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Studies directed on the synthesis of the pyrrole containing marine natural products Rigidin and Rigidin E via vinylogous iminium salts are described. The successful strategy relies on the formation of a 2,4-disubstituted pyrrole from a vinamidinium salt followed by acylation at the 5-position of pyrrole. Halogenation and aminocarbonylation at the 3-position of pyrrole followed by hydrolysis of the ester group at C-2 and subsequent Curtius rearrangement generates the pyrrolopyrimidine skeleton. A final deprotection step completes the synthesis of Rigidin and Rigidin E.

A new and efficient relay synthesis of the marine natural products polycitone A and B is described. The new strategy relies on the formation of 2,4-disubstituted pyrroles from a vinamidinium salt followed by electrophilic substitution at the 5-position of the pyrrole and Suzuki coupling at the 4-position to produce the tetrasubstituted heterocycle efficiently and with complete control of regiochemistry.

A vinylogous iminium salt derivative has been used to prepare a 2,3,4-trisubstituted pyrrole synthon in a regioselective, efficient and convenient manner. This pyrrole synthon was subsequently converted to the multidrug-resistant (MDR) reversal agent, Ningalin B hexamethyl ether, via alkylation, hydrolysis and oxidative lactonization steps. This methodology provides an alternative pathway to this important class of pyrrole containing marine natural products.

A variety of vinylogous iminium salt derivatives have been examined as useful precursors for the regiocontrolled synthesis of heterocyclic appended pyrazoles. The reaction conditions for such processes have been optimized and the regiochemical preferences have been determined. Such reaction sequences represent methodologies which may have useful applications for the preparation of biologically interesting substances.

Numerous novel pyrrole containing marine natural products have been shown to possess interesting biological properties. These compounds have been the synthetic targets of several research groups and we have previously reported synthetic methods which utilize vinylogous iminium salt derivatives as building blocks for analogous pyrrrole systems. We now report a novel and regiocontrolled synthesis of a known pyrrole synthetic precursor to the compounds Lukianol A and Lammelarin O dimethyl ether based on this synthetic methodology.

β-Trifluoromethyl vinamidinium salt 1 reacted cleanly with a variety of Grignard reagents 2 in tetrahydrofuran under reflux for 3 h to produce a mixture of diastereoisomers ( dl and meso ) of the corresponding difluoromethylene compounds 3 in good to excellent yields.

β-Fluorovinamidinium salt ( 1 ) reacted cleanly with a variety of Grignard reagents in tetrahydrofuran at room temperature, followed by acid workup, to produce the corresponding (Z)-α-fluoro-α,β-unsaturated aldehydes ( 3 ) in good to excellent yields.

β-Fluoro vinamidinium salt ( 1 ) reacted with 1.1 equiv. of methylene compounds activated with carbonyl or cyano groups in the presence of lithium diisopropylamide or sodium hydride and triethylamine in tetrahydrofuran at room temperature to give monofluorinated multifunctional dienaminones ( 3 ) and dienaminonitriles ( 5 ) in moderate to good yields. The reactions of 1 with 2.2 equiv. of enolates derived from β-keto esters at 80 °C gave the cyclization products, fluorinated isophthalates ( 6 ) in good yields, while a similar reaction with 2.2 equiv. of cyanoacetate and malononitrile produced the non-cyclic 1, 3-dienecarbonitriles ( 7 ) in excellent yields.

Novel β-polyfluoroalkoxy vinamidinium salts 3 and/or 4 were prepared in good yields by the reaction of N -(2-polyfluoroalkoxy-3,3-difluoro-1-propenyl) trimethylammonium iodides ( 2 ) with secondary amines in acetonitrile at 70 °C for 1 h. These vinamidinium salts readily reacted with bifunctional heteronucleophiles, such as amidines, guanidines and hydrazines, to give regiospecifically polyfluoroalkoxylated pyrimidines ( 6 ) and pyrazoles ( 8 ) in good yields. The one-pot procedure starting from N -(2,3,3-trifluoro-1-propenyl)trimethylammonium iodide ( 1 ), which was the precursor of 2 , was applicable for synthesizing the heterocyclic compounds in almost comparable yields with those obtained by the stepwise procedure using isolated 3 and 4 .

β-Trifluoromethylated vinamidinium salt (1) was prepared in high yield by the reaction between 3,3,3-trifluoropropanoic acid and phosphorus oxychloride in N,N-dimethylformamide at 70 °C for 1 h. This salt 1 reacted readily with bifunctional nitrogen nucleophiles, such as amidine and hydrazine derivatives, in acetonitrile or dimethyl sulfoxide to furnish the corresponding trifluoromethylated azaheterocycles in good yields.

