CN108586457B - indole carbocycle dearomatization synthesis method based on nitrogen atom α hydrogen migration strategy - Google Patents
indole carbocycle dearomatization synthesis method based on nitrogen atom α hydrogen migration strategy Download PDFInfo
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- C07D471/12—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 three hetero rings
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Abstract
the invention relates to a synthesis method of tetrahydroquinoline spiroindole derivatives, which is an indole carbocycle dearomatization synthesis method based on a nitrogen atom α hydrogen migration strategy, wherein indole compounds and aminobenzaldehyde compounds undergo nitrogen atom α hydrogen migration in the presence of hexafluoroisopropanol to finally obtain indole carbocycle dearomatization products.
Description
Technical Field
the invention belongs to the technical field of chemical synthesis, and particularly relates to an indole carbocycle dearomatization synthesis method based on a nitrogen atom α hydrogen migration strategy.
Background
The dearomatization of an aromatic compound refers to a process of derivatizing the aromatic compound by destroying the pi-electron conjugated system of the aromatic ring under certain conditions. With the development of organic synthetic chemistry, the "dearomatization" reaction has attracted more and more attention of organic chemists in recent years. Through the dearomatization reaction, aromatic compounds can be used as effective synthons in organic synthesis, and a plurality of mature dearomatization catalytic systems emerge.
By designing aromatic substrates (such as indole, naphthol and the like), products of tetrahydroquinoline indoline frameworks and cyclic conjugated ketene frameworks can be constructed. This backbone structure occupies a critical position in the field of organic chemistry due to the unique nucleophilic activity of the indole moiety in biologically active molecules and natural product molecules. In current dearomatization strategies for indoles, the substrate range is also limited to the substitution of the double bond of the pyrrole ring therein. For example, in 2012, the MacMillan group reported dearomatization of indole derivatives using an arylation dearomatization strategy using monovalent copper with a BOX ligand catalyzed aryl iodide to yield a product of chiral tetrahydropyrroloindoline skeleton (j.am. chem.soc.,2012,134, 10815-10818.). In 2013, Davie group achieved dearomatization of indole by cycloaddition dearomatization strategy, and catalyzed asymmetric cycloaddition of triazole to indole derivatives by chiral divalent metal rhodium complex, thus obtaining chiral dihydropyrroloindoline skeleton products (J.Am.chem.Soc.,2013,135, 6802-6805.).
In 2011 Seidel et al reported a tandem hydroshifting/cyclization reaction of 2-tetrahydroisoquinolinylbenzaldehyde with indole to give indolocarbazepine compounds (j.am.chem.soc.2011,2,233.). Indole and aldehyde firstly generate an indolyl methanol structure, the indolyl methanol structure is dehydrated to generate carbocation under acidic condition, and then hydrogen migration/cyclization reaction is carried out to obtain a target product. The reaction needs to be heated to 150 ℃ under microwave conditions to occur, and the harsh conditions also limit the application of the reaction, as shown in fig. 1.
In 2015, grandbin and schqinglong groups reported the reaction of 2-methylindole with o-tetrahydropyrrole benzaldehyde to produce hydrogenated indole spiro tetrahydroquinoline compounds (j.org.chem.2015,80, 1155-1162). The possible mechanism is that the carbocation generated by addition-dehydration of indole and aldehyde is used as a hydrogen acceptor to realize hydrogen migration reaction, and because 2-position of indole is substituted, the generated imine carbocation can only be captured by 3-position of indole to realize dearomatization reaction of indole, as shown in figure 2.
Von min and colleagues utilize chiral N, N' -dioxide ligand as a catalyst to carry out a series reaction, and a spiro indole tetrahydroquinoline product (Chem-Eur.J.2015,21,1632.) is synthesized under mild conditions.
But the functionalization of indole carbocycle is more difficult, the functionalization of carbocycle at present needs transition metal as catalyst, and other groups must be contained on pyrrole ring to exert guiding or steric hindrance. However, no effective synthesis strategy exists for the exploration of the functionalization of indole carbocycle by direct dearomatization.
The tertiary amine effect proves to be a good scheme in the aspect of constructing heterocyclic compounds, compared with the traditional scheme, the tertiary amine effect does not need an additional oxidant, and can be used for synthesizing heterocycles containing N/O, but the reaction conditions are harsh due to the high potential energy difference required in the [1, N ] -H migration process, such as high temperature condition, strong Lewis acid or Bronsted acid; and the reaction must be preceded by an electron deficient olefinic group which serves as a hydrogen acceptor.
