Conjugate hydrocyanation of aromatic enones using potassium hexacyanoferrate(II) as an eco-friendly cyanide source

Article abstract of DOI:10.1055/s-0032-1317179

A selective conjugate hydrocyanation of aromatic enones by a one-pot, two-step procedure using potassium hexacyanoferrate(II) as an original eco-friendly cyanide source, potassium hydroxide as a base, and benzoyl chloride as a promoter was described. This protocol has the advantages of a nontoxic cyanide source, high yield, and simple workup procedure. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317179

LETTER
▌2567
lCettoernjugate Hydrocyanation of Aromatic Enones Using Potassium Hexacyano-
ferrate(II) as an Eco-Friendly Cyanide Source
Conjugate Hydrocyanation of Aromatic Enones
Zheng Li,* Chenhui Liu, Yupeng Zhang, Rongzhi Li, Ben Ma, Jingya Yang
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, P. R. of China
Fax +86(931)7971989; E-mail: lizheng@nwnu.edu.cn
Received: 15.07.2012; Accepted after revision: 07.08.2012
tion. In addition, it has been described as an anti-aggluti-
Abstract: A selective conjugate hydrocyanation of aromatic
nating auxiliary for table salt (NaCl). K4[Fe(CN)6] is a
byproduct of coal chemical industry and commercially
available on a ton scale, and is even cheaper than KCN.
enones by a one-pot, two-step procedure using potassium hexacya-
noferrate(II) as an original eco-friendly cyanide source, potassium
hydroxide as a base, and benzoyl chloride as a promoter was de-
scribed. This protocol has the advantages of a nontoxic cyanide Recently, K4[Fe(CN)6] has been used as a cyanide source
source, high yield, and simple workup procedure.
for some substitution reactions to synthesize benzo-
nitriles,7 aroyl cyanides,8 benzyl cyanides,9 and cinnamo-
Key words: conjugate hydrocyanation, 1,4-addition, aromatic
enone, green chemistry, nucleophilic addition, potassium hexacya-
noferrate(II)
nitriles.10 Our current research focused on the cyanation of
unsaturated compounds including C=O or C=N by nu-
cleophilic addition reactions using K4[Fe(CN)6] as an eco-
friendly cyanide source.11 In this study, we report an effi-
The conjugate hydrocyanation of α,β-unsaturated ke- cient method for the conjugate hydrocyanation of unsatu-
tones, especially aromatic enones, is an important C–C rated compounds bearing both C=O and C=C bonds,
bond-forming reaction in synthetic organic chemistry aromatic enones, using K4[Fe(CN)6] as an original eco-
which can produce significant β-cyano ketones. β-Cyano friendly cyanide source.
ketones are valuable synthons in synthetic organic chem-
First chalcone was selected as a substrate for the conju-
istry.1 Therefore, many different methods for the synthe-
gate hydrocyanation of aromatic enones by a one-pot,
sis of β-cyano carbonyl compounds have been reported in
two-step procedure using K4[Fe(CN)6] as an original eco-
the past years, which mainly take advantage of HCN,2
friendly cyanide source (Scheme 1, R1, R2 = H). The reac-
KCN,3 and Et2AlCN4 as original cyanide sources. How-
tion was attempted under different conditions such as us-
ever, these cyanide sources are strong toxic chemicals.
