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      2-碘-3-(對甲苯磺酰氧基)苯基醚的選擇性合成

      2021-09-17 10:09:30潘峰王磊郭怡沈金瀅潘曉峰鄭衛(wèi)新
      關(guān)鍵詞:芳基氧基苯基

      潘峰,王磊,郭怡,沈金瀅,潘曉峰,鄭衛(wèi)新

      2-碘-3-(對甲苯磺酰氧基)苯基醚的選擇性合成

      潘峰,王磊,郭怡,沈金瀅,潘曉峰,鄭衛(wèi)新*

      (杭州師范大學(xué)材料與化學(xué)化工學(xué)院,浙江 杭州 311121)

      磺酰氧基鹵代芳基醚是一種多功能化合物,在眾多研究領(lǐng)域具有廣泛應(yīng)用價值。以2-碘間苯二酚為原料,經(jīng)化學(xué)計量的雙磺酰化、選擇性單側(cè)水解及與溴化物的親核取代反應(yīng),合成系列2-碘-3-(對甲苯磺酰氧基)苯基醚。結(jié)果表明,雙磺?;a(chǎn)物的選擇性單側(cè)水解比2-碘間苯二酚通過單烴基化進(jìn)行原料中2個對稱羥基的選擇性官能化更有優(yōu)勢。以低成本堿為水解試劑,探索反應(yīng)時間、溫度等因素對2,6-雙(對甲苯基磺酰氧基)碘苯單側(cè)選擇性水解的影響,水解產(chǎn)物核磁純度>99%,為對甲苯磺酰氧基碘代芳基醚的合成提供一種操作簡便、反應(yīng)條件溫和、成本低和選擇性高的方法。所有化合物結(jié)構(gòu)均經(jīng)1H-NMR、13C-NMR與高分辨質(zhì)譜等方法確定。

      磺酰氧基碘代苯基醚;合成;選擇性水解

      芳基醚是廣泛存在于許多天然產(chǎn)物[1-2]和藥物[3-5]分子中的重要骨架。芳環(huán)上官能團(tuán)的選擇性化學(xué)轉(zhuǎn)化是芳基醚官能化的重要策略,因此多官能化芳基醚的選擇性構(gòu)建在合成化學(xué)中具有重要意義?;酋Q趸獯蓟咽墙M建眾多具有生理活性分子的重要前體[6-10],其結(jié)構(gòu)式為

      其中,相鄰的鹵素與磺酰氧基在芳基衍生化中發(fā)揮了重要作用[11-12]。鹵素與磺酰氧基的活性差異可為選擇性官能化提供有效途徑[13-17]。此外,該化合物是苯炔這一活性物種的重要供體,通過環(huán)加成反應(yīng)參與多種活性物質(zhì)的合成[6,18]。

      磺酰氧基碘代芳基醚中因取代基性質(zhì)差異而擁有2種活性不同的C—O鍵,對應(yīng)苯二酚前體的選擇性反應(yīng)是該類化合物合成的主要策略,實現(xiàn)酚羥基高選擇性烴化與磺?;呛铣稍摶衔锏年P(guān)鍵。其合成方法主要有2種,一是先通過鹵代苯二酚的非完全烴化反應(yīng)進(jìn)行單側(cè)烴基化,再進(jìn)行磺?;?9-22]合成;二是通過鹵代芳基二酚的磺酰化-選擇性水解-衍生化合成。其中,三氟磺酰氧基的反應(yīng)較常見,例如1,6-雙(三氟磺酰氧基)碘苯可經(jīng)Cs2CO3作用脫去其中一個磺?;?3]。在常用磺?;?,對甲苯磺?;杀据^低,近年來在許多過渡金屬催化的偶聯(lián)反應(yīng)中表現(xiàn)出較好的活性和選擇性[24]。2,6-二羥基苯乙酮中的2個酚羥基可以通過控制計量的對甲苯磺酰氯進(jìn)行選擇性單磺酰化,繼而在未反應(yīng)的羥基鄰位發(fā)生碘代反應(yīng)生成碘代丁二酰亞胺(NIS)[25]。CLARK等[26]報道了3,5-雙磺酰氧基碘苯的單側(cè)選擇性水解。然而,對于磺酰氧基碘代芳基醚的合成前體,即2-鹵代雙對甲苯磺酰二苯酯的磺?;蜻x擇性水解,至今未見文獻(xiàn)報道。

