Basicities and structures of 4,4,6-trimethyl-2-arylamino-5,6-dihydro-4H-1,3-thiazines and 4,4,6-trimethyl-2-arylamino-5,6-dihydro-4H-1,3-oxazines

The relative basicities of 4,4,6-trimethyl-2-arylamino-5,6-dihydro-4H-1,3-thiazines and 4,4,6-trimethyl-2-arylamino-5, 6-dihydro-4H-1,3-oxazines, which are capable of amine-imine tautomerism, and of model compounds with fixed amine and imine structures were determined by potentiometric titration in methanol. Good correlation of the pK _a values with the Hammett constants in the investigated reaction series was found. The inapplicability of the use of the pK _a values of model compounds for the determination of the tautomeric equilibrium constants in the case of some N-heterocyclic amines of nonaromatic character with an aryl substituent attached to the exocyclic nitrogen atom of the amidine fragment of the molecule is demonstrated.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1621–1624, December, 1976.     

structure of 4,4,6-trimethyl-2-mylamino-5,6-dihydro-4H-1,3-thiazines and -oxazines

It is shown by means of IR, PMR, and UV spectra that 4,4,6-trimethyl-2-arylamino-5, 6-dihydro-4H-1,3-thlazines and 4,4,6-trimethyl-2-arylamino-5,6-dihydro-4H-1,3-oxazines in the crystalline state and in solution exist primarily in the amino form. It was found that ionization to give cations proceeds more readily in the case of 1,3-oxazines than in the case of 1,3-thiazines. In addition, a decrease in the ability to undergo intermolecular association and a decrease in the energy barrier to rotation about the N-heteroring bond are observed for 1,3-oxazines.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 346–352, March, 1977.     

Retro-ene reactions in heterocyclic synthesis,III. A new route to 4,5-dihydrooxazoles and 5,6-dihydro-4H-1,3-oxazines

Methyl (E)-4,4-dimethyl-5-oxo-2-pentenoate ( 1 , X = O) reacted with 1,2- or 1,3-aminoalcohols 3 to yield oxazolidines 4a-c or tetrahydro-1,3-oxazines 4d,e. The corresponding imino ester 1 (X = NBu-t) also gave 4 on reaction with 3 . Compounds 4 on heating at 230° yielded 4,5-dihydrooxazoles 5a-c or 5,6-dihydro-4H-1,3-oxazines 5d,e along with methyl 4-methyl-3-pentenoate ( 6 ).     

Reactions of nitrosonium hexafluorophosphate with some olefinic compounds in acetonitrile: one step synthesis of 4H-5,6-dihydro-1,2-oxazines

Reactions of nitrosonium hexafluorophosphate or tetrafluoroborate with olefins having aryl groups at an olefinic carbon atom at low temperature in acetonitrile afforded 4H-5,6-dihydro-1,2-oxazines with two aryl groups at C-4 and C-6 in fair to good yields.     

One-pot cyclizations of dilithiated oximes and hydrazones with epibromohydrin. Efficient synthesis of 6-hydroxymethyl-5,6-dihydro-4H-1,2-oxazines and oxazolo[3,4-b]pyridazin-7-ones

The one-pot cyclization of dilithiated oximes with epibromohydrin provided a convenient and regioselective approach to 6-hydroxymethyl-5,6-dihydro-4H-1,2-oxazines. The reaction of the latter with phosphorus tribromide resulted in a Beckmann rearrangement and formation of 5-bromomethyl-2-iminotetrahydrofurans. The reaction of dilithiated hydrazones with epibromohydrin afforded oxazolo[3,4-b]pyridazin-7-ones, which were formed by a novel domino cyclization.     

2-ethynylaziridines as chiral carbon nucleophiles: stereoselective synthesis of 1,3-amino alcohols with three stereocenters via allenylindium reagents bearing a protected amino group

Allenylindium reagents bearing a protected amino group were effectively prepared from N-protected 3-alkyl-2-ethynylaziridines by treatment with InI in the presence of Pd(PPh(3))(4) and H(2)O. Stereoselective addition of the allenylindium to aliphatic or aromatic aldehydes affords 1,3-amino alcohols bearing three contiguous chiral centers: while 2,3-trans-2-ethynylaziridines yield syn,syn-2-ethynyl-1,3-amino alcohols predominantly, 2,3-cis-aziridines give anti,syn isomers selectively. Synthesis of highly substituted ethynylazetidines is also described.     

