CN106366032B - 手性有机碱在水油两相体系制手性含硫吲哚化合物的应用 - Google Patents
手性有机碱在水油两相体系制手性含硫吲哚化合物的应用 Download PDFInfo
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- -1 benzazolyl compounds Chemical class 0.000 title claims abstract description 71
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 64
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 239000011593 sulfur Substances 0.000 title claims abstract description 34
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 67
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 59
- 239000000758 substrate Substances 0.000 claims description 32
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- 239000005864 Sulphur Substances 0.000 claims 1
- 125000005466 alkylenyl group Chemical group 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
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- 150000003384 small molecules Chemical class 0.000 abstract description 2
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical class ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Indole Compounds (AREA)
Abstract
手性有机碱在水油两相体系中制备手性含硫吲哚化合物的应用,是一种手性有机碱小分子在水油两相体系中催化硫醇对吲哚的不对称硫化方法,其用到的催化剂是小分子手性有机碱。对外消旋的对甲基苯磺酰基吲哚在碱性条件下生成得到的插烯亚胺中间体进行硫化后能得到相应的手性吲哚硫化物,其产率可达99%,其对映体过量可达到98%。本发明操作简便实用易行,催化剂商业可得,使用水作为溶剂,反应条件绿色温和,产率高,对映选择性好,且反应在水相中进行,对环境友好。此外,通过不对称硫化合成手性吲哚硫化物和及衍生化得到的二氢吲哚硫化物,都具有潜在的医用价值。
Description
技术领域
本发明涉及手性有机碱在水油两相体系中制备手性含硫吲哚化合物的应用,是一种应用水油两相体系小分子催化硫醇对吲哚的不对称硫化合成高对映选择性的含硫吲哚化合物的方法。
背景技术
水具有来源广泛,安全无毒、环境友好等特点,因此,在水相中进行化学反应符合绿色化学、经济有效、可持续发展的理念。(参考文献一:(a)Simon M.-O.;Li C.-J.Chem.Soc.Rev.2012,41,1415-1427(b)Li C.-J.Chem.Rev.2005,105,3095-3166.(c)Chanda A.;Fokin V.V.Chem.Rev.2009,109,725-748.)吲哚或二氢吲哚的骨架广泛存在于天然产物、农产物和药物产品分子中,因此,发展基于吲哚和二氢吲哚的化学方法学占据着非常重要的地位(参考文献二:(a)Sundberg R.J.The Chemistry of Indoles;AcademicPress:New York,1970.(b)Bandini M.,Eichholzer A.Angew.Chem.,Int.Ed.2009,48,9608-9644(c)Humphrey G.R.;Kuethe J.T.Chem.Rev.2006,106,2875-2911.)含硫的吲哚或二氢吲哚类化合物经实验证明,具有一定的生理活性。基于3位含硫吲哚类化合物目前主要还是以消旋的形式为主,至今没有报道过手性3位含硫吲哚类化合物(参考文献三:((a)Gao S.-J.,Tseng C.;Raju B.R.;Tsai C.-H.;Yao C.-F.Synlett2009,19,3201-3205(b)Wu X.-S.;Tian S.-K.Chem.Commun.2012,48,898-900.(c)Dar A.A.;Ali S.;Khan A.T.;Tetrahedron Lett.2014,55,486-489.(d)Khorshidi A.;Shariati S.RSC Adv.2014,4,41469-41475)。因此,合成具有光学纯的3位含硫吲哚类仍然是一个挑战。
自从对甲基苯磺酰基吲哚在2006年被合成出来以后,它就成为人们研究的热点目标。它被用于金属催化、相转移催化、有机小分子等一系列反应来合成具有吲哚骨架的各类化合物。(参考文献四:(a)Ballini,R.;Palmieri,A.;Petrini,M.;Torregiani,E.Org.Lett.2006,8,4093–4096;(b)Shaikh,R.R.;Mazzanti,A.;Petrini,M.;Bartoli,G.;Melchiorre,P.Angew.Chem.2008,120,8835–8838.Angew.Chem.,Int.Ed.2008,47,8707–8710;(c)Li,Y.;Shi,F.-Q.;He,Q.-L.;You,S.-L.Org.Lett.2009,11,3182–3185;(d)Dobish,M.C.;Johnston,J.N.Org.Lett.2010,12,5744–5747;(e)Jing,L.;Wei,J.;Zhou,L.;Huang,Z.;Li,Z.;Wu,D.;Xiang,H.;Zhou,X.Chem.Eur.J.2010,16,10955–10958;(f)Zheng,B.-H.;Ding,C.-H.;Hou,X.-L.;Dai,L.-X.Org.Lett.2010,12,1688–1691;(g)Cao,L.-L.;Ye,Z.-S.;Jiang,G.-F.;Zhou,Y.-G.Adv.Synth.Catal.2011,353,3352–3356;(h)Wang,J.;Zhou,S.;Lin,D.;Ding,X.;Jiang,H.;Liu,H.Chem.Commun.2011,8355–8357;(i)Fochi,M.;Gramigna,L.;Mazzanti,A.;Duce,S.;Fantini,S.;Palmieri,A.;Petrini,M.;Bernardi,L.Adv.Synth.Catal.2012,354,1373–1380;(j)Huang,J.-Z.;Wu,X.;Gong,L.-Z.Adv.Synth.Catal.2013,355,2531–2537;(k)Protti,S.;Palmieri,A.;Petrini,M.;Fagnoni,M.;Ballini,R.;Albini,A.Adv.Synth.Catal.2013,355,643–646;(l)Luo,J.;Wu,B.;Chen,M.-W.;Jiang,G.-F.;Zhou,Y.-G.Org.Lett.2014,16,2578–2581;(m)Wang R.-M.;Jing L.-H;Qin D.-B.Tetrahedron Lett.2015,56,2867-2870)。
