The 1,3-Dipolar Cycloadditions of Nitrile Oxides and Nitrile Imines to Alkyl Dicyanoacetates

The readily available alkyl dicyanoacetates 1 reacted with the 1,3-dipolar reagents arenecarbonitrile oxides 2 ′ and arenecarbonitrile imines 5 ′ to afford 1,2,4-oxadiazol and 1,2,4-triazol derivatives. The arenecarbonitrile oxides 2 ′ with electron-donating groups on the arene ring gave products 3a – d resulting from addition on both CN groups of 1 , and those with electron-withdrawing groups provided mono-adducts 4a – e (Scheme 1). Arylnitrile imines 5 ′ reacted with 1 to offer both bis- and mono-addition products (Scheme 2); the bis-adducts 8a , b possess an ester structure, whereas the mono-adducts 6a – d present a ketene-hemiacetal structure.     

Tautomeric structure of 1-methyldihydropyridazino-[3,4-b]quinoxalines in solution

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 1 with ethyl 2-ethoxymethylene-2-cyano-acetate or ethoxymethylenemalononitrile gave 6-chloro-2-[2-(2-cyano-2-ethoxycarbonylvinyl)-1-methylhy-drazino]quinoxaline 4-oxide 3a or 6-chloro-2-[2-(2,2-dicyanovinyl)-1-methylhydrazino]quinoxaline 3b , respectively. The reaction of 3a with a base afforded 7-chloro-1-methyl-1,5-dihydropyridazino[3,4-b]quinoxaline 4 . From the NOE spectral data, the 1-methyldihydropyridazino[3,4-b]quinoxalines 2a, 2b and 4 were found to exist as the 1,5-dihydro form in a dimethyl sulfoxide or trifluoroacetic acid/dimethyl sulfoxide solution.     

Site-selective photocycloadditions of 2-pyrones with electron-poor olefins and the derivation from the cycloadducts

Photosensitized cycloaddition of 4,6-dimethyl-2-pyrone ( 1 ) with methacrylonitrile ( 3b ) afforded two types of [2 + 2]cycloadducts, 4b and 6b , across the C₅-C₆ and C₃-C₄ double bonds in 1 , respectively. Photosensitized reactions of 1 with dimethyl maleate and dimethyl cyclobutene-1,2-dicarboxylate gave [2 + 2]cycload-ducts 4d, 4e across the C₅-C₆ double bond, in addition to [4 + 2]cycloadduct 9d or bicyclo[4.2.0]octadiene 10e . The photoreactions of methyl 2-pyrone-5-carboxylate ( 2 ) with 3b and 2-chloroacrylonitrile ( 3c ) gave [4 + 2]cycloadducts 5b, 5c in addition to [2 + 2]cycloadducts 11b and 11c across the C₅-C₆ double bond in 2 . The photocycloaddition mechanism was explained from results calculated by means of PM3-CI method. Namely, the site- and/or regio-selective products, 4, 5, 8, 9 and 10 were thought to come from the same site-selective radical intermediates in the case of electron-poor olefins. Pyrolysis and/or hydrolysis of the cycload-ducts 4e, 5b, 5c gave 5,6-dihydro-2-pyrone 12 or benzene derivatives.     

A convenient synthesis of novel pyridazino[3,4-b]quinoxaline and pyrazolo[3,4-b]quinoxaline utilizing 1,3-dipolar cycloaddition reaction

The reaction of 2,6-dichloroquinoxaline 4-oxide 4 with methylhydrazine gave 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 5, whose reaction with dimethyl acetylenedicarboxylate or 2-chloroacrylonitrile resulted in the 1,3-dipolar cycloaddition reaction to afford 7-chloro-3,4-bismethoxycarbonyl-1-methyl-1,2-dihydropyridazino[3,4-b]quinoxaline 6 or 6-chloro-3-hydroxymethylene-1-methyl-2,3-dihydro-1H-pyrazolo[3,4-b] quinoxaline hydrochloride 7, respectively.     

