CN108947997A - The copper catalysis series connection cyclization that a kind of oxygen participates in constructs N-5- carbonyl thiazole indoles - Google Patents
The copper catalysis series connection cyclization that a kind of oxygen participates in constructs N-5- carbonyl thiazole indoles Download PDFInfo
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- CN108947997A CN108947997A CN201810904660.0A CN201810904660A CN108947997A CN 108947997 A CN108947997 A CN 108947997A CN 201810904660 A CN201810904660 A CN 201810904660A CN 108947997 A CN108947997 A CN 108947997A
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- 0 CN(C)CCc1c[n]c2ccc(C[C@@](CO3)*C3=O)cc12 Chemical compound CN(C)CCc1c[n]c2ccc(C[C@@](CO3)*C3=O)cc12 0.000 description 1
- YKWDVPSXHZTCIY-UHFFFAOYSA-O COc1ccc2[nH]cc(C=[NH2+])c2c1 Chemical compound COc1ccc2[nH]cc(C=[NH2+])c2c1 YKWDVPSXHZTCIY-UHFFFAOYSA-O 0.000 description 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Cc(cccc1Cl)c1NC(c1cnc(Nc2cc(N3CCN(CCO)CC3)nc(C)n2)[s]1)=O Chemical compound Cc(cccc1Cl)c1NC(c1cnc(Nc2cc(N3CCN(CCO)CC3)nc(C)n2)[s]1)=O ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—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
- 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
- C07D417/04—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 directly linked by a ring-member-to-ring-member bond
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Abstract
The present invention relates to a kind of N-5- carbonyl thiazole indole derivatives and preparation method thereof, the N-5- carbonyl thiazole indole derivatives are formula (I) compound represented,Preparation method is that propargylamine shown in alkynyl isothiocyanates shown in formula (II) and formula (III) is carried out tandem reaction, obtains formula (I) compound represented；
Description
Technical field
The invention belongs to technology of fine chemicals, and in particular to N-5- carbonyl thiazole indole derivatives and its preparation side
Method.
Background technique
Contain nitrogen-containing heterocycle (J.Med.Chem.2014,57,10257.) in 59% small-molecule drug.Wherein, due to Yin
Diindyl structure is widely present in bioactive molecule and receives significant attention (Nat.Prod.Rep.2005,22,761.).At present
There are Fischer indole synthesis (Chem.Rev.1969,69,227.), metal catalytic using the method for more widely constructing indoles
Cyclization (J.Am.Chem.Soc.1991,113,6689.), transition metal-catalyzed C-H priming reaction
(Angew.Chem.Int. Ed.2009,48,8078-8081.) etc..For being connected with hetero-aromatic ring synthesis, common side on indole nitrogen
Method has Buchwald-Hartwig coupling reaction and Ullman coupling reaction.But for N-5- carbonyl thiazole indole derivatives
Synthesis effectively synthetic method currently not yet.
Isothiocyanates is a kind of group of functional diversity, can by as nucleopilic reagent (Org.Lett.2012,14
(20), 5314-5317.), electrophilic (Chem.Commun., 2017,53 (6), 1056-1059.) or radical scavenger
(Chem.Commun. 2016,52 (54), 8444-8447.) constructs various nitrogenous, sulphur atom heterocyclic compounds.
Tandem reaction is due to successively making full use of multiple C-C key or C-X key as reaction site, so its whole combined coefficient one
As than traditional multistep synthetic reaction high (Angew.Chem., Int.Ed.2006,45 (43), 7134-7186.).It is based on
This theory, this compound of alkynyl isothiocyanates has been designed to come out, and is widely used in constructing various heterocyclic compounds
Object (J.Org.Chem.2003,68 (9), 3454-3464.).Copper has from a wealth of sources for transition metal, and having can be with
The advantages of oxygen is used cooperatively, thus receive significant attention (Chem.Rev.2004,104,1047-1076.).In recent years in sky
The methodology of organic synthesis of copper catalysis under gas existence condition is widely studied.Wherein, the copper under air existence condition is catalyzed alkynes
Bifunctional dough reaction for carbonyls synthesis by largely report (J.Am.Chem.Soc.2010,132,28-
29.)。
Summary of the invention
The object of the present invention is to provide N-5- carbonyl thiazole indole derivatives and preparation method thereof.
The present invention provides a kind of N-5- carbonyl thiazole indole derivatives, wherein the N- thiazoline indole derivatives are formula
(I) compound represented:
Wherein, R1For hydrogen, hydroxyl, halogen, cyano, nitro, ester group, trifluoromethyl, trifluoromethoxy, amide groups, C1-C6
Alkyl, the alkoxy of C1-C6, the alkyl-substituted carbonyloxy group of C1-C4 and C1-C4 the carbonyloxy group that replaces of alkoxy in one
Kind is a variety of；
R2For the alkyl of the C1-C12, naphthenic base of C3-C6, substituted or unsubstituted phenyl, substituted or unsubstituted
Naphthalene, substituted or unsubstituted benzyl, substituted or unsubstituted phenethyl, substituted or unsubstituted phenylpropyl, substitution
Or unsubstituted benzene butyl, the nitrogen-containing heterocycle containing 1-10 carbon atom, the oxygen heterocycle containing 1-10 carbon atom, contain
The sulfur heterocyclic ring of 1-10 carbon atom；The substituted phenyl, substituted benzyl, substituted phenethyl, replaces substituted naphthalene
Phenylpropyl and the substituent group of substituted benzene butyl be each independently selected from hydroxyl, halogen, cyano, nitro, ester group, fluoroform
Base, trifluoromethoxy, amide groups, the alkyl of C1-C6, the alkoxy of C1-C6, the alkyl-substituted carbonyloxy group of C1-C4 and C1-C4
One of the carbonyloxy group or a variety of that replaces of alkoxy；
R3For hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene；The substituted phenyl replaces
The substituent group of naphthalene be each independently selected from hydroxyl, halogen, cyano, nitro, ester group, trifluoromethyl, trifluoromethoxy, amide
Base, the alkyl of C1-C6, the alkoxy of C1-C6, the alkyl-substituted carbonyloxy group of C1-C4 and C1-C4 the carbonyl oxygen that replaces of alkoxy
One of base is a variety of；
R4For from hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene；The substituted phenyl takes
The substituent group of the naphthalene in generation is each independently selected from hydroxyl, halogen, cyano, nitro, ester group, trifluoromethyl, trifluoromethoxy, acyl
Amido, the alkyl of C1-C6, the alkoxy of C1-C6, the alkyl-substituted carbonyloxy group of C1-C4 and C1-C4 the carbonyl that replaces of alkoxy
One of oxygroup is a variety of.
