SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2018, 50, 341–348 paper 341 en Syn thesis X. Min et al. Paper One-Pot Assembly towards ω-Substituted Arylbiurets from Aromatic Amines, Potassium Cyanate, and Glacial Acetic Acid Xiangting Mina O O Jianhui Liu*a,b KOCN, AcOH NH2 Ar b Ar N N NH2 Yawen Dong H2O/CH3CN (1:1), air H H Mustafa Hussainb 45–100 °C,12 h 17 examples via a one-pot reaction 51–87% a School of Petroleum and Chemical Engineering, Dalian University readily available starting materials of Technology, Panjin Campus, Panjin, Liaoning Province, easy operation procedure and good to excellent yields 124221, P. R. of China b State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, P. R. of China [email protected] Received: 10.07.2017 pounds have been widely used as key intermediates for the Accepted after revision: 13.09.2017 synthesis of cyanuric acid, derivatives of which are import- Published online: 23.10.2017 4 DOI: 10.1055/s-0036-1590934; Art ID: ss-2017-h0446-op ant compounds in medicinal and synthetic chemistry. Very few methods are known for the synthesis of ω- Abstract A novel, simple, and highly efficient method has been de- substituted arylbiurets. The most common route involves a signed for the synthesis of ω-substituted arylbiurets in a one-pot reac- two-step preparation (nitration followed by reaction with tion. The primary features of this protocol include readily available 5 starting materials, an easy work-up procedure, and yields of 51 to 87%. aniline), starting from the unsubstituted biurets (Scheme 1, ω-Substituted arylbiurets can be selectively prepared with an excess of a).1–3,6 However, the first nitration step requires the pres- potassium cyanate (KOCN). However, use of an excess of glacial acetic 7 ence of large amounts of concentrated H2SO4 and HNO3. acid (AcOH) switches the reaction towards the formation of N-mono- Given the use of strong acids and the excess of strong base substituted urea. needed for the following work-up procedure, this route Key words ω-substituted biuret, N-monosubstituted urea, potassium cannot meet the requirements of green synthesis. Further- cyanate, dicyanic acid, selective reactions more, because N-nitro compounds are potentially explo- sive, this procedure must be carried out behind a safety Over the past several decades, ω-substituted arylbiurets shield.8 In addition, the efficiency of the conversion for the have attracted considerable attention because of their im- entire reaction process is not satisfactory, with maximum Downloaded by: University of Oregon. Copyrighted material. portance in organic synthesis and material sciences. In par- yields of 40%.9 Furthermore, this route is only suitable for ticular, arylated biurets are of much value because of their condensation reactions with partially substituted aniline, unique and excellent properties such as their tendency to thereby restricting the range of potential substrates. There- form organic supramolecular networks with highly effi- fore, a more effective protocol for the synthesis of ω-substi- cient energy transfer,1 active photoresponsive compounds,2 tuted arylbiurets through an easy procedure with good and nanofilm structures.3 Moreover, these types of com- yield is highly desirable. NH2 Previous work H H H HNO3/H2SO4 H H R N N NH2 (a) H2N N NH2 N N NH2 40% O2N 40–70% O O O O O O R This work H H KOCN, AcOH N N NH2 17 examples NH2 R (b) R 51–87% O O R = aryl Scheme 1 Synthetic approach to ω-substituted arylbiuret derivatives © Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 341–348 342 Syn thesis X. Min et al. Paper It is well known that KOCN can be converted into cya- not significantly increased when only the amount of KOCN nate acid with excess acid in aqueous solution. If KOCN re- was increased. To our surprise, the yield of 2a unexpectedly acts with amines, N-monosubstituded ureas could be gen- decreased when the amounts of both KOCN and AcOH were erated.10 In addition, according to Davis and Blanchard,11 increased (Table 1, entries 1–3). HOCN dimerizes in solution to form dicyanic acid, with one The influence of the reaction temperature was then in- molecule of HOCN functioning in the usual manner in urea vestigated. The yields increased gradually as the tempera- formation and the second as an ammonia derivative. In- ture increased, but the positive effect was not obvious if the spired by these two observations, we hypothesized that the temperature