Scalable Preparation of 4，4－Disubstituted Six－Membered Cyclic Sulfones
4,4-二取代的六元环状砜的可扩展制备

ABSTRACT：We provide an account of synthetic strategies aimed at the efficient preparation of 4 －amino－4－methyltetrahydro－2H－thiopyran 1，1－dioxide（3），an important cyclic sulfone building block for medicinal chemistry．A practical and scalable protocol has been developed that readily gives access to the title compound from commercially available and inexpensive starting materials．In addition，this novel approach has enabled the synthesis of various related 4，4－ disubstituted cyclic sulfone derivatives that serve as valuable structural motifs for drug discovery．
摘要：我们介绍了旨在有效制备 4-氨基-4-甲基四氢-2H-硫代吡喃 1,1-二氧化物 （3） 的合成策略，这是一种重要的药物化学环砜构建单元.已经开发了一种实用且可扩展的方案，可以很容易地从市售且廉价的起始 materials.In 添加中获得标题化合物，这种新方法使各种相关的 4,4-二取代环砜的合成成为可能衍生物，可作为药物发现的有价值的结构基序。

Sulfones have found extensive applications as versatile building blocks in organic synthesis ${}^1$${}^1$^(1){ }^{1} and in the field of medicinal chemistry．${}^2$${}^2$^(2){ }^{2} Acting as ligands in a protein environ－ ment，sulfonyl groups frequently exhibit a dual character， functioning simultaneously as hydrogen bond acceptors as well as interacting with hydrophobic groups．${}^{2b}$${}^{2b}$^(2b){ }^{2 b} The unique properties of these polar，metabolically stable groups thus renders their incorporation especially attractive in pharma－ ceuticals．${}^3$${}^3$^(3){ }^{3} In some cases，conformationally restrained cyclic sulfones have been discovered to be particularly beneficial in enhancing binding to the biological targets，${}^4$${}^4$^(4){ }^{4} leading to diverse drug candidates containing this substructure being reported （Figure 1）．＇In particular，six－membered aliphatic sulfones are frequently explored as bioisosteres of tetrahydropyran and
砜类作为有机合成 ${}^1$${}^1$^(1){ }^{1} 和药物化学领域的多功能结构单元已得到广泛应用。 ${}^2$${}^2$^(2){ }^{2} 磺酰基在蛋白质环境中充当配体，经常表现出双重特性，同时作为氢键受体发挥作用，并与疏水基团相互作用。 ${}^{2b}$${}^{2b}$^(2b){ }^{2 b} 因此，这些极性、代谢稳定的基团的独特性质使其在制药中特别有吸引力。 ${}^3$${}^3$^(3){ }^{3} 在某些情况下，已发现构象抑制的环砜在增强与生物靶标的结合方面特别有益， ${}^4$${}^4$^(4){ }^{4} 导致报道了包含该亚结构的各种候选药物（图 1）。特别是，六元脂肪族砜经常作为生物等排体进行探索的四氢吡喃和

Figure 1．Importance of six－membered aliphatic sulfones in medicinal chemistry．
图 1.六元脂肪族砜在药物化学中的重要性。
piperidine derivatives due to their highly favorable pharmaco－ kinetic profiles．${}^6$${}^6$^(6){ }^{6}
哌啶衍生物，因为它们具有非常有利的药代动力学特征。 ${}^6$${}^6$^(6){ }^{6}
In an effort to enable preclinical toxicological studies in a medicinal chemistry project，we required facile and large－scale access to amides with an appended six－membered cyclic sulfone of the general structure 1 （Figure 2A）．A literature survey revealed that this moiety is commonly introduced via amide formation of a carboxylic acid with amino sulfide 2 ， followed by oxidation of the thioether functionality to the sulfone．For our purposes，this two－step approach was deemed unsuitable due to the sulfide oxidation not being tolerated by other incorporated functional groups as well as the high cost of 2．We instead were attracted to employ the more oxidized analogue，amino sulfone 3 （Figure 2B），in the amide－coupling step．Besides gaining access to 1 with increased synthetic efficiency，we importantly would avoid the problematic late－ stage oxidation．To the best of our knowledge，no synthesis of 3 has been reported in the literature，and due to limited commercial availability（at a prohibitive cost），sufficient quantities of this key building block could not be acquired in the short term．As such，we strove to develop a practical， efficient，and scalable protocol that would readily give access to decagram quantities of 3 ．Following consideration of various retrosyntheses，and assessing the availability of the respective starting materials within a short timeline，we prioritized ronte scouting efforts utilizing ketone 4 ，amine 5 ，sulfide 6 ，and
为了在药物化学项目中进行临床前毒理学研究，我们需要简单和大规模地获得酰胺，并附加了一般结构 1 的六元环砜（图 2A）.文献调查显示，该部分通常是通过羧酸与氨基硫化物 2 形成酰胺引入的，然后硫醚官能团氧化成砜.就我们的目的而言，这种两步方法被认为不合适，因为其他掺入的官能团不能容忍硫化物氧化以及 2 的高成本.相反，我们被吸引在酰胺偶联步骤中使用氧化程度更高的类似物氨基砜 3（图 2B）.除了获得提高合成效率的 1 外，我们还将重要地避免有问题的后期 oxidation.To 据我们所知，文献中没有 3 的合成报道，并且由于商业可用性有限（在成本高昂 term.As），因此，我们努力开发一种实用、高效且可扩展的方案，该方案将很容易获得 3 的十克量。在考虑了各种逆合成，并在短时间内评估了相应起始材料的可用性，我们优先考虑利用酮 4 、胺 5 、硫化物 6 和

Reseived：December 15， 2020 Published：January 8， 2021
发布日期：2020 年 12 月 15 日 发布日期：2021 年 1 月 8 日

A）Reported synthetic route to cyclic sulfone amides 1
A） 已报道的环砜酰胺合成路线 1

B）Route scouting to $\mathbf{3}$$\mathbf{3}$3\mathbf{3} from readily available precursors（this work）
B） $\mathbf{3}$$\mathbf{3}$3\mathbf{3} 从现成的前体进行路线侦察（这项工作）

