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Unusual ring transformation of 2-halogeno-N-phenacylpyridinium salts in reaction with secondary amines: a facile `one-pot' route to 1-amino-4-(oxazol-2-yl)butadienes
Eugene V. Babaev * and Alexander A. Tsisevich Chemistry Department, Moscow State University, 119899, Moscow, Russia Received (in Cambridge, UK) 14th December 1998, Accepted 14th December 1998

2-Halogeno-N-phenacylpyridinium salts 1 (Hal = Cl, Ar = p-NO2Ph; Hal = Br, Ar = Ph) in reaction with aliphatic secondary amines undergo an unusual ring transformation to 1-amino-4-(5-aryloxazol-2-yl)buta-1,3-dienes 9 and 10. The configuration of the products (1E,3E or 1E,3Z ) depends on the reaction temperature. A suggested mechanism for the transformation involves intermediate formation of 2-aryloxazolo[3,2-a]pyridinium salt 4.

Introduction
N-(Acylmethyl)-2-halogenopyridinium salts 1 are versatile intermediates useful in heterocyclic synthesis. The highly reactive halogen atom at the -position of the pyridinium ring can be easily substituted by an appropriate nucleophile, and further cyclocondensation involving the acylmethyl (e.g. phenacyl) group and the inserted nucleophile may lead to bicyclic heterocycles with a bridgehead nitrogen atom (Scheme 1).

in quite different manners, no attention has been paid to their reaction with secondary amines.

Results
We found that in reactions with secondary amines, 2-chloro-N( p-nitrophenacyl)pyridinium bromide 8 undergoes an unusual ring transformation to 1-amino-4-(oxazol-2-yl)buta-1,3-dienes 9a­e and 10a­e (Scheme 2).

Scheme 1

Thus, reactions of salts 1 with NaOH 1 and NaSH 2 lead to the intermediate N-(acylmethyl)-2-pyridones 2 and thiones 3 which may be further cyclized in acidic media to the oxazolo[3,2-a]pyridinium salts 4 3 or their sulfur analogs 5,2,4 respectively. One-pot cyclizations to imidazo[1,2-a]pyridinium salts 6 (X = NAlk, NAr, NNHAc) and N-oxides (X = NO ) were observed in the reactions of salts 1 with primary amines, acetylhydrazine and hydroxylamine.5­7 Similar cyclizations of the salts 1 leading to other families of condensed heterocycles with a-fused pyridine rings (indolizines, pyrido[2,1-c][1,2,4]triazines, pyrido[1,2-a :1 ,2 -c]imidazoles) were reported.1,5,8­10 Quite another reactivity pattern of the salts 1 is displayed in their reaction with sterically hindered tertiary amines. In these cases, the action of a base caused deprotonation of the methylene group leading to ylides 7 which, like many other pyridinium ylides, may be involved in 1,3-dipolar cycloaddition reactions.11 The intermediate enol betaines 7, however, were unstable and underwent thermal intramolecular closure of the oxazole ring leading to the cations 4.1,5 Although the salts 1 react with primary and tertiary amines

Scheme 2

The reaction between salt 8 and aliphatic secondary amines proceeds smoothly in high yield in refluxing acetonitrile, leading to deep purple compounds insoluble in water. According to the mass spectra and elemental analysis data (Table 1), the constitution of the products corresponds to the addition of a secondary amine molecule to the initial salt 8 with simultaneous elimination of HCl and HBr from such adducts. In the 1H NMR spectra of the products only the signals of NR2 groups are observed in the aliphatic region. The multiplets in the aromatic region are typical for 4-substituted 1-azolylbuta-1,3dienes,12­14 and the singlet of the oxazole ring proton appears at J. Chem. Soc., Perkin Trans. 1, 1999, 399­401 399


Table 1

Characteristics of aminooxazolylbutadienes 9 and 10 Found (%) (required) Compound (Formula) 9a, 9b, 9c, 9d, 9e 10e 10a 10b 10c 10d (C17H17N3O3) (C19H21N3O3) (C18H20N4O3) (C17H17N3O4) Yield (%) 85 93 95 95 97 83 Mp/ C (decomp.) 171­173 131­133 203­205 204­206 179­181 156­158 C 65.1 67.1 63.3 62.0
a b

