Benzoylation of Dianions:  Preparation of Monobenzoylated Derivatives of Symmetrical Secondary Diamines

Abstract

Monoacylated symmetrical secondary diamines are building blocks 1 or intermediates 2 widely used in the drug discovery process that are present in several investigational and established drugs. 3 Examples include the cardiotonic agent vesnarinone and the antihypertensive agent prazosin (Chart 1). Direct monoacylation of symmetrical diamines is frequently fraught with the complication associated with the tendency for bis-acylation to occur. To date, there are a number of indirect, multistep preparations of monoacylated symmetric secondary diamines from diamines 4,5 with the most common pathway involving the selective monoprotection of one nitrogen atom, followed by acylation of the remaining nitrogen and finally deprotection, to afford the desired product. 5 There have been few reports of the direct transformation of diamines to mono benzoyl diamines, 6-9 the main difficulty with this simple transformation being the formation of dibenzoyl diamines. 6 Under normal basic conditions using, for example, pyridine as the base and solvent, the dibenzoylated compound 4a was the dominant product, even through a large excess (10 equiv) of piperazine 1a was used (Scheme 1). A possible explanation of the uncontrollable dibenzoylation of symmetrical secondary diamines under these conditions is that the monobenzoylated intermediate 3a is more soluble in the solvent than piperazine 1a and reacts preferentially with the benzoyl chloride to provide predominantly the observed dibenzoylated product 4a.This problem has been resolved to some degree by application of a rather laborious procedure involving the multistep addition of starting materials with very cautious control of the pH (range 3.8-5.4) of the reaction mixture. 5,6 Similarly, Watthey and co-workers described the direct monoaroylation of piperazine and homopiperazine in moderate yields (46-60%) using AcOH as the solvent. 7 In this case, the authors took advantage of the fact that piperazine was mostly present as a monoacetate salt and the product remained in that form after the benzoylation. Alternative procedures have utilized benzoic acid 8 and benzoic esters 9 as coupling partners.After encountering several of these problems in the preparation of monobenzoylated piperazine derivatives, we sought a more reliable and predictable procedure that would be of general applicability. The criteria established for this new methodology were: (a) simple and readily available starting materials; (b) mild, preferably room temperature conditions; (c) the formation of the product cleanly in high yield.It was rationalized that the reactivity of the diamine could be altered by making the mono or disalt 5 of diamine 1, which should be more reactive toward an aroyl chloride than diamine 1 itself, thus affording the monoacylated product 3a under kinetical control (Scheme 2). In developing this strategy, several experimental protocols were explored: 1 (a) 1 equiv of BuLi, (b) 1 equiv of BzCl; 10 2 (a) 1 equiv of BuLi, (b) 1 equiv of TMSCl, (c) 1 equiv of BzCl; 11 3 (a) 2 equiv of BuLi, (b) ...

N-Monocarbamoyl Derivatives of Symmetrical Diamines with Antiviral Activity

“…Method A: Preparation of N-(6-Amino -2-pyridinyl)-N-tricyclo-[3.3.1.1 3,7 ]dec-1-ylurea (5a) Based on the protocol reported by Wang T. et al, 7) 1.6 M n-BuLi in n-hexane (1.71 ml, 2.73 mmol, 220 mol%) was added to a stirred solution of 2,6-diaminopyridine (1; 135 mg, 1.24 mmol, 100 mol%) in dry THF (6 ml) under N 2 atmosphere at room temperature. After stirring for 1 h, 1-adamantyl isocyanate (4a; 220 mg, 1.24 mmol, 100 mol%) was added to this solution, and the resulting mixture was then stirred for an additional 10 min.…”

“…The reactivity of the aromatic amines as an electrophile was weaker than that of the aliphatic amines, and the steric factor (bulkiness of the adamantyl group) apparently decreased the accessibility of the electrophiles to iso(thio)cyanate functionality in the molecules of 4a and 4b. In order to enhance the reactivity, the protocol used in the preparation of the monobenzoylated derivatives from acylation of the symmetrical diamines according to the procedure reported by Wang et al 7) was successfully applied. Therefore, one equivalent of isocyanate (4a) was added to the pretreated DAP with 2 eq of n-butyllithium to generate a dianion of DAP, at room temperature, resulting in the preferential formation of the N-monosubstituted product 5a in excellent yield (70%, entry 4; Method A).…”

Phenyl esters, preferred reagents for mono-acylation of polyamines in the presence of water

“…1 For example, Wang's group treated diamines with 2 equiv BuLi and reacted the resulting di-anions with 1 equiv acylating agents to give mono-acylated products. 3 The same group also achieved mono-acylation using 9-BBN to protect one of the two amino groups followed by acylation. 4 Christensen's group used alkyl phenyl carbonates for selective acylation of polyamines.…”

“…Excellent yields were obtained. 3 However, this method was only demonstrated for mono-benzoylation. Obviously, when acylating agents that contain acidic protons such as acetic anhydride are used, side reactions will occur.…”

“…The procedure is simple and environmentally benign, the starting materials are commercially available and inexpensive, and the substrate scope is broader than that of reported methods. 3,9 We expect that the method will become a favorite choice for organic and medicinal chemists and other scientists to prepare mono-acylated diamines.…”