Substituted 3-and 5-formylpyridin-2-ones in the synthesis of 1-aryl-1, 6-naphthyridinone derivatives

New 1-aryl-6-[2-(dimethylamino)vinyl]4-oxo-1,4-dihydropyrimidine-5-carbonitriles and 4-arylamino-2-oxo-1,2-dihydropyridine-3-carbonitriles containing electron-withdrawing substituents in the benzene ring were synthesized from enamino amides and dimethylformamide dialkylacetals. The influence of various dimethylformamide acetals on the yield of 3-(4-chloro-anilino)-2-cyano-5-(dimethylamino)penta-2,4-dienoic acid N-(dimethylamino)methyl-ideneamide was investigated in the reaction of these acetals with 3-(4-chloroanilino)-2-cyanocrotonamide. New 4-arylamino-5-formyl-2-oxo-1,2-dihydropyridine-3-carbonitriles and 4-arylamino-2-oxo-1,2-dihydropyridine-3-carbaldehydes containing electron-withdrawing substituents in the benzene ring were synthesized. The latter compounds were converted into new substituted l,6-naphthyridinones by the action of various CH acids. A new approach to the synthesis of 4-(4-fluoroanilino)-5-formyl-2-oxo-1,2-dihydropyridine-3-carbonitrile using dimethylformamide diisopropylacetal under mild conditions was developed. The comparative reactivity of the formyl group in the reactions of 4-arylamino-5-formyl-2-oxo-1,2-dihydropyridine-3-carbonitriles and in 4-arylamino-2-oxo-1,2-dihydropyridine-3-carb-aldehydes with malononitrile was determined using HPLC.     

Reactions of 2-oxo-2-dialkylamino-1,2-oxaphospholanes with acid chlorides

The reaction of acetyl chloride, chloroacetyl chloride, benzoyl chloride, and phosphorus trichloride with 2-oxo-2-dialkylamino-1,2-oxaphospholanes gives 2-oxo-2-chloro-1, 2-oxaphospholanes. Phosphorus pentachloride opens the 1,2-oxaphospholane ring with the formation of dimethylamido-3-chloroalkylphosphonyl chloride.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 6, pp. 1433–1434, June, 1990.     

Nitrogen bridgehead compounds. Part 80 unusual reaction of ethyl 9-bromo-4-oxo-6,7,8,9-tetr ahydro-4h-pyrido[1,2-a]pyrimidine-3-carboxylates and N-Methylaniline

The acid-catalysed intramolecular nucleophilic addition of the phenyl ring to the C(9a) = N(1) double bond of ethyl 9-(N-methyl-N-phenyl)-4-oxotetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylates, formed in the reactions of ethyl 9-bromo-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylates and N-methylaniline, gave the first examples of a new tetracyclic pyrimido[1′,2′:1,2]pyrido[3,2-b]indole ring system ( 7 ). X-ray diffraction analysis of 7a revealed that the annelation of the pyrimidine and piperidine rings is transoid, while that of the piperidine and pyrroline rings is cis, the piperidine ring adopts an unusual ⁶T₈ twisted boat conformation, while the pyrroline ring has a ⁹T_8a conformation.     

Diastereoselective Synthesis of Phosphines and Phosphoranes using Fluorinated Acetylacetones

Abstract

A two step formal insertion of 1,1,1,5,5,5-hexafluoro- (1) and l,l,l - trifluoropentane-2,4-dione (2) into the P-H bonds of phosphane gave the primary a-hydroxyphosphanes. precursors for 2-phospha-6-oxa-9- oxabicyclo[3.3.1]-nonane and 2,4,8-trioxa-6-phospha-adamantane, both formed diastereospecifically. The molecular structures of the two latter compounds were established by single-crystal X-ray structure analysis. Compound 1 reacted diastereospecifically with phosphonous acid dichlorides, RPCl₂ (R = Me, Et, iPr, tBu, Me₃SiCH₂, PhCH₂, Ph) to give in a concerted mechanism thermally stable tricyclicλ⁵σ⁵ P phosphoranes containing two five- and one six-membered ring. In one case hydrolysis gave 3,5-dihydroxy-2-oxo-1,2λ⁵σ⁴-oxaphospholane, whereas methanol added to the double bond in the six-membered ring furnishing two isomeric phosphoranes. When 2 was reacted withRPCl₂ (R = Et, Me₃SiCH₂, PhCH₂. Ph), diastereomerically pure regioisomeric phosphoranes were obtained. The solid state molecular structures of three λ⁵σ⁵P species exhibited two oxygen atoms in the axial position of a slightly distorted trigonal-bipyramidal geometry at phosphorus.     