The discovery of a catalytic effect of sand on the activity of KMnO4/NaIO4 or KMnO4/NaClO oxidant system provides a convenient method for double bond cleavage under mild conditions. An oxidative rearrangement of α-bromostyrene to 2-bromoacetophenone was also observed.

Oxidative cleavage of a variety of electrophilic double bond substrates has been effected under mild reaction conditions by sodium metaperiodate or sodium hypochlorite catalyzed by ruthenium oxide.

β-Fluorovinamidinium salt (2), readily prepared fromN-(2, 3, 3-trifluoro-1-propenyl)trimethyl-ammonium iodide (1) and diethylamine, reacted with bifunctional hetero nucleophiles such as amidine and guanidine hydrochlorides in the presence of a base to afford regiospecifically monofluorinated pyrimidines4 in good yields. The one-pot procedure starting from1 was applicable for synthesizing heterocyclic compounds4 in almost comparable yields.

A practical method for the high-yielding amine exchange of vinamidinium salts and their reduction to allylic amines (IV) is developed.

A three step synthesis of a novel 2-(1-benzotriazolyl)-vinamidinium salt is described along with its direct conversion to a series of unusual 5-(1-benzotriazolyl) pyrimidines, 4-(1-benzotriazolyl)-pyrazoles, and 4-(1-benzotriazolyl) pyrroles.

Studies directed at the synthesis of (Z)-5-benzylidene-4-arylpyrrol-2(5H)-ones from (Z)-3-aryl-3-haloenoic acids are described. The successful strategy relies on the preparation of (Z)-3-aryl-3-haloenoic acids from acetophenones through the corresponding (Z)-3-aryl-3-haloenals and the conversion of the (Z)-3-aryl-3-haloenoic acids to (Z)-5-benzylidene-4-aryl-5H-furan-2-ones. The furanones were subsequently treated with primary amines and dehydrated to the corresponding (Z)-5-benzylidene-4-arylpyrrol-2(5H)-ones.

Oxidative cleavage of a variety of electrophilic double bond substrates has been effected under mild reaction conditions by sodium metaperiodate or sodium hypochlorite catalyzed by ruthenium oxide.

β-Fluorovinamidinium salt (2), readily prepared fromN-(2, 3, 3-trifluoro-1-propenyl)trimethyl-ammonium iodide (1) and diethylamine, reacted with bifunctional hetero nucleophiles such as amidine and guanidine hydrochlorides in the presence of a base to afford regiospecifically monofluorinated pyrimidines4 in good yields. The one-pot procedure starting from1 was applicable for synthesizing heterocyclic compounds4 in almost comparable yields.

The discovery of a catalytic effect of sand on the activity of KMnO4/NaIO4 or KMnO4/NaClO oxidant system provides a convenient method for double bond cleavage under mild conditions. An oxidative rearrangement of α-bromostyrene to 2-bromoacetophenone was also observed.

Novel β-polyfluoroalkoxy vinamidinium salts 3 and/or 4 were synthesized in good yields by the reaction of N-(2-polyfluoroalkoxy-3,3-difluoro-1-propenyl)trimethylammonium iodides (2), prepared from N-(2,3,3-trifluoro-1-propenyl)trimethylammonium iodide (1), with secondary amines in MeCN at 70 °C for 1 h. The salts were also obtainable in comparable yields by the one-pot reaction of 1 with sodium polyfluoroalkoxide followed by treatment with amines.

β-Fluoro vinamidinium salt ( 1 ) reacted with 1.1 equiv. of methylene compounds activated with carbonyl or cyano groups in the presence of lithium diisopropylamide or sodium hydride and triethylamine in tetrahydrofuran at room temperature to give monofluorinated multifunctional dienaminones ( 3 ) and dienaminonitriles ( 5 ) in moderate to good yields. The reactions of 1 with 2.2 equiv. of enolates derived from β-keto esters at 80 °C gave the cyclization products, fluorinated isophthalates ( 6 ) in good yields, while a similar reaction with 2.2 equiv. of cyanoacetate and malononitrile produced the non-cyclic 1, 3-dienecarbonitriles ( 7 ) in excellent yields.

