Base-induced Ring Closure Research Articles

Synthesis of indazoles from 2-formylphenylboronic acids.

A method for the synthesis of indazoles was developed which involves a copper(ii) acetate catalysed reaction of 2-formylboronic acids with diazadicaboxylates followed by acid or base induced ring closure. Hydrazine dicarboxylates were also shown as competent reaction partners for the synthesis of indazoles, however, they required a stoichiometric amount of copper(ii) acetate for the C–N bond formation step. The transformation can be efficiently performed as a two step-one pot procedure to give a range of 1N-alkoxycarbonyl indazoles.

Practical two-step synthesis of enantiopure styrene oxide through an optimized chemoenzymatic approach.

Enantiopure styrene oxide (SO) and its derivatives are important building blocks for chiral synthesis. In this study, we developed an attractive "1-pot, 2-step" chemoenzymatic approach for producing enantiopure SO with 100% theoretical yield. This approach involved asymmetric reduction of α-chloroacetophenone by an alcohol dehydrogenase (ADH; step 1), followed by base-induced ring closure (epoxidation) of enantiopure 2-chloro-1-phenylethanol produced by the ADH (step 2). By-product formation during epoxidation was suppressed to <1% by adding methyl tert-butyl ether (MTBE) as the second phase. Therefore, with this optimized approach, ADH from Lactobacillus kefir (LkDH) successfully produced 1M (S)-SO, with 99% analytical yield and 97.8% enantiomeric excess (ee). In the preparation of (R)-SO, a semi-rational strategy of active pocket iterative saturation mutagenesis (ISM) was successfully used to inverse the enantioselectivity of LkDH (muDH2, F147L/Y190P/A202F/M206H/V196L/S96D/K97V), which produced the opposite enantiomer (R)-2-chloro-1-phenylethanol. Through the optimized chemoenzymatic approach, muDH2 was successfully used to prepare 1M (R)-SO, with 98.1% ee and 99.0% analytical yield. Our results indicated that this optimized chemoenzymatic approach could be used to produce both enantiomers of SO at concentrations as high as 120g/L within 14h, which is the highest concentration as far as we know. MuDH2 obtained through ISM also showed reversed enantioselectivity toward another 13 aromatic ketones, compared with wild-type (WT) LkDH. Furthermore, a molecular docking experiment demonstrated that muDH2 inverted the binding orientation of the substrate, which may be the reason for its inverse enantioselectivity.

Stereoselective synthesis of both enantiomers of trans-2-(diphenylmethylideneamino)cyclopropanecarboxylic acid using a chiral pool approach and their incorporation in dipeptides

The stereoselective synthesis of (1R,2R)- and (1S,2S)-trans-2-(diphenylmethylideneamino)cyclopropanecarboxylic acid has been accomplished in six steps starting from (2S)- and (2R)-β-benzyl N-(tert-butoxycarbonyl)aspartate, respectively. The key-step in the reaction sequence is a stereoselective base-induced ring closure with a good trans diastereoselectivity. These novel trans-β-ACC derivatives could be incorporated in dipeptides employing a standard peptide coupling technique.

Synthesis of 1-Alkyl-2-(trifluoromethyl)azetidines and Their Regiospecific Ring Opening toward Diverse α-(Trifluoromethyl)Amines via Intermediate Azetidinium Salts

A convenient approach toward nonactivated 1-alkyl-2-(trifluoromethyl)azetidines as a new class of constrained azaheterocycles was developed starting from ethyl 4,4,4-trifluoroacetoacetate via imination, hydride reduction, chlorination, and base-induced ring closure. Furthermore, the reactivity profile of these 2-CF(3)-azetidines was assessed by means of quaternization and subsequent regiospecific ring opening at C4 of the azetidinium intermediates by oxygen, nitrogen, carbon, sulfur, and halogen nucleophiles, pointing to a clear difference in reactivity compared to azetidines bearing other types of electron-withdrawing groups at C2.

Synthesis of novel β-aminocyclobutanecarboxylic acid derivatives by a solvent-free aza–Michael addition and subsequent ring closure

Novel β-aminocyclobutanecarboxylic acid derivatives were prepared via a sequential solvent-free aza-Michael addition of benzophenone imine across 3-halopropylidenemalonates and base-induced ring closure. These highly substituted cyclobutanedicarboxylic acid derivatives were subjected to a reactivity study which demonstrated the tendency of these donor-acceptor substituted four-membered rings to be converted into their corresponding ring-opened products.

ChemInform Abstract: A Pummerer-Type Novel Ring Fission of 2-Methylsulfinyl-5,6-dihydro-4H- 1,3,4-thiadiazine Derivatives: A Homologation of Aldehydes and Ketones.

