CN114605316A - Beta-aromatic heterocyclic-gamma-trifluoromethyl amine compound and synthesis method thereof - Google Patents

Beta-aromatic heterocyclic-gamma-trifluoromethyl amine compound and synthesis method thereof Download PDF

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CN114605316A
CN114605316A CN202210322224.9A CN202210322224A CN114605316A CN 114605316 A CN114605316 A CN 114605316A CN 202210322224 A CN202210322224 A CN 202210322224A CN 114605316 A CN114605316 A CN 114605316A
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朱庭顺
蓝建勇
林可隽
张星
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Sun Yat Sen University
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    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Abstract

The invention discloses a beta-aromatic heterocyclic-gamma-trifluoromethyl amine compound and a synthesis method thereof, and establishes a beta-aromatic heterocyclic-gamma-trifluoromethyl amine compound by means of a Smiles rearrangement strategy and electrochemical means to realize allylamine heteroaromatic ring trifluoromethylation. The initial raw materials required by the invention are easy to prepare, and the beta-aromatic heterocyclic-gamma-trifluoromethyl amine compound is constructed in one step without adding an oxidant and an additive into a reaction system. In addition, the reaction substrate has wide applicability, high functional group tolerance, and good regioselectivity and stereoselectivity. More importantly, our reaction strategy enables the late modification of complex biomolecules.

Description

Beta-aromatic heterocyclic-gamma-trifluoromethyl amine compound and synthesis method thereof
Technical Field
The invention relates to a beta-aromatic heterocyclic-gamma-trifluoromethyl amine compound and a synthesis method thereof.
Background
Heteroaromatic ethylamine compounds are widely found in drugs and bioactive Molecules such as dopamine, serotonin, betazole, ranitidine, etc. (chem. rev.2007,107, 274-302; chem. rev.2008,108, 1614-1641; Molecules 2018,23, 134-219). The efficient synthesis of the aromatic heterocyclic ethylamine derivative with a novel structure has important significance in pharmaceutical chemistry and agricultural chemistry research. Furthermore, fluoroalkyl functional groups that are biologically active, lipophilic, and metabolically stable are unique modulators in biologically active compounds. Therefore, the introduction of fluoroalkyl functional groups into the aromatic heterocyclic ethylamine compound has important synthetic significance. Generally, the most straightforward method for synthesizing such substrates is to achieve trifluoromethylheteroarylation of the double bond of allylamine compounds (formula Ib). Although trifluoromethylarylation of olefins has been achieved in the literature in different ways (J.Am.chem.Soc.2014,136, 10202-10205; Angew.chem.int.Ed.2021,60, 186-190; J.Am.chem.Soc.2021,143,9320-9326.), less trifluoromethylheteroarylation of allylamines has been reported (J.Org.chem.,2020,85, 6888-6896; Chin.chem.Lett.,2021,32, 258-262.). This transformation is efficiently achieved by free radical-initiated Smiles rearrangement. The Nevado group in 2013 achieved trifluoromethylarylation of acrylamide via the Smiles rearrangement strategy (j.am. chem. soc.2013,135,14480-14483), but the reaction was limited to activated olefins. Furthermore, the Jumper and other groups reported that aryl migration strategies effect trifluoromethylheteroarylation of non-activated olefins, indicating that the migration of aromatic heterocycles is preferred to the migration of aromatic rings (J.Am.chem.Soc.2017,139, 1388-1391; Angew.chem.Int.Ed.2018,57, 17156-17160; org.Lett.2019,21, 1857-1862).
In addition, the electrochemical organic synthesis is favored by scientists due to its characteristics of green, high efficiency, high reaction selectivity and the like (chem.Rev.2017,117, 13230-13319; chem.Soc.Rev.2021,50, 7941-. The development of trifluoromethyl free radicals is relatively mature by electrochemical means (Synlett 2002,10, 1697-1699; chem.Commun.2017,53, 10878-10881; chem.Commun.2018,54, 2240-2243; Org.Lett.2019,21, 7970-7975; chem.Commun.2021,57, 8284-8287; Chin.chem.Lett.2022,33, 221-224). Therefore, it is a research topic to develop a new method of beta-aromatic heterocyclic-gamma-trifluoromethyl amine compound with simple, high efficiency and wide applicability through the telephony approach.
