CN108218864B - 一种四氢-β-咔啉杂环化合物的绿色合成方法 - Google Patents
一种四氢-β-咔啉杂环化合物的绿色合成方法 Download PDFInfo
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- -1 tetrahydro-beta-carboline heterocyclic compound Chemical class 0.000 title claims abstract description 22
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 59
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims abstract description 34
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 239000001301 oxygen Substances 0.000 claims abstract description 30
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 30
- 239000003054 catalyst Substances 0.000 claims abstract description 27
- 239000002994 raw material Substances 0.000 claims abstract description 8
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- 238000006555 catalytic reaction Methods 0.000 claims abstract description 6
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- 238000009833 condensation Methods 0.000 claims abstract description 4
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- MOOUWXDQAUXZRG-UHFFFAOYSA-N 4-(trifluoromethyl)benzyl alcohol Chemical compound OCC1=CC=C(C(F)(F)F)C=C1 MOOUWXDQAUXZRG-UHFFFAOYSA-N 0.000 description 2
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- MOFLDTNKLMFGSU-UHFFFAOYSA-N bromobenzene;methanol Chemical compound OC.BrC1=CC=CC=C1 MOFLDTNKLMFGSU-UHFFFAOYSA-N 0.000 description 2
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- URIKPGVIMKEHQG-UHFFFAOYSA-N 1-(3-phenylprop-2-enyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole Chemical compound C(C=CC1=CC=CC=C1)C1NCCC=2C3=CC=CC=C3NC12 URIKPGVIMKEHQG-UHFFFAOYSA-N 0.000 description 1
- HPHJFDGJKPJDGN-UHFFFAOYSA-N 1-(4-bromophenyl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole Chemical compound C1=CC(Br)=CC=C1C1C(NC=2C3=CC=CC=2)=C3CCN1 HPHJFDGJKPJDGN-UHFFFAOYSA-N 0.000 description 1
- ILKMFTINEKPIRM-UHFFFAOYSA-N 1-(4-chlorophenyl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole Chemical compound C1=CC(Cl)=CC=C1C1C(NC=2C3=CC=CC=2)=C3CCN1 ILKMFTINEKPIRM-UHFFFAOYSA-N 0.000 description 1
- MQJWUWLVUZGILY-UHFFFAOYSA-N 1-(4-fluorophenyl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole Chemical compound C1=CC(F)=CC=C1C1C(NC=2C3=CC=CC=2)=C3CCN1 MQJWUWLVUZGILY-UHFFFAOYSA-N 0.000 description 1
