Search

3-(Hetero)arylmethyl derivatives of imidazo[1,2-a]pyridine have been synthesized by a novel one-pot method consisting of the Sonogashira coupling of tert-butyl prop-2-yn-1-yl(pyridin-2-yl)carbamate with different substituted (hetero)aryl bromides and cyclization of the in situ obtained intermediate substituted (hetero)aryl acetylene derivatives.

We report the deprotonation of a chiral nitrile and reaction of the resulting chiral organometallic species with a variety of electrophiles to give highly enantiomerically enriched 2-substituted nitrile products. The nitrile was treated with TMPMgCl and the resulting anion, an asymmetric alpha cyano Grignard species, was found to be configurationally stable at low temperature for a short time (half-life several minutes at −104 °C).

Chiral AlIII salen complexes were synthesized and used as catalysts for the asymmetric hydrocyanation of nitroolefins using 4-phenylpyridine N-oxide as an additive and trimethylsilyl cyanide (TMSCN) as a source of cyanide. An excellent yield of β-nitronitrile (87 %) and enantioselectivity (90 %) were achieved if (2-nitrovinyl)cyclohexane was used as a substrate at −15 °C in 16 h. To understand the interaction of the AlIII salen complex and additive, NMR and IR spectroscopic studies revealed that 4-phenylpyridine N-oxide acts both as an axial ligand and helps to activate the cyanide source TMSCN, which thereby increases the reactivity. A catalytic cycle was proposed based on the spectroscopic studies.

Chiral dimeric Mn(III) salen complex with 1 R , 2 R -(−)-diaminocyclohexane collar was immobilized on short channel large pore sized silica through a long linker of {(CH 2 ) 3 –NH–melamine–piperazine} to investigate its performance in enantioselective epoxidation of chromenes, indene, styrene and cis β-methyl styrene in the presence of pyridine N -oxide (Py N O) as an axial base using aqueous NaOCl as an oxidant at 0 °C. The immobilized catalyst system showed high turnover frequency (TOF) and enantioselectivity for the smaller and bulkier alkenes like styrene, indene, 2,2-dimethylchromene and 6-cyano-2,2-dimethylchromene (ee up to 98%). These results are the best reported for heterogeneous catalyst under biphasic reaction conditions and were comparable to the dimeric Mn(III) salen system under homogeneous condition. The performance of the immobilized catalyst was retained for six reuse experiments. This protocol was extended to the synthesis of an antihypertensive drug ( S )-Levchromakalim (ee 98%) at 1 g level.

A series of new chiral monomeric and dimeric macrocyclic Mn(III) salen complexes 1 – 4 with trigol linker were synthesized, characterized (by microanalysis, IR spectroscopy, UV–vis. spectroscopy, optical rotation, and mass spectrometry), and used as catalysts in the enantioselective epoxidation of styrene, cis β-methyl styrene, indene, and chromenes in the presence of several N -oxides as an axial base and NaOCl as an oxidant at 0 °C. With the use of chiral dimeric macrocyclic catalyst 3 (2.5 mol%), enantio-pure epoxides were achieved in excellent yields (>99%) and enantioselectivities (ee up to 98% in selected cases). The recycling was demonstrated with complex 4 (recyclable up to six cycles studied with retention of enantioselectivity) in the asymmetric epoxidation of styrene. The kinetic investigation with complex 4 for the epoxidation of styrene as the representative substrate showed the first-order dependence on the catalyst and the oxidant but independent on the initial concentration of the substrate.

Chiral macrocyclic V(V) salen complexes 1a – f derived from macrocyclic ligands obtained by the reaction of 1 R ,2 R -(−) diaminocyclohexane/(1 R ,2 R )-(+)-1,2-diphenylethylenediamine with bis-aldehydes 2 and 3 were synthesized and used as efficient catalysts in asymmetric cyanation reactions. The V(V) catalysts demonstrated excellent performance (product yields and ees up to 99%) with potassium cyanide (KCN) and sodium cyanide (NaCN). The catalytic system also performed very well with a safer source of cyanide-ethyl cyanoformate to give cyanohydrin carbonates in excellent yield and ee (up to 97%). The V(V) macrocyclic salen complex 1b retained its performance at multi-gram level and was conveniently recycled for a number of times.

Various ionic liquids ( IL 1 – 9 ) based on N -methyl N′ -alkyl imidazolium salts were explored as catalytic media in cyanoethoxycarbonylation of various aldehydes. The study revealed that the alkyl chain length and counter ion of the ionic liquid are critical for the product yield. The highest product yield of cyanohydrin carbonate (up to 96%) was obtained with C 5 alkyl chain with Br − as counter ion ( IL 3 ). On the other hand PF 6 − as counter ion failed to catalyze the cyanoethoxycarbonylation reaction.

Chiral dimeric vanadium (V) salen complex (10 mol%) derived from 5,5-Methylene di-[( S,S )-{ N -(3- tert -butyl salicylidine)- N′ -(3′,5′-di- tert -butyl salicylidene)]-1,2-cyclohexanediamine] with vanadyl suphate followed by auto oxidation was used as efficient catalyst for enantioselective Strecker reaction of N -benzylimines with TMSCN at −30 °C. Excellent yield (92%) of α-aminonitrile and high chiral induction was achieved (ee up to 94%) in case of 2-methoxy substituted N -benzylimines in 10 h. The catalytic system worked well up to four cycles with retention of enantioselectivity.

