The Structure of 3-Phenyl-4-(N-Carbamyl-1,4,2-Oxathiazolimin-3-yl)Sydnone,C11H7N5O4S·0.8 CH2Cl2

The title compound (M_r = 373) crystalizes in the othorhombic space group P bna with a = 10.410(2), b = 11.658(4), c = 23.108(3) Å, V = 2804.4 Å Z = 8. The single crystal intensity data were collected using MoK∞ radiation (λ = 0.7093Å) at room temperature. The crystal and molecular structure was solved with the final agreement index R = 0.039 for 1046 observed reflections. The bond lengths N(1)- C(7) and C(7)-C(8) of the title compound are slightly longer than those of 3-substituted sydnone derivatives. This may be attributed to the steric effect arising from the interaction of the phenyl ring and the 4-substituent with the neighboring atoms of sydnone ring. Both the title compound and 4-acetyl-3-(p-tolyl)sydnone have smaller dihedral angles between the sydnone ring and the plane of the sp² orbital of the double bond of the 4-substituent and both have shorter C(7)-C(9) bond lengths than those of other similar sydnone derivatives.     

Acid induced reactions of a sydnone ketoxime

3-(2-Acetylphenyl)sydnone oxime 1a reacts with acids (methanesulfonic-, p-toluenesulfonic, trifluoroacetic-acid or Amberlite IR 118) to give products apparently derived from protonation of the oxime oxygen or nitrogen atom followed by cyclization to the sydnone ring or interception by water.     

Synthesis of some substituted pyridylsydnones

Synthesis of the I-oxide ( 2 ) of the photochromic N-(3-pyridyl) sydnone ( 1 ), of N-(5-bromo-3-pyridyl) sydnone ( 3 ), and the I-oxide ( 4 ) of 3 were undertaken in order to study the effect on photochromism exerted by substituents on the pyridine ring. Compounds 2 and 3 were prepared via the corresponding aminopyridines and N-pyridylglycines by the general procedure used earlier to prepare 1 . The required amines, 3-aminopyridine I-oxide and 3-amino-5-bromopyridine, were obtained by Hofmann rearrangement of the corresponding amides. An excellent preparation of 5-bromonicotinamide was developed involving bromination in thionyl chloride followed by reaction of the bromoacid chloride with ammonia in chloroform. Proof of structure for 2 and 3 was accomplished by acid hydrolysis to the corresponding hydrazines, which were isolated, respectively, as acetophenone 3-pyridylhydrazone I-oxide and as 5-bromo-3-pyridylhydrazine hydrochloride. These products were identical with samples prepared by reduction of the respective diazotized amines. Sydnone 4 eluded preparation by this general procedure. 3-Amino-5-bromopyridine I-oxide was prepared conveniently from 5-bromonicotinamide but attempts to prepare the corresponding glycine by catalytic hydrogenation of a mixture of the amine and butyl glyoxylate afforded, in acid solution, N-(3-pyridyl)glycine and, in neutral or alkaline solution, the I-oxide of N-(3-pyridyl)glycine. Both products resulted from the reductive cleavage of the bromine atom. Neither 2 nor 3 was photochromic.     

Bromination of sydnones. II Bromination of 3-(2-aminophenyl)sydnone and related compounds

Bromination of 3-(2-aminophenyl)sydnone 2 under a variety of conditions is reported. The products obtained are interrelated by a series of subsequent reactions. One major product is the bromoaryl compound 8, the first example of bromination on the aryl rather than sydnone ring when the two are in competition. Surprisingly, bromoaminosydnone 9, prepared from its nitro analogue, was not among the products obtained by direct bromination of 2.     