- ITPCPUZQSFRMJO-UHFFFAOYSA-N 1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole Chemical compound C1=CC(OC)=CC=C1C1C(NC=2C3=CC=CC=2)=C3CCN1 ITPCPUZQSFRMJO-UHFFFAOYSA-N 0.000 description 1
- LCSGLJONOWTPBE-UHFFFAOYSA-N 1-(4-tert-butylphenyl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole Chemical compound C1=CC(C(C)(C)C)=CC=C1C1C(NC=2C3=CC=CC=2)=C3CCN1 LCSGLJONOWTPBE-UHFFFAOYSA-N 0.000 description 1
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- DARNQSDPWCIZTK-UHFFFAOYSA-N 1-fluoro-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole Chemical compound N1C2=CC=CC=C2C2=C1C(F)NCC2 DARNQSDPWCIZTK-UHFFFAOYSA-N 0.000 description 1
- INERHEQVAVQJBO-UHFFFAOYSA-N 1-phenyl-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole Chemical compound N1CCC(C2=CC=CC=C2N2)=C2C1C1=CC=CC=C1 INERHEQVAVQJBO-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
-
- B01J35/19—
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了一种四氢‑β‑咔啉杂环化合物的绿色合成方法，以醇类化合物为原料，在催化剂TEMPO和催化剂TBN催化下，色胺类化合物与醇在氧气下经氧化缩合环化的一锅串联反应得到四氢‑β‑咔啉类化合物，反应温度为40‑120℃，反应时间为6‑48小时。该方法使用廉价易得、来源广泛、稳定低毒、绿色的醇类化合物为原料，不使用任何过渡金属催化剂和配体，反应无需惰性气体保护，在氧气氛围下进行，使用廉价易得，相对绿色的醋酸为溶剂，易于操作，副产物为水，产物无重金属残留，绿色环保无污染。因此，本方法对反应条件的要求较低、适用范围较广，与已知方法相比优势明显，具有潜在广泛的应用前景。
Description
技术领域
本发明涉及化学合成技术领域，具体涉及一种四氢-β-咔啉杂环化合物的绿色合成方法。
背景技术
四氢-β-咔啉杂环结构是多种天然产物和重要药物的结构单元。以四氢-β-咔啉杂环为核心结构的药物包括haimine、(+)-harmicine、(+)-yohimbine、(+)-vellosimine、Tadalafil等等，种类繁多。众所周知，很多以四氢-β-咔啉杂环为核心结构的分子具有抗HIV、抗肿瘤、抗疟疾等生物活性。因此，四氢-β-咔啉环结构的合成一直是合成和药物化学家关注的焦点之一。
已知的四氢-β-咔啉杂环结构的合成方法包括传统的Pictet-Spengler缩合反应、Graebe-Ullmann偶联反应、Bischler-Napieralski反应等，主要以色胺及其衍生物和醛或活性较高的酮为原料。Pictet-Spengler反应常用催化剂包括布朗斯特酸如三氟乙酸、盐酸、冰醋酸、三氟甲磺酸、对甲苯磺酸、甲酸等，常用的路易斯酸如Yb(OTf)3、AuCl3/AgOTf等。由于Pictet-Spengler反应主要使用醛为原料，而醛臭味重毒性大且活泼不稳定难保存，每次使用前需纯化，存在很多缺点，另外有些方法还使用过渡金属催化剂和配体，导致产物中存在重金属残留，不适用于对金属残留要求很高的药物中间体合成，也限制了这些方法的进一步合成应用。
因此，开发无过渡金属催化剂参与的高效绿色合成四氢-β-咔啉杂环化合物的新方法对有机合成、生化和药物合成等多领域都是非常有意义的研究。
发明内容
针对现有技术存在的不足，本发明的目的在于提供一种四氢-β-咔啉杂环化合物的绿色合成方法，该方法使用来源广泛、廉价易得、稳定低毒的醇类为原料，在TEMPO和TBN的协同催化和醋酸溶剂条件下，实现色胺类化合物与醇进行高效率的氧化缩合环化串联反应制备四氢-β-咔啉环类化合物的绿色方法，副产物为水，高效无污染。
为实现上述目的，本发明提供了如下技术方案：一种四氢-β-咔啉杂环化合物的绿色合成方法，以醇类化合物为原料，在催化剂TEMPO和催化剂TBN催化下，色胺类化合物(无取代色胺和取代色胺等)与醇(如苄醇、肉桂醇、吡啶甲醇、噻吩甲醇及其取代的醇等)在氧气下经氧化缩合环化的一锅串联反应得到四氢-β-咔啉类化合物，反应温度为40-120℃，反应时间为6-48小时，反应式为：
其中：
R1可以是氢(H)，也可以是甲基、乙基等烷基、取代烷基、卤素原子、烷氧基等从简单到复杂的各种取代基。
R2可以是各种官能团取代在2-、3-、或4-位的苯基或其他取代芳基、取代呋喃、取代噻吩、取代吡啶等取代杂芳基，还可以是肉桂基、烯丙基、脂肪烷基等基团。
本发明所涉及的TEMPO和TBN催化剂商品有售，当TBN与TEMPO共同催化时，催化效率最高。
