A new, one-pot, three-component synthesis of 4H-pyrido[1,2-a]pyrimidines, 4H-pyrimido[1,2-a]pyrimidines, and 4H-pyrazino[1,2-a]pyrimidines

A new, one-pot and three-component synthesis of 4H-pyrido[1,2-a]pyrimidines, 4H-pyrimido[1,2-a]pyrimidines, and 4H-pyrazino[1,2-a]pyrimidines is described. The reactive 1:1 zwitterionic intermediate, formed by the addition of isocyanides to dialkyl acetylenedicarboxylates, was trapped by N-(2-heteroaryl)amides to yield a ketenimine intermediate, which was cyclized and then rearranged under the reaction conditions to afford the title compounds under mild reaction conditions in good yields. Single-crystal X-ray analysis conclusively confirms the structure of the obtained bridgehead bicyclic 6-6 heterocyclic compounds.     

A novel, one-pot, three-component synthesis of 4H-pyrido[1,2-a]pyrimidines

A novel, one-pot, three-component synthesis of 4H-pyrido[1,2-a]pyrimidines is described. The reactive 1:1 zwitterionic intermediate, formed by the addition of isocyanides to dialkyl acetylenedicarboxylates, was trapped by N-(2-pyridyl)amides to produce the title compounds under mild reaction conditions in good yields.     

Reaction between isocyanides and dialkyl acetylenedicarboxylates in the presence of 2,4-dihydro-3H-pyrazol-3-ones. One-pot synthesis of highly functionalized 7-oxo-1H,7H-pyrazolo[1,2-a]pyrazoles

The reactive 1:1 intermediate produced in the reaction between isocyanides and dialkyl acetylenedicarboxylates was trapped by 2,4-dihydro-3H-pyrazol-3-ones to yield highly functionalized 7-oxo-1H,7H-pyrazolo[1,2-a]pyrazoles in fairly good yields.     

Synthesis of indole analogues of the anti-Helicobacter pylori compounds CJ-13,015, CJ-13,102, CJ-13,104 and CJ-13,108

Racemic syntheses of indole analogues of four phthalide-containing anti-Helicobacter pylori agents CJ-13,015, CJ-13,102, CJ-13,104 and CJ-13,108 are reported via manipulation of a common intermediate. This intermediate was formed by the N-alkylation of 4,6-dimethoxyindole with a long chain bromide followed by further chain extension. Oxidation, acetylation, or Barton-McCombie deoxygenation of the intermediate followed by Wacker oxidation afforded three analogues whilst further reduction of one analogue afforded the final analogue.     

Enantioselective, chemoenzymatic synthesis, and absolute configuration of the antioxidant (−)-gloeosporiol

The natural antioxidant (−)-gloeosporiol, isolated as a peracetylated derivative from a culture of the fungus Colletotrichum gloeosporioides, has been enantioselectively prepared from 3,4-dihydroxybenzaldehyde by means of a chemoenzymatic synthesis. The key intermediate was obtained by resolution with a lipase from Pseudomonas cepacia. Its stereochemistry, initially assigned as R, according to the Kazlaukas empirical rule for secondary alcohols, was independently confirmed by NMR and chirooptic methods. This, in turn, allowed the assignment of compound (−)-1 as (−)-(2S,3R,4R)-2-(3′,4′dihydroxyphenyl)tetrahydrofuran-3,4-diol.     

Novel synthesis of 2,2-dialkyl-3-dialkylamino-2,3-dihydro-1H-naphtho[2,1-b]pyrans

2,2-Dialkyl-3-dialkylamino-2,3-dihydro-1H-naphtho[2,1-b]pyrans were prepared from 2-naphthol, a secondary amine, and 3-hydroxy-2,2-dialkylpropanal in the presence of a catalytic amount of p-toluenesulfonic acid. This one-pot reaction involves retro-aldol disintegration of 3-hydroxy-2,2-dialkylpropanal followed by formation of a Mannich base intermediate from 2-naphthol, a secondary amine, and formaldehyde (retro-aldol product). This Mannich base then disproportionates into a quinone methide intermediate and the secondary amine is regenerated. It then forms an enamine intermediate with 2,2-dialkylacetaldehyde (another retro-aldol product). Finally, the quinone methide intermediate undergoes electrocyclic ring closure with enamines to produce the title compounds.     

