Asymmetric diels alder reaction using pyrazole derivatives as a chiral catalyst

Abstract

N-Acylpyrazoles (1) were promising as good dienophiles, which were easily converted into the desired carboxylic derivatives. Bis(pyrazolyl)methanes, which were derived from chiral pyrazoles, showed the activity of chiral catalyst. Particularly 10 mol% of bis(isomenthopyrazol-1,1'-yl)methane (8 a) catalyzed enantioselectively the Diels Alder reaction up to 40 % ee by the formation of complex with Mg(ClO 4 ) 2 .J. Heterocyclic Chem., 40, 681(2003).Recently we have reported the preparation and the utilities of the optically active pyrazoles as a new chiral auxiliary [1,2], which has unique structure and properties different from the conventional chiral auxiliaries [3]. Since Evans reported the enantioselective Diels Alder reactions using the chiral catalyst such as 2,2-bis, many papers concerning the analogous box derivatives have appeared in the literature [5]. From the fact that pyrazoles are good ligands for various Lewis acids [6], optically active pyrazoles are expected to show effective chiral catalytic activities for various enantioselective syntheses. These optically active pyrazoles have already exhibited chiral catalytic activities in borane mediated reductions and dialkylzinc addition on the prochiral carbonyl compounds [7]. As an extension of the diastereoselective Diels Alder reaction using 3-phenyll-menthopyrazole [10], we will report here the utilities of optically active pyrazole derivatives for either a convenient dienophile or a chiral catalyst in enantioselective Diels Alder reactions.Results and Discussion. F i r s t l y, N-(α , β-unsaturated) acyl substituted pyrazoles were inspected using optically active box derivative as a chiral catalyst. When 1-acryloyl-3,5-dimethylpyrazole (1a) was treated with cyclopentadiene in the presence of M g [ (R,R)-Ph-box] complex, 1-(bicyclo[2.2.1]hept-5-ene-2-carbonyl)-3,5-dimethylpyrazole (2a) was afforded in 80 % yield with 86 % of Endo isomer ratio and 60 % ee of Endo isomer (Scheme 1). Under the same conditions from 3-acryloyloxazolidine-2-one (4a), 3-(bicyclo[2.2.1]hept-5-ene-2-carbonyl)oxazolidine-2-one (3a) was obtained in 80 % yield with 90 % of Endo isomer ratio and 30 % ee of E n d o i s o m e r. Moreover, the functionalization of 2 a i n t o various carboxylic derivatives was easy to realize by the action of appropriate nucleophiles under acidic or basic conditions. By the action of sodium alkoxide, 2a was converted into the corresponding bicyclo[2.2.1]hept-5-ene-2-carboxylic acid esters (5a) in 80 % ee. Alcoholysis of 2a was also successful in the presence of boron trifluoride in 75 % yield with complete retention of its configuration.From these results, N-(α , β-unsaturated) acyl substituted pyrazoles were concluded to be convenient dienophiles for the asymmetric Diels Alder reactions.As part of a series of studies concerning optically active 3 -p h e n y l -l-menthopyrazole, l-menthopyrazole, isomenthopyrazole, carvomenthopyrazole and carvoisomenthopyrazole were previously prepared by the formylation of menthone or carvomenthone using LDA [2]. The ...

Leveraging the Knorr Pyrazole Synthesis for the Facile Generation of Thioester Surrogates for use in Native Chemical Ligation

“…N‐acyl heterocycles are known to act as efficient acylating agents but N‐acylpyrazoles have been largely overlooked due to their modest reactivity, which is about 20 times less reactive than the corresponding N‐acylimidazole . Although N‐acylpyrazoles are widely studied in the realm of organic heterocyclic synthesis, their utility has been focused on ligands and mildly activated substrates for organometallic transformations . The relatively low reactivity towards endogenous nucleophiles and the ease of synthetic access presented an opportunity to adapt Knorr's synthesis for mild and selective in situ thioesterification.…”

“…[33,34] Although N-acylpyrazoles are widely studied in the realm of organic heterocyclic synthesis,t heir utility has been focused on ligands and mildly activated substrates for organometallic transformations. [35][36][37][38][39] Ther elatively low reactivity towards endogenous nucleophiles [33] and the ease of synthetic access presented an opportunity to adapt Knorrssynthesis for mild and selective in situ thioesterification.…”

Preparation of 2,6‐bis(l‐menthopyrzol‐3‐yl)pyridines and their catalytic activity for asymmetric diels alder reaction

“…These optically active pyrazoles have already exhibited chiral catalytic activity in the borane reduction and the dialkylzinc addition on the prochiral carbonyl compounds [22]. Furthermore, bis(pyrazolyl)-methanes, which were regarded as bidentate pyrazole ligand with C 2 symmetry, showed chiral catalytic activity for Diels Alder reaction by the formation of magnesium complex [23]. However, we have strongly desired to develop more effective catalyst of optically active pyrazole derivatives for a wide variety of synthetic reactions.…”

“…Here we will report the preparation of 2a and the related pyrazoles. Also, their chiral catalytic activities in the Diels Alder reaction will be discussed as the extension of the stereoselective Diels Alder reaction using menthopyrazoles [10,23].…”

Pyrazolo[4,3-a]quinindoline as a new highly fluorescent heterocyclic system: Design, synthesis, spectroscopic characterization and DFT calculations

“…Other pyrazoles include effective antirheumatoidal (SC-58635 Celecoxib) [12] and antiviral agents (Pyrazomycin) [13], hormone oxytocin agonists (WAY-VNA-932) [14] and selective Human C1s inhibitors [15]. Recently, pyrazoles became of interest as intermediates for fused pyrazoles [16], and also as chiral catalysts [17], ligands [18] or as moieties to enhance region-and stereo-selectivity [19].…”