One-pot preparation of carbamoyl benzotriazoles and their applications in the preparation of ureas, hydrazinecarboxamides and carbamic esters J. Serb. Chem. Soc. 81 (1) 13–22 (2016) UDC 547.495.2.05:547.53–304.9+ JSCS–4822 547.334’467.1+547.26’11 Original scientific paper 13 One-pot preparation of carbamoyl benzotriazoles and their applications in the preparation of ureas, hydrazinecarboxamides and carbamic esters HUI MAO, HUILI LIU, YAWEI TU, ZHIYUN ZHONG, XIN LV* and XIAOXIA WANG** Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, China (Received 26 January, revised 10 September, accepted 11 September 2015) Abstract: Carbamoyl benzotriazoles were conveniently synthesized in one-pot from carboxylic acids, diphenyl phosphorazidate (DPPA) and 1H-benzotriazole (BtH). The reactivity and applications of carbamoyl benzotriazoles were also explored. Carbamoyl benzotriazoles react smoothly with amino acids, hyd- razines and alcohols, thus providing facile access to the corresponding ureas, hydrazinecarboxamides and carbamic esters, respectively, in good to excellent yields. Keywords: carbamoyl benzotriazoles; amino acid-derived ureas; hydrazine- carboxamides; carbamic esters. INTRODUCTION Isocyanates represent a valuable class of compounds by virtue of their wide- spread applications in organic synthesis and medicinal chemistry.1–3 Never- theless, isocyanates are usually toxic and unstable, and should be stored carefully due to the ease of exothermic polymerization and sensitivity to moisture. Although they could be used by in situ generation, their direct availability is required in certain circumstances. Capture of isocyanates formed in situ by Wang resin provides a good solution and was successfully used in the synthesis of amines.4 On the other hand, carbamoyl azides5a,b and carbamoyl imidazolium salts5c have been developed as isocyanate substituents. It is noteworthy that car- bamoyl benzotriazoles6–10 may be a more promising alternative since they are crystalline, moderately reactive and can be stored with reasonably long shelf life. The currently available methods for the synthesis of carbamoyl benzotriazole include: 1) condensation between phosgene, amine and 1H-benzotriazole (BtH), or direct carbamoylation6 of BtH with carbamoyl chloride or isocyanates; 2) *,** Corresponding authors. E-mail: (*) lvxin@zjnu.cn; (**) wangxiaoxia@zjnu.cn doi: 10.2298/JSC150126069M 14 MAO et al. diazotization of o-aminophenylureas7; 3) the reaction between acyl azides and BtH;8,9 and 4) the reaction of carbamate salts with 1-chlorobenzotriazole in the presence of a base and PPh3.10 Despite the available methods, the more straightforward preparation of carbamoyl benzotriazoles from carboxylic acid remained unexplored. Besides, the application of carbamoyl benzotriazoles as an isocyanate substituent in the formation of a variety of compounds has not yet been sufficiently addressed. Herein, a facile one-pot synthesis of carbamoyl benzotriazoles from carbo- xylic acids, DPPA and BtH is reported. The use of carbamoyl benzotriazoles for the preparation of amino acid-derived ureas, hydrazinecarboxamides and carba- mic esters is demonstrated. RESULTS AND DISCUSSION The condensations between carboxylic acids, DPPA and an amine to afford urea are well established.11 However, the condensation involving BtH as the nucleophile to afford carbamoyl benzotriazoles, a promising carbamoyl reagent, remained unknown. In this study, 4-methylbenzoic acid, DPPA and BtH were initially used as the model substrates to optimize the reaction conditions (Scheme 1 and Table I). Scheme 1. One-pot reaction of 4-methylbenzoic acid, BtH and DPPA to form carbamoyl benzotriazoles. TABLE I. Optimization of the conditions for the one-pot synthesis of carbamoyl benzotriazole 2a; all reactions were performed under reflux Entry Base Base (equiv.) Solvent Time, h Yielda, % 1 Et3N 3.0 THF 8 trace 2 Et3N 2.0 THF 8 trace 3 Et3N 1.0 THF 10 41 4 K2CO3 1.0 THF 8 Trace 5 Na2CO3 1.0 THF 8 Trace 6 Et3N 1.0 Toluene 6 80 7 Et3N 1.0 1,4-Dioxane 6 37 aIsolated yields based on 1a Several bases were examined. Et3N (2.0 and 3.0 equiv.)11,12 afforded only a trace amount of the desired product (Table I, Entries 1 and 2). The use