Chiral AlIII salen complexes were synthesized and used as catalysts for the asymmetric hydrocyanation of nitroolefins using 4-phenylpyridine N-oxide as an additive and trimethylsilyl cyanide (TMSCN) as a source of cyanide. An excellent yield of β-nitronitrile (87 %) and enantioselectivity (90 %) were achieved if (2-nitrovinyl)cyclohexane was used as a substrate at −15 °C in 16 h. To understand the interaction of the AlIII salen complex and additive, NMR and IR spectroscopic studies revealed that 4-phenylpyridine N-oxide acts both as an axial ligand and helps to activate the cyanide source TMSCN, which thereby increases the reactivity. A catalytic cycle was proposed based on the spectroscopic studies.

Several chiral oxazoline-based organocatalysts are prepared and applied in the asymmetric allylation reaction of aldehydes with allyltrichlorosilane whereas, best results are achieved using OXA as catalyst shown here.

The title reaction affords a broad range of chiral α-cyano amines by employing TMS-CN as source of cyanide.

A chiral oxazoline-based organocatalyst has been found to efficiently catalyze asymmetric Strecker reactions of various aromatic and aliphatic N-benzhydrylimines with trimethylsilyl cyanide (TMSCN) as a cyanide source at -20 °C to give α-aminonitriles in high yield (96 %) with excellent chiral induction (up to 98 % ee). DFT calculations have been performed to rationalize the enantioselective formation of the product with the organocatalyst in these reactions. The organocatalyst has been characterized by single-crystal X-ray diffraction analysis, as well as by other analytical methods. This protocol has been extended to the synthesis of the pharmaceutically important drug molecule levamisole in high yield and with high enantioselectivity.

The asymmetric cyanation across C C, C O, and C N bonds ranks among the most important and well-studied reactions in asymmetric catalysis to achieve useful chiral building blocks for pharmaceuticals, agrochemicals, and specialty materials. The asymmetric cyanation reaction demands careful selection of a chiral catalyst and a cyanide source. A number of efficient and successful synthetic strategies have been developed that include asymmetric cyanation-utilizing enzyme, organocatalyst, and metal complexes as catalysts. As for the concern of the source of cyanide, inorganic cyanides, for example, NaCN and KCN; and organic cyanides, for example, trimethylsilyl cyanide, alkyl cyanoformates, acetone cyanohydrin, acetyl cyanide, alkyl cyanophosphorylates, etc. have been employed, depending upon the targeted substrates. Since the subject is vast, this chapter discusses in detail chiral-metal-complex-based catalytic asymmetric synthesis of cyanohydrins using different cyanide sources. An attempt is made to discuss the reaction mechanism involved in enantioselective cyanation reactions.

A first approach for catalytic asymmetric Strecker reaction of aldehydes with a secondary amine in the presence of sodium fluoride using hydroquinine as chiral catalyst was developed. The catalytic system gave α-aminonitriles in excellent yields (up to 95%) and high enantioselectivities (er up to 94:6). The efficacy of the chiral product was successfully fulfilled in the improved synthesis of (S)-clopidogrel (an antiplatelet agent).

Recyclable chiral amide-based organocatalyst 5 efficiently catalyzed asymmetric Strecker reaction of various aromatic and aliphatic N-benzhydrylimines with ethyl cyanoformate as cyanide source at −10 °C to give a high yield (95%) of α-aminonitriles with excellent chiral induction (ee, up to 99%) with the added advantage of recyclability. Based on experimental observations a probable mechanism was proposed for this reaction. This protocol with catalyst 5 was extended for the synthesis of (R)-phenylalanine and pharmaceutically important drug intermediate (R)-3-phenylpropane-1,2-diamine in high yield with high enantioselectivity.

Chiral macrocyclic V(V) salen complexes 1a – f derived from macrocyclic ligands obtained by the reaction of 1 R ,2 R -(−) diaminocyclohexane/(1 R ,2 R )-(+)-1,2-diphenylethylenediamine with bis-aldehydes 2 and 3 were synthesized and used as efficient catalysts in asymmetric cyanation reactions. The V(V) catalysts demonstrated excellent performance (product yields and ees up to 99%) with potassium cyanide (KCN) and sodium cyanide (NaCN). The catalytic system also performed very well with a safer source of cyanide-ethyl cyanoformate to give cyanohydrin carbonates in excellent yield and ee (up to 97%). The V(V) macrocyclic salen complex 1b retained its performance at multi-gram level and was conveniently recycled for a number of times.

A chiral dimeric vanadium(V)—salen complex smoothly catalyzes the asymmetric Strecker reaction of a variety of N-benzylimines with TmsCN.

A series of amino acid-based oxazoline compounds have been prepared and successfully applied to the enantioselective allylation reaction of aldehydes. The fine-tuning of the structure of the oxazolines led to (S,S)-4 as an efficient organocatalyst which gave homoallyl alcohols in good yield (up to 90%) and excellent ee (up to 99%) for a wide range of substrates including aromatic, hetero-aromatic and α,β-unsaturated aldehydes. The chiral organocatalyst was synthesized in three easy steps with an overall 88% yield and successfully recycled for up to three cycles. On the basis of the experimental observations and NMR studies, a probable mechanism was proposed for this reaction.