Aryl urea derivatives

In terms of chemical structure, this group of herbicides is characterised by an aryl or substituted aryl radical as substituent on one of the N-atoms of urea, while two methyl groups are attached to the other urea nitrogen. 

The first active member of this group, 3-(4-chlorophenyl)-l,l-dimethylurea (monuron, 6) was prepared in 1951 (Bucha and Todd, 1951). 

In the subsequent years intensive research work was carried out for the further development of the herbicidal compounds of this group by various substitutions of the phenyl group. This work continues today. A few new derivatives with higher selectivity and safer application than earlier compounds have been developed. On the basis of the patent literature, the introduction of further new compounds is to be expected. It is noteworthy that mainly European firms have excelled in the further development of this type. 

The most important substances of this group are l,l-dimethyl-3-phenylurea (fenuron, 5) 3-(4-chlorophenyl)-1,1-dimethylurea, (monuron, 6) 3-(3,4-dichlorophenyl)-1,1 -dimethylurea (diuron,7) 1,1 -dimethyl-3-(a,a,a-trifluoro-m-tolyl)urea (fluometuron, 8) l,l-dimethyl-3-( ,a,a-trifluoro-p-tolyl)urea (para-fluron, 9) 3-(3-chloro-/j-tolyl)-1,1-dimethylurea (chlortoluron, 10) 3-(3-chloro-4-methoxyphenyl)-l,l-dimethylurea (metoxuron, 11) 3-[(4-chlorophenoxy)phenyl]- 

1-dimethylurea (chloroxuron, 12) 3,4-(4-methoxyphenoxy)phenyl-1,1,-dimethylurea (difenoxuron, 13) 3-(lT 2, 2 -tetrafluoroethoxyphenyl)-1,1-dimethylurea (fluor- 

---

Urea herbicides with cycloaliphatic substituents may contain several kinds of cycloalkyl and cycloalkenyl radicals, but only those in which two methyl groups are the substituents on N 1 are of satisfactory activity. A longer alkyl chain reduces herbicidal efficiency, this is also true for aryl urea derivatives. 

An interesting oxidative carbonylation of anihne derivatives was pubhshed in 2009 [37]. The reaction proceeded under 1 bar of CO at room temperature with 5 mol% of [Pd(OTs)2(MeCN)2] as the precatalyst. Either cyclic imidates or methyl anthranilates can be easily generated, depending on the reaction conditions. The use of A -aryl urea derivatives with a terminal N-H moiety allowed for the generation of quinazolinones (Scheme 6.10). 

A sequential one-pot synthesis of unsymmetrical aryl urea derivatives was developed by arylation of N-substituted cyanamides under metal-free conditions, followed by a second N-arylation under copper-catalyzed conditions [96]. Chen and Chen devised the arylation of pyridine N-oxides with At21X via initial O-arylation followed by a 1,3-radical rearrangement to o-pyridinium phenolates, and arylation of pyridine N-amidates delivered o-pyridinium anilines (Scheme 5d) [97]. 

Booker-Milburn and Lloyd-Jones in 2009 revealed the cationic palladium-catalyzed carbonylation of aryl urea derivatives at room temperature under 1 atm of CO forming the cyclic imidates [31]. Key features of this procedure are the utilization of the Pd(OTs)2(MeCN)2 as the catalyst precursor and the powerful activating effect of the aniline -urea moiety in contrast with acetanilide (0% yield). For the A/ ,A/ -disubstituted substrates (Table 15.23), the yields were dropping with the steric bulk increasing, whereas for the AT-monosubstituted analogs, the trend was opposite. Prolonged reaction time resulted in low yields which can be rationalized by the reflection that the imidate products were sensitive to the added acid. 

Table 15.23 Represented products for the carbonylation of aryl urea derivatives. ...

Oxazoles are also obtained by the reaction of a-halogenoketones (78) with primary amides (the Bliimlein-Lewy synthesis), and this method is particularly appropriate for oxazoles containing one or more aryl groups as in (79). Formamide may also be used in this process, resulting in a free 2-position in the oxazole, and when a urea derivative (80) is used, 2-aminooxazoles (81) are formed (80ZOR2185, 78IJC(B)1030, 78JIC264). Numerous applications of these procedures are described in Chapter 4.18. 

The soluble polymer support was dissolved in dichloromethane and treated with 3 equivalents of chloroacetyl chloride for 10 min under microwave irradiation. The subsequent nucleophilic substitution utilizing 4 equivalents of various primary amines was carried out in N,N-dimethylformamide as solvent. The resulting PEG-bound amines were reacted with 3 equivalents of aryl or alkyl isothiocyanates in dichloromethane to furnish the polymer-bound urea derivatives after 5 min of micro-wave irradiation (Scheme 7.75). After each step, the intermediates were purified by simple precipitation with diethyl ether and filtration, so as to remove by-products and unreacted substrates. Finally, traceless release of the desired compounds by cyclative cleavage was achieved under mild basic conditions within 5 min of micro-wave irradiation. The 1,3-disubstituted hydantoins were obtained in varying yields but high purity. 