Studies on the Preparation and Biological Activities of 3-(O-Methoxybenzyl)Sydnone Derivatives and 3-(Fluorophenyl)Sydnones

Two new sydnones; 3-(o-methoxybenzyl)sydnone(1) and 3-(o-melhoxybenzyl)-4-morpholinomethylsydnone(2) were synthesized from o-methoxybenzylamine and ethyl bromoacetat in moderate yields. 3-(o-,m-,p-Fluorophenyl)sydnones were prepared from the corresponding fluoroaniline and chloroacetic acid in higher yields with a conventional method. From the biological activity test, 1 shows significant response of coronary dilation test, collagen induced platelet aggregation inhibition, local anesthetic and moderate cardiotropic activity. In addition, 1 also leads to anticonvuls, muscle relaxation and behavior depression. But 2 only shows inhibition of collagen induced platelet aggregation and antiwrithing. 3-(p-Fluorophenyl)sydnone (5) shows significant response of coronary dilation, collagen induced platelet aggregation inhibition, moderate cardiotropic activity, antiwrithing and local anesthetic But 3-(o-Fluorophenyl)sydnone(3) and 3-(m-fluorophenyl)sydnone(4) only show coronary dilation and moderate cardiotropic activity.     

Coupling and Cyclization of Sydnone Compounds

Cyclization were occurred via the coupling reactions of some mercuric chloride derivatives of sydnone with LiPdCl₃-CuCl₂. A unique six-membered ring, 3,3′-ethylene-4,4′-bissydnone, was obtained by the cyclization reation of 1,2-di[3-(4-chloromercuric)sydnonyl]ethane. However, the seven-membered 3,3′-trimethylene-4,4′-bissydnone and 1,3-di[3-(4-chloro)sydnonyl]-propane were obtained from the corresponding mercuric chlroide of sydnone. Onyl substitution reaction took place when 4,4′-di[3-(4-chloromercuric)sydnonyl]biphenyl, 4,4′-di[3-(4-chloromercuric)sydnonyl]benzene, di(p-[3-(4-chloromercuric)sydnonyl]-phenyl}methane and, di(p-[3-(4-chloromercuric)sydnonyl]phenyl]ether were treated using the same process.     

Acylation of Sydnones with Acetic Anhydride in the Presence of Montmorillonite K-10

Various 4-acetyl sydnones 2 can be prepared in good yield by reaction of the corresponding 3-arylsydnones (cf. 1) with acetic anhydride at ～ 110°C catalyzed by Montmorillonite K-10. The reaction fails where an ortho-keto moiety is present; therein sydnone ring cleavage occurs to form the corresponding indazole 3.     

Photochemical reactions. 142nd communication. Photochemistry of a 6,7-epoxy-1,3-diene of the ionone series

On singlet excitation (λ = 254 nm), the epoxydiene (E)- 3 underwent (E)/(Z)-isomerization, electrocyclic ring closure of the diene side chain leading to the cyclobutenes 4A + B , and rearrangement to the cyclohexanones 5A + B . Compounds 5A + B were presumably formed in a series of processes including a 1,3-acyl shift of the homoconjugated ketone 8 , arising from (Z)- 3 by a 1,5-H-shift accompanied by cleavage of the C,O-bond of the oxirane.     

Studies on the Synthesis of the Sydnone Derivatives and its Properties IV: The Diarylation of Sydnone Compound

In the presence of H₂SO₄, the sydnone rings were condensed with formaldehyde to give diarylation in 4-position of the sydnone rings: 3,3′-diphenyl-4,4′-methylenedisydnone is obtained from 3-phenylsydnone in 61% yield, and 3,3′-di-p-methylphenyl-4, 4′-methylenedisydnone is obtained from 3-(4′-methylphenyl)sydnone in 70% yield. And the possible reaction mechanism is discussed.     

Reactions of 4-Hydrazinocarbonylmethylene 3-Arylsydnones and 3-(4-Hydrazinocarbonylphenyl)sydnones

The phenyl ring of 3-(4-hydrazinocarbonylphenyl)sydnone activates a hydrazinocarbonyl group to undergo a series of reactions for preparing heterocyclic compounds including oxadiazoles, dihydropyrroles, and pyrroles. However, the hydrazinocarbonyl group on the C(4)-CH₂ resists a cyclization under the same reaction conditions.     