作为优选的，所述催化剂TEMPO和催化剂TBN均为非过渡金属催化剂，催化剂TEMPO是2,2,6,6-四甲基哌啶氮氧化物,催化剂TBN是亚硝酸叔丁酯。
作为优选的，所述催化剂TEMPO和催化剂TBN的用量均为10～100mol％。
作为优选的，所述催化剂TEMPO和催化剂TBN的用量采用15-30mol％。
作为优选的，在有溶剂条件下或在无溶剂条件下都能进行反应。
作为优选的，选择有溶剂条件下进行，溶剂采用醋酸溶剂。
作为优选的，在空气下或在氧气下都能进行反应，反应进行的温度选择40-80℃。
作为优选的，选择在氧气下进行反应，反应时间选择12—24小时。
本发明的优点是：与现有技术相比，本发明所使用的TEMPO和TBN催化剂已普遍商品化，可以直接购买得到。本发明使用廉价易得、来源广泛、稳定低毒、绿色的醇类化合物为原料，不使用任何过渡金属催化剂和配体，反应无需惰性气体保护，在氧气氛围下进行，使用廉价易得，相对绿色的醋酸为溶剂，易于操作，副产物为水，产物无重金属残留，绿色环保无污染。因此，本方法对反应条件的要求较低、适用范围较广，与已知方法相比优势明显，具有潜在广泛的应用前景。
下面结合说明书具体实施例对本发明作进一步说明。
具体实施方式
通过下述实施方式将有助于理解本发明，但并不限制于本发明的内容。
实施例1
色胺和苯甲醇制备1-苯基-四氢-β-咔啉
管形反应器中依次加入色胺(0.0801g,0.5mmol)，苯甲醇(0.0621ml，1.2equiv.)，TEMPO(0.0234g，30mol％)，TBN(0.0176ml，30mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在80℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率82％。1H NMR(500MHz,DMSO-d6):δ10.49(br s,1H),7.43(d,J＝8.0Hz,1H),7.36-7.28(m,5H),7.24(d,J＝8.0Hz,1H),7.02(t,J＝7.5Hz,1H),6.96(t,J＝7.5Hz,1H),5.15(s,1H),3.11-3.06(m,1H),2.98-2.94(m,1H),2.79-2.67(m,2H),1.87(s,1H).13C NMR(125.4MHz,DMSO-d6):δ142.7,135.9,134.9,128.5,128.1,127.2,126.8,120.5,118.2,117.5,111.0,108.2,56.4,40.9,21.9。
实施例2
色胺和4-甲氧基苯甲醇制备1-(4-甲氧基苯基)-四氢-β-咔啉
管形反应器中依次加入色胺(0.0801g,0.5mmol)，4-甲氧基苯甲醇(0.0745ml，1.2equiv.)，TEMPO(0.0234g，30mol％)，TBN(0.0176ml，30mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在80℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率94％。1H NMR(500MHz,DMSO-d6):δ10.44(br s,1H),7.41(d,J＝7.5Hz,1H),7.22(d,J＝7.5Hz,1H),7.20(d,J＝8.5Hz,2H),7.00(t,J＝7.5Hz,1H),6.95(t,J＝7.5Hz,1H),6.90(d,J＝8.5Hz,2H),5.12(s,1H),3.73(s,3H),3.11-3.09(m,1H),2.98-2.93(m,1H),2.79-2.66(m,2H),1.88(br s,1H).13C NMR(125.4MHz,DMSO-d6):δ158.6,135.9,135.1,134.5,129.6,126.8,120.5,118.1,117.5,113.5,111.0,108.0,55.9,55.1,41.1,21.9。
实施例3
色胺和4-甲基苯甲醇制备1-(4-甲基苯基)-四氢-β-咔啉
管形反应器中依次加入色胺(0.0801g,0.5mmol)，4-甲基苯甲醇(0.0733g，1.2equiv.)，TEMPO(0.0234g，30mol％)，TBN(0.0176ml，30mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在80℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率89％。1H NMR(500MHz,DMSO-d6):δ10.37(br s,1H),7.40(d,J＝7.5Hz,1H),7.21(d,J＝7.5Hz,1H),7.17-7.12(m,4H),6.99(t,J＝7.5Hz,1H),6.94(t,J＝7.5Hz,1H),5.04(s,1H),3.09-3.04(m,1H),2.94-2.89(m,1H),2.73-2.63(m,2H),2.28(s,1H).13C NMR(125.4MHz,DMSO-d6):δ140.1,136.2,135.9,135.5,128.6,128.3,126.8,120.4,118.1,117.4,110.9,108.1,56.3,41.3,22.2,20.7。
实施例4
色胺和3-甲基苯甲醇制备1-(3-甲基苯基)-四氢-β-咔啉