Substituted ureas are alkylated under solidrliquid phase-transfer catalytic conditions to yield the A -alkylated products to the exclusion of N- and Oalkylated derivatives [23]. Surprisingly, A-aryl ureas do not react under similar conditions. 

The Biginelli reaction is a cyclocondensation between ethylacetoacetate, an arylal-dehyde and urea derivatives to obtain dihydropyrimidines. Transfer this reaction to the solid-phase chemistry, allow the preparation of libraries of this kind of products (Scheme 3.18) [288]. 

A screening of (R)-bis-N-tosyl-BlNAM 151 and axially chiral (thio)urea derivatives 152-162 (10mol% loading 0.36 M catalyst concentration incorporating the N-aryl(alkyl) structural motif was performed at various reaction temperatures in di-chloroform using the asymmetric FC addition of N-methylindole to trans-Ji-nitrostyrene as model reachon (product 1 Scheme 6.158). The structure of bis(3,5-bistrifluoromethyl) phenyl functionalized binaphthyl bisthiourea 158 was identified... 

Other sources of C-4 include the Vilsmeier reagent formed from POCI3 and DMF, which gives 2,4-dichloroquin-azolines 839 with A -aryl-A -(phenoxycarbonyl)urea derivatives 838 <1998BML2891>. 

Urea derivatives (16) were obtained from 3-unsubstituted tetra-hydro-l,3-oxazines and aryl isocyanates.68... 

A dimeric capsule can also be formed by two different tetra-urea molecules, and in aprotic solvents a mixture of two tetra-urea derivatives usually contains not only the two homodimers but also the heterodimer in a more or less statistical ratio. This formation of heterodimers is an additional proof of the dimerization [39], which is also valid when other indications (e.g. m-coupled doublets for aryl protons) fail. As an example, sections of the spectra of tetra-tolylurea (1), tetra-hexylurea (3), and of a mixture of the two are shown in Figure 5.3a-c [37a],... 

Reaction of a primary cyclic enaminoester with aryl isocyanates yield urea derivatives, which can be cyclized to fused uracils10 (equation 6). 

Wenzel AG, Jacobsen EN (2002) Asymmetric catalytic Mannich reactions catalyzed by urea derivatives enantioselective synthesis of beta-aryl-beta-amino acids. J Am Chem Soc 124 12964-12965 Wertz PW, Miethke MC, Long SA, Stauss JS, Downing DT (1985) The composition of the ceramides from human stratum comeum and from comedones. J Invest Dermatol 84 410—412... 

In contrast to 2, the above derivatives incorporate four hydrogen bond donors. As a consequence, a favourable bonding situation is present in which the four secondary amine protons of each host can interact with the two charged carboxylate groups of the guest - see 4a and 4b. The proposed structure of the complex of the bis-urea derivative was supported by the existence of large NMR downfield shifts for both the inner and outer urea NH resonances in deutero-dimethyl sulfoxide and the observation of intramolecular H NOEs between the receptor aryl and the guest CH2 resonances in this solvent. A Job s plot confirmed the 1 1 stoichiometry of the product. 

A number of 2-aryl and 2-alkyl derivatives of 5,6-dihydro-1,3-4//-oxazine have been prepared in a similar way.118-120 An analogous reaction consists in thermal cyclization of N- (y-chloropropyl) -A -alkyl and -A -aryl ureas.110-112 121 122... 

Diary] and triaryl or naphthyl carbamates exhibit low herbicidal activity. The substitution of the aryl radical for a heterocyclic radical gives heterocyclic alkyl and dialkyl ureas, of which many examples have been prepared in recent years. The herbicidal activity of urea derivatives containing a heterocyclic radical, such as benzthiazole, thiazole, thiadiazole, oxadiazole and pyridine, is favourable if one or two methyl groups are substituted at the N -nitrogen. The carrier of total or selective action in these derivatives is presumably the heterocyclic part of the molecule. More recently several new groups of compounds have become known, mainly in the patent literature, for which the structure-activity on relationships are still to be elucidated. 

Dihydropyrimidones are valuable templates for development of pharmaceuticals and, consequently, a method for efficient N-arylation of the urea moiety, outlined in Scheme 15.60, has been reported by the groups of Larhed and Kappe [60]. As the authors remark in the paper, N3-arylated dihydropyrimidone derivatives cannot be synthesized by common Biginelli condensations, thus increasing the utility of this rapid and convenient procedure for introduction of chemical diversity to the heterocyclic backbone. 

---