我们组近期发展了一种在水油两相体系中的硫化方法(参考文献五:Guo W.-G;WuB.;Zhou X.Chen P.;Wang X.;Zhou Y.-G.;Liu Y.;Li C.;.Angew.Chem.,Int.Ed.2015,54,4522–4526.)。我们设想能否采用相似的策略,采取对甲基苯磺酰基吲哚作为底物,其在碱性条件下生成得到的插烯亚胺中间体进行硫化后能得到相应的3位手性吲哚硫化物,通过进一步衍生氢化后能得到相应的3位手性二氢吲哚硫化物
发明内容
本发明的目的是提供一种水油两相体系手性有机碱催化剂高度对映选择性催化硫醇对消旋对甲基苯磺酰基吲哚在碱性条件下生成得到的插烯亚胺中间体进行硫化后得到的手性吲哚硫化物的方法。本发明操作简便实用易行,催化剂商业可得,使用水作为溶剂,反应条件绿色温和。此外,通过不对称硫化合成手性吲哚硫化物和及衍生化得到的二氢吲哚硫化物,产率高,对映选择性好,且反应在水相中进行,对环境友好。
为实现上述目的,本发明的技术方案如下:
手性有机碱在水油两相体系中制备手性含硫吲哚化合物的应用,是一种水油两相体系中催化硫醇对吲哚的不对称硫化方法,是不对称硫化外消旋对甲基苯磺酰基吲哚得到相应的手性吲哚硫化物方法,其催化体系为在水相中使用手性有机碱催化剂,本发明以水作为溶剂,少量的有机溶剂作为共溶剂溶解有机物,手性有机碱作为催化剂,无机碱作为碱生成吲哚插烯亚胺中间体,以实现在水油两相体系中实现对吲哚的不对称硫化过程,反应式和条件如下:
式中:
温度:0℃至室温;
溶剂:水作为溶剂,加入一定量的有机溶剂以便将底物溶解;
时间:12-96小时;
碱:无机碱;
催化剂:手性有机碱催化剂
所述R1为甲基,苯基,氢,R2为苯基、1位萘基、1位噻吩基、C5烷基及含有取代基的苯环,苯环上的取代基为F、Cl、Br,Me、MeO、CF3、NO2中的一种,取代基个数为1,R3为F、Me,R4为三苯基甲基,Ts为对甲基苯磺酰基。
所述无机碱为碳酸钠、碳酸钾、碳酸氢钠、氢氧化钠、氢氧化钾、碳酸铯或磷酸钾中的一种或二种以上。无机碱的用量为相对于底物对甲基苯磺酰基吲哚用量的2到5倍当量,其中2倍当量和五倍当量对反应的进程(活性和选择性)没有明显实质的影响,考虑到原子经济有效的因素,2倍当量即可。
所述的手性有机碱催化剂为金鸡纳碱及其硫脲衍生物,用量为底物对甲基苯磺酰基吲哚用量的1-20mol%,考虑到时间效应和经济原子效应,催化剂的用量降至1%时反应时间较长,催化剂用量为20%时活性提高,对反应的选择性没有提高,因此其中催化剂的用量选为10mol%。
反应所用的有机溶剂为甲苯、二氯甲烷、异丙醇、四氢呋喃、三氯甲烷、1,2二氯乙烷中的一种或二种以上,另一种溶剂为水。
反应结束后加入反应体系2倍至5倍范围的饱和食盐水,考虑到原子经济效应,加入反应体系的2倍体积的饱和食盐水即可
反应步骤为:
在反应容器中投入手性有机碱催化剂(式中底物对甲基苯磺酰基吲哚用量的1-20mol%,再加入相对于底物对甲基苯磺酰基吲哚用量的2到5倍当量的无机碱,然后加入对甲基苯磺酰基吲哚和硫醇化合物,底物取对甲基苯磺酰基吲哚与硫醇的比为1/2-1/1.1,对于此混合物加入有机溶剂溶解,有机溶剂是相对于每0.1mmol底物对甲基苯磺酰基吲哚,加入量为200微升至2毫升,再加入水,水是相于每0.1mmol底物对甲基苯磺酰基吲哚;加入量为0.5毫升至四毫升,将此反应体系置于0℃至室温进行反应,反应结束后,分离纯化得产物。
所述手性有机碱催化剂为金鸡纳碱及其硫脲衍生物A-F
所述的无机碱为碳酸钠、碳酸钾、碳酸氢钠、氢氧化钠、氢氧化钾、碳酸铯或磷酸钾中的一种或二种以上;
反应所用的有机溶剂为甲苯、二氯甲烷、异丙醇、四氢呋喃、三氯甲烷、1,2二氯乙烷中的一种或二种以上。
本发明具有以下优点
1.反应在水油两相中进行,反应条件绿色温和。
2.反应活性和对映选择性高,核磁氢谱没有检测到副反应,因此分离方便,能获得高的对映体过量纯品。
3.能得到各种取代类型的手性吲哚硫类化合物。
4.催化剂商业可得,反应操作简便实用。
5.底物容易制备,反应简单有效,硫化反应条件温和。
6.得到的手性含硫吲哚类化合物可以进一步衍生化到手性二氢吲哚化合物中。
具体实施方式
下面通过实施例详述本发明,但本发明并不限于下述的实施例。
实施例1:条件的优化
在反应容器中投入手性有机碱催化剂(式1中底物1a用量的10mol%),加入两倍当量的无机碱,然后加入对甲基苯磺酰基吲哚和三苯硫醇,对此混合物加入0.5毫升有机溶剂溶解后,再加入水。将此反应体系位于特定的温度进行反应,反应结束后,加入反应体系体积两倍的饱和食盐水,用乙酸乙酯萃取,合并有机相,除去溶剂后直接柱层析分离得到纯的产物。反应式和催化剂结构如下:
其转化率以1,3,5-三甲氧基苯为内标由反应粗产物的1H NMR来确定,产物的对映体过量用手性液相色谱测定,详见表1。
表1.不对称吲哚硫化反应条件的优化a
[a]如无特殊说明,所有的反应均为1a(0.1毫摩尔),2(0.2毫摩尔,2当量),催化剂(10mol%)以及碱(0.2毫摩尔2当量)在室温下反应12小时(Unless otherwise noted,allreactions were carried out with 1a(0.1mmol),2(0.2mmol 2eq),catalyst(10mol%)and base(0.2mmol 2eq)at room temperature for 12h).[b]由反应完之后的粗产物经过核磁测定(Determined by 1HNMR spectroscopy of the crude mixture).[c]对映选择性由手性高效液相色谱测定(eewas determined by chiral HPLC).[d]反应是在0度下进行(The reaction was performed at 0℃).[e]反应是1a(0.2毫摩尔),2(0.24毫摩尔1.2当量)在4毫升的水和200微升的氯仿中进行(The reaction was performed with 1a(0.2mmol),2(0.24mmol 1.2eq)in 4mL H2O and 200uL CHCl3).[f]反应是1a(0.2毫摩尔),2(0.22毫摩尔1.1当量)在4毫升的水和200微升的氯仿中进行(The reaction wasperformed with 1a(0.2mmol),2(0.22mmol 1.1eq)in 4mL H2O and 200uL CHCl3).