      基于此,本文采用低成本堿高選擇性地實現(xiàn)2,6-雙對甲苯磺酰氧基2-碘苯的單側(cè)水解,經(jīng)親核取代反應(yīng)生成磺酰氧基碘代芳基醚,為磺酰氧基鹵代芳基醚的合成提供一種低成本、高效的方法。

      1 實驗

      1.1 實驗儀器與實驗原料

      Bruker Avance DMX500核磁共振儀,Bruker DMX300核磁共振儀,Shimadzu HRMS-EI-TOF型高分辨儀,顯微熔點儀X5。2-碘-1,3-苯二酚通過文獻(xiàn)[27]中方法合成。

      1.2 2,6-雙磺酰氧基碘苯的合成

      在250 mL燒瓶中加入2-碘代-1,3-苯二酚(4.72 g,20 mmol)、對甲苯磺酰氯(8.77 g,46 mmol)、碳酸鉀(11.06 g,80 mmol)和丙酮(100 mL),室溫下攪拌,薄層色譜(TLC)跟蹤至反應(yīng)完全。抽濾,濾渣用二氯甲烷洗滌,合并的有機(jī)相用飽和食鹽水洗滌,經(jīng)無水硫酸鎂干燥,旋蒸濃縮。用乙酸乙酯和石油醚對粗產(chǎn)物重結(jié)晶,得到白色晶體2,6-雙(對甲苯基)磺酰氧基碘苯。

      1.3 2-碘-3-(對甲苯磺酰氧基)苯酚的合成

      在1 L錐形瓶中加入2,6-雙磺酰氧基碘苯(23.3 g,42.8 mmol)和甲醇(100 mL),保持35 °C,滴加含KOH(5.0 g,89.1 mmol)的水-甲醇混合溶液(2.5 mL水,225 mL甲醇)。滴加完畢后保持溫度不變,攪拌3 h,升溫至45°C繼續(xù)攪拌15 min后冷卻至室溫,用水稀釋至總體積為800 mL,用濃度為5%的鹽酸中和,在4 °C下靜置2 d。過濾,將濾渣溶解在乙醚中,用10%的NaOH溶液萃取。分出的油狀物經(jīng)乙醚洗滌后用5%的鹽酸中和。混合物用乙醚萃取3次,合并的有機(jī)相經(jīng)硫酸鎂干燥,過濾,濃縮后得到2-碘-3-(對甲苯磺酰氧基)苯酚。

      1.4 2-碘-3-(對甲苯磺酰氧基)苯基醚的合成

      在250 mL燒瓶中加入2-碘-3-(對甲苯磺酰氧基)苯酚(7.80 g,20 mmol),鹵代烴(20 mmol),碳酸鉀(5.56 g,40 mmol)和乙腈(30 mL),室溫下攪拌,TLC跟蹤至反應(yīng)完全。加50 mL水稀釋,用乙酸乙酯萃取混合物,合并的有機(jī)相用飽和食鹽水洗滌,無水硫酸鎂干燥,過濾。用快速柱層析分離(石油醚()∶乙酸乙酯()=10∶1)粗產(chǎn)物,提純得到系列2-碘-3-(對甲苯磺酰氧基)苯基醚。

      2 結(jié)果與討論

      2.1 2-碘間苯二酚的選擇性烴化

      2-碘間苯二酚與芐溴的化學(xué)反應(yīng)方程式為

      首先,選擇烴化反應(yīng)作為單側(cè)選擇性取代的起點,室溫下將2-碘間苯二酚與堿在丙酮中混合,邊攪拌邊加入等物質(zhì)的量的芐溴。不同堿的反應(yīng)選擇性如表1所示。

