Regioselective Baeyer-Villiger lactonization of 2-substituted pyrrolidin-4-one. Synthesis of statine

Nine 2-substituted pyrrolidin-4-ones 4a-i were obtained via a series of functional group transformation of known prolinol 5 by facile six kinds of methodologies. The target structure of 1,3-amino alcohols 2a-i was constructed in the regioselective Baeyer-Villiger lactonization of ketones 4a-i and reduction of the resulting 4-substituted tetrahydro-1,3-oxazin-6-ones 3a-i. A new and straightforward synthesis of (3S,4S)-statine (6) has been established starting from trans-(2S,4R)-4-hydroxyproline (1).     

A novel transformation of 1-exo-substituted 2a-aroyl-1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones with sulfoxonium ylide to highly strained 2a-(1-arylethenyl)-1,2,2a,7b-tetrahydrocyclobuta[b]benzofurans

When 1-substituted 2a-aroyl-1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones (1) were treated with dimethylsulfoxonium methylide, 1-endo isomers (endo-1) gave 1-substituted 3-aroyl-1,2,4a,9b-tetrahydrodibenzofuran-4-ols (2) exclusively as expected. On the other hand, 1-exo isomers (exo-1) underwent a novel transformation to 1-substituted 2a-(1-arylethenyl)-1,2,2a,7b-tetrahydrocyclobuta[b]benzofurans (3), together with 2.     

Efficient synthesis and applications of 2-substituted azulene derivatives: towards highly functionalized carbo- and heterocyclic molecules

An efficient synthesis of 2-substituted azulene derivatives (3-6) was accomplished from ethyl 2-oxo-2H-cyclohepta[b]furan-3-carboxylate 1 and its derivative 2, which in turn were prepared from readily available tropolone. Compounds 1 and 2 were utilized to construct densely functionalized benz[a]azulene and azulene-furan frameworks (16-25, 29-34, 37, 38).     

A simple synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles

A simple four-step synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8 (or their 1H-pyrazol-3(2H)-one tautomers 8′) as the pyrazole analogues of histamine was developed. First, enamino lactam 3 was prepared as the key intermediate in two steps from 2-pyrrolidinone (1). Next, acid-catalysed ‘ring switching’ transformations of 3 with monosubstituted hydrazines 4 gave N-[(1-substituted 5-hydroxy-1H-pyrazol-4-yl)ethyl]benzamides 7a-k and N-[2-(2-heteroaryl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)ethyl]benzamides 7′l-o. Benzamides 7a-k and 7′l-o were finally hydrolysed by heating in 6 M hydrochloric acid to furnish 1-substituted 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8a-k and 4-(2-aminoethyl)-2-heteroaryl-1H-pyrazol-3(2H)-ones 8′l-o in good overall yields.     

1,3-Dipolar cycloaddition of diazoalkanes onto dimethyl 1-(formylamino)ethylenephosphonate: a new route to 1-aminocyclopropanephosphonic acids and 3-phosphorylated pyrazoles

Diazoalkanes regiospecifically react with dimethyl 1-(formylamino)ethylenephosphonate (1a) to afford 5-substituted dimethyl 3-(formylamino)-4,5-dihydro-3H-pyrazol-3-phosphonates 2 in high yields. Their thermal decomposition followed by hydrolysis provides a straightforward access to 2-substituted 1-aminocyclopropanephosphonic acids 4. Aromatization of 2 under acidic conditions leads to 3-phosphorylated pyrazoles 5.     

Synthesis and conformational analysis of 1,3,2-diazaphosphorino[6,1-a]isoquinolines, a new ring system

Through ring-closure reactions of N- or 1′-substituted 1-(2′-aminoethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines (5a-e) with phenylphosphonyl dichloride, 1- or 3-substituted 4-phenyl-1,3,4,6,7,11b-tetrahydro-2H-1,3,2-diazaphosphorino[6,1-a]isoquinolin-4-one diastereomers (7a-e and 8a-c,e), the first representatives of a new ring system, were prepared. The diastereomeric ratios in the cyclizations and the conformer (A-E) populations of the nitrogen-bridged tricyclic systems (7 and 8) were strongly influenced by the N- and 1′-substituents of the starting diamines. The conformational analysis of compounds 7 and 8 was performed by ¹H, ¹³C and ³¹P NMR methods.     

