A simple approach for the regioselective synthesis of imidazo[1,2-a]pyrimidiones and pyrimido[1,2-a]pyrimidinones

Several imidazo and pyrimido[1,2-a]pyrimidinones of type 1 and 2 were synthesized through intramolecular cyclization of pyrimidines 9 or pyrimidinones 10 bearing a variety of β and γ-aminoalcohols at the 2-position. Ring closure of the pyrimidinones of type 10 under Mitsunobu conditions lead to mixtures of both bicyclic regioisomers 1 and 2. Treatment of pyrimidines of type 9 with H₂SO₄ provided an efficient and operationally simple one-pot hydrolysis-cyclization procedure for obtaining imidazo and pyrimido[1,2-a]pyrimidinones 1 in good yields as the sole regioisomeric bicyclic product.     

A convenient synthesis of linear pyridinoimidazo[1,2-a]pyridine and pyrroloimidazo[1,2-a]pyridine cores

Two new imidazo[1,2-a]pyridine derivatives, pyridinoimidazo[1,2-a]pyridine (10) and pyrroloimidazo[1,2-a]pyridine (16), were synthesised from 2-amino-4-methyl-5-nitropyridine (1) by linear cyclisation, making use of dimethylformamide dimethylacetal (DMFDMA) as an agent of vinylamine functionalisation. This report describes first the formation of pyridine and pyrroloimidazopyridine from (1), and then the formation of pyridine-fused and pyrrolo-fused pyridine by the Friedländer method and reductive cyclisation followed by treatment of the resulting adduct with chloroacetaldehyde.     

Synthesis, structure, and electrochemical properties of biferrocenes annulated with 1,2-dithiin and 1,2-dithiin 1,1-dioxides

2,2″-Bis(N,N-dimethylaminosulfonyl)-1,1″-biferrocene (6), a precursor of biferrocenes annulated with 1,2-dithiin and 1,2-dithiin 1,1-dioxides, was prepared by a sequence of selective ortho-lithiation and dimerization reaction from N,N-dimethylaminosulfonylferrocene. New biferrocenes annulated with 1,2-dithiin (1) and 1,2-dithiin 1,1-dioxides (2) and (3) were successfully synthesized in satisfactory yields by the reaction of compound 6 with lithium aluminum hydride followed by treatment with chlorotrimethylsilane. The electrochemical properties of the biferrocenes (1)-(3) were furnished by voltammetric studies.     

Efficient synthesis of novel dipyridoimidazoles and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives

Novel dipyrido[1,2-a;3′,4′-d]imidazoles 7a-d, dipyrido[1,2-a;4′,3′-d]imidazoles 8a,c and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives 9a-d were synthesized by two pathways: thermal electrocyclic reaction of 3-alkenylimidazopyridine-2-oximes 10 and direct condensation of ethyl glycinate (or hydrazine) with 2,3-dicarbonylimidazo[1,2-a]pyridines 11.     

Synthesis and X-ray crystal structure of pyrrolo[1,2-a]benzimidazoles

Reaction of nitrilimines 1 with 2-cyanomethylbenzimidazole 2 gave the 3-arylazo-2-methylpyrrolo[1,2-a]benzimidazole 4a rather than the reported 2-arylazo-3-methylpyrrolo[1,2-a]benzimidazole 3a. The correct structure of the product was determined using X-ray crystal structure analysis. The similar reaction of nitrilimines with 2-aminobenzimidazole 5 gave the acyclic nucleophilic addition product 6.     

Synthesis of 2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-ones by the domino Michael addition retro-ene reaction of 2-alkoxyiminoimidazolidines and acetylene carboxylates

2-Alkoxyiminoimidazolidines 2-3 react with acetylene dicarboxylates and ethyl phenylpropiolate to give 8-alkoxy-imidazo[1,2-a]pyrimidin-5(3H)-ones C, which subsequently undergo a sterically induced multihetero-retro-ene fragmentation to give imidazo[1,2-a]pyrimidin-5(1H)-ones 4-7 together with formaldehyde or benzaldehyde. On the other hand, a similar reaction of 2-3 with ethyl propiolate gives corresponding 8-alkoxy-imidazo[1,2-a]pyrimidin-5(3H)-ones 8-10. The unsubstituted imidazo[1,2-a]pyrimidin-5(1H)-one 11 can be prepared by retro-ene reaction of 9 upon prolonged heating in refluxing ethanol. A direct synthetic approach to 1-formyl-7-phenyl-imidazo[1,2-a]pyrimidine-5(1H)-one 14 is reported using DMF/sulfonyl chloride as a new Vilsmeier-type N-formylating reagent.     

Substituent-induced regioselective synthesis of 1,2-teraryls and pyrano[3,4-c]pyran-4,5-diones from 2H-pyran-2-ones

Substituent-controlled regioselective synthesis of highly functionalized 1,2-teraryls 3a-k has been achieved through ring transformation of 6-aryl-4-(pyrrolidin-1-yl/piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1a-g by aryl acetones 2a-c in the presence of powdered KOH in DMF in very good yield. Under similar reaction conditions, 6-aryl-4-methylsulfanyl-2H-pyran-2-ones 5a-f afforded 1,7-diaryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-diones 6a-j as major products and 3,4-diaryl-2-methyl-6-methylsulfanylbenzonitriles as minor constituents 7a-j.     