Further, R1For hydrogen, hydroxyl, F, Cl, Br, I, cyano, nitro ,-COOCH3、‐COOCH2CH3, trifluoromethyl,
Trifluoromethoxy ,-NH-CO-CH3、‐NH‐CO‐CH2CH3, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, Zhong Ding
Base, tert-butyl, n-pentyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,
Tert-butoxy, n-pentyloxy-O-CO-CH3、‐O‐CO‐CH2CH3、‐O‐CO‐O‐CH3With-O-CO-O-CH2CH3One of or it is more
Kind；
R2For the alkyl of C1-C8, the naphthenic base of C3-C6, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene
Base, substituted or unsubstituted benzyl, substituted or unsubstituted phenethyl, substituted or unsubstituted phenylpropyl, replace
Or unsubstituted benzene butyl, the nitrogen-containing heterocycle containing 2-8 carbon atom, the oxygen heterocycle containing 2-8 carbon atom, contain 2-8
The sulfur heterocyclic ring of a carbon atom；The substituted phenyl, substituted naphthalene, substituted benzyl, substituted phenethyl, substituted benzene
The substituent group of propyl and substituted benzene butyl is each independently selected from hydroxyl, F, Cl, Br, I, cyano, nitro ,-COOCH3、‐
COOCH2CH3, trifluoromethyl, trifluoromethoxy ,-NH-CO-CH3、‐NH‐CO‐CH2CH3, methyl, ethyl, n-propyl, isopropyl,
Normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy,
Isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy ,-O-CO-CH3、‐O‐CO‐CH2CH3、‐O‐CO‐O‐CH3With-O-CO-
O‐CH2CH3One of or it is a variety of；
R3For hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene；The substituted phenyl replaces
The substituent group of naphthalene be each independently selected from hydroxyl, F, Cl, Br, I, cyano, nitro ,-COOCH3、‐COOCH2CH3, fluoroform
Base, trifluoromethoxy ,-NH-CO-CH3、‐NH‐CO‐CH2CH3, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group,
Sec-butyl, tert-butyl, n-pentyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, Zhong Ding oxygen
Base, tert-butoxy, n-pentyloxy ,-O-CO-CH3、‐O‐CO‐CH2CH3、‐O‐CO‐O‐CH3With-O-CO-O-CH2CH3One of
Or it is a variety of；
R4Hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene；The substituted phenyl, replace
The substituent group of naphthalene is each independently selected from hydroxyl, F, Cl, Br, I, cyano, nitro ,-COOCH3、‐COOCH2CH3, fluoroform
Base, trifluoromethoxy ,-NH-CO-CH3、‐NH‐CO‐CH2CH3, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group,
Sec-butyl, tert-butyl, n-pentyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, Zhong Ding oxygen
Base, tert-butoxy, n-pentyloxy ,-O-CO-CH3、‐O‐CO‐CH2CH3、‐O‐CO‐O‐CH3With-O-CO-O-CH2CH3One of
Or it is a variety of.
More specifically, formula (I) compound represented is selected from one of compound shown in following formula:
Phenyl (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-1)；
(2- (2- phenyl -1H- indoles -1-) thiazole -5-) p-methylphenyl ketone (I-2)；
(4- fluorophenyl) (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-3)；
(4- chlorphenyl) (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-4)；
(4- bromophenyl) (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-5)；
(2- (2- phenyl -1H- indoles -1-) thiazole -5-) (tolyl) ketone (I-6)；
Naphthalene -1- base (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-7)；
Phenyl (4- phenyl -2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-8)；
(2- (the chloro- 2- phenyl -1H- indoles -1- of 5-) thiazole -5-) (p-methylphenyl) ketone (I-9)；
(2- (5- methyl -2- phenyl -1H- indoles -1-) thiazole -5-) (p-methylphenyl) ketone (I-10)；
(2- (the fluoro- 2- phenyl -1H- indoles -1- of 5-) thiazole -5-) (aminomethyl phenyl) ketone (I-11)；
(2- (the bromo- 2- phenyl -1H- indoles -1- of 5-) thiazole -5-) (aminomethyl phenyl) ketone (I-12)；
(2- (6- methyl -2- phenyl -1H- indoles -1-) thiazole -5-) (aminomethyl phenyl) ketone (I-13)；
(2- (the chloro- 2- phenyl -1H- indoles -1- of 6-) thiazole -5-) (aminomethyl phenyl) ketone (I-14)；
P-methylphenyl (2- (2- (aminomethyl phenyl) -1H- indoles -1-) thiazole -5-) ketone (I-15)；
P-methylphenyl (2- (2- (p-methylphenyl) -1H- indoles -1-) thiazole -5-) ketone (I-16)；
(2- (2- (4- fluorophenyl) -1H- indoles -1-) thiazole -5-) p-methylphenyl ketone (I-17)；
(2- (2- (4- chlorphenyl) -1H- indoles -1-) thiazole -5-) p-methylphenyl ketone (I-18)；
(2- (2- (4- bromophenyl) -1H- indoles -1-) thiazole -5-) p-methylphenyl ketone (I-19)；
(2- (2- cyclopropyl -1H- indoles -1-) thiazole -5-) phenyl ketone (I-20)；
2- (2- phenyl -1H- indoles -1-) thiazole -5- formaldehyde (I-21).