      表1 2-碘間苯二酚與芐溴的反應(yīng)

      a:堿與2-碘間苯二酚的物質(zhì)的量之比為1.2∶1;b:以TLC跟蹤2-碘間苯二酚消失為準(zhǔn);c:核磁產(chǎn)率,括號內(nèi)產(chǎn)物比例由反應(yīng)混合物的1H-NMR確定,CH2Br2為內(nèi)標(biāo)。

      由表1可知,在有機(jī)堿(Entry 4和5)作用下單取代產(chǎn)物1的產(chǎn)率高于無機(jī)堿(Entry 1~3)作用下產(chǎn)物1的產(chǎn)率,且可通過色譜柱分離產(chǎn)物1和2,但反應(yīng)選擇性無法滿足高效合成的需求。嘗試用2-碘間苯二酚與等物質(zhì)的量的對甲苯磺酰氯進(jìn)行選擇性單側(cè)磺酰化,依然未獲得成功。

      2.2 2, 6-雙磺酰氧基碘苯的選擇性水解

      碘代間苯二酚在K2CO3作用下與對甲磺酰氯以物質(zhì)的量之比為2∶1發(fā)生反應(yīng),計量生成2,6-雙磺酰氧基碘苯。該化合物在溶劑為甲醇,堿為NaOH[26]的條件下可實現(xiàn)單側(cè)水解,生成2-碘-3-(對甲苯磺酰氧基)苯酚,水解反應(yīng)方程式為

      探索不同溫度下2,6-雙磺酰氧基碘苯的選擇性單側(cè)水解,結(jié)果見表2。

      表2 2,6-雙磺酰氧基碘苯的選擇性單側(cè)水解

      a:由于2,6-雙磺酰氧基碘苯不溶于反應(yīng)溶液,此處時間是指從堿溶液滴完至固體消失的時間。b:核磁產(chǎn)率,括號內(nèi)產(chǎn)物比例由反應(yīng)混合物的1H-NMR確定,CH2Br2為內(nèi)標(biāo)。

      由表2可知,在室溫25 ℃下,反應(yīng)時間較長,即使2,6-雙磺酰氧基碘苯經(jīng)歷12 h,仍未反應(yīng)完全。溫度每升高10 ℃,反應(yīng)明顯加快,完全水解產(chǎn)物增加。因此,先將溫度調(diào)至35 ℃反應(yīng)3 h,然后升溫至45 ℃反應(yīng)15 min,經(jīng)后處理無須提純可獲得核磁純度>99%的2-碘-3-(對甲苯磺酰氧基)苯酚(產(chǎn)率達(dá)86%),如圖1所示。該產(chǎn)物可達(dá)到后續(xù)合成應(yīng)用的需求。

      (ppm)

      2.32-碘-3-(對甲苯磺酰氧基)苯酚的親核取代反應(yīng)

      以乙腈為溶劑,2-碘-3-(對甲苯磺酰氧基)苯酚在K2CO3作用下與多種溴代烴發(fā)生親核取代反應(yīng),生成系列2-碘-3-(對甲苯磺酰氧基)苯基醚(產(chǎn)物5a~j),其中,產(chǎn)物5a為甲基-(3-對甲苯磺酰氧基-2-碘)苯基醚,產(chǎn)率為86%;產(chǎn)物5b為乙基-(3-對甲苯磺酰氧基-2-碘)苯基醚,產(chǎn)率為78%;產(chǎn)物5c為正丙基-(3-對甲苯磺酰氧基-2-碘)苯基醚,產(chǎn)率為79%;產(chǎn)物5d為異丙基-(3-對甲苯磺酰氧基-2-碘)苯基醚,產(chǎn)率為88%;產(chǎn)物5e為芐基-(3-對甲苯磺酰氧基-2-碘)苯基醚,產(chǎn)率為89%;產(chǎn)物5f為(2-苯基)乙基-(3-對甲苯磺酰氧基-2-碘)苯基醚,產(chǎn)率為88%;產(chǎn)物5g為(2’-溴)芐基-(3-對甲苯磺酰氧基-2-碘)苯基醚,產(chǎn)率為75%;產(chǎn)物5h為(2’-碘)芐基(3-對甲苯磺酰氧基-2-碘)苯基醚,產(chǎn)率為81%;產(chǎn)物5i為烯丙基-(3-對甲苯磺酰氧基-2-碘)苯基醚,產(chǎn)率為82%;產(chǎn)物5j為(3-對甲苯磺酰氧基-2-碘)苯氧基乙酸乙酯,產(chǎn)率為83%。產(chǎn)物5a~j的詳細(xì)數(shù)據(jù)請掃描右側(cè)二維碼。