A facile synthesis of pyrrolo[1,2-a]benzimidazoles and pyrazolo[3,4:4′,3′]pyrrolo[1,2-a]benzimidazole derivatives

Reaction of 2-cyanomethylbenzimidazole 1 with hydrazonoyl halides 2 led to formation of pyrrolo[1,2-a]benzimidazole derivatives 7. Similar reaction of 1 with halides 3 afforded 5-amino-4-(benzimidazol-2-yl)pyrazole derivatives 11 or 1-amino-2-arylpyrazolo[3,4:4′,3′]pyrrolo[1,2-a]benzimidazol-4-one 14 depending on the reaction conditions. The mechanisms of the studied reactions are discussed.     

Silicon-carbon unsaturated compounds. 73. Photolysis of cis- and trans-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane in the presence of tert-butyl alcohol and acetone

Irradiation of cis-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane (1a) in the presence of tert-butyl alcohol in hexane with a low-pressure mercury lamp bearing a Vycor filter proceeded with high stereospecificity to give cis-2,3-benzo-1-tert-butoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (2a), in 33% isolated yield, together with a 15% yield of 1-[(tert-butoxy)methylphenylsilyl]-4-(methylphenylsilyl)butane (3). The photolysis of trans-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane (1b) with tert-butyl alcohol under the same conditions gave stereospecifically trans-2,3-benzo-1-tert-butoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (2b) in 41% isolated yield, along with a 12% yield of 3. Similar photolysis of 1a and 1b with tert-butyl alcohol-d₁ produced 2a and 2b, respectively, in addition to 1-[(tert-butoxy)(monodeuteriomethyl)(phenyl)silyl]-4-(methylphenylsilyl)butane. When 1a and 1b were photolyzed with acetone in a hexane solution, cis- and trans-2,3-benzo-1-isopropoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (4a and 4b) were obtained in 25% and 23% isolated yield. In both photolyses, 1-(hydroxymethylphenylsilyl)-4-(methylphenylsilyl)butane (5) was also isolated in 4% and 5% yield, respectively. The photolysis of 1a with acetone-d₆ under the same conditions gave 4a-d₆ and 5-d₁ in 18% and 4% yields.     

2-Allyl-N-benzyl substituted α-naphthylamines as building blocks in heterocyclic synthesis. New and efficient syntheses of benz[e]naphtho[1,2-b]azepine and naphtho[1,2-b]azepine derivatives

A new series of 13-acetyl-7,12-dihydro-7-ethylbenz[e]naphtho[1,2-b]azepine (4a-d) and 2-aryl-4-hydroxy-2,3,4,5-tetrahydronaphtho[1,2-b]azepine derivatives (6a-d) have been synthesized from N-allyl-N-benzyl substituted α-naphthylamines (1a-d) by utilizing aromatic amino-Claisen rearrangement, intramolecular Friedel-Crafts alkylation and intramolecular dipolar 1,3-cycloaddition nitrone-olefin reactions.     

An efficient synthesis of (E)-(2-arylpyrazino[1,2-a]pyrimidine-4-ylidene)acetonitriles and cyanomethyl appended pyrimidines

A series of (E)-(2-arylpyrazino[1,2-a]pyrimidine-4-ylidene)acetonitriles 5a-j and aryl/heteroaryl tethered pyrimidin-4-yl acetonitriles 6a-e has been synthesized in excellent yields through base catalyzed ring transformation of suitably functionalized 2H-pyran-2-ones 3 using 2-aminopyrazine 4a and arylamidinium salts 4b, separately.     

Selective synthesis of bis[1,2]dithiolo[1,4]thiazines from 4-isopropylamino-5-chloro-1,2-dithiole-3-ones

Reaction of 4-isopropylamino-5-chloro-1,2-dithiole-3-ones 3 and S₂Cl₂ in acetonitrile gave selectively 3-oxo-bis[1,2]dithiolo[1,4]thiazine-5-thiones 1 by the addition of triethylamine and bis[1,2]dithiolo[1,4]thiazine-3,5-diones 5 under the action of formic acid. 3,5-Diones 5 were also obtained by intramolecular cyclization of N,N-bis(5-chloro-3-oxo[1,2]dithiol-4-yl)amines 6 with S₂Cl₂ in the presence of Et₃N.     

Rearrangement of 3-alkylidene-2-siloxy-tetrahydro-1,2-oxazines (ASENA). A new approach toward the synthesis of 3-α-hydroxyalkyl-5,6-dihydro-4H-1,2-oxazines

A new approach toward the synthesis of 3-α-hydroxyalkyl-5,6-dihydro-4H-1,2-oxazines 1 from available 5,6-dihydro-4H-1,2-oxazine N-oxides 2 has been described. The key step of the process—the rearrangement of 3-alkiliden-2-siloxy-tetrahydro-1,2-oxazines 3 (ASENA)—was thoroughly investigated. Optimal experimental conditions were developed. A possible pathway of the ASENA rearrangement was proposed.     

