Addition of Diazo Compounds ipso-C-H bond to Carbon Disulfide: Synthesis of 1,2,3-Thiadiazoles Under Mild Conditions

英文原文与中文译文逐段对照 · English original with Chinese translation

Lei Zhang, Beiqi Sun, Qianyi Liu, and Fanyang Mo

张雷，孙北奇，刘谦益，莫凡洋

J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00383 • Publication Date (Web): 19 Mar 2018 Downloaded from http://pubs.acs.org on March 19, 2018

《有机化学杂志》，刚接受的稿件 • DOI: 10.1021/acs.joc.8b00383 • 网络出版日期:2018 年 3 月 19 日 于 2018 年 3 月 19 日从 http://pubs.acs.org 下载

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Addition of Diazo Compounds ipso-C-H bond to Carbon Disulfide: Synthesis of 1,2,3-Thiadiazoles Under Mild Conditions

重氮化合物的 ipso-C-H 键与二硫化碳的加成反应:温和条件下 1,2,3-噻二唑的合成

Lei Zhang, Beiqi Sun, Qianyi Liu and Fanyang Mo*

张雷，孙北奇，刘谦益，莫凡洋*

${}^{ \dagger }$ Department of Energy and Resources Engineering, College of Engineering, Peking University, Beijing 100871, China. Supporting Information Placeholder

${}^{ \dagger }$ 能源与资源工程系，工程学院，北京大学，北京 100871，中国。支持信息占位符

ABSTRACT: We describe here an operationally simple and straightforward synthesis method for a series of diverse 4,5- disubstituted 1,2,3-thiadiazoles via the nucleophilic addition of $\alpha$ -diazo carbonyl compounds to carbon disulfide. This method fea-

摘要:我们在此描述了一种操作简单直接的合成方法，通过 $\alpha$ -重氮羰基化合物与二硫化碳的亲核加成反应，合成一系列多样的 4,5-二取代 1,2,3-噻二唑。该方法具有使用丰富且廉价的二硫化碳以及温和反应条件的特点。

tures using abundant and inexpensive carbon disulfide with mild reaction conditions.

使用丰富且廉价的二硫化碳，在温和的反应条件下进行反应。

1,2,3-thiadiazoles ${}^{1}$ are versatile heterocycles present in various pharmaceutical molecules. ${}^{2}$ Due to their biological activities, many derivatives of 1,2,3-thiadiazole are important in industry, medicine and agriculture (Scheme 1A). ${}^{3}$ To date, the known methods for synthesizing 1,2,3-thiadiazoles can be summarized as shown in Scheme 1B: a) cyclization of hydra-zones with thionyl chloride (Hurd-Mori synthesis); ${}^{4}$ b) treatment of $\alpha$ -diazo carbonyl compounds with Lawesson’s reagent (Wolff synthesis); ${}^{5}$ c) addition of diazomethane (Pech-mann synthesis) ${}^{6}$ or lithium (trimethylsilyl)diazomethane ${}^{7}$ to thiocarbonyl compounds; d) diazotization of $\alpha$ - enolicdithioesters; ${}^{8}$ and e) oxidative cyclization of $N$ - tosylhydrazones and sulfur. ${}^{9}$ Although these techniques are frequently used, the synthesis of 1,2,3-thiadiazoles remains an active research area.

1,2,3 - 噻二唑${}^{1}$是存在于各种药物分子中的多功能杂环化合物。${}^{2}$由于它们的生物活性，许多1,2,3 - 噻二唑衍生物在工业、医药和农业中都很重要(方案1A)。${}^{3}$迄今为止，已知的合成1,2,3 - 噻二唑的方法可总结如下(方案1B):a)腙与亚硫酰氯的环化反应(赫德 - 森合成法)；${}^{4}$b)用劳森试剂处理$\alpha$ - 重氮羰基化合物(沃尔夫合成法)；${}^{5}$c)将重氮甲烷(佩希曼合成法)${}^{6}$或锂(三甲基硅基)重氮甲烷${}^{7}$加成到硫羰基化合物上；d)$\alpha$ - 烯醇二硫酯的重氮化反应；${}^{8}$以及e)$N$ - 甲苯磺酰腙与硫的氧化环化反应。${}^{9}$尽管这些技术经常被使用，但1,2,3 - 噻二唑的合成仍然是一个活跃的研究领域。

Scheme 1. Introduction of 1,2,3-Thiadiazoles

方案1. 1,2,3 - 噻二唑的介绍

Recently, we have reported transition-metal-free diazo compounds ipso-C-H bond addition to carbon dioxide $\left( {\mathrm{{CO}}}_{2}\right)$ under very mild reaction conditions with the diazo group retained. ${}^{10}$ The resulting $\alpha$ -diazo carboxylate intermediate is readily converted to esters and amides in a one-pot manner (Scheme 2A). ${\mathrm{{CO}}}_{2}$ is a greenhouse gas that has been attracting much attention as an inexpensive, nontoxic, nonflammable, renewable and abundant C1 building block for organic synthesis. ${}^{11}$ Meanwhile, carbon disulfide $\left( {\mathrm{{CS}}}_{2}\right)$ , an analogue of ${\mathrm{{CO}}}_{2}$ , has long been used as a sulfur source for a variety of useful chemicals for agricultural, medicinal, and pharmaceutical applications. ${}^{12}$ As an extension of our previous work, here we report on diazo compound ipso-C-H bond addition to ${\mathrm{{CS}}}_{2}$ for the synthesis of 1,2,3-thiadiazoles under mild conditions (Scheme 2B).