水油两相体系中合成各种含硫吲哚化合物的操作步骤是,在反应容器中投入奎宁丁硫脲生物碱作为催化剂(式1中底物1a用量的10mol%),再加入底物1a,2倍当量的碳酸钠,然后加入对甲基苯磺酰基吲哚和三苯硫醇,对于此混合物加入三氯甲烷(底物溶解性较好时为200微升,底物溶解不好时为2毫升,具体可参见实施步骤)溶解后,再加入水(底物溶解性较好时为4毫升,底物溶解不好时为2毫升,具体可参见实施步骤)。将此反应体系位于零摄氏度温度进行搅拌反应,反应结束后,先加入反应体系体积两倍的饱和食盐水,再用乙酸乙酯萃取,合并有机相,除去溶剂后直接柱层析分离得到纯的产物。反应式和催化剂结构如下:
产率为分离收率,产物的对映体过量用手性液相色谱测定。
实施例2:水油两相体系中合成含硫吲哚化合物3a
在反应容器中投入奎宁丁硫脲生物碱(F)作为催化剂(式1中底物1a用量的10mol%),再加入2倍当量(底物1a)的碳酸钠,然后加入0.2mmol对甲基苯磺酰基吲哚(R1=CH3,R2=Ph,R3=H)和0.22mmol三苯硫醇,对于此混合物加入200微升的三氯甲烷溶解后,再加入4毫升的水。将此反应体系位于零摄氏度温度进行反应,反应时间为12h,反应结束后,先加入反应体系两倍的饱和食盐水,再用乙酸乙酯萃取,合并有机相,除去溶剂后直接柱层析分离得到纯的产物94.2mg的3a,产率为95%,其对映选择性为91%。
实施例3:水油两相体系中合成含硫吲哚化合物3b
操作步骤同实施例3a,其中(R1=Me,R2=4-ClC6H4,R3=H),反应时间为12h,得101.8mg的3b,产率为96%,其对映选择性为91%。
实施例4:水油两相体系中合成含硫吲哚化合物3c
操作步骤同实施例3a,其中(R1=Me,R2=2-ClC6H4,R3=H),反应时间为24h,得96mg的3c,产率为90.5%,其对映选择性为91%。
实施例5:水油两相体系中合成含硫吲哚化合物3d
操作步骤同实施例3a,其中(R1=Me,R2=3-ClC6H4,R3=H),由于底物溶解度原因,其中三氯甲烷和水各为2mL,反应时间为48h,得95.2mg的3d,产率为90%,其对映选择性为88%。
实施例6:水油两相体系中合成含硫吲哚化合物3e
操作步骤同实施例3a,其中(R1=Me,R2=4-FC6H4,R3=H),反应时间为36h得94.4mg的3e,产率为92%,其对映选择性为90.5%。
实施例7:水油两相体系中合成含硫吲哚化合物3f
操作步骤同实施例3a,其中(R1=Me,R2=4-BrC6H4,R3=H),反应时间为12h,得94.4mg的3f,产率为92%,其对映选择性为90.5%。
实施例8:水油两相体系中合成含硫吲哚化合物3g
操作步骤同实施例3a,其中(R1=Me,R2=4-CF3C6H4,R3=H),反应时间为24h,得91.9mg的3g,产率为82%,其对映选择性为98%。
实施例9:水油两相体系中合成含硫吲哚化合物3h
操作步骤同实施例3a,其中(R1=Me,R2=4-MeC6H4,R3=H),反应时间为12h,得83mg的3h,产率为75%,其对映选择性为91%。
实施例10:水油两相体系中合成含硫吲哚化合物3i
操作步骤同实施例3a,其中(R1=Me,R2=2-MeC6H4,R3=H),得91.8mg的3i,反应时间为12h,产率为90%,其对映选择性为92%。
实施例11:水油两相体系中合成含硫吲哚化合物3j
操作步骤同实施例3a,其中(R1=Me,R2=2-MeOC6H4,R3=H),反应时间为12h,得103mg的3j,产率为98%,其对映选择性为88%。
实施例12:水油两相体系中合成含硫吲哚化合物3k
操作步骤同实施例3a,其中(R1=Me,R2=2-NO2C6H4,R3=H),由于底物溶解度原因,其中三氯甲烷和水各为2mL,反应时间为36h,得103.4mg的3k,产率为96%,其对映选择性为97.5%。
实施例13:水油两相体系中合成含硫吲哚化合物3l
操作步骤同实施例3a,其中(R1=Me,R2=1-naphthyl,R3=H),反应时间为12h,得104.8mg的3l,产率为96%,其对映选择性为88%。
实施例14:水油两相体系中合成含硫吲哚化合物3m
操作步骤同实施例3a,其中(R1=Me,R2=2-thienyl,R3=H),反应时间为12h,得100.1mg的3m,产率为99%,其对映选择性为87%。
实施例15:水油两相体系中合成含硫吲哚化合物3n
操作步骤同实施例3a,其中(R1=Me,R2=C6H4,R3=F),由于底物溶解度原因,其中三氯甲烷和水各为2mL,反应时间为48h,得99.3mg的3n,产率为96%,其对映选择性为91%。
实施例16:水油两相体系中合成含硫吲哚化合物3o
操作步骤同实施例3a,其中(R1=Me,R2=C6H4,R3=Me),反应时间为12h,得97.2mg的3o,产率为95%,其对映选择性为89%。
实施例17:水油两相体系中合成含硫吲哚化合物3p
操作步骤同实施例3a,其中(R1=H,R2=C6H4,R3=Me),由于底物溶解度原因,其中三氯甲烷和水各为2mL,反应时间为72h,得72mg的3p,产率为75%,其对映选择性为8%。
实施例18:水油两相体系中合成含硫吲哚化合物3q
操作步骤同实施例3a,其中(R1=Ph,R2=C6H4,R3=H),由于底物溶解度原因,其中三氯甲烷和水各为2mL,反应时间为96h,得63.8mg的3q,产率为57%,其对映选择性为91%。