ing Lewis acids, Lewis bases, and organometallic
Recently, it has been reported that β-cyano carbonyl com-
compounds as catalysts at different temperatures in vari-
ous solvents. However, no product could be obtained for
this reaction because K4[Fe(CN)6] is too stable to release
cyanide ions under the studied conditions. In the later
pounds can be synthesized from α,β-unsaturated carbon-
yls using trimethylsilyl cyanide as a cyanide source.5 In
addition, β-cyanocarbonyl compounds have also been re-
ported to be obtained by using acetone cyanohydrin as a
study it was found that some acyl chlorides could effi-
cyanide source.6 However, trimethylsilyl cyanide is very
ciently promote the process of conjugate hydrocyanation
of K4[Fe(CN)6] to chalcone to give 1,4-adduct, β-cyano
ketone. The thermodynamically less stable 1,2-addition
sensitive to moisture and can easily release toxic hydro-
gen cyanide. Acetone cyanohydrin is unstable and also
easily releases toxic hydrogen cyanide under heating con-
product and other side reactions were not observed (Table
ditions. Furthermore, the preparations for both of them
1). Among the studied acyl chlorides, acetyl chloride had
also require strong toxic hydrogen cyanide as original ma-
no promoting effect on the reaction. It may be caused by
terial. Therefore, there is a need to explore environmental-
their volatility and instability (Table 1, entry 1). Furoyl
ly benign cyanating agents for cyanation reactions.
chloride could promote the reaction to gain the corre-
Potassium hexacyanoferrate(II), K4[Fe(CN)6], is nontoxic sponding product in moderate yield (Table 1, entry 4).
and is even used in the food industry for metal precipita- Aroyl chlorides could effectively promote the reaction to
O
CN
O
R1
PhCOCN
R2
R1
PhCOCl
160 °C
K4[Fe(CN)6]
R2
KOH, MeCN–H2O, 40 °C
Scheme 1 Conjugate hydrocyanation of aromatic enones using K4[Fe(CN)6] as a cyanide source
SYNLETT 2012, 23, 2567–2571
Advanced online publication: 10.09.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317179; Art ID: ST-2012-W0596-L
© Georg Thieme Verlag Stuttgart · New York

2568
Z. Li et al.
LETTER
give 1,4-adduct in high yield (Table 1, entries 2 and 3). In addition, it was found that bases also played a critical
Especially benzoyl chloride could afford the best yield role in the studied reaction. Some bases were examined
(Table 1, entry 2). The intermediates, acyl cyanides, could for the reaction of chalcone with K4[Fe(CN)6] using ben-
be isolated and identified from the reaction system.12 In zoyl chloride as a promoter. Potassium carbonate had no
addition, it was also found that only 0.2 equivalents of effect on the reaction. N,N-Dimethylaminopyridine
K4[Fe(CN)6] were needed for 1 mol of chalcone, which (DMAP), 1,4-diazabicyclo-[2.2.2]octane (DABCO), and
indicated that six CN– of K4[Fe(CN)6] could be fully uti- triethylamine (Et3N) could give the product in low yield
lized in this reaction. It is noteworthy to mention that (Table 2, entries 2–4). However, the reaction could pro-
K4[Fe(CN)6]·3H2O could not be used as cyanide source ceed smoothly in the presence of potassium hydroxide to
because it may cause hydration of promoters, acyl chlo- give β-cyano ketone in high yield (Table 2, entry 5).
rides, to form carboxylic acids in the first step of the one-
pot, two-step reaction.
Table 1 The Effect of Different Promoters on the Yield of Conjugate Hydrocyanation of Chalcone Using K4[Fe(CN)6] as a Cyanide Sourcea
O
CN
O
RCOCl
160 °C
K4[Fe(CN)6]
RCOCN
KOH, MeCN–H2O, 40 °C
Entry
1
Promoter
Reaction time (h)
24
Yield (%)b
0
O
Cl
O
Cl
2
19
87
O
Cl
3
4
19
19
72
48
Cl
Cl
O
O
a Reaction conditions: K4[Fe(CN)6] (0.4 mmol), promoter (2 mmol), chalcone (1.5 mmol) in MeCN (5 mL) and KOH (2.4 mmol) in H2O (3 mL).
b Isolated yield.