Aldehydes and ketones were converted into 2-methylsulfinyl-5,6-dihydro-4H-1,3,4-thiadiazines via the formation and base-induced ring-closure of N-alkylidene-N′-bis(alkylthio)methylenehydrazines followed by mCPBA oxidation. The subsequent Pummerer-type ring fission of the rings was performed by treating with trifluoroacetic anhydride or trifluoromethanesulfonic anhydride at −78 °C to give α,β-unsaturated esters and ketones in modest yields. Thus, this reaction sequence was regarded as being a new method for the two-carbon homologation of aldehydes and ketones.

Efficient Aziridination of Olefins Catalyzed by Mixed‐Valent Dirhodium(II,III) Caprolactamate.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Efficient Aziridination of Olefins Catalyzed by Mixed-Valent Dirhodium(II,III) Caprolactamate

[reaction: see text] A mild, efficient, and selective aziridination of olefins catalyzed by dirhodium(II) caprolactamate [Rh(2)(cap)(4).2CH(3)CN] is described. Use of p-toluenesulfonamide (TsNH(2)), N-bromosuccinimide (NBS), and potassium carbonate readily affords aziridines in isolated yields of up to 95% under extremely mild conditions with as little as 0.01 mol % Rh(2)(cap)(4). Aziridine formation occurs through Rh(2)(5+)-catalyzed aminobromination and subsequent base-induced ring closure. An X-ray crystal structure of a Rh(2)(5+) halide complex, formed from the reaction between Rh(2)(cap)(4) and N-chlorosuccinimide, has been obtained.

Total Synthesis of Eleutherobin and Eleuthosides A and B

The total synthesis of the cytotoxic marine natural products eleutherobin (1) and eleuthosides A (2) and B (3) is described. The strategy involves glycosidation of the (+)-carvone-derived intermediate 7 with the arabinose-derived trichloroacetimidate 9 followed by base-induced ring closure and elaboration to afford the dihydroxy eneynone 19. Selective hydrogenation of 19 led to the generation and intramolecular collapse of dienone 20 furnishing 21 and thence 22 with the required structural framework of the target molecules. Finally, esterification with mixed anhydride 24 followed by deprotection gave eleutherobin (1) which served as a precursor to eleuthosides A (2) and B (3). The α-glycoside anomer of eleutherobin, compound 27, was also synthesized by application of the developed chemistry, demonstrating the flexibility of the sequence in generating designed analogues for biological screening.

A Pummerer-Type Novel Ring Fission of 2-Methylsulfinyl-5,6-dihydro-4H-1,3,4-thiadiazine Derivatives: A Homologation of Aldehydes and Ketones

Abstract Aldehydes and ketones were converted into 2-methylsulfinyl-5,6-dihydro-4H-1,3,4-thiadiazines via the formation and base-induced ring-closure of N-alkylidene-N′-bis(alkylthio)methylenehydrazines followed by mCPBA oxidation. The subsequent Pummerer-type ring fission of the rings was performed by treating with trifluoroacetic anhydride or trifluoromethanesulfonic anhydride at −78 °C to give α,β-unsaturated esters and ketones in modest yields. Thus, this reaction sequence was regarded as being a new method for the two-carbon homologation of aldehydes and ketones.

A catalytic enantioselective synthesis of chiral monosubstituted oxiranes

A new catalytic enantioselective synthesis of monosubstituted oxiranes has been developed from achiral trichloromethyl ketones by (a) enantioselective carbonyl reduction, (b) selective bis-dechlorination and (c) base-induced ring closure of the resulting chlorohydrins.

Fluorine as an ortho-directing group in aromatic metalation: A two step preparation of substituted benzo[b]thiophene-2-carboxylates

A simple 2-step synthesis of B-ring substituted benzo[b]thiophene-2-carboxylates from aryl fluorides has been developed. The route involves a selective lithiation ortho to fluorine, followed by formylation, and subsequently, displacement of fluorine with thioglycollate and base-induced ring closure in a single operation.

Reinvestigation of the Base-Induced Ring Closure of Methylsulfonium Salts of N-Trityl-(S)-methioninehydroxamide and Derivatives.

Reinvestigation of the Base-Induced Ring Closure of Methylsulfonium Salts of N-Trityl-(S)-methioninehydroxamide and Derivatives.

Synthesis of 4-Amino-2(5H)-furanones through Intra- and Intermolecular Nitrile Addition of Ester Enolates. Construction of Carbon Framework of an Antitumor Antibiotic Basidalin

Abstract Two new routes to 4-amino-2(5H)-furanones are disclosed. The one is based on the reaction of a magnesium enolate of t-butyl acetate or propionate with O-protected cyanohydrins followed by acid-treatment which effects hydrolysis of the ester group, deprotection, olefin isomerization and lactonization all in a single operation. The other is base-induced ringclosure of α-acyloxy nitriles. The two methods are applied to construction of the carbon framework of an antitumor antibiotic basidalin.