最近，我们报道了在非常温和的反应条件下，重氮化合物的 ipso-C-H 键加成到二氧化碳 $\left( {\mathrm{{CO}}}_{2}\right)$ 上，同时保留重氮基团。${}^{10}$ 生成的 $\alpha$ -重氮羧酸酯中间体可以一锅法轻松转化为酯和酰胺(方案 2A)。${\mathrm{{CO}}}_{2}$ 是一种温室气体，作为一种廉价、无毒、不可燃、可再生且丰富的有机合成 C1 构建块，一直备受关注。${}^{11}$ 同时，二硫化碳 $\left( {\mathrm{{CS}}}_{2}\right)$，${\mathrm{{CO}}}_{2}$ 的类似物，长期以来一直被用作各种用于农业、医药和制药应用的有用化学品的硫源。${}^{12}$ 作为我们先前工作的延伸，在此我们报道了在温和条件下重氮化合物的 ipso-C-H 键加成到 ${\mathrm{{CS}}}_{2}$ 上以合成 1,2,3-噻二唑(方案 2B)。

Scheme 2. Diazo Compound ipso-C-H Bond Addition to ${\mathrm{{CO}}}_{2}$ and ${\mathrm{{CS}}}_{2}$

方案 2. 重氮化合物的 ipso-C-H 键与 ${\mathrm{{CO}}}_{2}$ 和 ${\mathrm{{CS}}}_{2}$ 的加成反应

To probe the feasibility of the nucleophilic addition of the diazo group to ${\mathrm{{CS}}}_{2}$ , we initiated our studies with ethyl diazo-acetate (EDA) 1a and benzyl bromide (BnBr) 2a as the standard substrates. Various organic and inorganic bases were examined in the initial studies. As shown in Table 1, with ${\mathrm{{Cs}}}_{2}{\mathrm{{CO}}}_{3}$ as the base, the desired product ethyl 5-(benzylthio)- 1,2,3-thiadiazole-4-carboxylate $3\mathrm{a}$ was obtained with ${38}^{ \circ }$ NMR yield (entry 1). CsF and ${\mathrm{{KO}}}^{\prime }\mathrm{{Bu}}$ turned out to be less effective in this transformation (entries 2 and 3) and organic bases, such as DBU and ${\mathrm{{Et}}}_{3}\mathrm{\;N}$ , were inactive (entries 4 and 5).

为了探究重氮基团对${\mathrm{{CS}}}_{2}$进行亲核加成的可行性，我们以重氮乙酸乙酯(EDA)1a和苄基溴(BnBr)2a作为标准底物开展了研究。在初步研究中考察了各种有机碱和无机碱。如表1所示，以${\mathrm{{Cs}}}_{2}{\mathrm{{CO}}}_{3}$作为碱时，以${38}^{ \circ }$ NMR产率得到了所需产物5-(苄硫基)-1,2,3-噻二唑-4-羧酸乙酯$3\mathrm{a}$(条目1)。结果表明，CsF和${\mathrm{{KO}}}^{\prime }\mathrm{{Bu}}$在该转化反应中效果较差(条目2和3)，而有机碱如DBU和${\mathrm{{Et}}}_{3}\mathrm{\;N}$则无活性(条目4和5)。

This suggested that bases with proper basicity might be a key issue for the desired transformation. Indeed, the yield was slightly improved with the use of KOH as the base (entry 6). 3a was then obtained with 73% yield by switching the solvent from MeCN to DMF (entry 7). Other solvents, such as DMSO, THF and 1,4-dioxane, were less efficient (entries 8-10). Finally, an improved yield (81%) was obtained by using 2.0 equivalent of ${\mathrm{{CS}}}_{2}$ (entry 11). The yield was not further improved by increasing the equivalency of ${\mathrm{{CS}}}_{2}$ to 5.0 (entry 12). However, the product 3a was not very stable during handling and the isolated yield diminished to about 10% compared with the NMR yield.

这表明具有适当碱度的碱可能是实现所需转化的关键因素。实际上，使用KOH作为碱时产率略有提高(条目6)。然后通过将溶剂从MeCN切换到DMF，以73%的产率得到了3a(条目7)。其他溶剂如DMSO、THF和1,4-二氧六环效率较低(条目8 - 10)。最后，通过使用2.0当量的${\mathrm{{CS}}}_{2}$，产率提高到了81%(条目11)。将${\mathrm{{CS}}}_{2}$的当量增加到5.0时，产率没有进一步提高(条目12)。然而，产物3a在处理过程中不太稳定，与NMR产率相比，分离产率降至约10%。

Table 1. Selected Optimization of Reaction Conditions ${}^{a}$

表1. ${}^{a}$反应条件的选定优化

${}^{a}$ Reaction conditions: EDA (0.5 mmol), BnBr (1.5 equiv), base (1.2 equiv), solvent $\left( {2\mathrm{\;{mL}}}\right)$ , reaction time ${12}\mathrm{\;h}$ , temperature ${50}^{ \circ }\mathrm{C}$ , sealed. n. d., not detected. ${}^{b}$ Yields were determined by ${}^{1}\mathrm{H}$ NMR spectroscopy with 1,1,2,2-tetrachloroethane used as internal standard. ${}^{c}$ Isolated yield.

${}^{a}$反应条件:EDA(0.5 mmol)，BnBr(1.5当量)，碱(1.2当量)，溶剂$\left( {2\mathrm{\;{mL}}}\right)$，反应时间${12}\mathrm{\;h}$，温度${50}^{ \circ }\mathrm{C}$，密封。n.d.，未检测到。${}^{b}$产率通过以1,1,2,2-四氯乙烷为内标的${}^{1}\mathrm{H}$ NMR光谱测定。${}^{c}$分离产率。

After obtaining the optimal yield for $\mathbf{{3a}}$ , we next conducted substrate scope studies with the results shown in Table 2. Various benzyl bromides were evaluated with various substituent groups for this reaction. Both para- and ortho- substituents (3b-3e) on benzyl bromides were tolerated, giving good yields. Additionally, allyl bromide (3f) was also a good reagent to facilitate the construction of 1,2,3-thiadiazoles. To further demonstrate the expansibility of this methodology, various $\alpha$ -diazo carbonyl compounds were synthesized and tested using this transformation. In general, all these types of diazo substrates were suitable for the reaction with the products obtained with moderate to good yields. Menthyl diazoace-tate was converted to 1,2,3-thiadiazole (3g) with 70% yield. XRD data was obtained for $3\mathrm{\;g}$ . Furthermore, $\alpha$ -diazo alkyl ketones (3h and 3i) also worked well, while $\alpha$ -diazo amides (3j and 3k) gave relatively low yields.