Figure 2．Retrosynthesis of amino sulfone 3.
图 2.氨基砜的逆合成 3.
divinyl sulfone 7 as viable，low－cost precursors．${}^8$${}^8$^(8){ }^{8} Herein，we summarize the exploration of various synthetic strategies including classical imine chemistry，$\alpha -\mathrm{C}-\mathrm{H}$$\alpha -\mathrm{C}-\mathrm{H}$alpha-C-H\alpha-\mathrm{C}-\mathrm{H} functionalization， Ritter reaction，and nitroalkane－Michael addition to ultimately establish an efficient and practical preparation of 3.
二乙烯基砜 7 作为可行的、低成本的前体。 ${}^8$${}^8$^(8){ }^{8} 在本文中，我们总结了包括经典亚胺化学、 $\alpha -\mathrm{C}-\mathrm{H}$$\alpha -\mathrm{C}-\mathrm{H}$alpha-C-H\alpha-\mathrm{C}-\mathrm{H} 官能团化、Ritter 反应和硝基烷烃-Michael 加成在内的各种合成策略的探索，最终建立了一种高效实用的 3 制备方法。

In an early synthetic undertaking，we envisioned that the high oxidation state of readily available precursor ketone 4 could be leveraged for developing a concise route to amino sulfone 3．Along these lines，we foresaw conversion of 4 to an imine，followed by nucleophilic 1，2－addition and deprotection of the resulting secondary amine derivative（Scheme 1）．In
在早期的合成工作中，我们设想了可以利用易得的前体酮 4 的高氧化态来开发一条通往氨基砜 3 的简洁路线.沿着这些思路，我们预见了 4 转化为亚胺，然后是亲核的 1,2-加成和所得仲胺衍生物的脱保护（方案 1）。

Scheme 1．Attempted Synthesis of Imine $8^a$$8^a$8^(a)8^{a}
方案 1.尝试合成亚胺 $8^a$$8^a$8^(a)8^{a}

${}^{\text{a}}$${}^{\text{a }}$^("a "){ }^{\text {a }} Selected condensation conditions investigated：toluene， ${110}^{\circ }\mathrm{C};4\mathrm{A}$${110}^{\circ }\mathrm{C};4\mathrm{A}$110^(@)C;4A110^{\circ} \mathrm{C} ; 4 \mathrm{~A} molecular sieves； $\mathrm{Ti}(\mathrm{OEt}{)}_4;{\mathrm{MgSO}}_4$$\mathrm{Ti}(\mathrm{OEt}{)}_4;{\mathrm{MgSO}}_4$Ti(OEt)_(4);MgSO_(4)\mathrm{Ti}(\mathrm{OEt})_{4} ; \mathrm{MgSO}_{4} ．
${}^{\text{a}}$${}^{\text{a }}$^("a "){ }^{\text {a }} 研究的选定冷凝条件：甲苯、 ${110}^{\circ }\mathrm{C};4\mathrm{A}$${110}^{\circ }\mathrm{C};4\mathrm{A}$110^(@)C;4A110^{\circ} \mathrm{C} ; 4 \mathrm{~A} 分子筛; $\mathrm{Ti}(\mathrm{OEt}{)}_4;{\mathrm{MgSO}}_4$$\mathrm{Ti}(\mathrm{OEt}{)}_4;{\mathrm{MgSO}}_4$Ti(OEt)_(4);MgSO_(4)\mathrm{Ti}(\mathrm{OEt})_{4} ; \mathrm{MgSO}_{4} .
practice，execution of this straightforward plan proved unexpectedly problematic：Condensation of ketone 4 with benzylamine or classical sulfinamides ${}^{10}$${}^{10}$^(10){ }^{10} under a variety of thermal or Lewis acid promoted conditions failed to provide imines of type 8，and instead，we observed formation of complex product mixtures．To avoid isolation of the supposedly unstable intermediate 8，telescoping the reaction mixture from the imine condensation with the ensuing organometal addition $({\mathrm{CH}}_3\mathrm{MgBr}$$\left({\mathrm{CH}}_3\mathrm{MgBr}\right.$(CH_(3)MgBr:}\left(\mathrm{CH}_{3} \mathrm{MgBr}\right. or ${\mathrm{CH}}_3\mathrm{Li})$$\left.{\mathrm{CH}}_3\mathrm{Li}\right)${:CH_(3)Li)\left.\mathrm{CH}_{3} \mathrm{Li}\right) to give 9 was also investigated，yet these attempts remained equally unsuccessful．
实践中，这个简单的计划的执行被证明是出乎意料的问题：酮 4 与苄胺或经典亚磺酰胺 ${}^{10}$${}^{10}$^(10){ }^{10} 在各种热或路易斯酸促进条件下的缩合未能提供 8 型亚胺，相反，我们观察到复合物产物的形成 mixtures.To 以避免分离据称不稳定的中间体 8，从亚胺缩合中伸缩反应混合物，随后添加 $({\mathrm{CH}}_3\mathrm{MgBr}$$\left({\mathrm{CH}}_3\mathrm{MgBr}\right.$(CH_(3)MgBr:}\left(\mathrm{CH}_{3} \mathrm{MgBr}\right. 有机金属或 ${\mathrm{CH}}_3\mathrm{Li})$$\left.{\mathrm{CH}}_3\mathrm{Li}\right)${:CH_(3)Li)\left.\mathrm{CH}_{3} \mathrm{Li}\right) 还调查了 To Give 9，但这些尝试同样没有成功。

In parallel to the attempted route outlined in Scheme 1，we were drawn to a distinct approach involving conversion of commercially available amine $5^{11}$$5^{11}$5^(11)5^{11} to the title $\alpha$$\alpha$alpha\alpha－tertiary amine 3 by introduction of the requisite methyl group via a formal $\alpha -$$\alpha -$alpha-\alpha- $\mathrm{C}-\mathrm{H}$$\mathrm{C}-\mathrm{H}$C-H\mathrm{C}-\mathrm{H} functionalization（Scheme 2）．In this respect，modified
与方案 1 中概述的尝试路线并行，我们被一种独特的方法所吸引，该方法涉及通过正式 $\alpha -$$\alpha -$alpha-\alpha- $\mathrm{C}-\mathrm{H}$$\mathrm{C}-\mathrm{H}$C-H\mathrm{C}-\mathrm{H} 官能化引入必要的甲基，将市售胺 $5^{11}$$5^{11}$5^(11)5^{11} 转化为叔 $\alpha$$\alpha$alpha\alpha 胺 3（方案 2）。

Scheme 2． $\mathit{\alpha }$$\mathit{\alpha }$alpha\boldsymbol{\alpha}－ $\mathrm{C}-\mathbf{H}$$\mathrm{C}-\mathbf{H}$C-H\mathrm{C}-\mathbf{H} Functionalization Approach ${}^{\mathit{\prime }}$${}^{\mathit{\prime }}$^('){ }^{\boldsymbol{\prime}}
方案 2. $\mathit{\alpha }$$\mathit{\alpha }$alpha\boldsymbol{\alpha} - $\mathrm{C}-\mathbf{H}$$\mathrm{C}-\mathbf{H}$C-H\mathrm{C}-\mathbf{H} 功能化方法 ${}^{\mathit{\prime }}$${}^{\mathit{\prime }}$^('){ }^{\boldsymbol{\prime}}