The synthesis of 4-halotetrahydropyrans and 4-halo-5,6-dihydro-2H-pyrans via the lewis acid promoted cyclization of acetals of homoallylic and homopropargylic alcohols

Ethyl vinyl ether, MEM chloride, and dihydropyran based acetals of homoallylic and homopropargylic alcohols cyclize in the presence of Lewis acids to give 4-halotetra-hydropyrans and 4-halo-5,6-dihydro-2H-pyrans, respectively.     

4H-1,2-benzoxazines with electron-withdrawing substituents on the benzene ring: synthesis and application as potent intermediates for oxygen-functionalized aromatic compounds

A new general method for synthesizing functionalized 4H-1,2-benzoxazine derivatives is described. Although 4H-1,2-benzoxazine is one of the fundamental structure of the oxazine group, no general synthetic method for the heterocycle has been established. We found that 3-methoxycarbonyl-4H-1,2-benzoxazine was obtained in good yield when methyl 2-nitro-3-phenylpropionate was treated with an excess amount of trifluoromethanesulfonic acid. This methodology was also applicable for the synthesis of 4H-1,2-benzoxazine rings functionalized with various electron-withdrawing substituents on the benzene ring. Furthermore, we also show that the resulting 4H-1,2-benzoxazines can be used as precursors of functionalized o-quinone methides and multisubstituted phenols. This type of heterocycle can be a potent intermediate to oxygen-fuctionalized aromatic compounds.     

Highly facialselective synthesis of pyranose 1,3-oxazines and their ring opening with nucleophiles: a novel entry to 2-C-branched glycosides

A TMSOTf-promoted cycloaddition of N-benzoyl-N,O-acetals with various glycals and 3-deoxy glycals affords pyranose 1,3-oxazines with high facial selectivity. In addition, a highly diastereoselective ring opening of the resulting pyranose 1,3-oxazines is reported. With diverse nucleophiles, these reactions take place upon heating at 80 °C. This novel ring-opening reaction affords structurally diversified 2-C-branched glycosides with three newly formed contiguous stereocenters.     

Azines and azoles: CXXIII. Three-component condensation of 5-acetyl-4-hydroxy-3,6-dihydro-2H-1,3-thiazine-2,6-dione with o-phenylenediamine and carbonyl compounds as a convenient synthesis of substituted 1,5-benzodiazepines

Readily accessible 5-acetyl-4-hydroxy-3,6-dihydro-2H-1,3-thiazine-2,6-dione reacted with an equimolar amount of o-phenylenediamine under mild conditions (propan-2-ol, 5 min, reflux) to give the corresponding Schiff base. Reactions of the latter with aldehydes and ketones in propan-1-ol in the presence of a catalytic amount of trifluoroacetic acid or in acetic acid led to the formation of 4-hydroxy-5-(2-R-2,3-dihydro-1H-1,5-benzodiazepin-4-yl)-2H-1,3-thiazine-2,6-diones.     

An efficient synthesis of enantiomerically enriched trifluoromethylated 1,2-diols and 1,2-amino alcohols with quaternary stereocenters by diastereoselective addition of TMSCF3 to chiral 2-acyl-1,3-perhydrobenzoxazines

TMSCF3 adds to chiral 2-acyl-1,3-perhydrobenzoxazines with total diastereoselectivity leading to quaternary trifluoromethyl alcohols. Further transformation of the addition products yields enantiomerically enriched trifluoromethylated 1,2-diols and 1,2-amino alcohols.     

Lewis acid mediated SN2-type nucleophilic ring opening followed by [4+2] cycloaddition of N-tosylazetidines with aldehydes and ketones: synthesis of chiral 1,3-oxazinanes and 1,3-amino alcohols

A highly efficient strategy for Cu(OTf)₂ mediated S_N2-type nucleophilic ring opening followed by [4+2] cycloaddition reactions of enantiopure 2-phenyl-N-tosylazetidines with various aldehydes and ketones afforded a variety of substituted 1,3-oxazinanes and 1,3-amino alcohols in excellent yields, excellent de and good to excellent ee. The proposed S_N2-type mechanism of the cycloaddition reaction is supported by experimental evidence.     

