New opinions on the amidoalkylation of hydrophosphorylic compounds

A new and milder version of the procedure for the synthesis of N-protected α-aminoalkylphosphorylic compounds by reaction of alkyl carbamates, aldehydes and hydrophosphorylic compounds in acetic anhydride/acetyl chloride and a new mechanism for this type of reaction are described. The isolation, for the first time, of N,N′-benzylidene- and N,N′-alkylidenebiscarbamates as intermediates from the reaction medium and studies of the direct reaction of pre-obtained biscarbamates and hydrophosphorylic compounds in acetic anhydride are reported. A new version of the mechanism for this reaction which includes an Arbuzov-type reaction is proposed.     

A new synthesis of cyanocyclopropanes by the intramolecular alkylation of magnesium carbenoids as the key reaction

Addition reaction of 1-chlorovinyl p-tolyl sulfoxides, derived from ketones and chloromethyl p-tolyl sulfoxide, with cyanomethyllithium gave adducts in quantitative yields. Treatment of the adducts with i-PrMgCl in THF resulted in the formation of cyanocyclopropanes via the intramolecular alkylation of the generated magnesium carbenoids. The intermediate of this reaction was proved to be a cyclopropylmagnesium chloride, and it was found to be reactive with electrophiles to give multi-substituted cyanocyclopropanes. The key reaction, intramolecular alkylation of magnesium carbenoid, is the first example for the reaction of the magnesium carbenoids with nitrile-stabilized carbanions.     

Microwave-induced domino-Knoevenagel-hetero Diels–Alder reaction—an easy route to di[1]benzopyrano[2,3-b:4′,3′-d]pyridine

MW-irradiation of a well-ground equimolar mixture of 2-(N-alkynyl-N-aryl)aminochromone-3-carbaldehyde and dimedone underwent domino-Knoevenagel-hetero Diels–Alder (DKHDA) reaction for nonterminal alkynes, whereas conventional heating of the above reaction mixture in ethanol in the presence of pyridine accomplished alkyne-carbonyl metathesis (ACM) reaction or both ACM and DKHDA reaction. Here is the first example of an organo-catalyzed ACM reaction.     

Copper-catalyzed Pummerer type reaction of α-thio aryl/heteroarylacetates: Synthesis of aryl/heteroaryl α-keto esters

A copper catalyzed Pummerer type reaction of α-thio aryl/heteroarylacetates is described for the first time. This transformation represents a new route to synthesize α-keto esters, which are important intermediates for pharmaceuticals and organic synthesis. The reaction proceeds via in situ generation of a thionium ion that undergoes hydrolysis to furnish α-keto esters in synthetically viable yields (up to 82%).     

Novel tetrahydroisoquinoline based organocatalysts for asymmetric Diels–Alder reactions: insight into the catalytic mode using ROESY NMR and DFT studies

For the first time an organocatalyst bearing a secondary nitrogen within a cyclohexane ring has been evaluated in the asymmetric Diels–Alder reaction. This organocatalyst is also the first of its kind based on a (1R,3S)-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline backbone. These catalysts were tested over a range of dienes and dienophiles and displayed promising chemical conversions of up to 100% with up to 64% ee with triflic acid as the cocatalyst. Density functional theory computational studies and 2D NMR spectroscopy were used to determine the structure of the intermediate iminium ion formed between the most efficient catalyst and cinnamaldehyde. The reaction profile for each of the four possibilities in this reaction were calculated and it was found that the iminium intermediate leading to the major product is higher in energy but kinetically preferred. The activation energies of all possible reaction paths were calculated and the results correlated with the observed products. These experiments revealed that the presence of both (E)- and (Z)-isomers of the cinnamaldehyde were contributing factors for the low enantioselectivity of the reaction products.     

Copper promoted desulfurization and C-N cross coupling reactions: Simple approach to the synthesis of substituted 2-aminobenzoxazoles and 2,5-disubstituted tetrazole amines

Copper-supported novel, facile and efficient methods for the synthesis of various 2-amino-benzoxazoles and 2,5-diphenyltetrazoleamines have been demonstrated. The reaction procedures are simple, with excellent substrate tolerance in good to high yields thus paving an excellent and useful way to establish a library of potentially active drug molecules. This methodology represents the first concept of copper-catalyst promoted domino C-N cross-coupling reaction towards the construction of 2-aminobenzoxazoles. In addition, we described report for the synthesis of 2,5-diaryltetrazoleamines using copper via inter molecular C-N cross-coupling reaction with aryl iodides. The proposed reaction mechanism involves copper based desulphurization/nucleophilic substitution and subsequent C-N cross-coupling reactions. We established numerous applications of this methodology for synthesizing diverse heterocyclic derivatives i.e. both electron rich and electron deficient systems.     