管形反应器中依次加入色胺(0.0801g,0.5mmol)，3-甲基苯甲醇(0.0722ml，1.2equiv.)，TEMPO(0.0234g，30mol％)，TBN(0.0176ml，30mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在80℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率80％。1H NMR(500MHz,DMSO-d6):δ10.40(br s,1H),7.40(d,J＝9.0Hz,1H),7.23-7.20(m,2H),7.11-7.06(m,3H),6.99(t,J＝7.0Hz,1H),6.94(t,J＝7.0Hz,1H),5.05(s,1H),3.10-3.06(m,1H),2.95-2.90(m,1H),2.77-2.63(m,2H),2.28(s,3H),1.85(s,1H).13CNMR(125.4MHz,DMSO-d6):142.9,137.1,135.9,135.3,128.9,127.9,127.8,126.8,125.6,120.4,118.1,117.4,111.0,108.1,56.6,41.3,22.2,21.0。
实施例5
色胺和2-甲基苯甲醇制备1-(2-甲基苯基)-四氢-β-咔啉
管形反应器中依次加入色胺(0.0801g,0.5mmol)，2-甲基苯甲醇(0.0733g，1.2equiv.)，TEMPO(0.0234g，30mol％)，TBN(0.0176ml，30mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在80℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率91％。1H NMR(500MHz,DMSO-d6):δ10.46(br s,1H),7.45(d,J＝7.5Hz,1H),7.24(t,J＝8.5Hz,2H),7.19(t,J＝7.0Hz,1H),7.08(t,J＝7.5Hz,1H),7.03(t,J＝7.5Hz,1H),6.98(t,J＝7.5Hz,1H),6.87(d,J＝7.5Hz,1H),5.33(s,1H),3.06-3.01(m,1H),2.97-2.92(m,1H),2.79-2.68(m,2H),2.46(s,3H).13C NMR(125.4MHz,DMSO-d6):δ140.7,136.8,135.9,135.3,130.4,128.6,127.0,126.9,125.3,120.4,118.1,117.4,110.9,108.7,53.5,40.9,22.3,18.8.
实施例6
色胺和4-叔丁基苯甲醇制备1-(4-叔丁基苯基)-四氢-β-咔啉
管形反应器中依次加入色胺(0.0801g,0.5mmol)，4-叔丁基苯甲醇(0.1062ml，1.2equiv.)，TEMPO(0.0234g，30mol％)，TBN(0.0176ml，30mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在80℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率71％。1H NMR(500MHz,DMSO-d6):δ10.42(br s,1H),7.40(d,J＝7.5Hz,1H),7.35(d,J＝8.0Hz,2H),7.21(d,J＝7.5Hz,1H),7.19(d,J＝8.0Hz,2H),6.99(t,J＝7.5Hz,1H),6.94(t,J＝7.5Hz,1H),5.05(s,1H),3.08-3.04(m,1H),2.93-2.89(m,1H),2.75-2.63(m,2H),1.27(s,9H),1.02(s,1H).13C NMR(125.4MHz,DMSO-d6):δ149.4,140.2,135.9,135.4,128.1,126.8,124.8,120.4,118.1,117.4,110.9,108.2,56.2,41.2,34.2,31.2,22.3。
实施例7
色胺和4-氟苯甲醇制备1-(4-氟苯基)-四氢-β-咔啉
管形反应器中依次加入色胺(0.0801g,0.5mmol)，4-氟苯甲醇(0.0655ml，1.2equiv.)，TEMPO(0.0234g，30mol％)，TBN(0.0176ml，30mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在80℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率75％。1H NMR(500MHz,DMSO-d6):δ10.56(br s,1H),7.46(d,J＝8.0Hz,1H),7.36-7.34(m,2H),7.28(d,J＝8.0Hz,1H),7.18(t,J＝8.5Hz,2H),7.06(t,J＝7.5Hz,1H),6.99(t,J＝7.5Hz,1H),5.24(s,1H),3.25-3.10(m,1H),3.03-2.99(m,1H),2.84-2.71(m,2H),1.91(s,1H).13C NMR(125.4MHz,DMSO-d6):δ161.4(d,J＝241.9Hz),139.3(d,J＝3.0Hz),135.9,135.1,130.2(d,J＝8.2Hz),128.3(d,J＝7.9Hz),126.8,120.5,117.9(d,J＝84.6Hz),114.7(d,J＝20.9Hz),111.0,108.3,55.8,41.2,22.1。