Relative Configuration and Conformation of 5-(Dimethoxyphosphoryl)-2-methoxy-1,2λ5-oxaphospholan-2-ones by Multinuclear NMR Spectroscopy

Information on the hitherto unknown relative configuration and on the conformation of the title compounds in solution can be derived from nuclear Overhauser effects and coupling constants. Whereas the bridged 5-(dimethoxyphosphoryl)-2-methoxy-1,2λ⁵-oxaphospholan-2-ones 6 and 7 are sterically strained and, therefore, conformationally rigid, the C(3)-unsubstituted compound 1 does not show a preferred solution conformation. Phenyl substituents at C(3) (compounds 2 – 5 ) tend to adopt a pseudoequatorial position, this way leading to a definite conformation of the respective compounds. The influence of the conformation on the NMR spectra is discussed. ³¹P-NMR Spectroscopy is ideally suited for the characterization and quantification of the isomers 2 – 5 present in the reaction mixture.     

Conformational mobility of the six-membered ring in 5-oxo-1,3-cyclohexadiene and its derivatives

Molecular mechanics and MNDO calculations showed that the six-membered ring in the molecule of 5-oxo-1,3-cyclohexadiene possesses high conformational mobility. The transition from a planar equilibrium conformation to a distorted sofa conformation in which the C(sp²)-C(=O)-C(sp³)-C(sp²) torsion angle is equal to ±30° increases the energy of the molecule by less than 1 kcal mol^–1. The influence of steric (R = Me, Et, Prⁱ, Bu^t) and electronic (R = NH₂, NO₂) effects of substituents R on the equilibrium conformation and mobility of the carbocycle has been analyzed. Both types of substituents at unsaturated C atoms do not change the equlibrium conformation or flexibility of the six-membered ring. Substituents at saturated C atoms cause the transition of the carbocycle to the distorted sofa conformation and significantly restrict its mobility. The electronic structures of 5-oxo-1,3-cyclohexadiene and its amino and nitro derivatives have been analyzed.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 849–854, May, 1995.     

Conformational analysis and steric effects of substituents in derivatives of 3-oxo-, 3-imino-, and 3-methylenecyclohexene

The equilibrium conformations and the inversion barriers of the rings in 3-oxo-, 3-imino-, 3-methylenecyclohexenes and in their methyl,tert-butyl, and phenyl derivatives were calculated by molecular mechanics. The unsubstituted molecules adopt a sofa conformation. The nonbonded interactions between substituents at positions 2 and 4 and the exocyclic double bond lead to a change in the conformation of the ring to a half-chair. The effect is enhanced as the volume of the substituent increases in the series of the oxo, imino, and methylene derivatives. Substituents at other positions of the ring affect only slightly the equilibrium conformation. The results of calculations were confirmed by X-ray structural analysis of 2-(4-benzoyloxybenzyl)-6-isopropyl-3-methylcyclohex-2-enone. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1995–2000, November, 1997.     

Analyse Conformationnelle par RMN du Proton des Oxo-2 Oxathiazannes-1,2,3 (Sulfinamates Cycliques) Diversement Substitués en 3, 4 et 6

In this study, carried out with 16 compounds, the chair form with an axial S?O group (CA) is found, in the absence of C-4, C-5 and C-6 substituents, to be the most stable (ΔG>8,4 kJ mole^?1), as previously reported for analogous cyclic sulfites. When methyl or tert-butyl substituents are present on the 4 and 6 carbon atoms, the conformation of the ring depends on their respective orientation towards the S?O group, and on the nature of the substituent of the nitrogen atom. For the trans isomers, the conformation remains anancomeric chair (CA) except when important gauche interactions exist: thus the strong Me/tBu gauche interaction in the 3-tert-butyl-4-t-methyl-2-r-oxo-1,2,3-oxathiazan induces a twist form with a 3,6-axis and an axial S?O group (CNA). When the 4- or 6-substituent is cis, the conformation of the sulfinamate may be either a chair form with an axial S?O group (CA), if the 4-substituent is a methyl, (even with a tert-butyl group in the 3-position which would be in the axial orientation) or a twist form with a 1,4-axis and an axial S?O group (COA) if the 4-substituent is a tert-butyl. Unlike cyclic sulfites, the equatorial SO chair form (CE) and the twist forms with a 2,3-axis and an isoclinal S?O group (CS, CS′) are rarely involved.     

