Pyridines and pyridinium salts from cyanoacetamides

Aust. J. Chem., 1976, 29, 1039-50

Pyridines and Pyridinium Salts from Cyanoacetamides*

Ailsa L. Cossey, Roger L. N. Hams, John L. Huppatz and John N. Phillips

Division of Plant Industry, CSIRO, P.O. Box 1600, Canberra City, A.C.T. 2601.

Abstract

Self-condensation of cyanoacetamides under the influence of phosphorus oxychloride leads to pyridines and pyridinium salts in high yield. The mechanism of the reaction is discussed and evidence for the structure of the products is described. The chemical activity of the new pyridine derivatives has been briefly explored.

During a general investigation of the synthetic utility of amide-acid chloride adducts, we examined the reaction of cyano-N,N-dialkylacetamides and cyano- N-alkylacetamides with phosphorus oxy~hloride. '~~

When, for example, cyano-N,N-dimethylacetamide and phosphorus oxychloride were heated together at 100°, a pale yellow crystalline solid, m.p. 108-109", was isolated in high yield. Analytical, chemical, and spectral data were consistent with the pyridine structure (I),' which followed from a consideration of its mode of formation by self-condensation of two moles of the cyanoacetamide.

NHMe

Extension of this reaction to cyano-N-alkylacetamides resulted in a different type of product. When cyano-N-methylacetamide and phosphorus oxychloride were heated together in chloroform a yellow crystalline precipitate was formed. This material proved to be a water-soluble salt for which the pyridinium salt structure (2) was proposed.'

This self-condensation of cyanoacetamides under the influence of phosphorus oxychloride is a general reaction of considerable versatility. A number of examples of

* A preliminary account of this work has been p u b l i ~ h e d ; ~ , ~ Part VI of 'Amide-Acid Chloride Adducts' (Part V, Aust. J. Chem., 1974, 27, 2635).

Cossey A. L., Harris, R. L. N., Huppatz, J. L., and Phillips, J. N., Angew. Chem., 1972, 84, 1183 (Angew. Chem., Znt. Ed. Engl., 1972, 11, 1098).

Cossey, A. L., Harris, R. L. N., Huppatz, J. L., and Phillips, J. N., Angew. Chem., 1972, 84, 1184 (Angew. Chem., Int. Ed. Engl., 1972, 11, 1099).

A. L. Cossey, R. L. N. Harris, J. L. Huppatz and J. N. Phillips

pyridine derivatives, which can conveniently be prepared in high yield by this reaction, are given in the Experimental section.

The Reaction Mechanism

The mechanism (Scheme 1) postulated for the reactions described above involves the condensation of an initially formed amide-acid chloride adduct (4) with its conjugate base (5) to give the key intermediate (6).

RR'S OPOCI, R'HS 0POCi2

H2 C when

I I /

/ ~ ~ o P o c ~ , a .NRR H+ R'

- + ' ci -

/ for the nature of R and R' see Tzbies 1 and 2 /

Scheme 1

The acid-promoted cyclization of this intermediate may occur by incorporation into a ring of the terminal nitrile nitrogen [(6a) 4 (7)] leading to pyridines, or, in the case of the monoalkyl compounds only, by incorporation of the terminal imidate nitrogen [(6b) -t (8)] leading to pyridinium salts.

In the early examples studied, pyridinium salts were obtained exclusively from monoalkyl cyanoacetamides and so it was concluded that the latter route [(6b) -+ (811 was favoured when both reaction courses were permitted. Further studies have now shown that when cyano-N-(s-alky1)acetamides are treated with phosphorus

Pyridines and Pyridinium Salts from Cyanoacetamides

oxychloride, pyridinium salts (8; R' = s-alkyl) are formed as the major product, but significant amounts of bis(s-alky1amino)pyridines (7; R = H, R' = s-alkyl) are also formed.

For example, when cyano-N-isopropylacetamide was treated with phosphorus oxychloride in chloroform, the expected pyridinium salt (8; R' = Pri) was obtained in 39 % yield. A second product, isolated in 31 % yield after chromatography of the remainder of the reaction mixture, was shown by microanalysis and high-resolution mass spectrometry to have the molecular formula C,,H,,ClN,. The n.m.r. spectrum indicated the presence of two dissimilar NHPri groups and a single aromatic proton and the infrared spectrum showed conjugated nitrile absorption, consistent with the pyridine (7; R = H, R' = Pri). Thus, it appeared that the reaction had followed both routes discussed above, giving significant amounts of both pyridine and pyridinium salt products.

Two alternative possibilities are apparent, however. A 1,3-alkyl shift in intermediate (6d) instead of prototropic rearrangement would give an isomeric di(isopropy1amino)- pyridine (9). The same product could also arise by a Dimroth type rearrangement of the intermediate (6d) or the pyridinium salt (8; R' = Pri).

