Palladium-Catalyzed Aerobic Oxidative Carbonylation of Amines Enables the Synthesis of Unsymmetrical N,N′-Disubstituted Ureas

Abstract

A ligand-free palladium-catalyzed aerobic oxidative carbonylation of amines for the synthesis of ureas, particular unsymmetrically N,N′-disubstituted ureas, which cannot be accessed by any other palladium-catalyzed oxidative carbonylation of amines to date, is presented. An array of symmetrical and unsymmetrical ureas were straightforwardly synthesized by using inexpensive, readily available, stable, and safe amines with good to excellent yields under a pressure of 1 atm. This novel method employs oxygen as the sole oxidant and offers an attractive alternative to transition-metal-based oxidant systems

Key words

amines - carbonylation - aerobic oxidation - synthetic methods - unsymmetrical ureas

Publication History

Received: 31 March 2021

Accepted after revision: 06 May 2021

Accepted Manuscript online:
06 May 2021

Article published online:
20 May 2021

• References and Notes

• 1a Wilhelm SM, Adnane L, Newell P, Villanueva A, Lovet JM, Lynch M. Mol. Cancer Ther. 2008; 7: 3129
• 1b Santella JB, Gardner DS, Duncia JV, Wu H, Dhar M, Cavallaro C, Tebben AJ, Carter PH, Barrish JC, Yarde M, Briceno SW, Cvijic ME, Grafstrom RR, Liu R, Patel SR, Watson AJ, Yang G, Rose AV, Vickery RD, Caceres-Cortes J, Caporuscio C, Camac DM, Khan JA, An Y, Foster WR, Davies P, Hynes J. J. Med. Chem. 2014; 57: 7550
• 1c Vishnyakova TP, Golubeva IA, Glebova EV. Russ. Chem. Rev. 1985; 54: 249
• 2 Bordwell FG, Algrim DJ, Harrelson JA. J. Am. Chem. Soc. 1988; 110: 5903
• 3a Guan A, Liu C, Yang X, Dekeyser M. Chem. Rev. 2014; 114: 7079
• 3b Xu H, Zuend SJ, Woll MG, Tao Y, Jacobsen EN. Science 2010; 327: 986
• 3c Zhang Z, Schreiner PR. Chem. Soc. Rev. 2009; 38: 1187
• 3d Veitch GE, Jacobsen EN. Angew. Chem. Int. Ed. 2010; 49: 7332
• 3e Howlader P, Das P, Zangrando E, Mukherjee PS. J. Am. Chem. Soc. 2016; 138: 1668
• 3f Lin B, Waymouth RM. J. Am. Chem. Soc. 2017; 139: 1645
• 4a Wu C, Cheng H, Liu R, Wang Q, Hao Y, Yu Y, Zhao F. Green Chem. 2010; 12: 1811
• 4b Xu M, Jupp AR, Stephan DW. Angew. Chem. Int. Ed. 2017; 56: 14277
• 4c Díaz DJ, Darko AK, McElwee-White L. Eur. J. Org. Chem. 2007; 4453
• 5a Huang X, Xu S, Tan Q, Gao M, Li M, Xu B. Chem. Commun. 2014; 50: 1465
• 5b Angyal A, Wolfling J, Puskas LG, Kanizsai I. Tetrahedron Lett. 2018; 59: 54
• 5c Slcombe RJ, Hardy EE, Saunders JH, Jenkins RL. J. Am. Chem. Soc. 1950; 72: 1888
