Pyrrolidines triazole

Scheme 9.35 Pyrrolidine-triazole organocatalysts (5c-g) for Michael additions.

Chiral pyrrolidine-triazole 91 (10 mol%), obtained by click chemistry , was used as catalyst in combination with TFA (1.5 mol%) in the aldol reaction between cyclohexanone (10 equiv.) and several aldehydes under solvent-free conditions at 0°C, affording the aldol products in good yields and diastereoselectivities (86-93% yield, 84-92% de) albeit with low enantioselectivities (23-28% ee) [161]. 

Finally, Sankararaman et al. have reported the synthesis of chiral nitro-chromenes on the basis of an asymmetric domino Michael-Henry reaction followed by dehydration, involving nitrostyrene and orlho-hydio-xybenzaldehyde. This reaction was catalysed by a novel C2-symmetric bis-(pyrrolidine-triazole)-based organocatalyst and provided only moderate yields (22-40%) and poor enantioselectivities (7-24% ee). 

In peptide syntheses, where partial racemization of the chiral a-carbon centers is a serious problem, the application of 1-hydroxy-1 H-benzotriazole ( HBT") and DCC has been very successful in increasing yields and decreasing racemization (W. Kdnig, 1970 G.C. Windridge, 1971 H.R. Bosshard, 1973), l-(Acyloxy)-lif-benzotriazoles or l-acyl-17f-benzo-triazole 3-oxides are formed as reactive intermediates. If carboxylic or phosphoric esters are to be formed from the acids and alcohols using DCC, 4-(pyrrolidin-l -yl)pyridine ( PPY A. Hassner, 1978 K.M. Patel, 1979) and HBT are efficient catalysts even with tert-alkyl, choles-teryl, aryl, and other unreactive alcohols as well as with highly bulky or labile acids. 

The 1,3-dipolar cycloaddition reactions to unsaturated carbon-carbon bonds have been known for quite some time and have become an important part of strategies for organic synthesis of many compounds (Smith and March, 2007). The 1,3-dipolar compounds that participate in this reaction include many of those that can be drawn having charged resonance hybrid structures, such as azides, diazoalkanes, nitriles, azomethine ylides, and aziridines, among others. The heterocyclic ring structures formed as the result of this reaction typically are triazoline, triazole, or pyrrolidine derivatives. In all cases, the product is a 5-membered heterocycle that contains components of both reactants and occurs with a reduction in the total bond unsaturation. In addition, this type of cycloaddition reaction can be done using carbon-carbon double bonds or triple bonds (alkynes). 

Ethyl 5-chloromethyl-l,2,3-triazole-4-carboxylate 332, obtained by cyclocondensation of 3-amino-4-azidofurazan with ethyl 4-chloroacetoacetate, is converted to pyrrolidine derivative 333 in 97% yield. Heating at reflux with 1 N HC1 deprotects the carboxylic group. The obtained acid 334 is treated with carbonyldiimidazole followed by pyridine-4-carboxylic acid amidrazone to provide product 335 in 25% yield. Compound 335 is a potent inhibitor of glycogen synthase kinase-3 (GSK-3) (Scheme 52) <2003JME3333>. 

Fathalla et al. reported that some [l,2,4]triazolo[4,3- ]quinazoles can be subjected to various transformations involving the triazole nitrogen atom <2000MOL1210>. Thus, treatment of 186 with formaldehyde and pyrrolidine... 

In the reaction of 4-diazotriazoles with morpholine, pyrrolidine [83DIS(B)(43)2557], and several other secondary amines (66JMC733), the corresponding triazenes 247 were obtained. Also, in the case of 4-diazo-l,2,3-triazole-5-carboxamide, these compounds could easily be obtained in organic solvents despite the competing intramolecular ring closure to 2,8-diazahypoxanthine. In aqueous media, the intermolecular coupling... 

Table XVll.A-4 lists 321 componnds, of which 116 are pyrroles, seventy-nine are pyrrolidines, and twenty-eight are pyr-rolines. There are sixteen pyrazoles listed in Table XVII.A-4. Sixty-two imidazoles, ten imidazolidines, and three imidazolines have been identified in tobacco and tobacco smoke. Five componnds with a 1,2,4-triazole ring have been identified in tobacco. Two compounds with a 1,2,3-triazole ring (as benzotriazoles) have been identified in tobacco and tobacco smoke. The componnds in Table XVII.A-4 exhibit a great deal of fnnctionality. Although each contains a five-membered A-containing ring, some are alcohols, ketones, sugar-amines, acids, esters, and imides. Of the 321 compounds listed in Table XVII.A-4, 256 are found in tobacco smoke, 117 are found in tobacco, and 52 are present in both tobacco and tobacco smoke.

Aromatic nitrogen heterocycles, especially triazoles and tetrazoles are the most common nucleophiles used in the organocatalysed aza-Michael reaction. 5-Phenyltetrazole undergoes conjugate addition with acyclic enals using the tri-fluoracetate salt of imidazolidinone (11.127), while the 1,4-addition of phenyl-tetrazole and 1,2,4-triazole (11.130) occurs with high ee using the enantiopure pyrrolidine catalyst (11.79). ... 

As for aminating agents, use of hydroxylamine provides a very simple and cheap procedure, while 1,1,1-trimethylhydrazOTiium iodide, 4//-l,2,4-triazol-4-amine, and S-(pyrrolidine-l-carbonothioyl)thiohydroxylamine usually afford better yields of the amination products. The feature of 4//-l,2,4-triazol-4-amine is that its applicatimi demands an inert atmosphere. 

Numerous 2-substituted pyrrolidine organocatalysts have been prepared from L-proline and its derivatives, and have been proven to be highly efficient for many asymmetric reactions. Representative organocatalysts have been selected and categorised on the basis of the 2-substituted group that includes di- and tri-amine (la-m), dithioacetal (2a-f), guanidine (2g-i), sulfonamide (3a-j), amide and thioamide (3k-n), urea (4a and 4e), thiourea (4b-d, f-j) and heterocycles such as tetrazole (5a,b), triazole (5c-g), imidazole (5h-j) and benzoimidazole (5k) (Figure 9.1). 

S. Matsuoka, Y. Tochigi, K. Takagi, M. Suzuki, Tetrahedron 2012, 68, 9836-9841. Sequential one-pot and three-component reactions of an N-heterocychc carbene to form 4-(l,2,4-triazol-5-ylidene)pyrrolidine-2,5-diones a tandem umpolung/ annulation sequence via deoxy-Breslow intermediates. 

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