The synthesis and reactivity of polysilylacetylenes: Diels—Alder reactions to give bis (silyl) benzenes

Six bis(silyl)acetylenes (XMe²Si? C?C? SiMe₂X) with the following varied silicon substituents X were prepared: 1 (Me, Me); 2 (H, H); 3 (C1, H); 4 (CI, CI); 5 (MeO, H); 6 (MeO, MeO). While 1 and 2 may be prepared by the reaction of dilithio- or bis(bromomagnesium)-acetylide with the appropriate chlorosilane, similar reactions designed to give 3–6 yielded oligomers, XMe₂Si? (? C?C? SiMe₂)_n? X, 7, X=CI, MeO, as the major products, indicating that the acetylenic functionality on silicon activates the chlorosilane towards nucleophilic substitution. Compounds 3 and 4 were prepared by free radical chlorination of 2. Methanolysis of 3 and 4 gave quantitative yields of 5 and 6 respectively. Compounds 1–6 undergo a Diels–Alder reaction with α-pyrone to produce, after loss of carbon dioxide, bis(silyl)-substituted benzene derivatives. The order of reactivity has been determined to be: 4=6>3=5>1>2, indicating that chloro or alkoxy substituents favor the cycloaddition with 2- pyrone. The adducts formed by compounds 3–6 undergo an unusually facile hydrolysis or elimination to give 1,1,3,3-tetramethyl-1,3-disila-2-oxaindane.     

New Studies on [2+3] Cycloadditions of Thermally Generated N‐Isopropyl‐ and N‐(4‐Methoxyphenyl)‐Substituted Azomethine Ylides

The thermal reaction of 1‐substituted 2,3‐diphenylaziridines 2 with thiobenzophenone ( 6a ) and 9H‐fluorene‐9‐thione ( 6b ) led to the corresponding 1,3‐thiazolidines (Scheme 2). Whereas the cis‐disubstituted aziridines and 6a yielded only trans‐2,4,5,5‐tetraphenyl‐1,3‐thiazolidines of type 7 , the analogous reaction with 6b gave a mixture of trans‐ and cis‐2,4‐diphenyl‐1,3‐thiazolidines 7 and 8 . During chromatography on SiO₂, the trans‐configured spiro[9H‐fluorene‐9,5′‐[1,3]thiazolidines] 7c and 7d isomerized to the cis‐isomers. The substituent at N(1) of the aziridine influences the reaction rate significantly, i.e., the more sterically demanding the substituent the slower the reaction. The reaction of cis‐2,3‐diphenylaziridines 2 with dimethyl azodicarboxylate ( 9 ) and dimethyl acetylenedicarboxylate ( 11 ) gave the trans‐cycloadducts 10 and 12 , respectively (Schemes 3 and 4). In the latter case, a partial dehydrogenation led to the corresponding pyrroles. Two stereoisomeric cycloadducts, 15 and 16 , with a trans‐relationship of the Ph groups were obtained from the reaction with dimethyl fumarate ( 14 ; Scheme 5); with dimethyl maleate ( 17 ), the expected cycloadduct 18 together with the 2,3‐dihydropyrrole 19 was obtained (Scheme 6). The structures of the cycloadducts 7b, 8a, 15b , and 16b were established by X‐ray crystallography.     

Preparation of 6-(nitron-c-yl)- and 6-(1,3-butadienyl)-2-pyrones and their cycloaddition reactions

6-(N-Substituted nitron-C-yl)-2-pyrones 1 and 6-(4-substituted 1,3-butadienyl)-2-pyrone 2 were prepared and their cycloaddition reactions with three kinds of diene systems were investigated. Namely, the reactions of 1 with methyl acrylate, vinyl crotonate and divinylsulfone took place at the nitrone moiety to afford 3-substituted isoxazolidines 9–14 , and that of 2 with maleimide took place at the 2-pyrone moiety to give a bis-adduct 17 via elimination of carbon dioxide.     