Synthesis of a benzodiazepine analogous sydnotriazepine

Starting from 3-benzylamino-4-benzoylsydnone ( 1 ) acylation to N-acetyl ( 2a ), N-chloroacetyl ( 2b ) and N-bromoacetyl ( 2c ) derivatives was successful. Treatment of 2b or 2c with liquid ammonia resulted in cleavage of the N-acyl group to give sydnone imine 3 instead of cyclisation to sydnotriazepine 8 . Condensation of 1 with protected glycines 5a-5c by dicyclohexylcarbodiimide yielded glycineamides 6a, 6b and 6c . Compound 6c was selectively deprotected and converted to sydnotriazepine 7, a benzodiazepine analogous sydnotriazepine.     

Bromination of sydnones. I. Reaction with 3-arylsydnones containing electron-donors on the aryl ring

Bromination has been examined for a series of 3-arylsydnones (1) with electron donors (dimethyl to dimethoxy) on the aryl ring. In no example was exclusive aryl ring bromination observed, however, exclusive sydnone ring bromination could be realized in every case. For two dimethoxyphenyl examples both aryl and sydnone ring bromination occurred.     

The mass spectra of sydnones

The mass spectra of thirty sydnoes have been interpreted; the types investigated include 3-aryl, 3-alkyl-, substituted 3-alkylsydnones; and bis sydnones. A characteristic fragmentation mode involves initial loss of NO and CO from the molecular ion, but peaks corresponding to alkylcarbonium ions dominate the spectra of 3-alkylsydnones; a cyclic mechanism is suggested for weak transitions involving loss of sydnone neutral molecule from the molecular ion. A mechanism is proposed for loss of chlorine radical from the molecular ion of 3-(2,4-dichlorophenethyl)sydnone. An unusual feature in the mass spectrum of trimethylenebis sydnone is rationalised on the basis of a precursor 1,2,3-oxadiazole ion. The effect of substituents in the aryl ring on the fragmentation of 3-arylsydnones is discussed.     

Mass spectra of some perfluoroalkyl and perfluoroalkylether substituted 1,2,4-oxadiazoles

Electron impact fragmentation patterns were obtained for 1,4-bis[(5-perfluoro-n-heptyl)-1,2,4-oxadiazolyl]-benzene, its perfluoroalkylether substituted analogue, 3,5-bis(perfluoroalkyl)-, 3,5-bis(perfluoroalkylether)- and 3-perfluoroalkylether-5-perfluoroalkyl-1,2,4-oxadiazoles. In the compounds containing the phenylene group the molecular ion constituted the base peak; the main process was the breakdown of the oxadiazole ring with concurrent liberation of the perfluoroalkyl or perfluoroalkylether nitrile molecule; cleavage of the fluorinated chain α to the oxadiazole ring was found to take place to a considerable degree. In the perfluorinated 1,2,4-oxadiazoles cleavage β to the oxadiazole ring occurred preferentially; fragmentation of the ring itself took place to a limited degree only. The 3-perfluoroalkylether-5-perfluoroalkyl-1,2,4-oxadiazole appeared to undergo the primary β-cleavage exclusively at the perfluoroalkylether sidechain.     

3-Substituted Sydnone Derivatives. Structures of 3-Cyclohexylsydnone and of Two Forms of 3-(3-Pyridyl)sydnone

The crystal and molecular structures of three sydnone derivatives are reported. The compound 3-cyclohexylsydnone crystallizes in space group C2/c of the monoclinic system with sixteen molecules in a cell of dimensions a = 19.326 (3), b = 9.471 (2), c = 20.005 (4)Å, β = 106.85(1)°. The structure has been refined to a final value of 0.0581 for the conventional R-factor based on 2222 independent observed intensities. Form I of 3-(3-pyridyl)sydnone crystallizes in space group P2/n of the monoclinic system with eight molecules in a cell of dimensions a = 7.317(2), b = 9.283 (2), c = 20.891 (6) Å, β = 99.61(2)°. The structure has been refined to a final value of 0.0514 for the conventional R-factor based on 1208 independent observed intensities. Form II of 3-(3-pyridyl)sydnone crystallizes in space group P2₁/c of the monoclinic system with eight molecules in a cell of dimensions a=9.073 (2), b = 22.267 (5). c = 7.494(2)Å, β = 112.15 (2)°. The structure has been refined to a final value of 0.0462 for the conventional R-factor based on 1330 independent observed intensities. Each of the three structures contains two crystallographically independent molecules in the cell. In the case of 3-cyclohexylsydnone, one of the independent molecules exhibits disorder around the exocyclic bond at N(3). A comparison of bond lengths indicates that the (electron donating) cyclohexyl group brings about enhanced electron density in the N(3)-C(4) bond, and possibly in the N(3)-N(2) bond. All three structures studied here exhibit intermolecular hydrogen bonding involving C(4)-H(4)…O(6) interactions. Although there are no stacking interactions in the cyclohexyl derivative, there is evidence for such interactions in the 3-pyridyl derivatives.     