These possibilities were eliminated by removal of the chlorine substituent from the pyridine by catalytic hydrogenation (cf.'). The n.m.r. spectrum of the product (10) indicated that the two aromatic protons were adjacent. It follows that the chlorine substituent was originally located next to the unsubstituted position of the pyridine nucleus, and the postulated structure (7; R = H, R' = Pri) is thus confirmed.

Mixtures of pyridinium salts and pyridines were also obtained from cyano-N- cyclopentyl- and cyano-N-cyclohexyl-acetamides. The isolation of both types of product in these reactions lends further support to the proposed mechanism.

Chemical Reactivity of the Pyridines The reactivity of position 5 in the pyridines (7) is not sufficient to permit bromination

in the absence of a catalyst, nor does nitration proceed readily. However, the 5-chloro derivative (11) of the pyridine (7; R = R' = Me) may be obtained from cyano- N,N-dimethylacetamide and phosphorus pentachloride in phosphorus oxychloride. Since the 5-chloro substituent cannot be introduced by treatment of the appropriate pyridine with phosphorus pentachloride under these conditions, chlorination must have occurred prior to pyridine formation. This is not unexpected since greater reactivity at this site can be predicted for the enamine intermediates and the ability of phosphorus pentachloride to act as a chlorinating agent is well documented.

Electrophilic substitution can be achieved in pyridines of the type (I ; R = R' = Me) by prior removal of the 6-chloro substituent. Thus, the bis(dimethy1amino)pyridine (12) readily undergoes nitration [+ (13)] and bromination [+ (14)], substitution taking place at position 5.

With a bulky substituent (e.g. Br) in position 5, it becomes possible to displace the dialkylamino substituent in position 4 with a chloro group [+ (15)] by heating


with phosphorus oxychloride in an open flask, a reaction not observed in the 5- unsubstituted pyridines. The driving force for this reaction is obscure; however, steric crowding of position 4 may force the dialkylamino group out of coplanarity with the pyridine ring and facilitate its displacement by a chloro group at this position. Removal of both halogens from (15) was achieved by catalytic hydrogenation giving the disubstituted pyridine (16).

The chloro substituent in (7; R = R' = Me) proved amenable to displacement under vigorous conditions by suitable nucleophiles. For example, reaction with boiling 2-aminoethanol gave the triaminopyridine (17), which was cyclized by polyphosphoric acid to the dihydroimidazolopyridine (18). The formation of the latter confirms the assignment of the chloro substituent in (7; R = R' = Me) to a position adjacent to the ring nitrogen.

YMe a YMe

(7; R = R' = ~ e )

/ -& HN NMez

NMe, NMe,

'-OH 67)

NMe ,

(15) (16) Scheme 2 Attempts to hydrolyse the nitrile group in (7; R = R' = Me) by heating in

90% H,SO, at 85-95" for 2 h resulted in its complete removal with concomitant displacement of the chloro substituent to give the pyridine (19). The corresponding


nitrile (2) was isolated as a minor by-product. Surprisingly, the nitrile group in (12) was not hydrolysed or removed under these conditions.

The spectral properties of the reaction products described above offer unequivocal proof of the substituent orientation in the pyridines. In the n.m.r. spectrum of the dehalogenated product (12) the two aromatic protons are ortho coupled ( J 6 Hz) implying that the chloro and hydrogen substituents in (7; R = R' = Me) occupy positions cc and ,8 to the ring nitrogen respectively. In the n.m.r. spectrum of the hydrolysis product (17) the two aromatic protons are meta coupled ( J 1.9 Hz); thus the nitrile group in (7; R = R' = Me) must have occupied the P' position with respect to the ring nitrogen, f@nked by the two dimethylamino substituents. In all the pyridine derivatives the high-resolution mass spectra show an M-CH,N peak, characteristic of 2-(N,N-dimethy1amin0)pyridines.~ The substitution patterns in Scheme 2 alone are consistent with this data.

Reactivity of the Pyridinium Salts The pyridinium salts (8) showed greater versatility in their reactions than did the

pyridines (7). Electrophilic substitution with bromine occurred readily in aqueous or methanolic

solution to give 5-bromo derivatives [e.g. (21)]. The chloro group at position 6 proved particularly labile and facile replacement with a variety of oxygen, sulphur, nitrogen and carbon nucleophiles led to a wide range of products [Scheme 3, in which the reactions of the pyridinium salt (8; R' = Me) are exemplary]. Thus,

YHMe YHMe

(25) X = NCX

\ (26) X = NTs (27) X = C(C&

NHMe

I I Scheme 3 Me (29) Me (30)

hydrolysis with water-triethylamine gave the pyridine (22) and aqueous sodium sulphide gave the corresponding pyridine thione (23). Reaction with both basic and acidic N-nucleophiles took place with comparable ease and amines, cyanamides and sulphonamides all gave 2-imino-l,2-dihydropyridine derivatives [(24), (25) and

Whittle, C. P., Tetrahedron Lett., 1968, 3698.


(26) respectively]. Malonodinitrile reacted under mild base catalysis to give 2-dicyano- methylene-l,2-dihydropyridines [e.g. (27)l.