Thermal [2+3]‐Cycloadditions of trans‐1‐Methyl‐2,3‐diphenylaziridine with CS and CC Dipolarophiles: An Unexpected Course with Dimethyl Dicyanofumarate

The thermal reaction of trans‐1‐methyl‐2,3‐diphenylaziridine (trans‐ 1a ) with aromatic and cycloaliphatic thioketones 2 in boiling toluene yielded the corresponding cis‐2,4‐diphenyl‐1,3‐thiazolidines cis‐ 4 via conrotatory ring opening of trans‐ 1a and a concerted [2+3]‐cycloaddition of the intermediate (E,E)‐configured azomethine ylide 3a (Scheme 1). The analogous reaction of cis‐ 1a with dimethyl acetylenedicarboxylate ( 5 ) gave dimethyl trans‐2,5‐dihydro‐1‐methyl‐2,5‐diphenylpyrrole‐3,4‐dicarboxylate (trans‐ 6 ) in accord with orbital‐symmetry‐controlled reactions (Scheme 2). On the other hand, the reactions of cis‐ 1a and trans‐ 1a with dimethyl dicyanofumarate ( 7a ), as well as that of cis‐ 1a and dimethyl dicyanomaleate ( 7b ), led to mixtures of the same two stereoisomeric dimethyl 3,4‐dicyano‐1‐methyl‐2,5‐diphenylpyrrolidine‐3,4‐dicarboxylates 8a and 8b (Scheme 3). This result has to be explained via a stepwise reaction mechanism, in which the intermediate zwitterions 11a and 11b equilibrate (Scheme 6). In contrast, cis‐1,2,3‐triphenylaziridine (cis‐ 1b ) and 7a gave only one stereoisomeric pyrrolidine‐3,4‐dicarboxylate 10 , with the configuration expected on the basis of orbital‐symmetry control, i.e., via concerted reaction steps (Scheme 10). The configuration of 8a and 10 , as well as that of a derivative of 8b , were established by X‐ray crystallography.     

Oxidation of 7,8‐diaminotheophylline with lead tetraacetate and reaction of the oxidation product, 6‐cyanoimino‐5‐diazo‐1,3‐dimethylpyrimidine‐2,4‐dione with alcohols or amines

Oxidation of 7,8‐diaminotheophylline (1) with lead tetraacetate in refluxing toluene gave a mixture of 3‐amino‐5,7‐dimethylpyrimido[4,5‐e][1,2,4]triazine‐6,8‐dione ( 2 ) and 6‐cyanoimino‐5‐diazo‐1,3‐dimethylpyrimidine‐2,4‐dione ( 4 ). The latter was transformed to 2 by the reaction with 1‐propanethiol in quantitative yield. The reaction of 4 with methanol, ethanol and 1‐propanol in the presence of rhodium ( II ) acetate gave 5‐alkoxy‐6‐(2‐alkyl‐3‐isoureido)‐1,3‐dimethylpyrimidine‐2,4‐diones ( 7a‐c ). A similar reaction of 4 with alkylamines such as n‐propylamine, n‐butylamine, isobutylamine and n‐hexylamine gave a mixture of 7‐alkyl‐8‐aminotheophyllines ( 8a‐d ) and (5‐alkylamino‐1,3‐dimethyl‐2,4‐dioxopyrimidin‐6‐yl)cyanamides ( 9a‐d ).     

Synthesis and structure elucidation of 3-methoxy-1-methyl-1H-1,2,4,-triazol-5-amine and 5-methoxy-1-methyl-1H-1,2,4,-triazol-3-amine

Previously it was shown that condensation of dimethyl N-cyanodithioimidocarbonate ( 1a ) with methylhydrazine gave predominantly 1-methyl-5-methylthio-1H-,2,4-triazol-3-amine ( 2 ), which was initially identified erroneously as the regioisomer l-methyl-3-methylthio-1H-1,2,4-triazol-5-amine ( 3 ). We have found that reaction of dimethyl N-cyanoimidocarbonate ( 1b ) with methyl hydrazine affords a high yield of 3-methoxy-1-methyl-1H-1,2,4-triazol-5-amine ( 4 ) rather than the regioisomer 5-methoxy-1-methyl-1H-1,2,4-triazol-3-amine ( 5 ). The structure assignment of 4 was confirmed by X-ray crystallographic analysis of the benzenesulfonyl isocyanate adduct 7 . Triazole 5 was obtained after reacting dimethyl N-cyanothioimidocarbonate ( 1c ) with methylhydrazine.     