Design, synthesis, and 1,3-dipolar cycloaddition of (5R)- [and (5S)]-5,6-dihydro-5-phenyl-2H-1,4-oxazin-2-one N-oxides as chiral (E)-geometry-fixed alpha-alkoxycarbonylnitrones

Optically pure (5R)- [and (5S)]-5,6-dihydro-5-phenyl-2H-1, 4-oxazin-2-one N-oxides [(5R)- and (5S)-2] were designed as chiral (E)-geometry-fixed alpha-alkoxycarbonylnitrones 1. The nitrones (5R)- and (5S)-2 were synthesized by three-step oxidation of (R)- and (S)-phenylglycinols [(R)- and (S)-3], condensation of the resulting (R)- and (S)-2-hydroxylamino-2-phenylethanols [(R)- and (S)-5] with glyoxylic acid, and cyclization of the intermediary nitrones (R)- and (S)-6b. The nitrone (5R)-2reacted with olefins 7-14 under mild conditions to afford the corresponding cycloadducts 15-22 as the main products via the least sterically demanding exo modes. Cycloadduct 30 obtained from (5S)-2 and cyclopentadiene was effectively elaborated to (1S,4S, 5R)-4-benzyloxycarbonylamino-2-oxabicyclo[3.3.0]oct-7-en-3-one (28), the key synthetic intermediate of carbocyclic polyoxin C.     

Palladium-catalyzed heteroannulation leading to heterocyclic structures with two heteroatoms: a highly regio- and stereoselective synthesis of (Z)-4-alkyl-2-alkyl(aryl)idene-3,4-dihydro-2H-1,4-benzoxazines and (Z)-3-alkyl(aryl)idene-4-tosyl-3,4-dihydro-2H-1,4-benzoxazines.

A highly convenient method has been developed for the synthesis of (Z)-4-alkyl-2-alkyl(aryl)idene-3,4-dihydro-2H-1,4-benzoxazines 9 and (Z)-3-alkyl(aryl)idene-4-tosyl-3,4-dihydro-2H-1,4-benzoxazines 34-38 through palladium-copper-catalyzed reactions. Aryl halides 7 reacted with 2-[N-alkyl(benzyl)-N-prop-2'-ynyl]aminophenyl tosylate 6 in the presence of (PPh3)2PdCl2 (3 mol %), CuI(5 mol %) in triethylamine at room temperature to yield 2-[N-alkyl(benzyl)-N-(3-aryl-prop-2'-ynyl)]-aminophenyl tosylates 8 in extremely good yields (72-96%). The latter could then be cyclized with KOH in ethanol-water to Z-9 in a highly regio- and stereoselective manner. Similarly, palladium-copper-catalyzed reaction of 2-(prop-2'-ynyloxy)aniline (21) with aryl iodides 7 led to 22-26 which after tosylation and cyclization with cuprous iodide in CH3CN in the presence of K2CO3 and Bu4-NBr led to the (Z)-3-alkyl(aryl)idene-4-tosyl 3,4-dihydro-2H-1,4-benzoxazines 34-38 in good overall yields. The Z-stereochemistry of the products was established from 1H NMR spectra, 3JCH values (between vinylic proton and methylenic carbon of the heterocyclic ring), NOE experiments, and X-ray analysis. The method was also found to be suitable for the synthesis of bis(benzoxazinylated) derivatives 17, 39, and 2-alkyl-3,4-dihydro-2H-1,4-benzoxazines 18. Our method for the synthesis of 3,4-dihydro-2H-1,4-benzoxazines is highly efficacious, using easily available starting materials under very mild conditions. Also the synthesis of some novel 5-substituted uracil derivatives 40 and 41 containing the benzoxazinyl moiety and of potential biological interest is being reported.     

The synthesis of 5,6-dihydro-6-methylthiazolo-[2,3-b] [1,3] benzodiazepines, 2,3,10,11-tetrahydro-10-methyl-1H-cyclopenta[4,5] thiazolo[2,3-b] [1,3] benzodiazepine,and 7,8,9,10,12,13-hexahydro-13-methylbenzothiazolo[2,3-b] [1,3]-benzodiazepine via 1,3,4,5-tetrahydro-5-methyl-2H-1,3-benzodiazepine-2-thione

Catalytic reductive scission of 4-methylcinnoline (V) with Raney nickel afforded o-amino-β-methylphenethylamine (IV) in 57% yield. Treatment of IV with carbon disulfide followed by thermal cyclization of the product furnished 1,3,4,5-tetrahydro-5-methyl-2H-1,3-benzodiazepine-2-thione (III). Reaction of III with ethyl chloroacetate, ethyl 2-bromohexanoate, ethyl 2-chloroacetoacetate, 2-bromo-2′-methoxyacetophenone, and 2-bromoacetophenone provided a series of substituted 5,6-dihydro-6-methylthiazolo[2,3-b][1,3]benzodiazepines. Condensation of III with 2-chlorocyclopentanone and 2-chlorocyclohexanone gave 2,3,10,11-tetrahydro-10-methyl-1H-cyclopenta[4,5]thiazolo[2,3-b][1,3]benzodiazepine and 7,8,9,10,12,13-hexahydro-13-methylbenzothiazolo[2,3-b][1,3]benzodiazepine, respectively. Structure assignments are discussed. None of the compounds possessed appreciable biological activity.     