在获得$\mathbf{{3a}}$的最佳产率后，我们接下来进行了底物范围研究，结果如表2所示。针对该反应评估了带有各种取代基的各种苄基溴。苄基溴上的对位和邻位取代基(3b - 3e)均能耐受，产率良好。此外，烯丙基溴(3f)也是促进1,2,3-噻二唑构建的良好试剂。为了进一步证明该方法的扩展性，合成了各种$\alpha$-重氮羰基化合物并使用该转化反应进行了测试。一般来说，所有这些类型的重氮底物都适用于该反应，产物产率适中至良好。薄荷基重氮乙酸酯以70%的产率转化为1,2,3-噻二唑(3g)。获得了$3\mathrm{\;g}$的XRD数据。此外，$\alpha$-重氮烷基酮(3h和3i)也表现良好，而$\alpha$-重氮酰胺(3j和3k)的产率相对较低。

Compared with the known methods shown in Scheme 1B, our synthetic strategy is more close to the catalog c: addition of diazo compounds to $\mathrm{C} = \mathrm{S}$ double bond. In reference 7, Ao-yama suggested a nucleophilic addition/cyclization mechanism for the conversion of lithium (trimethylsi-lyl)diazomethane and carbon disulfide to the 1,2,3-thiadiazole product. Meanwhile, as a good electrophile, carbon disulfide has ready reactivity with a variety of nucleophiles, ranging from carbon-centered nucleophiles (e. g. Grignard reagents) to oxygen-centered nucleophiles (e. g. alkoxy) and amines. ${}^{12c}$ Based on the above, we proposed that our reaction mechanism is also a normal deprotonation-nucleophilic addition/cyclization process (Scheme 3).

与方案1B中所示的已知方法相比，我们的合成策略更接近于目录c:重氮化合物与$\mathrm{C} = \mathrm{S}$双键的加成。在参考文献7中，青山提出了一种亲核加成/环化机理，用于将锂(三甲基硅基)重氮甲烷和二硫化碳转化为1,2,3-噻二唑产物。同时，作为一种良好的亲电试剂，二硫化碳与各种亲核试剂具有良好的反应活性，从碳中心亲核试剂(如格氏试剂)到氧中心亲核试剂(如烷氧基)和胺。${}^{12c}$基于以上内容，我们提出我们的反应机理也是一个正常的去质子化-亲核加成/环化过程(方案3)。

Table 2. Substrates Scope ${}^{a}$

表2.底物范围${}^{a}$

${}^{a}$ Reaction conditions: diazo compound ( ${0.5}\mathrm{{mmol}}$ ), RBr (1.5 equiv), KOH (1.2 equiv), solvent $\left( {2\mathrm{\;{mL}}}\right)$ , reaction time ${12}\mathrm{\;h}$ , temperature ${50}^{ \circ }\mathrm{C}$ , sealed.

${}^{a}$反应条件:重氮化合物(${0.5}\mathrm{{mmol}}$)，RBr(1.5当量)，KOH(1.2当量)，溶剂$\left( {2\mathrm{\;{mL}}}\right)$，反应时间${12}\mathrm{\;h}$，温度${50}^{ \circ }\mathrm{C}$，密封。

Scheme 3. Proposed Reaction Pathway

方案3. 提出的反应途径

In summary, we have developed an operationally simple method for the synthesis of 4,5-disubstituted 1,2,3-thiadiazoles via the nucleophilic addition of $\alpha$ -diazo carbonyl compounds to carbon disulfide. This method can be applied as an alternative to traditional synthesis methods of 1,2,3-thiadiazoles with carbon disulfide as the C1 building block with mild reaction conditions.

总之，我们开发了一种操作简单的方法，通过将$\alpha$-重氮羰基化合物亲核加成到二硫化碳上来合成4,5-二取代的1,2,3-噻二唑。该方法可作为以二硫化碳为C1结构单元的1,2,3-噻二唑传统合成方法的替代方法，反应条件温和。

EXPERIMENTAL SECTION

实验部分

General Information. All the solvents were purchased from ENERGY CHEMICAL and kept dry by molecular sieves. The products were purified by column chromatography on silica gel (300-400 mesh, from Qingdao, China). NMR spectra were measured on a Bruker ARX400 ( ${}^{1}\mathrm{H}$ at ${400}\mathrm{{MHz}},{}^{13}\mathrm{C}$ at ${100}\mathrm{{MHz}},{}^{19}\mathrm{\;F}$ at ${377}\mathrm{{MHz}}$ ) magnetic resonance spectrometer. The chemical shifts $\left( \delta \right)$ are reported as ppm using tetramethylsilane as the internal standard $(s =$ singlet, $d =$ doublet, $t =$ triplet, $q =$ quartet, ${dd} =$ doublet of doublets, ${dt} =$ doublet of triplets, $\mathrm{m} =$ multiplet) while the coupling constants $\left( J\right)$ were reported in Hertz (Hz). Infrared spectra were recorded on a Thermal Fisher Nicolet iS50 Fourier transform spectrometer (FT-IR) and were reported as wave numbers $\left( {\mathrm{{cm}}}^{-1}\right)$ . The HRMS data was obtained on a VG ZAB-HS mass spectrometer and a Brucker Apex IV FTMS spectrometer. The diazo starting materials were synthesized in the lab. For details, see Supporting Information.

一般信息。所有溶剂均购自ENERGY CHEMICAL，并通过分子筛保持干燥。产物通过硅胶柱色谱法(300 - 400目，来自中国青岛)进行纯化。核磁共振谱在Bruker ARX400(${}^{1}\mathrm{H}$ 在${400}\mathrm{{MHz}},{}^{13}\mathrm{C}$ 在${100}\mathrm{{MHz}},{}^{19}\mathrm{\;F}$ 在${377}\mathrm{{MHz}}$ )核磁共振仪上测定。化学位移$\left( \delta \right)$ 以ppm为单位报告，使用四甲基硅烷作为内标$(s =$ 单峰，$d =$ 双峰，$t =$ 三重峰，$q =$ 四重峰，${dd} =$ 双二重峰，${dt} =$ 双三重峰，$\mathrm{m} =$ 多重峰)，而耦合常数$\left( J\right)$ 以赫兹(Hz)为单位报告。红外光谱在Thermal Fisher Nicolet iS50傅里叶变换光谱仪(FT - IR)上记录，并以波数$\left( {\mathrm{{cm}}}^{-1}\right)$ 报告。高分辨质谱数据在VG ZAB - HS质谱仪和Bruker Apex IV FTMS质谱仪上获得。重氮起始原料在实验室中合成。详情见支持信息。

General procedure for the synthesis of 1,2,3-thiadiazoles. In a glove box, charge a $4\mathrm{\;{mL}}$ vial equipped with a stir bar with potassium hydroxide (0.6 mmol, 1.2 equiv), dimethyl formamide $\left( {2\mathrm{\;{mL}}}\right)$ , the diazo compound $\left( {{0.5}\mathrm{{mmol}}}\right)$ , carbon disulfide (1.0 mmol, 2.0 equiv), bromide (0.75 mmol, 1.5 equiv) in succession. Then, seal the vial and stir the mixture at ${50}{}^{ \circ }\mathrm{C}$ for ${12}\mathrm{\;h}$ . Then, wash the reaction mixture with ${20}\mathrm{\;{mL}}$ ethyl acetate and water $\left( {3 \times {20}\mathrm{\;{mL}}}\right)$ . Separate the organic layer and dry over ${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$ . After removal of the solvent, purify the residue by column chromatography (silica gel) to afford the desired product.