Reaction of Tertiary 2-Chloroketones with Cyanide Ions: Application to 3-Chloroquinolinediones

3-Chloroquinoline-2,4-diones react with cyanide ions in dimethyl formamide to give 3-cyanoquinoline-2,4-diones in small yields due to the strong hindrance of the substituent at the C-3 atom. Good yields can be achieved if the substituent at this position is the methyl group. In the methanol solution, the reaction proceeds by an addition mechanism to form 2-oxo-1a,2,3,7b-tetrahydrooxireno[2,3-c]quinoline-7b-carbonitriles, from which 4-hydroxy-3-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-4-carbonitriles are subsequently formed by opening of the epoxide ring with methanol. Some minor products of these reactions have also been isolated. The ¹H, ¹³C and ¹⁵N NMR spectra of the prepared compounds were measured, and all resonances were assigned using appropriate two-dimensional spectra.     

Addition conjuguée dans le thf-hmpt d'arylacétonitriles lithies aux cyclohexèn-2 ones substituées: intervention des facteurs stériques et électroniques

The reaction of lithiated arylacetonitriles 2a-c with 2-cyclohexenones 3-9 in THF-HMPA (80:20 v/v) at ?70° leads in all cases but one to δ-ketoalkylnitriles, resulting from 1,4-addition. The only case where some 1,2-addition takes place is the reaction of 2a with 4,4-dimethyl 2-cyclohexenone 7. The formation of allylic alcoholates, products of 1,2-addition, is shown to be reversible in this solvent mixture. However, in several cases, kinetic control of 1,4-addition is demonstrated. The rate of formation of 1,4-addition products depends upon the arylacetonitrile substituents: 2a >2b >2c (i.e. the higher lying the nucleophile HOMO the faster the reaction). It is also sensitive to the cyclohexenone substituents; although methyl on C-2 and gem-dimethyl on C-5 or t-butyl on C-4 have small influence on the reaction rate, methyl on C-3 or gem dimethyl on C-4 induce a noticeable rate decrease. The addition, of 2b on 4-t-butyl 2-cyclohexenone 8 leads, at the early stage, to a predominating isomer 15b, to which the trans diaxial configuration of the substituents has been attributed by 250 MHz ¹H NMR. A single transition state model, reagent-like, where the nucleophile approaches the C-C bond by the less hindered face of the 2-cyclohexenone in a 1,2-diplanar conformation, the CN substituent being directed towards the C=0 group, accounts for all the substituent effects and the stereoselectivity observed.     

Conformational Studies of a Six-Membered Phostone

Abstract

Although 1,3,2-dioxaphosphorinanes generally assume chair conformations,¹ there are examples in which the ring adopts the boat or twist-boat form.¹ Recent studies on the synthesis, stereochemistry, and reactivity of 2-alkoxy-2-oxo-1,2-oxaphosphorinanes (phostones) have revealed both cis and trans isomers of 3-(diphenylhydroxymethyl)-2-ethoxy-2-oxo-1,2-axaphosphorinane² to assume a chair conformation in the solid state. In the present work, the conformational properties of cis and trans-3-methoxycarbonyl-2-methoxy-2-oxo-1,2-oxaphosphorinanes were investigated by X-ray analysis, variable temperature ³¹P, ¹H and ¹H{³¹P} NMR spectroscopy, molecular mechanics, and semiempirical calculations. The X-ray crystal structure of the trans isomer revealed a chair dormation with equatorial phosphoryl and carbomethoxy groups. No changes were observed in the ³¹P NMR spectra of either isomer in the temperature range of 183–333 K. A complete set of vicinal J_HH coupling constants was extracted from the ¹H{³¹P} spectra of each isomer taken at five temperatures over the range of 213–293 K and refined by simulation of the spectra. The best-fit analysis of this data using a generalized Karplus equation³ revealed that the conformation of the trans isomer in solution was close to that found in the solid state. This conformation corresponded to the global energy minimum calculated by both molecular mechanics and PM3 semiempirical method. A substantial contribution from an inverted chair conformation of the cis isomer had to be assumed to achieve a reasonable fit of the coupling constants calculated from the generalized Karplus equation.     

