Synthesis of 2-Substituted-5-halo-2,3-dihydro-4(H)-pyrimidin-4-ones and Their Derivatization Utilizing the Sonogashira Coupling Reaction in the Enantioselective Synthesis of α-Substituted β-Amino Acids

Abstract

A convenient, one-pot procedure for the synthesis of 1-benzoyl-2(S)-substituted-5-iodo-2,3-dihydro-4(H)-pyrimidin-4-ones by tandem decarboxylation/beta-iodination of the corresponding 6-carboxy-perhydropyrimidin-4-ones was developed. In addition, several 1-benzoyl-2(S)-substituted-5-bromo-2,3-dihydro-4(H)-pyrimidin-4-ones were readily prepared by bromination of 1-benzoyl-2(S)-substituted-2,3-dihydro-4(H)-pyrimidin-4-ones. Subsequently, Sonogashira coupling of the halogenated heterocyclic enones with various terminal alkynes produced 1-benzoyl-2(S)-isopropyl-5-alkynyl-2,3-dihydro-4(H)-pyrimidin-4-ones in good yields. Hydrogenation of the unsaturated C-C moieties in the Sonogashira products followed by acid hydrolysis afforded highly enantioenriched alpha-substituted beta-amino acids.

Functionalization of (2S)‐Isopropyl‐5‐iodo‐2,3‐dihydro‐4(H)‐pyrimidin‐4‐ones by a Suzuki–Miyaura Cross‐Coupling Reaction Using Aryltrifluoroborate Salts: Convenient Enantioselective Preparation of α‐Substituted β‐Amino Acids

“…The reaction of 3-thiophenetrifluoroborate afforded the cross-coupled product in 78 % yield (Table 2, Entry 2), whereas 4-cyanophenyltrifluoroborate and 4-chlorophenyltrifluoroborate afforded the cross-coupled products in 60 and 59 % yield, respectively (Table 2, Entries 9 and 15). Additionally, the 4-formyltrifluoroborate afforded the desired product in 62 % yield ( [12] with the former product always predominating, as anticipated in terms of a more facile approach of the reducing agent from the face of the double bond opposite the isopropyl group [6,7] (Scheme 5).…”

“…The potassium phenyltrifluoroborate was collected as a white crystalline solid. [12] A suspension of the carboxylic acid (2S,6S)-1a [15b] (1.0 mmol), DIB (644 mg, 2.0 mmol), and iodine (253 mg, 1.0 mmol) in CH 2 Cl 2 (20 mL) was stirred at ambient temperature until TLC showed disappearance of the starting material (4-4.5 h). BF 3 ·OEt 2 (0.25 mL, 2 equiv.)…”

“…[10] In view of the structural similarity between 5-iodopyrimidinone (S)-3a and various 5-halouracils that show antiviral activity, [11] reaction conditions were developed for the decarboxylation/β-iodination of (2S,6S)-1a to provide (S)-3a as the single product (Scheme 2). [12] Scheme 2. Preparation of 5-iodopyrimidinone (S)-3a.…”

Recent Developments in the Synthesis of β‐Amino Acids

“…Based on this precedent, D ıaz-S anchez et al [23] developed a one-pot procedure for the synthesis of 1-benzoyl-2(S)-substituted-5-iodo-dihyhydropyrimidin-4-one, for instance (S)-17, by tandem decarboxylation/b-iodination of the corresponding 6-carboxy-perhydropyrimidin-4-ones and subsequent Sonogashira coupling of the halogenated heterocyclic enones with various terminal alkynes to produce 1-benzoyl-2(S)-isopropyl-5-alkynyl-2,3-dihyhydropyrimidin-4-ones (S)-18, in good 7.3 Chiral Pool: Enantioselective Synthesis j299 yields (59-88%). Hydrogenation of the unsaturated alkynyl moieties in the Sonogashira product with Raney nickel followed by acid hydrolysis under microwave irradiation afforded the a-substituted b-amino acid (S)-2-(aminomethyl)-4-phenylbutanoic acid, (S)-19, in high enantiomeric excess (Scheme 7.18).…”

“…Representative Experimental Procedure: Synthesis of (S)-2-(Aminomethyl)-4-phenylbutanoic Acid, (S)-19 [20][21][22][23] First…”