parameters which generally leads to
rapid optimization and more reproducible reaction condi-
tions. The direct control of reaction mixture temperature;
carry out with the IR sensors.
A mixture of the aryl halide (1 mmol), K4[Fe(CN)6]0.3
H2O (0.22 mmol), TBAB (1 mmol), CN-ortho-palladated
catalyst (0.5 mol %) and K2CO3 (1 mmol) was added to
DMF (3 mL) in a round-bottomed flask equipped with
condenser and placed into the Milestone microwave. Ini-
tially using a microwave power of 600 W, the temperature
was ramped from room temperature to 130 °C and then
held at this temperature until the reaction was completed.
During this time, the power was modulated automatically
to keep the reaction mixture at 130 °C. The mixture was
stirred continuously using an appropriate magnet during
the reaction. After the reaction was completed, the mixture
was cooled to room temperature and diluted with water
(30 ml) and ethyl acetate (30 ml). The organic layer was
dried over MgSO4, filtered and the solvent was evaporated
using rotary evaporator. The residue was purified by silica
gel column chromatography or by recrystallization using
ethanol and water. The products were characterized by
comparing their m.p., IR, 1H, 13C NMR spectra with those
found in the literature.
Among the selected bases, K2CO3 acted as the most
effective one. A low yield was obtained in the case of no
addition of the base. Several different solvents such as
toluene, DMF, NMP, DMAc, dioxane, methanol and eth-
anol were examined. The best results were obtained in
DMF as a microwave absorbing polar aprotic solvent and
K2CO3 as base.
Under these conditions and by using a 1:1 molar ratio of
9-bromophenanthrene to K4[Fe(CN)6] in 20 min 9-cyan-
ophenanthrene occurred in 64 % yield (Table 1, entry 7),
and 22 % 9,90-biphenanthrene was formed due to homo
coupling reaction of 9-bromophenanthrene as by-product,
and with lapse of time the yield of desired product did not
change. The presence of free cyanide ion in the solution
can deactivate the catalyst [37]. K4[Fe(CN)6] as weakly
ionizable source due to the inertness of the complex and its
large CFSE that cause to little releasing of CN- in the
reaction media has more advantages over the other cya-
nation sources [21]. Moreover, as each mol of K4[Fe(CN)6]
contains sixfold cyanide ions, we also investigated 1:0.22
4-Acetylbenzonitrile (Table 2, entry 6): M.p. 57–60 °C,
1H-NMR (400 MHz, ppm, CDCl3, TMS): d = 8.1 (d, 2H,
J = 8.0 Hz), 7.8 (d, 2H, J = 8.4 Hz), 2.7 (s, 3H), 13C-
NMR (100 MHz, ppm, CDCl3): d = 196.5, 139.9, 119.1,
132.5, 128.7, 117.9, 116.4, 26.8, FT-IR (KBr, cm-1): m
2221, 1694.
4-Methoxybenzonitrile (Table 2, entry 7): M.p.