These reactions help to establish the relative positions of substituents in the pyridinium salts (8). The chloro substituent must be either ortho or para to the ring nitrogen in order for the numerous substitution products to exist as dihydropyridone tautomers or derivatives thereof. That the chloro and cyano substituents are adjacent is clearly demonstrated by the formation of thieno[2,3-blpyridines [e.g. (28)] and pyrazolo[3,4-blpyridines [e.g. (29)] on reaction of the pyridinium salts with methyl thioglycollate and hydrazine hydrate respectively. Replacement of the chloro substituent by hydrogen with Raney nickel catalyst gave products [e.g. (30)] in which the two aromatic protons were not adjacent. The substituent configuration given in structure (8) is fully consistent with all the above observations.

The N-methyl and N-ethyl pyridinium salts in the series were thermally stable. However, high homologues tended to lose their ring N-substituent readily on heating in a suitable high-boiling solvent. This dealkylation reaction was generally most facile with N-s-alkyl-substituted pyridinium salts.

For example, the N-cyclohexyl compound (8; R' = C6H,,) gave the pyridine (31; R' = C6Hll) on heating briefly in boiling o-dichlorobenzene. N-s-Alkyl- pyridinium salts bearing a 5-bromo substituent were even more readily dealkylated, possibly due to the lower basicity of the pyridine ring. Thus, (32; R' = C6HIl) was converted into the pyridine (33; R' = C,Hll) merely on recrystallization from ethanol (Scheme 4).

NH R'

Scheme 4

The convenient transformation of the pyridinium salts (8) into the tetrasubstituted pyridines (31) provides a new series of pyridines of quite different substituent pattern to the original group (7) and further enhances the versatility of the cyanoacetamide- phosphorus oxychloride reaction.

Experimental Analyses were performed by the Australian Microanalytical Service, Melbourne. Infrared

spectra were determined with a Perkin-Elmer 457 spectrophotometer and the n.m.r. spectra were obtained on a Varian A60 spectrometer, Kieselgel 0.05-92 mm (E. Merck) was used for column chromatography,


(a) The Cyanoacetamides (3)

The cyano-N,N-dialkylacetamides were prepared from ethyl cyanoacetate and the appropriate secondary amine by literature methods4-' (see Table 1 below), except in the case of cyano-N,N- diethylacetamide (3 ; R = R' = Et). This compound had been prepared previously by allowing 2-chloro- N,N-diethylacetamide and sodium cyanide to react in dimethyl sulphoxide? It is more conveniently prepared as follows. Ethyl cyanoacetate (33.9 g) and diethylamine (29.2 g) were heated together in a steel pressure bomb (capacity 500 ml) at 180-200' for 4 h. After cooling, the crude product was distilled under vacuum and cyano-N,N-diethylacetamide (3; R = R' = Et) was obtained (72% yield) as a colourless oil, b.p. 112-115°/005 mm (lit? 115"/0.1 mm).

The cyano-N-alkylacetamides were prepared by the following general procedure. Ethyl cyanoacetate (0.5 moll and the appropriate primary amine (0.6 mol) were dissolved in ether (200ml). The mixture was allowed to stand at room temperature 1-2 days and the precipitated product was collected by filtration and washed with cold ether. Yields were 85-95 %. The following cyano-N- alkylacetamides had not been recorded previously: cyano-N-hexylacetamide (3; R = H, R' = n-C6H13), m.p. 74-75' (Found: C, 64.1 ; H, 9.6; N, 16.2. C9H16N20 requires C, 64.2; H, 9.6; N, 16.6 %). Cyano-N-octylaretamide (3 ; R = H, R' = C8H1 ,), m.p. 67-69" (Found : C, 67.1; H, 10.1; N , 14.0. CllHzoNzO requires C , 67.3; H, 10.3; N , 14.3%). Cyano-N- isopropylacetamide (3; R = H, R' = Pr'), m.p. 73-74' (Found: C, 57.1 ; H, 7.9; N 22.0. C6Hl0N20 requires C, 57.1; H, 8.0; N, 22.2%).

(b) The Pyridines (7)

The following procedure is typical. Cyano-N,N-dimethylacetamide (11.2 g, 0.1 mol) and phosphorus oxychloride (33.7 g, 0.22 mol)

were heated together on a steam bath under a reflux condenser protected from moisture for 2 h. The orange viscous reaction mixture was cooled, cautiously poured into ice-water and neutralized with sodium hydroxide solution. The crude product was collected, washed with cold water and crystallized from aqueous ethanol.

6-Chloro-2,4-bis(N,N-dimethylamino)pyride-3-cabonitrile (9.4 g, 84 %) (7; R = R' = Me) was obtained as pale yellow needles, m.p. 108-109°. P.m.r. (CDC13) 6 3.13 (s, 6H, NMeJ, 3.18 (s, 6H, NMe,), 6.00 (s, lH, aromatic). The mass spectrum showed the parent ion at mle 224 (C1 = 35). The i.r, spectrum showed sharp absorption at 2180 cm-' in the nitrile region.