1,2,3 - 噻二唑的一般合成步骤。在手套箱中，向一个装有搅拌棒的$4\mathrm{\;{mL}}$ 小瓶中依次加入氢氧化钾(0.6 mmol，1.2当量)、二甲基甲酰胺$\left( {2\mathrm{\;{mL}}}\right)$ 、重氮化合物$\left( {{0.5}\mathrm{{mmol}}}\right)$ 、二硫化碳(1.0 mmol，2.0当量)、溴化物(0.75 mmol，1.5当量)。然后，密封小瓶并在${50}{}^{ \circ }\mathrm{C}$ 下搅拌混合物${12}\mathrm{\;h}$ 。然后，用${20}\mathrm{\;{mL}}$ 乙酸乙酯和水$\left( {3 \times {20}\mathrm{\;{mL}}}\right)$ 洗涤反应混合物。分离有机层并通过${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$ 干燥。除去溶剂后，通过柱色谱法(硅胶)纯化残余物以得到所需产物。

Ethyl 5-(benzylthio)-1,2,3-thiadiazole-4-carboxylate(3a). ${}^{13}$ Yellowish-green solid, yield ${78}\% \left( {{110}\mathrm{{mg}}}\right) ;\mathrm{{mp}} = {83} - {84}{}^{ \circ }\mathrm{C}$ ; ${\mathrm{R}}_{\mathrm{f}} = {0.25}$ (petroleum ether: EtOAc = 10:1); petroleum ether: EtOAc = 100:1 ~ 50:1 as eluent; ${}^{1}$ H NMR (400 MHz, CDCl ${}_{3}$ ) $\delta = {7.47} - {7.30}\left( {\mathrm{\;m},5\mathrm{H}}\right) ,{4.51}\left( {\mathrm{q}, J = {7.1}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{4.26}\left( {\mathrm{\;s},2\mathrm{H}}\right)$ , ${1.46}\left( {\mathrm{t}, J = {7.1}\mathrm{\;{Hz}},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ NMR (100 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 164.4, 160.8, 146.4, 133.6, 129.14, 129.08, 128.6, 62.1, 42.3, 14.4.

5 - (苄硫基) - 1,2,3 - 噻二唑 - 4 - 羧酸乙酯(3a)。${}^{13}$ 黄绿色固体，产率${78}\% \left( {{110}\mathrm{{mg}}}\right) ;\mathrm{{mp}} = {83} - {84}{}^{ \circ }\mathrm{C}$ ；${\mathrm{R}}_{\mathrm{f}} = {0.25}$ (石油醚:乙酸乙酯 = 10:1)；以石油醚:乙酸乙酯 = 100:1 ~ 50:1 作为洗脱剂；${}^{1}$ ^1H NMR(400 MHz，CDCl${}_{3}$ )$\delta = {7.47} - {7.30}\left( {\mathrm{\;m},5\mathrm{H}}\right) ,{4.51}\left( {\mathrm{q}, J = {7.1}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{4.26}\left( {\mathrm{\;s},2\mathrm{H}}\right)$ ，${1.46}\left( {\mathrm{t}, J = {7.1}\mathrm{\;{Hz}},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ ^{13}C NMR(100 MHz，${\mathrm{{CDCl}}}_{3}$ )δ 164.4，160.8，146.4，133.6，129.14，129.08，128.6，62.1，42.3，14.4。

Ethyl5-((4-methylbenzyl)thio)-1,2,3-thiadiazole-4- carboxylate (3b). White solid, yield 68% (100 mg); mp = 93- ${94}^{ \circ }\mathrm{C};{\mathrm{R}}_{\mathrm{f}} = {0.25}$ (petroleum ether: EtOAc = 10:1); petroleum ether: EtOAc = 100:1 ~ 50:1 as eluent; 1H NMR (400 MHz, ${\mathrm{{CDCl}}}_{3})\delta = {7.32}\left( {\mathrm{\;d}, J = {8.0}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{7.17}\left( {\mathrm{\;d}, J = {7.9}\mathrm{\;{Hz}},2\mathrm{H}}\right)$ , ${4.51}\left( {\mathrm{q}, J = {7.1}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{4.23}\left( {\mathrm{\;s},2\mathrm{H}}\right) ,{2.35}\left( {\mathrm{\;s},3\mathrm{H}}\right) ,{1.46}(\mathrm{t}, J =$ 7.1 Hz, 3H). ${}^{13}\mathrm{C}$ NMR (100 MHz, CDCl ${}_{3}$ ) δ 164.5, 160.8, 146.4, 138.6, 130.5, 129.8, 129.0, 62.1, 42.1, 21.2, 14.4. IR (film) 2984, 2921, 1732, 1701, 1439, 1309, 1271, 1209, 1065, 1021,842. HRMS (ESI): calcd for ${\mathrm{C}}_{13}{\mathrm{H}}_{15}{\mathrm{\;N}}_{2}{\mathrm{O}}_{2}{\mathrm{\;S}}_{2}{}^{ + }{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ : 295.0569; found: 295.0563.

5-((4-甲基苄基)硫代)-1,2,3-噻二唑-4-羧酸乙酯(3b)。白色固体，产率68%(100mg)；熔点=93 - ${94}^{ \circ }\mathrm{C};{\mathrm{R}}_{\mathrm{f}} = {0.25}$(石油醚:乙酸乙酯=10:1)；以石油醚:乙酸乙酯=100:1~50:1为洗脱剂；1H NMR(400MHz，${\mathrm{{CDCl}}}_{3})\delta = {7.32}\left( {\mathrm{\;d}, J = {8.0}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{7.17}\left( {\mathrm{\;d}, J = {7.9}\mathrm{\;{Hz}},2\mathrm{H}}\right)$，${4.51}\left( {\mathrm{q}, J = {7.1}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{4.23}\left( {\mathrm{\;s},2\mathrm{H}}\right) ,{2.35}\left( {\mathrm{\;s},3\mathrm{H}}\right) ,{1.46}(\mathrm{t}, J =$7.1Hz，3H)。${}^{13}\mathrm{C}$NMR(100MHz，CDCl${}_{3}$)δ164.5，160.8，146.4，138.6，130.5，129.8，129.0，62.1，42.1，21.2，14.4。IR(薄膜)2984，2921，1732，1701，1439，1309，1271，1209，1065，1021，842。高分辨质谱(电喷雾电离):计算值为${\mathrm{C}}_{13}{\mathrm{H}}_{15}{\mathrm{\;N}}_{2}{\mathrm{O}}_{2}{\mathrm{\;S}}_{2}{}^{ + }{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$:295.0569；实测值:295.0563。