      親核取代反應(yīng)方程式為

      產(chǎn)物5a~j的結(jié)構(gòu)式如下:

      3 結(jié)論

      以2-碘間苯二酚為原料,經(jīng)磺酰化、選擇性水解、親核取代反應(yīng),合成了系列磺酰氧基鹵代芳基醚。以低成本堿為水解試劑,實現(xiàn)2,6-雙(對甲苯基)磺酰氧基鹵代苯的單側(cè)選擇性水解,水解產(chǎn)物核磁純度>99%,為對甲苯磺酰氧基碘代芳基醚的合成提供了一種低成本、高效的方法。

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      [27]TSUJIYAMA S I, SUZUKI K. Preparation of benzocyclobutenone derivatives based on an efficient generation of benzynes[J]Organic Syntheses, 2007, 84: 272-284. DOI:10.15227/orgsyn.084.0272

      Selective synthesis of 2-iodophenyl-3-(-tosyloxy) 4-methylbenzenesulfonate

      PAN Feng, WANG Lei, GUO Yi, SHEN Jinying, PAN Xiaofeng, ZHENG Weixin

      (311121)

      Halogenated sulfonyloxyaromatic ether has been regarded as the polyfunctionalized organic compound with wide applications in lots of fields. Using 2-iodoresorcinol as the starting material, series of iodonated alkyloxy 4-methylbenzenesulfonate were synthesized in high yields via stoichiometrical bissulfonylation, selective monohydrolysis of 2-iodo-1,3-phenylene bis(4-methylbenzenesulfonate) followed by nucleophilic substitution to various organobromides. Procedure for preparation of 3-hydroxy-2-iodophenyl-(4-methylbenzenesulfonate) was explored. It was found that the monodesulfonylation of bissulfonate was much more favorite than monohydrocarbylation for selective functionalization of the two symmetrical hydoxyls in 2-iodoresorcinol. Using low-cost alkali system, the reaction time, temperature of the monohydrolysis of the 2,6-bis(tosyloxy)iodobenzene had been investigated. The monohydrolysis product, 3-hydroxy-2-iodophenyl-(4-methylbenzenesulfonate), were obtained in the purity of above 99% in1H-NMR without further purification. This study provides a synthetic method of 3-alkyloxy-2-iodophenyl 4-methylbenzenesulfonate, which had the advantages of simple operation, mild reaction conditions, low cost and high selectivity. The structures of all the products were verified by1H-NMR,13C-NMR and HRMS, et al.

      3-(-tosyloxy)-2-iodophenyl ether; synthesis; selective monohydrolysis

      10.3785/j.issn.1008-9497.2021.05.009

      O 627

      A

      1008?9497(2021)05?579?05

      2020?01?01.

      國家自然科學(xué)基金資助項目(20972037).

      潘峰(1994—),ORCID: https://orcid.org/0000-0001-7016-2484,男,碩士研究生,主要從事導(dǎo)向金屬有機(jī)合成研究,E-mail: pfgz0419@163.com.

      ,ORCID: https://orcid.org/0000-0003-4149-8100,E-mail:wxzheng@hznu.edu.cn.

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