The present invention also provides a kind of preparation method of above-mentioned N-5- carbonyl thiazole indole derivatives, this method includes as follows
Step: in the presence of a catalyst, in the presence of additive, under Oxygen Condition, in organic solvent, by alkynes shown in formula (II)
Base isothiocyanates carries out tandem reaction with propargylamine shown in formula (III), obtains formula (I) compound represented；
The molar ratio of alkynyl isothiocyanates shown in formula (II) and the dosage of propargylamine class compound shown in formula (III)
For 1:0.8-2.0, preferably 1:1-1.5.
The catalyst be stannous chloride, cuprous bromide, cuprous iodide, be hydrated trifluoracetic acid copper, copper chloride, copper bromide,
One of dimethyl sulphide cuprous bromide is a variety of；
The molar ratio of the dosage of alkynyl isothiocyanates shown in formula (II) and catalyst is 1:0.1-0.3.
The organic solvent is acetonitrile, methylene chloride, dichloroethanes, toluene, dimethylformamide and dimethyl acetamide
One of or it is a variety of；
The dosage of the organic solvent makes the concentration of alkynyl isothiocyanates shown in formula (II) be 0.05-0.5mmol/
mL。
The additive is water.
Wherein, the molar ratio of the dosage of the alkynyl isothiocyanates and additive is 1:1-10, preferably 1:3-7.
The condition of the tandem reaction includes: that temperature is 95-120 DEG C, time 10-24h.
The purposes of above-mentioned N-5- carbonyl thiazole indole derivatives is also claimed in the present invention, is used to prepare small molecule medicine
Object.
Specific embodiment
The present invention provides a kind of N-5- carbonyl thiazole indole derivatives preparation methods, wherein N-5- carbonyl thiazole Yin
Diindyl derivative is formula (I) compound represented:
Wherein, R1For hydrogen, hydroxyl, halogen, cyano, nitro, ester group, trifluoromethyl, trifluoromethoxy, amide groups, C1-C6
Alkyl, the alkoxy of C1-C6, the alkyl-substituted carbonyloxy group of C1-C4 and C1-C4 the carbonyloxy group that replaces of alkoxy in one
Kind is a variety of；
R2For the alkyl of the C1-C12, naphthenic base of C3-C6, substituted or unsubstituted phenyl, substituted or unsubstituted
Naphthalene, substituted or unsubstituted benzyl, substituted or unsubstituted phenethyl, substituted or unsubstituted phenylpropyl, substitution
Or unsubstituted benzene butyl, the nitrogen-containing heterocycle containing 1-10 carbon atom, the oxygen heterocycle containing 1-10 carbon atom, contain
The sulfur heterocyclic ring of 1-10 carbon atom；The substituted phenyl, substituted benzyl, substituted phenethyl, replaces substituted naphthalene
Phenylpropyl and the substituent group of substituted benzene butyl be each independently selected from hydroxyl, halogen, cyano, nitro, ester group, fluoroform
Base, trifluoromethoxy, amide groups, the alkyl of C1-C6, the alkoxy of C1-C6, the alkyl-substituted carbonyloxy group of C1-C4 and C1-C4
One of the carbonyloxy group or a variety of that replaces of alkoxy；
R3For hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene；The substituted phenyl replaces
The substituent group of naphthalene be each independently selected from hydroxyl, halogen, cyano, nitro, ester group, trifluoromethyl, trifluoromethoxy, amide
Base, the alkyl of C1-C6, the alkoxy of C1-C6, the alkyl-substituted carbonyloxy group of C1-C4 and C1-C4 the carbonyl oxygen that replaces of alkoxy
One of base is a variety of；
R4For from hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene；The substituted phenyl takes
The substituent group of the naphthalene in generation is each independently selected from hydroxyl, halogen, cyano, nitro, ester group, trifluoromethyl, trifluoromethoxy, acyl
Amido, the alkyl of C1-C6, the alkoxy of C1-C6, the alkyl-substituted carbonyloxy group of C1-C4 and C1-C4 the carbonyl that replaces of alkoxy
One of oxygroup is a variety of.
In the present invention, the specific example of the alkyl of C1-C12 for example can be with are as follows: methyl, ethyl, n-propyl, isopropyl,
Normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, positive decyl, positive 11
Alkyl, dodecyl etc..
The alkyl of C1-C6, the alkyl of C1-C4 can be selected from the specific example of above-mentioned alkyl and carry out meeting phase
It should limit.
The alkoxy of C1-C6 can be the alkane that the specific example of the above-mentioned alkyl for meeting the restriction of 1-6 carbon atom is formed
Oxygroup.
The specific example of the naphthenic base of C3-C6 for example can be with are as follows:Deng.
