Zinc cyanide mediated direct α-cyanation of isonicotinic acid N-oxide. Application to the synthesis of FYX-051, a xanthine oxidoreductase inhibitor

Article abstract of DOI:10.1016/j.tetlet.2008.05.029

Reaction of isonicotinic acid N-oxide 1a with dimethylcarbamoyl chloride and zinc cyanide in CH₃CN at 120 °C gave the corresponding 2-cyanoisonicotinamide 2a in a good yield. This strategy was applied to the synthesis of FYX-051·TsOH 8, a xanthine oxidoreductase inhibitor.

Full text of DOI:10.1016/j.tetlet.2008.05.029

Tetrahedron Letters 49 (2008) 4369–4371
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Tetrahedron Letters
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Zinc cyanide mediated direct a-cyanation of isonicotinic acid N-oxide.
Application to the synthesis of FYX-051, a xanthine oxidoreductase inhibitor
Zhibao Huo a, Teruo Kosugi b, Yoshinori Yamamoto a,
*
a Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
b Fukuzyu Pharmaceuticals Co., Ltd, Toyama 939-8261, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of isonicotinic acid N-oxide 1a with dimethylcarbamoyl chloride and zinc cyanide in CH3CN at
120 °C gave the corresponding 2-cyanoisonicotinamide 2a in a good yield. This strategy was applied to
the synthesis of FYX-051ꢀTsOH 8, a xanthine oxidoreductase inhibitor.
Received 16 March 2008
Revised 28 April 2008
Accepted 7 May 2008
Available online 10 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Zinc cyanide
a-Cyanation
Pyridine N-oxide
2-Cyanoisonicotinamide
Isonicotinic acid N-oxide
COOH
CONHNHBoc
TMSCN
The synthesis of substituted cyanopyridines has been of consid-
erable interest because the structural framework of cyanopyridines
is often found in important biologically active compounds.1 Cyana-
tion of pyridine N-oxides is one of the most useful synthetic meth-
ods for the formation of cyano-substituted pyridines.2 Efficient
methods for the synthesis of various cyanopyridines and their
derivatives from pyridine N-oxides have been developed. For
example, the reaction of cyanide ions with pyridine N-oxides in
the presence of an acylating agent3 or with pyridine N-oxide qua-
ternary salts provides the corresponding cyanopyridines in good
yields.4,5
ClCO2Et, Et3N
CH2Cl2
NH2NHBoc
N+
O-
N+
O-
(CH3)2NCOCl
CONHNH2
CONHNHBoc
TsOH . H2O
AcOEt
3/2 TsOH
N
CN
N
CN
NH
N
R
N
(CH3)2NCOCl
R
N
CN
NC
TMSCN / CH2Cl2
N
N+
O-
or
ð1Þ
N
NaOMe
N
CN
KCN / CH3CN
FYX-051
R = H; 2,3, or 4-Me; 3-CO2Me; 3-CN; 3-Cl; 3-OMe
Scheme 1.
FYX-051, 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-
carbonitrile,6 is a new xanthine oxidoreductase (XOR) inhibitor
developed by Fuji Yakuhin Co., Ltd XOR catalyzes the last two reac-
tions of purine catabolism, that is, the hydroxylation of hypoxan-
thine to xanthine and of xanthine to uric acid. FYX-051 was
synthesized by Fukuzyu pharmaceuticals Co., Ltd (Toyama, Japan)
according to the reaction sequence shown in Scheme 1.
First, commercially available isonicotinic acid N-oxide was pro-
tected by Boc-hydrazine, and the resulting protected pyridine N-
oxide was treated with expensive TMSCN in the presence of
(CH3)2NCOCl, giving the a-cyanopyridine derivative in 69% yield.
Then, deprotection of the Boc group was needed before condensa-
tion with para-cyanopyridine (Scheme 1). It would be advanta-
geous to avoid the protection–deprotection steps and also to
avoid the use of expensive TMSCN. Therefore, development of a
new method for direct cyanation from isonicotinic acid N-oxide
* Corresponding author. Tel.: +81 22 795 6581; fax: +81 22 795 6784.