实施例8
色胺和4-氯苯甲醇制备1-(4-氯苯基)-四氢-β-咔啉
管形反应器中依次加入色胺(0.0801g,0.5mmol)，4-氯苯甲醇(0.0855g，1.2equiv.)，TEMPO(0.0234g，30mol％)，TBN(0.0176ml，30mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在80℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率64％。1H NMR(500MHz,DMSO-d6):δ10.47(br s,1H),7.43-7.37(m,3H),7.3(d,J＝8.0Hz,2H),7.23(d,J＝7.5Hz,1H),7.02(t,J＝7.5Hz,1H),6.96(t,J＝7.5Hz,1H),5.13(s,1H),3.08-3.03(m,1H),2.98-2.93(m,1H),2.77-2.65(m,2H),1.89(s,1H).13C NMR(125.4MHz,DMSO-d6):δ142.0,135.9,134.8,131.7,130.3,127.9,126.8,120.6,118.2,117.5,111.0,108.4,55.8,41.1,22.1。
实施例9
色胺和4-溴苯甲醇制备1-(4-溴苯基)-四氢-β-咔啉
管形反应器中依次加入色胺(0.0801g,0.5mmol)，4-溴苯甲醇(0.1122g，1.2equiv.)，TEMPO(0.0234g，30mol％)，TBN(0.0176ml，30mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在80℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率65％。1H NMR(500MHz,DMSO-d6):δ10.46(br s,1H),7.52(d,J＝8.0Hz,2H),7.42(d,J＝8.0Hz,1H),7.25-7.22(m,3H),7.02(t,J＝7.5Hz,1H),6.96(t,J＝7.5Hz,1H),5.12(s,1H),3.08-3.04(m,1H),2.98-2.93(m,1H),2.78-2.65(m,2H),1.89(s,1H).13C NMR(125.4MHz,DMSO-d6):δ142.5,135.9,134.8,130.9,130.6,128.5,126.8,120.6,120.2,118.2,117.5,111.0,108.3,55.9,41.1,22.1。
实施例10
色胺和4-硝基苯甲醇制备1-(4-硝基苯基)-四氢-β-咔啉
管形反应器中依次加入色胺(0.0961g,1.2equiv.)，4-硝基苯甲醇(0.0766g，0.5mmol)，TEMPO(0.0395g，50mol％)，TBN(0.0293ml，50mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在40℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率42％。1H NMR(500MHz,DMSO-d6):δ10.55(br s,1H),8.22(d,J＝9.0Hz,2H),7.58(d,J＝9.0Hz.2H),7.45(d,J＝7.5Hz,1H),7.25(d,J＝8.0Hz,1H),7.04(t,J＝8.0Hz,1H),6.98(t,J＝7.5Hz,1H),5.25(s,1H),3.05-2.96(m,2H),2.79-2.67(m,2H),1.24(s,1H).13C NMR(125.4MHz,DMSO-d6):δ150.9,146.7,136.0,134.1,129.7,126.8,123.2,120.8,118.3,117.7,111.1,108.6,55.7,40.9,22.0。
实施例11
色胺和3-硝基苯甲醇制备1-(3-硝基苯基)-四氢-β-咔啉
管形反应器中依次加入色胺(0.0801g,0.5mmol)，3-硝基苯甲醇(0.0712ml，1.2equiv.)，TEMPO(0.0234g，30mol％)，TBN(0.0176ml，30mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在80℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率56％。1H NMR(500MHz,DMSO-d6):δ10.54(br s,1H),8.18(d,J＝7.5Hz,2H),7.79(d,J＝7.5Hz,1H),7.65(t,J＝8.0Hz,1H),7.45(d,J＝7.5Hz,1H),7.25(d,J＝8.0Hz,1H),7.04(t,J＝7.5Hz,1H),6.98(t,J＝7.5Hz,1H),5.29(s,1H),3.09-2.97(m,2H),2.81-2.68(m,2H),1.24(s,1H).13C NMR(125.4MHz,DMSO-d6):δ147.7,145.5,136.0,135.2,134.2,129.6,126.8,122.9,122.2,120.8,118.4,117.7,111.1,108.6,55.7,41.2,21.9.
