Synthesis of Aroylguanidines by an Unexpected Demethylation-Addition Cascade

Abstract

A simple and efficient method was developed for the synthesis of N-aroyl-N′-arylguanidines under mild conditions by an unexpected demethylation-addition cascade reaction of readily available N-cyanoimidates with aryl amines. Moreover, 1-aryl-2-aminoquinazolin-4(1H)-ones and 2-(arylamino)quinazolin-4(3H)-ones can also be prepared by selective cyclization reactions of (2-fluorobenzoyl)-or (2-nitrobenzoyl)guanidines, respectively. This method provided two attractive strategies for the preparation 2-aminoquinazolinones derivatives from inexpensive reactants.Acylguanidines have attracted a great deal of attention, not only because of the range of significant biological activities that they have shown in medical studies, 1 but also because they are useful building blocks for several natural and therapeutic products of biological significance. 2 Derivatives of acylguanidines are among the most potent inhibitors of Na + /H + exchange 3 and they also have shown remarkable activities as potent α v β 3 antagonists, 4 thrombin inhibitors, 5 and histamine H 2 receptors. 6 The usefulness of acylguanidines is highlighted by the range of marketed drugs of this class, which include the sympatholytic guanfacine, 7 the diuretic amiloride, 8 and the Na + /H + exchange inhibitors cariporide 9 and eniporide. 10 Additionally, acylguanidines have also been reported to be potentially useful in the treatment of glaucoma, 11 osteoporosis, 12 and cardiac ischemia and reperfusion, 11,13 as well as acting as antihypertensives, 14 antifungal agents, 15 and plant-protection agents. 16 BMS-344577, an aroylguanidine-based lactam derivative, has progressed to the advanced preclinical development stage because of its potent activity as an inhibitor of blood-coagulation factor Xa. 17 Besides their biological activities, N-aroyl-N′-arylguanidines have also been used in syntheses of polysubstituted guanidines. 18 Furthermore, several nitrogencontaining heterocycles, including highly bioactive guanosines, 19 can be prepared by using acylguanidines as starting materials. [20][21][22][23] Because of the importance of acylguanidines in various roles, several methods have been reported for their synthesis. 24 However, in comparison with N-polysubstituted acylguanidines, the routes to N-acyl-N′-arylguanidines are limited to several representative approaches, including reactions of acylcyanamides with aniline hydrochloride in refluxing toluene or xylenes, 25 acylation of guanidines with carbonic acid in the presence of 1,1′-carbonyldimidazole, 21 solid-phase synthesis of disubstituted acylguanidines; 26 and the reaction of acylthioureas with hexamethyldisilazane in the presence of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide to give acylguanidines. 27 Although these synthetic methods can be used to synthesize N-acyl-N′-arylguanidines, the poor selectivity of the acylation reaction and the need to protect imino groups represent considerable disadvantages. Other disadvantages include the multistep nature of the reactions, low efficiencies in the preparation...

Palladium(0)-Catalyzed Carbonylative One-Pot Synthesis of N-Acylguanidines

“…(91 mg, 75%). Compound 5m is known and spectral data were in agreement with the proposed structure and matched those reported in the literature …”

“…Another approach is to prepare acylguanidines from N -cyanobenzamides, , which generally are prepared by reacting the corresponding acyl chloride and sodium cyanamide. − They have also been prepared via radical reactions including the rearrangement reaction of acylcyanamides and diphenyldisulfide followed by subsequent reaction with amines and the synthesis of polycyclic acylguanidines via a radical cascade cyclization reaction . Notably, the synthesis of acylguanidines from cyanoimidates has been proposed to proceed via an N -cyanobenzamide intermediate stemming from amine-promoted demethylation of the cyanoimidate starting material . We and others have previously shown that N -cyanobenzamides can be prepared from readily available aryl halides − and how these compounds can be utilized as valuable precursors in the synthesis of N -heterocycles .…”

“…40 Notably, the synthesis of acylguanidines from cyanoimidates has been proposed to proceed via an Ncyanobenzamide intermediate stemming from amine-promoted demethylation of the cyanoimidate starting material. 41 We and others have previously shown that N-cyanobenzamides can be prepared from readily available aryl halides 42−44 and how these compounds can be utilized as valuable precursors in the synthesis of N-heterocycles. 45 Additionally, direct carbonylation using guanidine nucleophiles has been employed as a strategy to prepare N-acylguanidines.…”

Synthesis of 2-Aminoquinazolinones via Carbonylative Coupling of ortho-Iodoanilines and Cyanamide

“…Several synthetic methods are available for the preparation of quinazolinones and 2-aminoquinazolinones, , including fusion of anthranilic acid with amides, amidation of 2-aminobenzoic acids and its derivatives, , reaction of resin-bound isothioureas with isatoic anhydrides, and acylation of ortho -fluorobenzoic acids with substituted guanidines and subsequent ring closure . Furthermore, 1-aryl-2-aminoquinazolin-4-ones and 2-(arylamino)­quinazolin-4-ones have been obtained from the reaction of N -cyanoimidates and arylamines . However, these reactions are often performed under harsh reaction conditions and require multistep procedures or complex intermediates, and there is still a need for new and efficient methods to prepare this important ring system.…”