Asymmetric cyclopentannelation: camphor-derived auxiliary

The scope of an enantioselective cyclopentannelation reaction that makes use of allenyl ether-derived nucleophiles has been probed. The enantioselectivity is induced by a traceless chiral auxiliary that is easily derived from camphor. It has been shown that for gamma-substituted allene ethers that are axially chiral, very high enantiomeric excesses of cyclopentenone products are observed in the matched cases. Two fundamentally different mechanisms are observed, one for the cyclizations of allenyl ketones (see eq 7), the other for the cyclizations of allenyl alcohols (see eq 11). The methodology is versatile, efficient, and well-suited for applications in synthesis.     

Multistep parallel synthesis of substituted 5-aminobenzimidazoles in solution phase

An efficient solution-phase parallel synthesis of multisubstituted 5-aminobenzimidazoles is described. The two fluorine atoms of 1,5-difluoro-2,4-dinitrobenzene (DFDNB) are sequentially and quantitatively replaced by nucleophiles. Simultaneous reduction of aromatic m-dinitro groups by Pd-C/HCOONH(4) results in 2,4,5-benzenetriamines, which are continuously condensed with aldehydes to successfully construct the benzimidazole ring without additional oxidants. The free aromatic amino group is further modified by anhydrides, isocyanates, isothiocyanates, and sulfonyl chlorides. All the reactions involved here are highly effective in giving the desired products at room temperature. Four diversity points are introduced in the final products.     

Synthesis and Spectral Characterization of Novel Bis‐thiazole Derivatives via Ring Closure of Benzo[d]thiazol‐2‐amine,Various α‐Haloketones,and S‐Nucleophiles

Novel functionalized bis‐thiazole derivatives ( 4a–d , 9a , b , 13a–e , and 16a–d ) were synthesized in good to excellent yields (70–90%) via the ring closure of benzo[d ]thiazol‐2‐amine and various α‐haloketones in the presence of carbon disulfide or aryl isothiocyanates as S‐nucleophiles. The structures of newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, elemental analysis, and mass spectroscopy techniques.     

Reaction of metallo S-alkyl N-cyanodithioiminocarbonates and alkyl N-cyanocarbamates with hydrazine. A novel preparation of 5-amino-3-mercapto-1,2,4-triazole

Metal salts of S-alkyl-N-cyanodithioiminocarbonates 7 react as electrophiles with hydrazine hydrate to form 5-amino-3-mercapto-1H-1,2,4-triazole 1 . The novel 4-cyanothiosemicarbazide 9 is proposed as the intermediate which cyclizes to the aromatic triazole. The rate determining step is addition of hydrazine to the iminocarbonate and is second order. Other nucleophiles such as substituted hydrazines and amines failed to react. Exchange of either or both sulfurs with oxygen leads to decomposition or mixtures of products.     

Synthesis of 2-isopropylidenehydrazinylthiazole and its subsequent annelation to the corresponding thiazolo[2,3-c]-s-triazole

An unequivocal synthesis of a new thiazolo[2,3-c]-s-triazole substituted at the C-5 position by a very useful methyl triphenylphosphonium salt has been achieved starting from the corresponding 2-isopropylidenehydrazinylthiazole and formic acid. Ring closure was found to be very easy without isolation of a formylhydrazino intermediate. The thiazole derivative was prepared from isopropylidenethiosemicarbazide and (3-chloro-2-oxo)propyltriphenylphosphonium chloride in a good yield.     

Iron-promoted one-pot approach: Synthesis of isothiocyanates

Abstract

We have established a facile and versatile synthesis for the construction of isothiocyanates from their respective amines in the presence of an eco-friendly, inexpensive, easily available Iron catalyst under mild conditions. This reaction provides the target products through the formation of thiocarbamate salt as an intermediate. Both aromatic amines and aliphatic amines provided the respective target products in moderate to high yield under optimized reaction conditions. However, electron withdrawing substituents were difficult to give target product at room temperature, whereas, they obtained final products in good yield at moderate temperature. In addition, mechanistic studies were revealed that the synthetic route involved iron based subsequent reactions of addition and removal of sulfur.     