of inorg- PREPARATION OF CARBAMOYL BENZOTRIAZOLES AND THEIR APPLICATIONS 15 anic bases, such as K2CO3 and Na2CO3, did not result in any improvement (ent- ries 4 and 5). Considering that isocyanates may be sensitive to acids13a and bases under elevated temperatures,13b the reaction under neutral conditions was attempted. To our delight, reducing the amount of Et3N to 1 equiv. afforded the desired product 2a in 41 % yield (Table I, Entry 3). Different solvents were also screened (Entries 3, 6 and 7) and the use of toluene afforded the product in 80 % yield. With the optimal conditions in hand, various carboxylic acids were used for the preparation of carbamoyl benzotriazoles. The results are summarized in Scheme 2 and Table II. Scheme 2. One-pot preparation of carbamoyl benzotriazoles. TABLE II. One-pot preparation of carbamoyl benzotriazoles from carboxylic acids, BtH and DPPA; all reactions were performed under reflux Entry R1 Product 2 Time, h Yielda, % 1 2a 6 80a, 85b 2 2b 6 76 3 2c 6 71 4 2d 6 70 5 2e 6 83 6 2f 6 55 7 2g 6 53 8 2h 6 55 9 2i 6 –c 10 2j 6 49 11 2k 6 45 12 CH3– 2l 8 50 13 n-C3H7– 2m 8 57 14 i-C3H7– 2n 8 57 16 MAO et al. TABLE II. Continued Entry R1 Products 2 Time, h Yielda, % 15 n-C6H13– 2o 8 58 16 2p 8 46 17 2q 8 42 aIsolated yields on 1 mmol scale; bisolated yield on 10 mmol scale; cno desired product was obtained A variety of carboxylic acids could be converted directly into the respective carbamoyl benzotriazole in moderate to good yields. In general, aromatic carbo- xylic acids bearing an electron-donating aryl (Table II, entries 1–5) gave better results than those with an electron-withdrawing aryl (entries 6–8). Heterocyclic nicotinic acid afforded 2k in 45 % yield, while no desired product was obtained using p-nitrobenzoic acid (entry 9). 2-(Naphthalen-1-yl)acetic acid and other ali- phatic carboxylic acids (entries 10 and 12–15) generally afforded relatively lower yields (entries 12–17). The potential for large-scale preparation was also inves- tigated. Running the reaction of 4-methylbenzoic acid on the 10 mmol scale gave a slightly better yield than that obtained on the 1 mmol scale (entry 1). In order that carbamoyl benzotriazoles be an alternative to isocyanate, it is necessary to demonstrate their usage in the preparation of ureas and carbamates14 since isocyanates have played a very important role in the preparation of these compounds. Herein, an investigation was undertaken to examine the reactivity of carbamoyl benzotriazoles towards amino acids, hydrazines and alcohols to deter- mine their potential in the preparation of various ureas, hydrazinecarboxamides and carbamic esters. Previously, it was reported that carbamoyl benzotriazoles reacted with amines smoothly under mild conditions.8 Here amino acids were used to explore the application of carbamoyl benzotriazoles in the synthesis of chiral ureas (Scheme 3 and Table III), which may possess important biological activities. For example, azadipeptide nitriles are used as novel cysteine protease inhibitors.15 Geldern also reported the structure–activity relationship of other urea derivatives of amino acids in an attempt to improve the potency of a novel series of azole- -based endothelin-A (ETA) selective antagonists.16 Scheme 3. The aminoacylation of amino acids with carbamoyl benzotriazoles. The reaction of carbamoyl benzotriazole 2b with L-phenylalanine was real- ized using the procedure reported for the acylation of amino acids using N-acyl PREPARATION OF CARBAMOYL BENZOTRIAZOLES AND THEIR APPLICATIONS 17 benzotriazoles.17 To our delight, the reaction gave the desired product 4a in 91 % yield at r.t. in the presence of Et3N (1.5 equiv.) in CH3CN–H2O (2:1, V/V, Table III, entry 1). TABLE III. Preparation of ureas via aminoacylation of amino acids with carbamoyl benzo- triazoles Entry R1 Compounds 3 Products 4 Time, h Yielda, % 1 2b 3a 4a 0.5 91 2 3b 4b 0.5 94 3 3c 4c 0.5 90 4 3d 4d 0.5 92 5 3e 4e 0.5 80 6 3f 4f 0.5 94 7 3g 4g 0.5 72 8 3h 4h 10 85 9 2a 3a 4i 0.5 90 10 3c 4j 0.5 95 11 2h 3a 4k 0.5 91 12 n-C3H7– 2m 3a 4l 24 96 aIsolated yields based on carbamoyl benzotriazoles As shown in Table III, the aminoacylation of various natural amino acids was investigated. Generally, the reactions between amino acids and carbamoyl benzotriazoles afforded the corresponding ureas in excellent yields within 0.5 h (entries 1–6). For L-proline, as long as 10 h was required to obtain 85 % yield (entry 8). It is worth noting that good chemoselectivity for the acylation of L- serine was observed, where the amino group reacted selectively, but not the hyd- roxyl group (entry 7). Generally, the substituent on the aromatic ring did not affect the efficiency of the reaction (entries 9–11). The method was also appli- cable for the reactions of aliphatic carbamoyl benzotriazole (entry 12). 