Ethyl 5-((2-methylbenzyl)thio)-1,2,3-thiadiazole-4- carboxylate (3c). White solid, yield 59% (87 mg); mp = 90- ${91}^{ \circ }\mathrm{C};{\mathrm{R}}_{\mathrm{f}} = {0.25}$ (petroleum ether: EtOAc = 10:1); petroleum ether: EtOAc = 100:1 ~ 50:1 as eluent; ${}^{1}\mathrm{H}$ NMR (400 MHz, ${\mathrm{{CDCl}}}_{3}){\delta 7.41} - {7.15}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{4.50}\left( {\mathrm{q}, J = {7.1}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{4.25}(\mathrm{\;s}$ , 2H), 2.43 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H). ${}^{13}\mathrm{C}$ NMR (100 MHz, CDCl3) δ 164.8, 160.8, 146.2, 137.2, 131.6, 131.0, 130.0, 129.0, 126.6, 62.1, 41.0, 19.3, 14.4. IR (film) 2980, 2932, 1730, 1701, 1439, 1310, 1272, 1209, 1065, 1020, 842, 780. HRMS (ESI): calcd for ${\mathrm{C}}_{13}{\mathrm{H}}_{15}{\mathrm{\;N}}_{2}{\mathrm{O}}_{2}{\mathrm{\;S}}_{2}{}^{ + }{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ : 295.0569; found: 295.0562.

5-((2-甲基苄基)硫代)-1,2,3-噻二唑-4-羧酸乙酯(3c)。白色固体，产率59%(87mg)；熔点=90 - ${91}^{ \circ }\mathrm{C};{\mathrm{R}}_{\mathrm{f}} = {0.25}$ (石油醚:乙酸乙酯 = 10:1)；以石油醚:乙酸乙酯 = 100:1~50:1为洗脱剂；${}^{1}\mathrm{H}$核磁共振(400MHz，${\mathrm{{CDCl}}}_{3}){\delta 7.41} - {7.15}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{4.50}\left( {\mathrm{q}, J = {7.1}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{4.25}(\mathrm{\;s}$ ，2H)，2.43(s，3H)，1.45(t，J = 7.1Hz，3H)。${}^{13}\mathrm{C}$核磁共振(100MHz，CDCl3)δ164.8，160.8，146.2，137.2，131.6，131.0，130.0，129.0，126.6，62.1，41.0，19.3，14.4。红外(薄膜)2980，2932，1730，1701，1439，1310，1272，1209，1065，1020，842，780。高分辨质谱(电喷雾电离):计算值为${\mathrm{C}}_{13}{\mathrm{H}}_{15}{\mathrm{\;N}}_{2}{\mathrm{O}}_{2}{\mathrm{\;S}}_{2}{}^{ + }{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ : 295.0569；实测值:295.0562。

Ethyl5-((4-bromobenzyl)thio)-1,2,3-thiadiazole-4- carboxylate (3d). White solid, yield 64% (115 mg); mp = 93- ${94}^{ \circ }\mathrm{C};{\mathrm{R}}_{\mathrm{f}} = {0.20}$ (petroleum ether: EtOAc = 10:1); petroleum ether: EtOAc = 100:1 ~ 50:1 as eluent; ${}^{1}\mathrm{H}$ NMR (400 MHz, ${\mathrm{{CDCl}}}_{3}){\delta 7.55} - {7.48}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{7.32}\left( {\mathrm{\;d}, J = {8.5}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{4.51} \; \left( {\mathrm{q}, J = {7.1}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{4.21}\left( {\mathrm{\;s},2\mathrm{H}}\right) ,{1.46}\left( {\mathrm{t}, J = {7.1}\mathrm{\;{Hz}},3\mathrm{H}}\right) .{}^{13}\mathrm{C}$ NMR (100 MHz, CDCl3) δ 163.8, 160.7, 146.5, 132.7, 132.3, 130.7, 122.8, 62.2, 41.6, 14.3. IR (film) 2984, 1730, 1700, 1487, 1440, 1310, 1271, 1210, 1066, 1012, 842, 780. HRMS (ESI): calcd for ${\mathrm{C}}_{12}{\mathrm{H}}_{12}{\mathrm{{BrN}}}_{2}{\mathrm{O}}_{2}{\mathrm{\;S}}_{2}^{ + }{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ : 358.9518; found: 358.9512.

5-((4-溴苄基)硫代)-1,2,3-噻二唑-4-羧酸乙酯(3d)。白色固体，产率64%(115mg)；熔点=93 - ${94}^{ \circ }\mathrm{C};{\mathrm{R}}_{\mathrm{f}} = {0.20}$ (石油醚:乙酸乙酯 = 10:1)；以石油醚:乙酸乙酯 = 100:1~50:1为洗脱剂；${}^{1}\mathrm{H}$核磁共振(400MHz，${\mathrm{{CDCl}}}_{3}){\delta 7.55} - {7.48}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{7.32}\left( {\mathrm{\;d}, J = {8.5}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{4.51} \; \left( {\mathrm{q}, J = {7.1}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{4.21}\left( {\mathrm{\;s},2\mathrm{H}}\right) ,{1.46}\left( {\mathrm{t}, J = {7.1}\mathrm{\;{Hz}},3\mathrm{H}}\right) .{}^{13}\mathrm{C}$ 核磁共振(100MHz，CDCl3)δ163.8，160.7，146.5，132.7，132.3，130.7，122.8，62.2，41.6，14.3。红外(薄膜)2984，1730，1700，1487，1440，1310，1271，1210，1066，1012，842，780。高分辨质谱(电喷雾电离):计算值为${\mathrm{C}}_{12}{\mathrm{H}}_{12}{\mathrm{{BrN}}}_{2}{\mathrm{O}}_{2}{\mathrm{\;S}}_{2}^{ + }{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ : 358.9518；实测值:358.9512。