Nitrogen-containing heterocycle containing 1-10 carbon atom can be unsaturated nitrogen heterocycle, be also possible to be saturated azacyclo-, as long as
By Elemental composition of nitrogen and carbon atom number that the heterocycle has is 1-10 in the ring structure of its heterocycle, such as it can be and not take
It is generation or C1-C6 alkyl-substituted pyrroles, unsubstituted or C1-C6 alkyl-substituted pyrrolidine, unsubstituted
Either the alkyl-substituted imidazoles of C1-C7, unsubstituted or C1-C7 alkyl-substituted hydrogenation imidazoles, it is unsubstituted or
The alkyl-substituted pyridine of C1-C5, unsubstituted or C1-C5 alkyl-substituted hydrogenated pyridine, unsubstituted or C1-
It is the alkyl-substituted pyrazoles of C7, unsubstituted or C1-C7 alkyl-substituted hydrogenation pyrazoles, unsubstituted or C1-C7
Alkyl-substituted thiazole, unsubstituted or C1-C7 alkyl-substituted hydrogenation thiazole, unsubstituted or C1-C7 alkyl
Substituted oxazole, unsubstituted or C1-C7 alkyl-substituted hydrogenation oxazole etc..It wherein, can be with as the alkyl of substituent group
It is selected accordingly in described alkyl specific example from the above, the substitution of these alkyl can be single-point, can also
To be the substitution of multiple spot, there is no particular limitation to this by the present invention.
Oxygen heterocycle containing 1-10 carbon atom can be unsaturated oxa- ring, be also possible to saturated oxygen heterocycle, as long as
By Elemental composition of oxygen and carbon atom number that the heterocycle has is 1-10 in the ring structure of its heterocycle, such as it can be and not take
It is generation or C1-C6 alkyl-substituted furans, unsubstituted or C1-C6 alkyl-substituted hydrogenation furans, unsubstituted
Either the alkyl-substituted oxazole of C1-C7, unsubstituted or C1-C7 alkyl-substituted hydrogenation oxazole, it is unsubstituted or
The alkyl-substituted 1,3- benzo two of C1-C3 dislikes luxuriant, unsubstituted or C1-C2 alkyl-substituted evil of 1,4- benzo two etc..
Sulfur heterocyclic ring containing 1-10 carbon atom can be unsaturated thia ring, be also possible to be saturated thia ring, as long as
By Elemental composition of sulphur and carbon atom number that the heterocycle has is 1-10 in the ring structure of its heterocycle, such as it can be and not take
It is generation or C1-C6 alkyl-substituted thiophene, unsubstituted or C1-C6 alkyl-substituted hydrogenation thiophene, unsubstituted
The either alkyl-substituted thiazole of C1-C7, unsubstituted or C1-C7 alkyl-substituted hydrogenation thiazole etc..
Preferably, R1For hydrogen, hydroxyl, F, Cl, Br, I, cyano, nitro ,-COOCH3、-COOCH2CH3, trifluoromethyl, three
Fluorine methoxyl group ,-NH-CO-CH3、-NH-CO-CH2CH3, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, Zhong Ding
Base, tert-butyl, n-pentyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,
Tert-butoxy, n-pentyloxy ,-O-CO-CH3、-O-CO-CH2CH3、 -O-CO-O-CH3With-O-CO-O-CH2CH3One of or
It is a variety of；
Preferably, R2For the alkyl of C1-C8, the naphthenic base of C3-C6, substituted or unsubstituted phenyl, replace or not
Substituted naphthalene, substituted or unsubstituted benzyl, substituted or unsubstituted phenethyl, substituted or unsubstituted phenylpropyl alcohol
Base, the nitrogen-containing heterocycle containing 2-8 carbon atom, containing 2-8 carbon atom contains oxa- at substituted or unsubstituted benzene butyl
Ring, the sulfur heterocyclic ring containing 2-8 carbon atom；The substituted phenyl, substituted naphthalene, substituted benzyl, substituted benzene second
The substituent group of base, substituted phenylpropyl and substituted benzene butyl be each independently selected from hydroxyl, F, Cl, Br, I, cyano, nitro ,-
COOCH3、-COOCH2CH3, trifluoromethyl, trifluoromethoxy ,-NH-CO-CH3、 -NH-CO-CH2CH3, methyl, ethyl, positive third
Base, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy,
N-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy ,-O-CO-CH3、-O-CO-CH2CH3、-O-CO-O-
CH3With-O-CO-O-CH2CH3One of or it is a variety of；
Preferably, R3For hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene；The substituted benzene
Base, substituted naphthalene substituent group be each independently selected from hydroxyl, F, Cl, Br, I, cyano, nitro ,-COOCH3、-
COOCH2CH3, trifluoromethyl, trifluoromethoxy ,-NH-CO-CH3、-NH-CO-CH2CH3, methyl, ethyl, n-propyl, isopropyl,
Normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy,
Isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy ,-O-CO-CH3、-O-CO-CH2CH3、-O-CO-O-CH3With-O-CO-
O-CH2CH3One of or it is a variety of；
Preferably, R4Hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene；The substituted phenyl,
The substituent group of substituted naphthalene is each independently selected from hydroxyl, F, Cl, Br, I, cyano, nitro ,-COOCH3、-COOCH2CH3, three
Methyl fluoride, trifluoromethoxy ,-NH-CO-CH3、-NH-CO-CH2CH3, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl
It is base, sec-butyl, tert-butyl, n-pentyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, secondary
Butoxy, tert-butoxy, n-pentyloxy ,-O-CO-CH3、-O-CO-CH2CH3、-O-CO-O-CH3With-O-CO-O-CH2CH3In
It is one or more.