18 MAO et al. Maintaining the chirality of the amino acid was proved by polarimetric anal- ysis of (R)-3-phenyl-2-(3-phenylureido)propanoic acid 4a, the [α] value of which was found to be +51.51°, in good accordance with the literature value.18 The Katritzky group also demonstrated that no racemization of the amino acid deri- vative occurred under the same conditions.19 Bis-nucleophilic hydrazines were also reacted with carbamoyl benzotriazoles (Scheme 4 and Table IV). For methylhydrazine, the more electrophilic nitrogen atom (with methyl attached) was aminoacylated without any promoter and compounds 6a and 6b were obtained in excellent yields (Table IV, entries 1 and 2). Phenylhydrazine, however, was aminoacylated on the terminal nitrogen and the yields were relatively lower (Table IV, entries 3 and 4) even in the presence of NaH. Without NaH, no aminoacylation of the phenylhydrazine occurred. Scheme 4. The aminoacylation of hydrazines with carbamoyl benzotriazoles. TABLE IV. Preparation of hydrazinecarboxamides via aminoacylation of hydrazines with carbamoyl benzotriazoles; the reaction was promoted by 1.5 equiv. of NaH (based on 2) in dry toluene at r.t. or at 40 C Entry R1 R2 Base Products 6 Time, h Yielda, % 1 2b CH3– – 6a 10 90 2 2h CH3– – 6b 10 89 3 2b NaH 6c 10 45 4 C2H5– 2r NaH 6d 60 41 aIsolated yields based on carbamoyl benzotriazoles Finally, the use of carbamoyl benzotriazoles for the synthesis of carbamic esters was explored. Thus the reaction of 2b with ethanol was performed. With toluene as the solvent at 70–78 °C, the reaction afforded the desired compound 8b in 80 % yield. As shown in Scheme 5 and Table V, all the carbamoyl benzotriazoles exam- ined smoothly afforded the desired carbamic esters in good yields. In combin- ation with the convenience in the purification of the products, the aminoacylation PREPARATION OF CARBAMOYL BENZOTRIAZOLES AND THEIR APPLICATIONS 19 of alcohols with carbamoyl benzotriazoles provides a facile route to prepare car- bamic esters. Scheme 5. The aminoacylation of alcohols with carbamoyl benzotriazoles. TABLE V. Preparation of carbamic esters via aminoacylation of alcohols with carbamoyl benzotriazoles Entry R1 R2 Products 8 Time, min Yield, %a 1 2b C2H5 8a 30 83 2 2b n-C4H9 8b 30 80 3 2a C2H5 8c 30 77 4 2a n-C4H9 8d 30 78 5 2h C2H5 8e 45 85 6 2h n-C4H9 8f 45 85 aIsolated yields based on carbamoyl benzotriazoles EXPERIMENTAL THF and toluene were dried over Na. Other commercial reagents were used without further purification, and all solvents were of reagent grade. All reaction mixtures were stirred magnetically and were followed by TLC analysis at 254 nm. Flash column chromatography was performed using 100–200 mesh silica. Melting points are uncorrected. The IR spectra were recorded using KBr disks or as films using a Nicolet-670 FTIR spectrometer with absorption in cm-1. The 1H-NMR and 13C-NMR spectra were determined on a Bruker AC-400 spectrometer as CDCl3 or DMSO-d6 solutions. The J values are in Hertz and the chemical shifts are expressed in ppm downfield from internal TMS. Elemental analysis was realized on an EA 1110 instrument. Polarimetry was performed according to the literature18 on an Anton Paar MCP200 modular circular polarimeter. Among the compounds, carbamoyl benzotriazoles 2a, 2b, 2e, 2f, 2h and 2o, urea 4l, hydrazinecarboxamide 6c and carbamic esters 8a–f are known. Other carbamoyl benzo- triazoles and products including 2c, 2d, 2g, 2j–2n, 2p, 2q, 4a–k, 6a, 6b and 6d are new compounds. The analytical and spectral data of compounds are given in the Supplementary material to this paper. General