Figure BDA0003570496310000021
The invention content is as follows:
the invention aims to overcome the defects of the prior art and provides a beta-aromatic heterocyclic-gamma-trifluoromethyl amine compound and a synthesis method thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
a beta-aromatic heterocyclic-gamma-trifluoromethyl amine compound has the following structure:
Figure BDA0003570496310000022
R1selected from the group consisting of-Ac, -Boc, -Piv, -Bz, -Pym, glycyl, alanyl, β -alanyl, 3-azetidinoyl, γ -alanyl, levulinoyl, 3- (4-biphenylcarbonyl) propionyl, 3,7, 12-trioxa-5 β -cholanyl;
R2is-CH3；
R3Is selected from-CH3、-Bn、-Ph；
n is 1 or 2;
Figure BDA0003570496310000031
selected from benzothiazole, thiazole, 2-chlorothiophene, 2-bromothiophene, thiophenecarboxylic acidMethyl ester, 2-chloro-4-acetylthiophene, 1,3, 4-thiadiazole, pyrimidine, pyridine, quinoline and naphthyl;
Rfis selected from-CF3、-CF2H；
The synthesis method of the beta-heteroaromatic-gamma-trifluoromethyl amine compound comprises the following steps: dissolving a substrate 1, a substrate 2 and lithium perchlorate in a mixed solvent of acetonitrile and water under the air condition, wherein the anode is reticular glassy carbon (RVC, 100PPI, 0.8cm x 0.8cm x1cm), the cathode is a platinum sheet (1cm x1cm), and the mixture is stirred at room temperature under a constant current of 10mA for 1.08 hours to obtain a corresponding product 3; the reaction formula is shown as follows:
Figure BDA0003570496310000032
wherein R is1、R2、R3As previously described. The yield of the beta-aromatic heterocyclic-gamma-trifluoromethyl amine compound 3 obtained in the reaction is 25 to 83 percent. Diastereomer ratio up to 20: 1, the chiral center of the chiral allylamine can be maintained. The optical purity was determined by ultra performance phase chromatography (UPCC).
Substituent R3The larger the volume of the substituent(s), the greater the steric hindrance with the trifluoromethyl group in the intermediate transition state of the five-membered ring, which keeps the trifluoromethyl group away from the substituent R3Thereby the aromatic heterocyclic ring is substituted with the substituent R3In the trans position, and the substituent R3The larger the volume of the substituent(s), the higher the diastereomer ratio, when R is3Phenyl can reach 20: 1.
the beta-aromatic heterocyclic-gamma-trifluoromethyl amine compound obtained by the invention can remove a protecting group under the action of hydrochloric acid and is further derivatized to obtain a thiourea compound. In addition, the aromatic heterocyclic ring is 2-chloro-4-acetylthiophene, and the acetyl group can be reduced under the action of sodium borohydride, and the ring can be closed under an acidic condition to obtain the dihydropyridinothiophene compound. The reaction formula is as follows:
Figure BDA0003570496310000041
compared with the prior art, the invention has the following beneficial effects: the invention establishes a beta-aromatic heterocyclic-gamma-trifluoromethyl amine compound by means of a Smiles rearrangement strategy and electrochemical means to realize allylamine heteroaromatic ring trifluoromethylation. The initial raw materials required by the invention are easy to prepare, and the beta-aromatic heterocyclic-gamma-trifluoromethyl amine compound is constructed in one step without adding an oxidant and an additive into a reaction system. In addition, the reaction substrate has wide applicability, high functional group tolerance, and good regioselectivity and stereoselectivity. More importantly, our reaction strategy enables the late modification of complex biomolecules.
