Vilsmeier-Haack-Arnold formylations of aliphatic substrates withN-chloromethylene-N,N-dimethylammonium salts

Abstract

609In 1927, Anton Vilsmeier, a young thirty-three years old German chemist at the University of Erlangen [1], published with his coworker Albrecht Haack [2] a rather short paper [3], dealing with the formylation of aromatics, activated by electrondonating substituents, with phosphorus oxytrichloride (POCl 3 ) and N-methylformanilide (MFA) to give, after hydrolysis of the primary electrophilic substitution product, the corresponding aromatic aldehydes according to Scheme 1.A first, singular example of such a formylation reaction was already found by Dimroth and Zoeppritz in 1902 [4]. However, Vilsmeier and Haack discovered the general applicability of this formylation reaction to a variety of activated Abstract. The classical electrophilic substitution of activated aromatics with the Vilsmeier-Haack reagent N-chloromethylen-N,N-dimethylammonium chloride (Schemes 1 and 2) has been more recently extended to a great variety of aliphatic substrates, mainly due to the work of Arnold. In this review, a collection of representative examples for these henceforth called Vilsmeier-Haack-Arnold (VHA) formylation reaction of aliphatics is given: the reaction of polymethine cyanines, merocyanines, and other vinylogous iminium salts with the VHA reagent gives, after hydrolysis of the primary substitution products, trialdehydes such as triformylmethane (Scheme 3); VHA reaction with ene-diamines and diene-diamines yields N,N-dialkylaminomalonaldehydes and tetraalaromatic and heteroaromatic substrates [3]. The mechanistic classification of the Vilsmeier-Haack (VH) formylation reaction into the group of common electrophilic substitution reactions was later on proposed by Wizinger [5]. Nowadays,

5-Substituted 2-amino-4,6-dihydroxypyrimidines and 2-amino-4,6-dichloropyrimidines: synthesis and inhibitory effects on immune-activated nitric oxide production

“…This synthetic issue was resolved by application of a modified synthetic procedure for the preparation of 4,6-dichloro-2,5-bis{[(dimethylamino)methylene]amino}pyrimidine (Daluge et al, 2000). The use of the Vilsmeier-Haack-Arnold reagent (Reichardt, 1999), followed by immediate deprotection of the (dimethylamino)methylene protecting groups, gave final compounds B2-B11 (Scheme 1). The final step was carried out according to the method described in the literature (Daluge et al, 2000), which was modified in order to obtain B2-B11 directly from the reaction mixture by simple precipitation and filtration (for details see experimental).…”

Development of Scalable Synthesis of 5-Butyl-4-(4-methoxyphenyl)-6-phenylpyrimidin-2-amine (WQE-134), a Dual Inhibitor of Nitric Oxide and Prostaglandin E2 Production

“…4.2. Ethyl 2-Butyl-3-oxo-3-phenylpropanoate (7). 13 Ethyl 3-oxo-3-fenylpropanoate (6, 200 mL, 1.15 mol) was added dropwise to a solution of sodium ethoxide (140 g, 2.07 mol) in anhydrous ethanol (600 mL).…”

“…5-Butyl-4-(4-methoxyphenyl)-6-phenylpyrimidin-2-amine 5 (WQE-134, 5, Scheme 1) was selected for further preclinical development as an antiinflammatory agent, especially for its potential to treat ulcerative colitis. The original synthetic route toward compound 5 was based on 2-amino-5-butyl-4,6-dichloropyrimidine (3), 5 a common precursor for the whole series of polysubstituted pyrimidines, which was conveniently prepared by condensation of diethyl 2-butylmalonate (1) with guanidine under basic conditions, followed by chlorination with the Vilsmeier−Haack−Arnold reagent 7 and subsequent removal of the dimethylaminomethylene moiety (Scheme 1). The tandem Suzuki−Miyaura cross-coupling reactions 8 of obtained 4,6dichloropyrimide intermediate 3 with (4-methoxyphenyl)boronic and phenylboronic acids gave the desired product 5 in a satisfactory overall (five steps) yield of 40% (Scheme 1).…”