First application of chiral ionic liquids in asymmetric Baylis-Hillman reaction

The first example of the use of chiral ionic liquids as reaction media in the asymmetric Baylis-Hillman reaction was described using N-alkyl-N-methylephedrinium salts. Good yields and significant enantiomeric excesses were obtained.     

Highly Z/E stereoselective approach to β-iodo aza Morita-Baylis-Hillman adducts

A multicomponent reaction between sulfonyl-protected imines, magnesium iodide, and acetylenic esters or ketones is described. The resulting β-iodo aza Morita-Baylis-Hillman adducts were obtained in good yields and excellent Z/E stereoselectivities. The reaction showed good tolerance for sulfonyl protecting groups, as well as for acetylenic ketones and esters. This work presents the first synthetic approach to β-iodo aza Morita-Baylis-Hillman adducts.     

Synthesis of a novel betaine-type asphalt emulsifier and its investigation by online FTIR spectrophotometry

A novel betaine-type asphalt emulsifier, 3-(dodecyloxy)-2-hydroxypropan-N-carboxymethyl-N,N-dimethylammonium chloride, has been synthesized in a three-step reaction from lauryl alcohol, epichlorohydrin, dimethylamine, and chloroacetic acid. The optimum reaction conditions were obtained for synthesis of 2-(dodecyloxymethyl)oxirane in the first step. The yield reaches 75.7 % under the optimum conditions of reaction temperature 50 °C, reaction time 5 h, feedstock mole ratio of epichlorohydrin to lauryl alcohol 1.4, basicity 33.3 %. The structures of the three products were identified by FTIR. Synthesis of 2-(dodecyloxymethyl)oxirane in the first step was monitored by online FTIR, and an intermediate was detected. On the basis of the experimental data, a plausible reaction mechanism was proposed for the reaction. The critical micelle concentration (CMC) of the final product is low, 8.8 × 10^?5 mol/L. The surface tension at the CMC is 21.2 mN/m. This product is an excellent emulsifier for asphalt. The prepared bituminous emulsion had high storage stability. The emulsifier is a rapid-set asphalt emulsifier.     

Chiral base-catalyzed aldol reaction of trimethoxysilyl enol ethers: effect of water as an additive on stereoselectivities

An aldol reaction of trimethoxysilyl enol ether catalyzed by lithium binaphtholate is described. The aldol reaction of trimethoxysilyl enol ether derived from cyclohexanone under anhydrous conditions predominantly afforded the anti-aldol adduct with moderate enantioselectivity, whereas the reaction under aqueous conditions predominantly resulted in the syn-adduct and the enantioselectivity of the syn-adduct was considerably improved. The best enantioselectivity was obtained in the reaction of trimethoxysilyl enol ether derived from 1-indanone with cyclohexanecarboxaldehyde (97% ee (syn)). This is the first example of an aldol reaction of trimethoxysilyl enol ether catalyzed by a chiral base.     

Facile synthesis of (β-chlorodifluoroethyl)phosphonates via chlorination reaction of difluoroalkyl diazo derivatives with HCl

An efficient chlorination reaction of in situ generated (β-diazo-α,α-difluoroethyl)phosphonates has been achieved with hydrochloric acid as a chlorine source under mild and operationally convenient conditions. The reaction does not need any catalyst and tolerates a wide scope of substrates, which affords the (β-chlorodifluoroethyl)phosphonate products in good to excellent yields. This reaction represents the first example of the halogenation of difluoroalkyl diazo compounds, and also provides an easy way for the synthesis of difluoromethylenephosphonate-containing compounds.     

Kinetics of addition of butyllithium onto diisopropenylbenzene

The kinetics of the addition reaction between butyllithium and diisopropenylbenzene (DIB) were investigated in non-polar solvents. It has been established that the two double bonds of meta-DIB are almost isoreactive, as expected; for the para-isomer however the first addition is faster than the second. The overall rate of reaction is also greater for para-DIB. This kinetic study is of great use, since the diadduct behaves as an efficient bifunctional anionic initiator which can be used in non-polar solvents.     