The specific implementation mode is as follows:
example 1: synthesis of 3 a:
N-allyl-N- (benzothiazole-2-sulfonyl) acetamide (R) in a 10mL three-necked flask under air conditions1Is a group of-Ac,
Figure BDA0003570496310000042
is benzothiazole, n is 1, R2is-H, R3is-H, Rf is CF3)1a (59.2mg, 0.2mmol), sodium trifluoromethanesulfonate 2(62.4mg,0.4mmol,2.0equiv.) and lithium perchlorate electrolyte (63.6mg,0.1M.) are dissolved in a mixed solvent of acetonitrile and water (3:1v/v,6.0mL), the anode is reticulated vitreous carbon (RVC, 100PPI, 0.8cm x 0.8cm x1cm), the cathode is a platinum sheet (1cm x1cm), after complete reaction under constant current of 10mA at room temperature, the mixed solution is added with ethyl acetate and saturated ammonium chloride solution for extraction three times, washed with water, washed with saturated common salt, dried, and subjected to column chromatography separation after removal of the solvent under reduced pressure to obtain a product 3 a;
Figure BDA0003570496310000043
6.25(s,1H),3.72(m,2H),2.89(m,1H),2.75–2.45(m,1H),1.94(s,3H)；13C{1H}NMR(101MHz,CDCl3)δ170.6,170.5,153.0,134.7,126.4,126.1(q.J＝275Hz),125.4,123.0,121.8,43.4,38.2(q,J＝2.6Hz),36.7(q,J＝29.0Hz),23.2；19F NMR(376MHz,CDCl3)δ-64.08.
example 2: synthesis of 3b
Replacement of substrate 1 by R1The rest of the experimental work was performed with reference to example 1.
Figure BDA0003570496310000051
NMR(101MHz,CDCl3)δ170.5,155.9,153.1,134.8,126.3,126.2(q,J＝275Hz),125.3,123.0,121.7,79.9,44.7,38.7,36.5(q,J＝29.1Hz),28.3.19F NMR(377MHz,CDCl3)δ-64.11.
Example 3: synthesis of 3c
Replacement of substrate 1 by R1The rest of the experimental work is according to example 1.
Figure BDA0003570496310000052
9H).13C{1H}NMR(101MHz,CDCl3)δ178.9,170.6,153.0,134.5,126.4,126.1(q,J＝275Hz),125.4,122.9,121.8,43.3,38.8,37.9(d,J＝2.8Hz),36.8(q,J＝29.1Hz),27.5.19F NMR(377MHz,CDCl3)δ-64.18.
Example 4: synthesis of 3d
Replacement of substrate 1 by R1The rest of the experimental work is with reference to example 1.
Figure BDA0003570496310000053
–2.85(m,1H),2.70(m,1H).13C{1H}NMR(101MHz,CDCl3)δ170.6,167.8,153.0,134.6,134.0,131.7,128.6,127.0,126.4,126.1(q,J＝276Hz),125.5,123.0,121.8,43.6,38.1(q,J＝2.5Hz),36.9(q,J＝29.2Hz).19F NMR(376MHz,CDCl3)δ-64.06.
Example 5: synthesis of 3e
Replacement of substrate 1 by R1The rest of the experimental work is with reference to example 1.
Figure BDA0003570496310000061
170.7,162.1,158.0,153.1,134.8,126.3(q,J＝276Hz),126.2,125.2,123.0,121.6,111.1,45.8,38.3(q,J＝2.6Hz),36.6(q,J＝28.9Hz).19F NMR(377MHz,CDCl3)δ-64.00.
Example 6: synthesis of 3f
Substrate 1 was changed to Het ═ thiazole and the rest of the experimental work was referred to example 1.
Figure BDA0003570496310000062
13C{1H}NMR(101MHz,CDCl3)δ170.7,170.0,142.7,126.1(q,J＝277.1Hz),119.0,43.6,37.1(q,J＝2.7Hz),37.0(d,J＝28.8Hz),23.13.19F NMR(376MHz,CDCl3)δ-64.14.
Example 7: synthesis of 3g
The substrate 1 was replaced by Het ═ 2-chlorothiophene and the rest of the experimental work was performed with reference to example 1.
Figure BDA0003570496310000063
CDCl3)δ170.4,142.4,128.8,126.1,125.9(q,J＝277Hz),124.8,45.0,38.4(q,J＝28.5Hz),36.1(q,J＝2.5Hz),23.1；19F NMR(377MHz,CDCl3)δ-63.82.
Example 8: synthesis for 3h
Substrate 1 was changed to Het ═ thiazole and the rest of the experimental work was referred to example 1.
Figure BDA0003570496310000071
145.3,129.9,126.0(q,J＝275Hz),125.9,110.9,45.0,38.4(q,J＝28.4Hz),36.1(q,J＝2.8Hz),23.2.19F NMR(376MHz,CDCl3)δ-63.78.
Example 9: synthesis of 3i
The substrate 1 was exchanged for Het ═ thiazole methyl formate and the rest of the experimental work was performed with reference to example 1.