Ethyl5-((4-fluorobenzyl)thio)-1,2,3-thiadiazole-4- carboxylate (3e). White solid, yield ${56}\% \left( {{84}\mathrm{{mg}}}\right)$ ; mp $= {63}$ - ${64}^{ \circ }\mathrm{C};{\mathrm{R}}_{\mathrm{f}} = {0.20}$ (petroleum ether: EtOAc = 10:1); petroleum ether: EtOAc = 100:1 ~ 50:1 as eluent; 1H NMR (400 MHz, ${\mathrm{{CDCl}}}_{3})\delta$ 7.42 $\left( {\mathrm{{dd}}, J = {8.5},{5.2}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{7.06}(\mathrm{t}, J = {8.5}\mathrm{\;{Hz}}$ , $2\mathrm{H}),{4.51}\left( {\mathrm{q}, J = {7.1}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{4.24}\left( {\mathrm{\;s},2\mathrm{H}}\right) ,{1.46}(\mathrm{t}, J = {7.1}\mathrm{\;{Hz}}$ , 3H). ${}^{13}\mathrm{C}$ NMR (100 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 164.0 (d, $J = {2.1}\mathrm{\;{Hz}}$ ), 161.5,160.8,146.4,130.9 (d, $J = {8.4}\mathrm{\;{Hz}}$ ),129.4 (d, $J = {3.3}$ Hz), 116.2, 116.0, 62.2, 41.6, 14.3. ${}^{19}\mathrm{\;F}$ NMR (377 MHz, CDCl ${}_{3}$ ) δ -112.5 - -112.6 (m). IR (film) 2984,1730,1700, 1508, 1439, 1310, 1271, 1210, 1159, 1064, 1017, 842, 780. HRMS (ESI): calcd for ${\mathrm{C}}_{12}{\mathrm{H}}_{12}{\mathrm{{FN}}}_{2}{\mathrm{O}}_{2}{\mathrm{\;S}}_{2}{}^{ + }{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ : 299.0319; found: 299.0311.

5-((4-氟苄基)硫基)-1,2,3-噻二唑-4-羧酸乙酯 (3e)。白色固体，产率 ${56}\% \left( {{84}\mathrm{{mg}}}\right)$ ；熔点 $= {63}$ - ${64}^{ \circ }\mathrm{C};{\mathrm{R}}_{\mathrm{f}} = {0.20}$ (石油醚:乙酸乙酯 = 10:1)；以石油醚:乙酸乙酯 = 100:1 ~ 50:1 为洗脱剂；1H NMR (400 MHz, ${\mathrm{{CDCl}}}_{3})\delta$ 7.42 $\left( {\mathrm{{dd}}, J = {8.5},{5.2}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{7.06}(\mathrm{t}, J = {8.5}\mathrm{\;{Hz}}$ , $2\mathrm{H}),{4.51}\left( {\mathrm{q}, J = {7.1}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{4.24}\left( {\mathrm{\;s},2\mathrm{H}}\right) ,{1.46}(\mathrm{t}, J = {7.1}\mathrm{\;{Hz}}$ , 3H)。${}^{13}\mathrm{C}$ NMR (100 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 164.0 (d, $J = {2.1}\mathrm{\;{Hz}}$ )，161.5，160.8，146.4，130.9 (d, $J = {8.4}\mathrm{\;{Hz}}$ )，129.4 (d, $J = {3.3}$ Hz)，116.2，116.0，62.2，41.6，14.3。${}^{19}\mathrm{\;F}$ NMR (377 MHz, CDCl ${}_{3}$ ) δ -112.5 - -112.6 (m)。红外光谱(薄膜):2984、1730、1700、1508、1439、1310、1271、1210、1159、1064、1017、842、780。高分辨质谱(电喷雾电离):计算值 ${\mathrm{C}}_{12}{\mathrm{H}}_{12}{\mathrm{{FN}}}_{2}{\mathrm{O}}_{2}{\mathrm{\;S}}_{2}{}^{ + }{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ :299.0319；实测值:299.0311。

Ethyl 5-(allylthio)-1,2,3-thiadiazole-4-carboxylate (3f). Yellow oil, yield ${50}\% \left( {{58}\mathrm{{mg}}}\right) ;{\mathrm{R}}_{\mathrm{f}} = {0.25}$ (petroleum ether: EtOAc = 10:1); petroleum ether: EtOAc = 100:1 ~ 50:1 as eluent; ${}^{1}\mathrm{H}$ NMR (400 MHz, CDCl ${}_{3}$ ) δ 5.90 (m,1H),5.50 (dd, $J = {17.0},{0.7}\mathrm{\;{Hz}},1\mathrm{H}),{5.38}\left( {\mathrm{\;d}, J = {10.1}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{4.52}(\mathrm{q}, J = \; {7.1}\mathrm{\;{Hz}},2\mathrm{H}),{3.71}\left( {\mathrm{\;d}, J = {6.7}\mathrm{{Hz}},2\mathrm{H}}\right) ,{1.47}\left( {\mathrm{t}, J = {7.1}\mathrm{\;{Hz}},3\mathrm{H}}\right)$ . ${}^{13}\mathrm{C}$ NMR (100 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 164.3,160.8,146.7,129.9, 121.7, 62.1, 40.6, 14.4. IR (film) 2984, 1730, 1701, 1438, 1307, 1271, 1207, 1063, 1020, 930, 842. HRMS (ESI): calcd for ${\mathrm{C}}_{8}{\mathrm{H}}_{11}{\mathrm{\;N}}_{2}{\mathrm{O}}_{2}{\mathrm{\;S}}_{2}{}^{ + }{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ : 231.0256; found: 231.0254.

5-(烯丙硫基)-1,2,3-噻二唑-4-羧酸乙酯(3f)。黄色油状物，产率${50}\% \left( {{58}\mathrm{{mg}}}\right) ;{\mathrm{R}}_{\mathrm{f}} = {0.25}$(石油醚:乙酸乙酯 = 10:1)；石油醚:乙酸乙酯 = 100:1至50:1作为洗脱剂；${}^{1}\mathrm{H}$核磁共振(400兆赫，CDCl${}_{3}$)δ5.90(多重峰，1H)，5.50(双重峰，$J = {17.0},{0.7}\mathrm{\;{Hz}},1\mathrm{H}),{5.38}\left( {\mathrm{\;d}, J = {10.1}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{4.52}(\mathrm{q}, J = \; {7.1}\mathrm{\;{Hz}},2\mathrm{H}),{3.71}\left( {\mathrm{\;d}, J = {6.7}\mathrm{{Hz}},2\mathrm{H}}\right) ,{1.47}\left( {\mathrm{t}, J = {7.1}\mathrm{\;{Hz}},3\mathrm{H}}\right)$。${}^{13}\mathrm{C}$核磁共振(100兆赫，${\mathrm{{CDCl}}}_{3}$)δ164.3，160.8，146.7，129.9，121.7，62.1，40.6，14.4。红外光谱(薄膜)2984，1730，1701，1438，1307，1271，1207，1063，1020，930，842。高分辨质谱(电喷雾电离):计算值为${\mathrm{C}}_{8}{\mathrm{H}}_{11}{\mathrm{\;N}}_{2}{\mathrm{O}}_{2}{\mathrm{\;S}}_{2}{}^{ + }{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$:231.0256；实测值:231.0254。