H (65.6) (67.3) (63.5) (62.4) 5.0 6.5 5.7 5.2 (5.5) (6.2) (5.9) (5.2)

m/z (%) 311 339 340 327 (M (M (M (M , , , , 30), 52), 49), 32), 241 241 241 241 (100), (100), (100), (100), 195 195 195 195 (47) (26) (21) (35)

a

Lit., 179­180 C. Lit., 160­161 C.
1

14

b

14

Table 2

H NMR spectra of 1E,3E-butadienes 9 (400 MHz, CDCl3, Me4Si)
H

Molecule 9a 9b 9c 9d 9e
a

1-H 6.90 6.71 6.55 6.54 6.59

2-H 5.18 5.23 5.36 5.39 5.34

3-H 7.30 7.31 7.27 7.26 7.30

4-H 5.94 5.94 6.01 6.04 5.98

H

oxazole

Ar 7.71, 7.71, 7.71, 7.72, 7.72, 8.24 8.24 8.24 8.24 8.24

NR

2

J1,2, J2,3, J3,4/Hz 3.30 1.74, 3.30 2.45, 3.21 3.75 3.15 12.1, 12.4, 12.2, 12.2, 12.2, 11.3, 11.6, 11.0, 11.0, 11.6, 15.6 15.0 16.2 15.6 15.1

a

7.48 7.48 7.48 7.49 7.49

1.96, 1.59, 2.32, 3.17, 1.60,

Ref. 14.
1

Table 3

H NMR spectra of 1E,3Z-butadienes 10
H

a

Molecule 10a 10b 10c 10d 10e
a c

1-H, 2-H, 3-H 6.30, 6.94, 6.53 6.41, 6.74, 6.52 6.58­6.60 6.55­6.65 6.53­6.58

4-H 5.63 5.62 5.69 5.74 5.64

H

oxazole

Ratio 9 : 10 5:1 6:1 7:1 9:1 5:1

b

c d

7.57 7.56 7.56 7.56 7.56

e, f

Signals of the groups p-NO2C6H4 and NR2 overlap with that for the 1E,3E isomers. b The ratio of isomers obtained by general method (3 h, 82 C). c Ref. 15. d Ref. 14. e The ratio 9e : 10e = 1 : 10 if reagents were kept for 1 h at 20 C. f The ratio was 1 : 2 if the mixture obtained initially was refluxed for a further 1 h at 82 C.

7.5 ppm. The intense bands in the UV spectra of the products (max = 455­465 nm) typical for conjugated dienes with intramolecular charge transfer, and the diene band ( = 1625 cm 1) in their IR spectra also confirm the structure of the 1-amino-4(oxazol-2-yl)butadienes. In the mass spectra the peak m/z 241 (loss of NR2 fragment) was the most intense one for all the products, and it may be associated with the probable closure of the pyridinium ring in the molecular ion. According to their 1H NMR spectra the butadienes are formed as mixtures of 1E,3E-(9) and 1E,3Z-isomers (10), with a clear predominance (85­90%) of the stereoisomers 9 in all cases. The chromatographic properties of the isomeric pairs were identical. The configuration of each isomer clearly follows from the coupling constants in the 1H NMR spectra and was additionally confirmed by NOESY measurements. Spectral characteristics of the products 9 and 10 are shown in Tables 2 and 3.