Figure BDA0003570496310000072
NMR(101MHz,CDCl3)δ170.2,163.2,148.5,131.5,127.9,127.7,126.3(q,J＝276Hz),52.2,44.0,36.8(q,J＝28.3Hz),33.2(q,J＝2.7Hz),23.1.19F NMR(376MHz,CDCl3)δ-63.98.
Example 10: synthesis of 3j
Substrate 1 was changed to Het ═ 2-chloro-4-acetylthiophene and the rest of the experimental work was referenced to example 1.
Figure BDA0003570496310000073
δ194.4,170.8,150.7,136.7,128.5,127.4,126.0(q,J＝275Hz),45.0,38.0(q,J＝28.7Hz),34.2(q,J＝2.8Hz),30.1,23.1.19F NMR(376MHz,CDCl3)δ-63.98.
Example 11: synthesis of 3k
Substrate 1 was changed to Het ═ 1,3, 4-thiadiazole and the rest of the experimental work was referred to example 1.
Figure BDA0003570496310000081
(q,J＝29.1Hz),35.0(q,J＝2.5Hz),23.1,15.6.19F NMR(376MHz,CDCl3)δ-64.01.
Example 12: synthesis of 3l
The substrate 1 was replaced by Het ═ pyrimidine and the rest of the experimental work was referred to example 1.
Figure BDA0003570496310000082
CDCl3)δ170.5,169.6,157.3,126.6(q,J＝277.0Hz),119.6,42.7,42.4(q,J＝2.4Hz),35.4(q,J＝28.7Hz),23.2.19F NMR(376MHz,CDCl3)δ-64.20.
Example 13: synthesis of 3m
Substrate 1 was changed to Het ═ pyridine and the rest of the experimental work was referred to example 1.
Figure BDA0003570496310000083
1H),1.94(s,3H).13C{1H}NMR(101MHz,CDCl3)δ170.6,160.4,149.5,137.2,126.5(q,J＝275Hz),123.8,122.5,43.6,40.3(d,J＝2.4Hz),36.4(q,J＝28.3Hz),23.2.19F NMR(376MHz,CDCl3)δ-64.03.
Example 14: synthesis of 3n
Substrate 1 was changed to Het ═ quinoline, and the rest of the experimental work was referred to example 1.
Figure BDA0003570496310000091
13.3,6.7Hz,2H),3.03(m,1H),2.73(m,1H),1.80(s,2H).13C{1H}NMR(101MHz,CDCl3)δ170.2,149.3,146.4,138.8,136.9,129.1,128.8,127.7,126.8(q,J＝276Hz),126.5,121.2,44.6,36.6,(q,J＝27.8Hz),36.3,23.2.19F NMR(377MHz,CDCl3)δ-63.96.
Example 15: synthesis of 3o
The substrate 1 was replaced by Het ═ naphthalene ring and the rest of the experimental work was referred to example 1.
Figure BDA0003570496310000092
13C{1H}NMR(101MHz,CDCl3)δ170.4,136.7,134.1,131.8,129.16,128.02,126.67,126.5(q,J＝275Hz),125.97,125.41,123.52,122.48,44.38,37.74(q,J＝28.2Hz),32.7,23.10.19F NMR(376MHz,CDCl3)δ-63.67.
Example 16: synthesis of 3p
Replacement of substrate 1 by R2The rest of the experimental work is with reference to example 1.
Figure BDA0003570496310000093
CDCl3)δ175.9,170.4,152.8,134.6,126.3,126.1(q,J＝277Hz),125.4,123.1,121.7,48.6,42.5,42.2(d,J＝27.7Hz),23.4,23.0.19F NMR(376MHz,CDCl3)δ-59.57.
Example 17: synthesis of 3q
Substrate 1 was changed to n-2 and the rest of the experimental work was according to example 1.
Figure BDA0003570496310000101
2H),1.86(s,3H).13C{1H}NMR(101MHz,CDCl3)δ172.3,170.5,152.8,134.6,126.4,126.0(q,J＝276Hz),125.4,122.9,121.8,39.1(q,J＝28.6Hz),37.0,36.6(q,J＝2.7Hz),35.3,23.1.19F NMR(376MHz,CDCl3)δ-64.01.
Example 18: synthesis of 3r
Replacement of substrate 2 by Rf＝CF2HSO2Na, the rest of the experimental work was according to example 1.