实施例19:水油两相体系中合成含硫吲哚化合物3r
操作步骤同实施例3a,其中(R1=Me,R2=iBu,R3=H),反应时间为60h,得75.1mg的3r,产率为79%,其对映选择性为96%。
实施例20:水油两相体系中合成含硫吲哚化合物3s
操作步骤同实施例3a,其中(R1=Me,R2=C6H4,R3=Ph),反应时间为60h,得71.8mg的3s,产率为75%,其对映选择性为98%。
实施例21:含硫吲哚化合物的衍生化
在反应瓶中投入0.4mmol3a化合物,加入2mL乙酸,搅拌五分钟后,分批次投入六当量的氰基硼氢化钠,并用点板跟踪反应。当点板显示原料已经消失时,停止反应,用2mol/L的氢氧化钠溶液将此反应体系的pH调至大于7,然后用乙酸乙酯萃取多次,将有机溶液合并,减压旋转除去溶剂后直接柱层析分离得到纯的产物4,产物的对映体过量用手性液相色谱测定。
将上步所得的二氢吲哚含硫化合物4置于25mL反应瓶中,加入合适的搅拌子,然后加入1mL二氯甲烷,搅拌5分钟后,对此体系加入100微升三氟醋酸和100微升三乙基硅烷,室温搅拌至点板显示原料消失。然后对此反应体系加入饱和碳酸氢钠溶液至没有气泡冒出。用乙酸乙酯萃取多次,将有机溶液合并,所得有机溶剂真空浓缩后直接柱层析分离得到纯的产物5(产率为分离收率,产物的对映体过量用手性液相色谱测定),反应式如下:
Daicel AD-H column);正己烷:异丙醇=95:5,流速为0.5毫升每分钟,检测波长为254纳米,主要峰的保留时间为14.4分钟,另一个对映体的保留时间为18.7分钟(n-hexane/i-PrOH 95:5at 0.5mL/min,λ=254nm,tmajor=14.4min,tminor=18.7min);[α]20 D=+31.40(c=0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.86(d,J=7.1Hz,1H),7.60(s,1H),7.35(dt,J=6.5,3.9Hz,6H),7.32-7.28(m,1H),7.25-7.21(m,1H),7.18(d,J=7.1Hz,2H),7.15-7.00(m,13H),4.82(s,1H),2.06(s,3H).13C NMR(101MHz,CDCl3)δ144.8,143.3,135.4,130.6,130.1,129.4,128.0,127.9,127.7,126.6,126.0,121.2,120.5,119.4,113.9,110.2,77.4,77.1,76.8,69.7,46.8,12.4.高分辨质谱{HRMS(ESI)m/z[M+Cl]-}计算为(calcd.for)C35H29ClNS:530.1709,found:530.1714.
AD-H column);正己烷:异丙醇=95:5,流速为0.5毫升每分钟,检测波长为254纳米,主要峰的保留时间为18.7分钟,另一个对映体的保留时间为16.7分钟;(n-hexane/i-PrOH95:5at 0.5mL/min,λ=254nm,tminor=16.7min,tmajor=18.7min);[α]20 D=+37.40(c=0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.77(d,J=7.6Hz,1H),7.65(s,1H),7.37(dd,J=6.7,2.9Hz,6H),7.32–7.27(m,2H),7.18-7.04(m,13H),7.01(d,J=8.6Hz,2H),4.81(s,1H),2.09(s,3H).13C NMR(101MHz,CDCl3)δ144.6,141.8,135.4,131.6,130.7,130.1,129.4,129.2,127.9,127.8,126.7,121.4,120.1,119.6,113.6,110.4,69.7,46.0,12.4.高分辨质谱{HRMS(ESI)m/z[M+Cl]-}计算为(calcd.for)C35H28Cl2NS:564.1320,found:564.1339.
Daicel AD-H column);正己烷:异丙醇=95:5,流速为0.5毫升每分钟,检测波长为254纳米,主要峰的保留时间为14.4分钟,另一个对映体的保留时间为18.7分钟(n-hexane/i-PrOH 95:5at 0.5mL/min,λ=254nm,tmajor=16.9min,tminor=24.7min);[α]20 D=+194.39(c=0.5,CHCl3).1H NMR(400MHz,CDCl3)δ8.15(dd,J=7.9,1.0Hz,1H),7.80(d,J=7.7Hz,1H),7.66(s,1H),7.48-7.37(m,6H),7.21(d,J=7.5Hz,1H),7.17-7.01(m,12H),7.00-6.87(m,2H),5.37(s,1H),2.33(s,3H).13C NMR(101MHz,CDCl3)δ144.3,139.4,135.4,132.7,131.4,131.2,130.0,129.1,127.8,127.3,127.1,126.6,126,121.2,120.2,119.4,111.9,110.3,69.3,44.0,13.5.高分辨质谱{HRMS(ESI)m/z[M+Cl]-}计算为(calcd.for)C35H28Cl2NS:564.1320,found:564.1339.