In addition, in the synthesis method based on the tertiary amino effect, there are other competing reactions, for example, imine positive ions generated by hydrogen migration of hydroxyl group ortho-position attack can construct seven-membered rings, eight-membered rings can be generated by positive ions generated by hydroxyl group attack, and these cannot realize dearomatization.
Therefore, an indole carbocyclic ring dearomatization method is needed, which can synthesize some molecules with complex even multidimensional structures based on an indole skeleton with high efficiency and high selectivity so as to expand the application of indole in organic synthesis reaction.
Disclosure of Invention
the invention aims to provide an indole carbocycle dearomatization synthesis method based on a nitrogen atom α hydrogen migration strategy, which has the advantages of simple and practical operation, good yield, green and economical reaction and environmental protection.
The synthesis method provided by the invention comprises the following steps:
indole compound A and amino formaldehyde compound B are reacted to obtain the tetrahydroquinoline spiroindole derivative, and the reaction is carried out in an alcohol solvent.
The tetrahydroquinoline spiroindole derivative is any one of compounds shown in a formula I:
wherein
In formula I, the dotted line represents an optional single bond;
n is 1 or 2;
R1any one of hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, nitro, methoxy, cyano, p-phenylacetyl, p-methoxyphenylethynyl, thienyl, borate and methyl acrylate; and is
R2Is selected from any one of methyl, phenyl and p-methylphenyl.
The indole compound A is any one of compounds shown in a formula II;
the amino formaldehyde compound B is any one of compounds shown in a formula III:
wherein
In the formulas II and III, the dotted line represents an optional single bond;
n is 1 or 2;
R1any one of hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, nitro, methoxy, cyano, p-phenylacetyl, p-methoxyphenylethynyl, thienyl, borate and methyl acrylate; and is
R2Is selected from any one of methyl, phenyl and p-methylphenyl.
The alcohol solvent is hexafluoroisopropanol.
The molar ratio of the compound A to the compound B is 1.3: 1.
The reaction is carried out at 25 ℃.
The invention provides a synthesis method of a compound shown as a formula I, which comprises the following steps:
adding the compound A and the compound B into hexafluoroisopropanol according to a proportion, stirring and reacting at 25 ℃, and concentrating and purifying after the reaction is finished to obtain a tetrahydroquinoline spiroindole derivative;
the reaction is represented by the following formula:
the concentration of the compound A in the reaction system is 0.065M, and the concentration of the compound B in the reaction system is 0.05M.
The technical scheme of the invention has the following beneficial effects:
the invention discloses a synthesis method of tetrahydroquinoline spiroindole derivatives, which is an indole carbon ring dearomatization synthesis method based on a nitrogen atom α -position hydrogen migration strategy, provides a brand-new strategy for the functionalization of indole carbon rings, and provides a new synthesis idea of complex multi-membered ring products.
Drawings
FIG. 1 shows the construction of indole cyclic compounds by Bronsted acid-catalyzed neutral redox;
FIG. 2 is a diagram of a hydrogen migration/cyclization promoted dearomatization of indole.
Detailed Description
The foregoing aspects of the present invention are further illustrated by the specific embodiments provided in the following examples, which should not be construed as limiting the scope of the above-described subject matter of the present invention to the following examples by those skilled in the art; all the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials, instruments and the like used in the following examples are commercially available unless otherwise specified.
Example 1
Taking a compound A1(4-hydroxyindole) 0.13mmol and Compound B1Adding 0.1mmol of (2-pyrrolidine benzaldehyde) into a reaction bottle, adding 2mL of HFIP hexafluoroisopropanol, reacting at 25 ℃ by stirring, determining the reaction condition by TLC thin layer chromatography, concentrating the reaction product by rotary evaporation after the reaction is finished, and purifying and separating on a silica gel column.
The separated product was analyzed by detection, and the analytical data result is as follows, the obtained product was the target product, and the yield was 72%.