Palladium mediated synthesis of isoindolinones and isoquinolinones

The palladium-catalyzed reactions of 2-iodo-N-substituted benzamides 5-10 with acrylic esters 11-14 led to N-substituted-3-alkylisoindolinone esters 15-22 in good yields. The esters of isoindolinones 15-22 underwent hydrolysis reactions yielding the N-aryl-1,2,3,4-tetrahydro-1-oxoisoquinoline-3-carboxylic acid 26-31 in good yields.     

Highly stereoselective synthesis of para-substituted (E)-N-styrylcarbazoles via sequential silylative coupling-Hiyama coupling reaction

A series of new para-substituted (E)-(N)-styrylcarbazoles, i.e., eight (E)-9-[2-(aryl)ethenyl]-9H-carbazoles (5-12) and 1,4-bis[(E)-2-(9H-carbazol-9-yl)vinyl]benzene (13), have been synthesized in high yield and stereoselectively by a sequential silylative coupling-Hiyama coupling reaction, i.e., coupling of commercially available 9-vinylcarbazole with vinyltriethoxysilane or divinyltetramethyldisiloxane in the presence of [RuHCl(CO)(PCy₃)₂] (I), followed by Pd (II) catalyzed cross-coupling with para-substituted iodobenzenes.The tandem procedure has facilitated the synthesis of 13. X-ray structures of the intermediate silylvinylcarbazole (4), as well as products 12 and 13 have been obtained.     

Synthesis of 4-substituted azepino[3,4-b]indole-1,5-diones

Mono- or dibromo derivatives 2 and 3 were prepared by an efficient two-step route from 10-methyl-azepino[3,4-b]indole-1,5-dione 1. Elimination reaction on 2 gave access to 4-bromo-10-methyl-2H,10H-azepino[3,4-b]indole-1,5-diones 4. Finally, 4-substituted 10-methyl-2H,10H-azepino[3,4-b]indole-1,5-diones 6-14 were synthesised in good yields from 4 via palladium-mediated cross-coupling reactions.     

Synthesis of conformationally constrained analogues of RGD tripeptide

Convergent syntheses of N-functionalized (3S,4S)-3-amino-4-vinyl-piperidin-2-one 10, trans-3-substituted proline 18 and (3S)-3-amino-piperidin-2-one 28 are developed. By incorporating these building blocks to an appropriate position, conformationally constrained analogues of RGD tripeptide (Arg-Gly-Asp) 2, 3 and 4 are designed and synthesized.     

Substituted coumarin amidines: useful building blocks for the preparation of [1]benzopyrano[4,3-b]pyridin-5-one and [1]benzopyrano[4,3-d]pyrimidin-5-one derivatives

The synthesis of [1]benzopyrano[4,3-b]pyridin-5-ones 4a-f and 4g-j starting from 3-formylcoumarin and 3-cyanocoumarin N-functionalized amidines 3a-f and 3g-j, respectively, was reported. The ring-closure reaction mechanism, under basic or acidic media, was proposed. Furthermore, the reaction of 3-formylamidines 3a,c-f with ammonium acetate gave good yields of 2-substituted [1]benzopyrano[4,3-d]pyrimidin-5-ones 7.     

Convenient synthesis of t-butyl Z-3-substituted glycidates under conditions of phase-transfer catalysis

Reactions of mixtures of t-butyl E- and Z-3-substituted glycidates 1a-h with 50% aq. sodium hydroxide and a catalyst, benzyltriethylammonium chloride, TEBAC in dichloromethane (phase-transfer catalysis, PTC) led to preferential hydrolysis of the E-isomers to afford pure (90-98%) t-butyl Z-3-substituted glycidates 1a-i in good yields; PTC cleavage of glycidates additionally substituted at C-2, 1g or C-3, 1h,i suggests that an aryl group in the Z isomers hampers attack of HO⁻ on the carbonyl carbon atom. As described in the literature, the diastereoselective PTC synthesis of Z-3-substituted glycidates and glycidonitriles consists of fast hydrolysis of E isomers present in mixtures with Z ones.     