59–61 °C, 1H-NMR (400 MHz, ppm, CDCl3, TMS):
d = 7.6 (d, 2H, J = 8.0 Hz), 6.9 (d, 2H, J = 8.4 Hz), 3.8
123

J IRAN CHEM SOC
Table 1 Optimization of the reaction conditions for the cyanation reaction under microwave irradiation
Entry
Solvent
Base
Catalyst (mol %)
Temp (°C)
Time (min)
Conversiona (%)
1
NMP
DMAc
Toluene
EtOH
MeOH
Dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
NaOAc
KOH
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.4
0.3
1
130
130
120
70
20
20
20
20
20
20
20
10
20
10
15
20
8
45
29
5
2
3
4
14
–
5
55
6
90
14
64
55
100
100
90
60
100
–
7
130
130
130
130
130
130
130
130
130
130
130
130
130
130
8b
9b
10c
11c
12c
13c
14c
15
16
17
18
19
20
–
30
20
20
20
20
20
20
0.5
0.5
0.5
0.5
0.5
0.5
50
70
62
54
16
5
CsF
–
Reaction conditions: 9-bromophenanthrene (1 mmol), K4[Fe(CN)6]0.3 H2O (1 mmol), base (1 mmol), CN-ortho-palladated catalyst (mol %),
solvent (3 mL)
a
Determined by GC with dodecane as internal standard with respect to aryl halide
b
K4[Fe(CN)6] (0.22 mmol)
c
K4[Fe(CN)6] (0.22 mmol), TBAB (1 mmol)
Scheme 1 Cyanation of aryl
halides using K4[Fe(CN)6] and
CN-ortho-palladated catalyst
123

J IRAN CHEM SOC
Table 2 Cyanation reaction of aryl halides with K4[Fe(CN)6] using ortho-palladated catalyst under microwave irradiation
Entry
ArX
Product
Time (min)
Yield (%)a
Reference
1
Iodobenzene
Benzonitrile
5
8
90
87
83
90
83
85
84
90
86
88
90
82
93
74
78
[37]
[38]
[14]
[37]
[38]
[37]
[38]
[39]
[39]
[39]
[18]
[18]
[18]
[37]
[37]
2
4-Iodoanisole
4-Methoxybenzonitrile
4-Cyanobenzoic acid
Benzonitrile
3
4-Bromobenzoic acid
Bromobenzene
9
4
6
5
4-Bromobenzonitrile
4-Bromoacetophenone
4-Bromoanisole
4-Cyanobenzonitrile
4-Acetylbenzonitrile
4-Methoxybenzonitrile
4-Nitrobenzonitrile
4-Nitrobenzonitrile
4-Chlorobenzonitrile
3-Chlorobenzonitrile
1-Naphthonitrile
7
6
10
9
7
8
1-Iodo-4-nitrobenzene
1-Bromo-4-nitrobenzene
1-Bromo-4-chlorobenzene
1-Bromo-3-chlorobenzene
1-Bromonaphthalene
9-Bromophenanthrene
Chlorobenzene
5
9
7
10
11
12
13
14
15
6
5
10
10
14
10
Phenanthrene-9-carbonitrile
Benzonitrile
4-Chloroacetophenone
4-Acetylbenzonitrile
Reaction conditions: aryl halide (1 mmol), K4[Fe(CN)6]0.3 H2O (0.22 mmol), K2CO3 (1 mmol), TBAB (1 mmol), CN-ortho-palladated catalyst
(0.5 mol %), DMF (3 ml), 130 °C, 600 W
a
Isolated yield
Table 3 Cyanation reaction of aryl halides with K4[Fe(CN)6] using ortho-palladated catalyst under conventional heating
Entry
ArX
Product
Time (h)
Yield (%)a
1
2
3
4
5
6
4-Iodoanisole
4-Methoxybenzonitrile
Benzonitrile
2
2
3
2
1
5
80
87
81
80
80
63
Bromobenzene
4-Bromobenzonitrile
1-Bromo-4-nitrobenzene
1-Bromo-4-chlorobenzene
Chlorobenzene
4-Cyanobenzonitrile
4-Nitrobenzonitrile
4-Chlorobenzonitrile
Benzonitrile
Reaction conditions: aryl halide (1 mmol), K4[Fe(CN)6]0.3 H2O (0.22 mmol), K2CO3 (1 mmol), TBAB (1 mmol), CN-ortho-palladated catalyst
(0.5 mol %), DMF (3 ml), 130 °C, Oil bath
a
Isolated yield
molar ratio of aryl halide to K4[Fe(CN)6]. The cyano
product was obtained in 60 % yield in 10 min and con-
version completed in 20 min (Table 1, entries 8–9). In
order to improve the time and yield reaction, tetrabutyl-
ammonium bromide (TBAB) was added into the mixture
reaction. By using TBAB as an additive and 0.22 mmol of
K4[Fe(CN)6] full conversions were achieved in 10 min
(Table 1, entry 10), and only trace amounts of homocou-
pling product were detected.
The optimized reaction conditions were used for cya-
nation of a vast range of aryl halides under microwave
irradiation conditions (Scheme 1), and the results are
summarized in Table 2. As this catalytic system is not
sensitive to oxygen, the reactions were carried out under air
atmosphere.