Table 1. Pyridines (7) from cyano-N,N-dialkylacetamides (3)

Lit. ref. Pyridine (7) Yield M.p. Found (%) Calc. (%) to (3) R R' ( %) CC) C H N C H N

5 Me Me 84 108-109 53.8 5-6 24.6 53.5 5.8 24.9 4 Et Et 76 oil 59.7 7.5 19.8 59.9 7.5 20.0 7 Me Ph 76 115-116 68.8 4.9 15.9 68.9 4.9 16.1 5 -(CHz)4- 86 129-131 60.5 6.0 20.2 60.7 6.2 20.2 5,6 -(CHAO(CHz)z- 81 127-128 54.2 5.8 18.0 54.4 5.5 18.1

Compounds prepared by the above procedure are listed in Table 1. In the case of (7; R = R' = Et), the product was extracted into chloroform, and purified by chromatography through a short column of silica gel. An analytical sample was prepared by short-path distillation under high vacuum.

Schwarz, M., Bodenstein, 0. F., and Fales, J. H., J. Econ. Entomol., 1971, 64, 576. Osdene, T. S., Santilli, A. A., McCardle, L. E., and Rosenthale, M. E., J. Med. Chem., 1967, 10,

1965. Whitehead, C. W., and Traverso, J. J., J. Am. Chem. Soc., 1955,77, 5867. 'Beilsteins Handbuch der Qrganischen Chemie' 4th Edn, Vol, 12, p. 294 (Springer: Berlin 19291,


(c) The Pyridinium Salts (8)

(A) The following procedure is typical. Cyano-N-methylacetamide (9.8 g, 0.1 mol) was dissolved in chloroform (50 ml) and phosphorus

oxychloride (15.3 g, 0.1 mol) added. The reaction mixture was warmed on a steam bath under reflux for 2 h, during which time the product crystallized. It was collected and recrystallized from methanol. 6-Amino-2-chloro-3-cyano-l-methyl-4-methylaminopyridinium chloride (9.4 g, 80 %) (8 ; R' = Me) was obtained as a pale yellow solid, m.p. > 250'. F.m.r. [(CD&SO] 6 2.87 (d collapsing to s on deuteration, 3H, NHMe), 3.73 (s, 3H, NMe), 6.00 (s, lH, aromatic). Broad variable absorption in the region 6 4.0-7.0 indicated the presence of other exchangeable protons. The i.r. spectrum showed absorption at 2220 (nitrile) and 1620 cm-' (C=N). The mass spectrum showed a molecular ion for the free base at mle 196 (C1 = 35).

In cases where R' was higher alkyl, the pyridinium salts were soluble in chloroform and were isolated as follows. On completion of the reaction period, the chloroform was removed under vacuum and the residue cautiously treated with methanol. The pyridinium salts crystallized, were collected, washed with cold methanol and air-dried. Analytical samples were prepared by crystallization from methanol or ethanol.

Compounds prepared by the above method are listed in Table 2?,9

Table 2. Pyridinium salts (8) and pyridines (7; R = H) from cyano-N-alkylacetamides (3; R = H) R = H for all compounds; yields in %; melting points in "C

C P ~ (3) Salt (8) Pyridine (7) Found (%) Calc. (%) Ref. R' Yield M.p. Yield M.p. C H N C H N

(B) Reactions involving cyano-N-s-alkylacetamides and phosphorus oxychloride also yielded pyridines (7; R = H, R' = s-alkyl). These compounds were isolated after the recovery of the pyridinium salts by treatment with methanol as described above. The methanol mother liquors were diluted with water, neutralized with sodium hydroxide solution and extracted with chloroform. The chloroform extracts were washed with water, dried and chromatographed on a silica gel column with chloroform as eluent. The first fractions yielded the pyridine, which solidified on removal of the solvent and was crystallized from ethanol. Examples of compounds prepared in this way are also given in Table 2.

(d) Reactions of the Pyridines (7)

(i) Catalytic hydrogenation.-6-Chloro-2,4-bis(dimethylamino)pyridine-3-carbonitrile (7; R = R' = Me) (9 g) was dissolved in ethanol (LOO ml) containing sodium acetate (3.5 g) and hydrogenated at room temperature and pressure using 5% Pd-C catalyst. When hydrogen uptake ceased, the catalyst was removed by filtration and the solvent removed under vacuum. The oily residue was taken up in chloroform and the chloroform solution washed with water and dried. The product was purified by chromatography on a short silica gel column using chloroform-light petroleum (b.p. 40-60") (1 : 1) as eluent. It was obtained as a colourless oil which subsequently solidified.

Nark, K. G., and Bhat, Y. N., Q. 3. Indian Chem. Soc., 1927,4, 547 (Chem. Abstr., 1928,22, 2353). Nark, K. G., and Shah, L. D., J. Indian Chem. Soc., 1931, 8, 29 (Chem. Abstr., 1931, 25, 3619).