The chemical formula is as follows: c19H18N2O
Precise molecular weight: 290.1419
Molecular weight: 290.3660
Structural formula (xvi):
yield: 72 percent
1H nuclear magnetic resonance (500MHz, DMSO) δ 11.62(s,1H),7.08(t, J ═ 7.6Hz,1H),7.01(d, J ═ 7.4Hz,1H),6.93(s,1H),6.74(d, J ═ 9.9Hz,1H), 6.61-6.49 (m,2H),6.43(s,1H),5.61(d, J ═ 9.9Hz,1H),3.69(dd, J ═ 9.8,5.8Hz,1H),3.48(t, J ═ 7.8Hz,1H),3.21(d, J ═ 15.6Hz,1H),3.09(dd, J ═ 16.6,9.0Hz,1H),2.54(s,1H),1.89(d, J ═ 15.6Hz,1H), 1.68 (dd, 10.8H), 1H, 1.9.8H, 1H, 1.8 (d, 1.8, 1H);13c nuclear magnetic resonance (126MHz, DMSO). delta. 195.6,143.3,140.3,134.1,129.3,127.8,121.8,119.808,119.2,117.8,115.4,110.9,105.5,64.7,48.1,47.5,39.1,27.6,23.5 high resolution Mass Spectrometry (ESI): calcd. for C19H18N2O[M+H]291.1419, the actual value is 291.1421.
In the following examples 2 to 13, the starting compound A and compound B were reacted in a molar ratio of 1.3: 1.
Example 2
Raw materials: 4-hydroxyindole, 4-trifluoromethyl-2-pyrrolidinobenzaldehyde
Reaction conditions are as follows: 25 ℃/HFIP
The product is as follows: the chemical formula is as follows: c20H17F3NO3
Precise molecular weight: 358.1293
Molecular weight: 358.3642
Structural formula (xvi):
yield: 85 percent of
1H nuclear magnetic resonance (500MHz, CDCl)3)δ8.54(s,1H),7.11(d,J＝7.7Hz,1H),6.82(d,J＝8.3Hz,2H),6.69(s,2H),6.63(d,J＝10.0Hz,1H),5.78(d,J＝9.9Hz,1H),3.90(dd,J＝10.0,5.5Hz,1H),3.53(t,J＝8.0Hz,1H),3.47(d,J＝15.9Hz,1H),3.20(dd,J＝16.7,8.5Hz,1H),2.67(d,J＝16.0Hz,1H),1.96(dd,J＝17.2,9.8Hz,2H),1.91–1.80(m,1H),1.38–1.21(m,1H)；13C nuclear magnetic resonance (126MHz, CDCl)3) Delta 196.3,143.0,140.1,135.2,129.3,125.7,123.5,120.4,119.6,116.6,111.5(m),106.7,106.4(m),64.8,48.4,47.2,39.1,27.5,23.5 high resolution Mass Spectrometry (ESI): calcd. for C20H17F3NO3[M+H]+359.1371, the actual value is 359.1379.
Example 3
Raw materials: 4-hydroxyindole, 4-cyano-2-pyrrolidinobenzaldehyde
Reaction conditions are as follows: 25 ℃/HFIP
The product is as follows: the chemical formula is as follows: c20H17N3O
Precise molecular weight: 315.1372
Molecular weight: 315.3760
Structural formula (xvi):
yield: 80 percent of
1H nuclear magnetic resonance (500MHz, DMSO) δ 7.20(d, J ═ 7.4Hz,1H),6.95(s,1H),6.92(d, J ═ 7.5Hz,1H),6.88(s,1H),6.76(d, J ═ 9.9Hz,1H),6.44(s,1H),5.53(d, J ═ 9Hz,1H), 3.77-3.66 (m,1H),3.54(t, J ═ 8.8Hz,1H),3.21(d, J ═ 16.2Hz,1H), 3.15-3.05 (m,1H),2.63(d, J ═ 16.2Hz,1H),1.89 (J, J ═ 18.2,8.2Hz,2H),1.70 (ddh), 7.5, 7.7, 1H), 1H (1H), 1.27.27 (d, J ═ 8.8.2 Hz, 1H);13c nuclear magnetic resonance (126MHz, DMSO). delta. 199.8,148.3,145.1,137.9,134.9,130.5,126.8,126.7,124.9,123.8,123.3,123.1,123.1,117.7,117.6,115.1,110.4,69.3,52.3,51.9,43.8,32.3,28.2 high resolution Mass Spectrometry (ESI): calcd. for C20H17N3O[M+H]+316.1372, the actual value is 316.1378.