Figure BDA0003570496310000102
126.4,125.5,123.0,121.8,115.7(t,J＝239.6Hz),43.0,38.7(t,J＝5.4Hz),36.9(t,J＝22.2Hz),23.2.19F NMR(376MHz,CDCl3)δ-115.29(dd,J＝417.4Hz,J＝285.7Hz).
Example 19: synthesis of 3s
Replacement of substrate 1 by R3The rest of the experimental work is with reference to example 1.
Figure BDA0003570496310000103
J＝12.5,11.8Hz,1H),2.08(s,3H),1.08(d,J＝6.7Hz,3H).13C{1H}NMR(101MHz,CDCl3)δ169.9,169.4,153.2,134.4,126.4,126.3(q,J＝276Hz),125.5,123.0,121.7,48.1,42.0(q,J＝2.5Hz),37.7(q,J＝28.7Hz),23.6,19.7.19F NMR(377MHz,CDCl3)δ-64.39.
Example 20: synthesis of 3s
Replacement of substrate 1 by R3Methyl group, the rest of the experimental manipulationsReference is made to example 1.
Figure BDA0003570496310000111
1H),2.60(m,1H),2.02(s,3H),1.13(d,J＝6.8Hz,3H).13C{1H}NMR(101MHz,CDCl3)δ169.7,168.7,153.0,134.7,126.3,126.2(q,J＝275Hz),125.4,123.2,121.6,48.3,42.9(q,J＝2.5Hz),36.4(q,J＝29.1Hz),23.5,16.7.19F NMR(377MHz,CDCl3)δ-64.37.
Example 21: synthesis of 3t
Replacement of substrate 1 by R3The rest of the experimental work is according to example 1.
Figure BDA0003570496310000112
2.12(s,3H).13C{1H}NMR(101MHz,CDCl3)δ170.0,169.4,153.1,137.1,134.4,129.1,128.7,126.9,126.5,126.1(J＝276Hz),125.7,123.1,121.8,54.0,39.7,38.6(q,J＝2.5Hz),38.1(q,J＝28.5Hz),23.6.19F NMR(377MHz,CDCl3)δ-64.20.
Example 22: synthesis of 3u
Replacement of substrate 1 by R3The rest of the experimental work was done according to example 1 Ph.
Figure BDA0003570496310000113
7.57–7.44(m,1H),7.44–7.33(m,1H),7.18(qd,J＝4.3,1.6Hz,3H),7.05–6.95(m,2H),5.57(dd,J＝9.1,4.4Hz,1H),3.83(dt,J＝8.8,4.1Hz,1H),3.05(m,1H),2.77(m,1H),2.14(s,3H).13C{1H}NMR(101MHz,CDCl3)δ169.8,169.2,152.8,139.4,134.4,128.6,127.7,126.3,126.1(q,J＝275Hz),125.5,124.8,122.9,121.7,56.1,43.2(q,J＝2.5Hz),38.0(q,J＝28.8Hz),23.5.19F NMR(376MHz,CDCl3)δ-64.37.
Example 23: synthesis of 3v
Replacement of substrate 1 with R1Glycyl, Het for thiazole, rest of the experimental proceduresReference is made to example 1.
Figure BDA0003570496310000121
J＝8.4,5.0Hz,1H),2.87(s,3H),2.82–2.66(m,1H),2.55(ddt,J＝15.1,10.5,5.2Hz,1H),1.42(s,9H).13C{1H}NMR(101MHz,CDCl3)δ169.9,169.5,155.5,142.8,126.0(q,J＝277.0Hz),119.0,80.7,53.0,43.1,37.1,36.8,35.8,28.2.19F NMR(376MHz,CDCl3)δ-64.13.
Example 24: synthesis of 3w
Replacement of substrate 1 by R1Het is replaced by 2-chlorothiophene, and the rest of the experimental work is referred to example 1.
Figure BDA0003570496310000122
0.7H),3.58(m,0.3H),3.40(m,1.3H),3.25(m,0.7H),2.58–2.28(m,2H),1.63(m,3H).13C{1H}NMR(101MHz,CDCl3)δ169.7,169.5,167.8,167.7,142.1,142.0,134.5,134.4,131.7,128.7,125.9(q,J＝276Hz),125.9,125.9,125.0,123.6,123.6,49.5,49.3,45.1,44.91,38.2(q,J＝28.5Hz),38.0(q,J＝28.6Hz),36.0(q,J＝2.6Hz),35.9(q.J＝2.5Hz),15.11,14.97.19F NMR(376MHz,CDCl3)δ-63.83.