Crystallization from aqueous ethanol gave 2,4-bis(dimethy1amino)pyridine-3-carbonitrile (12) (6.1 g, 80%) as cream-coloured needles, m.p. 57-58" (Found: C, 63.1 ; H, 7.3 ; N, 29.1. CloH14N4 requires C, 63.1 ; H, 7.4; N, 29.45 %). P.m.r. (CDCI,) 6 3.10 (s, 6H, NMeJ, 3.15 (s, 6H, NMe2), 6.0 and 7.82 (ABq, J 6 , 2H, aromatic).

Similarly, hydrogenation of 6-chloro-2,4-di(isopropylamino)pyridine-3-carbonitrie (7; R = H, R' = Pri) gave 2,4-di(isopropy1amino)pyridine-3-carbonitrile (lo), which was obtained as a pale yellow oil (75%) after purification by bulb distillation (Found: C, 68.1; H, 9.0; N, 22.6. Cl4HZ2N4 requires C, 68.3 ; H, 9.0; N, 22.7 %). P.m.r. (CDCI3) 6 1.2 (s, 6H, CHMe,), 1 .3 (s, 6H, CHMe,), 3.75 (m, lH, CHMe2), 4.35 (m, lH, CHMe,), 4.65 (broad, exchangeable, 2H, NH), 5.9 and 7.9 (ABq, J 6, 2H, aromatic).

(ii) Chemical reduction.-6-Chloro-2,4-bis(dimethylamino)pyridine-3-carbonitrile (3 g) and zinc dust (3 g) were heated under reflux in glacial acetic acid (40 ml) for 5 h. The solution was decanted from residual zinc, poured into water (100 ml) and rendered strongly alkaline with 40% sodium hydroxide solution. The mixture was extracted with ether and the ether extracts washed with water, dried and evaporated. The oily residue solidified and recrystallization from aqueous ethanol gave 3-cyano-2,4-bis(dimethy1amino)pyridine (2.4 g, 96 %) identified with the product obtained in (i) above.

(iii) Bromination.-2,4-Bis(dimethylamino)pyridine-3-carbonitrie (12) (4.5 g) in glacial acetic acid (50 ml) was treated with a solution of bromine in glacial acetic acid (16 ml of 25 % w/v solution) and the mixture allowed to stand at room temperature overnight. Water was added and an oil precipitated and slowly solidified. The solid product was then collected and crystallized from aqueous ethanol. 5-Bromo-2,4-bis(dimethylamino)pyridine-3-carbonitrile (14) (4.8 g, 75 %) was obtained as pale yellow plates, m.p. 75-76" (Found: C, 4 4 4 ; H, 4.9; N, 20.6. CIOHl1BrN4 requires C, 4 4 6 ; H, 4.9; N, 20.8%).

6-Chloro-2,4-bis(dimethylamino)pyridine-3-carbonitrile (7; R = R' = Me) failed to undergo bromination under the above conditions.

(iv) Nitration.-2,4-Bis(dimethylamino)pyridine-3-carbonitrile (12) (4.4 g) was dissolved in conc. sulphuric acid (20 ml) and conc. nitric acid (sp. gr. 1.4) (2 g) was added dropwise with stirring so that the temperature of the mixture did not exceed 20". After 3 h at room temperature the mixture was poured onto ice, brought to pH 5 with sodium hydroxide solution and the product collected. After crystallization from ethanol, 2,4-bis(dimethylamino)-5-nitropyridine-3-carbonitrile (13) (1.4 g, 52%) was obtained as bright yellow needles, m.p. 156-158' (Found: C, 51.1; H, 5.5; N, 29.5. C10H13N502 requires C, 51.1 ; H, 5.6; N, 29.8%).

(v) Displacement of the dimethylamino group.-5-Bromo-2,4-bis(dimethy1amino)pyridine-3- carbonitrile (1.35 g) and phosphorus oxychloride (5 g) were heated together on a steam bath in an open flask for 18 h. The viscous mixture was treated with ice-water and then brought to pH 5 with sodium hydroxide solution. The product was extracted into chloroform and the extracts washed with water and dried. Evaporation of the chloroform gave a brown solid which was purified by chromatography through a short silica gel column with chloroform-light petroleum (b.p. 40-60") (1 : 1) as eluent. After crystallization from ethanol, 5-bromo-4-chloro-2-dimethylaminopyridine-3- carbonitrile (15) (0.9 g, 70 %) was obtained as colourless needles, m.p. 119-121" (Found: C, 36.8 ; H,2 .6 ; N, 16.1. C8H7BrClN3 requires C,36.9; H,2 .7 ; N, 16.1%). P.m.r. (CDCI,) 6 3.25 (s, 6H, NMe,), 8.15 (s, lH, aromatic).

The above reaction may also be carried out using concentrated hydrochloric acid instead of phosphorus oxychloride but the yield is significantly reduced (c. 40%).

