Alkylamino‐Directed One‐Pot Reaction of N‐Alkyl Anilines with CO, Amines and Aldehydes Leading to 2,3‐Dihydroquinazolin‐4(1H)‐ones

Abstract

An economical and efficient approach to pharmaceutically and biologically significant 2,3dihydroquinazolin-4(1H)-ones has been disclosed. The one-pot multicomponent reaction was performed through a palladium-catalyzed ortho-selective oxidative carbonylation of N-substituted anilines with CO and primary amines, and subsequent condensation with aldehydes in MeCN by using alkylamino as the directing group, KI/AcOH as the additives, and Cu(OAc) 2 as the oxidant. This intriguing straightforward method features embedded directing strategy, simple starting materials, mild conditions, high atom/step economic economy, broad substrate scope and good product diversity.Keywords: CÀH activation; 2,3-dihydroquinazolin-4(1H)-ones; embedded directing group; N-alkyl anilines; palladium 2,3-Dihydroquinazolin-4(1H)-ones (DHQAs) are an important class of nitrogen-containing heterocycles with a wide range of pharmaceutical and biological activities such as anticancer, [1] 1 reverse transcriptase, [16] inosine 5'-monophosphate dehydrogenase, [17] protein kinase C-q, [18] transient receptor potential melastatin 2 19 inhibition. For exam-ple, evodiamine [2a,4a,20] and metolazone [10b,21] are typical representatives of clinically significant DHQA medications ( Figure 1).Due to their immense and important biological activities, the synthesis of DHQAs has attracted considerable interests. Among the established synthetic protocols, the typical procedures involve cyclocondensation of o-amino-benzamides (usually obtained by ammonolysis of isatoic anhydride) with aldehydes (Scheme 1a), [3a,22] reductive cyclization of onitrobenzamides or o-azidobenzamides with carbonyl compounds (Scheme 1b), [23] cyclocondensation of isatoic anhydrides, primary amines (or ammonium salts) and aldehydes (Scheme 1c), [2b,5a,22a,24] and cyclocondensation of o-aminobenzonitriles with carbonyl compounds (Scheme 1d). [25] Despite the above advances, however, one major drawback associated with all the above approaches is that the N 1 -containing starting materials applied in these protocols are usually Figure 1. Representative examples of clinically significant DHQA medications.

Fe3O4@Sap/Cu(ii): an efficient magnetically recoverable green nanocatalyst for the preparation of acridine and quinazoline derivatives in aqueous media at room temperature

“…39 In addition, one-pot three-component condensation reaction of (a) aromatic aldehydes, phenylhydrazine, and isatoic anhydride or (b) aromatic aldehydes, 2-aminobenzophenone, and ammonium acetate, for the synthesis of quinazolines are the common and key reactions in the synthesis of these compounds. 40 To now, several methods have been reported for the one-pot multi-component condensation synthesis of acridine and quinazoline derivatives, 41 employing a wide variety of catalysts such as Fe 3 O 4 /HT-SMTU-Zn II , 42 SBA/AuNP, 43 [Nbdm][OH], 44 Co-aminobenzamid@Al-SBA-15, 45 a-chymotrypsin, 46 Pd(OAc) 2 , 47 KCC-1/Pr-SO 3 H, 48 and CuCl 2 , 49 Co-alanine complex, 50 55 Despite the usefulness of these catalysts, they also have some limitations including high toxicity, use of expensive materials, complex synthetic processes, long reaction times, and sometimes low yields.…”

Gold(I)-Catalyzed Tandem Synthesis of Polycyclic Dihydroquinazolinones

“…The method showed good compatibility for electron-withdrawing and electrondonating functional groups such as chloro, bromo, nitro, alkyl, and methoxy groups. The substrates containing electron-withdrawing substituents (1m-p) smoothly afforded the cyclized products 2m-p at room temperature in excellent yields (92-97%, entries [12][13][14][15]. The substrates containing electron-donating substituents (1q-t) also provided the corresponding cyclized products in good to excellent yields (72-91%, entries [16][17][18][19].…”

“…More specifically, fused dihydroquinazolinones such as cruciferane [10], phaitanthrin D [11], evodiamine [12], and their synthetic congeners [13,14] have attracted medicinal chemists' attention due to their unique structural features and promising bioactivities, which have prompted the research on synthetic dihydroquinazolinones with pharmacological potential (Figure 1). Although various synthetic approaches to bicyclic dihydroquinazolinone scaffolds have been described [15][16][17][18][19][20], effective strategies for more complex tri-and polycyclic dihydroquinazolinones, which operate under mild conditions on readily accessible simple substrates, are rare and of high value. Thus far, a number of synthetic methodologies for various heterocyclic systems have been developed.…”

Advances in Synthesis of 2,3-Dihydroquinazolin-4(1H)-ones

“…Proposed mechanism of reaction of o-aminobenzonitrile with aldehydes/ketones to 2,3-dihydroquinazolin-4-(1H)-ones 得的 N-烷基苯胺为底物合成 2,3-二氢喹啉-4(1H)-酮类 化合物的新方法: 在 Pd(OAc) 2 催化下, N-烷基苯胺可与 CO、 胺、 醛经氨基邻位 C-H 键选择性活化, "一锅法" 多组分串联反应得到目标产物(Eq. 13)[74] .该反应的机理如 Scheme 19 所示.在 Pd(OAc) 2 催化 下, N-烷基苯胺首先与 CO 作用, 分别经 I、II 转化为邻 氨基苯甲酸(III), 然后 III 再与 Pd(OAc) 2 、CO 作用, 经 IV、 V 转变为靛红酸酐(VI). VI 在酸的活化作用下经 VII 胺解生成邻氨基苯甲酰胺(VIII), 最后 VIII 再与醛反应 关环生成目标产物 IX[74] .…”

“…13)[74] .该反应的机理如 Scheme 19 所示.在 Pd(OAc) 2 催化 下, N-烷基苯胺首先与 CO 作用, 分别经 I、II 转化为邻 氨基苯甲酸(III), 然后 III 再与 Pd(OAc) 2 、CO 作用, 经 IV、 V 转变为靛红酸酐(VI). VI 在酸的活化作用下经 VII 胺解生成邻氨基苯甲酰胺(VIII), 最后 VIII 再与醛反应 关环生成目标产物 IX[74] .…”