One-pot three-component reaction of isocyanides, dialkyl acetylenedicarboxylates and phthalhydrazide: synthesis of highly functionalized 1H-pyrazolo[1,2-b]phthalazine-5,10-diones

Protonation of the highly reactive 1:1 intermediate produced in the reaction between alkyl isocyanides and electron-deficient acetylenic esters with phthalhydrazide, leads to a vinylisonitrilium cation, which undergoes an addition reaction with the conjugate base of the phthalhydrazide to produce dialkyl 3-(alkylamino)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine-1,2-dicarboxylates in fairly good yields at room temperature.     

Facile synthesis of 1H-pyrazolo[1,2-a]pyridazine-5,8-dione derivatives by a one-pot, three-component reactions

Protonation of the highly reactive 1:1 intermediate produced in the reaction between alkyl or aryl isocyanides and electron-deficient acetylenic esters with 3,6-dihydroxypyridazine, leads to a vinylisonitrilium cation, which undergoes an addition reaction with the conjugate base of the 3,6-dihydroxypyridazine to produce dialkyl 3-(alkyl or arylamino)-5,8-dioxo-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazine-1,2-dicarboxylates in good yields at room temperature.     

Synthesis of N-hydroxyenamide, a potential precursor of chartelline

In our synthetic plan for chartelline A-C, a compound including N-hydroxyenamide moiety was designed as an important intermediate. Synthesis of the required N-hydroxyenamide by N-acylation of a suitable oxime derivative has been developed using model compounds.     

AsLn2, a luciferin-related modified tripeptide from the bioluminescent earthworm Fridericia heliota

AsLn2, an unusual modified peptide, was isolated from the bioluminescent earthworm Fridericia heliota (Enchytraeidae). Its structure, elucidated by NMR and mass spectrometry, includes residues of tyrosine, CompX (a novel tyrosine modification product, reported in the accompanying paper), and N(omega)-acylated lysine. Chromatography, UV, and ¹H NMR data imply a close structural similarity of AsLn2 with F. heliota luciferin. AsLn2 appears to be an intermediate or by-product in F. heliota luciferin biosynthesis.     

Efficient synthesis of 9H-pyrrolo[1,2-a]indol-9-one derivatives based on active manganese dioxide promoted intramolecular cyclization

A series of 9H-pyrrolo[1,2-a]indol-9-ones have been prepared via in-situ sequential oxidation of [2-(1H-pyrrol-1-yl)phenyl]methanols promoted by active manganese dioxide. The procedure led to title compounds in good yields under mild conditions, without the need to isolate the intermediate aldehydes.     

A new method for pyrrole peri-annulation: synthesis of 1H-1,5,7-triazacyclopenta[c,d]phenalenes from 1H-perimidines

New methods for the synthesis of 1H-1,5,7-triazacyclopenta[c,d]phenalenes have been developed based on a sequence involving Schmidt reaction of keto-perimidines and acylation of the intermediate amides with 1,3,5-triazines or carboxylic acids. The same synthetic sequence starting from the corresponding alkylperimidine includes acylation with acetic acid as the first step.     

The fragmentation reaction of 16R-bromopregnane-3S,20S-diol

16R-Bromopregnane-3S,20S-diol reacted with potassium t-butoxide to afford androst-16-en-3S-ol in a moderate yield via fragmentation reaction. The latter is a key intermediate for the synthesis of 5α-androst-16-en-3-one, as boar sex pheromone, and other steroidal drugs. In addition, 16R,20S-epoxypregnane-3S-ol was also obtained as a major product by changing the reaction solvent.     