We examined the electronic effects on the resulted
yields and conversion times of the reactions. Cyanation
reactions were performed using either electron-releasing or
electron-withdrawing groups on benzene rings and found
that these groups did not show any significant effect on
yields and reaction times. I and Br substituted aryl halides
are most reactive; however, Cl analogs are cheaper and
more readily available. Aryl chlorides are converted to aryl
nitriles more slowly and with less yields in comparison to
the similar aryl iodides and bromides (Table 2, entries
14–15). The chemoselectivity of the procedure was
We also optimized the concentration of catalyst,
employing various amounts of catalyst for this reaction.
The low palladium concentration usually led to a long
period of reaction as increasing the amount of palladium
catalyst shortened the reaction time, but did not increase
the yield of 9-cyanophenanthrene. The best result was
obtained when the cross-coupling reaction was carried out
with 0.5 mol % of dimeric complex.
123

J IRAN CHEM SOC
References
examined using 3- and 4-choloro-bromobenzene. In these
reactions, Br acted as better leaving group (Table 2, entries
10–11).
1. C. Yang, J.M. Williams, Org. Lett. 6, 2837 (2004)
2. V.Y. Kukushkin, A.J.L. Pombeiro, Chem. Rev. 102, 1771 (2002)
3. M. Sundermeier, A. Zapf, S. Mutyala, W. Baumann, J. Sans, S.
Weiss, M. Beller, Chem. Eur. J. 9, 1828 (2003)
4. Z. Rappoport, The Chemistry of the Cyano Group (Interscience
Publishers, London, 1970)
5. H.R. Chobanian, B.P. Fors, L.S. Lin, Tetrahedron Lett. 47, 3303
(2006)
6. R.C. Larock, In Comprehensive Organic Transformations (VCH,
New York, 1989), pp. 819–995
7. S.J. Collier, P. Langer, Sci. Synth. 19, 403 (2004)
8. M. Hatsuda, M. Seki, Tetrahedron 61, 9908 (2005)
9. A. Kleemann, J. Engel, B. Kutscher, D. Reichert, Pharmaceutical
Substances: Syntheses, Patents, Applications, 4th edn. (Georg
Thieme, Stuttgart, 2001)
10. K.W. Rosenmund, E. Struck, Ber. Dtsch. Chem. Ges. 2, 1749 (1919)
11. T. Schareina, A. Zapf, M. Beller, J. Organomet. Chem. 689, 4576
(2004)
12. G.A. Ellis, T.M. Romney-Alexander, Chem. Rev. 87, 779 (1987)
13. I.P. Beletskaya, A.S. Sigeev, A.S. Peregudov, P.V. Petrovskii, J.
Organomet. Chem. 689, 3810 (2004)
14. A. Littke, M. Soumeillant, R.F. Kaltenbach, R.J. Cherney, C.M.
Tarby, S. Kiau, Org. Lett. 9, 1711 (2007)
15. X. Jia, D. Yang, S. Zhang, J. Cheng, Org. Lett. 11, 4716 (2009)
16. M. Sundermeier, S. Mutyala, A. Zapf, A. Spannenberg, M. Bel-
ler, J. Organomet. Chem. 684, 50 (2003)
17. M. Sundermeier, A. Zapf, M. Beller, Angew. Chem. Int. Ed. 42,
1661 (2003)
18. A.R. Hajipour, K. Karami, A. Pirisedigh, Appl. Organomet.
Chem. 24, 454 (2010)
19. A.R. Hajipour, K. Karami, Gh Tavakoli, A. Pirisedigh, J. Orga-
nomet. Chem. 696, 819 (2011)
20. A.R. Hajipour, F. Abrisham, Gh Tavakoli, Transit. Met. Chem.
36, 725 (2011)
