Trisubstituted ureas

Optimal conditions for the synthesis of symmetrically disubstituted or tetra-substituted ureas as well as of unsymmetrically disubstituted or trisubstituted ureas have, however, been developed (see also next Section). 

The methodology did not work for secondary amines, thus suggesting the formation of an isocyanate as intermediate (Scheme 27, MX2 = Pdl2, [OX] = (1/2) O2]. However, by reacting a primary amine in the presence of a secondary nucleophilic amine, a general and selective synthesis of trisubstituted ureas has been achieved, through trapping of the isocyanate intermediate by the secondary amine (Eq. 52) [274,275]. 

The combinatorial library synthesis of a diverse set of trisubstituted ureas has been described [64]. The synthetic pathway involves the prehminary preparation of various nitrophenylcarbamates from commercially available nitrophenyl chlorofor-mate and a selection of amines allowing for wide scope in the divergence of the final urea products. In a further reaction of the nitrophenylcarbamates with a second amine, the urea was generated. Simultaneous addition of an electrophilic and basic scavenger resin removed all by-products, again allowing rapid isolation of the products in excellent yield and purity (Scheme 2.43). 

Scheme 2.43 Combinatorial library synthesis of trisubstituted ureas.

Trisubstituted ureas have been obtained, under mild conditions (333 K, 0.1 MPa, 6h), in the presence of pyridine, from primary amines, C02 and hexaalkylphos-phorous triamides, P(NR2)3 [124]. The latter compounds are able to react with C02 by converting into phosphocarbamate species, P(02CNR2)3 (NR2) (x = 1, 2). The yields of ureas R2NC(C))NHR" were almost quantitative, if based on one amino group of P(NR2)3, but could not be further improved by the addition of an excess of primary amine. This indicates that, in general, only one of the three P-N bonds of P(NR2)3 takes part in the reaction. 

The reaction of amide chlorides with IV-unsubstituted carbaminic acid esters or lV,, -trisubstituted ureas or thioureas affords the corresponding amidinium salts in good yields. 

Almost all of the urea compounds with good herbicidal action are trisubstituted ureas, containing a free imino hydrogen. According to the receptor theory, this hydrogen plays a role in the formation of the hydrogen bond (for details see the section on the mode of action). 

A more recent study investigated microwave-assisted parallel synthesis of di and trisubstituted ureas from carbamates bound on modified Marshall resin [60]. Modification of the resin was achieved by treatment with p-nitrophenyl chloroformate and N-methylmorpholine (NMM) in dichloromethane at low temperatures. The resulting resin was further modified by attachment of a variety of amines to obtain a set of polymer-bound carbamates (Scheme 16.39). 

The majority of the most important of the wide variety of methods for preparing mono-, di-, and trisubstituted ureas [723, 727] fall into three main groups [728]. 

Although numerous methods are available for the preparation of symmetrical and unsymmetrical di- or trisubstituted ureas in good to excellent yields, the only hitherto reported synthesis of unsymmetrical tetrasubstituted ureas involves reaction of a carbamoyl chloride (prepared from a secondary amine and phosgene) with a secondary amine [754]. Moreover, this method, as used more recently [755, 756], suffers from several drawbacks. An excess of amine and/or the use of an acid scavenger (such as pyridine or triethylamine) is required, and the carbamoyl chloride intermediate can be both unstable and difficult to isolate when needed. Moreover, the production of hydrochloric acid prevents the application of this method when acid-sensitive functionalities are present. N,N -Carbonyldibenzotriazole can be utilized to synthesize N,N,N, N -unsymmetrical tetrasubstituted ureas 1023 by a... 

Although all attempts to prepare tetraethylurea from diethylamine and carbon dioxide failed (the main product at 160 °C was tetraethylthiourea), the co-carbony-lation of butylamine and diethylamine gave trisubstituted urea in 42% yield at 80 °C [778],... 

Yamazaki N, Tomioka T, Higashi F (1975) Trisubstituted ureas and thioureas from hexa-alkylphosphorous triamides, primary amines, and carbon dioxide or carbon disulfide. Synthesis 384—385... 

Recently, studies in urea synthesis have focused on transition-metal-catalyzed reactions. Buchwald et al. reported a Pd-catalyzed cross-coupling of aryl chlorides with sodium cyanate, which represented a practical way to synthesize unsymmet-rical ureas [50]. The protocol allows for the synthesis of unsymmetrical N,N -di-and A. A. A -trisubstituted ureas in one pot and is tolerant of a wide range of functional groups (Scheme 5.19). Insight into the mechanism of aryl isocyanate formation was gleaned through studies of the transmetalation and reductive... 

M/V.N -Trisubstituted ureas afford chloroformamidine derivatives (eq 25), while A/iiV -disubstituted ureas and thioureas produce carbodiimides (eq 26). When carbamoyl chlorides are treated with the reagent in MeCN, they are converted into isocyanates (eq 27). Dehydration of A -substituted formamides provides access to isocyanides (eq 28). ... 

Chlorination and Dehydration of Substituted Carboxamide Groups. Secondary amides and A, N,Af-trisubstituted ureas possessing an N-H bond are converted to imidoyl chlorides - and... 

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