Table 2 The Effect of Bases on the Yield of Conjugate Hydrocyanation of Chalcone Using K4[Fe(CN)6] as a Cyanide Sourcea
O
CN
O
PhCOCl
160 °C
K4[Fe(CN)6]
PhCOCN
base, MeCN–H2O, 40 °C
Entry
Base
Reaction time (h)
Yield (%)b
1
2
3
4
5
K2CO3
DMAP
DABCO
Et3N
24
19
19
19
19
0
17
15
35
87
KOH
a Reaction conditions: K4[Fe(CN)6] (0.4 mmol), benzoyl chloride (2 mmol), chalcone (1.5 mmol) in MeCN (5 mL) and base (2.4 mmol) in H2O
(3 mL).
b Isolated yield.
Synlett 2012, 23, 2567–2571
© Georg Thieme Verlag Stuttgart · New York

LETTER
Conjugate Hydrocyanation of Aromatic Enones
2569
Table 3 The Effect of Solvents on the Yield of Conjugate Hydrocyanation of Chalcone Using K4[Fe(CN)6] as a Cyanide Sourcea
O
CN
O
PhCOCl
160 °C
K4[Fe(CN)6]
PhCOCN
KOH, solvent, 40 °C
Entry
Solvent
Reaction time (h)
Yield (%)b
1
2
3
4
5
6
7
PhMe
Et2O
24
24
19
19
19
19
19
0
0
THF
27
23
65
74
87
DMF
MeOH
EtOH
MeCN
a Reaction conditions: K4[Fe(CN)6] (0.4 mmol), benzoyl chloride (2 mmol), chalcone (1.5 mmol) in solvent (5 mL) and KOH (2.4 mmol) in
H2O (3 mL).
b Isolated yield.
The solvents also have significant effects on the reaction moter and potassium hydroxide as a base (Scheme 1 and
(Table 3). It was found that some nonpolar solvents, such Table 4).13 The different aromatic enones bearing elec-
as diethyl ether and toluene, were not available for the re- tron-donating groups, such as methyl and methoxy, and
action (Table 3, entries 1 and 2). However, the reaction in electron-withdrawing groups, such as chloro, bromo, and
polar solvents such as THF, DMF, MeOH, EtOH, and nitro, could conduct 1,4-addition reactions smoothly to
MeCN could give the desired product in moderate to high give β-cyano ketones in high yield. The substituents on ar-
yield (Table 3, entries 3–7). Among them, MeCN was the omatic enones have no obvious effect on the yield of prod-
best solvent for the reaction.
ucts.
Depending on the promising findings above, various con- A plausible mechanism for conjugate hydrocyanation of
jugate hydrocyanations of K4[Fe(CN)6] to aromatic K4[Fe(CN)6] to aromatic enones is shown in Scheme 2.
enones were examined using benzoyl chloride as a pro- K4[Fe(CN)6] first reacts with benzoyl chloride to form
O
H2O, OH–
Ph
K4[Fe(CN)6]
Cl
O
CN–
Ph
CN
O
KCl, FeCl2
Ph
O–
O
R2
R1
CN O–
CN
O
H2O
R1
R2
R2
R1
A
OH–
Scheme 2 The proposed mechanism for conjugate hydrocyanation of aromatic enones using K4[Fe(CN)6] as a cyanide source
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2567–2571

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Z. Li et al.
LETTER
Table 4 Conjugate Hydrocyanation of Aromatic Enones Using K4[Fe(CN)6] as a Cyanide Sourcea
O
CN
O
R1
PhCOCN
R2
R1
PhCOCl
160 °C
R2
K4[Fe(CN)6]
KOH, MeCN–H2O, 40 °C
Entry
R1
R2
H
Reaction time (h)
Yield (%)b
1
2
H
H
H
H
H
19
24
20
18
20
18
20
18
22
18
20
17
15
22
20
21
87
78
78
85
74
82
85
88
75
82
88
92
89
71
86
76
4-Me
3
4-OMe
4-Cl
4-O2N
H
4
5
6
4-Me
4-Me
4-Me
4-OMe
4-OMe
4-Cl
7
4-Me
4-Cl
H
8
9
10
11
12
13
14
15
16
4-Me
H
4-Cl
4-Me
4-Cl
H
4-Cl
2,4-Cl2
3-Br
H
4-O2N
H
a Reaction conditions: K4[Fe(CN)6] (0.4 mmol), benzoyl chloride (2 mmol), aromatic enones (1.5 mmol) in MeCN (5 mL) and KOH (2.4 mmol)
in H2O (3 mL).