${}^a$${}^a$^(a){ }^{a} Reagents and conditions：（a） $10,1,2$$10,1,2$10,1,210,1,2－dichloroethane， ${23}^{\circ }\mathrm{C}$${23}^{\circ }\mathrm{C}$23^(@)C23^{\circ} \mathrm{C} ；（b） ${\mathrm{CH}}_3\mathrm{Li},\mathrm{N},\mathrm{N},\mathrm{N},\mathrm{N}$${\mathrm{CH}}_3\mathrm{Li},\mathrm{N},\mathrm{N},\mathrm{N},\mathrm{N}$CH_(3)Li,N,N,N,N\mathrm{CH}_{3} \mathrm{Li}, \mathrm{N}, \mathrm{N}, \mathrm{N}, \mathrm{N}－tetramethylethyldiamine，toluene， ${\mathrm{Et}}_2\mathrm{O},-78$${\mathrm{Et}}_2\mathrm{O},-78$Et_(2)O,-78\mathrm{Et}_{2} \mathrm{O},-78 to 23 ${}^{\circ }\mathrm{C}$${}^{\circ }\mathrm{C}$^(@)C{ }^{\circ} \mathrm{C}（ $43\mathrm{\%}$$43\mathrm{\%}$43%43 \% ，two steps）；（c） ${\mathrm{H}}_5{\mathrm{IO}}_6,{\mathrm{CH}}_3\mathrm{CN},{\mathrm{H}}_2\mathrm{O},0^{\circ }\mathrm{C}$${\mathrm{H}}_5{\mathrm{IO}}_6,{\mathrm{CH}}_3\mathrm{CN},{\mathrm{H}}_2\mathrm{O},0^{\circ }\mathrm{C}$H_(5)IO_(6),CH_(3)CN,H_(2)O,0^(@)C\mathrm{H}_{5} \mathrm{IO}_{6}, \mathrm{CH}_{3} \mathrm{CN}, \mathrm{H}_{2} \mathrm{O}, 0^{\circ} \mathrm{C} ；（d）acid－base extraction（71\％）．
${}^a$${}^a$^(a){ }^{a} 试剂和条件：（a） $10,1,2$$10,1,2$10,1,210,1,2 -二氯乙烷， ${23}^{\circ }\mathrm{C}$${23}^{\circ }\mathrm{C}$23^(@)C23^{\circ} \mathrm{C} ;(b） ${\mathrm{CH}}_3\mathrm{Li},\mathrm{N},\mathrm{N},\mathrm{N},\mathrm{N}$${\mathrm{CH}}_3\mathrm{Li},\mathrm{N},\mathrm{N},\mathrm{N},\mathrm{N}$CH_(3)Li,N,N,N,N\mathrm{CH}_{3} \mathrm{Li}, \mathrm{N}, \mathrm{N}, \mathrm{N}, \mathrm{N} -四甲基乙基二胺，甲苯， ${\mathrm{Et}}_2\mathrm{O},-78$${\mathrm{Et}}_2\mathrm{O},-78$Et_(2)O,-78\mathrm{Et}_{2} \mathrm{O},-78 至 23 ${}^{\circ }\mathrm{C}$${}^{\circ }\mathrm{C}$^(@)C{ }^{\circ} \mathrm{C} （ $43\mathrm{\%}$$43\mathrm{\%}$43%43 \% ，两步）;(c） ${\mathrm{H}}_5{\mathrm{IO}}_6,{\mathrm{CH}}_3\mathrm{CN},{\mathrm{H}}_2\mathrm{O},0^{\circ }\mathrm{C}$${\mathrm{H}}_5{\mathrm{IO}}_6,{\mathrm{CH}}_3\mathrm{CN},{\mathrm{H}}_2\mathrm{O},0^{\circ }\mathrm{C}$H_(5)IO_(6),CH_(3)CN,H_(2)O,0^(@)C\mathrm{H}_{5} \mathrm{IO}_{6}, \mathrm{CH}_{3} \mathrm{CN}, \mathrm{H}_{2} \mathrm{O}, 0^{\circ} \mathrm{C} ;(d)酸碱萃取 （71\%）。
conditions of Corey＇s seminal and bioinspired protocol for generation of ketimines were investigated．${}^{12}$${}^{12}$^(12){ }^{12} In the first step， amine 5 underwent quinone－mediated oxidation to afford intermediate ketimine 11 as a result of condensation followed by an in situ［1，5］H－shift．Subsequent addition of methyllithium then furnished amine 12．We found orthoperi－ odic acid to be superior to reported oxidative hydrolytic workup conditions ${({\mathrm{I}}_2,\text{aq}\mathrm{NaOH})}^{12\mathrm{d}}$${\left({\mathrm{I}}_2,\text{ aq }\mathrm{NaOH}\right)}^{12\mathrm{d}}$(I_(2)," aq "NaOH)^(12d)\left(\mathrm{I}_{2}, \text { aq } \mathrm{NaOH}\right)^{12 \mathrm{~d}} for detaching the hydroxyarene and，following an acid－base extraction，enabling clean isolation of amino sulfone 3．Although this outlined synthetic route to 3 is concise，it proved problematic for scale－ up due to the necessity for a large excess of methyllithium（ 6 equiv）in the conversion of 11 to 12 and the poor solubility of starting amine 5 ．Furthermore，the high price of 5 compared less favorably to the other precursors（Figure 2B）．
