Short communication
The Direct Formation of 2-Cyano-4-amidopyridine via O-Cyanation of 4-Amidopyridine Oxide with Dimethylcarbamoyl Chloride and Cheap Potassium Cyanide
Zhibao Huo,1 Teruo Kosugi2 and Yoshinori Yamamoto1*
1 Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan 2 Fukuzyu Pharmaceuticals Co., Ltd, Toyama 939-8261, Japan * Corresponding author: E-mail: yoshi@mail.tains.tohoku.ac.jp
Received: 01-09-2008 Dedicated to Professor Blanko Stanovnik on the occasion of his 70'' birthday
Abstract
Reaction of 4-amidopyridine N-oxide with dimethylcarbamoyl chloride and potassium cyanide in CH3CN at 120 °C gave the corresponding 2-cyano-4-amidopyridine in a good yield.
Keywords: Potassium cyanide, a-cyanation, pyridine N-oxide, 2-cyano-4-amido pyridine, 4-amidopyridine N-oxide.
1. Introduction
The synthesis of substituted cyanopyridines has been of considerable interest because the structural framework of cyanopyridines is often found in important biologically active compounds.1 Cyanation of pyridine N-oxide is one of the most useful synthetic methods for the formation of cyano-pyridines.2 Due to their potential importance, several synthetic methods from substituted 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 quaternary salts provides the corresponding cyanopyridines in good yields (Eq. 1).4'5
FYX-051, 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl) pyridine-2-carbonitrile,6 is a new xanthine oxidoreducta-
se (XOR) inhibitor developed by Fuji Yakuhin Co., Ltd. XOR catalyzes the last two reactions of purine catabo-lism, i.e. the hydroxylation of hypoxanthine 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 protected by Boc-hydrazine, and the resulting protected pyridine N-oxide was treated with expensive TM-SCN in the presence of (CH3)2NCOCl, giving the a-cya-nopyridine derivative in 69% yield. Then, deprotection of the Boc group was needed before condensation with pa-ra-cyanopyridine (Scheme 1). It would be advantageous 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 4-ami-dopyridine N-oxide 3 using a cheap cyanation reagent was needed.
2. Results and Discussion
Recently, we reported an convenient method for the direct synthesis of 2-cyanoisonicotinamide 2 from isoni-cotinic acid N-oxide 1 using zinc cyanide as a cyanation
Scheme 1
reagent (Eq. 2).7 This finding enabled the synthesis of FYX-051 ■ TsOH from the pyridine ^-oxide using cheap cyanation reagent, Zn(CN)2 (Scheme 2).7 Encouraged by this finding, we thought that 4-amidopyridine ^-oxide 3 would be converted to the corresponding a-cyanopyridi-ne 4 using Zn(CN)2 (Eq. 3). However, the reaction of 3 with Zn(CN)2 and dimethylcarbamoyl chloride gave 4 in a low yield (Table 1, entry 4). Accordingly, it is clear that Zn(CN)2 is not applicable to the a-cyanation of 4-ami-dopyridine N-oxides although it gave a good result in the case of isonicotinic acid N-oxide 1.
We examined the cyanation of 4-amidopyridine Noxide 3 with various cyanides and acylating agents (Eq 4, Table 1).8 Dimethylcarbamoyl chloride was found to be
the best acylating agent among the cyanating agents we tested, and KCN gave the best result in CH3CN (entry 1). Use of other cyanide sources such as NaCN, AgCN and Zn(CN)2 afforded product 4 in lower yields (entries 2-4), and no products was detected in the presence of CuCN and Hg(CN)2 (entries 5 and 6). The use of benzoyl chloride and lithium chloride did not lead to any product formation (entries 7-9).