Synthesis of nitrogen-containing heterocycles. 4. A facile route to new 1, 2, 4-triazole derivatives

The reaction of amino-N(4),N(4)-dimethylaminornethylenehydrazones 1 of some aliphatic carbonyl compounds with ethyl ethoxymethylenecyanoacetate 2 gave directly symmetrical gem-bis(3-dimethylamino-1, 2, 4-triazol-1-yl)alkanes 4 and (3-dimethylamino-1, 2, 4-triazol-1-yl)alkenes 5 at room temperature, with the former being major product. On the other hand, the reaction of amino- N (4)-methylaminomethylenehydrazone homologue 1 of aliphatic ketone with 2 gave ethyl 2-alkyl-5-methylamino[1, 2, 4]triazolo[1, 5-c]pyrimidine-8-carboxylate 7 as the only product with elimination of alkane.     

The Synthesis of Naphthosultine and Benzodisultines and Their Pyrolysis with Dienophiles: Studies on o‐Naphthoquinodimethane and Bis‐o‐Quinodimethane

Sealed tube reactions of the naphthosultine 8 with a series of electron‐deficient dienophiles (fumaronitrile, N‐phenylmaleimide, dimethyl fumarate, and dimethyl acetylenedicarboxylate) in toluene at 180 °C gave corresponding 1:1 cycloadducts 11–14 in various amounts along with rearranged naphthosulfolene 7 in 67–95% yields. The reaction of 1,2,4,5‐tetra(bromomethyl)benzene with Rongalite (sodium form aldehyde sulfoxylate) and tetrabutylammonium bromide in DMF gave benzodisultines 17 and 18 in a combined yield of 56%. Sealed tube reactions of benzodisultines 17 and 18 with a series of dienophiles in xylene at 200 °C gave corresponding 1:1 and 1:2 cycloadducts 20–27 . The results suggested that thermal extrusion of sulfurdioxide from these sultines led to either o‐naphthoquinodimethane 6 (from 8 ) or bis‐o‐quinodimethane 19 (from 17 and 18 ); sub sequent trapping of these reactive intermediates by dienophiles and SO₂ gave various 1:1 and 1:2 Diels‐Alder ad ducts in modest to excellent yields.     

Reaction of 2,6-dibutylaminohepta-2,5-dien-4-one with malononitrile

Malononitrile reacted with the title compound to give 6-amino-5-cyano-2-(3,3-dicyano-2-methylallylidene-4-methyl-2H-pyran (3). Treatment of 3 with hot 80% sulfuric acid yielded 4,7-dimethyl-56-hydroxy-2(1H)quinolone. With concentrated aqueous sodium hydroxide, 3 gave 5-amino-3,6-dicyano-4,7-dimethyl-2(1H)quinolone and 5-amino-6-carbamoyl-3-cyano-4,7-dimethyl-2(1H)quinolone. The reaction of 3 with hydrochloric in acetic acid gave a mixture of 6-amino-3,7-dicyano-2,8-dimethyl-4-quinolizone and 3-cyano-4-methyl-6-(3,3-dicyano-2-methylallyl)-2-pyrone. Compound 3 also reacted with methylamine, butylamine and piperidine to give 8-amino-5-cyano-4-methyl-2-pyridone, 6-bulylamino-5-cyano-4-methyl-2-pyridone and 5-eyano-4-methyl-6-piperidino-2-pyridone respectively.     

Electrophilic substitution reactions of indole alkaloids with α,β-unsaturated carbonyl compounds in the presence of K10 montmorillonite

Reactions of indole, 1-methylindole, and 3-methylindole with dimethyl acetylenedicarboxylate in the presence of K10 montmorillonite as a catalyst led to the formation of the corresponding dimethyl 2,2-bis(indolyl)butanedioates. The reaction of 2-methylindole with dimethyl acetylenedicarboxylate gave dimethyl 2-(2-methyl-1H-indol-3-yl)maleate and dimethyl 2-methyl-1H-1-benzoazepine-3,4-dicarboxylate. Dimethyl 1,5-dimethyl-1H-1-benzoazepine-3,4-dicarboxylate was obtained by treatment of 1,3-dimethylindole with dimethyl acetylenedicarboxylate using K10 clay as a catalyst. Published in Russian in Zhurnal Organicheskoi Khimii, 2006, Vol. 42, No. 6, pp. 900–902. The text was submitted by the authors in English.     

