Synthesis of unsymmetrical phenylurea derivatives ...

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Cite this: New J. Chem., 2015, 39, 805

Synthesis of unsymmetrical phenylurea derivatives via oxidative cross coupling of aryl formamides with amines under metal-free conditions†

Received (in Montpellier, France) 27th September 2014, Accepted 18th November 2014

Nagireddy Veera Reddy, Pailla Santhosh Kumar, Peddi Sudhir Reddy, Mannepalli Lakshmi Kantam and Kallu Rajender Reddy*

DOI: 10.1039/c4nj01668h www.rsc.org/njc

A new synthetic approach for phenylurea derivatives involving the cross coupling of N-aryl formamides with amines through the formation of isocyanate intermediates in the presence of hypervalent iodine reagents is described.

The unsymmetrical urea derivatives have significant importance in the fields of medicine, biology and materials science.1–3 Several of these derivatives are found in biologically active compounds4 and often serve as important intermediates5 and bi-functional organocatalysts6 in organic synthesis. The prevalence of the urea functional group in medicinal chemistry is attributed to metabolic stability of the N–C(O)–N linkage and to the large number of variations possible. Among them, phenylureas have attracted special attention because of their herbicidal properties as well as other agricultural applications (Fig. 1). Revelation of 3-(4-chlorophenyl)-1,1-dimethylurea (monuron) possessing herbicidal properties led to studies on a large number of unsymmetrical phenylurea derivatives.7 Others such as fenuron, diuron and siduron have been widely used as herbicide chemicals. Furthermore, isoproturon has been shown to play an effective role in herbicide chemistry that inhibits photosynthesis of plants.8 The other derivative, N-butyl-N-methyl-N0 -(3,4-dichlorophenyl)urea

Fig. 1

Examples of herbicides with unsymmetrical phenylurea derivatives.

Inorganic and Physical Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500 007, India. E-mail: [email protected], [email protected]; Fax: +91-040-27160921 † Electronic supplementary information (ESI) available: Experimental procedure, characterization data, and 1H, 13C, IR and mass spectra. See DOI: 10.1039/c4nj01668h

(neburon), has been commercially exploited as an efficient herbicide on the wheat and strawberry fields.9,10 Most of the commercially accessible procedures for the synthesis of ureas and their derivatives are derived by reacting suitable amines with phosgene,11 isocyanates,12 or dimethyl carbonate.13 However, with the growing concern over the environment and stringent legislations by the governments, replacements for toxic phosgene routes are in great demand. Although alternative routes such as Curtius and Hofmann rearrangements14 as well as oxidative carbonylation of amines with CO and direct carbonylation of amines have been reported,15 additional synthetic steps involved in preparing the starting precursors, expensive metal catalysts, the use of CO gas and high pressure conditions are some of the issues to be handled.16 Moreover, these methods have limitations particularly in the synthesis of unsymmetrical urea derivatives. Therefore, the development of new synthetic protocols to prepare unsymmetrical urea derivatives through non-toxic routes under mild conditions has become an important area of research. In recent years, functional group transformations involving oxidative cross couplings have emerged as important synthetic strategies in organic chemistry.17 Notable among them are the cross couplings involving formamide functionalities.18 In continuation of our ongoing research work on functional group transformations involving oxidation reactions,19 we have been exploring the application of formamide functionalities in cross-coupling chemistry. During these investigations, formamides have been successfully transformed into carbamates (I, II, and III),20a–c amides (IV)20d and ureas (V).20e However, the use of formamides in large excess (as self solvents) made these reactions applicable to only a handful of substrates, in particular to N,N 0 -dialkyl formamides (Scheme 1). Interestingly, our recent work revealed that aryl formamides could be utilized in stoichiometric quantities and transformed into carbamates using hypervalent iodine reagents in the presence of alcohols (VI).20f We have postulated here the formation of carbamates via isocyanate intermediates, which is a direct transformation rather than the rearrangements involved in

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Scheme 1 group.

Organic transformations involving the formamide functional

Scheme 2

Synthesis of phenyl urea derivatives via isocyanate intermediates.

Curtius and Hofmann procedures (Scheme 2). Looking at the synthetic importance of phenylureas in agrochemical applications, we have extended the above concept towards the synthesis of unsymmetrical phenylureas, and the results are presented in this work. For the initial optimization studies, N-phenyl formamide and dibutylamine were chosen as reacting partners and reactions were performed by varying solvents and oxidants under metal and metal-free conditions, and results are summarized in Table 1. Reactions with [bis(acetoxy)iodo]benzene [PhI(OAc)2] as the oxidant in dichloromethane (DCM) at room temperature did not lead to any product formation (Table 1, entry 1). A similar observation was also made using THF as the solvent at 60 1C (Table 1, entry 3), whereas a marginal improvement in product formation was