21. M. Sundermeier, A. Zapf, M. Beller, Eur. J. Inorg. Chem. 3513 (2003)
22. T. Schareina, R. Jackstell, T. Schulz, A. Zapf, A. Cott, M. Gotta,
M. Beller, Adv. Synth. Catal. 351, 643 (2009)
23. M. Islam, P. Mondal, K. Tuhina, A. Singha Roy, S. Mondal, D.
Hossain, J. Organomet. Chem. 695, 2284 (2010)
24. C.O. Kappe, Angew. Chem. Int. Ed. 43, 6250 (2004)
25. M. Becker, A. Schulz, K. Voss, Synth. Commun. 41, 1042 (2011)
26. R.R. Srivastav, S.E. Collibee, Tetrahedron Lett. 45, 8895 (2004)
27. M. Alterman, A. Hallberg, J. Org. Chem. 65, 7984 (2000)
28. A. Zhang, J.L. Neumeyer, Org. Lett. 5, 201 (2003)
29. A.R. Hajipour, K. Karami, A. Pirisedigh, A.E. Ruoho, Amino
Acids 37, 537 (2009)
The optimized reaction conditions were also used for the
cyanation reaction of some of aryl halides under conven-
tional heating. The results summarized in Table 3 showed
that the use of homogenous metal catalysts in conjunction
with microwave irradiation improved the yields of the
reactions and decreased the reaction times in comparison to
the traditional heating methods. Under conventional heat-
ing in the large-scale conditions (50 mmol), the cyano
product was obtained in lower yield and the amount of
homo coupling by-product was increased.
A general proposed mechanism for cyanation reaction
has been presented contains conversion of Pd(II) pre-cat-
alyst to Pd(0), followed by the oxidative addition of aryl
halide to Pd(0) to form aryl palladium (II) intermediate.
After due to the reaction between this intermediate and
K4[Fe(CN)6] and reductive elimination steps, the desired
cyanated products were obtained and the Pd(0) formed in
the main catalytic cycle [11, 40].
To evaluate the proposed mechanism of catalytic
system, we carry out the mercury drop test. In the pre-
sence of a heterogeneous catalyst, mercury leads to the
amalgamation of the surface of catalyst. In contrast,
Hg(0) cannot have a poisoning effect on homogeneous
palladium complexes, where the Pd(II) metal centre is
tightly bound to the ligand. When a drop of Hg(0) was
added to the reaction mixture and heated under men-
tioned optimized condition; no aryl nitrile product was
obtained and no catalytic activity observed for the cat-
alyst. The data obtained can be rationalized
Pd(0):Pd(II) cycle.
a
Conclusion
In conclusion, we have developed a fast and efficient
methodology for the cyanation of aryl halides using non-
toxic potassium hexacyanoferrate(II) as the cyanide source
under microwave irradiation. Catalytic amounts of CN-
dimeric ortho-palladated complex as catalyst converted
different aryl halides to the corresponding benzonitriles
with high yields and short reaction times. In comparison to
conventional thermal conditions, these reactions were
completed in shorter reaction times under microwave
irradiation.
30. A.R. Hajipour, F. Rafiee, Tetrahedron Lett. 53, 526 (2012)
31. A.R. Hajipour, K. Karami, A. Pirisedigh, Inorg. Chim. Acta 370,
531 (2011)
32. A.R. Hajipour, K. Karami, F. Rafiee, Appl. Organomet. Chem.
26, 27 (2012)
33. A.R. Hajipour, F. Rafiee, Appl. Organomet. Chem. 25, 542 (2011)
34. A.R. Hajipour, F. Rafiee, J. Organomet. Chem. 696, 2669 (2011)
35. A.R. Hajipour, F. Rafiee, Tetrahedron Lett. 52, 4782 (2011)
36. A.R. Hajipour, F. Rafiee, Appl. Organomet. Chem. 27, 412
(2013)
37. Y.L. Ren, Z.F. Liu, S.B. He, S. Zhao, J.J. Wang, R.Q. Niu, W.P.
Yin, Org. Process Res. Dev. 13, 764 (2009)
Acknowledgments We gratefully acknowledge the funding support
received for this project from the Isfahan University of Technology
(IUT), IR Iran National Elite Foundation, IR, Iran. Further financial
support from the Center of Excellence in Sensor and Green Chemistry
Research (IUT) is gratefully acknowledged.
38. P.Y. Yeung, C.M. So, C.P. Lau, F.Y. Kwong, Org. Lett. 13, 648
(2011)
39. I.A. Azath, P. Suresh, K. Pitchumani, New J. Chem. 36, 2334 (2012)
40. S. Erhardt, V.V. Grushin, A.H. Kilpatrick, S.A. Macgregor, W.J.
Marshall, D.C. Roe, J. Am. Chem. Soc. 130, 4828 (2008)
123