E-mail address: yoshi@mail.tains.tohoku.ac.jp (Y. Yamamoto).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.029

4370
Z. Huo et al. / Tetrahedron Letters 49 (2008) 4369–4371
Table 1
O
COOH
O
Effect of cyanide sources and solvents on the formation of 2-cyanoisonicotinamide 2a
O
from 1aa
O
C
N
+
N
Cl
Entry
Cyanide source
Solvent
Yield of 2ab (%)
N+
O-
HCl
Cl-
1
2
3
4
5
6
7
8
9
10
11
12
13
Zn(CN)2
AgCN
Hg(CN)2
KCN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
DMF
1,4-Dioxane
AcOEt
Toluene
CH3CN
CH3CN
CH3CN
69 (66)c
42
37
N+
1a
3
O
O
35
N
CuCN
nrd
Zn(CN)2
Zn(CN)2
Zn(CN)2
Zn(CN)2
Zn(CN)2
Zn(CN)2
Zn(CN)2
Zn(CN)2
15
32
(42)
43 (43)
52 (47)
(66)e
62 (58)f
67 (66)g
CON
CON
Zn(CN)2
CN
H
N
O
O
O
C
N
CN
ZnCl2 + CO2
N
OH
4
2a
a
N
The reaction of 1a with a cyanating agent (1.5 equiv Zn(CN)2 or 3 equiv KCN,
CuCN, and AgCN) was carried out in the presence of 3 equiv of dimethylcarbamoyl
chloride at 120 °C for 12 h.
Scheme 2. A plausible mechanism for the formation of 2a.
b
1H NMR yield using dibromomethane as an internal standard. Isolated yield is
shown in parentheses.
c
Reaction time was 5 h.
Starting material was recovered.
2 equiv of dimethylcarbamoyl chloride were used.
1 equiv of Zn(CN)2 was used.
of dimethylcarbamoyl chloride and zinc cyanide did not exert a
strong influence on the product yield (entries 11 and 12). A
decrease in the reaction temperature to 100 °C also did not affect
the product yield (entry 13).
d
e
f
g
Reaction temperature was 100 °C.
Next, we investigated the effect of acylating agents, and the
results are summarized in Table 2. Dimethylcarbamoyl chloride
was found to be the best acylating agent. The product 2a was
isolated in 66% yield when the reaction was carried out at 120 °C
for 5 h in the presence of 3 equiv of dimethylcarbamoyl chloride
(entry 1). The use of benzoyl chloride and lithium chloride did
not lead to any product formation (entries 2 and 3).
A plausible mechanism for the Zn(CN)2 mediated synthesis of 2-
cyanoisonicotinamide 2a is illustrated in Scheme 2. At the initial
stage of the reaction, the intermediate 1-acyloxypyridinium ion 3
is formed as mentioned in previous literature.2,3d,4b,5 The a-cyana-
tion through reaction of 3 with Zn(CN)2 and elimination of carbon
dioxide afford the intermediate 4. Removal of N,N-dimethylcarba-
mic acid from 4 gives 2-cyanoisonicotinamide 2a.
using a cheap cyanation reagent was needed. Herein, we report a
convenient, direct and one-step synthesis of 2-cyanoisonicotin-
amide 2a from isonicotinic acid N-oxide 1a using zinc cyanide
(1.5 equiv) in the presence of dimethylcarbamoyl chloride
(2 equiv) in CH3CN at 120 °C (Eq. 2). Furthermore, this newly
developed method was successfully applied for the synthesis of
FYX-051ꢀTsOH 8 (vide infra).
COOH
CON
O
C
CH3CN
120 oC
+
+
Zn(CN)2
N
Cl
ð2Þ
N+
O-
1a
N
CN
2a
R
R
O
C
CH3CN
120 o
Initially, we examined the cyanation of isonicotinic acid N-
oxide 1a with various cyanides in the presence of dimethylcarba-
moyl chloride (Table 1).7 Among the cyanating agents we tested,
Zn(CN)2 gave the best result in CH3CN (entry 1). No product was
detected in the presence of CuCN (entry 5), and use of other cya-
nide sources such as AgCN, Hg(CN)2, and KCN afforded 2a in mod-
erate yields (entries 2–4). Other solvents such as THF, DMF, 1,4-
dioxane, ethyl acetate, and toluene, instead of acetonitrile, gave
the product in lower yields (entries 6–10). Decreasing the amount
+
+
Zn(CN)2
(1.5 eq)
N
Cl
N+
O-
C
N
CN
ð3Þ
(2 eq)
2b
, 67% (3 h)
1b, R = H
1c
2c, 62% (8 h)
, R = 4-CN
Thus, direct a-cyanation of the pyridine N-oxide 1a substituted
with a carboxylic acid has been achieved using cheap Zn(CN)2. To
determine the applicability of this new method, we examined
O
Table 2
O
Effect of acylating agents on the formation of 2-cyanoisonicotinamide 2a from 1aa
(3 eq)
C Cl
N
N
NH
Entry
Acylating agent
Time (h)
Yield of 2a, %b
N
N
Zn(CN)2 (1.5 eq)
N
N
N
O
NC
N
N
CH3CN,
N+
1
5
69 (66)
N
C
Cl
-O
120 oC, 12 h
N
6
7
66%
O
2
12
12
nrc
nrc
C
Cl
H
N
N
TsOH . H2O (3 eq)
IPA / toluene (1 : 1)
3
LiCl
(4)
NC
TsOH
N
N
a
The reaction of 1a with Zn(CN)2 (1.5 equiv) was carried out in the presence of
3 equiv of acylating agent at 120 °C in CH3CN.
