Recent Advances in the Synthesis of CF₃-Substituted Triazoles and Tetrazoles

Abstract

Trifluoromethylated triazoles and tetrazoles have emerged as increasingly important heterocycles in pharmaceuticals, agrochemicals, catalysis, and materials. As a consequence, great attention has been paid to the efficient synthesis of these valuable CF 3-containing molecules. Herein, the advances in the past decade towards the synthesis of CF 3-substituted triazoles and tetrazoles are summarized. The remarkable progress in the utilization of versatile CF 3-functionalized building blocks including CF 3-containing alkynes, CF 3-containing carbonyl compounds, CF 3-containing pyrones and trifluorodiazoethane (CF 3 CHN 2) is demonstrated accordingly.

Fluoroalkyl N-sulfonyl hydrazones: An efficient reagent for the synthesis of fluoroalkylated compounds

“…As a type of N-heterocycles, 1,2,3-triazoles have found significant applications in chemistry, biology, and materials sciences [40,41]. However, the existing methods for preparing them always necessitate harsh reaction conditions and poor regioselectivity [42][43][44]. In 2019, Wang and co-workers [45] established an efficient approach for the synthesis of various 1,4-disubstituted or 1,4,5-trisubstituted 1,2,3-triazoles (14) using the [4+1] cycloaddition of α,α-difluoro-Ntosyl hydrazones (12) with primary amines (13).…”

“…In the absence of azides, metals, or oxidants, this reaction smoothly generates desirable products in moderate to good yields with outstanding functional group tolerance. Notably, this strategy is a more efficient alternative to the traditional alkyne-azide cycloaddition method, which requires an azide and transition metal or stoichiometric oxidant [42][43][44]. The proposed mechanism begins with the formation of intermediate 12-1, followed by the release of a fluoride anion to form azo alkene 12-2.…”

Elemental Sulfur and Dimethyl Sulfoxide‐Promoted Oxidative Cyclization of Trifluoroacetimidohydrazides with Methylhetarenes for the Synthesis of 3‐Hetaryl‐5‐trifluoromethyl‐1,2,4‐triazoles

“…Trifluoromethyl‐substituted 1,2,4‐triazole frameworks exist in many bioactive molecules and pharmaceuticals, [ 7 ] exhibiting various unique physicochemical and biological properties due to the existence of trifluoromethyl group. [ 8 ] Therefore, tremendous effort has been devoted to the efficient synthesis of trifluoromethyl‐1,2,4‐triazoles and our group has also explored several facile synthetic protocols for preparing this kind of important heterocycle from trifluoroacetimidoyl chloride and its derivatives. [ 9 ] Very recently, we reported a TBAI/TBHP mediated synthesis of 3‐hetaryl‐5‐trifluoromethyl‐1,2,4‐triazoles via oxidative cyclization of trifluoroacetimidohydrazides with methylhetarenes (Scheme 1a).…”

Aryl Diazonium Salts in Concerted Cycloaddition Reactions

“…Diels-Alder反应是经典的构建六元环状化合物的高效方法，并于1950年获得诺贝尔化学奖，其 中典型的亲双烯体(dienophile)主要为含有吸电子取代基的烯烃或炔烃化合物，而芳香重氮盐作为亲 双烯体的研究相对较少。1919年Meyer [13] 报道了对硝基苯基重氮盐可以同反式-戊二烯发生反应，但 受限于当时简陋的科研条件， 反应产物被推定为线性结构， 而非环加成产物。 直到五十多年后的1973 年，Sheppard课题组证明了1,6-二氢哒嗪才是上述反应的真正产物(图2) [14] 。实验表明：二烯烃的结 构对该反应具有很大影响，反式-戊二烯能够顺利发生该反应，而顺式-戊二烯即使反应6小时也观察 不到任何产物的生成，基于此作者指出该反应经历[4 + 2]协同环加成反应机理；同时Sheppard和其合 作者对上述反应进行底物扩展，发现非硝基取代的芳基重氮盐形成的1,6-二氢哒嗪产物，可以进一步 发生原位氧化从而得到哒嗪盐类化合物 [15] 。之后到了1984年，Huisgen及其合作者 [16] 又研究了对硝基 苯基重氮盐与其他双烯体的 [ [17] 。四氮唑 的传统合成方法主要依赖叠氮化物和腈之间的[3 + 2]偶极环加成反应 [18][19][20][21] ，虽然该策略可有效构建 单取代或1,5-双取代四氮唑，但2,5-双取代四氮唑化合物的合成仍存在着相当大的挑战。1955年德国 Huisgen等人 [22] 发现对硝基苯基重氮盐与重氮甲烷可发生[3 + 2]偶极环加成反应，以12%的收率得到 一个芳基四氮唑产物(图3A)。但由于文献没有提供具体实验操作，重氮甲烷危险性高，产物收率极 低，产物结构表征不完备，并未引起广泛关注。为克服这一局限，天津大学马军安团队 [23] [24] 、重氮磷酸酯(Seyferth-Gilbert试剂) [25] 、重氮羰基化合物 [26] 、香豆素修饰的重氮 化合物 [27] 以及重氮乙腈 [28] [29] 。 三氮唑的N-H芳基化或C-H官能化是获得多取代三氮唑类化合物的常规策略之一， 但是苛刻的反应条件、区域选择性问题和比较局限的底物范围限制了三氮唑类化合物的多样性和功 能性。近年来，国内学者发展了芳香重氮盐参与的偶极环加成反应，逐渐成为构建多取代三氮唑类 化合物的一种有效策略。 2018年苏州大学万小兵课题组 [30] 报道了重氮乙酸乙酯、芳香重氮盐和腈的一锅三组分反应，用 于合成三取代1,2,4-三氮唑(图4A)。机理研究表明，铜催化剂首先与重氮乙酸乙酯反应形成铜卡宾物 种，其进一步与腈反应生成腈叶立德中间体，该1,3-偶极子与芳基重氮盐的[3 + 2]环加成过程为反应 的关键步骤，所得三氮唑中间体在碱作用下发生异构，生成最终的三取代1,2,4-三氮唑产物。随后， 天津大学马军安课题组 [31,32] 进一步实现了芳香重氮盐与三氟重氮乙烷、苯磺酰基二氟重氮乙烷、重 氮乙腈在腈类溶剂中的一锅三组分环加成反应(图4B-D)，可分别用于合成含有三氟甲基、二氟甲基、 氰基取代的1,2,4-三氮唑，并可应用于药物类似物及手性配体的构建，有良好的拓展应用潜力。近期， 华中师范大学陈加荣小组 [33]…”