实施例12
色胺和4-三氟甲基苯甲醇制备1-(4-三氟甲基苯基)-四氢-β-咔啉
管形反应器中依次加入色胺(0.0801g,0.5mmol)，4-三氟甲基苯甲醇(0.0821ml，1.2equiv.)，TEMPO(0.0234g，30mol％)，TBN(0.0176ml，30mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在80℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率60％。1H NMR(500MHz,DMSO-d6):δ10.48(br s,1H),7.69(d,J＝8.0Hz,2H),7.51(d,J＝8.0Hz,2H),7.43(d,J＝8.0Hz,1H),7.23(d,J＝8.0Hz,1H),7.02(t,J＝7.0Hz,1H),6.96(t,J＝7.0Hz,1H),5.18(s,1H),3.05-2.94(m,2H),2.76-2.66(m,2H).13C NMR(125.4MHz,DMSO-d6):δ147.9,135.9,134.5,129.2,127.8(d,J＝31.5Hz),126.8(d,J＝4.0Hz),124.9(q,J＝3.3Hz),124.4(d,J＝271.1Hz),120.7,118.3,117.6,111.0,108.5,56.1,41.1,22.1。
实施例13
色胺和2-萘甲醇制备1-(2-萘基)-四氢-β-咔啉
管形反应器中依次加入色胺(0.0801g,0.5mmol)，2-萘甲醇(0.0949g，1.2equiv.)，TEMPO(0.0234g，30mol％)，TBN(0.0176ml，30mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在80℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率65％。1H NMR(500MHz,DMSO-d6):δ10.47(br s,1H),7.89-7.85(m,3H),7.77(s,1H),7.49-7.47(m 3H),7.45(d,J＝7.5Hz,1H),7.22(d,J＝8.0Hz,1H),7.01(t,J＝7.0Hz,1H),6.97(t,J＝7.0Hz,1H),5.29(s,1H),3.18-3.13(m,1H),3.02-2.98(m,1H),2.85-2.69(m,2H),1.89(s,1H).13C NMR(125.4MHz,DMSO-d6):δ140.7,136.0,135.4,132.8,132.5,127.8,127.6,127.4,127.0,126.9,126.8,125.9,125.7,120.5,118.2,117.6,111.1,108.3,56.9,41.6,22.3。
实施例14
色胺和3-吡啶甲醇制备1-(3-吡啶)-四氢-β-咔啉
管形反应器中依次加入色胺(0.0801g,0.5mmol)，3-吡啶甲醇(0.0655g，1.2equiv.)，TEMPO(0.0234g，30mol％)，TBN(0.0176ml，30mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在80℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率63％。1H NMR(500MHz,DMSO-d6):δ10.58(br s,1H),8.54(s,1H),8.49(d,J＝5.0Hz,1H),7.61(d,J＝7.5Hz,1H),7.43(d,J＝7.5Hz,1H),7.34(q,J＝5.0Hz,1H),7.23(d,J＝8.0Hz,1H),7.02(t,J＝7.5Hz,1H),6.96(t,J＝7.5Hz,1H),5.16(s,1H),3.07-3.03(m,1H),2.98-2.94(m,1H),2.78-2.65(m,2H),1.85(s,1H).13C NMR(125.4MHz,DMSO-d6):δ149.7,148.3,138.4,136.0,135.8,134.4,126.8,123.3,120.6,118.2,117.6,111.0,108.5,54.2,41.1,22.0。
实施例15
色胺和2-吡啶甲醇制备1-(2-吡啶)-四氢-β-咔啉