Facile synthesis of regio-isomeric naphthofurans and benzodifurans

Naphtho[1,2-b]furans 1a-f, naphtho[2,1-b]furans 2a-f, benzo[1,2-b:5,4-b′]difurans 3a-b, benzo[1,2-b:4,5-b′]difurans 4a-b, and benzo[1,2-b:4,3-b′]difurans 5a-b were synthesized by base-catalyzed cyclization reaction of the corresponding o-alkoxybenzoylarene derivatives. The o-alkoxybenzoylarenes were obtained from the etherification reaction of the o-hydroxybenzoylarenes, which were prepared either by the reaction of methoxyarenes with benzoyl chloride in the presence of aluminum chloride or by photo-Fries rearrangement of aryl benzoates.     

Intramolecular rearrangement of 1,3-bistriflate ester of thiacalix[4]arene to 1,2-counterpart: an efficient di-O-protection method for the stereoselective synthesis of anti-1,2-diethers

A net anti-selective dialkylation of the proximal hydroxy groups of thiacalix[4]arene 2 is achieved for the first time via the initial protection of the two proximal hydroxy groups of compound 2 with Tf moieties by intramolecular rearrangement of easily preparable 1,3-bistriflate ester 3 to 1,2-counterpart 4, followed by anti-selective dialkylation of the remaining hydroxy groups with alkyl halides or under the Mitsunobu conditions and subsequent removal of the Tf moieties.     

Synthesis of (S)-2-amino-7-methoxytetralin and isoindolo[1,2-a]isoquinolinone derivatives from l-aspartic acid

This paper describes a new total synthesis for (S)-2-amino-7-methoxytetralin, (S)-7-MeO-AT, from l-aspartic acid in an overall yield of 10% over nine steps. The major loss was ascribed to a key intramolecular Friedel–Crafts cyclization step, which afforded up to 36% yield. Attempts to perform a Friedel–Crafts cyclization of an intermediate phthalimide protected amino alcohol 13 did not give the desired protected (S)-7-MeO-AT. On the other hand, two new isoindolo[1,2-a]isoquinolinone derivatives 14 and 15, were isolated in 21 and 11% yield, respectively. The yield of 15 was improved to 70%.     

First allylboration of organic compounds with the NN double bond. Synthesis of N-allylpyrazolidines and allyl-1,2-diphenylhydrazine

Triallylborane adds to the NN double bond of pyrazolines 1 and 2 at 0 °C giving after deboronation the corresponding N-allylpyrazolidines 4 and 5. Further transformations of allylpyrazolidine 4 including the cyclopropane ring opening were studied. Allylboration of azobenzene with triallylborane gives rise to 1-allyl-1,2-diphenylhydrazine.     

Stabilization of (N-methyleneamino)imidoylketenes: synthesis of dipyrazolo[1,2-a;1′,2′-d][1,2,4,5]tetrazines

Thermolysis of substituted methyl 1-methyleneamino-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates 2a,b led to substituted dimethyl 3,9-dioxo-1,5,7,11-tetrahydro-1H,7H-dipyrazolo[1,2-a;1′,2′-d][1,2,4,5]tetrazine-1,7-dicarboxylates 4a,b and methyl 2,5-dihydro-5-oxo-1H-pyrazole-3-carboxylates 5a,b as minor products. The structure of compound 4a was determined by X-ray crystallography. The proposed mechanism of this conversion includes generation of (N-methyleneamino)imidoylketenes 6a,b and its intramolecular transformation to azomethine imines—5-oxo-2,5-dihydropyrazole-1-methylium-2-ides 7a,b, which undergo dimerization in head-to-tail manner yielding products 4a,b and partially hydrolyse to compounds 5a,b.     

A one-pot synthesis and 1,3-dipolar cycloaddition of [1,2]dithiolo[4,3-b]indole-3(4H)-thiones

Treatment of N-substituted 2-methyl-1H-indoles 1 with S₂Cl₂ and DABCO in chloroform gave the corresponding [1,2]dithiolo[4,3-b]indole-3(4H)-thiones 5 by the addition of triethylamine in high yield. 1,2-Dithiole-3-thiones 5 underwent cycloaddition with one or two DMAD equivalents to afford either 2-(3-thioxo-1,3-dihydro-2H-indol-2-ylidene)-1,3-dithioles 10 or fused 4,5-dihydrothiopyrano[3,2-b]indoles 9.     

Novel 6-substituted benzothiazol-2-yl indolo[1,2-c]quinazolines and benzimidazo[1,2-c]quinazolines

The synthetic route to and a preliminary biological evaluation of novel indolo[1,2-c]quinazolines (8) and benzimidazo[1,2-c]quinazolines (9) are described. The products were obtained by condensation of the appropriate diamines (e.g. 2-(2-aminophenyl)indole or 2-(2-aminophenyl)benzimidazole) with 2-cyanobenzothiazoles. This work further demonstrates the general applicability of microwaves for a facile and rapid access to original heterocycles with potential pharmaceutical value.