Improved asymmetric S(N)Ar reaction of beta-dicarbonyl compounds catalyzed by quaternary ammonium salts derived from cinchona alkaloids

The scope and limitation of the asymmetric nucleophilic aromatic substitution reaction of alpha-substituted 1,3-dicarbonyl compounds and activated aromatic systems catalyzed by N-benzyl-O-benzoylcinchoninium or cinchonidinium salts are presented. Several novel O-benzoylcinchona alkaloid derived salts have been prepared and evaluated as catalysts in this reaction, which can proceed with enantioselectivites up to 96% ee. Various 1,3-dicarbonyl compounds and activated aromatic systems are evaluated for the aromatic nucleophilic substitution reaction, and it has been found that the yield and enantioselectivity are very dependent on the substrate and reagent. The scope of the functionalization of the products to, e.g., spiro-oxoindole, a ring-opening reaction of 1,3 alpha,alpha-disubstituted dicarbonyl compounds with several nucleophiles, and the diastereoselective reduction of the keto functionality in the optically active S(N)Ar product are reported.     

Practical synthesis of functionalized 1,5-disubstituted 1,2,4-triazole derivatives

A general approach for the synthesis of 1,5-disubstituted-1,2,4-triazole compounds is described. A series of new oxamide-derived amidine reagents can be accessed in excellent yield with minimal purification necessary. Typically, these amidine reagents are stable crystalline solids and in certain cases were found to exist in a cyclic form as determined by NMR spectroscopy. Under optimized conditions, the direct reaction of these prepared reagents with various hydrazine hydrochloride salts efficiently generates the target triazoles. Both aromatic and aliphatic hydrazines react readily with the amidine reagents under very mild reaction conditions, delivering desired 1,5-disubstituted-1,2,4-triazole derivatives in good yields.     

Computational Study of the Mechanism and Selectivity of Palladium‐Catalyzed Propargylic Substitution with Phosphorus Nucleophiles

The mechanism and sources of selectivity in the palladium‐catalyzed propargylic substitution reaction that involves phosphorus nucleophiles, and which yields predominantly allenylphosphonates and related compounds, have been studied computationally by means of density functional theory. Full free‐energy profiles are computed for both H‐phosphonate and H‐phosphonothioate substrates. The calculations show that the special behavior of H‐phosphonates among other heteroatom nucleophiles is indeed reflected in higher energy barriers for the attack on the central carbon atom of the allenyl/propargyl ligand relative to the ligand‐exchange pathway, which leads to the experimentally observed products. It is argued that, to explain the preference of allenyl‐ versus propargyl‐phosphonate/phosphonothioate formation in reactions that involve H‐phosphonates and H‐phosphonothioates, analysis of the complete free‐energy surfaces is necessary, because the product ratio is determined by different transition states in the respective branches of the catalytic cycle. In addition, these transition states change in going from a H‐phosphonate to a H‐phosphonothioate nucleophile.     

Fluorinated alcohols as promoters for the metal-free direct substitution reaction of allylic alcohols with nitrogenated, silylated, and carbon nucleophiles

The direct allylic substitution reaction using allylic alcohols in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) and 2,2,2-trifluoroethanol (TFE) as reaction media is described. The developed procedure is simple, works under mild conditions (rt, 50 and 70 °C), and proves to be very general, since different nitrogenated nucleophiles and carbon nucleophiles can be used achieving high yields, especially when HFIP is employed as solvent and aromatic allylic alcohols are the substrates. Thus, sulfonamides, carbamates, carboxamides, and amines can be successfully employed as nitrogen-based nucleophiles. Likewise, silylated nucleophiles such as trimethylsilylazide, allyltrimethylsilane, trimethylsilane, and trimethylsilylphenylacetylene give the corresponding allylic substitution products in high yields. Good results for the Friedel-Crafts adducts are also achieved with aromatic compounds (phenol, anisole, indole, and anilines) as nucleophiles. Particularly interesting are the results obtained with electron-rich anilines, which can behave as nitrogenated or carbon nucleophiles depending on their electronic properties and the solvent employed. In addition, 1,3-dicarbonyl compounds (acetylacetone and Meldrum's acid) are also successfully employed as soft carbon nucleophiles. Studies for mechanism elucidation are also reported, pointing toward the existence of carbocationic intermediates and two working reaction pathways for the obtention of the allylic substitution product.     