AD-H column);正己烷:异丙醇=97:3,流速为0.3毫升每分钟,检测波长为254纳米,主要峰的保留时间为30.8分钟,另一个对映体的保留时间为34.5分钟(n-hexane/i-PrOH 97:3at0.3mL/min,λ=254nm,tmajor=30.8min,tminor=34.5min);[α]20 D=+65.80(c 0.5,CHCl3).1HNMR(400MHz,CDCl3)δ7.77(d,J=7.2Hz,1H),7.68(s,1H),7.37(ddd,J=8.0,5.4,2.7Hz,6H),7.29(t,J=5.5Hz,2H),7.18-7.10(m,10H),7.09-7.05(m,1H),7.00(s,1H),6.98–6.90(m,2H),4.82(s,1H),2.16(s,3H).13C NMR(101MHz,CDCl3)δ145.2,144.5,135.4,133.48,130.7,130.1,129.4,129.1,127.9,127.9,127.8,126.7,126.0,121.5,120.0,119.7,113.6,110.4,69.7,46.2,12.5.高分辨质谱{HRMS(ESI)m/z[M+Cl]-}计算为(calcd.for)C35H28Cl2NS:564.1320,found:564.1343.
using Daicel AD-H column);正己烷:异丙醇=95:5,流速为0.5毫升每分钟,检测波长为254纳米,主要峰的保留时间为15.3分钟,另一个对映体的保留时间为18.6分钟(n-hexane/i-PrOH 95:5at 0.5mL/min,λ=254nm,tmajor=15.3min,tminor=18.6min);[α]20 D=+66.00(c 0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.76(d,J=7.5Hz,1H),7.62(s,1H),7.38-7.30(m,6H),7.27(d,J=6.6Hz,1H),7.22(s,1H),7.15-7.05(m,12H),6.70(t,J=8.7Hz,2H),4.79(s,1H),2.07(s,3H).13C NMR(101MHz,CDCl3)δ162.4,160.0,144.6,139.0,135.4,130.1,129.4,129.3(d,J=8Hz),127.9,127.7,126.6,121.4,120.2,119.6,114.6(d,J=22Hz),110.35,69.7,45.9,12.4.19F NMR(377MHz,CDCl3)δ-115.74.高分辨质谱{HRMS(ESI)m/z[M+Cl]-}计算为(calcd.for)C35H29ClNS:548.1615,found:548.1624.
determined by chiral stationary phase HPLC analysis using Daicel AD-Hcolumn);正己烷:异丙醇=95:5,流速为0.5毫升每分钟,检测波长为254纳米,主要峰的保留时间为19.9分钟,另一个对映体的保留时间为16.9分钟(n-hexane/i-PrOH95:5at0.5mL/min,λ=254nm,tminor=16.9min,tmajor=19.9min);[α]20 D=+66.00(c=0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.78(d,J=7.6Hz,1H),7.65(s,1H),7.38(dd,J=6.7,3.0Hz,6H),7.32(dd,J=8.1,3.4Hz,1H),7.27-7.24(m,1H),7.18-7.12(m,12H),7.03(d,J=8.5Hz,2H),4.81(s,1H),2.09(s,3H).13C NMR(101MHz,CDCl3)δ144.6,142.3,135.5,130.9,130.1,129.6,129.46,128,127.8,126.7,121.5,120.1,119.8,119.6,113.5,110.4,69.8,46.1,12.4.高分辨质谱{HRMS(ESI)m/z[M+Cl]-}计算为(calcd.for)C35H28BrClNS:608.0814,found:608.0834.
using Daicel AD-H column);正己烷:异丙醇=95:5,流速为0.3毫升每分钟,检测波长为254纳米,主要峰的保留时间为20.4分钟,另一个对映体的保留时间为28.3分钟(n-hexane/i-PrOH 95:5at 0.3mL/min,λ=254nm,tmajor=20.4min,tminor=28.3min);[α]20 D=+137.19(c=0.5,CHCl3).1H NMR(400MHz,CDCl3)δ8.50(d,J=7.9Hz,1H),7.74(d,J=7.8Hz,1H),7.67(s,1H),7.45(dd,J=8.0,1.5Hz,6H),7.33(t,J=7.7Hz,3H),7.21(d,J=7.6Hz,1H),7.17–7.07(m,11H),5.76(s,1H),2.25(s,3H).13C NMR(101MHz,CDCl3)δ144.3,139.3,135.3,132.4,131.5,130.9,130.0,127.7,127.2,126.2,126.1(q,J=7Hz),124.3(q,J=273Hz),121.2,120.1,119.3,112.40,110.3,69.1,43.2,13.4,13.34.19F NMR(377MHz,CDCl3)δ-57.01.高分辨质谱{HRMS(ESI)m/z[M+Cl]-}计算为(calcd.for)C36H28ClF3NS:598.1583,found:598.1599.
AD-H column);正己烷:异丙醇=97:3,流速为0.3毫升每分钟,检测波长为254纳米,主要峰的保留时间为36分钟,另一个对映体的保留时间为33.7分钟(n-hexane/i-PrOH 97:3at0.3mL/min,λ=254nm,t minor=33.7min,tmajor=36.0min);[α]20 D=+9.20(c=0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.91–7.84(m,1H),7.55(s,1H),7.36(dt,J=7.0,4.0Hz,6H),7.33-7.28(m,1H),7.23(dd,J=6.7,1.8Hz,1H),7.16-7.09(m,12H),6.91(d,J=8.0Hz,2H),4.81(s,1H),2.24(s,3H),2.02(s,3H).13C NMR(101MHz,CDCl3)δ144.8,140.4,135.6,135.5,130.6,130.2,129.5,128.8127.8,127.7,126.5,121.2,120.6,119.4,113.9,110.2,69.7,46.5,21.0,12.3.高分辨质谱{HRMS(ESI)m/z[M+Cl]-}计算为(calcd.for)C36H31ClNS:544.1866,found:544.1878.
AD-H column);正己烷:异丙醇=95:5,流速为0.5毫升每分钟,检测波长为254纳米,主要峰的保留时间为13.7分钟,另一个对映体的保留时间为23.4分钟(n-hexane/i-PrOH 95:5at0.5mL/min,λ=254nm,tmajor=13.7min,tminor=23.4min);[α]20 D=+174.99(c=0.5,CHCl3).1H NMR(400MHz,CDCl3)δ8.06(d,J=7.7Hz,1H),7.72(d,J=7.6Hz,1H),7.64(s,1H),7.38(dd,J=6.7,3.0Hz,5H),7.29(q,J=4.5Hz,2H),7.21(d,J=7.3Hz,1H),7.14-7.01(m,11H),6.93(t,J=7.0Hz,1H),6.77(d,J=7.5Hz,1H),5.03(s,1H),2.21(s,3H),1.75(s,3H).13C NMR(101MHz,CDCl3)δ144.6,140.1,135.2,135.0,131.2,130.1,129.9,129.9,129.4,127.9,127.6,126.5,126.0,125.2,121.2,120.1,119.3,110.2,69.4,43.9,19.8,13.4.高分辨质谱{HRMS(ESI)m/z[M+Cl]-}计算为(calcd.for)C36H31ClNS:544.1866,found:544.1890.