The bromochloropyridine (15) was dehalogenated as follows: a mixture of the pyridine (2 g), sodium acetate (2 g) and 5% Pd/C catalyst (0.5 g) in ethanol (100 ml) was hydrogenated at room temp.12 atm until uptake of hydrogen ceased. The filtered solution was evaporated under vacuum, the product taken up in chloroform (50 ml), washed with water and dried by filtration. Removal of the solvent gave an oil (0.85 g, 78 %)which was purified by bulb distillation at 20 mm and identified as 2-dimethylaminopyridine-3-carbonituile (16) (Found: C , 65.0; H, 6.0; N, 28.7. CgH9N3 requires C, 65.3 ; H, 6.2; N, 28.6 %). The mass spectrum showed a molecular ion at mle 147 and the major fragmentation was loss of CH3N (M-29 peak at mle 118; metastable at m/e 94.7). The infrared spectrum showed two nitrile absorptions at 2210 (major) and 2250 cm-' (minor). P.m.r. (CDC13) 6 3.3 (s, 6H, NMe2), 6.6, 7.7, 8.27 (each q, lH, H5, H4, H6).

(vi) Displacement of the chloro substituent.-The pyridine (7; R = R' = Me) (6.7 g) was heated under reflux with 2-aminoethanol(20 ml) for 1 h. Water was added and the precipitate collected and


crystallized from acetonelight petroleum (b.p. 60-80") to give 2,4-bis(dimethy1amino)-6-(2'-hydroxy- ethy1amino)pyridine-3-carbonitrile (17) as colourless needles (5.5 g, 66%), m.p. 81-84" (Found: C, 57.9; H, 7.6; N, 27.9. C12H18N50 requires C, 58.0; H, 7.3; N, 28.2%).

The foregoing triaminopyridine (0.5 g) was intimately mixed with polyphosphoric acid (c. 10 g) and heated on a steam bath for 2 h. Water was added and the mixture brought to pH 8 with 10% NaOH and extracted with chloroform (3 x 20 ml). The washed, dried extract was evaporated, leaving a pale yellow oil (0.5 g) which crystallized on standing. Recrystallization from acetone-light petroleum (b.p. 60-80") gave 5,7-bis(dimethylamino)-2,3-dihydvoimidazo[1,2-a]pyridine-6-carb0nitrile (18) as pale yellow needles, m.p. 143", which rapidly hydrated on standing (hydrate, m.p. 87-89") (Found: C, 62.1 ; H, 7.3; N, 30.2. C12H,,N5 requires C 62.3; H, 7.4; N, 30.3 %). P.m.r. (CDCI,) S 2.85, 3.05 (s, each 6H, NMe,), 3.90 (s, 4H, CHZCH,), 5.25 (s, lH, H7).

(vii) Hydrolysis.-The pyridine (7; R = R' = Me) (2 g) was heated on a steam bath with 90% H2S04 (20 ml) for 2 h. Ice was added and the mixture brought to pH 5 with 50% NaOH. The solution was extracted with chloroform (3 x 50 ml), the combined chloroform extracts washed with 10% NaOH (2 x 10 ml), water (1 x 50 ml) and dried by filtration. A solid (1.2 g) was obtained on removal of the chloroform and on crystallization from benzene-light petroleum (b.p. 60-80") gave 4,6- bis(dimethy1amino)-2(IH)-pyridone (19) as buff prismatic needles, m.p. 236-238" (dec.) (Found: C, 59.9; H, 8 .3; N, 23.45. C9H15N30 requires C, 59.6; H, 8.3; N, 23.2%). P.m.r. (CDC13) 6 2.90 (d, 6H, NMe2), 2.95 (d, 6H. NMe,), 4.72, 5.02 (both d, lH, H 3, H 5 resp., meta coupled, J 1.9). There was no nitrile absorption in the infrared but strong absorptions at 1585 and 1625 cm-I were apparent (C=N and C=O resp.).

The alkaline washings above were brought to pH 5 by the addition of acetic acid and extracted with chloroform (2 x 20 ml). Workup of the extract as above gave a residue (0.2 g) which crystallized from acetone as slender colourless needles, m.p. 196-198" (dec.), identified as the compound 2,4-bis- ( d i m e t h y l a m i n o ) - 6 - 0 x 0 - 1 , 6 - d i h y d r o p y r i d i n (20) (Found : C, 57.9; H, 7.0. Cl0HI4N4O requires C, 58.2; H, 6.8 %). The infrared spectrum showed a nitrile absorption at 2185 cm-I and broad strong absorptions at 1585 and 1650 cm-I (C=N and C=O resp.). P.m.r. (CDCI,) 6 3 .0 (s, 6H, NMe,), 3 . 2 (s, 6H, NMe,), 5.1 (s, 1 H, H 3, exchangeable).

