Trisubstituted guanidines

The symmetrical anhydride is less reactive and consequently more selective in its reactions than the O-acylisourea. Although the latter can acylate both N- and O-nucleophiles, the symmetrical anhydride will only acylate V-nuclcophilcs. This means that the hydroxyl groups of the side chains of serine, threonine, and tyrosine that have not been deprotonated are not acceptors of the acyl group of the symmetrical anhydride. An additional feature of this approach to carbodiimide-mediated reactions is that it avoids a possible side reaction between the carbodiimide and the iV-nucleophilc, which gives a trisubstituted guanidine [(C6HuN)2C=N-CHR5CO-... 

Scheme 7.6 Synthesis of di- and trisubstituted guanidines on a modified four-arm PEG-support.

A series of trisubstituted guanidines has been prepared by Drewry et al.19 a-Bromo-p-toluamide was converted to the azide by reaction with sodium... 

The phosgenation of N,N -dialkyl- and N-alkyl-N -arylureas at 110-120 °C in chlorobenzene, followed by reaction with amines affords N,N, N"-trisubstituted guanidines via the intermediate chloroformamidines. ... 

The solid phase synthesis of trisubstituted guanidines was achieved in the research group of D.H. Drewery by utilizing the aza-Wittig reaction. The reaction of solid-supported alkyl iminophosphorane and aryl or alkyl Isothiocyanates afforded carbodiimides, which upon treatment with primary or secondary amines provided the trisubstituted guanidines. ... 

Dihydrothienocoumarins that have analgesic activity without anti-inflammatory activity have been synthesized. Compounds of type (154), with antibacterial, antifungal, and other activities, have been synthesized. Some NN N"-trisubstituted guanidines that contain thiophen rings and have anti-inflammatory properties have been synthesized. " Nitrosation of methapyrilene in vitro has been studied. 

Drew 1997 Drewry, D.H., Gerritz, S.W. and Linn, J.A., Solid-Phase Synthesis of Trisubstituted Guanidines, Tetrahedron Lett., 38 (1997) 3377-3380. 

With N,N -disubstituted guanidines the problem arises whether 1,2,5- (XXXV) or 1,3,5-trisubstituted biguanides (XXXVI) are produced, or a mixture of both. Relevant experiments (5) show that the former (XXXV) are in fact obtained to the exclusion of the latter. 

Reaction is terminated at the desired monoaddition-stage by using free guanidine (base), and acetone as solvent (376, 377). Guanidine salts and carbodiimides in dimethylformamide, in spite of the presence of excess of the former, yield 1,2,6-trisubstituted isomelamines (XLIII), presmnably by loss of arylamine from the intermediate labile triguanide (XLII) (375). 

Ostresh, J. M. Schoner, C. C. Hamashin, V. T. Nefzi, A. Meyer, J.-P. Houghten, R. A. Solid-Phase Synthesis of Trisubstituted Bicyclic Guanidines via Cyclization of Reduced /V-Acylated Dipeptides, J. Org. Chem. 1998, 63, 8622-8623. 

Fig. 8. Solid-phase synthesis of a trisubstituted bicyclic guanidine library.

A small library of di- and trisubstituted pyrimidines was prepared by condensation of amidines and guanidines with a range of alkynones. The reaction could be performed under conventional conditions (reflux in acetonitrile, ca. 82 °C), albeit 2 hours was required for the reaction to go to completion. Microwave dielectric heating in sealed vessels at 120 °C (ca. 38 °C above the boiling point of acetonitrile) diminished the reaction time to 40 min [120,121] (Scheme 46). 

Ostresh JM, Schoner CC, Hamashin VT, Nefzi A, Meyer J-P, Houghten RA (1998) Solid-phase synthesis of trisubstituted bicyclic guanidines via cyclization of reduced n-acylated dipeptides. J Org Chem 63 8622-8623... 

With /V-acylthioamides the reaction proceeds very slowly and the products are difficult to purify. Therefore, the Af-acylthioamides 32 are first converted into the S -alkyl derivatives 33 by the reaction with alkyl halides under strongly basic conditions. The resulting A -acylthioimi-dates 33 react with amidines and guanidines in alcoholic solution in the presence of sodium alkoxide to form 2,4,6-trisubstituted 1,3,5-triazines 34 in moderate to good yields.438,439 This procedure is an extension of the synthesis of trisubstituted 1,3,5-triazines from A -acylimidates 17 and amidines (vide supra).325... 

In a standard method, 1,3-diketones are cyclocondensed with amidines, ureas, thioureas and guanidines giving 4,6-di- and 2,4,6-trisubstituted pyrimidines 4, 2-pyrimidones 5, 2-thiopyrimidones 6 and 2-aminopyrimidines 7 respectively Pinner synthesis) [140] ... 

Chloro-l,3-dimethylimidazolium chloride (DMC) [26] (R =R = Me, L = H in 11, Scheme 4.8a) not only acts as a powerful dehydration agent but also has unique and versatile abilities to chlorinate primary alcohols, to oxidize primary and secondary alcohols and to reduce sulfoxides and so on. In addition, DMC easily reacts with amines to yield the corresponding guanidines. Thus, methods of preparing monocyclic and bicyclic systems by application of DMC chemistry in the key steps have been developed [27] the reaction of DMC-type chloroamidine compounds with amines for trisubstituted mono-cyclic guanidines [27a] (Scheme 4.8a), the intramolecular cyclization of thiourea derivatives after activation with DMC for monosubstituted or disubstituted monocyclic and bicyclic guanidines [27b] (Scheme 4.8b), and the DMC mediated cyclization of... 

The kinetic resolution of racemic 1-phenylethyl bromide was examined in the alkylation of benzoic acid using trisubstituted monocyclic guanidines as chiral sources [67]. (R)-Excess ester was obtained in 96% yield even with 15% ee, when the reaction was carried out in benzene with l,3-dimethyl-(45,55)-diphenyl-2-[(15)-phenylethylimino]imidazolidines [27a] (Scheme 4.25). 

A convenient method for the synthesis of substituted pyrimidines involves the reaction of amidine or guanidine derivatives with a 1,3-dielectrophilic, three-carbon unit. Synthesis of 2,4,5-trisubstituted pyrimidines from Baylis-Hillman adducts and amidines is a good example. The ester group in the reactant can be replaced with acetyl and cyano groups, and the corresponding products are isolated in moderate to excellent yields. 

Van der Eycken s group [27] also recently reported a flexible synthesis toward polysubstituted 2-aminoimidazoles (see Scheme 9). A key step in their synthesis involved the use of silver (I) as a catalyst to heterocyclize guanidine derivatives to provide the desired 1,4,5-trisubstituted 2-aminoimidazole derivatives. 

In 2013, Zhao et al. described a highly diastereo- and enantioselective synthesis of trisubstituted cyclohexanols based on a one-pot sequential tandem Henry-Michael reaction catalysed by a combination of a chiral cinchona alkaloid thiourea and 1,1,3,3-tetramethyl guanidine. This process occurred between nitromethane and 7-oxo-hept-5-en-l-als, providing the corresponding tandem chiral products as almost single diastereomers... 

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