Furopyridines. XX. Wittig-horner reaction of a phosphonate of reissert analogues of furo[3,2-c]-, -[2,3-c]- and -[3,2-b]pyridines

Furo[3,2-c]-( 1a ), -[2,3-c]- ( 1b ) and -[3,2-b]pyridine ( 1c ) were reacted with isopropyl chloroformate and trimethyl phosphite to give dimethyl 5-isopropoxycarbonyl-4,5-dihydrofuro[3,2-c]pyridine-4-phosphonate ( 2a ), dimethyl 6-isopropoxycarbonyl-6,7-dihydrofuro[2,3-c]pyridine-7-phosphonate ( 2b ) and dimethyl 4-isopropoxycarbonyl-4,7-dihydrofuro[3,2-b]pyridine-7-phosphonate ( 2c ) as unstable syrups. Reaction of 2b and 2c with n-butyllithium and then with benzaldehyde, p-methoxybenzaldehyde, p-cyanobenzalde-hyde or propionaldehyde afforded the normal Wittig reaction products 5b-H, 5b-OMe, 5b-CN, 5b-Et, 5c-H, 5c-H, 5c-OMe and 5c-CN , except for 2b with propionaldehyde. While, the same reactions of compound 2a and the reaction of 2b with propionaldehyde afforded the unexpected products, 5-isopropoxycar-bonylfuro[3,2-c]pyridinio-4-aryl-(or ethyl)methoxides 3a-H, 3a-OMe, 3a-CN and 3a-Et , 4-(1′-aryl(or ethyl)-1′-hydroxymethyl)furo[3,2-c]pyridines 4a-H, 4a-OMe, 4a-CN and 4a-Et accompanying formation of the normal products. Treatment of the normal Wittig reaction products with lithium diisopropylamide and then with acetone gave the derivatives alkylated at the 2-or the benzylic positions.     

Synthesis of a Glyoxalase I Inhibitor from Streptomyces griseosporeus NIIDAet OGASAWARA

The pseudolactones 6 and 12 were prepared in a straightforward way from methyl α-D -glucopyranoside and methyl α-D -mannopyranoside, respectively. The pseudolactone 6 reacted with tert-butyl lithioacetate to give the protected, trihydroxylated cyclohexenone carboxylate 7 (51 %). The sterically hindered, L-ribo-configurated pseudolactone 12 reacted with diethyl ethylphosphonate and dimethyl methylphosphonate to give the protected trihydroxycyclohexenones 17 (49 %) and 18 (62 %), respectively. The hydroxymethylated cyclohexenone 21 was obtained from 18 by treatment with Me₂AlSPh and then formaldehyde, oxidation of the product 19 , and elimination. Deprotection of 21 gave 2 , identical with KD16-Ul. Esterification of 2 gave 1 , identical with the title compound. Alternatively, 1 was obtained in higher yields by esterification of 21 , followed by deprotection of the hydroxy groups. This synthesis gave 1 and 2 from methyl α-D -mannopyranoside in an overall yield of 18 and 20 %, respectively, confirming their absolute configuration.     

Reaction of 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)]-hydrazinoquinoxaline 4-oxide with dimethyl acetylenedicarboxylate

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 4a with methyl or phenyl isothiocyanate gave 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7a or 6-chloro-2-[1-methyl-2-(N-phenylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7b , respectively, whose reaction with dimethyl acetylenedicarboxylate afforded 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-3-methyl-4-oxo-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8a or 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-4-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8b , respectively.     