As shown in Figure 1, the time profile of the reaction of 3, monitored by NMR, indicated that the starting substrate 3 was consumed completely within 4 h. However, the formation of 4 reached to plateau after 2.5 h and the yield (60%) did not increase significantly even at a prolonged reaction time. The reason why the curve of de-
Table 1. Effect of cyanide sources and acylating agents on the formation of 2-cyano-4-amidopyridine 4 from 3.a
entry acylating agent cyanide source yield of 4, %'
O
II
Ph—C-CI
KCN
NaCN
AgCN
Zn(CN)2
CuCN
Hg(CN)2
KCN Zn(CN)2
KCN
64c
20
49
21d
nrf
_d,f
a The reaction of 3 with a cyanating agent was carried out in the presence of 3 equiv of acylating agent in CH3CN at 120 °C for 12 h. b Isolated yields. c Reaction time was 4 h. d 1.5 equiv of Zn(CN)2 and Hg(CN)2 were used. e Starting material decomposed. f Starting material was recovered
Figure 1. Time profile of the cyanation of 3 (0.1 mmol) in the presence of 3 eq dimethylcarbamoyl chloride and 3 eq KCN in CH3CN at 120 °C.	3
crease of the starting material does not correspond well to that of increase of product formation is not clear.
Next, we investigated the effect of solvents, reaction temperature and amount of cyanides and acylating agents, and the results are summarized in Table 2. CH3CN and THF gave the product in good yields (entries 1 and 2). Use of DMF, CH2Cl2, 1,4-dioxane, and AcOEt, instead of CH3CN, gave the product in lower yields (entries 3-6). Other solvents such as H2O, mixture of CH3CN and H2O, toluene, DMSO and Et2O were inefficient and no desired product was obtained (entries 7-11). Decreasing the
amount of dimethylcarbamoyl chloride gave a low yield (entry 12). The product 4 was isolated in 64% yield when the reaction was carried out at 120 °C for 4 h in the presence of 2 equiv of potassium cyanide (entry 13). Decrease of reaction temperature from 120 °C to 100 °C did not affect the product yield (entry 15).
A plausible mechanism for the KCN mediated synthesis of 2-cyano-4-amidopyridine 4 is illustrated in Scheme 2. At the initial stage of the reaction, the intermediate 1-acyloxypyridinium ion A is formed as mentioned in the previous literatures.2,3d,4b,5 The a-cyanation through

f
nt
Table 2. Effect of solvents, amount of cyanide sources and acylating agents and temperature on the formation of 2-cyano-4-amidopyridine 4 from 3.a
entry	solvent	acylating agent (eq)	cyanide source (eq)	temp (°C)	time (h)	yield of 4, %b
1	CH3CN	3	3	120	4	64
2	THF	3	3	120	12	61
3	DMF	3	3	120	12	37c
4	CH2Cl2	3	3	120	12	15c
5	1,4-dioxane	3	3	120	12	20c
6	AcOEt	3	3	120	12	13c
7	H2O	3	3	120	12	nr
8	CH3CN + H2O	3	3	120	12	nr
9	Toluene	3	3	120	12	nr
10	DMSO	3	3	120	12	nr
11	Et2O	3	3	120	12	nr
12	CH23CN	2	3	120	24	37c,d
13	CH33CN	3	2	120	4	64
14	CH33CN	3	1	120	24	47c,e
15	CH33CN	3	2	100	7	64
16	CH33CN	3	3	70	24	25c,f
a The reaction of 3 with 3 equiv of cyanating agent was carried out in the presence of 3 equiv of acylating agent inCH3CN at 120 °C. b Isolated yields. c 1H NMRyield using j5-xylene as an internal standard. d 15% of 3 was recovered. e 10% of 3 was recovered. f 35% of 3 was recovered.
the reaction of A with KCN affords the intermediate B. Removal of ^,^-dimethylcarbamic acid from B gives 2-cyano-4-amidopyridine 4.
3. Conclusion
We have developed an efficient method for the direct formation of 2-cyano-4-amidopyridine from 4-amidopyri-dine ^-oxide using cheap potassium cyanide as a cyana-ting agent.
4. References
1.	(a) R. N. Butler, In Comprehensive Heterocyclic Chemistry; A. R. Katritzky, C. W. Rees, Pergamon: Oxford, 1984; Vol. 5, p 791; (b) R. A. Abramovitch, E. M. Smith, 'The Chemistry of Heterocyclic Compounds', A. Weissberget, E. C. Taylor, eds., John Wiley and Sons, New York, Vol. 14, Suppl. Part 2, 1974, p 114-117; (c) C. A. Lipinski, J. L. LaMattina, P. J. Oates, J. Med. Chem. 1986, 29, 2154-2163.