In a preferred embodiment of the invention, formula (I) compound represented is selected from chemical combination shown in following formula
One of object:
Phenyl (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-1)；
(2- (2- phenyl -1H- indoles -1-) thiazole -5-) p-methylphenyl ketone (I-2)；
(4- fluorophenyl) (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-3)；
(4- chlorphenyl) (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-4)；
(4- bromophenyl) (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-5)；
(2- (2- phenyl -1H- indoles -1-) thiazole -5-) (tolyl) ketone (I-6)；
Naphthalene -1- base (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-7)；
Phenyl (4- phenyl -2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-8)；
(2- (the chloro- 2- phenyl -1H- indoles -1- of 5-) thiazole -5-) (p-methylphenyl) ketone (I-9)；
(2- (5- methyl -2- phenyl -1H- indoles -1-) thiazole -5-) (p-methylphenyl) ketone (I-10)；
(2- (the fluoro- 2- phenyl -1H- indoles -1- of 5-) thiazole -5-) (aminomethyl phenyl) ketone (I-11)；
(2- (the bromo- 2- phenyl -1H- indoles -1- of 5-) thiazole -5-) (aminomethyl phenyl) ketone (I-12)；
(2- (6- methyl -2- phenyl -1H- indoles -1-) thiazole -5-) (aminomethyl phenyl) ketone (I-13)；
(2- (the chloro- 2- phenyl -1H- indoles -1- of 6-) thiazole -5-) (aminomethyl phenyl) ketone (I-14)；
P-methylphenyl (2- (2- (aminomethyl phenyl) -1H- indoles -1-) thiazole -5-) ketone (I-15)；
P-methylphenyl (2- (2- (p-methylphenyl) -1H- indoles -1-) thiazole -5-) ketone (I-16)；
(2- (2- (4- fluorophenyl) -1H- indoles -1-) thiazole -5-) p-methylphenyl ketone (I-17)；
(2- (2- (4- chlorphenyl) -1H- indoles -1-) thiazole -5-) p-methylphenyl ketone (I-18)；
(2- (2- (4- bromophenyl) -1H- indoles -1-) thiazole -5-) p-methylphenyl ketone (I-19)；
(2- (2- cyclopropyl -1H- indoles -1-) thiazole -5-) phenyl ketone (I-20)；
2- (2- phenyl -1H- indoles -1-) thiazole -5- formaldehyde (I-21).
The present invention provides a kind of preparation methods of above-mentioned N-5- carbonyl thiazole indole derivatives, this method comprises: urging
In the presence of agent, in the presence of additive, under Oxygen Condition, in organic solvent, by the different sulphur cyanogen of alkynyl shown in formula (II)
Acid esters carries out tandem reaction with propargylamine shown in formula (III), obtains formula (I) compound represented；
The preparation process can be represented by following routes one:
Route one:
According to the present invention, formula (II) and formula (III) compound represented can specifically be selected according to required formula (I)
It selects, R1, R2, R3, R4As described above, details are not described herein by the present invention.
Preferably, the dosage of alkynyl isothiocyanates shown in formula (II) and propargylamine class compound shown in formula (III)
Molar ratio be 1:0.8-2.0, preferably 1:1-1.5.
Preferably, the catalyst be stannous chloride, cuprous bromide, cuprous iodide, be hydrated trifluoracetic acid copper, copper chloride,
Copper bromide, one of dimethyl sulphide cuprous bromide or a variety of.
Wherein, the dosage of the catalyst can change in a wider range, such as the different sulphur cyanogen of alkynyl shown in formula (II)
The molar ratio of the dosage of acid esters and catalyst is 1:0.1-0.5, preferably 1:0.1-0.3.
Preferably, the organic solvent is acetonitrile, methylene chloride, dichloroethanes, toluene, dimethylformamide and dimethyl
One of acetamide is a variety of.
Preferably, the dosage of the organic solvent makes the concentration of alkynyl isothiocyanates shown in formula (II) be 0.05-
0.5mmol/mL。
Preferably, the additive is water.
Wherein, the dosage of the additive can change in a wider range, such as the different sulphur cyanogen of alkynyl shown in formula (II)
The molar ratio of the dosage of acid esters and additive is 1:1-10, preferably 1:3-7.
Under preferable case, the condition of the tandem reaction includes: that temperature is 90-150 DEG C (preferably 95-120 DEG C), the time
For 10-24h.
Following embodiments can be used to further illustrate the present invention, but be not intended to limit the present invention.
Embodiment 1:
The synthesis of phenyl (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-1)
Substrate alkynyl phenyl isothiocyanate II-1 (0.2mmol, 1equiv) is added in dry Schlenk pipe, alkynes third
Amine derivative III-1 (0.3mmol, 1.5equiv), CuI (0.040mmol, 20mol%), H2O (1.0mmol, 5equiv) and
Toluene (3.0 mL).Reaction system is first placed under oxygen atmosphere to be stirred to react 20 minutes at room temperature, is then stirred to react in 150 DEG C
15h.After the reaction was completed, precipitation, silica gel column chromatography obtain target product I-1.Yellow oil, yield 64%.1H NMR
(400MHz, CDCl3) δ 8.34 (d, J=8.2Hz, 1H), 8.09 (s, 1H), 7.82 (d, J=7.6Hz, 2H), 7.62 (dd, J
=16.4,7.2Hz, 2H), 7.56-7.48 (m, 2H), 7.45 (s, 5H), 7.36 (t, J=7.2Hz, 1H), 7.30 (t, J=
7.2Hz,1H),6.79(s, 1H).13C NMR(100MHz,CDCl3)δ187.1,165.0,146.6,140.2,138.2,
137.6,136.8,132.8,130.9, 130.1,129.3,129.2,129.0,128.8,128.7,124.6,123.3,
120.8,113.8,109.7.HRMS(ESI)calcd for C24H17N2OS[M+H]+381.1056,found 381.1071.
Compound I-2 to I-21 is completed by referring to the step of I-1.