Allylic Functionalization of Unactivated Olefins with Grignard Reagents

New advances in the functionalization of unactivated olefins with carbon nucleophiles have provided more efficient and practical approaches to convert inexpensive starting materials into valuable products. Recent examples have been reported with stabilized carbon nucleophiles, tethered carbon nucleophiles, diazoesters, and trifluoromethane donors. A general method for functionalizing olefins with aromatic, aliphatic, and vinyl Grignard reagents was developed. In a one‐pot process, olefins are oxidized by a commercially available reagent to allylic electrophiles, which undergo selective copper‐catalyzed allylic alkylation with Grignard reagents. Products are formed in high yield and with high regioselectivity. This was utilized to synthesize a series of skipped dienes, a class of compounds that are prevalent in natural products and are difficult to synthesize by known allylic alkylation methods.     

Biphilic properties of substituted triphenylphosphoranylideneacetonitriles bearing 4,5-Di(arylsulfonyl)-1,3-thiazol-2-yl fragments at the ylide center

Phosphonium ylides stabilized by nitrile and 4,5-di(arylsulfonyl)-1,3-thiazol-2-yl fragments show biphilic reactivity. They react with aromatic aldehydes upon heating revealing a noticeable activity of ylide center and are condensed with typical nucleophiles at C⁴ center of the thiazole ring with the elimination of arylsulfonyl group under mild conditions. New 1,3-thiazole derivatives were obtained whose structures were proved by chemical, spectal and X-ray structural investigations.     

The Chemistry of Stable Carbenes. Part 2. Benzoin-type condensations of formaldehyde catalyzed by stable carbenes

Stable carbenes derived from thiazole, 1H-imidazole, and 4H-1,2,4-triazole are efficient catalysts for benzointype condensations of formaldehyde. Catalysts derived from N-substituted thiazolium salts trimerize formaldehyde to dihydroxyacetone ( II ). Catalysts based on 1,4-disubstituted 4H-1,2,4-triazol-1-ium salts give glycolaldehyde ( I ) as the main product and no II , whereas N,N′-disubstituted 1H-imidazol-3-ium salts yield mixtures of both products. The isolation of several intermediates in the catalytic cycle provide a better insight into the reaction mechanism.     

Reactions of Chlorosulfanyl Derivatives of Cyclobutanones with Different Nucleophiles

The reactions of 3‐chloro‐3‐(chlorosulfanyl)‐2,2,4,4‐tetramethylcyclobutan‐1‐one ( 2 ) with N, O, S, and P nucleophiles occur by substitution of Cl at the S‐atom. Whereas, in the cases of secondary amines, alkanols, phenols, thiols, thiophenols, and di‐ and trialkyl phosphates, the initially formed substitution products were obtained, the corresponding products with allyl and propargyl alcohols undergo a [2,3]‐sigmatropic rearrangement to give allyl and allenyl sulfoxides, respectively. Analogous substitution reactions were observed when 3‐chloro‐3‐(chlorodisulfanyl)‐2,2,4,4‐tetramethylcyclobutan‐1‐one ( 3 ) was treated with N, O, and S nucleophiles. The reaction of 3 with Et₃P led to an unexpected product via cleavage of the S? S bond (cf. Scheme 13). In the reactions of 2 with primary amines and H₂O, the substitution products react further via elimination of HCl to yield the corresponding thiocarbonyl S‐imides and the thiocarbonyl S‐oxide, respectively. Whereas the latter could be isolated, the former were not stable but could be intercepted by MeOH (Scheme 4) or adamantanethione (Scheme 5). The structures of some of the substitution products were established by X‐ray crystallography.     

Reactions of 1-glucosyl-5-nitro-1,2,4-triazole with nucleophiles

1-Glucosyl-5-nitro-1,2,4-triazole reacted with nucleophiles, such as water, aziridine, chloride ion and 4-dimethylaminopyridine to give the corresponding 5-substituted 1-glucosyl-1,2,4-triazole derivatives.     

Conjugate addition nitro-Mannich reaction of carbon and heteroatom nucleophiles to nitroalkenes

The conjugate addition nitro-Mannich reactions of ethyl-β-nitroacrylate (1) and β-nitrostyrene (2) with electron rich aromatic nucleophiles, stabilized carbanions, alcohols, amines, thiols, and diphenyl phosphine oxide were investigated. The one pot conjugate addition nitro-Mannich reaction was unsuccessful except for the addition of alkoxides to 2 in alcohol as solvent. Isolation of the conjugate addition products followed by deprotonation with ⁿBuLi and treatment with a simple imine in the presence of TFA led to β-nitroamine derived products. Products derived from 1 spontaneously cyclised in only a few examples and on the whole led to inherently unstable products. Products derived from 2 were isolated as their trifluoroacetamides, gave good yields of single diastereoisomers for aromatic and alkoxide nucleophiles and the structures were verified by single crystal X-ray crystallography. Products derived from amine nucleophiles were isolated in low yields while sulfur nucleophiles gave poor diastereoselectivities.     