b Isolated yield.
benzoyl cyanide. Then benzoyl cyanide is attacked by wa- Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SupInpfioomgrattr
o
nSupprigI
o
tnnofrmat
ter in the presence of hydroxyl ions to produce a cyanide
ion in situ, which subsequently reacts with aromatic
enones by 1,4-additions to form intermediates A. Interme-
diates A combine with the hydrogen ion from water to
produce the final products, β-cyano ketones.
References and Notes
(1) (a) Krogsgaard-Larsen, P.; Froelund, B.; Kristiansen, U.;
Frydenvang, K.; Ebert, B. Eur. J. Pharm. Sci. 1997, 5, 355.
(b) Krogsgaard-Larsen, P.; Froelund, B.; Joergensen, F. S.;
Schousboe, A. J. Med. Chem. 1994, 37, 2489.
(2) Gerrits, P. G.; Marcus, J.; Birikaki, L.; Gen, A. Tetrahedron:
Asymmetry 2001, 12, 971.
(3) (a) Utsugi, M.; Kamada, Y.; Miyamoto, H.; Nakada, M.
Tetrahedron Lett. 2007, 48, 6868. (b) Nagata, W.; Yoshioka,
M.; Murakami, M. J. Am. Chem. Soc. 1972, 94, 4654.
(4) (a) Dahuron, N.; Langlois, N. Synlett 1996, 51.
(b) Benedetti, F.; Berti, F.; Garau, G.; Martinuzzi, I.;
Norbedo, S. Eur. J. Org. Chem. 2003, 1973.
(5) (a) Hayashi, M.; Kawabata, H.; Inoue, K. Carbohydr. Res.
2000, 325, 68. (b) Hayashi, M.; Kawabata, H.; Shimono, S.;
Kakehi, A. Tetrahedron Lett. 2000, 41, 2591. (c) Yadav, L.
D. S.; Awasthi, C.; Rai, A. Tetrahedron Lett. 2008, 49, 6360.
(d) Sammis, G. M.; Danjo, H.; Jacobsen, E. N. J. Am. Chem.
Soc. 2004, 126, 9928. (e) Mita, T.; Sasaki, K.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 514. (f) Iida, H.;
In summary, an efficient method for conjugate hydrocya-
nation of aromatic enones by a one-pot, two-step proce-
dure using K4[Fe(CN)6] as an original eco-friendly
cyanide source, benzoyl chloride as a promoter, and po-
tassium hydroxide as a base by selective 1,4-addition re-
actions has been developed. The protocol has advantages
of using nontoxic, nonvolatile, and inexpensive cyanide
source, high yield, and simple workup procedure. Further
investigations employing other kinds of enones are under
way and will be reported in due course.
Acknowledgment
The authors thank the National Natural Science Foundation of Chi-
na (21162024) and Provincial Natural Science Foundation of Gansu
(1107RJZA189) for the financial support of this work.
Synlett 2012, 23, 2567–2571
© Georg Thieme Verlag Stuttgart · New York

LETTER
Moromizato, T.; Hamana, H.; Matsumoto, K. Tetrahedron
Conjugate Hydrocyanation of Aromatic Enones
2571
Ma, Y. H.; Li, Z. J. Organomet. Chem. 2012, 705, 70.
Lett. 2007, 48, 2037. (g) Yang, J. Y.; Wang, Y. X.; Wu, S.
X.; Chen, F. X. Synlett 2009, 3365. (h) Yang, J. Y.; Chen, F.