Example 4
Raw materials: 4-hydroxyindole, 4-chloro-2-pyrrolidinobenzaldehyde
Reaction conditions are as follows: 25 ℃/HFIP
The product is as follows: the chemical formula is as follows: c19H17ClN2O
Precise molecular weight: 324.1029
Molecular weight: 324.8080
Structural formula (xvi):
yield: 76 percent of
1H nuclear magnetic resonance (500MHz, DMSO) δ 11.64(s,1H),7.01(d, J ═ 7.7Hz,1H),6.94(s,1H),6.75(d, J ═ 9.9Hz,1H),6.53(d, J ═ 7.4Hz,2H),6.44(s,1H),5.58(d, J ═ 9.9Hz,1H),3.70(dd, J ═ 9.7,5.8Hz,1H),3.49(t, J ═ 8.6Hz,1H),3.14(d, J ═ 15.8Hz,1H),3.09(d, J ═ 8.3Hz,1H),2.56(s,1H),1.88(dd, J ═ 17.2,7.8, 2H),1.74 (d, J ═ 8.3Hz,1H), 1.64H, 1.22-1H), 1.22-10 (m);13c nuclear magnetic resonance (126MHz, DMSO). delta. 195.3,144.4,140.3,133.6,132.2,130.5,121.9,119.1,118.8,118.1,114.6,109.9,105.6,64.5,47.7,47.5,38.6,27.5,23.5 high resolution Mass Spectrometry (ESI): calcd. for C19H17ClN2O[M+H]+325.1108, the actual value is 325.1110.
Example 5
Raw materials: 4-hydroxyindole, 4-methyl acrylate-2-pyrrolidinebenzaldehyde
Reaction conditions are as follows: 25 ℃/HFIP
The product is as follows: the chemical formula is as follows: c23H22N2O3
Precise molecular weight: 374.1630
Molecular weight: 374.4400
Structural formula (xvi):
yield: 60 percent of
1H nuclear magnetic resonance (500MHz, CDCl)3)δ8.87(s,1H),7.66(d,J＝15.9Hz,1H),7.04(d,J＝7.3Hz,1H),6.83–6.72(m,2H),6.64(t,J＝12.5Hz,3H),6.41(d,J＝15.9Hz,1H),5.80(d,J＝9.8Hz,1H),3.88(s,1H),3.81(s,3H),3.52(t,J＝8.3Hz,1H),3.46(d,J＝16.1Hz,1H),3.19(d,J＝8.4Hz,1H),2.65(d,J＝16.0Hz,1H),2.01–1.88(m,2H),1.87–1.78(m,1H),1.29(d,J＝10.3Hz,1H)；13C nuclear magnetic resonance (126MHz, CDCl)3) Delta 200.9,172.8,143.3,129.3,127.8,119.0,115.3,110.3,99.3,98.8,74.4,62.3,46.7,42.1,37.3,27.9,25.9,23.4 high resolution Mass Spectrometry (ESI): calcd. for C23H22N2O3[M+H]+375.1630, the actual value is 375.1631.
Example 6
Raw materials: 4-hydroxyindole, 4-p-phenylacetyl-2-pyrrolidinebenzaldehyde
Reaction conditions are as follows: 25 ℃/HFIP
The product is as follows: the chemical formula is as follows: c27H24N2O2
Precise molecular weight: 408.1838
Molecular weight: 408.5010
Structural formula (xvi):
yield: 72 percent
1H nuclear magnetic resonance (500MHz, CDCl)3)δ8.40(s,1H),8.02(d,J＝7.8Hz,2H),7.71(d,J＝7.7Hz,2H),7.14(d,J＝7.5Hz,1H),6.87(d,J＝7.5Hz,1H),6.81(s,1H),6.74(s,1H),6.70(s,1H),6.64(d,J＝9.9Hz,1H),5.91(d,J＝10.0Hz,1H),3.99–3.89(m,1H),3.59(t,J＝7.9Hz,1H),3.52(d,J＝15.8Hz,1H),3.27(d,J＝8.5Hz,1H),2.70(d,J＝15.9Hz,1H),2.64(s,3H),2.04–1.93(m,2H),1.90(dd,J＝11.9,5.4Hz,1H),1.35–1.29(m,1H)；13C nuclear magnetic resonance (126MHz, CDCl)3) Delta 197.9,196.5,146.7,143.4,140.1,139.2,135.8,135.6,129.6,128.8,127.2,120.3,120.2,119.7,116.3,114.2,108.8,106.6,64.8,49.0,47.2,39.1,27.6,26.7,23.6 high resolution Mass Spectrometry (ESI): calcd. for C27H24N2O2[M+H]+409.1838, the actual value is 409.1840.