研究了 Corey 的开创性和生物启发方案中用于生成酮胺的条件。 ${}^{12}$${}^{12}$^(12){ }^{12} 在第一步中，胺 5 经过醌介导的氧化，由于缩合，然后是原位[1,5]H-shift.随后添加甲基锂，然后提供胺 12.我们发现邻周酸优于已报道的氧化水解检查条件 ${({\mathrm{I}}_2,\text{aq}\mathrm{NaOH})}^{12\mathrm{d}}$${\left({\mathrm{I}}_2,\text{ aq }\mathrm{NaOH}\right)}^{12\mathrm{d}}$(I_(2)," aq "NaOH)^(12d)\left(\mathrm{I}_{2}, \text { aq } \mathrm{NaOH}\right)^{12 \mathrm{~d}} 用于分离羟基芳烃，并在酸碱萃取后实现氨基砜 3 的清洁分离.虽然这种概述的 3 合成路线简洁明了，但由于在 11 到 12 的转化中必须大量过量的甲基锂（6 当量）和起始胺 5 的溶解度差，因此证明在放大方面存在问题.此外，5 的高价格与其他前驱体相比较差（图 2B）。
At this stage we returned to a strategy involving imine chemistry and it was envisioned that utilizing sulfide 6 ，rather than the more oxidized analogue 4 （Figure 2B），might render the corresponding imine formation feasible and obviate the putative interference of the sulfone functionality in this step （Scheme 3，left）．Indeed，titanium（IV）ethoxide successfully promoted condensation of 2－methyl－2－propanesulfinamide with 6 to give imine 14，albeit in moderate yield due to the instability of this intermediate．${}^{13}$${}^{13}$^(13){ }^{13} After methylmagnesium bromide addition to 14 furnished 15，we explored installation of the sulfone．Using $m$$m$mm－CPBA or Oxone，we encountered concomitant oxidation of the sulfinamide moiety，affording the corresponding sulfone－sulfonamide product．Cleavage of the $\mathrm{N}-\mathrm{S}$$\mathrm{N}-\mathrm{S}$N-S\mathrm{N}-\mathrm{S} bond in this sterically encumbered sulfonamide required harsh conditions（trifluoromethanesulfonic acid， ${23}^{\circ }\mathrm{C},4\mathrm{h}$${23}^{\circ }\mathrm{C},4\mathrm{h}$23^(@)C,4h23^{\circ} \mathrm{C}, 4 \mathrm{~h} ） and resulted in a very low yield（ $<5\mathrm{\%}$$<5\mathrm{\%}$< 5%<5 \% ）of amino sulfone 3. Therefore，we resorted to first convert 15 to carbamate 16， which cleanly underwent oxidation to afford the corresponding sulfone．Finally，treatment of this intermediate with hydro－ chloric acid unveiled the $\alpha$$\alpha$alpha\alpha－tertiary amine and，after filtration， provided spectroscopically pure amino sulfone salt $(3\cdot \mathrm{HCl})$$(3\cdot \mathrm{HCl})$(3*HCl)(3 \cdot \mathrm{HCl}) ． The outlined synthetic approach proved scalable and later allowed preparation of $>350\mathrm{g}$$>350\mathrm{g}$> 350g>350 \mathrm{~g} of $3\cdot \mathrm{HCl}$$3\cdot \mathrm{HCl}$3*HCl3 \cdot \mathrm{HCl} ．While serviceable，the instability of the intermediate imine 14 was a clear drawback in
在这个阶段，我们回到了涉及亚胺化学的策略，并设想使用硫化物 6 而不是更氧化的类似物 4（图 2B），可能会使相应的亚胺形成变得可行，并消除此步骤中砜官能团的假定干扰（方案 3，左）.事实上，钛 （IV） 乙氧化物成功地促进了 2-甲基-2-丙亚胺与 6 的缩合，得到亚胺 14，尽管由于它的不稳定性，产率适中中间体。 ${}^{13}$${}^{13}$^(13){ }^{13} 在甲基溴化镁加入 14 后 15，我们探索了砜类的安装.使用 $m$$m$mm -CPBA 或 Oxone，我们遇到了亚磺酰胺部分的伴随氧化，得到了相应的砜磺酰胺产品.这种空间位阻磺酰胺中的 $\mathrm{N}-\mathrm{S}$$\mathrm{N}-\mathrm{S}$N-S\mathrm{N}-\mathrm{S} 键裂解需要苛刻的条件（三氟甲磺酸， ${23}^{\circ }\mathrm{C},4\mathrm{h}$${23}^{\circ }\mathrm{C},4\mathrm{h}$23^(@)C,4h23^{\circ} \mathrm{C}, 4 \mathrm{~h} ），并导致非常低的产率（ $<5\mathrm{\%}$$<5\mathrm{\%}$< 5%<5 \% ）氨基砜 3.因此，我们首先将 15 转化为氨基甲酸酯 16，氨基甲酸酯 16 经过氧化，得到相应的砜，最后，用盐酸处理该中间体，露出 $\alpha$$\alpha$alpha\alpha 叔胺，过滤后得到光谱纯的氨基砜盐 $(3\cdot \mathrm{HCl})$$(3\cdot \mathrm{HCl})$(3*HCl)(3 \cdot \mathrm{HCl}) 。概述的合成方法被证明是可扩展的，后来允许制备 $>350\mathrm{g}$$>350\mathrm{g}$> 350g>350 \mathrm{~g} $3\cdot \mathrm{HCl}$$3\cdot \mathrm{HCl}$3*HCl3 \cdot \mathrm{HCl} .虽然可以使用，但中间 imine 14 的不稳定性是一个明显的缺点

