A Convenient Synthesis of Ethyl 3-Aminopropanedithioate (β-Alanine Ethyl Dithioester)

Abstract

A five-step sequence allowing the preparation of ethyl 3-aminopropanedithioate from N -(Boc)-b -alanine via the key intermediate N -(Boc)-b -alaninethioacyl-N -phthalimide is described.Esters of dithiocarboxylic acids are versatile tools in organic synthesis. 1,2 Their traditional precursors are dithioacid salts and thioacyl halides, the related thioacids are prepared by the reaction of carbon disulfide either with organometallic reagents and nucleophilic carbanions, or with aromatic compounds under FriedelÐCrafts conditions. 3,4 Thiohydrolysis of imidothiolates prepared from nitrile-or thioamide precursors constitutes another valuable method of dithioesters synthesis. 3,4 Lastly, thionation of thioesters has been achieved by the use of Lawesson's reagent 4 . 5,6 The previous methods can be readily applied to the simple cases of aromatic and non-functionalized aliphatic compounds. On the other hand, the preparation of aminodithioester derivatives appeared somewhat more difficult. Amino nitriles are the usual precursors 7Ð9 and, recently, a modified procedure of the Pinner reaction has also been proposed. 10 In the course of the total synthesis of a drug precursor, we required the b -alanine dithioester building block. We tried to prepare the N -protected compound using the classical methods, i.e. a) by the reaction of 2-( N -phthalimido)aminobromoethane with magnesium, followed by CS 2 and MeI and b) by the reaction of ethyl 3-( N -tert -butoxycarbonyl)aminopropanethioate (2) with Lawesson's reagent 4 (Scheme 1). The first route failed. The second one gave only poor yields of the required dithioester 3 , probably as a result of the lack of selectivity of the thionation reagent 4 towards the thioester carbonyl versus the carbamate function. Therefore, we decided to consider the primary amide 5 as the starting material (Scheme 2). The selective thionation of primary carboxamides in the presence of carbamate protecting groups has been well established. 11,12 N -(Boc)-b -alanine (1) was activated with 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) in the presence of ammonium bicarbonate 13 to furnish the corresponding amide 5 , which was purified by crystallization. Scheme 1 Scheme 2Downloaded by: University of Liverpool. Copyrighted material.

Preparation of 8-Substituted Xanthine CVT-124 Precursor by Late Stage Pyrimidine Ring Closure

“…The N -benzyl endo compound 2b is a key component in the synthesis of CVT-124 ( 1 ), and this process should therefore be amenable to the preparation of chiral 1 from the requisite chiral endo imidate 5 . Precursor 5 is accessible from known (−)-(1 S ,2 S )-5-norbornene-2-carboxylic acid ( 18 , Scheme ) by straightforward chemistry via primary amide 14 . , It should be mentioned that work was developed to provide an alternative route to the preparation of 1 , which is currently prepared by a more classical route similar to the chemistry described in Scheme…”

Synthesis of ω-Aminodithioesters

“…The commercially available N-alkyl and N-aryl pyrrolidin-2-ones (g-lactams) could be directly transformed into pyrrolidin-2thiones 10-12 with Lawesson's reagent (Equation 2 in Scheme 4). For the preparation of 1-benzoyl thionolactams, the corresponding bto e-lactams were first treated with Lawesson's reagent (13,15,17,19), then N-acylated with benzoyl chloride (Equation 3 in Scheme 4); the g-, dand e-thionolactams (16,18,20) were recovered in good yields but not the b-thionolactam 14 due to extensive polymerization during the thionation step.…”

“…[12][13][14][15][16][17] In the course of a program dedicated to the 18 F-radiolabeling of perfluorinated amine derivatives (to be incorporated in nitroimidazolic markers of hypoxia), we became interested in dithioester compounds 1a,b (Scheme 1) as precursors of [ 18 F]CF 3 and [ 18 F]C 2 F 5 motifs by an oxidative fluorodesulfurization reaction using 1,3-dibromo-5,5-dimethylhydantoin (DBH) and [ 18 F]HF•pyridine. 18,19 We had already prepared 1a (X = H; R = Et); 20 the key step for the dithioester formation was the nucleophilic substitution of a thioacyl-N-phthalimide intermediate 21 with ethanethiol. The same strategy could be applied for the synthesis of 1b, but with lower yields.…”

Synthesis of 2,4,5-Trisubstituted Thiazoles via Lawesson’s Reagent-Mediated Chemoselective Thionation–Cyclization of Functionalized Enamides

“…Within this group, Hantzsch thiazole synthesis (and its modified versions), entailing the condensation of a suitably substituted α-haloketone (or its equivalents) with thioamide, has proven to be a powerful method for the synthesis of 2,4,5-substituted thiazoles. Other methods of synthesizing substituted thiazoles include the reaction of α-aminonitriles with CS 2 , COS, isothiocyanates, and dithiocarboxlic acids. , The thionation–cyclization of α-acylaminoketones (or related precursors) with various thionation agents (e.g., P 2 S 5 , Lawesson’s or Belleau’s reagent, H 2 S) (Gabriel synthesis) is also a promising method for the synthesis of substituted thiazoles . However, this method is not well explored, probably because of the lack of availability of structural variants of α-acylaminocarbonyl compounds.…”