Benzoxadiazocines, benzothiadiazocines and benzotriazocines-IV : Ring closure of 1-(2-[n-(2-chloroethyl and 2-hydroxyethyl)-n-methylamino]phenyl)-3-phenylthioureas. tetrahydroquinoxaline vs.dihydro-3,1,6-benzothiadiazocine and hexahydro-1,3,6-benzotriazocinethione formation

While base induced ring closure of 1-(2-[N-(alkylsulfonyl and arylsulfonyl)-N-(2-chloroethyl)amino]phenyl)-3-phenylthioureas 1 had furnished the corresponding type 2 dihydro-3,1,6-benzothiadiazocine derivatives rather than the isomeric hexahydro-1,3,6-benzotriazocinethiones ( 3) or tetrahydroquinoxalines ( 4), base induced ring closure of the related N-(2-chloroethyl)-N-Me derivatives 9a- 9c, 10a and lOb furnishes type 14 tetrahydroquinoxalines. 14a is obtained also by treating the N-(2-hydroxyethyl)-N-Me derivative 11 with the triphenylphosphine-diethyl azodicarboxylate (DEAD) reagent. In situ replacement of the chlorine atom of compound 9a by iodine in the absence of base as well as treatment of 1-(2-[N-(2-hydroxyethyl)-N-methylamino]phenyl)-1-methyl-3-phenylthiourea ( 18) with the triphenyl-phosphine-DEAD reagent furnishes the benzimidazole derivatives 16 and 22, respectively, whose formation may be rationalised by assuming the intermediacy of the dihydro- and tetrahydro-3,1,6-benzothiadiazocine derivatives 12a · HI and 20, respectively, and their subsequent ring contraction.

Synthesis of 3-hydroxy-2,3,4,5-tetrahydro-3-methyl[1]benzoxepins by ring-closure of isoprenyl terminal epoxides

Terminal olefins (13), obtained from reactions oftertiary chlorides (10) with triphenylmethyl-lithium, were converted into epoxides (14); base-induced ring-closure of the latter gave 2-hydroxymethyl-2-methylchromans (15) and 3-hydroxy-2,3,4,5-tetrahydro-3-methyl[1]benzoxepins (17). Dehydration of the tetrahydrobenzoxepin (17a) furnished dihydro[1] benzoxepins.

Base-induced ring closure of bis-dithioacetals via an apparent carbenoid. A novel route to functionalized cyclobutanes and cyclopentanes

Base-induced ring closure of bis-dithioacetals via an apparent carbenoid. A novel route to functionalized cyclobutanes and cyclopentanes

α-Amino-sulphonic acid derivatives. Part II. Synthesis and ring closure of some iodomethylsulphonyl-benzamidines and -guanidines

The synthesis of a representative number of N(1)-substituted N(2)-iodomethylsulphonylbenzamidines is reported, together with the new general synthesis of N(1)N(3)-disubstituted N(2)-sulphonylguanidines by the interaction of sulphonamides and carbodi-imides in the presence of base. The base-induced ring closure of these iodomethylsulphonyl compounds has been shown to provide a route to 3-aryl- and 3-arylamino-4-aryl-and-alkyl-Δ2-1,2,4-thiadiazoline 1,1-dioxides.

Intramolecular oxime–acyl attack: new routes to 1,2,4-triazine 4-oxides and 1,2,3-triazoles

A number of 3-substituted 1,2,4-triazine 4-oxides and their deoxy-analogues have been synthesised via an intramolecular condensation between neighbouring oxime and acylhydrazone functions. The condensation takes place only in molecules of rigidly favourable geometry, such as the oxime-acylhydrazones of 1,2-naphthaquinone, in which oxime and acyl group are rigidly held in positions sterically favourable for interaction. In molecules of less rigid geometry, oxime-acylhydrazones derived from benzil, for example, ring-closure does not take place. The exact nature of the product of cyclisation depends on the structure of the acyl group. Thus oxime-guanyl-hydrazones yield 3-amino-1,2,4-triazine 4-oxides, and oxime-semicarbazones cyclise to the analogous 3-hydroxycompounds. On the other hand, the 3-amino-triazine oxides formed on cyclisation of oxime-thiosemicarbazones undergo deoxygenation concurrently with formation, and the ultimate products are the analogous deoxy-compounds. The ring-closure process, which is formally an addition–elimination reaction at acyl carbon, is subject to catalysis by either acid or base, or both.Replacement of the acyl group in the oxime-acylhydrazone by structures which bear an electron-deficient atom other than carbon causes a considerable modification in the chemistry of the compounds. Thus oxime-OO′-di-phenylphosphorohydrazones undergo a base-induced ring-closure to 1,2,3-triazoles while the analogous oxime-toluene-p-sulphonylhydrazones decompose spontaneously with the formation of the related 1-hydroxy-1,2,3-triazoles. Mechanisms are suggested for the ring-closure processes discussed.