Daicel AD-H column);正己烷:异丙醇=95:5,流速为0.5毫升每分钟,检测波长为254纳米,主要峰的保留时间为21分钟,另一个对映体的保留时间为25.7分钟(n-hexane/i-PrOH95:5at 0.5mL/min,λ=254nm,tmajor=21.0min,tminor=25.7min);[α]20 D=+6.80(c 0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.86(d,J=7.2Hz,1H),7.59(s,1H),7.36(dd,J=6.7,2.9Hz,6H),7.24(d,J=7.0Hz,1H),7.19-7.03(m,13H),6.63(d,J=8.7Hz,2H),4.80(s,1H),3.71(s,3H),2.02(s,3H).13C NMR(101MHz,CDCl3)δ157.9,144.8,135.6,135.5,130.5,130.1,128.0,127.8,127.7,126.5,121.2,120.5,119.4,114.1,113.4,110.2,69.7,55.3,46.1,12.3.高分辨质谱{HRMS(ESI)m/z[M+Cl]-}计算为(calcd.for)C36H31ClNOS:560.1815,found:560.1825.
Daicel AD-H column);正己烷:异丙醇=90:10,流速为1毫升每分钟,检测波长为254纳米,主要峰的保留时间为80.6分钟,另一个对映体的保留时间为14.6分钟(n-hexane/i-PrOH90:10at 1.0mL/min,λ=254nm,tmajor=8.6min,tminor=14.6min);[α]20 D=+61.20(c=0.5,CHCl3).1H NMR(400MHz,CDCl3)δ8.37–8.28(m,1H),7.70(s,1H),7.54(d,J=8.0Hz,1H),7.52-7.43(m,6H),7.39(dd,J=8.0,1.2Hz,1H),7.30(d,J=7.7Hz,1H),7.20-7.02(m,12H),7.01-6.93(m,1H),6.00(s,1H),2.25(s,3H).13C NMR(101MHz,CDCl3)δ148.3,144.2,135.8,135.4,131.7,131.4,131.4,129.9,127.9,127.1,126.8,126.7,124.2,121.5,119.7,119.5,111.8,110.4,69.2,41.6,12.8.HRMS(ESI)m/z[M+Cl]-calcd.forC35H28ClN2O2S:575.1560,found:575.1567.
AD-H column);正己烷:异丙醇=97:3,流速为0.3毫升每分钟,检测波长为254纳米,主要峰的保留时间为40.7分钟,另一个对映体的保留时间为43.9分钟(n-hexane/i-PrOH 97:3at0.3mL/min,λ=254nm,tmajor=40.7min,tminor=43.9min);[α]20 D=+84.79(c=0.5,CHCl3).1HNMR(400MHz,CDCl3)δ8.09(d,J=7.2Hz,1H),7.91(d,J=7.1Hz,1H),7.67(d,J=8.0Hz,1H),7.54(d,J=8.2Hz,1H),7.48(d,J=9.0Hz,2H),7.43-7.35(m,6H),7.27(td,J=7.6,3.7Hz,2H),7.21(d,J=8.0Hz,1H),7.19-7.06(m,4H),7.04-6.99(m,8H),5.73(s,1H),2.12(s,3H).13C NMR(101MHz,CDCl3)δ144.5,137.4,135.2,133.8,131.5,130.7,130.0,128.5,127.9,127.8,127.7,127.0,126.5,125.4,125.1,125.0,123.5,121.1,120.2,119.5,112.9,110.3,69.3,43.0,13.3.HRMS(ESI)m/z[M+Cl]-calcd.for C39H31ClNS:580.1866,found:580.1869.
Daicel AD-H column);正己烷:异丙醇=97:3,流速为0.3毫升每分钟,检测波长为254纳米,主要峰的保留时间为15.8分钟,另一个对映体的保留时间为23.2分钟(n-hexane/i-PrOH 97:3at 0.3mL/min,λ=254nm,tmajor=15.8min,tminor=23.2min);[α]20 D=+56.40(c0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.71(d,J=7.8Hz,1H),7.62(s,1H),7.39–7.32(m,6H),7.28(d,J=4.1Hz,1H),7.20-7.10(m,10H),7.10-7.06(m,1H),7.04(dd,J=5.2,1.1Hz,1H),6.70(dd,J=5.0,3.6Hz,1H),6.65-6.58(m,1H),4.98(d,J=0.7Hz,1H),1.97(s,3H).13C NMR(101MHz,CDCl3)δ148.0,144.7,135.5,131.1,130.1,127.7,127.4,126.7,126.3,125.4,124.5,121.4,120.5,119.4,113.7,110.2,69.9,42.1,12.1.HRMS(ESI)m/z[M+Cl]-calcd.for C33H27ClNS2:536.1273,found:536.1278.
=97:3,流速为0.3毫升每分钟,检测波长为254纳米,主要峰的保留时间为19.2分钟,另一个对映体的保留时间为17.8分钟(n-hexane/i-PrOH 95:5at 0.5mL/min,λ=254nm,tminor=17.8min,tmajor=19.2min);[α]20 D=+15.00(c 0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.56(s,1H),7.51(dd,J=10.2,2.4Hz,1H),7.35(dd,J=6.8,2.9Hz,6H),7.17(t,J=5.2Hz,2H),7.15-7.03(m,13H),6.85(td,J=9.0,2.5Hz,1H),4.77(s,1H),2.04(s,3H).13C NMR(101MHz,CDCl3)δ158.9,156.5,144.6,143.0,132.7,131.8,130.0,128.2,127.8,127.7,126.6,126.2,110.6(d,J=10Hz),110.1,109.3(d,J=26Hz)105.5(d,J=24Hz),69.8,46.6,12.5.19F NMR(377MHz,CDCl3)δ-122.75.高分辨质谱{HRMS(ESI)m/z[M+Cl]-}计算为(calcd.for)C35H28ClFNS:548.1615,found:548.1639.
