Facile preparation of alkoxybenzoxazoles via direct SNAr on the benzoxazole ring

The synthesis of alkoxybenzoxazoles is in general quite challenging. During our investigation, we discovered that C-4 and C-7 fluoro precursors undergo S_NAr with alkoxides affording moderate to excellent yields of substituted product.     

Route selection in the synthesis of C-4 and C-6 substituted thienopyrimidines

Three different routes have been investigated for the preparation of 6-aryl-N-(1-arylethyl)thienopyrimidin-4-amines. First the possibilities of selective Suzuki reactions on 6-bromo-4-chlorothienopyrimidine were investigated. The preference for mono arylation at C-6 could be increased, in the case of Pd(PPh₃)₄ catalysis, by reducing the water content of the reaction, or by using less electron rich Pd-ligands. The highest selectivity was obtained with Pd(OAc)₂ or Pd₂(dba)₃, while reactions with the more electron rich Pd(PPh₃)₄ and especially XPhos gave a lower mono- to dicoupled product ratio. Secondly, two alternative strategies avoiding this selectivity issue were tested. Suzuki reaction on C-6 of 6-bromothienopyrimidin-4(3H)-one (three examples) proceeded in 70-89% yield using Pd(PPh₃)₄ in dioxane/water. Similar conditions on 4-amino-6-bromo-thienopyrimidine (eight examples) gave 67-95% yield. The reaction could be performed with boronic acids containing nonprotected phenolic groups in the ortho, meta and para positions. By prolonging the reaction time, coupling with sterically crowded arylboronic acids was also efficient. Diarylation of 6-bromo-4-chlorothienopyrimidine gave the corresponding 4,6-diarylated derivatives in 71-80% yield depending on the nature of the arylboronic acid.     

Silver(1) ion catalyzed substitution reactions: stereoelectronic control in an SN1 mechanism

Stereochemistry of the acetolysis of 4-, 6α- and 6β-bromocholest-4-en-3-ones using silver acetate was established, and the reactions were interpreted to proceed $\text{via}$ a stereoelectronically controlled S_N1 mechanism.     

First SNAr reaction using TDAE-initiated carbanions in quinazoline series

We report herein the first example of a S_NAr reaction using TDAE-initiated carbanions in quinazoline series. The o-nitrobenzyl carbanion, formed by the action of TDAE on o-nitrobenzyl chloride, reacts with 4-chloro-2-trihalomethylquinazolines 4 and 5 via a S_NAr mechanism. This enabled a new series of 4-benzyl-2-trihaloquinazoline derivatives to be synthesized in good yields under mild reaction conditions offering promising prospects for pharmacomodulation.     

On the stereochemistry of the solvolytic c/d ring cleavage of the 1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a] quinolizine system

A model sequence for the synthesis of C-mavacurine-type alkaloids is elaborated to demonstrate that substitution at C-12b in the reactions of the amines (4) with cyanogen bromide and methanol (Scheme 6) proceeds with stereospecific inversion of configuration. The same stereospecificity is observed in the analogous reactions of 4, or their O-acetates (5), with benzyl chloroformate and methanol (Scheme 8). To account for the stereospecificity an S_N1-type process at C-12b is proposed (Scheme 7).     

Efficient and regioselective functionalization of imidazo[1,2-b]pyridazines via palladium-catalyzed cross-coupling reaction and SNAr

The synthesis of 3,6-disubstituted-2-phenylimidazo[1,2-b]pyridazine derivatives by palladium cross-coupling and S_NAr reactions is described. Sonogashira and Stille cross-coupling reactions were investigated to introduce alkynyl, alkenyl, and aryl at the 3-position of imidazo[1,2-b]pyridazines. Then, at the 6-position, palladium-catalyzed N-arylation and direct S_NAr were used to introduce amines and alcohols.     

Synthesis of 7-(E)-alkenyl-4-amino-3-quinolinecarbonitriles via Pd-mediated Heck, Stille, and Suzuki reactions

A regio- and stereoselective synthesis of 7-(E)-alkenyl-4-amino-3-quinolinecarbonitriles via Pd-mediated coupling reactions was developed. The comparison and optimization of stereoselectivity of the Heck, Stille, and Suzuki reactions of 7-bromo or 7-triflate-3-quinolinecarbonitrile are described. Compound 7 and 10 were potent inhibitors of Src kinase and Raf/Mek activity, respectively.     

Convergent procedure for the synthesis of trifluoromethyl-containing N-(pyridinyl-triazolyl)pyrimidin-2-amines

This study describes a simple and efficient procedure to synthesize a novel series of fourteen 4-substituted N-(5-pyridinyl-1H-1,2,4-triazol-3-yl)-6-(trifluoromethyl)pyrimidin-2-amines, where the 4-substituents are H, CH₃, C₆H₅, 4-FC₆H₄, 4-CH₃C₆H₄, 4-CH₃OC₆H₄ and 2-Furyl; from the cyclocondensation reaction of N-[5-(pyridinyl)-1H-1,2,4-triazol-3-yl]guanidines with 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones. The reactions were carried out in ethanol under reflux for 18 h and led to 40-68% yields. N-(Pyridyl-triazolyl)guanidine precursors were further obtained from reactions of cyanoguanidine with nicotinic or isonicotinic acid hydrazides and the halogenated enones from trifluoroacetylation of enolethers or acetals.     