Example 7
Raw materials: 4-hydroxyindole, 4-thienyl-2-pyrrolidinobenzaldehyde
Reaction conditions are as follows: 25 ℃/HFIP
The product is as follows: the chemical formula is as follows: c23H20N2OS
Precise molecular weight: 372.1296
Molecular weight: 372.4860
Structural formula (xvi):
yield: 60 percent of
1H nuclear magnetic resonance (500MHz, DMSO) δ 11.64(s,1H), 7.59-7.47 (m,1H),7.45(s,1H),7.12(s,1H),7.05(d, J ═ 7.5Hz,1H),6.95(s,1H),6.82(d, J ═ 7.5Hz,1H),6.76(s,2H),6.45(s,1H),5.65(d, J ═ 9.9Hz,1H), 3.80-3.68 (m,1H),3.58(t, J ═ 8.4Hz,1H), 3.26-3.11 (m,2H),2.56(d, J ═ 15.8Hz,1H),1.90(d, J ═ 22.7, 2H), 1.74-1.65 (m,1H), 1.21.21H, 21(d, 10H), 1H);13c nuclear magnetic resonance (126MHz, DMSO). delta. 195.5,144.9,143.6,140.3,134.0,133.4,129.9,128.7,125.2,123.4,121.8,119.8,119.2,117.9,113.0,107.6,105.6,64.7,48.2,47.5,38.9,27.6,23.5 high resolution Mass Spectrometry (ESI): calcd. for C23H20N2OS[M+H]+373.1296, the actual value is 373.1291.
Example 8
Raw materials: 4-hydroxyindole, 5-methoxy-2-pyrrolidinobenzaldehyde
Reaction conditions are as follows: 25 ℃/HFIP
The product is as follows: the chemical formula is as follows: c20H20N2O2
Precise molecular weight: 320.1525
Molecular weight: 320.3920
Structural formula (xvi):
yield: 55 percent of
1H nuclear magnetic resonance (500MHz, DMSO) δ 11.59(s,1H),6.92(s,1H),6.71(dd, J ═ 17.0,7.6Hz,3H),6.49(d, J ═ 8.5Hz,1H),6.41(s,1H),5.62(d,J＝9.9Hz,1H),3.64(d,J＝7.6Hz,3H),3.63–3.54(m,1H),3.42(t,J＝8.0Hz,1H),3.20(d,J＝15.8Hz,1H),3.10–2.99(m,1H),2.47(s,1H),1.92–1.75(m,2H),1.66(dd,J＝11.9,5.9Hz,1H),1.19–1.08(m,1H)；13C nuclear magnetic resonance (126MHz, DMSO). delta. 195.6,150.5,140.3,137.9,134.3,121.7,121.0,119.2,117.8,115.4,113.5,111.9,105.5,64.9,55.8,48.7,48.1,39.1,27.5,23.6. high resolution Mass Spectrometry (ESI): calcd. for C20H20N2O2[M+H]+321.1603, the actual value is 321.1602.
Example 9
Raw materials: 4-hydroxyindole, 5-chloro-2-pyrrolidinobenzaldehyde
Reaction conditions are as follows: 25 ℃/HFIP
The product is as follows: the chemical formula is as follows: c19H17ClN2O
Precise molecular weight: 324.1029
Molecular weight: 324.8080
Structural formula (xvi):
yield: 54 percent
1H nuclear magnetic resonance (500MHz, DMSO) δ 11.65(s,1H),7.10(d, J ═ 8.2Hz,2H),6.94(s,1H),6.76(d, J ═ 9.8Hz,1H),6.53(d, J ═ 8.3Hz,1H),6.44(s,1H),5.57(d, J ═ 9.8Hz,1H), 3.76-3.62 (m,1H),3.48(t, J ═ 8.3Hz,1H),3.17(d, J ═ 15.8Hz,1H), 3.12-3.00 (m,1H),2.56(d, J ═ 15.9Hz,1H),1.87(d, J ═ 21.8Hz,2H),1.69(d, J ═ 5, 1H), 1.23.09 (d, J ═ 1H);13c nuclear magnetic resonance (126MHz, CDCl)3) Delta 200.0,146.9,145.1,138.4,133.5,133.4,132.1,132.1,126.7,126.6,123.9,123.5,122.9,122.8,116.8,110.3,69.4,52.5,52.4,43.5,32.3,28.3 high resolution Mass Spectrometry (ESI): calcd. for C19H17ClN2O[M+H]+325.1029, the actual value is 325.1032.