${}^a$${}^a$^(a){ }^{a} Reagents and conditions：（a）$t\mathrm{BuS}(\mathrm{O}){\mathrm{NH}}_2,\mathrm{Ti}(\mathrm{OEt}{)}_4,\mathrm{THF},{70}^{\circ }\mathrm{C}$$t\mathrm{BuS}(\mathrm{O}){\mathrm{NH}}_2,\mathrm{Ti}(\mathrm{OEt}{)}_4,\mathrm{THF},{70}^{\circ }\mathrm{C}$tBuS(O)NH_(2),Ti(OEt)_(4),THF,70^(@)Ct \mathrm{BuS}(\mathrm{O}) \mathrm{NH}_{2}, \mathrm{Ti}(\mathrm{OEt})_{4}, \mathrm{THF}, 70^{\circ} \mathrm{C} （ $52\mathrm{\%}$$52\mathrm{\%}$52%52 \% ）；（b） ${\mathrm{CH}}_3\mathrm{MgBr}$${\mathrm{CH}}_3\mathrm{MgBr}$CH_(3)MgBr\mathrm{CH}_{3} \mathrm{MgBr} ，THF， $0^{\circ }\mathrm{C}(36\mathrm{\%})$$0^{\circ }\mathrm{C}(36\mathrm{\%})$0^(@)C(36%)0^{\circ} \mathrm{C}(36 \%) ；（c） $4\mathrm{M}\mathrm{HCl},\mathrm{EtOAc},20$$4\mathrm{M}\mathrm{HCl},\mathrm{EtOAc},20$4MHCl,EtOAc,204 \mathrm{M} \mathrm{HCl}, \mathrm{EtOAc}, 20 ${}^{\circ }\mathrm{C}(85\mathrm{\%})$${}^{\circ }\mathrm{C}(85\mathrm{\%})$^(@)C(85%){ }^{\circ} \mathrm{C}(85 \%) ；（d）（ Boc${)}_2\mathrm{O},{\mathrm{NEt}}_3,{\mathrm{CH}}_2{\mathrm{Cl}}_2,{50}^{\circ }\mathrm{C}(95\mathrm{\%})$${)}_2\mathrm{O},{\mathrm{NEt}}_3,{\mathrm{CH}}_2{\mathrm{Cl}}_2,{50}^{\circ }\mathrm{C}(95\mathrm{\%})$)_(2)O,NEt_(3),CH_(2)Cl_(2),50^(@)C(95%))_{2} \mathrm{O}, \mathrm{NEt}_{3}, \mathrm{CH}_{2} \mathrm{Cl}_{2}, 50^{\circ} \mathrm{C}(95 \%) ；（e）oxone， ${\mathrm{NaHCO}}_3,{\mathrm{CH}}_3\mathrm{CN},{\mathrm{H}}_2\mathrm{O},0$${\mathrm{NaHCO}}_3,{\mathrm{CH}}_3\mathrm{CN},{\mathrm{H}}_2\mathrm{O},0$NaHCO_(3),CH_(3)CN,H_(2)O,0\mathrm{NaHCO}_{3}, \mathrm{CH}_{3} \mathrm{CN}, \mathrm{H}_{2} \mathrm{O}, 0 to ${20}^{\circ }\mathrm{C}(75\mathrm{\%})$${20}^{\circ }\mathrm{C}(75\mathrm{\%})$20^(@)C(75%)20^{\circ} \mathrm{C}(75 \%) ；（f） $4\mathrm{M}\mathrm{HCl},1,4-$$4\mathrm{M}\mathrm{HCl},1,4-$4MHCl,1,4-4 \mathrm{M} \mathrm{HCl}, 1,4- dioxane， 0 to ${20}^{\circ }\mathrm{C}(96\mathrm{\%})$${20}^{\circ }\mathrm{C}(96\mathrm{\%})$20^(@)C(96%)20^{\circ} \mathrm{C}(96 \%) ；（g） ${\mathrm{CH}}_3\mathrm{Li}$${\mathrm{CH}}_3\mathrm{Li}$CH_(3)Li\mathrm{CH}_{3} \mathrm{Li} ，THF，$-{78}^{\circ }\mathrm{C}(90\mathrm{\%})$$-{78}^{\circ }\mathrm{C}(90\mathrm{\%})$-78^(@)C(90%)-78^{\circ} \mathrm{C}(90 \%) ；（h） ${\mathrm{ClCH}}_2\mathrm{CN},{\mathrm{H}}_2{\mathrm{SO}}_4,\mathrm{AcOH},{\mathrm{CH}}_2{\mathrm{Cl}}_{2}0$${\mathrm{ClCH}}_2\mathrm{CN},{\mathrm{H}}_2{\mathrm{SO}}_4,\mathrm{AcOH},{\mathrm{CH}}_2{\mathrm{Cl}}_{2}0$ClCH_(2)CN,H_(2)SO_(4),AcOH,CH_(2)Cl_(2)0\mathrm{ClCH}_{2} \mathrm{CN}, \mathrm{H}_{2} \mathrm{SO}_{4}, \mathrm{AcOH}, \mathrm{CH}_{2} \mathrm{Cl}_{2} 0 to ${20}^{\circ }\mathrm{C}(62\mathrm{\%})$${20}^{\circ }\mathrm{C}(62\mathrm{\%})$20^(@)C(62%)20^{\circ} \mathrm{C}(62 \%) ；（i）thiourea， $\mathrm{AcOH},\mathrm{EtOH},{80}^{\circ }\mathrm{C}$$\mathrm{AcOH},\mathrm{EtOH},{80}^{\circ }\mathrm{C}$AcOH,EtOH,80^(@)C\mathrm{AcOH}, \mathrm{EtOH}, 80^{\circ} \mathrm{C} ；（j）（Boc）${}_2\mathrm{O},2\mathrm{M}$${}_2\mathrm{O},2\mathrm{M}$_(2)O,2M{ }_{2} \mathrm{O}, 2 \mathrm{M} aq $\mathrm{NaOH},1,4$$\mathrm{NaOH},1,4$NaOH,1,4\mathrm{NaOH}, 1,4－dioxane， 0 to ${20}^{\circ }\mathrm{C}$${20}^{\circ }\mathrm{C}$20^(@)C20^{\circ} \mathrm{C}（ $60\mathrm{\%}$$60\mathrm{\%}$60%60 \% ，two steps）． $\mathrm{THF}=$$\mathrm{THF}=$THF=\mathrm{THF}= tetrahydrofuran， $\mathrm{Ac}={\mathrm{CH}}_3\mathrm{CO},\mathrm{Boc}=$$\mathrm{Ac}={\mathrm{CH}}_3\mathrm{CO},\mathrm{Boc}=$Ac=CH_(3)CO,Boc=\mathrm{Ac}=\mathrm{CH}_{3} \mathrm{CO}, \mathrm{Boc}= $\mathrm{C}(\mathrm{O})\mathrm{O}t\mathrm{Bu},\mathrm{DME}=1,2$$\mathrm{C}(\mathrm{O})\mathrm{O}t\mathrm{Bu},\mathrm{DME}=1,2$C(O)OtBu,DME=1,2\mathrm{C}(\mathrm{O}) \mathrm{O} t \mathrm{Bu}, \mathrm{DME}=1,2－dimethoxyethane．