2.	(a) E. Ochiai, 'Aromatic Amine Oxides', Elsevier: Amsterdam, 1976, p 269; (b) A. R. Katritzky, J. M. Lagowski, 'Chemistry of the Heterocyclic ^-Oxides', Academic Press, London, 1971, p 300; (c) W. E. Feely, E. M. Beavers, J. Am. Chem. Soc. 1959, 81, 4004-4007.
3.	(a) S. Ruchirawat, N. Phadungkul, M. Chuankamnerdkarn, C. Thebtaranonth, Heterocycles 1977, 6, 43-46; (b) D. Bhattac-
harjee, F. D. Popp, J. Heterocycl. Chem. 1980, 17, 12071209; (c) S. Veeraragharan, D. Bhattacharjee, F. D. Popp, Ibid. 1981, 18, 443-446; (d) W. K. Fife, J. Org. Chem. 1983, 48, 1375-1377; (e) H. Vorbruggen, K. Krolikiewicz, Synthesis
1983,	316-319; (f) Idem, Heterocycles 1984, 22, 93-96; (g) T. Sakamoto, S. Kaneda, S. Nishimura, H. Yamanaka, Chem. Pharm. Bull. 1985, 33, 565-571; (h) Y. Tagawa, Y. Higuchi, K. Yamagata, K. Shibata, D. Teshima, Heterocycles 2004, 63, 2859-2862.
4.	(a) E. Ochiai, I. Nakayama, Yakugaku Zasshi, 1945, 65, 582584; (b) Y. Kobayashi, I. Kumadaki, Chem. Pharm. Bull. 1969, 17, 510-514; (c) W. K. Fife, B. D. Boyer, Heterocycles
1984,	22, 1121-1124.
5.	The preparation of 1-dimethylaminocarbonyloxypyridinium ions was reported previously, see: P. Bergthaller, Ger. Offen. 2, 408, 813 (Cl. C07D), Sept. 4, 1975, 25 pp., Chem. Abstr. 84, P43859p (1976).
6.	H. Nakamura, A. Ono, T. Sato, S. Kaneda, (Fuji Yakuhin Co., Ltd., Japan). Jpn. Kokai Tokkyo Koho (2005), 10 pp.
7.	Z. Huo, T. Kosugi, Y. Yamamoto, Tetrahedron Lett. 2008, 49, 4369-4371.
8.	The procedure for the synthesis of 2-cyano-4-amidopyridine 4
is as follows. To a 5 mL screw capped vial equipped with a magnetic stirring bar were added 4-amidopyridine N-oxide (50.6 mg, 0.2 mmol), dimethylcarbamoyl chloride (0.056 mL, 0.6 mmol), potassium cyanide (26.0 mg, 0.4 mmol), and ace-tonitrile (2 mL) under an argon atmosphere. The reaction mixture was stirred at 120 °C for 4 h, and the progress of the reaction was monitored by TLC (hexane/ethyl acetate; 2/1). 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 minutes. 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, hexa-ne/ethyl acetate; 10/1 ~2/1) to afford product 4 in 64% yield. (33.6 mg). 1H NMR (300 MHz, CDClj): 5 1.51 (9H, s), 7.86 (1H, d, J = 5.0 Hz), 8.07 (1H, s), 8.88 (1H, d, J = 5.0 Hz); 13C NMR (75 MHz, CDClj): 26.85, 48.54, 80.65, 116.08, 121.90, 124.54, 125.97, 133.84, 141.27, 151.50; IR (KBr) 2980, 2239, 1706, 1666, 1364, 1156, 762 cm-1; HRMS (EI) Calcd for C12H14N403 ([M+Na]+) 285.0958. Found 285.0958.
Povzetek
Opisana je reakcija 4-amidopiridin N-oksida z dimetilkarbamoil kloridom in kalijevim cianidom v acetonitrilu pri 120 °C, ki je vodila do ustreznega 2-ciano-4-amidopiridina z dobrim iskoristkom.