Example 25: synthesis of 3 ×
Replacement of substrate 1 by R1β -alanyl, Het to thiazole, and the rest of the experimental procedure refer to example 1.
Figure BDA0003570496310000131
3.32(m,2H),2.85(s,3H),2.76(m,1H),2.57(m,1H),2.44(s,2H),1.44(s,9H).13C{1H}NMR(101MHz,CDCl3)δ171.4,169.5,156.5,142.8,126.1(q,J＝277.3Hz),119.0,79.9,45.3,43.6,37.1(q,J＝2.6Hz),36.6(d,J＝29.0Hz),35.3,34.8,28.4.19F NMR(376MHz,CDCl3)δ-64.14.
Example 26: synthesis of 3y
Replacement of substrate 1 by R1The rest of the experimental work is referred to example 1.
Figure BDA0003570496310000132
3.78(m,3H),3.16(p,J＝8.5Hz,1H),2.90(m,1H),2.63(m,1H).13C{1H}NMR(101MHz,CDCl3)δ172.0,170.3,156.3,152.9,136.4,134.6,128.5,128.1,127.9,126.5,126.0(q,J＝275Hz),125.6,122.9,121.8,66.8,51.8,43.4,38.0(q,J＝2.7Hz),36.8(q,J＝29.1Hz),33.6.19F NMR(376MHz,CDCl3)δ-64.02.
Example 27: synthesis of 3z
Replacement of substrate 1 by R1For 3- γ -alanyl, Het is replaced by thiazole and the rest of the experimental work is referred to example 1.
Figure BDA0003570496310000133
6.93(s,0.64H),6.17(s,0.36H),5.10(s,2H),3.69(m,3H),3.29(t,J＝6.7Hz,2H),2.90(s,3H),2.78(m,1H),2.61(m,1H),2.13(m,2H),1.83(p,J＝6.9Hz,2H).13C{1H}NMR(101MHz,CDCl3)δ173.1,172.5,169.8,156.9,156.2,142.7,136.8,130.2,128.5,128.0,127.9,127.8,126.2(q,J＝274Hz),119.0,67.1,48.0,43.7,43.6,37.3,36.7(q,J＝28.2Hz),34.6,33.9,33.1,23.5.19F NMR(376MHz,CDCl3)δ-64.07.
Example 28: synthesis of 3z1
Substrate 1 is exchanged for R1For 3- γ -alanyl, Het is replaced by 2-chlorothiophene and the rest of the experimental work is referred to example 1.
Figure BDA0003570496310000141
2.53–2.40(m,2H),2.36(t,J＝6.4Hz,2H),2.16(s,3H).13C{1H}NMR(101MHz,CDCl3)δ207.8,172.3,142.3,128.7,126.0,126.0(q,J＝277Hz),124.9,44.9,38.5,38.2(q,J＝28.4Hz),36.0(q,J＝2.7Hz),29.9,29.8.19F NMR(376MHz,CDCl3)δ-63.84.
Example 29: synthesis of 3z2
Substrate 1 is exchanged for R1For 3- (4-biphenylcarbonyl) propanoyl, Het is replaced by thiazole and the rest of the experimental work is referred to example 1.
Figure BDA0003570496310000142
2H),7.41(t,J＝7.2Hz,1H),7.28(d,J＝3.1Hz,1H),6.62(t,J＝5.5Hz,1H),3.85–3.77(m,1H),3.78–3.63(m,2H),3.39(t,J＝6.5Hz,2H),2.89–2.75(m,1H),2.71–2.57(m,3H).13C{1H}NMR(101MHz,CDCl3)δ198.4,172.7,170.2,146.0,142.7,139.8,135.2,129.0,128.8,128.7,128.3,127.3,126.1(q,J＝275Hz),119.1,43.7,37.3(q,J＝2.5Hz),37.0(q,J＝28.8Hz),34.0,30.2.19F NMR(376MHz,CDCl3)δ-64.04.
Example 30: synthesis of 3z3
Substrate 1 is exchanged for R1The rest of the experimental work is carried out with reference to example 1, with 3,7, 12-trioxa-5 β -cholanyl and Het replaced by thiazole.