• 5d Wei Y, Liu J, Lin S, Ding H, Liang F, Zhao B. Org. Lett. 2010; 12: 4220
• 5e Kulkarni AR, Garai S, Thakur GA. J. Org. Chem. 2017; 82: 992
• 6a Bigi F, Maggi R, Sartori G. Green Chem. 2000; 2: 140
• 6b Li X.-Q, Wang W.-K, Han Y.-X, Zhang C. Adv. Synth. Catal. 2010; 352: 2588
• 6c Padiya KJ, Gavade S, Kardile B, Tiwari M, Bajare S, Mane M, Gaware V, Varghese S, Harel D, Kurhade S. Org. Lett. 2012; 14: 2814
• 6d Ran X, Long Y, Yang S, Peng C, Zhang Y, Qian S, Jiang Z, Zhang X, Yang L, Wang Z, Yu X. Org. Chem. Front. 2020; 7: 472
• 7a Barnard CF. J. Organometallics 2008; 27: 5402
• 7b Wu X.-F, Neumann H. ChemCatChem 2012; 4: 447
• 7c Gabriele B, Mancuso R, Salerno G. Eur. J. Org. Chem. 2012; 6825
• 7d Wu X.-F, Neumann H, Beller M. ChemSusChem 2013; 6: 229
• 7e Tafesh AM, Weiguny J. Chem. Rev. 1996; 96: 2035
• 8a Zhao Y, Jin L, Li P, Lei A. J. Am. Chem. Soc. 2008; 130: 9429
• 8b Giri R, Lam JK, Yu J.-Q. J. Am. Chem. Soc. 2010; 132: 686
• 8c Dieck HA, Laine RM, Heck RF. J. Org. Chem. 1975; 40: 2819
• 8d Alper H, Hartstock FW. J. Chem. Soc., Chem. Commun. 1985; 1141
• 8e Mozaffari M, Nowrouzi N. Eur. J. Org. Chem. 2019; 7541
• 8f Gabriele B, Salerno G, Mancuso R, Costa M. J. Org. Chem. 2004; 69: 4741
• 8g Gabriele B, Mancuso R, Salerno G, Costa M. Chem. Commun. 2003; 486
• 8h Zheng S, Peng X, Liu J, Sun W, Xia C. Helv. Chim. Acta 2007; 90: 1471
• 8i Orito K, Miyazawa M, Nakamura T, Horibata A, Ushito H, Nagasaki H, Yuguchi M, Yamashita S, Yamazaki T, Tokuda M. J. Org. Chem. 2006; 71: 5951
• 8j Guan Z.-H, Lei H, Chen M, Ren Z.-H, Bai Y, Wang Y.-Y. Adv. Synth. Catal. 2012; 354: 489
• 8k Shi F, Deng Y, SiMa T, Yang H. Tetrahedron Lett. 2001; 42: 2161
• 8l Didgikar MR, Joshi SS, Gupte SP, Diwakar MM, Deshpande RM, Chaudhari RV. J. Mol. Catal. A: Chem. 2011; 334: 20
• 8m Li C.-L, Peng J.-B, Qi X, Ying J, Wu X.-F. New J. Chem. 2018; 42: 12472
• 9a Chen B, Peng J.-B, Ying J, Qi X, Wu X.-F. Adv. Synth. Catal. 2018; 360: 2820
• 9b Wang L, Wang H, Li G, Min S, Xiang F, Liu S, Zheng W. Adv. Synth. Catal. 2018; 360: 4585
• 9c Zhao J, Li Z, Yan S, Xu S, Wang M.-A, Fu B, Zhang Z. Org. Lett. 2016; 18: 1736
• 10a Cao Z, Zhu Q, Lin Y.-W, He W.-M. Chin. Chem. Lett. 2019; 30: 2132
• 10b Yu D, Xu F, Li D, Han W. Adv. Synth. Catal. 2019; 361: 3102
• 10c Zhao HY, Du HY, Yuan XR, Wang TJ, Han W. Green Chem. 2016; 18: 5782
• 10d Jin FL, Han W. Chem. Commun. 2015; 51: 9133
• 10e Cheng L, Zhong Y, Ni Z, Du H, Jin F, Rong Q, Han W. RSC Adv. 2014; 4: 44312
• 10f Xu F, Han W. Chin. J. Org. Chem. 2018; 38: 2519