Scheme 3

Discussion
There are two possible mechanisms for the transformation of the pyridinium salt 8 to oxazoles 9 and 10. The first one, involving initial opening of the pyridinium ring followed by cyclization of the open chain to the oxazole ring, looks improbable. Much more probable is the alternative mechanism, which involves intermediate formation of the oxazolo[3,2-a]pyridinium cation 12 followed by further opening of the six-membered fragment (Scheme 3). 400 J. Chem. Soc., Perkin Trans. 1, 1999, 399­401

Both steps of such a mechanism have parallels in heterocyclic chemistry. At the first step, secondary amine acts as the base, converting the salt 8 to the enol betaine 11 followed by intramolecular ring closure to the stable aromatic cation 12. This step is completely parallel to the cyclization of salts 1 under the action of tertiary amines to cations 4 via intermediates 7.1,5 At the second step, the molecule of amine acts as the nucleophile, transforming the cation 12 to the ring opening products 9 and 10 via the adduct 13. This step also has direct experimental evidence: conversion of cations 4­6 to various 1-amino-4azolylbutadienes is well known.12­15 In our experiments we found that the reactions of morpholine with either salt 8 or 2-( p-nitrophenyl)oxazolo[3,2-a]pyridinium perchlorate 14 under the same conditions (82 C, MeCN, 3 h) lead to the same product.


A specific feature of the ring-opening reactions of various pyrrolopyridinium cations to azolylbutadienes is that the configuration of the dienes depends dramatically on the reaction temperature.12­15 One would expect an analogous influence of the temperature on the ratio of the products 9 : 10 formed from the salt 8 via oxazolopyridinium cation 12. Indeed, when the salt 8 was allowed to react with piperidine at room temperature, the ratio 9e : 10e was 1 : 10, whereas this ratio was changed to 5 : 1 in refluxing acetonitrile (see Table 3). Previously, only the 1E,3Z-isomer 10d had been obtained by the ring opening of the perchlorate 14 with morpholine at 20 C.15 We found that the complementary isomer 9d (almost free from 10d) may be obtained in refluxing acetonitrile by reaction of morpholine with either perchlorate 14 (90% yield) or the pyridinium salt 8 (yield 95%). Theoretical calculations confirmed that all-(E ) isomers 9 are more stable than the 1E,3Z-isomers 10. According to MNDO calculations 15 the difference in energy between isomers 9e and 10e is 5.7 kcal mol 1. We found that no isomerization of butadiene 10e to 9e was observed at room temperature (keeping in CH3CN for 3 days). However, such isomerization readily occurred in refluxing acetonitrile: after 1 h of heating the ratio 9e : 10e is changed from 1 : 10 to 1 : 2. Azolyldienes are widely used in heterocyclic synthesis.16,17 The specific practical importance of the discussed class of oxazolylbutadienes 9 and 10 is their recently-found antimicrobial activity 15 and also the possibility of their utilisation as non-linear optic materials. The discovered `one-pot' ring transformation, therefore, opens a novel route to this class of dienes starting from easily available pyridinium salts 1. In order to expand the series of 1-(acylalkyl)-2-halopyridinium salts involved in such reactions, we investigated the reaction of 1-acetonyl-2-bromoand 2-bromo-1-phenacylpyridinium bromides with piperidine. In the first case only an unstable oily product was obtained, whereas for the second case, the desired 1-(4-phenyloxazol-2-yl)-4-piperidinobuta-1,3-diene with all-(E ) configuration was formed in moderate yield.

of anhydrous CH3CN and 2 ml of piperidine was stirred at 20 C for 1 h, poured into water (100 ml) and the precipitate was filtered, washed with water (3 в 50 ml) and dried at 20 C. (1E,3E )-1-Morpholino-4-[5-( p-nitrophenyl)oxazol-2-yl]buta1,3-diene 10d A mixture of perchlorate 14 (2 mmol) in 20 ml of anhydrous CH3CN and 1.7 ml of morpholine was refluxed for 3 h, cooled and poured into water (100 ml). The precipitate was filtered, washed with water (3 в 50 ml) and dried at 20 C giving 0.59 g (90%) of butadiene 10d. The product was identical (mp, TLC, 1 H NMR spectra) with the compound obtained by the general method from the pyridinium salt 8 and morpholine. (1E,3E )-1-Piperidino-4-(5-phenyloxazol-2-yl)buta-1,3-diene The product was obtained according to the general method from 2-bromo-1-phenacylpyridinium bromide and piperidine. The product (early described 19 as a yellow oil) was an amorphous dark yellow solid (56%); mp 104­106 C. 1H NMR and IR spectra were identical with the authentic sample.