was increased to more than 80 °C (Table 1, use of dicyanic acid to react with amine may lead to ω-sub- entries 4–8). Solvent effects were then studied. To keep the stituted biuret. Here, we report an efficient and simple reaction system homogeneous and to avoid reaction with method for the preparation of ω-substituted arylbiurets the HOCN, the solvent should be carefully chosen to be mis- (Scheme 1, b). The key features of the reaction include read- cible with water and must not contain hydroxyl, amino, or ily available and safer starting materials, easy operational thiol groups.12 After careful comparison, we selected the procedure, and good to excellent yields. mixture of water and acetonitrile (1:1) as our reaction me- Initially, this investigation was carried out by using ani- dium. The use of water alone lowered the yield to 30%, but line (1a) as a substrate to optimize the reactions conditions, the mixture with two other polar aprotic solvents, includ- including the amount of reagents, temperature, solvent, and ing DMF and DMSO, gave the corresponding biuret in 61% acid type (Table 1). In our screening for the optimal amount and 74% yield, respectively (entries 9–11). Although the ad- of KOCN and AcOH, we observed that the yield of 2a was dition of DMF and DMSO made the product distribution more favorable toward 2a instead of 3a (entries 9–11), the Table 1 Optimization of the Reaction Conditionsa acetonitrile–water mixture was finally chosen because of its slightly better effect (entry 7 vs. entries 9–11). Next, we O O O KOCN, AcOH examined the type of acid used (entries 12 and 13). HCl and + NH2 solvent, air N N NH2 N NH2 TsOH gave almost identical results, with yields of 65% and H H H 67%, respectively. Therefore, of the several acids investigat- 1a 2a 3a ed, AcOH appeared to be optimal, because of the weaker 13 Entry Solvent Temp (°C) Time (h) 2a (%) 3a (%) acidity, which met the pH requirements of this system. However, if AcOH was present in excess, no desired 2a was 1H2O/CH3CN (1:1) 50 0.5 63 33 isolated (entry 14). In contrast, this kind of reaction also c 2 H2O/CH3CN (1:1) 50 0.5 64 31 failed in the presence of NaOH, indicating the possible in- d 3 H2O/CH3CN (1:1) 50 0.5 42 55 volvement of cyanic acid in this reaction (entry 15). All of the above reactions were performed under air without pro- 4H2O/CH3CN (1:1) 40 12 57 40 tection from an N atmosphere. 5HO/CH CN (1:1) 60 12 70 24 2 2 3 With the optimal conditions in hand, we investigated 6HO/CH CN (1:1) 70 12 74 20 2 3 the versatility of this methodology by using different aro- Downloaded by: University of Oregon. Copyrighted material. 7H2O/CH3CN (1:1) 80 12 76 16 matic amines. A collection of ω-substituted arylbiurets was 8H2O/CH3CN (1:1) 90 12 70 25 easily prepared in good to high yields as shown in Table 2. When the reaction of 1a was conducted under the opti- 9H2O80123067 mized conditions, 2a was obtained in 76% yield (entry 1). A 10 H2O/DMF (1:1) 80 12 61 36 series of halogenated anilines was then studied. Whereas 11 H O/DMSO (1:1) 80 12 74 23 2 the yields of 2b, 2f, and 2g were all greater than 80% (en- e 12 H2O/CH3CN (1:1) 80 12 65 31 tries 2, 6, and 7), the yields of 2c, 2d and 2e were not ideal f 13 H2O/CH3CN (1:1) 80 12 67 32 at first (ca. 60%) because of incomplete conversion. When g 14 H2O/AcOH 45 12 – 80 the reaction temperature was reduced to 70 °C and the h amounts of both KOCN and AcOH were increased, satisfac- 15 H2O/CH3CN (1:1) 45 12 – – tory yields were obtained (83, 86, and 82% for 2c, 2d and 2e, a Reaction conditions: phenylamine (1a; 102 mg, 1.1 mmol), KOCN (5.28 mmol), H2O (6 mL), CH3CN (6 mL), 80 C add glacial AcOH (2.64 mmol), respectively, entries 3–5). Alkyl substituted anilines 1h–k after 1 h a second portion of glacial AcOH (2.64 mmol) was added. were conducive to the occurrence of this reaction, and the b Yield of isolated product. c Reaction conditions: KOCN (777 mg, 9.6 mmol), glacial AcOH (2.64 products 2h–j were obtained in excellent yield of more than mmol), after 1 h a second portion of glacial AcOH (2.64 mmol) was added. 80%, with the exception of 2k, for which a somewhat di- d Reaction conditions: KOCN (712 mg, 8.8 mmol), glacial AcOH (264 mg, 4.4 mmol), after 1 h a second portion of glacial AcOH (264 mg, 4.4 mmol) minished yield was obtained (69%) (entries 8–11). Surpris- was added. ingly, 1h and 1i showed better selectivity and only afforded e HCl instead of AcOH. f TsOH instead of AcOH.