5,6-Dichloro-2,4-bis(dimethylamino)pjridine-3carbonitrile (I]).-Cyano-N,N-dimethylacetamide (3.4 g) was added in portions to a mixture of phosphorus pentachloride (6.3 g) in phosphorus oxychloride (9.2 g) and the mixture treated as described in (b) above. The crude product (3.0 g, red oil) was chromatographed on a silica gel column (30 by 40 cm) with chloroform-light petroleum (b.p. 40-60") (1 : 1) as eluent. 5,6-Dichloro-2,4-bis(dimethylamino)pyridine-3-carbonitrile (1.2 g, 31 %) was obtained in the first fractions. It was crystallized from aqueous ethanol and had m.p. 98-99" (Found: C, 46.2; H, 4.6; N, 21.4. CloH12C12N4 requires C, 4 6 3 ; H, 4.7; N, 21.6 %). Subsequent fractions contained 6-chloro-2,4-bis(dimethylamino)pyridine-3-carbonitrile (1.3 g, 38 %), which was crystallized from aqueous ethanol and had m.p. 107-109", alone or when mixed with a sample obtained as in (b) above.

The pyridine (7; R = R' = Me) was recovered unchanged when treated with PC15 in POCl, as described above.

(e) Reactions of the Pyridinium Salts (8)

(i) Bromination.-6-Amino-2-chloro-3-cyano-l-methyl-4-methylaminopyridinium chloride (8; R' = Me) (0.01 mol) was dissolved in water (50 ml) and bromine (0.012 mol) added to the rapidly stirred solution which was then warmed 30 min on a water bath. On cooling, 6-arnino-5-bromo-2- chloro-3-cyano-I-methyl-4-methylaminopyridini bromide (21) had crystallized (75 % yield). The product was isolated and crystallized from ethanol, m.p. 228-229" (dec.) (Found: C, 27.1 ; H, 2.5; Br, 45.1; N, 16.0. C8H9Br2ClN4 requires C, 26.9; H, 2.5; Br, 4 4 8 ; N, 15.7%).

(ii) Reaction with water.-The pyridinium salt (8; R' = Me) (0.01 mol) was dissolved in hot water, triethylamine (0.04 mol) added and the solution warmed until homogeneous. 6-Amino-l- methyl-4-methylamino-2-oxo-1,2-dihydropyridine-3-carbonitrile (22) precipitated on cooling (75% yield). The material was isolated by filtration and dried, m.p. 1230" (Found: C, 53.9; H, 5.7; N, 31.5. C8HloN40 requires C, 53.9; H, 5.7; N, 31.4%).

(iii) Reaction with sodium su1phide.-The pyridinium salt (8 ; R' = Me) (0.01 mol) was dissolved in water and sodium sulphide (0.03 mol) added. 6-Amino-I-methyl-4-methylamino-2-thioxo-1,2- dihydropyridine-3-carbonitrile (23) precipitated immediately and was filtered and dried (90 % yield). It


has m.p. >230° (Found: C, 49.5; H, 5.3; N, 28.4. C8Hl0N4S requires C, 49.4; H, 5.3; N, 28.8%). (iv) Reaction with amines.-The pyridinium salt (8; R' = Me) (2.3 g) was suspended in methanol

(50 ml) and triethylamine (1 .5 ml) and benzylamine (1 .3 ml) added. The mixture was warmed until homogeneous and set aside. After some time, 6-amino-2-benzylamino-3-cyano-1-methyl-4- methylaminopyridinium chloride (24,HCl) crystallized as pale yellow needles (2.2 g, 73 %). The compound was firmly hydrated and lost water at 155", finally melting at 249-250" with decomposition (Found: C,56.4; H,5 .9 ; N,21.65. C15H17C1N5,HZ0 requires C,56.2; H,6 ,0 ; N,21.8%). The free base was obtained by neutralizing a solution of the salt in water with 10% NaOH and crystallized from aqueous ethanol as colourless plates, m.p. 149-150" (dec.) after losing water at 95-100" (Found: C, 63.3; H, 6.85; N, 24.6. Cl5Hl7N5,HZO requires C, 63.1 ; H, 6.7; N, 24.6 %). P.m.r. [(CD,),SO] 6 2.75 (d, 3H, J 5, NHMe), 3.39 (s, 5H, 2H exchangeable, NMe and H,O), 4.78 (s, 2H, NCH,Ph), 4.82 (s, lH, H5), 5.90 (broad, exchangeable, lH, NHMe), 6.81 (s, 2H exchangeable, NHZ), 7.1-7.5 (m, 5H, C6H5). The doublet at 2.75 collapsed to a singlet on deuteration.

(v) Reaction with cyanamide.-The pyridinium salt (8; R' = Me) (0.01 mol) was treated with cyanamide (0.011 mol) and triethylamine (0.01 mol) and thereaction was carried out as in (iv) above. 6-Amino-2-cyanoimino-I-methyl-4-methylaminopyridine-3-carbonitrile (25) was obtained in 82% yield, m.p. >230° (Found: C, 53.4; H, 5.0; N, 41.9. C9HloN, requires C, 53.4; H, 5.0; N, 41.6%).

(vi) Reaction with sulphonamides.-The pyridinium salt (8; R' = Me) (0.01 mol) reacted with p-toluenesulphonamide (0.011 mol) as described in (iv) above. 6-Amino-1-methyl-4-methylamino- 2-(4'-toluenesulphonylimino)pyridine-3-carbonitrile (26) was obtained in 72% yield, m.p. >230° (Found: C, 54.2; H, 5.5; N, 21.4. C15H17N502S requires C, 54.4; H, 5.2; N, 21.1%).