钟,检测波长为254纳米,主要峰的保留时间为11.6分钟,另一个对映体的保留时间为11.6分钟;(n-hexane/i-PrOH 95:5at 0.5mL/min,λ=254nm,tmajor=11.6min,tminor=15.2min);[α]20 D=+89.99(c 0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.58(s,1H),7.51(s,1H),7.37(dt,J=13.0,7.3Hz,6H),7.30(dd,J=10.9,4.2Hz,1H),7.18(d,J=7.2Hz,2H),7.16-7.10(m,9H),7.05(dt,J=8.3,6.7Hz,3H),6.94(d,J=8.2Hz,1H),4.82(s,1H),2.47(s,3H),2.05(s,3H).13C NMR(101MHz,CDCl3)δ144.8,143.3,133.7,130.8,130.2,129.5,128.5,128.1,127.9,127.7,126.6,125.9,122.8,120.1,113.6,109.9,69.7,46.821.8,12.4.高分辨质谱{HRMS(ESI)m/z[M+Cl]-}计算为(calcd.for)C36H31ClNS:544.1866,found:544.1885.
chiral stationary phase HPLC analysis using Daicel AD-H column);正己烷:异丙醇=97:3,流速为0.3毫升每分钟,检测波长为254纳米,主要峰的保留时间为73.9分钟,另一个对映体的保留时间为78.7分钟(n-hexane/i-PrOH 97:3at 0.3mL/min,λ=254nm,tmajor=73.9min,tminor=78.7min);[α]20 D=-0.8(c=0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.80(s,1H),7.40–7.35(m,6H),7.30-7.24(m,3H),7.17-7.08(m,14H),7.00-6.94(m,2H),4.76(s,1H).13C NMR(101MHz,CDCl3)δ144.7,143.3,136.4,130.1,129.5,128.2,128.2,127.7,126.6,126.4,123.4,122.1,119.9,119.4,118.0,111.08,69.4,47.1.高分辨质谱{HRMS(ESI)m/z[M+Cl]-}计算为(calcd.for)C34H27ClNS:516.1553,found:516.1571.
AD-H column);正己烷:异丙醇=95:5,流速为0.5毫升每分钟,检测波长为254纳米,主要峰的保留时间为36.1分钟,另一个对映体的保留时间为15.8分钟;(n-hexane/i-PrOH 95:5at0.5mL/min,λ=254nm,tminor=15.8min,tmajor=36.1min);[α]20 D=+95.59(c=0.5,CHCl3).1H NMR(400MHz,CDCl3)δ8.16(d,J=7.7Hz,1H),7.86(s,1H),7.45(d,J=7.8Hz,1H),7.36-7.21(m,7H),7.08-7.10(m,10H),7.03(dd,J=8.3,6.1Hz,3H),6.92-6.95(m,5H),6.87-6.79(m,2H),4.91(s,1H).13C NMR(101MHz,CDCl3)δ144.6,142.9,136.5,135.6,132.5,129.7,129.4,128.9,128.7,128.6,128.6,128.2,128.0,127.9,127.4,127.4,126.4,126.1,122.6,122.5,120.0,113.9,111.0,69.845.9.高分辨质谱{HRMS(ESI)m/z[M+Cl]-}计算为(calcd.for)C40H31ClNS:592.1866,found:592.1893.
AD-H column);正己烷:异丙醇=95:5,流速为0.5毫升每分钟,检测波长为254纳米,主要峰的保留时间为9.9分钟,另一个对映体的保留时间为14.7分钟(n-hexane/i-PrOH 95:5at0.5mL/min,λ=254nm,tmajor=9.9min,tminor=14.7min);[α]20 D=+198.79(c=0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.82(d,J=7.1Hz,1H),7.57(s,1H),7.42(d,J=7.2Hz,6H),7.28-7.10(m,12H),3.47(d,J=8.5Hz,1H),2.14(t,J=12.0Hz,1H),1.94(s,3H),1.16-1.01(m,1H),0.86-0.96(m,1H),0.51(d,J=6.4Hz,3H),0.33(d,J=6.3Hz,3H).13C NMR(101MHz,CDCl3)δ145.3,135.9,130.4,130.1,127.7,126.5,121.2,120.4,119.2,113.3,110.3,100.0,68.8,46.3,41.1,26.0,23.7,20.7,12.1.高分辨质谱{HRMS(ESI)m/z[M+Cl]-}计算为(calcd.for)C33H33ClNS:510.2022,found:510.2046
AD-H column);正己烷:异丙醇=95:5,流速为0.5毫升每分钟,检测波长为254纳米,主要峰的保留时间为9.4分钟,另一个对映体的保留时间为15.3分钟(n-hexane/i-PrOH 95:5at0.5mL/min,λ=254nm,tmajor=9.4min,tminor=15.3min);[α]20 D=+219.38(c=0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.66(s,2H),7.50-7.42(m,6H),7.32-7.27(m,1H),7.25-7.14(m,9H),7.14-7.05(m,2H),3.42(dd,J=11.6,4.0Hz,1H),2.08(s,3H),1.99-1.81(m,1H),1.30–1.16(m,2H),0.88(dt,J=13.6,6.3Hz,2H),0.76(ddd,J=13.5,9.0,5.2Hz,1H),0.60(t,J=7.3Hz,3H).13C NMR(101MHz,CDCl3)δ145.3,130.8,130.1,129.4,128.0,128.0,127.7,126.5,121.1,119.2,113.5,110.3,68.7,42.5,37.3,30.4,22.2,14.0,12.3.高分辨质谱{HRMS(ESI)m/z[M+Cl]-}计算为(calcd.for)C33H33ClNS:510.2022,found:510.2046.
stationary phase HPLC analysis using Daicel AD-H column);正己烷:异丙醇=97:3,流速为0.5毫升每分钟,检测波长为254纳米,主要峰的保留时间为90.2分钟,另一个对映体的保留时间为41.7分钟(n-hexane/i-PrOH 97:3at 0.3mL/min,λ=254nm,t minor=41.7min,tmajor=90.2min);1H NMR(400MHz,CDCl3)δ7.42(d,J=7.3Hz,6H),7.29–7.09(m,11H),7.09–6.94(m,3H),6.68(dd,J=13.1,7.1Hz,3H),6.44(d,J=7.7Hz,1H),3.75-3.62(m,1H),3.58(d,J=5.5Hz,1H),3.02–2.88(m,1H),0.91(d,J=6.6Hz,3H).13C NMR(101MHz,CDCl3)δ144.7,141.7,130.1,129.3,128.1,127.8,127.7,127.6126.8,126.7,126.1,122.2,119.0,110.4,69.7,59.2,50.5,50.0,14.7.高分辨质谱{HRMS(ESI)m/z[M+Na]+}计算为(calcd.for)C35H31NNaS:520.2075,found:520.2086.