${}^a$${}^a$^(a){ }^{a} 试剂和条件：（a） $t\mathrm{BuS}(\mathrm{O}){\mathrm{NH}}_2,\mathrm{Ti}(\mathrm{OEt}{)}_4,\mathrm{THF},{70}^{\circ }\mathrm{C}$$t\mathrm{BuS}(\mathrm{O}){\mathrm{NH}}_2,\mathrm{Ti}(\mathrm{OEt}{)}_4,\mathrm{THF},{70}^{\circ }\mathrm{C}$tBuS(O)NH_(2),Ti(OEt)_(4),THF,70^(@)Ct \mathrm{BuS}(\mathrm{O}) \mathrm{NH}_{2}, \mathrm{Ti}(\mathrm{OEt})_{4}, \mathrm{THF}, 70^{\circ} \mathrm{C} （ $52\mathrm{\%}$$52\mathrm{\%}$52%52 \% ）;(b） ${\mathrm{CH}}_3\mathrm{MgBr}$${\mathrm{CH}}_3\mathrm{MgBr}$CH_(3)MgBr\mathrm{CH}_{3} \mathrm{MgBr} ，THF， $0^{\circ }\mathrm{C}(36\mathrm{\%})$$0^{\circ }\mathrm{C}(36\mathrm{\%})$0^(@)C(36%)0^{\circ} \mathrm{C}(36 \%) ;(c） $4\mathrm{M}\mathrm{HCl},\mathrm{EtOAc},20$$4\mathrm{M}\mathrm{HCl},\mathrm{EtOAc},20$4MHCl,EtOAc,204 \mathrm{M} \mathrm{HCl}, \mathrm{EtOAc}, 20 ${}^{\circ }\mathrm{C}(85\mathrm{\%})$${}^{\circ }\mathrm{C}(85\mathrm{\%})$^(@)C(85%){ }^{\circ} \mathrm{C}(85 \%) ;(d)( Boc ${)}_2\mathrm{O},{\mathrm{NEt}}_3,{\mathrm{CH}}_2{\mathrm{Cl}}_2,{50}^{\circ }\mathrm{C}(95\mathrm{\%})$${)}_2\mathrm{O},{\mathrm{NEt}}_3,{\mathrm{CH}}_2{\mathrm{Cl}}_2,{50}^{\circ }\mathrm{C}(95\mathrm{\%})$)_(2)O,NEt_(3),CH_(2)Cl_(2),50^(@)C(95%))_{2} \mathrm{O}, \mathrm{NEt}_{3}, \mathrm{CH}_{2} \mathrm{Cl}_{2}, 50^{\circ} \mathrm{C}(95 \%) ;(e）氧酮， ${\mathrm{NaHCO}}_3,{\mathrm{CH}}_3\mathrm{CN},{\mathrm{H}}_2\mathrm{O},0$${\mathrm{NaHCO}}_3,{\mathrm{CH}}_3\mathrm{CN},{\mathrm{H}}_2\mathrm{O},0$NaHCO_(3),CH_(3)CN,H_(2)O,0\mathrm{NaHCO}_{3}, \mathrm{CH}_{3} \mathrm{CN}, \mathrm{H}_{2} \mathrm{O}, 0 ;( ${20}^{\circ }\mathrm{C}(75\mathrm{\%})$${20}^{\circ }\mathrm{C}(75\mathrm{\%})$20^(@)C(75%)20^{\circ} \mathrm{C}(75 \%) f） $4\mathrm{M}\mathrm{HCl},1,4-$$4\mathrm{M}\mathrm{HCl},1,4-$4MHCl,1,4-4 \mathrm{M} \mathrm{HCl}, 1,4- 二氧六环，0 至 ${20}^{\circ }\mathrm{C}(96\mathrm{\%})$${20}^{\circ }\mathrm{C}(96\mathrm{\%})$20^(@)C(96%)20^{\circ} \mathrm{C}(96 \%) ;(g）， ${\mathrm{CH}}_3\mathrm{Li}$${\mathrm{CH}}_3\mathrm{Li}$CH_(3)Li\mathrm{CH}_{3} \mathrm{Li} THF， $-{78}^{\circ }\mathrm{C}(90\mathrm{\%})$$-{78}^{\circ }\mathrm{C}(90\mathrm{\%})$-78^(@)C(90%)-78^{\circ} \mathrm{C}(90 \%) ;(h） ${\mathrm{ClCH}}_2\mathrm{CN},{\mathrm{H}}_2{\mathrm{SO}}_4,\mathrm{AcOH},{\mathrm{CH}}_2{\mathrm{Cl}}_{2}0$${\mathrm{ClCH}}_2\mathrm{CN},{\mathrm{H}}_2{\mathrm{SO}}_4,\mathrm{AcOH},{\mathrm{CH}}_2{\mathrm{Cl}}_{2}0$ClCH_(2)CN,H_(2)SO_(4),AcOH,CH_(2)Cl_(2)0\mathrm{ClCH}_{2} \mathrm{CN}, \mathrm{H}_{2} \mathrm{SO}_{4}, \mathrm{AcOH}, \mathrm{CH}_{2} \mathrm{Cl}_{2} 0 至 ${20}^{\circ }\mathrm{C}(62\mathrm{\%})$${20}^{\circ }\mathrm{C}(62\mathrm{\%})$20^(@)C(62%)20^{\circ} \mathrm{C}(62 \%) ;(i）硫脲， $\mathrm{AcOH},\mathrm{EtOH},{80}^{\circ }\mathrm{C}$$\mathrm{AcOH},\mathrm{EtOH},{80}^{\circ }\mathrm{C}$AcOH,EtOH,80^(@)C\mathrm{AcOH}, \mathrm{EtOH}, 80^{\circ} \mathrm{C} ;(j）（Boc） ${}_2\mathrm{O},2\mathrm{M}$${}_2\mathrm{O},2\mathrm{M}$_(2)O,2M{ }_{2} \mathrm{O}, 2 \mathrm{M} 水- $\mathrm{NaOH},1,4$$\mathrm{NaOH},1,4$NaOH,1,4\mathrm{NaOH}, 1,4 二氧六环，0 至 ${20}^{\circ }\mathrm{C}$${20}^{\circ }\mathrm{C}$20^(@)C20^{\circ} \mathrm{C} （ $60\mathrm{\%}$$60\mathrm{\%}$60%60 \% ，两步）。 $\mathrm{THF}=$$\mathrm{THF}=$THF=\mathrm{THF}= 四氢呋喃， $\mathrm{Ac}={\mathrm{CH}}_3\mathrm{CO},\mathrm{Boc}=$$\mathrm{Ac}={\mathrm{CH}}_3\mathrm{CO},\mathrm{Boc}=$Ac=CH_(3)CO,Boc=\mathrm{Ac}=\mathrm{CH}_{3} \mathrm{CO}, \mathrm{Boc}= $\mathrm{C}(\mathrm{O})\mathrm{O}t\mathrm{Bu},\mathrm{DME}=1,2$$\mathrm{C}(\mathrm{O})\mathrm{O}t\mathrm{Bu},\mathrm{DME}=1,2$C(O)OtBu,DME=1,2\mathrm{C}(\mathrm{O}) \mathrm{O} t \mathrm{Bu}, \mathrm{DME}=1,2 -二甲氧基乙烷。
this route and a major factor affecting the low overall yield （ $\sim 9\mathrm{\%}$$\sim 9\mathrm{\%}$∼9%\sim 9 \% ），thus prompting us to pursue further strategies．
这条路线是影响总产量偏低的主要因素（ $\sim 9\mathrm{\%}$$\sim 9\mathrm{\%}$∼9%\sim 9 \% ），从而促使我们寻求进一步的策略。
As an alternative to the sulfinyl imine route，we investigated installation of the amine functionality after introduction of the methyl group via formal nitrogen addition to a tertiary carbocation．Accordingly，in the first step，sulfide 6 was treated with methyllithium to furnish tertiary alcohol 17 in $90\mathrm{\%}$$90\mathrm{\%}$90%90 \% yield on a 100 g scale（Scheme 3，right）．Initially we pursued a Ritter reaction ${}^{14}$${}^{14}$^(14){ }^{14} of 17 with acetonitrile（not shown）to give the corresponding $\alpha$$\alpha$alpha\alpha－tertiary acetamide．However，under various forcing acidic，basic，or hydridic ${}^{14}$${}^{14}$^(14){ }^{14} conditions，the ensuing $N$$N$NN－ acetyl deprotection could not be smoothly accomplished；the reaction resulted in either unreacted starting material or led to nonspecific decomposition．