(vii) Reaction with malononitrile.-The pyridinium salt (8; R' = Me) (0.01 rnl) was dissolved in water and malononitrile (0.66 g, 0.01 mol) and triethylamine (2.0 g, 0.02 mol) added. After a few minutes, 6'-amino-3'-cyano-l'-methyl-4'-methylamino-l',2'-dihydvopyridin-2'-ylidenemalonodi- nitrile (27) crystallized (1.7 g, 75 %), m.p. > 240" (Found: C, 58.2; H, 4.4; N, 36.9. Cl1Hl0N6 requires C, 58.4; H, 4.5; N, 37.2%).

(viii) Reaction with methyl thioglycol1ate.-The pyridinium salt (8; R' = Me) (0.5 g) was added to a solution of sodium (0.12 g) in methanol (50 ml) containing methyl thioglycollate (0.25 ml). The mixture was refluxed for 2 h, the methanol removed under vacuum and the residue treated with water. The yellow-brown product (0.5 g) was collected, washed with water and oven-dried. Recrystallization from a large volume of methanol gave methyl 3,6-diamino-7-methyl-4-methyl- iminothieno[2,3-blpyridine-2-carboxylate (28) as yellow-green microprisms, m.p. 260-261' (dec.) (rapid heating) (Found: C, 49.5; H, 5.7; N, 21.0. Cl1Hl4N4O2S requires C 49.6; H, 5.3; N,21.0%). P.m.r.[(CD3)2S0]62.8(s,3H,NMe),3~35(s,3H,NMe),4~7(s,3H,OMe),5~25 (s, IH, H4), 5.6-7.2 (broad exchangeable, 4H, NH).

(ix) Reaction with hydrazine.-The pyridinium salt (8; R' = Me) (0.01 mol) reacted with hydrazine hydrate (0.011 mol) in methanol (50 ml) at room temperature. The product, 3,6-diamino- 7-methyl-4-methylaminopyvazolo[3,4-b]pyridinium chlovide (29,HCl) crystallized with one mole of water of crystallization (72% yield), m.p. > 230' (Found: C, 38.7; H, 6.0; C1, 14.4; N, 34.1. C8HI,ClN6,H,0 requires C, 38.9; H, 6.1 ; C1,14.4; N, 34.1 %).

(x) Catalytic hydrogenation.-The pyridinium salt (8; R' = Me) (0.01 mol) was dissolved in methanol containing anhydrous sodium acetate (0.025 mol) and Raney nickel catalyst (c. 2 g) was added. The mixture was hydrogenated at room temperature and 2 atm pressure until hydrogen uptake ceased. The catalyst was removed by filtration and the product isolated as its hydrochloride. 6-Amino-3-aminomethyl-l-methyl-4-methylaminopyvidinium chlovide hydrochloride (30) (87% yield), m.p. >230°, was purified by crystallization from methanol (Found: C, 40.1; H, 6.7; C1,29.5; N, 23.0. C8H16ClZN4 requires C, 40.2; H, 6.7; C1,29.7; N, 23.4%).

(xi) Dealky1ation.-(A) The pyridinium salt (8; R' = C6H11) (0.01 mol) was suspended in o-dichlorobenzene (25 ml) and the mixture boiled under reflux for 15 min. Most of the solvent was then removed by distillation and, after cooling, the residue was treated with light petroleum (b.p. 40-60"). The precipitated product was collected by filtration, washed with light petroleum and crystallized from aqueous ethanol. 6-Amino-2-chloro-4-cyclohexylaminopyvidine-3-carbonitvile (31; R' = CsHll) was obtained as pale yellow plates, m.p. 168-169' (yield 84%) (Found: C 57.4; H, 6.1; N, 22.6. CI2Hl5C1N4 requires C, 5 7 5 ; H, 6.0; N, 22.4%).

(B) The pyridinium salt (8; R' = C6Hll) was brominated as described in (i) above.

1050 A. L. Cossey, R. L. N. Harris, 3. L. Huppatz and J. N. Phillips

The pyridinium salt (32; R' = C6H11) was collected and the crude material (yield 79%) had m.p. > 230". When purification by crystallization was attempted, the pyridinium salt dealkylated and 6-amino-5-bromo-2-chloro-4-cyclohexylaminopyridine-3-cabonitrile (33; R' = CsHll) crystallized as pale yellow plates, m.p. 155-157" (Found: C, 44.0; H, 4.2; Br, 24.2; N, 16.9. C12H14BrC1N4 requires C, 43.7; H, 4.3; Br, 24.2; N, 17.0%).

Acknowledgments

The authors wish to thank Miss Catherine Foster and Mrs Doris Gudel for valuable technical assistance.

Manuscript received 30 January 1976

Documents

Pyridines and pyridinium salts from cyanoacetamides