13C chemical shifts and conformational analysis of S-methylthiolanium cations

The ¹³C NMR spectra of all cations obtained by methylation at sulphur of the mono-and dimethylthiolanes are reported. The methyl substituent on sulphur affects the shieldings of the adjacent carbons in a manner which allows easy identification of the cis and trans isomers. For most compounds the ¹³C pattern is consistent with a half-chair ring conformation with maximum staggering at C-3, C-4. Only with methyl groups at the 1,2-or 1,2,3-positions is the half-chair appreciably deformed. It is suggested that in these cases the preferred conformation is a quasi-envelope with C-3 at the top.     

Steroids and sex hormones. Quassinoid bitter principles. I. 1-oxo-2-methoxy-4 alpha-methyl-17 beta-hydroxy-delta2-5 alpha-androstene as a model for the ring a structure of quassine]

Starting from 3-oxo-17β-hydroxy-Δ¹-5α-androstene (2b) the preparation of 1-oxo-2-methoxy-4α-methyl-17β-hydroxy-Δ²-5α-androstene (9), a compound with the ring A structure of quassine (1) is described. The key problem of the reaction sequence is shown to be the monomethylation at C(4).     

Ring conformations of 2-substituted 2-oxo-4-methyl-1,3,2-dioxaphosphorinanes. Evidence for a boat conformation in equilibrium with two interconverting chairs

The 220 MHz proton NMR spectra of three isomeric pairs of 2-R-2-oxo-4-methyl-1,3,2-dioxaphosphorinanes, where R = methoxy (1a, b), methyl (2a, b) and dimethylamino (3a, b) (a represents the trans and b the cis arrangement of R and the 4-methyl group) were analyzed by iterative computer techniques. Ten ring conformations, two chairs, two half-chairs and six boats were initially considered as being possible contributors to the overall solution conformations. Compounds 1a, 2a, 2b and 3b were all concluded to exist as single chair conformations with the 4-methyl group equatorially oriented (eqch). In addition to 68% of compound 3a being in that eqch conformation, however, significant concentrations of the chair form containing an axially oriented 4-methyl group (axch, 16%) and a boat conformation containing an equatorially oriented 4-methyl group with phosphorus and C-5 serving as the bow and stern (eq25, 16%) were also postulated. Similarly, it was suggested that 1b contained 60% eqch, 20% axch and 20% of the boat eq25. From the data for compounds 2a and b it was concluded that in the chair conformations of 2-oxo species the phosphorus substituent orientation has little effect upon the ³J(POCH) coupling constants.     

Carbon-13 nuclear magnetic resonance spectra of some methyl and phenyl substituted 2H-azirines

Carbon-13 n.m.r. spectra have been obtained for some methyl and phenyl substituted 2H-azirines. The higher field resonance of C-2 than that of the corresponding aziridine carbon is interpreted in terms of ring strain. Substituent effects on the chemical shifts of the azirine ring carbons are discussed. A set of additivity parameters for the methyl and phenyl groups are obtained which can be used for the calculation of the chemical shifts of the azirine ring carbons. The substituent effect of an azirine ring on the chemical shift of benzene is also discussed in comparison with those of some other substituents. A high degree of s character (48.5%) in the exocyclic orbital of C-3 is indicated by a large J(¹³C-3,H) value (242.5 Hz).     

A novel glycoside lactone derivative with a 2-C-unsaturated diester substituent

The title 4,6-O-benzyl­idene-α-d -gluco­pyran­oside (systematic name: methyl 4-methoxy-2-oxo-8-phenyl-1,2,5a,6,9a,9b-hexa­hydro-4H,8H-7,9-dioxa­cyclo­penta­[c]­chromene-3-carboxyl­ate), C₁₈H₁₈O₈, has been synthesized from the reaction of methyl 4,6-O-benzyl­idene-α-d -2-ketogluco­pyran­oside with diethyl or di­methyl malonate. The compound adopts a chair–chair conformation. The newly formed five-membered ring is fused to the gluco­pyran­oside ring along the C₂—C₃ bond and is planar with an r.m.s. deviation of 0.0091 Å.     