Atropoenantiomerism of the Z-adduct of 2,3-diethoxycarbonyi-6,6-dimethyl-5,6-dihydro-4-pyridone with dimethyl acetylenedicarboxylate: synthesis and structure in solution and in the crystal

The title adduct (1) was synthesized, and its conformationally and configurationally rigid chiral structure in solution and in the crystal was established by NMR spectroscopy and by X-ray structural analysis. Atropoenantiomers of1 were observed by the¹H NMR method in the presence of a chiral shift reagent. A barrier to their interconversïon was determined, G^x > Z5 kcal mol^–1 (200 °C).Translated fromItvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1796–1799, July, 1996.     

Nickel(II) and zinc(II) complexes with N-(5,6-dihydro-4H-1,3-thiazin-2-yl)-2-aminobenzimidazole (BzTz): Synthesis,spectral and structural characterization

The reaction of nickel and zinc chlorides and nitrates with the ligand N-(5,6-dihydro-4H-1,3-thiazin-2-yl)-2-aminobenzimidazole (BzTz) leads to the formation of the new complexes: [NiCl₂(BzTz)₂] (1), [Ni(NO₃)(BzTz)₂(H₂O)₃](NO₃) (2), [ZnCl₂(BzTz)₂] (3) and [Zn(NO₃)₂(BzTz)₂] (4). They have been characterized by spectroscopic methods (electronic, infrared and NMR) and magnetic susceptibility measurements. Additionally, the crystal structures of the complexes 1 and 3 have been determined by X-ray single-crystal diffraction. The ligand exhibits the N-benzimidazole coordination mode on interacting with the metal centers. The X-ray structure of the complexes 1 and 3 reveals a distorted tetrahedral coordination geometry around the metal center, with the metallic atoms coordinated to two chlorine atoms and two benzimidazole nitrogen atoms. These two complexes are isostructural, crystallizing in the monoclinic system and Cc space group. In complex 2 the geometry around the nickel atom could be described as a distorted octahedron whereas in case of complex 4 the zinc atom is in a distorted tetrahedral environment.     

Brönsted acid ionic liquid-catalyzed direct benzylation, allylation and propargylation of 1,3-dicarbonyl compounds with alcohols as well as one-pot synthesis of 4H-chromenes

Recyclable ionic Brönsted acid was prepared in nearly quantitative yield by reacting 1-butylimidazole with an equimolar amount of 1,3-propanesultone, followed by treatment with an equimolar amount of trifluoromethanesulfonic acid. The ionic Brönsted acid-catalyzed direct benzylation, allylation and propargylation of 1,3-dicarbonyl compounds with various alcohols in ionic liquid [N-ethyl-N-methyl imidazolium trifluoromethanesulfonate (EMIOTf)], at 100 °C for 3 h proceeded smoothly to give the corresponding products in good to excellent yields without the use of any hazardous or volatile solvents and without any by-product such as salts. Furthermore, tandem benzylation-cyclization-dehydration of 1,3-dicarbonyl compounds to give functionalized 4H-chromenes was also achieved in this catalytic reaction.     

Efficient synthesis of 4-(2'-alkenyl)-2,5-dihydrofurans and 5,6-dihydro-2H-pyrans via the Pd-catalyzed cyclizative coupling reaction of 2,3- or 3,4-allenols with allylic halides

In the absence of a base, palladium(II) catalysts, such as PdCl(2), PdCl(2)(CH(3)CN)(2), Pd(OAc)(2), and [(pi-C(3)H(5))PdCl](2), can catalyze the cyclizative coupling reaction of 2,3- or 3,4-allenols with allylic halides in DMA at room temperature to provide 2,5-dihydrofurans and 5,6-dihydro-2H-pyrans, respectively, in moderate to good yields. Under similar reaction conditions, nonsubstituted 2,3-allenol 1s affords bimolecular cyclizative coupling product 5s as the major product. The scope of the reaction and its mechanism have been studied briefly. On the basis of the experimental results, the transformation was believed to proceed via a divalent palladium-catalyzed pathway.