Novel approach towards 3,7-disubstituted 1,6-naphthyridin-4(1H)-ones exploiting cross-coupling and SNAr reactions of a dihalogenated compound

A new route towards the synthesis of a series of 3,7-disubstituted 1,6-naphthyridin-4(1H)-ones in moderate to good yields is reported. The strategy involves the preparation of a 3,7-dihalogenated compound that undergoes differential functionalization using palladium-catalyzed cross-coupling and S_NAr reactions.     

Preparation of 4-heteroaryl-4-cyanopiperidines via SNAr substitution reactions

The scope and limitations of S_NAr substitution reactions of metalated 4-cyanopiperidines with heterocyclic halides were explored. These facile reactions provide rapid access to a wide range of 4-heteroaryl-4-cyanopiperidines and have resulted in improved yields, faster reaction times, and lower temperatures than previously published synthetic methods.     

Reaction of indium ate complexes with allylic compounds. Controlling SN2/SN2′ selectivity by solvents

Vinyl and methylindium ate complexes (indates) were prepared and both the tendency of immigration and regioselectivity toward cinnamyl bromide were investigated. The vinyl group was more preferably transferred than the Me group, giving a regioisomeric mixture of S_N2 and S_N2′ products. The ratio of S_N2/S_N2′ selectivity can be controlled by solvents; in the presence of polar solvents, such as N-butylpyrrolidone (NBP) and THF, the S_N2′ product was mainly obtained, whereas the S_N2 product was selectively prepared in solutions containing hexane. The vinylindium compound, generated by the reaction of allylic-type diindium reagents with imine, was also converted to the corresponding vinyl indate, which was allowed to react with allyl chloride to give a three-component coupling product.     

A novel method to enable SNAr reaction of aminopyrrolopyrazoles

Here we report mild, environmentally-friendly reaction conditions which enable the addition-elimination S_NAr reaction between weakly reactive substrates--an aminopyrrolopyrazole template and several substituted pyrimidines. The method was developed during our efforts to synthesize a series of novel P21-activated kinase (PAK) inhibitors.     

The unexpected cyclization routes of N,N′-bis(oxotrifluoroalkenyl)-1,3-phenylenediamines in polyphosphoric acid medium

The unexpected results of the cyclization reactions of N,N′-bis(oxotrifluoroalkenyl)-1,3-phenylenediamines [1,3-C₆H₄-(NHCRCHC(O)CF₃)₂], where R = H, Me, and Ph, in a strongly acidic medium (PPA), allowing the synthesis of new trifluoromethylated heterocycles containing the 1,7-phenanthroline nucleus in 32-40% yields and 7-aminoquinolines (38-40% yields), is reported. The bis-enaminoketone intermediates were easily isolated from the reactions of 4-alkoxy-4-alkyl(aryl)-1,1,1-trifluoroalk-3-en-2-ones with 1,3-phenylenediamine in ethanol under mild conditions (68-86% yields).     

4-Ferrocenylpyridine- and 4-Ferrocenyl-3-ferrocenylmethyl-3,4-dihydropyridine-3,5-dicarbonitriles: Multi-Component Synthesis, Structures and Electrochemistry

The reactions of 2-cyano-3-ferrocenylacrylonitrile (1) with malononitrile (2) in a MeOH/H₂O or 2-PrOH/H₂O medium in the presence of Na₂CO₃ afforded 6-alkoxy-2-amino-4-ferrocenylpyridine-3,5-dicarbonitriles 3a,b (multi-component condensation) and 6-alkoxy-2-amino-4-ferrocenyl-3-ferrocenylmethyl-3,4-dihydropyridine-3,5-dicarbonitriles 4a,b (multi-component cyclodimerization). Analogous reactions of 1 with 2 in an MeOH/H₂O medium in the presence of NaOH, piperidine, or morpholine gave compounds 3a, 4a and 2-amino-4-ferrocenyl-6-hydroxy-, 6-piperidino- and 6-morpholinopyridine-3,5-dicarbonitriles 3c-e, respectively. The structures of the compounds 3b, 4a and 4b were established by the spectroscopic data and X-ray diffraction analysis. The electrochemical behaviour of compounds 3b, 3d and 4b was investigated by means of cyclic voltammetry.     

Preparation of 6-aminoquinazolin-4(3H)-ones via direct SNAr on the quinazoline ring

The preparation of 6-aminoquinazolin-4(3H)-ones requires the use of platinum–metal group catalysis on the corresponding C-6-iodo or 6-bromo precursors. Herein, we report to our knowledge the first successful S_NAr reaction directly at the unactivated C-6 position of the quinazolin-4(3H)-one nucleus.     