The characterization result of gained compound is as follows:
(2- (2- phenyl -1H- indoles -1-) thiazole -5-) p-methylphenyl ketone (I-2)
Light yellow solid, yield 59%, 130-132 DEG C of of fusing point1H NMR(400MHz,CDCl3) δ 8.32 (d, J=
8.4Hz, 1H), 8.09 (s, 1H), 7.74 (d, J=8.0Hz, 2H), 7.64 (d, J=7.6Hz, 1H), 7.48-7.41 (m,
5H), 7.36 (t, J=7.2Hz, 1H), 7.32-7.27 (m, 3H), 6.79 (s, 1H), 2.44 (s, 3H)13C NMR(100MHz,
CDCl3)δ186.8, 164.7,146.2,143.8,140.2,138.2,137.1,134.8,130.9,130.0,129.4,
129.2,129.2,129.1,128.8, 124.5,123.3,120.8,113.7,109.5,21.7.HRMS(ESI)calcd
for C25H19N2OS[M+H]+395.1213, found 395.1232.
(4- fluorophenyl) (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-3)
Light yellow solid, yield 60%, 121-123 DEG C of of fusing point1H NMR(400MHz,CDCl3) δ 8.35 (d, J=
8.4Hz, 1H), 8.07 (s, 1H), 7.90-7.83 (m, 2H), 7.64 (d, J=7.2Hz, 1H), 7.49-7.42 (m, 5H),
7.39-7.34 (m, 1H), 7.30 (td, J=7.6,1.2Hz, 1H), 7.22-7.15 (m, 2H), 6.79 (s, 1H)13C NMR
(100MHz,CDCl3)δ 185.5,165.6(d,JC-F=253Hz), 165.1,146.4,140.1,138.1,136.4,133.8
(d,JC-F=3Hz), 131.5 (d, JC-F=9Hz), 130.9,130.1,129.3,129.2,128.8,124.6,123.4,
120.8,115.9(d,JC-F=22Hz), 113.9,109.8.HRMS (ESI) calcd for C24H16FN2OS[M+H]+
399.0962,found399.0970.
(4- chlorphenyl) (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-4)
Light yellow solid, yield 52%, 147-149 DEG C of of fusing point1H NMR(400MHz,CDCl3) δ 8.36 (d, J=
8.0Hz, 1H), 8.06 (s, 1H), 7.80-7.74 (m, 2H), 7.64 (d, J=7.6Hz, 1H), 7.48 (d, J=8.5Hz,
2H), 7.45 (s, 5H), 7.37 (t, J=7.6Hz, 1H), 7.31 (t, J=7.6Hz, 1H), 6.79 (s, 1H)13C NMR
(100MHz,CDCl3)δ 185.8,165.3,146.6,140.1,139.3,138.1,136.2,135.8,130.8,130.4,
130.2,129.4,129.2,129.1, 128.9,124.6,123.4,120.9,113.9,109.9.HRMS(ESI)calcd
for C24H16ClN2OS[M+H]+415.0666, found415.0680.
(4- bromophenyl) (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-5)
Light yellow solid, yield 50%, 158-160 DEG C of of fusing point1H NMR(400MHz,CDCl3) δ 8.36 (d, J=
8.4Hz, 1H), 8.06 (s, 1H), 7.70 (d, J=7.6Hz, 2H), 7.65 (d, J=8.0Hz, 3H), 7.46 (s, 5H),
7.40-7.34 (m, 1H), 7.31 (t, J=7.2Hz, 1H), 6.80 (s, 1H)13C NMR(100MHz,CDCl3)δ185.9,
165.3,146.5, 140.1,138.1,136.3,136.2,132.0,130.8,130.5,130.2,129.4,129.2,
128.9,127.9,124.6,123.4, 120.8,114.0,109.9.HRMS(ESI)calcd for C24H16BrN2OS[M+H
]+459.0161,found459.0171.
(2- (2- phenyl -1H- indoles -1-) thiazole -5-) (tolyl) ketone (I-6)
Orange l, yield 64%.1H NMR(400MHz,CDCl3) δ 8.33 (d, J=8.4Hz, 1H), 8.10 (s,
1H), 7.65 (d, J=8.0Hz, 1H), 7.62 (d, J=4.8Hz, 2H), 7.48-7.43 (m, 5H), 7.42-7.38 (m, 2H),
7.37-7.34 (m, 1H), 7.30 (t, J=7.2Hz, 1H), 6.79 (s, 1H), 2.43 (s, 3H)13C NMR(100MHz,
CDCl3)δ 187.3,164.9,146.6,140.2,138.7,138.2,137.6,136.9,133.6,130.9,130.1,
129.5,129.2,129.1, 128.8,128.5,126.2,124.5,123.3,120.8,113.8,109.6,21.4.HRMS
(ESI)calcd for C25H19N2OS [M+H]+395.1213,found 395.1210.
Naphthalene -1- base (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-7)
Yellow solid, yield 47%, 58-60 DEG C of of fusing point1H NMR(400MHz,CDCl3) δ 8.36 (d, J=8.0Hz,
1H), 8.17 (d, J=5.6Hz, 1H), 8.02 (d, J=8.4Hz, 1H), 7.91 (d, J=5.6Hz, 1H), 7.88 (s, 1H),
7.74 (d, J=6.8Hz, 1H), 7.64 (d, J=7.2Hz, 1H), 7.54 (d, J=6.4Hz, 3H), 7.47 (s, 5H), 7.35
(t, J=7.2Hz, 1H), 7.30 (t, J=7.2Hz, 1H), 6.79 (s, 1H)13C NMR(100MHz,CDCl3)δ188.7,
165.6,147.7,140.2, 138.2,138.2,135.2,133.9,132.0,130.9,130.4,130.2,129.4,
129.2,128.9,128.5,127.6,127.5, 126.8,125.3,124.6,124.3,123.4,120.8,114.1,
110.0.HRMS(ESI)calcd for C28H19N2OS[M+H]+ 431.1213,found431.1223.