Domino reaction of 3-nitro-2-(trifluoromethyl)-2H-chromenes with 2-(1-phenylalkylidene)malononitriles: synthesis of functionalized 6-(trifluoromethyl)-6H-dibenzo[b,d]pyrans and a rare case of [1,5] sigmatropic shift of the nitro group

A variety of functionalized 6-(trifluoromethyl)-6H-dibenzo[b,d]pyrans were easily synthesized in good yields under mild conditions by a domino reaction of 3-nitro-2-(trifluoromethyl)-2H-chromenes with 2-(1-phenylethylidene)- and 2-(1-phenylpropylidene)malononitriles. In the latter case, intermediate 7-amino-10-methyl-10-nitro-9-phenyl-6-(trifluoromethyl)-10,10a-dihydro-6H-benzo[c]chromene-8-carbonitriles were isolated as a result of a rare [1,5] sigmatropic shift of the nitro group.     

Free radical and isomerisation processes during the electrochemical fluorination of n-butyryl chloride, i-butyryl chloride and pivaloyl chloride in anhydrous hydrogen fluoride

Electrochemical perfluorination (ECPF) of the title compounds containing primary, secondary and tertiary carbon atoms was carried out in anhydrous hydrofluoric acid (AHF). Detailed analysis of major and minor products suggest that carbon chain isomerisation involving cyclo-propane intermediate is more prevalent during ECPF of i-butyryl chloride when compared to n-butyryl chloride. Simple statistical probability involving free radical intermediates also support this observation. ECPF involving cyclo-propane intermediate is even more prevalent in pivaloyl chloride containing three methyl substituents. In this case, perfluorinated cyclo-propane intermediates were also observed in the product sample. Distribution of minor perfluorinated and partially fluorinated products also suggest the predominant role of normal free radical pathway involving single-electron transfer.     

Experimental and computational study of intermolecular migration of N,N-dimethylcarbamoyl group from N(7) to N(1) on a 7-azaindoline derivative

N,N-Dimethylcarbamoylation of the anilinic nitrogen atom N(1) on the spiro 7-azaindoline consists of two steps. The first step is N,N-dimethylcarbamoylation of the pyridyl nitrogen atom N(7), leading to the formation of an isolable intermediate. The second step is intermolecular migration of the N,N-dimethylcarbamoyl group from the pyridyl nitrogen atom N(7) to the anilinic nitrogen atom N(1). We accomplished optimization of the reaction conditions based on the revealed reaction mechanism and a large scale synthesis of compound 3 in quantitative yield.     

An improved synthesis of 2-(1,2,4-thiadiazol-5-yl)pyridine by interception of an intermediate involved in a competing cyclisation reaction

Reaction of thiopicolinamide with N,N′-dimethylformamide dimethyl acetal leads to the formation of 3-(dimethylamino)-1-methylthioimidazo[1,5-a]pyridine (3). However, the course of the reaction can be diverted to produce the title compound (1) in good yield by timely interception of the intermediate thioacylamidine (2).     

Reaction of benzoyl chlorides with Huisgen's zwitterion: synthesis of functionalized 2,5-dihydro-1H-pyrroles and tetrasubstituted furans

The 1:1 intermediate generated by the addition of alkyl(aryl) isocyanides to dimethyl acetylenedicarboxylate is trapped by benzoyl chloride to yield functionalized 2,5-dihydro-1H-pyrroles. The presence of electron-withdrawing groups at the para position of benzoyl chloride leads to tetrasubstituted furans. The structures of these products were confirmed by single-crystal X-ray diffraction studies.     

An improved synthesis of (2E,4Z)-6-(benzyloxy)-4-bromohexa-2,4-dien-1-ol

An improved synthesis of (2E,4Z)-6-(benzyloxy)-4-bromohexa-2,4-dien-1-ol has been devised. This new route increases the throughput and yield of the diene product by circumventing a low yielding preparation of boronic acid intermediate as well as removing the need to use multi-gram quantities of highly toxic thallium salts. In the process of developing this new route, a higher yielding preparation of (E)-3-hydroxyprop-1-enylboronic acid was also achieved.     

Stereoselective 1,5-rearrangement of vinylketene-N,O-acetals: novel vinylogous Ferrier reaction

Vinylketene-N,O-acetals underwent Lewis acid-induced 1,3- or 1,5-rearrangement to afford the corresponding C-alkylated products. 1,5-Rearrangement proceeded predominantly in dichloromethane, and it is quite interesting to achieve an unprecedented high degree of asymmetric induction in such a remote position. Crossover experiments indicated that the reaction proceeded through an ion pair intermediate.