异丙醇=90:10,流速为0.7毫升每分钟,检测波长为254纳米,主要峰的保留时间为29.6分钟,另一个对映体的保留时间为16.8分钟,(n-hexane/i-PrOH 90:0at 0.7mL/min,λ=254nm,t minor=16.8min,t major=29.6min);1H NMR(400MHz,CDCl3)δ7.48-7.27(m,5H),6.95(t,J=7.6Hz,1H),6.61(d,J=7.7Hz,1H),6.40(t,J=7.5Hz,1H),5.96(d,J=7.5Hz,1H),4.25–4.13(m,2H),4.02(dd,J=11.5,7.2Hz,1H),2.02(d,J=5.4Hz,1H),1.30(d,J=6.3Hz,3H).13C NMR(101MHz,CDCl3)δ150.9,144.5,129.1,128.7,128.4,127.8,127.5,125.6,118.6,110.1,58.7,52.1,43.4,16.1.高分辨质谱{HRMS(ESI)m/z[M+Na]+}计算为(calcd.for)C16H18NS:256.1160,found:256.1162.
如实施案例1,当催化剂为如下图所示的非金鸡纳碱及其硫脲衍生物的手性有机碱(G-I)时,所得产物的手性含硫吲哚化合物的对映选择性较低,详见表2:
表2.其他手性有机碱催化不对称吲哚硫化反应a
[a]如无特殊说明,所有的反应均为1a(0.1毫摩尔),2(0.2毫摩尔,2当量),催化剂(10mol%)以及碱(0.2毫摩尔2当量)在室温下反应12小时(Unless otherwise noted,allreactions were carried out with 1a(0.1mmol),2(0.2mmol 2eq),catalyst(10mol%)and base(0.2mmol 2eq)at room temperature for 12h).[b]由反应完之后的粗产物经过核磁测定(Determined by 1HNMR spectroscopy of the crude mixture).[c]对映选择性由手性高效液相色谱测定(eewas determined by chiral HPLC).
本发明采用一种水油两相体系中手性有机碱催化硫醇对吲哚的不对称硫化方法,是对消旋的对甲基苯磺酰基吲哚在碱性条件下生成得到的插烯亚胺中间体进行硫化后能得到相应的手性吲哚硫化物,其产率可达99%,其对映体过量可达到98%。本发明操作简便易行,原料及催化剂均简单易得,使用水作为溶剂,反应条件绿色温和,产率高,对映选择性好,且反应在水相中进行,对环境友好。此外,通过不对称硫化合成手性吲哚硫化物和及衍生化得到的二氢吲哚硫化物,都具有潜在的医用价值。
Claims (8)
1.手性有机碱在水油两相体系制手性含硫吲哚化合物的应用,其特征在于:
所述手性有机碱为以下A-F物质的一种或两种以上;
其催化体系为在水油两相中使用手性有机碱催化硫醇对吲哚的不对称硫化方法;
制备手性含硫吲哚化合物反应式和条件如下:
式中:
温度:0℃至室温;
溶剂:水作为溶剂,加入有机溶剂以便将底物溶解;
时间:12-96小时;
碱:无机碱;
催化剂:手性有机碱,也称为手性有机碱催化剂;
所述R1为甲基、苯基或氢,R2为苯基、1位萘基、1位噻吩基、C5烷基或含有取代基的苯环,苯环上的取代基为F、Cl、Br,Me、MeO、CF3、NO2中的一种,取代基个数为1,R3为F或Me,R4为三苯基甲基,Ts为对甲基苯磺酰基。
2.如权利要求1所述的应用,其特征在于:
反应步骤为:在反应容器中投入手性有机碱催化剂,手性有机碱催化剂为底物对甲基苯磺酰基吲哚用量的1-20mol%,再加入相对于底物对甲基苯磺酰基吲哚用量的2到5倍摩尔当量的无机碱,然后加入对甲基苯磺酰基吲哚和硫醇化合物,对甲基苯磺酰基吲哚与硫醇的比为1/2-1/1.1,于此混合物中加入有机溶剂溶解,相对于每0.1mmol底物对甲基苯磺酰基吲哚有机溶剂的加入量为200微升至2毫升,再加入水,相于每0.1mmol底物对甲基苯磺酰基吲哚水的加入量为0.5毫升至4毫升,将此反应体系置于0℃至室温进行反应,反应结束后,分离纯化得产物。
3.如权利要求2所述的应用,其特征在于:
反应结束后,先加入相对于反应体系体积用量2倍至5倍范围的饱和食盐水,再用乙酸乙酯萃取,合并有机相,除去溶剂后直接柱层析分离得到纯的产物。
4.如权利要求1或2所述的应用,其特征在于:所用的无机碱为碳酸钠、碳酸钾、碳酸氢钠、氢氧化钠、氢氧化钾、碳酸铯或磷酸钾中的一种或二种以上。
5.如权利要求1或2所述的应用,其特征在于:反应中无机碱使用量和甲基苯磺酰基吲哚摩尔比为2:1,底物取对甲基苯磺酰基吲哚与硫醇的比为1/2-1/1.1,底物取甲基苯磺酰基吲哚与催化剂的摩尔比例是10:1。
6.如权利要求1或2所述的应用,其特征在于:反应所用的有机溶剂为甲苯、二氯甲烷、异丙醇、四氢呋喃、三氯甲烷、1,2二氯乙烷中的一种或二种以上。
7.如权利要求1或2所述的应用,其特征在于:所述反应式为对甲基苯磺酰基吲哚和三苯硫醇,无机碱为碳酸钠,溶剂为三氯甲烷和大量的水作为溶剂时,温度为0℃时,催化剂为奎宁丁硫脲衍生催化剂所述结果最佳。
8.如权利要求7所述的应用,其特征在于:当对甲基苯磺酰基吲哚底物用量为0.2mmol时,三氯甲烷的用量为200微升,水的用量为4毫升。
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