3-Amino- and 3-acylamido-2-phosphonopyridines: synthesis by Pd-catalyzed P-C coupling, structure and conversion to pyrido[b]-anellated PC-N heterocycles

Palladium catalyzed cross-coupling of 3-amino- and 3-acylamido-2-bromopyridines 1a-f with triethyl phosphite allowed the synthesis of 3-amino- and 3-acylamido pyridine-2-phosphonic acid diethyl esters 2a-f, whereas nickel catalysts, although providing access to related anilido-2-phosphonates, proved inactive. Reduction of the aminophosphonate 2a with LiAlH₄ afforded 3-amino-2-phosphinopyridine (3a), which was cyclocondensed with dimethylformamide dimethyl acetal (DMFA) via phosphaalkene intermediates 4a to the novel pyrido[b]-anellated 1,3-azaphosphole 5a. Reaction of amidophosphonates 2b-f with LiAlH₄ did not result in the expected reductive cyclization, as shown by closely related anilido-2-phosphonates, but led to product mixtures containing N-secondary 3-amino-2-phosphinopyridines 3b-f as the main or major component. The conversion of 3b,d,e with DMFA to 5b,d,e provides first examples of N-substituted pyrido[b]-anellated azaphospholes. Structures were confirmed by multinuclear NMR and X-ray crystallography (for 2c, 3b).     

One-pot facile conversion of Baylis-Hillman adduct into N-alkyl 3-(E)-alkylidene-5-substituted sulfonylpiperidine-2,6-dione. Formal synthesis of tacamonine

A stepwise [3+3] strategy to N-alkyl 3-(E)-alkylidene-5-substituted sulfonylpiperidine-2,6-dione 1 used various N-alkyl α-substituted sulfonylacetamides 2 and α,β-unsaturated esters 3 as starting materials. α,β-Unsaturated esters 3 were generated by Baylis-Hillman reaction. A ring closure mechanism was proposed for the reactions. This method provides a convenient formal synthesis of tacamonine.     

Rapid synthesis of tetrahydro-4H-pyrazolo[1,5-a]diazepine-2-carboxylate

Hydrazines condense with dimethyl 2-pyrrolidino-4-oxo-2-pentenedioate in the presence of aq. HCl to form N-substituted pyrazole-3,5-dicarboxylates 2. Complex bicyclic derivatives, such as pyrazolo-oxazine 3a, pyrazolo-oxazepine 3b, pyrazolo-pyrazine 4a, and pyrazolo-diazepine 4b, were generated using 2-hydrazinoethanol, 3-hydrazinopropanol, 2-hydrazinoethylamine, and 3-hydrazinopropylamine.     

Synthesis and reactivity of para-substituted benzoylmethyltellurium(II and IV) compounds: observation of intermolecular C-H-O hydrogen bonding in the crystal structure of (p-MeOC6H4COCH2)2TeBr2

Bis(p-substituted benzoylmethyl)tellurium dibromides, (p-YC₆H₄COCH₂)₂TeBr₂, (Y=H (1a), Me (1b), MeO (1c)) can be prepared either by direct insertion of elemental Te across C_Rf-Br bonds (where C_Rf refers to α-carbon of a functionalized organic moiety) or by the oxidative addition of bromine to (p-YC₆H₄COCH₂)₂Te (Y=H (2a), Me (2b), MeO (2c)). Bis(p-substituted benzoylmethyl)tellurium dichlorides, (p-YC₆H₄COCH₂)₂TeCl₂ (Y=H (3a), Me (3b), MeO (3c)), are prepared by the reaction of the bis(p-substituted benzoylmethyl)tellurides 2a-c with SO₂Cl₂, whereas the corresponding diiodides (p-YC₆H₄COCH₂)₂TeI₂ (Y=H (4a), Me (4b), MeO (4c)) can be obtained by the metathetical reaction of 1a-c with KI, or alternatively, by the oxidative addition of iodine to 2a-c. The reaction of 2a-c with allyl bromide affords the diorganotellurium dibromides 1a-c, rather than the expected triorganotelluronium bromides. Compounds 1-4 were characterized by elemental analyses, IR spectroscopy, ¹H, ¹³C and ¹²⁵Te NMR spectroscopy (solution and solid-state) and in case of 1c also by X-ray crystallography. (p-MeOC₆H₄COCH₂)₂TeBr₂ (1c) provides, a rare example, among organotellurium compounds, of a supramolecular architecture, where C-H-O hydrogen bonds appear to be the non-covalent intermolecular associative force that dominates the crystal packing.     