Meso-ionic compounds. XI,photochromic 4-halogeno-3-(3-pyridyl)sydnones

Halogenation of 3-(3-pyridyl)sydnone with N-halosuccinimides in chloroform afforded the 4-halogeno-3-(3-pyridyl)sydnones where X = CI, Br, I. The 4-chloro- and 4-bromopyridylsydnones were photochromic. 3-(3-Pyridyl)sydnone was obtained in both high yield and purity by dehydration of N-nitroso-N-(3-pyridyl)glycine with trifluoroacetic anhydride.     

The mass spectrum of 1-(2-thienyl) hexane-1-13C

The mass spectrum of 1-(2-thienyl) hexane-1-¹³C is reported. The principal fragmentation routes ofthe parent ion are delineated. Beta cleavage of the alkyl chain predominates, and the label retention indicates that the alpha carbon atom remains with the charged ring moiety. A substantial part of the m/e 97 ion undergoes a ring expansion to a six membered ring. A small amount of alpha cleavage of the alkyl chain occurs with the expected loss of the label. Further fragmentation of the ions from initial alpha or beta cleavage produces similar fragment ions. It is noted that many of the neutral particles lost in the formation of the fragment ions are typical of those encountered in the alkylbenzenes or other aromatic ion systems.     

A novel urocanic acid derivative from skin tissue extracts; (E)-3-[1-(1,1-dimethyl-3-oxobutyl)imidazol-4-yl]propenoic acid

A novel derivative of urocanic acid ( 1 ) had been isolated from acetone extracts of rabbit skin tissue. It proved to be (E)-3-[1-(1,1-dimethyl-3-oxobutyl)imidazol-4-yl]propenoic acid ( 3c ), potentially a much better ultraviolet screening agent than urocanic acid. Sterical effect of dimethyl groups in the side chain adjacent to the imidazole ring of 3c on its solubility is also discussed.     

Structural modification studies of 3-piperonylsydnone. III. Some analogs of 3-piperonylsydnone and 2,4-diamino-5-piperonylpyrimidine

In a continued structural modification study of the antimalarial compounds 3-piperonylsydnone and 2,4-diamino-5-piperonylpyrimidine, the related piperonyl derivatives of ψ-1,2,3;4-oxatriazole, ψ-1,3,5-oxadiazole, pyrazole, tetrazole, 1,2,4-triazine, pyrrolidine, amino- and sulfamoyl-1,2,4-triazole, as well as some sydnones and diaminopyrimidines with side chains other than the piperonyl group have been synthesized. 3-(3,4-Ethylenedioxyphenyl)sydnone was found to double the survival time of Plasmodium berghei infected mice. The other compounds are not as active.     

Acetylation and Debromination of Sydnones Accelerated by Ultrasound

In the presence of a catalytic amount of 60% perchloric acid, 4-acetyl-3-substituted sydnones were obtained more conveniently with greater yields by the sonochemical reaction of 3-substituted sydnone with acetic anhydride. Some 4-acetylsydnones which are difficult to synthesize by a known process were obtained in 17-68% yields. 4-Bromo-3-(bromoaryl)sydnones with activated zinc powder dispersed in methanol were debrominated regioselectively by ultrasound in high yields (60-96%). 3-(2′-/4′-Amino-3′,5′-dibromophenyl)sydnone is synthesized easily from 3-(2′/4′-aminophenyl)sydnone by reduction, bromination and debromination subsequently.