管形反应器中依次加入色胺(0.0801g,0.5mmol)，2-吡啶甲醇(0.0579ml，1.2equiv.)，TEMPO(0.0234g，30mol％)，TBN(0.0176ml，30mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在80℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率77％。1H NMR(500MHz,DMSO-d6):δ11.43(br s,1H),8.79(d,J＝4.0Hz,1H),8.21(d,J＝8.0Hz,1H),7.97(t,J＝8.0Hz,1H),7.62(dd,J1＝8.0Hz,J2＝17.5Hz,2H),7.56(t,J＝6.0Hz,1H),7.23(t,J＝7.5Hz,1H),7.07(t,J＝7.5Hz,1H),4.03(t,J＝8.0Hz,2H),2.91(t,J＝8.0Hz,2H).13C NMR(125.4MHz,DMSO-d6):δ155.7,155.5,148.3,137.1,136.6,127.3,124.7,124.3,123.7,120.9,119.4,119.3,116.1,113.0,48.4,18.7。
实施例16
色胺和2-噻吩甲醇制备1-(2-噻吩)-四氢-β-咔啉
管形反应器中依次加入色胺(0.0801g,0.5mmol)，2-噻吩甲醇(0.0568ml，1.2equiv.)，TEMPO(0.0234g，30mol％)，TBN(0.0176ml，30mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在80℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率47％。1H NMR(500MHz,DMSO-d6):δ10.65(br s,1H),7.40(d,J＝5.5Hz,2H),7.27(d,J＝8.0Hz,1H),7.04-6.95(m,4H),5.37(s,1H),3.09-2.97(m,2H),2.70-2.61(m,2H).13CNMR(125.4MHz,DMSO-d6):δ147.8,135.8,134.9,126.7,126.4,125.2,124.9,120.7,118.2,117.6,111.1,107.5,51.6,40.6,22.0。
实施例17
色胺和肉桂醇制备1-(肉桂基)-四氢-β-咔啉
管形反应器中依次加入色胺(0.0801g,0.5mmol)，肉桂醇(0.0808g，1.2equiv.)，TEMPO(0.0316g，30mol％)，TBN(0.0234ml，30mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在40℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率33％。1H NMR(500MHz,DMSO-d6):δ10.75(br s,1H),7.46(d,J＝8.0Hz,2H),7.38(d,J＝8.0Hz,1H),7.33(t,J＝7.5Hz,1H),7.28(d,J＝8.0Hz,1H),7.24(t,J＝7.5Hz,1H),7.01(t,J＝7.5Hz,1H),6.94(t,J＝7.5Hz,1H),6.65(d,J＝16.0Hz,1H),6.57(dd,J1＝6.5Hz,J2＝16.0Hz,1H),4.68(d,J＝6.5Hz,1H),3.19-3.14(m,1H),2.98-2.94(m,1H),2.66-2.59(m,2H),1.23(s,1H).13C NMR(125.4MHz,DMSO-d6):δ136.9,135.8,135.1,130.7,130.1,128.5,127.3,127.0,126.3,120.4,118.1,117.4,110.9,107.3,54.3,41.2,22.2。
实施例18
5-甲氧基色胺和苯甲醇制备1-苯基-6-甲氧基-四氢-β-咔啉
管形反应器中依次加入5-甲氧基色胺(0.0951g,0.5mmol)，苯甲醇(0.0621ml，1.2equiv.)，TEMPO(0.0234g，30mol％)，TBN(0.0176ml，30mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在80℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率58％。1H NMR(500MHz,DMSO-d6):δ10.25(br s,1H),7.34-7.25(m,5H),7.11(d,J＝8.5Hz,1H),6.91(d,J＝2.0Hz,1H),6.65(dd,J1＝2.5Hz,J2＝8.5Hz,1H),5.07(s,1H),3.75(s,3H),3.07-3.03(m,1H),2.95-2.90(m,1H),2.74-2.61(m,2H).13C NMR(125.4MHz,DMSO-d6):δ152.9,143.1,135.9,131.0,128.4,128.0,127.1,126.4,111.6,110.2,108.1,99.9,56.6,55.4,41.2,22.3。
实施例19
5-甲基色胺盐酸盐和苯甲醇制备1-苯基-6-甲基-四氢-β-咔啉