observed by raising the temperature of the DCM solvent (Table 1, entry 2). However, a sharp rise with maximum yield (85%) was noticed when [bis(trifluoroacetoxy)iodo]benzene [PhI(OCOCF3)2] was used as the oxidant (Table 1, entry 4). No further improvement in product formation was observed using copper catalysts in the presence of TBHP or H2O2 as the terminal oxidant (Table 1, entries 5–7). Under the optimized reaction conditions, the general applicability of this method was further evaluated using structurally diverse aryl formamides, and results are shown in the Table 2. In the presence of [PhI(OCOCF3)2] as the oxidant, different formamides reacted with dibutylamine to afford the corresponding urea products in excellent yields (Table 2, 3a–3g). A slight drop in yields was observed when the aryl ring system was substituted with electron-withdrawing groups (Table 2, 3d and 3e) compared to the electron-donating groups (Table 2, 3b and 3c). Substitutions at the ortho-position of aryl formamides with ethyl- and benzyl-groups do not have much influence on the product yields (Table 2, 3f and 3g). Moreover, we could not observe the oxidation of benzylic carbon in these two cases. Because of the synthetic importance of phenylureas bearing N,N 0 ’-dimethylamine groups, we next looked at the reactivity of aryl formamides with di-methylamine under the optimized Table 2 Direct synthesis of N-phenylurea (3) derived from N-aryl formamides (1) and amines (2)a,b

Table 1 Optimization studies of phenylurea synthesis for the reaction between N-phenyl formamide and dibutylaminea

Entry

Oxidant

Solvent

Temp. (1C)

Isolated yield (%)

1 2 3 4 5 6 7

PhI(OAc)2 PhI(OAc)2 PhI(OAc)2 PhI(OCOCF3)2 TBHP, Cu(OAc)2 TBHP, Cu(OAc)2 H2O2, Cu(OAc)2

DCM DCM THF DCE DCE DCE DCE

rt 40 60 rt rt 60 60

NR 10 NR 85 20 40 NR

a

Reaction conditions: N-phenyl formamide (1 mmol), dibutylamine (2 mmol), solvent (3 mL,), oxidant (1 mmol), MS 4 Å, N2, 2 h.

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a

Reaction conditions: N-aryl formamide (1 mmol), amine (2 mmol), dichloroethane (3 mL), [bis(trifluoroacetoxy)iodo]benzene (1 mmol), MS 4 Å, N2, 2 h. b Isolated yields.


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Table 3

Letter Formation of symmetrical ureas derived from N-aryl formamidesa,b

a

Reaction conditions: N-aryl formamide (4) (1 mmol), H2O (5 mmol), dichloroethane (3 mL,), oxidant (1 mmol), rt, 2 h. b Isolated yields.

conditions. These reactions provided products 3h–3j in good yields and among them 3h and 3i are important fungicides and are known as fenuron and monuron, respectively. Reactions of secondary amines such as N-ethylbutan-1-amine, N-ethylaniline and di-benzylamine with aryl formamides resulted in the corresponding ureas in good to excellent yields (Table 2, 3k–3o). We could also extend the present method successfully using cyclic amines viz., pyrrolidine, 2-methylpiperidine and morpholine providing the phenylureas in more than 80% yields (Table 2, 3p–3t). Our attempts using primary amines such as aniline and butylamine were not successful. We could observe the formation of small amounts of azo-compounds, which could result from anilines or through the decomposition of formamides. Formation of azo-compounds from anilines was recently reported by Majee, Hajra and co-workers using hypervalent iodine reagents.21 Upon adding a small amount of water under the standard reaction conditions and performing the reaction in the absence of external nucleophiles at room temperature, we observed the formation of symmetrical urea derivatives (Table 3). This could be because of the decomposition of isocyanate intermediates, which led to the formation of anilines and their subsequent coupling with N-aryl formamides resulted in symmetrical urea derivatives in moderate yields (Table 3). A mechanism involving amidoiodanes is generally proposed for the Hofmann rearrangement of amides to isocyanates using hypervalent iodine reagents.22 Moreover, isocyanate formation has also been proposed previously by the transformation of aryl formamides to carbamates using lead(IV) acetate.23 Based on these reports as well as our recent investigation on carbamate synthesis from aryl formamides using hypervalent iodine reagents,20f we tentatively propose the formation of isocyanate intermediates via amidoiodanes (Scheme 3).24 Moreover, GC-MS analysis of the reaction mixtures in the absence of amines clearly reveals the formation of isocyanate intermediates. In summary, we have reported a mild and efficient procedure for the synthesis of unsymmetrical phenylurea derivatives

Scheme 3

Plausible mechanism for isocyanate formation.

involving the cross coupling of N-aryl formamides with amines through the formation of isocyanate intermediates in the presence of hypervalent iodine reagents. Although there are practical difficulties with respect to cost and side product formation using hypervalent iodine reagents, the direct transformation of N-aryl formamides via isocyanate formation may have a synthetic importance over Hofmann- and Curtius-type rearrangements. Moreover, the easy synthesis of aryl formamides and their transformation into isocyanate intermediates can be readily utilized for various organic transformations, which are currently under investigation in our laboratory. In a reaction vessel, 1 mmol of N-aryl formamide was dissolved in 3 mL of dichloroethane (solvent), and [bis(trifluoroacetoxy)iodo]benzene (oxidant, 1 mmol) was slowly added to the solution with stirring over a period of 2 minutes in the presence of molecular sieves (4 Å) under a nitrogen atmosphere. Then 2 mmol of amine was added to the above reaction mixture and the reaction mixture was stirred for two hours at room temperature. The reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mixture was filtered through a silica gel bed using ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a petroleum ether–ethyl acetate mixture as an eluent to afford the corresponding products. The products were confirmed by 1H, 13C NMR, IR and mass spectroscopic analysis.

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