Construction of N‐Boc‐2‐Alkylaminoquinazolin‐4(3H)‐Ones via a Three‐Component, One‐Pot Protocol Mediated by Copper(II) Chloride that Spares Enantiomeric Purity

Abstract

Chiral 2‐alkylquinazolinones are key synthetic intermediates, but their preparation in high optical purity is challenging. Thus, a multicomponent procedure integrating anthranilic acids, N‐Boc‐amino acids, and amines in the presence of methanesulfonyl chloride, N‐methylimidazole, and copper(II) chloride was developed to mildly afford N‐Boc‐2‐alkylaminoquinazolin‐4(3H)‐ones with excellent preservation of enantiomeric purity (>99% ee). Copper(II) chloride was essential to retaining enantiopurity, and reaction component structural changes were well tolerated, resulting in an efficient, all‐in‐one procedure that promotes sequential coupling, lactonization, aminolysis, and cyclization in good yields. The method was applied to the rapid assembly of four key intermediates used in the synthesis of high profile quinazolinones, including several PI3K inhibitor drugs.

Dihydropyrazinoquinazolinones via SN2 Sulfamidate Ring-Opening and a Sequential Quinazolinone–Amidine Rearrangement Strategy (SQuAReS)

“…This material was crudely purified by normal phase chromatography (2.5−5% acetone in hexanes) to afford Boc-protected quinazolinone intermediates. 23 The Boc-protected intermediate (1 equiv) was resuspended in anhydrous CH 2 Cl 2 in a 50 mL round-bottom flask. This flask was cooled to 0 °C, and then trifluoroacetic acid (10 equiv) was added dropwise.…”

“…22 Chiral quinazolinones 9g−j were prepared through a method that spares enantiopurity during assembly, generally affording products in high enantiopurity (Scheme 1b, path iii). 23 Notably, that protocol works by coordinating the nitrogen atom of quinazolinone-appended N-Boc protected primary amines. In the case of 9i and 9j, the intermediary N-Boc protected secondary amines (R 2 = methyl) lacked that coordination site, thus accounting for the erosion of enantiopurity.…”

Piperazinobenzodiazepinones: New Encephalitic Alphavirus Inhibitors via Ring Expansion of 2-Dichloromethylquinazolinones

“…Treatment of 5-fluoroisatoic anhydride 12 with iodine and aniline afforded derivative 11i , while 11j was prepared in a three-step protocol from methyl 2-amino-5-cyanobenzoate 13 . Employing a modified version of our previously published procedure 24 for quinazolinone core assembly, the 2-dichloromethylquinazolinones 14a – j were constructed using 2,2-dichloroacetyl chloride to form bis-amides in situ (not shown) that underwent TMSCl/NEt 3 -mediated ring-closure in yields ranging from 18 to 81%.…”

Diastereoselective, Multicomponent Synthesis of Pyrrolopyrazinoquinazolinones via a Tandem Quinazolinone Rearrangement/Intramolecular Ring Closure of Tautomeric (Z)-Benzamidines

“…In our work involving quinazolinone formation and subsequent rearrangement to the benzamidines, we determined that the 4 N HCl conditions used for N-Boc deprotection of quinazolinones and the subsequent free-base reaction using triethylamine (necessary for promoting the benzamidine formation) do not erode the stereochemical integrity of similar quinazolinone substrates. 20 We did not know, however, if the resulting pyrrolopyrazinoquinazolinones were susceptible to epimerization at the activated C5 position once the new scaffold was assembled, as some structurally similar quinazolinediones have been reported to racemize spontaneously. 21 As such, a purified minor product, iodo derivative 21b, was resubmitted to the last step of the reaction sequence employing NEt 3 in methanol at 100 °C for 1 h. If the C5 stereocenter was susceptible to racemization, we expected that the minor isomer might thermodynamically equilibrate to afford the diastereomeric ratio that was observed for 21a:21b when the entire synthetic sequence leading to these products was implemented.…”

“…As noted above, we anticipated that the relative C5/C13a stereochemistry was established in the Ugi reaction by virtue of preferred iminium ion geometry and facial selectivity of isonitrile attack; however, it was possible that some epimerization of the newly formed stereocenter occurred at a subsequent point in the synthetic process leading to pyrrolopyrazinoquinazolinone formation. In our work involving quinazolinone formation and subsequent rearrangement to the benzamidines, we determined that the 4 N HCl conditions used for N -Boc deprotection of quinazolinones and the subsequent free-base reaction using triethylamine (necessary for promoting the benzamidine formation) do not erode the stereochemical integrity of similar quinazolinone substrates . We did not know, however, if the resulting pyrrolopyrazinoquinazolinones were susceptible to epimerization at the activated C5 position once the new scaffold was assembled, as some structurally similar quinazolinediones have been reported to racemize spontaneously .…”