管形反应器中依次加入5-甲基色胺盐酸盐(0.1054g,0.5mmol)，苯甲醇(0.0621ml，1.2equiv.)，TEMPO(0.0117g，15mol％)，TBN(0.0089ml，15mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在60℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率92％。1H NMR(500MHz,DMSO-d6):δ10.45(br s,1H),7.38-7.31(m,5H),7.22(s,1H),7.13(d,J＝8.0Hz,1H),6.85(d,J＝8.0Hz,1H),5.30(s,1H),3.16-3.11(m,1H),3.07-3.02(m,1H),2.86-2.71(m,2H),2.37(s,3H).13C NMR(125.4MHz,DMSO-d6):δ140.7,134.4,133.3,128.8,128.2,127.8,126.7,122.3,117.3,110.9,107.5,56.2,40.8,21.2。
实施例20
6-氟色胺和苯甲醇制备1-苯基-7-氟-四氢-β-咔啉
管形反应器中依次加入6-氟色胺(0.0891g,0.5mmol)，苯甲醇(0.0621ml，1.2equiv.)，TEMPO(0.0234g，30mol％)，TBN(0.0176ml，30mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在80℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率78％。1H NMR(500MHz,DMSO-d6):δ10.54(br s,1H),7.40-7.27(m,6H),6.98(d,J＝9.0Hz,1H),6.81(d,J＝9.0Hz,1H),5.06(s,1H),3.08-3.04(m,1H),2.94-2.90(m,1H),2.75-2.63(m,2H),1.23(s,1H).13C NMR(125.4MHz,DMSO-d6):δ158.5(d,J＝232.2Hz),142.9,135.9(d,J＝3.4Hz),135.8(d,J＝12.5Hz),128.4,128.1,127.2,123.7,118.2(d,J＝10.2Hz),108.4,106.3(d,J＝24.1Hz),97.1(d,J＝25.5Hz),56.5,41.2,22.1。
实施例21
5-氯色胺和苯甲醇制备1-苯基-6-氯-四氢-β-咔啉
管形反应器中依次加入5-氯色胺(0.1156g,0.5mmol)，苯甲醇(0.0621ml，1.2equiv.)，TEMPO(0.0078g，15mol％)，TBN(0.0059ml，15mol％)和冰醋酸(0.5ml)，抽换气三次封管氧气，然后在60℃,搅拌下反应24h。TLC监测反应完全后，产物用柱色谱分离提纯，分离收率64％。1H NMR(500MHz,DMSO-d6):δ10.70(br s,1H),7.48(s,1H),7.34(d,J＝7.0Hz,1H),7.30-7.25(m,4H),7.03(d,J＝8.5Hz,1H),5.10(s,1H),3.10-3.05(m,1H),2.96-2.91(m,1H),2.77-2.64(m,2H).13C NMR(125.4MHz,DMSO-d6):δ142.8,137.3,134.4,128.4,128.1,128.0,127.2,122.9,120.3,116.8,112.4,108.3,56.6,41.1,22.0。
上述实施例对本发明的具体描述，只用于对本发明进行进一步说明，不能理解为对本发明保护范围的限定，本领域的技术工程师根据上述发明的内容对本发明作出一些非本质的改进和调整均落入本发明的保护范围之内。
Claims (3)
1.一种四氢-β-咔啉杂环化合物的绿色合成方法，以醇类化合物为原料，其特征在于：在30mol％催化剂TEMPO和30mol％催化剂TBN催化下、以醋酸为溶剂、色胺类化合物与醇在氧气下经氧化缩合环化的一锅串联反应得到四氢-β-咔啉类化合物，反应温度为40-120℃，反应时间为6-48小时，反应式为：
其中：
R1是氢；
R2是官能团取代在2-、3-、或4-位的苯基、肉桂基、烯丙基或脂肪烷基；
所述催化剂TEMPO和催化剂TBN均为非过渡金属催化剂，催化剂TEMPO是2,2,6,6-四甲基哌啶氮氧化物，催化剂TBN是亚硝酸叔丁酯。
2.根据权利要求1所述的一种四氢-β-咔啉杂环化合物的绿色合成方法，其特征在于：在氧气下反应进行的温度选择40-80℃。
3.根据权利要求1所述的一种四氢-β-咔啉杂环化合物的绿色合成方法，其特征在于：在氧气下进行反应的反应时间选择12—24小时。
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