Acknowledgements
We thank the Russian Foundation of Basic Research (Grant 96-03-32953a) and Nippon Soda Co. Ltd. for generous support of this work.

References
1 H. Pauls and F. Krohnke, Chem. Ber., 1976, 109, 3653. 2 B. Blank, N. W. DiTullio, A. J. Krog and H. L. Saunders, J. Med. Chem., 1978, 21, 489. 3 C. K. Bradsher and M. Zinn, J. Heterocycl. Chem., 1967, 4, 66. 4 H. Pauls and F. Krohnke, Chem. Ber., 1976, 109, 3646. 5 C. K. Bradsher, R. D. Brandau, J. E. Boilek and T. L. Hough, J. Org. Chem., 1969, 34, 2129. 6 E. S. Hand and W. W. Paudler, J. Org. Chem., 1978, 43, 658. 7 A. M. Demchenko, V. A. Chumakov, K. G. Nazarenko, A. N. Krasovskii, V. V. Pirozhenko and M. O. Lozinskii, Khim. Geterotsikl. Soedin., 1995, 5, 644. 8 R. A. Nugent and M. Murphy, J. Org. Chem., 1987, 52, 2206. 9 H. Pauls and F. Krohnke, Chem. Ber., 1977, 110, 1294. 10 E. V. Babaev, S. V. Bozhenko and D. A. Maiboroda, Russ. Chem. Bull. (Engl. Transl.), 1995, 44, 2203 (Original: Izv. Akad. Nauk, Ser. Khim., 1995, 11, 2298, in Russian). 11 P. B. Terent'ev, S. M. Vinogradova and A. N. Kost, Khim. Geterotsikl. Soedin., 1980, 5, 651. 12 Gy. Hajos and A. Messmer, J. Heterocycl. Chem., 1984, 21, 809. 13 A. Messmer, Gy. Hajos and G. Timari, Tetrahedron, 1992, 48, 8451. 14 E. V. Babaev, A. V. Efimov, D. A. Maiboroda and K. Jug, Eur. J. Org. Chem., 1998, 1, 193. 15 D. A. Maiboroda, E. V. Babaev and L. V. Goncharenko, Khim.Farm. Zh. (Russ.), 1998, 6, 24. 16 Z. Reidl, Gy. Hajos, A. Messmer and G. Kollenz, J. Heterocycl. Chem., 1993, 30, 819. 17 A. Gelleri and A. Messmer, Tetrahedron, 1973, 44, 4295. 18 D. A. Maiboroda and E. V. Babaev, Chem. Heterocycl. Compd. (Engl. Transl.), 1995, 11, 1251. 19 E. V. Babaev, D. A. Maiboroda and K. Yu. Pasichnichenko, Khim. Geterotsikl. Soedin., 1997, 3, 397.

Experimental
General 2-Chloro-N-( p-nitrophenacyl)pyridinium bromide 8,15 2bromo-1-phenacylpyridinium bromide 6 and 2-( p-nitrophenyl)oxazolo[3,2-a]pyridinium perchlorate 14 14 were obtained according to published data. Reaction of 2-chloro-N-( p-nitrophenacyl)pyridinium bromide with secondary amines (general method) A mixture of 0.5 g (1.4 mmol) of the pyridinium salt 8 in 25 ml of anhydrous CH3CN and 5.6 mmol of secondary amine was refluxed for 3 h, cooled and poured into water (100 ml). The deep purple precipitate was filtered, washed with water (3 в 50 ml) and dried at 20 C. The properties of oxazolylbutadienes 9 and 10 are given in Tables 1­3. (1E,3Z )-4-[5-( p-Nitrophenyl)oxazol-2-yl]-1-piperidylbuta-1,3diene 9e A mixture of 0.2 g (0.56 mmol) of the pyridinium salt 8 in 25 ml

Paper 8/09694E

J. Chem. Soc., Perkin Trans. 1, 1999, 399­401

401