Although the mixture 1:1 CO/O₂ falls in the explosivity field, the pressure is ambient pressure and did not cause any problems during the reaction process. Previous studies also used the mixture for oxidative carbonylation, see also:
• 11a Shao A, Gao M, Chen S, Wang T, Lei A. Chem. Sci. 2017; 8: 2175
• 11b Ren L, Jiao N. Chem. Asian J. 2014; 9: 2411

Although the precise role of the iodide additive remains elusive, some experimental observation can provide insight into its role. In the absence of iodide additive palladium black can be observed on the stir bar after the model reaction completed, while in the presence of NaI palladium black disappeared. This is probably because iodide in oxidative aminocarbonylation can be oxidized into iodine enabling oxidation Pd⁰ to Pd^II to maintain an efficient catalytic activity, as described in previous reports:
• 12a Mancuso R, Della Ca’ N, Veltri L, Ziccarelli I, Gabriele B. Catalysts 2019; 9: 610
• 12b Veltri L, Giofrè SV, Devo P, Romeo R, Dobbs AP, Gabriele B. J. Org. Chem. 2018; 83: 1680
• 12c Zhao H, Han W. Eur. J. Org. Chem. 2016; 4279
• 13 General Procedure for the Synthesis of 2a A 25 mL Schlenk flask was charged with Pd(OAc)₂ (0.01 mmol, 2.3 mg), NaI (0.25 mmol, 37.8 mg), DABCO (0.1 mmol, 11.3 mg), and PEG-400 (2.0 mL) before standard cycles of evacuation and back-filling with mixture of CO and O₂ (1:1, 1 atm). Aniline 1a (0.5 mmol, 46.5 mg) was added successively. The mixture was stirred at room temperature for the indicated time. At the end of the reaction, the reaction was quenched by saturated aqueous NaCl solution (15 mL) and extracted with ethyl acetate (3 × 15 mL). The organic phases were combined and concentrated under vacuum. The residue was purified by column chromatography on silica gel with a gradient eluant of petroleum ether and ethyl acetate affording 2a as a white solid (42.4 mg, 80%); mp 239.2–240.1 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.65 (s, 2 H), 7.44 (dd, J = 8.0, 1.2 Hz, 4 H), 7.29–7.25 (m, 4 H), 6.98 ppm (t, J = 8 Hz, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 152.6, 139.7, 128.9, 121.9, 118.2 ppm
• 14 The ratio of amines has a clear impact on the selectivity of the reaction. In the case of oxidative carbonylation of 4-fluoroaniline (1m) and aniline (1n), when the ratio is 1:1, the unsymmetrical urea 2ma was obtained in 62% yield, accompanied with a 30% yield of a symmetrical urea 2m from 4-fluoroaniline. Further increasing the ratio to 1:2 resulted in enhancing the selectivity (2ma: 78% yield; 2m: 15% yield). When the ratio is 1:4, 2ma can have a high yield (87%) and selectivity (2m: less than 5% yield). If 1m is used in excess, the main product is 2m: Zhang C, Jiao N. Angew. Chem. Int. Ed. 2010; 49: 6174
• 15a Dombek D, Angelici RJ. J. Organomet. Chem. 1977; 134: 203
• 15b Zhao J, Li Z, Song S, Wang M.-A, Fu B, Zhang Z. Angew. Chem. Int. Ed. 2016; 55: 5545
• 15c Chow SY, Stevens MY, Odell LR. J. Org. Chem. 2016; 81: 2681
• 15d Miloserdov FM, Grushin VV. Angew. Chem. Int. Ed. 2012; 51: 3668
• 15e Hiwatari K, Kayaki Y, Okita K, Ukai T, Shimizu I, Yamamoto A. Bull. Chem. Soc. Jpn. 2004; 77: 2237
• 15f Pri-Bar I, Schwartz J. J. Org. Chem. 1995; 60: 8124