Cognizant that haloacetyl groups can generally be cleaved under milder conditions with thiourea，${}^{16}$${}^{16}$^(16){ }^{16} we thus turned to converting tertiary alcohol 17 into the related chloroacetamide 18．Although on a small scale （ $<1\mathrm{g}$$<1\mathrm{g}$< 1g<1 \mathrm{~g} ）this Ritter reaction proceeded well using standard conditions，${}^{17}$${}^{17}$^(17){ }^{17} formation of a thick reaction mixture complicated stirring upon scale－up，and the isolated yield of 18 dropped significantly．Careful experimentation revealed that dropwise addition of a solution of 17 and chloroacetonitrile in dichloromethane to a mixture of sulfuric and acetic acid at 0 ${}^{\circ }\mathrm{C}$${}^{\circ }\mathrm{C}$^(@)C{ }^{\circ} \mathrm{C} circumvented these issues，and chloroacetamide 18 could be prepared in $62\mathrm{\%}$$62\mathrm{\%}$62%62 \% yield on an 80 g scale．Next，removal of the haloacetyl group was achieved in a mixture of boiling ethanol and acetic acid in the presence of thiourea；the precipitated amine salt was directly converted to carbamate 16，thus
作为亚磺酰亚胺路线的替代方案，我们研究了通过向叔碳阳离子中正式加氮引入甲基后胺官能团的安装.因此，在第一步中，用甲基锂处理硫化物 6 以提供 $90\mathrm{\%}$$90\mathrm{\%}$90%90 \% 叔醇 17 的产量为 100 g （方案 3，右）.最初我们进行 17 与乙腈（未显示）的 Ritter 反应 ${}^{14}$${}^{14}$^(14){ }^{14} ，得到相应的 $\alpha$$\alpha$alpha\alpha 然而，在各种强制酸性、碱性或氢化 ${}^{14}$${}^{14}$^(14){ }^{14} 条件下，随后的 $N$$N$NN 乙酰脱保护无法顺利完成;反应导致未反应的起始材料或导致非特异性分解。认识到卤乙酰基通常可以在较温和的条件下与硫脲裂解， ${}^{16}$${}^{16}$^(16){ }^{16} 因此我们转向将叔醇 17 转化为相关的氯乙酰胺 18.尽管在小规模 （ $<1\mathrm{g}$$<1\mathrm{g}$< 1g<1 \mathrm{~g} ）该 Ritter 反应在标准条件下进行良好， ${}^{17}$${}^{17}$^(17){ }^{17} 形成浓稠的反应混合物，放大后搅拌复杂，分离出 18 的产率显着下降。仔细实验表明，将 17 和氯乙腈在二氯甲烷中的溶液滴加到 0 的硫酸和乙酸混合物中可以 ${}^{\circ }\mathrm{C}$${}^{\circ }\mathrm{C}$^(@)C{ }^{\circ} \mathrm{C} 避免这些问题，氯乙酰胺 18 可以在 $62\mathrm{\%}$$62\mathrm{\%}$62%62 \% 接下来，在硫脲存在下，在沸腾的乙醇和乙酸混合物中去除卤乙酰基，将沉淀的胺盐直接转化为氨基甲酸酯 16，从而
intercepting the sulfinyl imine route．Importantly，installation of the tert－butyl carbamate facilitated removal of the 2 － aminothiazol－ $4(5\mathrm{H})$$4(5\mathrm{H})$4(5H)4(5 \mathrm{H})－one byproduct at this stage and enabled facile liquid－liquid extraction of the product from the aqueous reaction mixture in the ensuing oxidation step．The described synthetic route proved practical and readily enabled prepara－ tion of $\mathbf{3}\mathbf{0}\mathbf{g}$$\mathbf{3}\mathbf{0}\mathbf{g}$30g\mathbf{3 0 ~ g} of $\mathbf{3}\cdot \mathbf{H}\mathbf{C}\mathbf{l}$$\mathbf{3}\cdot \mathbf{H}\mathbf{C}\mathbf{l}$3*HCl\mathbf{3} \cdot \mathbf{H C l} in the largest single pass conducted （24\％overall yield from 6）．
重要的是，叔丁基氨基甲酸酯的安装有助于在此阶段去除 2-氨基噻唑- $4(5\mathrm{H})$$4(5\mathrm{H})$4(5H)4(5 \mathrm{H}) -一副产物，并能够在随后的氧化步骤中轻松地从水反应混合物中萃取产物.所描述的合成路线被证明是可行的，并且很容易在最大的单程中进行制备 $\mathbf{3}\mathbf{0}\mathbf{g}$$\mathbf{3}\mathbf{0}\mathbf{g}$30g\mathbf{3 0 ~ g} $\mathbf{3}\cdot \mathbf{H}\mathbf{C}\mathbf{l}$$\mathbf{3}\cdot \mathbf{H}\mathbf{C}\mathbf{l}$3*HCl\mathbf{3} \cdot \mathbf{H C l} （24\%总产率从 6 开始）。
While the outlined route proved serviceable，we realized that，due to the need for chromatographic purification，further scalability would become unfavorable and time－consuming． Additionally，we were drawn to the opportunity of further simplifying the synthetic sequence and importantly gaining modular access to novel analogues of 3 ．Thus，we finally turned our attention to a distinct synthetic route starting from divinyl sulfone 7，which based on its use as a popular cross－linking agent is cheap and widely available in bulk quantities．We formally aimed to stitch together this bifunctional Michael acceptor with an ethylamine equivalent to give the desired six－ membered ring heterocycle（Figure 2B）．In practice，initial attempts of a base－mediated Michael reaction of nitroethane with 7 led to formation of large amounts of polymeric material and only trace amounts of nitro sulfone 19 could be detected in the reaction mixture（Scheme 4A）．A survey of inorganic
虽然概述的路线被证明是可行的，但我们意识到，由于需要色谱纯化，进一步的可扩展性将变得不利且耗时。此外，我们被进一步简化合成序列的机会所吸引，重要的是获得对 3 的新型类似物的模块化访问.因此，我们最终将注意力转向了从二乙烯砜 7 开始的独特合成路线，该路线基于其用作流行的交联剂而便宜且我们正式的目标是将这种双功能 Michael 受体与乙胺当量拼接在一起，得到所需的六元环杂环（图 2B）.在实践中，硝基乙烷与 7 的碱介导的 Michael 反应的初步尝试导致形成大量的聚合物材料，并且在反应混合物中只能检测到微量的硝基砜 19（方案 4A）.无机物调查

