前面几期文章分专题给大家推介了硫酸乙稀酯在有机合成中的应用，（JMC | 硫酸乙烯酯（DTD）作为羟乙基化试剂参与增碳反应 & OPRD | 硫酸乙烯酯（DTD）通过亲核二取代实现环丙基化 & JOC | 硫酸乙烯酯通过“一锅法” [N + 2 + n] 环化构建五元环 & JACS | 硫酸乙烯酯（DTD） 与β-氨基醇通过单烷基化构建吗啡啉及其衍生物）详细内容可点开文末推荐阅读部分的超链接进入原文查看。
本期内容将为大家推介一款Boc-氨乙基化试剂，即tert-Butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide，1,2,3-氧杂噻唑烷-3-羧酸叔丁酯2,2-二氧化物，CAS号：459817-82-4，它可用于高效构建吗啉或者哌嗪并环结构。
该化合物与硫酸乙稀酯结构类似，都把离去基团藏在一个被SO2活化的五元环里。也正是由于N-磺酰氧羧酸酯环结构（“氧噻唑啉二氧化物环”）结构的存在，其活性通常比常见的溴代物更高。当亲核体（如-OH, -NH）被碱（NaH、KOtBu）去质子化后，亲核体进攻氧噻唑啉环上与氧相连的碳原子，五元环发生开环，脱去SO2的同时会断开N-S键，完成Boc-胺乙基化生成O/N-CH2CH2NHBoc 的产物。
示例一 苯并哌嗪的构建
WO2023235809：一种CGAS抑制剂药物，由Eli Lilly & Co.（Eli Lilly & Co.）公司最早进行研发。目前全球最高研发状态为：药物发现，作用机制：CGAS抑制剂。
Intermediate 100 Ethyl 1-[2-(tert-butoxy carbonylamino)ethy|]-6,7-dichloro-indole-2-carboxylate
Suspend ethyl 6, 7-dichloro-IH-indole-2-carboxylate (10.0 g, 36.8 mmol) and Cs2CO3 (24.0 g, 73.6 mmol) in DMF (100 mL) and add tert-butyl 1, 2, 3-oxathiazolidine-3-carboxylate 2,2-dioxide (13.0 g, 55.3 mmol). Stir overnight at RT. Quench with 1N aqueous HCI at 0°C and extract with EtOAc, wash with brine, dry over anhydrous Na2SO4, filter and concentrate. Purify by flash column chromatography (EtOAc/petroleum ether) to yield ethyl 1-[2-(tert-butoxycarbonylamino) ethyl]-6, 7-dichloro-indole-2-carboxylate (12.6 g, 29.8 mmol, 81% Yield).
Intermediate 101 tert-Butyl (2-(6,7-dichloro-2-(hydroxymethyl)-1H-indol-1-yl)ethyl)carbamate
Dissolve ethyl 1-[2-(tert-butoxycarbonylamino)ethy1]-6, 7-dichloro-indole-2-carboxylate (15.0 g, 59.7 mmol) in DCM (150 mL). Add DIBALH dropwise (140 mL, 140 mmol, IM in toluene) at -78°C under N2 atmosphere. Stir for 1 hour at RT. Dilute with DCM, quench with saturated aqueous potassium sodium tartrate and stir overnight at RT. Extract with DCM, wash with brine, dry over anhydrous Na2SO4, filter and concentrate. Trituate (ethyl acetate/petroleum ether = 10:1) to yield tert-butyl (2-(6, 7-dichloro-2-(hydroxymethyl)-1H-indol-1-yl)ethyl)carbamate (9.45 g, 25.0 mmol, 71% Yield).
Intermediate 102 tert-Butyl 6,7-dichloro-3,4-dihydropyrazino[1,2-a]indole-2(1H)-carboxylate
Dissolve lert-butyl (2-(6, 7-dichloro-2-(hydroxymethyl)-1H-indol-1-
yl)ethyl) carbamate (27.0 g, 63.8 mmol) in DCM (250 mL). Add Et3N (29,0 mL, 208 mmol) and MsCl (15.9 g, 137 mmol) at°C. Stir overnight at RT. Quench with saturated aqueous NaHCO3 and extract with DCM, wash with brine, dry over anhydrous Na2SO4, filter and concentrate to yield (1-(2-((tert-butoxycarbonyl)amino)ethyl)-6,7-dichloro-IH-indol-2-yl)methyl methanesulfonate. Resuspend in THF (250 mL), add t-BuOK (13.5 g. 119 mmol). Stir and heat at 60°C for 2 hours. Cool to RT, quench with water, extract with ElOAc, wash with brine, dry over anhydrous Na2SO4 filter and concentrate. Purify by flash column chromatography (EIA c/petroleum ether) to yield tert-butyl 6, 7-dichloro-3,4-dihydropyrazino[1, 2-a]indole-2(1H)-carboxylate (14.6 g, 41.9 mmol, 72% Yield).
示例二 苯并吗啡啉的构建
第二个案例看起来很简单，实际上涉及到了一个Smiles Rearrangement过程。首先我们先看下Smiles重排的反应机理：
苯并吗啡啉结构常见于药物设计中，通常需要经吗啉酮还原得到。如果再有其他取代基引入，就会产生选择性问题，而Boc-氨乙基化试剂就能避免这个问题。
X-ray确认产物结构：
机理预测如下：
General experimental procedure for the preparation of adduct 5
NaH (60 % dispersion in mineral oil, 40 mg, 1.01 mmol) was added to a solution of phenol 4 (211 mg, 1.01 mmol) in anhydrous DMF (10 mL) and the resultant mixture stirred at r.t. for 5 minutes. Cyclic sulfamidate 3 (200 mg, 0.84 mmol) was added and the mixture stirred at r.t. for 15 h prior to being concentrated in vacuo. The mixture was washed with saturated aq. NaCl and extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were concentrated in vacuo to afford amine 5. This material was suitable for subsequent applications without any further purification.
For analysis, a small portion was isolated by Column chromatography (EtOAc/hexane: 5:95).
General experimental procedure for the preparation of dihydrobenzo[1,4]oxazines 6
In a 10 mL round bottom flask, Cu(OAc)2.H2O (0.2 equiv), Cs2CO3 (3 equiv), and compound 5 (60 mg) were dissolved in NMP (5.0 mL). The mixture was stirred at 90°C, and the progress of the reaction monitored by TLC. After 24 h the solvent was evaporated in vacuo and the residue diluted with CH2Cl2 (20 mL), washed with water (2×10 mL) and brine (2×10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/hexane: 10:90) to afford Boc-benzoxazine 6.
参考文献
1. WO/2023/235809 CGAS INHIBITORS. https://patentscope./search/en/detail.jsf?docId=WO2023235809
2. Copper-catalysed cross-coupling affected by the Smiles rearrangement: a new chapter on diversifying the synthesis of chiral fluorinated 1,4-benzoxazine derivatives. RSC Adv., 2015,5, 83576-83580. https:///10.1039/C5RA18897K