procedure for the one-pot synthesis of carbamoyl benzotriazoles 2 To a solution of carboxylic acid (1.0 mmol) in dry toluene (20 mL) was added Et3N (1.0 mmol, 101 mg), diphenyl phosphorazidate (1.0 mmol, 275 mg) and 1H-benzotrizole (1.0 mmol, 119 mg). The mixture was stirred under reflux until completion of the reaction 20 MAO et al. (monitored by TLC). The reaction mixture was cooled to r.t., and washed successively with water (10 mL), saturated Na2CO3 (10 mL) and brine (10 mL). The combined organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a residue, which was purified by recrystallization from toluene or by column chromatography on silica gel using EA–PE (1:20, boiling range 60–90 C) as the eluent to give the pure products 2a–2q. General procedure for the synthesis of the amino acid-derived ureas 4 To a solution of compound 2 (1 mmol) in CH3CN (16 mL) and H2O (8 mL) was added an amino acid (1.1 mmol). Et3N (1.5 mmol, 152 mg) was then added dropwise. The mixture was stirred at r.t. until completion of the reaction (monitored by TLC). The acetonitrile was removed, and the residue was extracted by ethyl acetate (10 mL). The organic phase was washed successively with 10 % HCl (5 mL), saturated Na2CO3 solution (5 mL) and brine (5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the pure products 4a–4l. General procedure for the synthesis of hydrazinecarboxamides 6a and 6b To a solution of compound 2 (1 mol) in dry toluene (5 mL) was added methylhydrazine (1.1 mmol, 51 mg). The mixture was stirred at r.t. until completion of the reaction (monitored by TLC). Then THF (10 mL) was added, and the mixture was washed with saturated Na2CO3 (35 mL) and brine (5 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography on silica gel using EA–PE (1:1) as the eluent to give the pure products 6a and 6b. General procedure for the synthesis of hydrazinecarboxamides 6c and 6d To a solution of compound 2 (1 mol) in dry toluene (5 mL) was added aromatic hyd- razine (1.1 mmol, 119 mg) and NaH (1.5 mmol, 36 mg). The mixture was stirred at r.t. or 40°C until the completion of the reaction (monitored by TLC). Then THF (10 mL) was added, and the mixture was washed with Na2CO3 (35 mL) and brine (5 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography on silica gel using EA/PE (EA/PE = 1:1) as the eluent to give the pure product 6c and 6d. General procedure for the synthesis of carbamic esters 8a–f A round bottom flask was charged with compound 2 (1.0 mmol), alcohol (1.1 mmol) and toluene (5 mL). The mixture was stirred at 80 °C until completion of the reaction (monitored by TLC). The reaction mixture was cooled to r.t. whereby a white solid pre- cipitated that was filtered off. The filter cake was washed by ethanol (5 mL) to give the pure products 8a–f. CONCLUSIONS In summary, a convenient one-pot synthesis of carbamoyl benzotriazoles from carboxylic acid, DPPA and BtH was developed. The carbamoyl benzotri- azoles showed good reactivity and chemoselectivity towards amino acids, hyd- razines and alcohols, and provided facile access to amino acid-derived ureas, hydrazinecarboxamides and carbamic esters. Together with the properties of being stable and easily to handle, carbamoyl benzotriazoles show promise for use as a practical substitute for isocyanates. PREPARATION OF CARBAMOYL BENZOTRIAZOLES AND THEIR APPLICATIONS 21 SUPPLEMENTARY MATERIAL The physical, analytical and spectral data for the synthesized compounds and their spectra are available electronically from http://www.shd.org.rs/JSCS/, or from the corres- ponding authors on request. Acknowledgement. This work was financially supported by the National Natural Science Foundation of China (No. 20802070). И З В О Д СИНТЕЗА КАРБАМОИЛ-БЕНЗОТРИАЗОЛА И ЊИХОВА ПРИМЕНА У СИНТЕЗИ УРЕЕ, ХИДРАЗИНКАРБОКСАМИДА И ЕСТАРА КАРБАМИНСКЕ КИСЕЛИНЕ HUI MAO, HUILI LIU, YAWEI TU, ZHIYUN ZHONG, XIN LV и XIAOXIA WANG Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, China Карбамоил-бензотриазоли су синтетисани у једном реакционом кораку, полазећи од карбоксилних киселина, дифенил фосфоразидата (DPPA) и 1H-бензотриазола (BtH). Испитана је реактивност и примена карбамоил-триазола. 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