Phenyl (4- phenyl -2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-8)
Yellow solid, yield 40%, 191-193 DEG C of of fusing point1H NMR(400MHz,CDCl3) δ 8.43 (d, J=8.4Hz,
1H), 7.66 (d, J=7.6Hz, 1H), 7.58 (d, J=7.2Hz, 2H), 7.55-7.51 (m, 2H), 7.50-7.44 (m, 5H),
7.40-7.30 (m, 3H), 7.19 (dt, J=12.0,7.6Hz, 5H), 6.80 (s, 1H)13C NMR(100MHz,CDCl3)δ
189.0, 161.0,155.1,140.2,138.1,137.0,133.9,132.9,131.1,130.2,129.8,129.7,
129.2,129.1,129.0, 128.8,128.1,128.1,124.5,123.2,120.8,113.9,109.2.HRMS(ESI)
calcd for C30H20N2OS[M+H]+ 457.1369,found457.1362.
(2- (the chloro- 2- phenyl -1H- indoles -1- of 5-) thiazole -5-) (p-methylphenyl) ketone (I-9)
Yellow solid, yield 63%, 131-133 DEG C of of fusing point1H NMR(400MHz,CDCl3) δ 8.26 (d, J=8.8Hz,
1H), 8.08 (s, 1H), 7.76-7.72 (m, 2H), 7.60 (d, J=2.0Hz, 1H), 7.47-7.43 (m, 5H), 7.33-7.28
(m, 3H), 6.71 (d, J=0.8Hz, 1H), 2.45 (s, 3H)13C NMR(100MHz,CDCl3)δ186.7,164.3,
146.0,143.9, 141.4,137.2,136.5,134.7,130.4,130.2,130.1,129.6,129.4,129.2,
128.9,128.7,124.6,120.2, 115.0,108.6,21.7.HRMS(ESI)calcd for C25H18ClN2OS[M+H]+
429.0823,found429.0832.
(2- (5- methyl -2- phenyl -1H- indoles -1-) thiazole -5-) (p-methylphenyl) ketone (I-10)
Yellow solid, yield 45%, 129-131 DEG C of of fusing point1H NMR(400MHz,CDCl3) δ 8.21 (d, J=8.8Hz,
1H), 8.07 (s, 1H), 7.74 (d, J=8.0Hz, 2H), 7.48-7.40 (m, 6H), 7.30 (d, J=8.0Hz, 2H), 7.17
(dd, J=8.4,1.2Hz, 1H), 6.71 (s, 1H), 2.48 (s, 3H), 2.44 (s, 3H)13C NMR(100MHz,CDCl3)δ
186.7, 164.9,146.2,143.6,140.2,136.6,136.6,134.9,132.8,131.1,130.0,129.4,
129.1,128.7,125.9, 120.6,113.5,109.4,21.7,21.4.HRMS(ESI)calcd for C26H21N2OS[M+
H]+409.1369, found409.1381.
(2- (the fluoro- 2- phenyl -1H- indoles -1- of 5-) thiazole -5-) (aminomethyl phenyl) ketone (I-11)
Orange solids, yield 32%, 39-41 DEG C of of fusing point1H NMR(400MHz,CDCl3) δ 8.33 (dd, J=8.8,
4.4Hz, 1H), 8.08 (s, 1H), 7.62 (s, 2H), 7.46 (s, 5H), 7.43-7.36 (m, 2H), 7.29 (dd, J=8.8,
2.0Hz, 1H), 7.08 (td, J=9.2,2.4Hz, 1H), 6.74 (s, 1H), 2.43 (s, 3H)13C NMR(100MHz,
CDCl3)δ187.3, 164.7,159.6(d,JC-F=253Hz), 146.4,141.6,138.7,137.5,136.8,134.5,
133.7,130.5,130.1,129.9 (d,JC-F=11Hz), 129.6,129.4,128.9,128.6,126.2,115.1 (d,
JC-F=9Hz), 112.3 (d, JC-F=25Hz), 109.3 (d, JC-F=4Hz), 106.1 (d, JC-F=24Hz), 21.4.HRMS
(ESI)calcd for C25H18FN2OS[M+H]+ 413.1118,found 413.1121.
(2- (the bromo- 2- phenyl -1H- indoles -1- of 5-) thiazole -5-) (aminomethyl phenyl) ketone (I-12)
Orange solids, yield 65%, 81-83 DEG C of of fusing point1H NMR(400MHz,CDCl3) δ 8.23 (d, J=9.2Hz,
1H), 8.09 (s, 1H), 7.76 (d, J=2.0Hz, 1H), 7.63-7.60 (m, 2H), 7.48-7.44 (m, 6H), 7.43-7.41
(m, 1H), 7.41-7.36 (m, 1H), 6.71 (d, J=0.8Hz, 1H), 2.43 (s, 3H)13C NMR(100MHz,CDCl3)δ
187.2, 164.4,146.4,141.3,138.7,137.5,137.1,136.8,133.7,130.8,130.3,130.1,
129.6,129.4,128.9, 128.6,127.2,126.2,123.3,116.4,115.5,108.6,21.4.HRMS(ESI)
calcd for C25H18BrN2OS [M+H]+473.0318,found473.0323.