SN(ANRORC) mechanism XX. Degenerate ring transformations in reactions of 1,2,4,5-tetrazines with hydrazine

Evidence is presented that the hydrazinolysis of 3-amino- (5) and 3-bromo-6-methyl-1,2,4,5-tetrazine ( 7 ) into the 3-hydrazino-6-methyl-1,2,4,5-tetrazine ( 6* ) with ¹⁵N-labelled hydrazine leads to incorporation of ¹⁵N in the 1,2,4,5-tetrazine ring. Thus in the hydrazino-deamination and hydrazino-debromination a S_N(ANRORC) mechanism is operative. Based on quantitative mass spectrometry it was found that 20-25% of both 5 and 7 reacts according to this S_N-(ANRORC) mechanism. The mechanism of these degenerate ring transformations is discussed.     

Investigations into the cine-Amination of 4-Substituted-5-bromopyrimidines by potassium amide in liquid ammonia

The cine-amination of some 4-R-5-bromopyrimidines (t-butyl, phenyl, methoxyl, piperidine, methyl, methylamino, anilino, amino) by potassium amide in liquid ammonia has been studied. Evidence is presented that the conversion into the corresponding 4-substituted-6-aminopyrimidines can proceed in part via an S_N(ANRORC) mechanism, involving an open-chain intermediate, provided that the substituent at C-4 does not contain an acidic proton in the α-position to the pyrimidine ring. 5-Bromo-4-piperidinopyrimidine yields the tele-amination product, 2-amino-4-piperidinopyrimidine, alongside the 6-amino derivative. It is proven that the tele-amination does not proceed via an S_N(ANRORC) mechanism.     

On the dichotomy of the SN2/ET reaction pathways: an apparent SN2 reactivity in the reaction of naphthalene dianion with alkyl fluorides

Dilithium naphthalene (Li₂C₁₀H₈) displays a S_N2 reactivity profile in its reaction with alkyl fluorides (n-, s- and t-octyl fluoride). S_N2 seems to be the dominant mechanism operating with primary alkyl fluorides, which presumably turns into competition with ET as we move to secondary and tertiary alkyl fluorides. Significantly, lithium naphthalene (LiC₁₀H₈) seems to have also an important nucleophilic component when reacting with alkyl fluorides, in contrast to the previously proposed general ET process valid for all alkyl halides. These results explain the observed distribution of products and are reinforced by a complete analysis of the products originated by the reaction with 6-halohexenyl radical probes, whose main alkylation products are described here for the first time.     

Reactivity of some 3-substituted derivatives of 2,6-dihalogenopyridines towards potassium amide in liquid ammonia [a]

Reactions of 2,6-dichloro-3-phenyl-, 2,6-dibromo-3-phenyl-, 2,6-dichloro-3-dimethylamino- and 2,6-dibromo-3-dimethylaminopyridine with potassium amide in liquid ammonia were investigated. Whereas 2,6-dichloro-3-phenylpyridine yields 4-amino-2-benzylpyrimidine, from 2,6-dibromo-3-phenylpyridine as a product of a novel ring fission 2-amino-l-cyano-l-phenyl-but-l-en-3-yne was isolated, together with 4-amino-6-bromo-3-phenylpyridine and 2,6-diamino-3-phenylpyridine. It was shown that neither 2-amino-6-bromo-3-phenyl- nor 6-amino-2-bromo-3-phenylpyridine are intermediates in the formation of the 2,6-diamino derivative, as these bromo compounds are transformed in the basic medium into 1,3-dicyano-l-phenylpropene. From both 2,6-di-chloro-3-dimethylamino- and 2,6-dibromo-3-dimethylaminopyridine mixtures are obtained from which only 2-amino-l-cyano-l-dimethylamino-but-l-en-3-yne and 4-amino-6-halogeno-3-dimethylaminopyridine were isolated. Mechanisms for the reactions studied are proposed, i.e. a S_N(ANRORC) mechanism for the aminodebromination of 2,6-dibromo-3-phenylpyridine into the corresponding 2,6-diamino compound.     

Epimerization at C-2 of 2-substituted thiazolidine-4-carboxylic acids

2(R,S)-5,5-Trimethylthiazolidine-4-(S)-carboxylic acid ( 1a ), with a 3.3 to 1 predominance of the 2S (cis) isomer, was shown to epimerize at the C-2 position in neutral, protic solvents. This was manifested by mutarotation concomitant to changes in the ratios of the C-4 methine proton resonances in the nmr spectrum. Compound 1a was stable in dilute sodium carbonate solution, but underwent rapid equilibration in 1N hydrochloric acid. Acetylation of 1a gave an acetyl derivative ( 2a ) with exclusively 2S,4S stereochemistry. Chiral integrity at C-2 was proved by conversion of both 2a and its enantiomer 2b via their munchnone derivatives to enantiomeric dimethyl 1,1,3,5-tetramethyl-1H,2H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylates ( 4a and 4b ). Acetylation of 2-(R,S)-phenyl-5,5-dimethylthiazolidine-4(S)-carboxylic acid, afforded both the 2 S ,4S ( 6a ) and 2R,4S ( 6b ) epimers. Epimerization of 6a at C-4 gave the 2S,4R isomer ( 6c ) which was enantiomeric with 6b .