Facile Synthesis and Antimicrobial Activity of 5‐Amino‐3‐methyl‐1‐phenyl‐1H‐thieno[3,2‐c]pyrazole‐6‐carbonitrile and Their Derivatives

5‐Amino‐thieno[3,2‐c]pyrazole derivative 2 was prepared by Gewald reaction in a one‐pot procedure. The amino group of compound 2 like primary aromatic amine formed the diazonium salt when treated with NaNO₂/HCl, followed by coupling with different nucleophiles to yield the azo coupling products 3a – d . The reactivity of 5‐amino‐thienopyrazole 2 has been investigated towards different electrophilic reagents such as aromatic aldehydes, alkyl halide, acid chloride, acid anhydride, phenyl isothiocyanate, carbon disulfide, ethyl glycinate, and thioacetamide, which afforded the reaction products 4 – 14 , respectively.     

Synthesis and Reactions of Trifluoromethyl-Substituted 1,3,5-Triazines

A variety of di- and trifluoromethyl-s-triazines are prepared following straightforward synthetic protocols from simple, commercially available starting materials. Trichloromethyl-substituted triazine electrophiles are obtained in good yield and react with amine nucleophiles to afford aminotriazine products in good to excellent yield. The nucleophilic aromatic substitution reaction is broad in scope and proceeds smoothly with both aromatic and aliphatic (primary, secondary, and branched) amines in the presence of non-participating functional groups including alcohols, carboxylic acids, indoles, and common amine protecting groups. Furthermore, most reactions require only a catalytic amount of 4-DMAP with no stoichiometric base and are complete within two hours at ambient temperature.     

Regiocontrolled, palladium-catalyzed bisfunctionalization of allenyl esters. Multicomponent coupling approaches to highly substituted alpha,beta-unsaturated delta-lactones

A palladium-catalyzed regioselective bisfunctionalization of allenyl esters with boronic acids (nucleophiles) and aldehydes (electrophiles) was demonstrated. The three-component coupling afforded alpha,beta-unsaturated delta-lactones under mild conditions and with excellent chemo-, regio-, and diastereoselectivity. Aromatic, heteroaromatic and vinylic boronic acids (R1B(OH)2) reacted with ethyl 2,3-butadienoate and benzaldehyde to afford the corresponding 4-R(1),6-Ph-disubstituted alpha,beta-unsaturated delta-lactones in 62-78% yields. Lactones derived from aromatic, heteroaromatic, and vinylic aldehydes were isolated in 51-58% yields, while aliphatic aldehydes were less reactive. The regiochemistry of bisfunctionalization of allenyl ester homologues remained controlled by the ester substituent, and the reactions afforded cis-4,5,6-trisubstituted alpha,beta-unsaturated delta-lactones and esters of (Z)-syn-3,4,5-trisubstituted-5-hydroxy-2-pentenoic acids in combined 47-65% yields. The superior performance of a pi-allylpalladium(II) dimer catalyst featuring an auxiliary allyl ligand derived from beta-pinene, among diverse palladium(II) catalysts, was demonstrated. A catalytic cycle involving an unsymmetrical bis-pi-allylpalladium complex as the key intermediate was proposed, and the communication highlights the synthetic potential of such intermediates. However, the efficiency of asymmetry transfer remained low (<20%).     

Nucleophilic and electrophilic substitutions of difluoropropargyl bromides

Fundamental organic reactions like nucleophilic and electrophilic substitutions have seldom been studied on fluorinated propargyl or allenyl modules, when the carbon atom undergoing substitution is bonded to two fluorine atoms. Herein we report a practical synthesis of difluoropropargyl bromides from substituted acetylenes and dibromodifluorometane using a wide variety of alkyl, aryl or silyl substrates. The synthesis of O-, S- and carboxylic acid derivatives of difluoropropargyl bromide is also described. These compounds are suitable starting materials for the synthesis of electrophilically substituted difluoropropargyl derivatives via magnesium and fluoride promoted reactions. An indium-mediated reaction of silyldifluoropropargyl bromide, followed by electrophilic trapping with bromine led to a very useful bromoallene, which was then used in reactions with nucleophiles (C, O, N, P, S, Hal) to yield a de facto bimolecular nucleophilic substitution of a difluoropropargyl bromide.