Synthesis of dihydroquinazolines from 2-aminobenzylamine: N³-aryl derivatives with electron-withdrawing groups

Abstract

The sequential N-functionalization of 2-aminobenzylamine (2-ABA) followed by cyclodehydration allowed for a straightforward and efficient synthesis of 3,4-dihydroquinazolines with N-aryl substituents bearing electron-withdrawing groups. The sequence involves an initial SNAr displacement, N-acylation and MW-assisted ring closure. Remarkably, the uncatalyzed N-arylation of 2-ABA led to the monosubstitution product using equimolar amounts of both reagents. The individual steps were optimized achieving good to excellent overall yields of the desired heterocycles, avoiding additional protection and deprotection steps. A mechanistic interpretation for the cyclodehydration reaction promoted by trimethylsilyl polyphosphate (PPSE) is also proposed on the basis of literature data and our experimental observations.

Polyphosphoric Acid Esters Promoted Synthesis of Quinazolin-4(3H)-imines from 2-Aminobenzonitrile

“…It could involve initial dehydration of the amide leading to the extremely reactive nitrilium ion intermediate ( I ). Nitrilium cations are known to be obtained by dehydration of N- substituted amides and are intermediates frequently found in the synthesis of heterocycles. ,, Once produced, the in situ generated nitrilium cation undergoes a tandem amination/cyclization process leading to QI 1 . The ease of the intramolecular step depends on the nucleophilic character of the formally sp 2 nitrogen in the cyano-amidine intermediate II , which is in agreement with the fact that the reaction for N -aryl derivatives requires significantly higher temperatures than for N -alkyl QIs.…”

“…These mild reagents, which are soluble in many organic solvents, activate nitrogen and oxygen containing functional groups toward nucleophilic attack. These features make them useful in transformations where other Lewis acids are not effective. , We have used these reagents to promote intramolecular reactions leading to heterocyclic amidines, dihydroquinazolines, , amidine N- oxides, 2-iminoazacyclohexanes, oxazolines, thiazolines, and their higher homologues. , In this work, we investigate the use of PPA esters in the synthesis of QIs from 2-ABN and easily available secondary amides.…”

New efficient synthesis of polysubstituted 3,4-dihydroquinazolines and 4H-3,1-benzothiazines through a Passerini/Staudinger/aza-Wittig/addition/nucleophilic substitution sequence

“…neuroprotective [10], antiproliferative and antifungal activities [11]. Due to the significant bioactive properties of the 3,4-dihydroquinazoline and 4H-3,1-benzothiazine moieties, many preparation procedures have appeared in the literature for the synthesis of their derivatives [12][13][14][15][16][17][18][19][20][21][22]. For example (Scheme 1), a one-pot Tf 2 O-mediated assembly of amides, amines, and ketones provided 3,4-dihydroquinazolines in good yields via successive triflic anhydride-mediated amide dehydration, ketimine addition, and Pictet-Spengler-like cyclization processes [12].…”

One-Pot Three-Component Synthesis of 3,4-Dihydroquinazoline Derivatives

“…因 此, 3,4-二氢喹唑啉的合成方法在过去的几十年里备受 关注. 文献已经报道了许多制备 3,4-二氢喹唑啉的方 法 [9][10][11][12][13] , 然而大多条件比较苛刻, 要用到金属催化或特 殊试剂, 我们尝试找到一种条件温和且高效合成 3,4-二 氢喹唑啉衍生物的新方法.多组分反应(MCR)具有原子利用率高、底物适用范 围广且操作简单等优点, 在新药研发和材料合成等方面 备受人们的青睐 [14][15][16] . 近年来, Ugi 多组分反应广泛应 用于杂环化合物的合成 [17] .…”

“…因 此, 3,4-二氢喹唑啉的合成方法在过去的几十年里备受 关注. 文献已经报道了许多制备 3,4-二氢喹唑啉的方 法 [9][10][11][12][13] , 然而大多条件比较苛刻, 要用到金属催化或特 殊试剂, 我们尝试找到一种条件温和且高效合成 3,4-二 氢喹唑啉衍生物的新方法.…”