Reaction of cyclic imidates with α,β‐unsaturated esters: Synthesis of new pyrrolo[2,1‐b]‐1,3‐oxazine and pyrido[2,1‐b]‐1,3‐oxazine derivatives

The cycloaddition reaction of cyclic imidates, 2‐benzyl‐5,6‐dihydro‐4H‐1,3‐oxazines 1a , 1b , 1c , 1d , 1e , 1f , with dimethyl acetylenedicarboxylate 2 , trimethyl ethylenetricarboxylate 4 , or dimethyl 2‐(methoxymethylene)malonate 6 afforded new fused heterocyclic compounds, such as methyl (6‐oxo‐3,4‐dihydro‐2H‐pyrrolo[2,1‐b]‐1,3‐oxazin‐7‐ylidene)acetates 3a , 3b , 3c , 3d , 3e , 3f (71–79%), dimethyl 2‐(6‐oxo‐3,4,6,7‐tetrahydro‐2H‐pyrrolo[2,1‐b]‐1,3‐oxazin‐7‐yl)malonates 5b , 5c , 5d , 5e , 5f (43–71%), or methyl 6‐oxo‐3,4‐dihydro‐2H,6H‐pyrido[2,1‐b]‐1,3‐oxazine‐7‐carboxylates 7a , 7b , 7c , 7d , 7e , 7f (32–59%), respectively. In these reactions, 1a , 1b , 1c , 1d , 1e , 1f (cyclic imidates, iminoethers) functioned as their N,C‐tautomers (enaminoethers) 2 to α,β‐unsaturated esters 2 , 4, and 6 to give annulation products 3 , 5 , and 7 following to the elimination of methanol, respectively. J. Heterocyclic Chem., (2011).     

Tandem Hydroformylation/Reductive Amination of 3‐Allyl‐2‐methylquinazolin‐4(3H)‐one

The 3‐allyl‐2‐methylquinazolin‐4(3H)‐one ( 1 ), a model functionalized terminal olefin, was submitted to hydroformylation and reductive amination under optimized reaction conditions. The catalytic carbonylation of 1 in the presence of Rh catalysts complexed with phosphorus ligands under different reaction conditions afforded a mixture of 2‐methyl‐4‐oxoquinazoline‐3(4H)‐butanal ( 2 ) and α,2‐dimethyl‐4‐oxoquinazoline‐3(4H)‐propanal ( 3 ) as products of ‘linear’ and ‘branched’ hydroformylation, respectively (Scheme 2). The hydroaminomethylation of quinazolinone 1 with arylhydrazine derivatives gave the expected mixture of [(arylhydrazinyl)alkyl]quinazolinones 5 and 6 , besides a small amount of 2 and 3 (Scheme 3). The tandem hydroformylation/reductive amination reaction of 1 with different amines gave the quinazolinone derivatives 7 – 10 . Compound 10 was used to prepare the chalcones 11a and 11b and pyrazoloquinazolinones 12a and 12b (Scheme 4).     

Iron Carbonyl Induced Reactions of Norbornene Derivatives with Substituted Acetylenes

Photochemical reactions of norbornadiene with substituted acetylenes in the presence of Fe(CO)₅ gave various products of different types, depending on the nature of the acetylene. The results are summarized in Table 1. The cyclopentanone 1 was always formed in these reactions. In the reaction of disubstituted acetylenes such as dimethyl acetylenedicarboxylate and ethyl phenylpropiolate, the cyclopentenones 2 and 5 were formed, respectively. By contrast, propiolic esters produced the cyclohexenones 3 and 4 , in which the ester group was attached on the β carbon with respect to the keto group. Plausible mechanisms for the formation of these products are shown in Schemes 7 and 8. The reaction of diphenylacetylene gave the cyclohexendione 7 as well as the cyclopentenone 6 . Two enedione products 8 and 9 were obtained from the reaction of phenylacetylene. Compound 9 was converted to the aromatic diacetate 13 by heating with acetic anhydride in pyridine. On irradiation in the presence of Fe(CO)₅ norbornene reacted similarly with dimethyl acetylenedicarboxylate and phenylacetylene to give the cyclopentenone 14 and the cyclohexenone 15 , respectively. Compound 15 , upon heating, isomerized to hydroquinone 16 , which on acetylation gave the diacetate 17 .