273410-39-2

Upstream product

• 109-05-7 2-Methylpiperidin 
• 100-07-2 4-methoxy-benzoyl chloride 
• 98-88-4 benzoyl chloride 
• 3197-42-0 (S)-2-methylpiperidine 
• 54731-09-8 N-tosyl-L-prolyl chloride 
• 1346681-71-7 (1E)-4-hydroxy-1-mesityl-4-methylpent-1-en-3-one 
• 432550-82-8 N-benzoyl-N-ethanoylamino-2-[(S)-1-tert-butyldimethylsilyloxy-2-methylpropyl]quinazolin-4(3H)-one 

Relevant academic research and scientific papers

Acylative kinetic resolution of racemic methyl-substituted cyclic alkylamines with 2,5-dioxopyrrolidin-1-yl (: R)-2-phenoxypropanoate

The diastereoselective acylation of a number of racemic methyl-substituted cyclic alkylamines with active esters of 2-phenoxypropanoic acid was studied in detail. The ester of (R)-2-phenoxypropanoic acid and N-hydroxysuccinimide was found to be the most selective agent. The highest stereoselectivity was observed in the kinetic resolution of racemic 2-methylpiperidine in toluene at -40 °C (selectivity factor s = 73) with the predominant formation of (R,R)-amide (93.7% de). To explain the observed stereoselectivity, DFT modelling of the transition states in the reactions of the title acylating agent with 2-methylpiperidine and 2-methylpyrrolidine was performed. The calculated values were in good agreement with experimental data. It has been demonstrated that the acylation proceeds via a concerted mechanism, in which the addition of an amine occurs simultaneously with the elimination of the hydroxysuccinimide fragment. The high stereoselectivity of the (R,R)-amide formation is largely ensured by the lower steric hindrances in the transition states as compared to the formation of (R,S)-amide.

Asymmetric synthesis of N-N axially chiral compoundsviaorganocatalytic atroposelectiveN-acylation

Compared with the well-developed C-C and C-N axial chirality, the asymmetric synthesis of N-N axial chirality remains elusive and challenging. Herein we report the first atroposelectiveN-acylation reaction of quinazolinone type benzamides with cinnamic anhydrides for the direct catalytic synthesis of optically active atropisomeric quinazolinone derivatives. This reaction features mild conditions and a broad substrate scope and produces N-N axially chiral compounds with high yields and very good enantioselectivities. Besides, the synthetic utility of the protocol was proved by a large scale reaction, transformation of the product and the utilization of the product as an acylation kinetic resolution reagent. Moreover, DFT calculations provide convincing evidence for the interpretation of stereoselection.

N-tosyl-(S)-prolyl chloride in kinetic resolution of racemic heterocyclic amines

The kinetic resolution of racemic heterocyclic amines via acylation with N-tosyl-(S)-prolyl chloride was systematically investigated. It was established that racemic mixtures of aromatic amines could be resolved with high efficiency, while the acylation of 2- and 3-methylpiperidines occurred with low diastereoselectivity. A method for the preparation of enantiomerically pure (3R)-7,8-difluoro-3-methyl-3,4-dihydro-2H-[1,4]benzoxazine was developed.

Catalytic kinetic resolution of cyclic secondary amines

The catalytic resolution of racemic cyclic amines has been achieved by an enantioselective amidation reaction featuring an achiral N-heterocyclic carbene catalyst and a new chiral hydroxamic acid cocatalyst working in concert. The reactions proceed at room temperature, do not generate nonvolatile byproducts, and provide enantioenriched amines by aqueous extraction.

Kinetic resolution of amines with enantiopure 3-N,N-diacylaminoquinazolin-4(3H)-ones

The title compounds (DAQs) are chiral when the two N-acyl groups are different because of the absence of rotation around the N-N bond (a chiral axis). Enantiopure DAQs have been obtained by incorporation of a chiral centre in enantiopure form either into the substituent at the Q2-position or into one of the N-acyl groups, or into both, followed by separation of diastereoisomers. This separation is unnecessary in one case because conversion of the N-monoacylaminoquinazolinone (MAQ) into the DAQ is completely diastereoselective. Neither is separation of diastereoisomers necessary with 3-[N,N-di-(S)-2-acetoxypropanoylamino]-2-diphenylmethylquinazolin-4(3H)-one 37a: this DAQ 37a has its N-N bond rendered a chiral axis by the bias in its imide moiety wholly in favour of one exo/endo conformation. The high chemoselectivity exhibited by N,N-diacetyl- or N,N-dibenzoylaminoquinazolinones in reaction with the less hindered of two secondary amines (pyrrolidine in the presence of 1 eq. of piperidine) has a stereoselective counterpart: reaction of the above enantiopure DAQs enantioselectively with racemic amines leading to kinetic resolution. Using 1 eq. of DAQ and 2 eq. of amine, both the derivatised and unreacted amine enantiomers are recovered with high enantiomeric excess (ee) (better than 90% ee in some cases). Some of the higher ees are found in the recovered amides where non-chemoselective attack on both N-acyl groups of the DAQ has occurred: from the opposite configurations of the amine component in the two amides and from the low enantiopurity of the recovered unreacted amine, reaction of each of the N-acyl groups with complementary enantiomers of the amine is occurring (parallel kinetic resolution). Although higher ees are, in general, obtained using secondary amines, high ees are obtained in some cases using 1-phenylethylamine and, in particular, amino acid esters (valine and alanine). The sense of enantioselectivity in the reactions of these DAQs with amines is controlled by the configuration of the N-N axis: replacing the Q group in an N-(S)-2-acetoxypropanoyl-N-acetyl-bearing DAQ by phthalimide, thus eliminating the N-N chiral axis, drastically reduces the level of kinetic resolution.

3-(N,N-diacylamino)quinazolin-4(3H)-ones as enantioselective acylating agents for amines

The presence of an N-N chiral axis in a 3-(N-benzoyl-N- isobutanoyl)aminoquinazolin-4(3H)-one (DAQ) bearing a chiral substituent in the 2-position of the quinazolinone allows separation of two enantiopure diastereoisomers; one of these diastereoisomers reacts with racemic 2- methylpiperidine to give (R)(+)-1-benzoyl-2-methylpiperidine (95% ee) and (S)-2-methylpiperidine (91% ee) even using stoichiometric quantities of reagents (1 equiv. DAQ: 2 equiv. amine). (C) 2000 Elsevier Science Ltd.