Scheme 4．Nitroethane－Michael Approach＂
方案 4.硝基乙烷-迈克尔方法”
A）Two－step synthesis of amino sulfone $3{}^{\text{a}}$$3{}^{\text{a }}$3^("a ")3{ }^{\text {a }}
A） 氨基砜 $3{}^{\text{a}}$$3{}^{\text{a }}$3^("a ")3{ }^{\text {a }} 的两步法合成

${}^a$${}^a$^(a){ }^{a} Reagents and conditions：（a）DBU， ${\mathrm{CH}}_2{\mathrm{Cl}}_{2}23{}^{\circ }\mathrm{C}(80\mathrm{\%})$${\mathrm{CH}}_2{\mathrm{Cl}}_{2}23{}^{\circ }\mathrm{C}(80\mathrm{\%})$CH_(2)Cl_(2)23^(@)C(80%)\mathrm{CH}_{2} \mathrm{Cl}_{2} 23{ }^{\circ} \mathrm{C}(80 \%) ；（b） ${\mathrm{H}}_2$${\mathrm{H}}_2$H_(2)\mathrm{H}_{2} （ 50 psi ）， $\mathrm{Rh}/\mathrm{C}$$\mathrm{Rh}/\mathrm{C}$Rh//C\mathrm{Rh} / \mathrm{C}（ $1\mathrm{mol}\mathrm{\%}$$1\mathrm{mol}\mathrm{\%}$1mol%1 \mathrm{~mol} \% ）， $\mathrm{MeOH},75{}^{\circ }\mathrm{C}$$\mathrm{MeOH},75{}^{\circ }\mathrm{C}$MeOH,75^(@)C\mathrm{MeOH}, 75{ }^{\circ} \mathrm{C}（ $95\mathrm{\%}$$95\mathrm{\%}$95%95 \% ）．${}^b$${}^b$^(b){ }^{b} Active methylene compound，divinyl sulfone，DBU， ${\mathrm{CH}}_2{\mathrm{Cl}}_2{23}^{\circ }\mathrm{C}$${\mathrm{CH}}_2{\mathrm{Cl}}_2{23}^{\circ }\mathrm{C}$CH_(2)Cl_(2)23^(@)C\mathrm{CH}_{2} \mathrm{Cl}_{2} 23^{\circ} \mathrm{C} ．Yield of isolated products after purification by flash chromatography on silica gel．${}^c\mathrm{Ar}=$${}^c\mathrm{Ar}=$^(c)Ar={ }^{c} \mathrm{Ar}= 0 －F－phenyl．${}^{\text{d}}{\mathrm{Ar}}^{\prime }=p$${}^{\text{d }}{\mathrm{Ar}}^{\prime }=p$^("d ")Ar^(')=p{ }^{\text {d }} \mathrm{Ar}^{\prime}=p－Cl－phenyl．TMG＝1，1，3，3－tetramethylguanidine， DBU $=1,8$$=1,8$=1,8=1,8－diazabicyclo［5．4．0］undec－7－ene．
${}^a$${}^a$^(a){ }^{a} 试剂和条件：（a）DBU， ${\mathrm{CH}}_2{\mathrm{Cl}}_{2}23{}^{\circ }\mathrm{C}(80\mathrm{\%})$${\mathrm{CH}}_2{\mathrm{Cl}}_{2}23{}^{\circ }\mathrm{C}(80\mathrm{\%})$CH_(2)Cl_(2)23^(@)C(80%)\mathrm{CH}_{2} \mathrm{Cl}_{2} 23{ }^{\circ} \mathrm{C}(80 \%) ;(b） ${\mathrm{H}}_2$${\mathrm{H}}_2$H_(2)\mathrm{H}_{2} （ 50 psi）， $\mathrm{Rh}/\mathrm{C}$$\mathrm{Rh}/\mathrm{C}$Rh//C\mathrm{Rh} / \mathrm{C} （ $1\mathrm{mol}\mathrm{\%}$$1\mathrm{mol}\mathrm{\%}$1mol%1 \mathrm{~mol} \% ）， $\mathrm{MeOH},75{}^{\circ }\mathrm{C}$$\mathrm{MeOH},75{}^{\circ }\mathrm{C}$MeOH,75^(@)C\mathrm{MeOH}, 75{ }^{\circ} \mathrm{C} （ $95\mathrm{\%}$$95\mathrm{\%}$95%95 \% ）. ${}^b$${}^b$^(b){ }^{b} 活性亚甲基化合物，二乙烯砜，DBU， ${\mathrm{CH}}_2{\mathrm{Cl}}_2{23}^{\circ }\mathrm{C}$${\mathrm{CH}}_2{\mathrm{Cl}}_2{23}^{\circ }\mathrm{C}$CH_(2)Cl_(2)23^(@)C\mathrm{CH}_{2} \mathrm{Cl}_{2} 23^{\circ} \mathrm{C} .在硅胶上快速色谱纯化后分离产物的产量。 ${}^c\mathrm{Ar}=$${}^c\mathrm{Ar}=$^(c)Ar={ }^{c} \mathrm{Ar}= 0 -F-苯基。 ${}^{\text{d}}{\mathrm{Ar}}^{\prime }=p$${}^{\text{d }}{\mathrm{Ar}}^{\prime }=p$^("d ")Ar^(')=p{ }^{\text {d }} \mathrm{Ar}^{\prime}=p -Cl-苯基.TMG=1,1,3,3-四甲基胍，DBU $=1,8$$=1,8$=1,8=1,8 -二氮杂双环[5.4.0]十一-7-烯。
and organic bases across various solvents eventually revealed the combination of 1，8－diazabicyclo［5．4．0］undec－7－ene（DBU） in dichloromethane to be uniquely effective for this trans－ formation．Under the optimized conditions（ 1.1 equiv DBU， dropwise addition of 7），the undesired polymerization was largely suppressed，and after a simple aqueous hydrochloric
在各种溶剂中的有机碱最终揭示了 1,8-二氮杂双环[5.4.0]十一氮杂-7-烯 （DBU） 在二氯甲烷中的结合对这种转变具有独特的效果.在优化条件下（1.1 当量 DBU，滴加 7），不需要的聚合在很大程度上被抑制，并且在简单的盐酸水溶液之后