Figure BDA0003570496310000151
(m,2H),2.98–2.65(m,4H),2.53(m,1H),2.39–2.03(m,11H),2.03–1.89(m,4H),1.84–1.72(m,2H),1.58(m,1H),1.36(s,3H),1.27(m,3H),1.02(s,3H),0.78(m,3H).13C{1H}NMR(101MHz,CDCl3)δ212.1,209.2,208.8,173.9,170.1,142.7,126.1(q,J＝277.2Hz),119.1,56.9,51.8,49.0,46.8,45.6,45.5,45.0,43.6,42.8,38.6,37.3(d,J＝2.6Hz),37.0(d,J＝28.6Hz),36.4,36.0,35.4,35.2,33.4,31.0,27.6,25.1,21.9,18.7,11.8.19F NMR(376MHz,CDCl3)δ-64.07.
Yellow oil 4
Figure BDA0003570496310000152
Hz,1H),2.85(m,1H),2.73(m,1H).13C{1H}NMR(101MHz,CDCl3)δ181.0,170.6,126.0(q,J＝275Hz),152.8,135.6,134.5,130.1,127.5,126.3,125.5,125.4,122.9,121.7,48.5,37.4(q,J＝2.3Hz),37.1(q,J＝29.1Hz).19F NMR(377MHz,CDCl3)δ-63.93.
Yellow oil 5
Figure BDA0003570496310000153
3.14(dd,J＝13.5,11.0Hz,0.66H),2.74–2.43(m,1.35H),2.28(m,1H),2.14(s,3H),1.44(d,J＝6.7Hz,1H),1.34(d,J＝6.8Hz,2H).13C{1H}NMR(101MHz,CDCl3)δ168.9,168.7,138.8,137.3,135.6,133.3,129.3,129.1,125.9(q,J＝276Hz),125.8(q,J＝276Hz),124.9,124.2,50.9,46.7,45.1,39.7,38.4(q,J＝29Hz),38.2(q,J＝29Hz),31.9(q,J＝2.3Hz),30.8(q,J＝2.4Hz),21.7,21.4,20.7,19.5.19F NMR(377MHz,CDCl3)δ-63.31,-63.42.
A summary of examples 1-30 is shown in Table 1.
TABLE 1 electrochemical approach highly regioselective aromatic heterocyclic trifluoromethylation of allylamines
Figure BDA0003570496310000161
Figure BDA0003570496310000171

Claims (3)

1. A beta-aromatic heterocyclic-gamma-trifluoromethyl amine compound has the following structure:
Figure FDA0003570496300000011
wherein R is1Selected from the group consisting of-Ac, -Boc, -Piv, -Bz, -Pym, glycyl, alanyl, β -alanyl, 3-azetidinoyl, γ -alanyl, levulinoyl, 3- (4-biphenylcarbonyl) propionyl, 3,7, 12-trioxa-5 β -cholanyl;
R2is-CH3；
R3Is selected from-CH3、-Bn、-Ph；
n is 1 or 2;
Figure FDA0003570496300000012
selected from benzothiazole, thiazole, 2-chlorothiophene, 2-bromothiophene, methyl thiophenecarboxylate, 2-chloro-4-acetylthiophene, 1,3, 4-thiadiazole, pyrimidine, pyridine, quinoline and naphthalene rings;
Rfis selected from-CF3、-CF2H。
2. A method for synthesizing β -heterocyclic- γ -trifluoromethylamine compounds according to claim 1, comprising the steps of: under the air condition, dissolving a substrate 1, a substrate 2 and lithium perchlorate in a mixed solvent of acetonitrile and water, and stirring at room temperature under 10mA constant current to obtain a corresponding product 3; the reaction formula is shown as follows:
Figure FDA0003570496300000013
3. the method of synthesis according to claim 2, wherein the anode used for the constant current is reticulated vitreous carbon and the cathode is a platinum sheet.
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CN101687772A (en) * 2007-07-02 2010-03-31 瑟维尔实验室 Novel naphthalene derivatives, process for the preparation thereof and pharmaceutical compositions containing same
US20170008847A1 (en) * 2014-02-18 2017-01-12 Nissan Chemical Industries, Ltd. Alkynyl pyridine-substituted amide compound and pesticide
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