N
80 oC, 8 h
quant
1H NMR yield using dibromomethane as an internal standard. Isolated yield is
b
8
shown in parentheses.
c
Starting material was recovered.
Scheme 3.

Z. Huo et al. / Tetrahedron Letters 49 (2008) 4369–4371
4371
4. (a) Ochiai, E.; Nakayama, I. Yakugaku Zasshi 1945, 65, 582; (b) Kobayashi, Y.;
Kumadaki, I. Chem. Pharm. Bull. 1969, 17, 510; (c) Fife, W. K.; Boyer, B. D.
Heterocycles 1984, 22, 1121.
5. The preparation of 1-dimethylaminocarbonyloxypyridinium ions was reported
previously, see: Bergthaller, P. Ger. Offen. 2,408,813 (Cl. C07D), September 4,
1975, 25 pp; Chem. Abstr. 1976, 84, P43859 p.
the reactions of 1b and 1c. The a-cyanation of pyridine N-oxide
(1b) and 4-cyanopyridine N-oxide (1c) proceeded very smoothly,
giving the desired products 2b and 2c in good yields under the
reaction conditions described previously (Eq. 3). Next, we applied
this new method for an alternative synthesis of FYX-051 (Scheme
3). The pyridine N-oxide 6 substituted with a triazole group at
the para-position was obtained easily via reaction of 4-cyanopyri-
dine N-oxide with isonicotinic hydrazide, which was commercially
available. The reaction of 6 with 1.5 equiv of Zn(CN)2 and 3 equiv of
(CH3)2NCOCl in CH3CN at 120 °C for 12 h gave the corresponding a-
cyanation product 7 in 66% yield.8 Deprotection of the N-carbam-
oyl group was carried out with 3 equiv of TsOHꢀH2O, giving FYX-
051ꢀTsOH 8 in quantitative yield (Eq. 4).9
6. Nakamura, H.; Ono, A.; Sato, T.; Kaneda, S. Jpn. Kokai Tokkyo Koho, Fuji Yakuhin
Co., Ltd, Japan, 2005, 10 pp.
7. The procedure for the synthesis of 2-cyanoisonicotinamide 2a is as follows: To a
5 mL screw capped vial equipped with a magnetic stirring bar were added
isonicotinic acid N-oxide (27.8 mg, 0.2 mmol), dimethylcarbamoyl chloride
(0.04 mL, 0.4 mmol), zinc cyanide (35.2 mg, 0.3 mmol), and acetonitrile (2 mL)
under an argon atmosphere. The reaction mixture was stirred at 120 °C for 5 h,
and the progress of the reaction was monitored by TLC (hexane/ethyl acetate;
1/1). After complete consumption of the starting material, the reaction mixture
was cooled to room temperature and water was added, and stirring was
continued for 5–15 min. The organic layer was separated, and the aqueous layer
was extracted three times with 5 mL of ethyl acetate. The combined ethyl
acetate layers were dried over anhydrous sodium sulfate and the solvents were
removed under reduced pressure, and the residue was purified by column
chromatography (silica gel, hexane/ethyl acetate; 5/11/1) to afford product 2a in
66% yield. (23.1 mg). Mp: 97–99 °C; 1H NMR (300 MHz, CDCl3): d 2.97 (3H, s),
3.14 (3H, s), 7.52 (1H, d, J = 5.0 Hz), 7.71 (1H, s), 8.80 (1H, d, J = 5.0 Hz); 13C NMR
(75 MHz, CDCl3): 35.07, 38.93, 116.42, 124.28, 126.04, 133.94, 145.01, 151.29,
166.49; IR (KBr) 3291, 2240, 1698, 1632, 1385, 880 cmꢁ1; HRMS (EI) calcd for
C9H9N3O ([M+Na]+) 198.0638, found 198.0637.