X. Chin. J. Chem. 2010, 28, 981. (i) Yang, J. Y.; Wu, S. X.;
Chen, F. X. Synlett 2010, 2725. (j) Yang, J. Y.; Shen, Y. B.;
Chen, F. X. Synthesis 2010, 1325.
(e) Hu, X. C.; Zhao, Z. X.; Li, Z. Phosphorus, Sulfur Silicon
Relat. Elem. 2012, 187, 1003. (f) Li, Z.; Ma, Y. H.; Xu, J.;
Shi, J. H.; Cai, H. F. Tetrahedron Lett. 2010, 51, 3922.
(12) The analytical data for the isolated representative acyl
cyanides are given below.
(6) (a) Provencher, B. A.; Bartelson, K. J.; Liu, Y.; Foxman, B.
W.; Deng, L. Angew. Chem. Int. Ed. 2011, 50, 10565.
(b) Ellis, J. E.; Davis, E. M.; Brower, P. L. Org. Process Res.
Dev. 1997, 1, 250. (c) Armstrong, A.; Convine, N. J.;
Popkin, M. E. Synlett 2006, 1589.
Benzoyl Cyanide
White solid. IR (KBr): 2224 (CN), 1679 (C=O) cm–1. 1H
NMR (400 MHz, CDCl3): δ = 8.15–8.13 (m, 2 H), 7.82–7.78
(m, 1 H), 7.63–7.59 (m, 2 H). 13C NMR (100 MHz, CDCl3):
δ = 167.8, 136.8, 133.2, 130.4, 129.5, 112.6.
(7) (a) Schareina, T.; Zapf, A.; Beller, M. Tetrahedron Lett.
2005, 46, 2585. (b) Schareina, T.; Zapf, A.; Beller, M. J.
Organomet. Chem. 2004, 689, 4576. (c) Schareina, T.; Zapf,
A.; Beller, M. Chem. Commun. 2004, 1388. (d) Weissman,
S. A.; Zewge, D.; Chen, C. J. Org. Chem. 2005, 70, 1508.
(e) Grossman, O.; Gelman, D. Org. Lett. 2006, 8, 1189.
(f) Schareina, T.; Zapf, A.; Beller, M. Tetrahedron Lett.
2007, 48, 1087. (g) Li, L. H.; Pan, Z. L.; Duan, X. H.; Liang,
Y. M. Synlett 2006, 2094. (h) Velmathi, S.; Leadbeater, N.
E. Tetrahedron Lett. 2008, 49, 4693. (i) Chen, G.; Weng, J.;
Zheng, Z. C.; Zhu, X. H.; Cai, Y. Y.; Cai, J. W.; Wan, Y. Q.
Eur. J. Org. Chem. 2008, 3524. (j) Cheng, Y. N.; Duan, Z.;
Yu, L. J.; Li, Z. X.; Zhu, Y.; Wu, Y. J. Org. Lett. 2008, 10,
901. (k) Franz, A. W.; Popa, L. N.; Müller, T. J. J.
(13) General Procedure
The mixture of K4[Fe(CN)6] (0.4 mmol) and benzoyl
chloride (2 mmol) was heated at 160 °C for 3 h, then the
reaction system was cooled to 40 °C, and aromatic enone
(1.5 mmol) in MeCN (5 mL) and KOH (2.4 mmol) in H2O
(3 mL) were added. The mixture was further stirred at
40 °C for the appropriate time indicated in Table 4. After
completion of the reaction, monitored by TLC, the resulting
mixture was filtered to remove the solids, and the filtrate was
concentrated and isolated by column chromatography using
PE–EtOAc (10:1) as eluent to give the pure product. The
analytical data for representative products are shown below.