Regioselective synthesis of 1- and 4-substituted 7-oxopyrazolo[1,5-a]pyrimidine-3-carboxamides

The synthesis of 7-substituted pyrazolo[1,5-a]pyrimidine-3-carboxamides was studied. First, methyl 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (5) was prepared in three steps from methyl 5-amino-1H-pyrazole-4-carboxylate (3). Treatment of 5 with POCl₃ gave the highly reactive 7-chloro derivative 10, which was reacted with amines, benzyl alcohol, and phenylboronic acid in the presence of Pd-catalyst to give the corresponding 7-substituted derivatives 11. Hydrolysis of the esters 5 and 11 followed by amidation gave the corresponding carboxamides 16a–h and 15. Regioselectivity of N-alkylation of 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid derivatives 5 and 16 was tunable by the carboxy function. Alkylation of the secondary amides 16a–f furnished the 1-alkyl derivatives 17a–f, whereas the ester 5 and the tertiary amides 16g,h gave the 4-alkyl derivatives 14a–d and 16m,n, selectively.     

New 2-functionalized 2H-3,4-dihydro-1,4-benzothiazin-3-ones and their application in the synthesis of spiro heterocycles

The reaction of 2-chloro-3,4-dihydro-2H-1,4-benzothiazin-3-ones 1 with enamines is an efficient synthetic method to produce 2-substituted derivatives. The resulting bifunctional compounds such as 6a,b, 7c,d and 8b react with hydrazines to furnish the spiro derivatives of N-aminopyrrole or 3-pyridazinone depending on the direction of the primary nucleophilic attack and the nature of the nucleophile. Under the reaction conditions, spiro pyridazinones 13 are converted into the 3-pyridazinone-4-carboxylic acid derivatives 9 via the 1,4-thiazine ring opening.     

Asymmetric synthesis of 3-substituted unsaturated prolines from chiral sulfoximine substituted allyl titanium(IV) complexes

An asymmetric synthesis of the 3-substituted Δ^3,4-unsaturated prolines 7a-e and 3-substituted 4-methylene prolines 14a-c starting from the corresponding γ,δ-unsaturated α-amino acids 4a-e and 11a-c, respectively, is described. Amino acid derivatives 4a-e and 11a-d were obtained through aminoalkylation of the corresponding sulfoximine substituted allyl titanium(IV) complexes 2a-e and 10a-d, respectively, with the N-tert-butylsulfonyl imino ester 3. Activation of sulfoximines 4a-e and 11a-c through methylation of the sulfoximine group followed by a KF mediated isomerization of the vinyl aminosulfoxonium salts 5a-e and 12a-c, respectively, to the corresponding allyl aminosulfoxonium salt 6a-e and 13a-c, respectively, and a subsequent intramolecular nucleophilic substitution of the allylic aminosulfoxonium group afforded the enantio- and diastereomerically pure proline derivatives in medium to high yields.     

Reactions of 2-hydroxybenzophenones with Corey-Chaykovsky reagent

A variety of 2-hydroxybenzophenones on reaction with Corey-Chaykovsky reagent underwent unprecedented rearrangements leading to 3-substituted benzofurans 8 and one-carbon homologated compounds 9 and 12. Compounds 9 could further be quantitatively transformed to 2-substituted benzofuran derivatives 10.