In conclusion, we have reported a convenient method for the
direct synthesis of 2-cyanoisonicotinamide from isonicotinic acid
N-oxide using zinc cyanide as a cyanation reagent. Furthermore,
this strategy was applied to the synthesis of FYX-051ꢀTsOH, a
xanthine oxidoreductase inhibitor.
8. Data for 7: Mp: 112–113 °C; 1H NMR (300 MHz, CDCl3): d 3.17 (3H, s), 3.29 (3H,
s), 8.07–7.99 (3H, m), 8.21 (1H, m), 8.78 (2H, d, J = 5.0 Hz), 8.89 (1H, d,
J = 5.0 Hz); 13C NMR (75 MHz, CDCl3): 37.83, 39.28, 120.74, 125.32, 127.12,
132.08, 134.70, 135.73, 136.66, 150.02, 150.55, 151.76, 153.37, 160.14; IR (KBr)
References and notes
1. (a) Butler, R. N. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
W., Eds.; Pergamon: Oxford, 1984; Vol. 5, p 791; (b) Abramovitch, R. A.; Smith, E.
M.. In The Chemistry of Heterocyclic Compounds; Weissberget, A., Taylor, E. C.,
Eds.; John Wiley and Sons: New York, 1974; Vol. 14, Part 2, p 114; (c) Lipinski, C.
A.; LaMattina, J. L.; Oates, P. J. J. Med. Chem. 1986, 29, 2154.
2. (a) Ochiai, E. Aromatic Amine Oxides; Elsevier: Amsterdam, 1976; (b) Katritzky, A.
R.; Lagowski, J. M. Chemistry of the Heterocyclic N-Oxides; Academic Press:
London, 1971; (c) Feely, W. E.; Beavers, E. M. J. Am. Chem. Soc. 1959, 81, 4004.
3. (a) Ruchirawat, S.; Phadungkul, N.; Chuankamnerdkarn, M.; Thebtaranonth, C.
Heterocycles 1977, 6, 43; (b) Bhattacharjee, D.; Popp, F. D. J. Heterocycl. Chem.
1980, 17, 1207; (c) Veeraragharan, S.; Bhattacharjee, D.; Popp, F. D. J. Heterocycl.
Chem. 1981, 18, 443; (d) Fife, W. K. J. Org. Chem. 1983, 48, 1375; (e) Vorbruggen,
H.; Krolikiewicz, K. Synthesis 1983, 316; (f) H.Vorbruggen; Krolikiewicz, K.
Heterocycles 1984, 22, 93; (g) Fife, W. K.; Boyer, B. D. Heterocycles 1984, 22, 1211;
(h) Sakamoto, T.; Kaneda, S.; Nishimura, S.; Yamanaka, H. Chem. Pharm. Bull.
1985, 33, 565; (i) Tagawa, Y.; Higuchi, Y.; Yamagata, K.; Shibata, K.; Teshima, D.
Heterocycles 2004, 63, 2859.
2921, 2242, 1716, 1605, 1456, 1091, 836, 749 cmꢁ1
; HRMS (EI) calcd for
C
16H13N7O ([M+H]+) 320.1254, found 320.1253.
9. The procedure for the synthesis of FYX-051ꢀTsOH 8 from 7 is as follows: To a 5 mL
screw capped vial equipped with a magnetic stirring bar were added compound
7 (63.8 mg, 0.2 mmol), TsOHꢀH2O (114.1 mg, 0.6 mmol), and IPA/toluene (1/1,
1.4 mL). The reaction mixture was stirred at 80 °C for 8 h, and the progress of the
reaction was monitored by TLC (ethyl acetate). After complete consumption of
the starting material, the solvents were removed under reduced pressure, the
residue was washed three times with ethyl acetate (3 mL), and the solid product
obtained was dried to afford FYX-051ꢀTsOH 8 in quantitative yield as a white
solid (84.0 mg). Mp: 236–238 °C; 1H NMR (500 MHz, DMSO-d6): d 2.27 (3H, s),
7.10 (2H, d, J = 8.0 Hz), 7.45 (2H, d, J = 8.0 Hz), 8.57–8.27 (4H, m), 8.98–8.91 (3H,
m); 13C NMR (75 MHz, DMSO-d6): 20.87, 117.08, 122.87, 122.88, 123.82, 125.18,
125.19, 125.61, 128.39, 133.65, 133.66, 136.04, 138.37, 143.70, 144.80, 152.48.
HRMS (EI) calcd for C13H8N6 ([M–TsOH+H]+) 249.0883, found 249.0884.