Syntheses of (R) [4-2H2] 2-Amino-3-Butenoic Acid (Vinylglycine) and (R) [4-2H2, 5-2H3] Methionine

Treatment of (R) methionine sulfoxide with NaOD led to exchange of the C-4 methylene and C-5 methyl protons; exchange of the chiral C-2 proton did not occur. Reducation with mercaptoacetic acid gave (R)-[4-²H₂, 5-²H₃] methionine. The latter was converted into its carbobenzyloxy methyl ester sulfoxide, pyrolysis of which followed by deprotection yielded (R)-[4-²H₂] vinylglcine as the hydrochloride.     

Reaction of ethyl 4-aryl-6-bromomethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates with N-methylmorpholinium 3-cyano-1,4-dihydro- and 3-cyano-1,4,5,6-tetrahydropyridine-2-thiolates

Alkylation of N-methylmorpholinium 4-Ar¹-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates using ethyl 4-Ar-6-bromomethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates (10 % KOH, DMF) gives mixtures of diastereomers of ethyl 4-Ar-6-[(4-Ar¹-3-cyano-1,4,5,6-tetrahydropyridin-2-ylthio)methyl]-1-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates in overall 30-58 % yield. Under these conditions the N-methylmorpholinium 4-Ar1-5-(N-Ar²-carbamoyl)-3-cyano-6-methyl-1,4-dihydropyridine-2-thiolates undergo aromatization of the dihydropyridine ring to give ethyl 4-Ar-6-[4-Ar¹-5-(N-Ar²-carbamoyl)-3-cyano-6-methylpyridin-2-ylthio)methyl]-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates (37-51 %). In the absence of KOH, only the substituted pyridine-2(1 H)-thione is formed as a product of oxidation of the dihydropyridine ring in the starting substrate. Some of the alkylation products obtained possess weak or moderate antibacterial activity towards the specific strains of Escherichia coli and Bacillus subtilis but are inactive towards Candida albicans and Staphylococcus aureus.     

Isomerisierung von Methoxy- und Carbomethoxysubstituierten Cycloalkyl- und Alken-radikalkationen

The very complex isomerization patterns of methoxy and carbomethoxy substituted cycloalkanes (3- to 7-membered rings) have been investigated using collisional activation, metastable ion characteristics and field ionization kinetics. The extent of isomerization depends on both the ring size and the substituent. Irrespective of the electronic properties of the substituent, ring opening involves exclusively the C-1? C-2 bond whereby linear alkene radical cations are formed. In the case of OCH₃- and COOCH₃ substituents the position of the resulting double bond (terminal or α,β-unsaturated) is determined more by the ring size of the precursor molecules and less by the electronic properties of the substituents. Contrary to these findings alklyl substituted cycloalkanes (3- to 5-membered rings) rearrange exclusively to terminal alkene radical cations. The barrier for double bond isomerization seems to be substantially influenced by substituents.     

Phosphorinane and Enol Rings in One Molecule. Evidence for Reciprocal Stabilization of Half-Chair Conformations

Abstract.

The X-ray crystal structure of 2-(2′,4′-dioxo-3′-pentyl)-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane (2) reveals significant half-chair distortion of the axially oriented cisenol ring. The molecule also undergoes in-plane deformations. R(O...O) = 2.410 Å in the enol moiety indicates a very strong hydrogen bonding. The enol content, δ_OH and thermodynamic parameters for the axial-equatorial conformational and keto-enol equilibriums were obtained from ¹H, ³¹P NMR and IR measurements in comparison with the planar 4,6-dimethyl isomer (1) containing equatorially oriented enol ring. The X-ray single crystal structure of 5,5-dimethyl-2-(methoxycarbonyl-3′-oxo-2′-butyl)-2-oxo-1,3,2-dioxaphosphorinane (3) reveals the unusual half-chair conformation of the dioxaphosphorinane cycle disposed a trans-enol ring substituent. ¹H, ³¹P NMR and IR solution data support the same structure displays a strong conformational preference while the minor forms are chair conformers with an axial or equatorial cis-enol ring.