Example 10
Raw materials: 4-hydroxyindole, 2-perhydroisoindolylbenzaldehyde
Reaction conditions are as follows: 25 ℃/HFIP
The product is as follows: chemistryFormula (II): c23H24N2O
Precise molecular weight: 344.1889
Molecular weight: 344.4580
Structural formula (xvi):
yield: 70 percent of
1H nuclear magnetic resonance (500MHz, DMSO) δ 11.43(s,1H),6.91(t, J ═ 7.6Hz,1H),6.82(d, J ═ 7.1Hz,1H),6.77(s,1H),6.54(d, J ═ 9.9Hz,1H),6.36(dd, J ═ 14.6,7.6Hz,2H),6.29(s,1H),5.41(d, J ═ 9.9Hz,1H),3.82(d, J ═ 9.7Hz,1H),3.08(d, J ═ 9.2Hz,1H),3.02(d, J ═ 15.2Hz,2H),2.33(s,1H),1.92(d, J ═ 5.4Hz,1H),1.60(s,1H),1.48(t, 1H), 1.9.9H, 1H, 13H), 13.13 (d, J ═ 9.9Hz, 1H);13c nuclear magnetic resonance (126MHz, DMSO). delta. 195.9,143.8,140.1,134.6,128.9,127.8,121.8,119.6,119.3,117.4,115.1,110.5,105.5,64.3,55.4,54.1,47.5,37.0,28.6,26.1,25.2,21.6. high resolution Mass Spectrometry (ESI): calcd. for C23H24N2O[M+H]+345.1889, the actual value is 345.1893.
Example 11
Raw materials: 2-phenyl-4-hydroxyindole, 2-pyrrolidinobenzaldehyde
Reaction conditions are as follows: 25 ℃/HFIP
The product is as follows: the chemical formula is as follows: c25H22N2O
Precise molecular weight: 366.1732
Molecular weight: 366.4640
Structural formula (xvi):
yield: 51 percent
1H nuclear magnetic resonance (500MHz, DMSO) δ 12.11(s,1H),7.75(d, J ═ 7.5Hz,2H),7.44(t, J ═ 7.3Hz,2H),7.29(t, J ═ 7.1Hz,1H),7.10(t, J ═ 7.5Hz,1H),7.04(d, J ═ 7.1Hz,1H),6.93(s,1H),6.82(d, J ═ 9.8Hz,1H),6.55(t, J ═ 6.8Hz,2H),5.70(d, J ═ 9.8Hz,1H), 3.80-3.68 (m,1H),3.50(t, J ═ 8.4Hz,1H),3.25(d, J ═ 15.6, 1H),3.12(d, 1H), 3.5.5.5.5.5.8 (d, 1H), 3.5.6, J ═ d, 1H8.4Hz,1H),2.59(d,J＝15.6Hz,1H),1.92(s,2H),1.80–1.68(m,1H),1.26–1.19(m,1H)；13C nuclear magnetic resonance (126MHz, CDCl)3) Delta 200.3,148.0,146.3,139.7,139.4,136.6,134.1,132.6,132.2,129.4,125.1,124.5,122.4,120.2,115.6,107.5,107.5,69.5,53.0,52.3,43.9,32.4,28.3 high resolution Mass Spectrometry (ESI): calcd. for C25H22N2O[M+H]+367.1732, the actual value is 367.1735.