Novel β-polyfluoroalkoxy vinamidinium salts 3 and/or 4 were prepared in good yields by the reaction of N -(2-polyfluoroalkoxy-3,3-difluoro-1-propenyl) trimethylammonium iodides ( 2 ) with secondary amines in acetonitrile at 70 °C for 1 h. These vinamidinium salts readily reacted with bifunctional heteronucleophiles, such as amidines, guanidines and hydrazines, to give regiospecifically polyfluoroalkoxylated pyrimidines ( 6 ) and pyrazoles ( 8 ) in good yields. The one-pot procedure starting from N -(2,3,3-trifluoro-1-propenyl)trimethylammonium iodide ( 1 ), which was the precursor of 2 , was applicable for synthesizing the heterocyclic compounds in almost comparable yields with those obtained by the stepwise procedure using isolated 3 and 4 .

β-Fluorovinamidinium salt ( 1 ) reacted cleanly with a variety of Grignard reagents in tetrahydrofuran at room temperature, followed by acid workup, to produce the corresponding (Z)-α-fluoro-α,β-unsaturated aldehydes ( 3 ) in good to excellent yields.

An alternative preparation of a 2-iminovinamidinium salt from phosphonoacetic acids is described along with its application to the synthesis of 5-formylpyrimidines and masked 4-formylpyrazoles.

Studies directed at the synthesis of polycitone and storniamide natural products via vinylogous iminium salts and microwave accelerated Vilsmeier-Haack formylations are described. The successful strategy relies on the formation of a 2,4-disubstituted pyrrole or a 2,3,4-trisubstituted pyrrole from a vinamidinium salt or vinamidinium salt derivative followed by formylation at the 5-position of the pyrrole. Subsequent transformations of the selectively formylated pyrroles lead to efficient and regiocontrolled relay syntheses of the respective pyrrole containing natural products.

β-Trifluoroethoxy vinamidinium salts 1 reacted smoothly with various types of the carbanions, generated by treatment of ketones, esters, amide and nitriles with LDA, to give the corresponding trifluoroethoxylated multifunctional dienamine derivatives 3 in moderate to good yields. On the other hand, the reaction of 1 with lithium acetylide and other carbanions derived from methyl compounds bearing sulfonyl, sulfinyl, and phosphonyl groups produced the corresponding α,β-unsaturated aldehydes 5 in good yields.

The reaction of hydrazine hydrate with certain 2-substituted styryl-4-quinazolones results in the formation of a novel tricyclic heterocycle and not the previously reported acyl hydrazide. A mechanistic rationale is presented.

A variety of quaternary ammonium salts derived from 2-aryl-3-(N, N-dimethylamino)-1-propenes have been converted to the corresponding alkyl and fluoroalkyl ethers by displacement of the ammonium group. This procedure represents an efficient means for the construction of 2-aryl substituted allylic ethers.

Novel β-polyfluoroalkoxy vinamidinium salts 3 and/or 4 were synthesized in good yields by the reaction of N-(2-polyfluoroalkoxy-3,3-difluoro-1-propenyl)trimethylammonium iodides (2), prepared from N-(2,3,3-trifluoro-1-propenyl)trimethylammonium iodide (1), with secondary amines in MeCN at 70 °C for 1 h. The salts were also obtainable in comparable yields by the one-pot reaction of 1 with sodium polyfluoroalkoxide followed by treatment with amines.

Par reaction avec le bromure de methyl-Mg ou avec des alkyl-lithium, on obtient les aryl-2 alcenes-1 correspondants. Par reduction avec NaBH 4 , obtention des aryl-2 propenes

A variety of quaternary ammonium salts derived from 2-aryl-3-(N, N-dimethylamino)-1-propenes have been converted to the corresponding alkyl and fluoroalkyl ethers by displacement of the ammonium group. This procedure represents an efficient means for the construction of 2-aryl substituted allylic ethers.

A series of α-substituted styrene analogs have been reacted with sodium perborate in acetic acid to produce l-acetoxy-2-aryl-2-propanol analogs in good yield. The reaction constitutes a mild and convenient method for the oxidation of styrene type double bonds.

Effets du solvant, du temps, de la temperature, du groupe depart et du nucleophile sur les reactions d'halogenures d'aryle et d'heteryle avec des trifluoro-2,2,2 ethanolates

The reactions of an unsubstituted vinamidinium salt with organometallic reagents, borane, and DIBAL-H are described. The products of these reactions were unsaturated aldehydes, and allylic amines. The reaction conditions and possible mechanistic implications are also discussed.

Substitution par reaction de nitro- et fluoro-, benzonitrile, -diphenylsulfone, -benzophenone, benzaldehyde, -acetophenone, -benzamide, -benzene-sulfonamide avec des polyfluoroalcanolate de sodium