(1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl 5-(benzylthio)- 1,2,3-thiadiazole-4-carboxylate (3g). White solid, yield 70% (136 mg); mp $= {102} - {103}^{ \circ }\mathrm{C};{\mathrm{R}}_{\mathrm{f}} = {0.30}$ (petroleum ether: EtOAc = 20:1); petroleum ether: EtOAc = 100:1 ~ 50:1 as eluent; ${}^{1}\mathrm{H}$ NMR (400 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 7.50 - 7.29 (m,5H), 5.08 – 5.01 (m, 1H), 4.25 (s, 2H), 2.23 – 2.11 (m, 1H), 2.07- ${2.00}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.80} - {1.48}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{1.23}(\mathrm{{dd}}, J = {23.2},{12.0}\mathrm{\;{Hz}}$ , 1H), 1.18-1.07 (m, 1H), 0.92 (dd, J = 10.8, 6.8 Hz, 6H), 0.80 (d, $J = {7.0}\mathrm{\;{Hz}},3\mathrm{H}).{}^{13}\mathrm{C}$ NMR (100 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 164.2, 160.4, 146.7, 133.7, 129.1, 129.1, 128.6, 76.5, 46.8, 42.4, 40.8, 34.1, 31.6, 26.2, 23.4, 22.0, 20.8, 16.3. IR (film) 2954, 2926, 2869, 1729, 1698, 1436, 1311, 1272, 1214, 1064, 980, 837, 704. HRMS (ESI): calcd for ${\mathrm{C}}_{20}{\mathrm{H}}_{27}{\mathrm{\;N}}_{2}{\mathrm{O}}_{2}{\mathrm{\;S}}_{2}{}^{ + }{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + } : {391.1508}$ ; found: 391.1502.

(1S,2R,5S)-2-异丙基-5-甲基环己基 5-(苄硫基)-1,2,3-噻二唑-4-羧酸酯(3g)。白色固体，产率 70% (136 mg)；熔点$= {102} - {103}^{ \circ }\mathrm{C};{\mathrm{R}}_{\mathrm{f}} = {0.30}$ (石油醚:乙酸乙酯 = 20:1)；以石油醚:乙酸乙酯 = 100:1 ~ 50:1 作为洗脱剂；${}^{1}\mathrm{H}$核磁共振(400 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 7.50 - 7.29 (m,5H), 5.08 – 5.01 (m, 1H), 4.25 (s, 2H), 2.23 – 2.11 (m, 1H), 2.07 - ${2.00}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.80} - {1.48}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{1.23}(\mathrm{{dd}}, J = {23.2},{12.0}\mathrm{\;{Hz}}$ , 1H), 1.18 - 1.07 (m, 1H), 0.92 (dd, J = 10.8, 6.8 Hz, 6H), 0.80 (d, $J = {7.0}\mathrm{\;{Hz}},3\mathrm{H}).{}^{13}\mathrm{C}$核磁共振(100 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 164.2, 160.4, 146.7, 133.7, 129.1, 129.1, 128.6, 76.5, 46.8, 42.4, 40.8, 34.1, 31.6, 26.2, 23.4, 22.0, 20.8, 16.3。红外(薄膜)2954, 2926, 2869, 1729, 1698, 1436, 1311, 1272, 1214, 1064, 980, 837, 704。高分辨质谱(电喷雾电离):计算值为${\mathrm{C}}_{20}{\mathrm{H}}_{27}{\mathrm{\;N}}_{2}{\mathrm{O}}_{2}{\mathrm{\;S}}_{2}{}^{ + }{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + } : {391.1508}$ ；实测值:391.1502。

1-(5-(Benzylthio)-1,2,3-thiadiazol-4-yl)ethan-1-one (3h). Yellow solid, yield ${64}\% \left( {{80}\mathrm{{mg}}}\right) ;\mathrm{{mp}} = {100} - {101}^{ \circ }\mathrm{C};{\mathrm{R}}_{\mathrm{f}} = {0.20}$ (petroleum ether: EtOAc = 20:1); petroleum ether: EtOAc = 100:1 as eluent; ${}^{1}\mathrm{H}$ NMR (400 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 7.39 m,5H), 4.23 (s, 2H), 2.85 (s, 3H). ${}^{13}\mathrm{C}$ NMR (100 MHz, CDC1 ${}_{3}$ ) δ 192.4, 164.1, 154.0, 133.6, 129.2, 129.1, 128.6, 42.8, 28.8. IR (film) 3063, 3032, 2915, 1672, 1413, 1273, 1175, 1066, 910, 790,705,604. HRMS (ESI): calcd for ${\mathrm{C}}_{11}{\mathrm{H}}_{11}{\mathrm{\;N}}_{2}{\mathrm{{OS}}}_{2}{}^{ + }{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ : 251.0307; found: 251.0308.

1-(5-(苄硫基)-1,2,3-噻二唑-4-基)乙-1-酮(3h)。黄色固体，产率${64}\% \left( {{80}\mathrm{{mg}}}\right) ;\mathrm{{mp}} = {100} - {101}^{ \circ }\mathrm{C};{\mathrm{R}}_{\mathrm{f}} = {0.20}$(石油醚:乙酸乙酯 = 20:1)；以石油醚:乙酸乙酯 = 100:1为洗脱剂；${}^{1}\mathrm{H}$核磁共振(400兆赫，${\mathrm{{CDCl}}}_{3}$)δ7.39(多重峰，5H)，4.23(单峰，2H)，2.85(单峰，3H)。${}^{13}\mathrm{C}$核磁共振(100兆赫，CDCl${}_{3}$)δ192.4，164.1，154.0，133.6，129.2，129.1，128.6，42.8，28.8。红外光谱(薄膜)3063，3032，2915，1672，1413，1273，1175，1066，910，790，705，604。高分辨质谱(电喷雾电离):计算值为${\mathrm{C}}_{11}{\mathrm{H}}_{11}{\mathrm{\;N}}_{2}{\mathrm{{OS}}}_{2}{}^{ + }{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$:251.0307；实测值:251.0308。