4-Oxo-2,4-diphenylbutanenitrile (Table 4, Entry 1)
White solid; mp 120–122 °C. IR (KBr): 1681 (C=O), 2238
(CN) cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.51 (dd, 1 H,
J = 5.6, 18.0 Hz, CHCHaHCO), 3.74 (dd, 1 H, J = 7.6,
18.0 Hz, CHCHbHCO), 4.58 (dd, J = 6.0, 6.4 Hz, 1 H,
ArCHCH2), 7.26–7.43 (m, 7 H, ArH), 7.58–7.62 (m, 1 H,
ArH), 7.92–7.94 (m, 2 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 31.9, 44.5, 120.6, 127.5, 128.1, 128.4, 128.8,
129.3, 133.9, 135.2, 135.6 194.6 ppm. Anal. Calcd for
C16H13NO (235.28): C, 81.68; H, 5.57; N, 5.95. Found: C,
81.59; H, 5.56; N, 5.97.
Tetrahedron Lett. 2008, 49, 3300. (l) Ren, Y. L.; Liu, Z. F.;
Zhao, S.; Wang, J. J. Catal. Commun. 2009, 10, 768.
(m) Ren, Y. L.; Wang, W.; Zhao, S.; Tian, X. Z.; Wang, J. J.
Tetrahedron Lett. 2009, 50, 4595. (n) Ren, Y. L.; Wang, W.;
Zhao, S.; Tian, X. Z.; Wang, J. J. Org. Process Res. Dev.
2009, 13, 764. (o) Becker, M.; Schulz, A.; Voss, K. Synth.
Commun. 2011, 41, 1042. (p) Gerber, R.; Oberholzer, M.;
Frech, C. M. Chem. Eur. J. 2012, 18, 2978. (q) Yeung, P. Y.;
Tsang, C. P.; Kwong, F. Y. Tetrahedron Lett. 2011, 52,
7038. (r) Anbarasan, P.; Neumann, H.; Beller, M. Chem.
Eur. J. 2011, 17, 4217.
4-(4-Methoxyphenyl)-4-oxo-2-phenylbutanenitrile
(Table 4, Entry 3)
(8) Li, Z.; Shi, S. Y.; Yang, J. Y. Synlett 2006, 2495.
(9) (a) Ren, Y. L.; Dong, C. H.; Zhao, S.; Sun, Y. P.; Wang, J.
J.; Ma, J. Y.; Hou, C. D. Tetrahedron Lett. 2012, 53, 2825.
(b) Ren, Y. L.; Yan, M. J.; Zhao, S.; Sun, Y. P.; Wang, J. J.;
Yin, W. P.; Liu, Z. F. Tetrahedron Lett. 2011, 52, 5107.
(10) Saha, D.; Adak, L.; Mukherjee, M.; Ranu, B. C. Org.
Biomol. Chem. 2012, 10, 952.
(11) (a) Zhao, Z. X.; Li, Z. Eur. J. Org. Chem. 2010, 5460. (b) Li,
Z.; Tian, G. Q.; Ma, Y. H. Synlett 2010, 2164. (c) Zhao, Z.
X.; Li, Z. J. Braz. Chem. Soc. 2011, 22, 148. (d) Hu, X. C.;
Oil. IR (KBr): 1676 (C=O), 2243 (CN) cm–1. 1H NMR (400
MHz, CDCl3): δ = 3.37 (dd, J = 6.0, 17.6 Hz, 1 H,
CHCHaHCO), 3.60 (dd, J = 8.4, 17.6 Hz, 1 H,
CHCHbHCO), 3.79 (s, 3 H, CH3), 4.49 (dd, J = 6.0, 8.0 Hz,
1 H, ArCHCH2), 6.85 (d, J = 6.8 Hz, 2 H, ArH), 7.23–7.37
(m, 5 H, ArH), 7.83 (d, J = 6.8 Hz, 2 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 31.9, 44.1, 55.5, 113.9, 120.8, 127.4,
128.3, 128.7, 129.2, 130.4, 135.4, 164.0, 193.0 ppm. Anal.
Calcd for C17H15NO2 (265.31): C, 76.96; H, 5.70; N, 5.28.
Found: C, 76.80; H, 5.71; N, 5.30.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2567–2571

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