Truncated diastereoselective Passerini reaction, a rapid construction of polysubstituted oxazole and peptides having an α-hydroxy-β-amino acid component

The reaction of aldehydes and ketones, including aliphatic and aromatic ones, with amides of α-isocyano-β-phenylpropionic acid in toluene in the presence of lithium bromide gives 2,4,5-trisubstituted oxazoles in good to excellent yield. Protected chiral α-amino aldehydes participate in this reaction to give, after hydrolysis of the oxazoles, norstatine-containing peptides in good overall yield. The nucleophilic addition of isonitriles to N,N-dibenzylphenylalanal is investigated for the first time and is found to be stereoselective leading predominantly to the anti-adduct (dr=9/1). On the other hand, the reaction between the N-Boc phenylalanal and isonitrile is non-stereoselective.     

The aza-xylylene Diels-Alder approach for the synthesis of naturally occurring 2-alkyl tetrahydroquinolines

The recently discovered intramolecular aza-xylylene Diels-Alder reaction, based on a 1,4-dehydrohalogenation reaction, was extended in terms of substrates and leaving groups allowing the assembly of tetrahydroquinolines in two synthetic steps. Intramolecular cleavage of a thiocarbamate using triphenylphosphine and tetrachloromethane (Appel conditions) to give chloromethyl phenylisocyanate has been presented for the first time. The synthetic feasibility of this process was demonstrated in the first total syntheses of the alkaloids rac-Angustureine and 1-methyl-2-propyltetrahydroquinoline.     

Studies in N-amino-3-aza Cope rearrangements

The first examples of a N-amino-3-aza Cope rearrangement as well as the first N-amino-anion 3-aza Cope rearrangement are reported. These occur in good to excellent yields and in short reaction times.     

Total synthesis of cannabisin F

A practical eight-step synthesis of lignanamide cannabisin F starting from vanillin is reported for the first time. This synthetic strategy applies the aldol reaction followed by the Wittig reaction to afford the key 8-O-4′-neolignan intermediate diacid. The diacid was condensed with N,O-protected tyramine giving, after deprotection, cannabisin F.     

Asymmetric synthesis of α,β-substituted γ-amino acids via conjugate addition

The first conjugate addition reaction of organocuprates to N-enoyl oxazolidinone where a N-protected γ-nitrogen atom and an α-methyl group are present into α, β-unsaturated system is described. This reaction gave anti-products in moderate yields and high diastereomeric ratios. The anti-products have two contiguous stereogenic centers, one formed by the conjugate addition reaction and the other by a diastereoselective protonation reaction. The removal of chiral oxazolidinone moiety and N-deprotection of amino group furnished chiral α, β-disubstituted γ-amino acids.     

Metal-free oxidative amide formation with N-hydroxysuccinimide and hypervalent iodine reagents

An oxidative amide formation using N-hydroxysuccinimide and hypervalent iodine reagents was developed. The method enables a wide range of aldehydes and amines to be coupled under mild reaction conditions providing amide in good to excellent yield. The radical species in the reaction mixture was observed for the first time using ESR measurement, and along with other mechanistic investigations, a plausible mechanism of the reaction was proposed.     

Domino Michael/aza-Wittig reaction in the diastereoselective construction of spiro[azepane-4,3′-oxindoles]

A convenient synthetic strategy for the diastereoselective assembly of spiro[azepane-4,3′-oxindoles] was developed via a Staudinger/Michael/aza-Wittig/reduction/N-deprotection reaction sequence starting from PMB-protected oxindole-substituted ethylazides. The key step of the method is a domino self-catalytic Michael/aza-Wittig reaction wherein the phosphazene moiety acts first as the catalyst and then as the reactant, resulting in the formation of a seven-membered N-heterocycle.     

Convergent synthesis of panclicin-D via intramolecular SN2 displacement approach

A convergent enantioselective synthesis of panclicin-D has been reported from simple octanal using syn aldol reaction via intramolecular S_N2 displacement reaction for the first time towards the construction of anti-β-lactones in panclicin-D. The key steps involved are C-allylation, asymmetric aldolization under Crimmins condition, intramolecular S_N2 displacement, and Mitsunobu esterification reaction.