1-(5-(Benzylthio)-1,2,3-thiadiazol-4-yl)-4-methylpentan-1- one (3i). Yellow oil, yield ${62}\% \left( {{95}\mathrm{{mg}}}\right) ;{\mathrm{R}}_{\mathrm{f}} = {0.20}$ (petroleum ether: EtOAc = 40:1); petroleum ether: EtOAc = 100:1 as eluent; ${}^{1}\mathrm{H}$ NMR (400 MHz, CDC ${\mathrm{l}}_{3}$ ) δ 7.48 - 7.28 (m,5H),4.23 $\left( {\mathrm{s},2\mathrm{H}}\right) ,{3.28}\left( {\mathrm{t}, J = {7.2}\mathrm{\;{Hz}}2\mathrm{H}}\right) ,{1.68}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{0.95}(\mathrm{\;d}, J = {6.4}$ Hz, 6H). ${}^{13}\mathrm{C}$ NMR (100 MHz, CDCl ${}_{3}$ ) δ 195.4, 164.0, 153.7, 133.7, 129.2, 129.0, 128.6, 42.7, 39.3, 32.9, 27.8, 22.4. IR

1-(5-(苄硫基)-1,2,3-噻二唑-4-基)-4-甲基戊-1-酮(3i)。黄色油状物，产率${62}\% \left( {{95}\mathrm{{mg}}}\right) ;{\mathrm{R}}_{\mathrm{f}} = {0.20}$(石油醚:乙酸乙酯 = 40:1)；以石油醚:乙酸乙酯 = 100:1为洗脱剂；${}^{1}\mathrm{H}$核磁共振(400兆赫，CDC${\mathrm{l}}_{3}$)δ7.48 - 7.28(多重峰，5H)，4.23$\left( {\mathrm{s},2\mathrm{H}}\right) ,{3.28}\left( {\mathrm{t}, J = {7.2}\mathrm{\;{Hz}}2\mathrm{H}}\right) ,{1.68}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{0.95}(\mathrm{\;d}, J = {6.4}$赫兹，6H)。${}^{13}\mathrm{C}$核磁共振(100兆赫，CDCl${}_{3}$)δ195.4，164.0，153.7，133.7，129.2，129.0，128.6，42.7，39.3，32.9，27.8，22.4。红外光谱(film) 2954, 2927, 2867, 1669, 1495, 1414, 1271, 1139, 1112, 1044,1026,908,703. HRMS (ESI): calcd. ${\mathrm{C}}_{15}{\mathrm{H}}_{18}{\mathrm{\;N}}_{2}{\mathrm{{NaOS}}}_{2} \; {\left\lbrack \mathrm{M} + \mathrm{{Na}}\right\rbrack }^{ + } : {329.0753}$ . Found: 329.0753.

(5-(Benzylthio)-1,2,3-thiadiazol-4-

yl)(morpholino)methanone (3j). White solid, yield 47% (75 mg); mp = 96-97°C; ${\mathrm{R}}_{\mathrm{f}} = {0.50}$ (petroleum ether: EtOAc = 1:1); petroleum ether: EtOAc $= {10} : 1 \sim 5 : 1$ as eluent; ${}^{1}\mathrm{H}$ NMR (400 MHz, CDCl ${}_{3}$ ) 6 7.45 - 7.29 (m, 5H), 4.23 (s, 2H), 4.08 (s, 2H), ${3.79}\left( {\mathrm{\;m}, J = {25.0}\mathrm{\;{Hz}},6\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ NMR $\left( {{100}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 162.6, 160.2, 150.1, 134.2, 129.2, 129.0, 128.5, 67.2, 66.9, 48.0, 43.3, 42.2. IR (film) 2964, 2913, 2859, 1616, 1472, 1443, 1302, 1269, 1218, 1114, 1076, 1030, 968, 705. HRMS (ESI): calcd for ${\mathrm{C}}_{14}{\mathrm{H}}_{16}{\mathrm{\;N}}_{3}{\mathrm{O}}_{2}{\mathrm{\;S}}_{2}^{ + }{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + } : {322.0678}$ ; found: 322.0671.

(5-(Benzylthio)-1,2,3-thiadiazol-4-yl)(pyrrolidin-1-

yl)methanone (3k). White solid, yield 39% (60mg); mp = 124- ${125}^{ \circ }\mathrm{C};{\mathrm{R}}_{\mathrm{f}} = {0.60}$ (petroleum ether: EtOAc = 1:1); petroleum ether: EtOAc = 10:1 ~ 5:1 as eluent; 1H NMR (400 MHz, ${\mathrm{{CDCl}}}_{3})\delta$ 7.43 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{7.38} - {7.28}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{4.21}\left( {\mathrm{\;s},2\mathrm{H}}\right) ,{4.02} \; \left( {\mathrm{t}, J = {6.6}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{3.72}\left( {\mathrm{t}, J = {6.7}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{2.08} - {1.85}(\mathrm{\;m}$ , 4H). ${}^{13}\mathrm{C}$ NMR (100 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 163.0,159.8,150.6,134.3, 129.2, 128.9, 128.3, 49.4, 47.2, 42.3, 26.6, 23.9. IR (film) 2970, 2875, 1610, 1468, 1454, 1374, 1256, 1079, 843, 710. HRMS (ESI): calcd for ${\mathrm{C}}_{14}{\mathrm{H}}_{16}{\mathrm{\;N}}_{3}{\mathrm{{OS}}}_{2}^{ + }{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ : 306.0729; found: 306.0729.

ASSOCIATED CONTENT

相关内容

Supporting Information

支持信息

Preparation of substrates, NMR spectra, and X-ray single crystal structure of compound $3\mathbf{g}$ .

底物的制备、核磁共振谱以及化合物$3\mathbf{g}$的X射线单晶结构。

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Notes

注释

The authors declare no competing financial interest.

作者声明不存在相互竞争的财务利益。

ACKNOWLEDGMENT

致谢

The project was supported by the Natural Science Foundation of China (Grants 21502003 and 21772003). We also thank the “1000-Youth Talents Plan”, Peking University for start-up funds.

The project was supported by the Natural Science Foundation of China (Grants 21502003 and 21772003). We also thank the “1000-Youth Talents Plan”, Peking University for start-up funds.

REFERENCES

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