Example 12
Raw materials: 2-p-tolyl-4-hydroxyindole, 2-pyrrolidinobenzaldehyde
Reaction conditions are as follows: 25 ℃/HFIP
The product is as follows: the chemical formula is as follows: c26H24N2O
Precise molecular weight: 380.1889
Molecular weight: 380.4910
Structural formula (xvi):
yield: 55 percent of
1H nuclear magnetic resonance (500MHz, DMSO) δ 12.04(s,1H),7.64(d, J ═ 5.9Hz,2H),7.25(d, J ═ 5.5Hz,2H),7.06(d, J ═ 33.2Hz,2H),6.86(s,1H),6.80(d, J ═ 9.4Hz,1H),6.55(s,2H),5.68(d, J ═ 9.3Hz,1H),3.72(s,1H),3.50(s,1H),3.25(d, J ═ 15.4Hz,1H),3.11(d, J ═ 7.2Hz,1H),2.58(d, J ═ 15.7Hz,1H),2.34(s,3H),1.91(s,2H),1.72(s,1H), 1.11 (s,1H),1.32 (m);13c nuclear magnetic resonance (126MHz, CDCl)3) Delta 200.3,148.0,146.1,141.5,139.6,139.5,134.7,134.1,133.9,132.6,129.4,125.1,124.5,122.4,120.2,115.7,106.9,106.8,69.5,52.9,52.3,45.3,45.2,45.1,45.0,44.9,44.8,44.6,44.4,44.3,43.9,32.4,28.3,26.0 high resolution Mass Spectrometry (ESI): calcd. for C26H24N2O[M+H]+381.1889, the actual value is 381.1893.
Example 13
Raw materials: 4-hydroxy carbazole, 2-pyrrolidine benzaldehyde
Reaction conditions are as follows: 25 ℃/HFIP
The product is as follows: the chemical formula is as follows: c23H20N2O
Precise molecular weight: 340.1576
Molecular weight: 340.4260
Structural formula (xvi):
yield: 73 percent
1H nuclear magnetic resonance (500MHz, DMSO) δ 12.13(s,1H),8.04(d, J ═ 7.0Hz,1H),7.49(d, J ═ 7.3Hz,1H), 7.32-7.17 (m,2H),7.09(t, J ═ 7.5Hz,1H),7.03(d, J ═ 7.0Hz,1H),6.93(d, J ═ 9.9Hz,1H),6.55(t, J ═ 8.8Hz,2H),5.99(d, J ═ 9.9Hz,1H),3.79(dd, J ═ 9.2,6.0Hz,1H),3.49(t, J ═ 7.7Hz,1H),3.31(s,1H),3.12(d, J ═ 8.2, 1H), 1H, 3.78 (d, J ═ 7.7, 1H), 1H, 3.78 (d, J ═ 7, 1H), 1H;13c nuclear magnetic resonance (126MHz, DMSO). delta. 194.9,146.9,143.2,140.5,137.3,129.3,127.9,124.5,124.0,123.0,120.9,119.6,118.1,115.5,112.7,111.0,110.7,64.7,48.7,47.5,40.5,40.4,40.3,40.3,40.2,40.1,39.9,39.8,39.7,39.5,39.1,27.7,23.5. high resolution Mass Spectrometry (ESI): calcd. for C23H20N2O[M+H]+341.1576, the actual value is 341.1580.
The foregoing is directed to preferred embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow. However, any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention are within the protection scope of the technical solution of the present invention.
Claims (3)
1. an indole carbocycle dearomatization synthesis method based on a nitrogen atom α hydrogen migration strategy is characterized in that:
adding the compound A and the compound B into hexafluoroisopropanol according to a proportion, stirring and reacting at 25 ℃, and concentrating and purifying after the reaction is finished to obtain a tetrahydroquinoline spiroindole derivative; the compound A is shown as a formula II; the compound B is shown as a formula III; the prepared tetrahydroquinoline spiroindole derivative is shown as a formula I;
the reaction is represented by the following formula:
wherein
In formulas I-III, the dotted line represents an optional single bond;
n is 1 or 2;
R1any one of hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, nitro, methoxy, cyano, p-phenylacetyl, p-methoxyphenylethynyl, thienyl, borate and methyl acrylate; and is
R2Is selected from any one of methyl, phenyl and p-methylphenyl.
2. The method of synthesis according to claim 1, characterized in that: the molar ratio of the compound A to the compound B is 1.3: 1;
3. the method of synthesis according to claim 2, characterized in that: the concentration of the compound A in the reaction system is 0.065M, and the concentration of the compound B in the reaction system is 0.05M.
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