(2- (6- methyl -2- phenyl -1H- indoles -1-) thiazole -5-) (aminomethyl phenyl) ketone (I-13)
Yellow solid, yield 45%, 110-112 DEG C of of fusing point1H NMR(400MHz,CDCl3)δ8.13(s,1H),8.11
(s, 1H), 7.63 (s, 2H), 7.52 (d, J=8.0Hz, 1H), 7.43 (s, 5H), 7.41-7.36 (m, 2H), 7.13 (d, J=
8.0Hz,1H), 6.74(s,1H),2.52(s,3H),2.43(s,3H).13C NMR(100MHz,CDCl3)δ187.3,165.1,
146.6,139.6, 138.6,138.6,137.6,136.8,134.7,133.6,131.1,123.0,129.5,129.0,
128.8,128.5,126.9,126.2, 124.8,120.4,113.7,109.6,22.1,21.4.HRMS(ESI)calcd for
C26H21N2OS[M+H]+409.1369, found409.1372.
(2- (the chloro- 2- phenyl -1H- indoles -1- of 6-) thiazole -5-) (aminomethyl phenyl) ketone (I-14)
Orange solids, yield 55%, 139-141 DEG C of of fusing point1H NMR(400MHz,CDCl3)δ8.41(s,1H),8.11
(s, 1H), 7.63 (s, 2H), 7.55 (d, J=8.4Hz, 1H), 7.46 (s, 5H), 7.43-7.37 (m, 2H), 7.27 (dd, J=
8.4,2.0Hz, 1H),6.75(s,1H),2.44(s,3H).13C NMR(100MHz,CDCl3)δ187.2,164.4,146.4,
140.7,138.7, 138.4,137.5,137.2,133.7,130.4,130.4,130.1,129.5,129.4,128.9,
128.6,127.6,126.2,123.9, 121.5,114.2,109.1,21.4.HRMS(ESI)calcd for C25H18ClN2OS
[M+H]+429.0823, found429.0832. p-methylphenyls (2- (2- (aminomethyl phenyl) -1H- indoles -1-) thiazole -
5-) ketone (I-15)
Yellow solid, yield 50%, 105-107 DEG C of of fusing point1H NMR(400MHz,CDCl3) δ 8.33 (d, J=8.0Hz,
1H), 8.09 (s, 1H), 7.75 (d, J=8.0Hz, 2H), 7.63 (d, J=7.6Hz, 1H), 7.35 (t, J=7.2Hz, 1H),
7.33-7.27 (m, 5H), 7.26 (t, J=6.0Hz, 1H), 7.22 (d, J=7.2Hz, 1H), 6.77 (s, 1H), 2.45 (s,
3H),2.40(s,3H). 13C NMR(100MHz,CDCl3)δ186.8,164.9,146.2,143.7,140.4,138.6,
138.2,136.9,134.9,130.8, 130.6,130.1,129.4,129.2,128.6,127.2,124.4,123.2,
120.7,113.8,109.4,21.7,21.5.HRMS(ESI) calcd for C26H21N2OS[M+H]+409.1369,
found409.1362.
P-methylphenyl (2- (2- (p-methylphenyl) -1H- indoles -1-) thiazole -5-) ketone (I-16)
Orange solids, yield 56%, 145-147 DEG C of of fusing point1H NMR(400MHz,CDCl3) δ 8.33 (d, J=8.4Hz,
1H), 8.09 (s, 1H), 7.75 (d, J=8.4Hz, 2H), 7.63 (d, J=7.2Hz, 1H), 7.37-7.33 (m, 3H), 7.32-
7.28(m, 3H),7.28–7.22(m,2H),6.75(s,1H),2.45(s,3H),2.43(s,3H).13C NMR(100MHz,
CDCl3)δ186.9,164.9,146.3,143.7,140.3,139.4,138.1,136.9,134.9,130.0,129.6,
129.4,129.2,127.9, 124.3,123.2,120.7,113.8,109.3,21.7,21.5.HRMS(ESI)calcd for
C26H21N2OS[M+H]+409.1369, found409.1372
(2- (2- (4- fluorophenyl) -1H- indoles -1-) thiazole -5-) p-methylphenyl ketone (I-17)
Yellow solid, yield 49%, 126-128 DEG C of of fusing point1H NMR(400MHz,CDCl3) δ 8.30 (d, J=8.4Hz,
1H), 8.09 (s, 1H), 7.75 (d, J=8.0Hz, 2H), 7.64 (d, J=8.0Hz, 1H), 7.46-7.40 (m, 2H), 7.39-
7.34(m, 1H),7.33–7.28(m,3H),7.17–7.10(m,2H),6.76(s,1H),2.45(s,3H).13C NMR
(100MHz, CDCl3)δ186.7,164.4,163.3(d,JC-F=249Hz), 146.2,143.8,139.1,138.1,
137.1,134.8,131.9(d, JC-F=9Hz), 129.4,129.2,129.0,127.1 (d, JC-F=3Hz), 124.6,
123.3,120.8,116.0(d,JC-F=22 Hz), 113.7,109.6,21.7.HRMS (ESI) calcd for C25H18FN2OS
[M+H]+413.1118,found 413.1112.
(2- (2- (4- chlorphenyl) -1H- indoles -1-) thiazole -5-) p-methylphenyl ketone (I-18)
Yellow solid, yield 48%, 158-160 DEG C of of fusing point1H NMR(400MHz,CDCl3) δ 8.24 (d, J=7.6Hz,
1H), 8.11 (s, 1H), 7.76 (d, J=8.0Hz, 2H), 7.64 (d, J=7.6Hz, 1H), 7.42-7.36 (m, 5H), 7.34-
7.28 (m, 3H), 6.79 (d, J=0.8Hz, 1H), 2.45 (s, 3H)13C NMR(100MHz,CDCl3)δ186.7,164.3,
146.2, 143.9,139.0,138.3,137.4,135.2,134.7,131.0,129.5,129.5,129.2,129.1,
129.0,124.7,123.4, 120.9,113.4,109.8,21.7.HRMS(ESI)calcd for C25H18ClN2OS[M+H]+
429.0823,found429.0833
(2- (2- (4- bromophenyl) -1H- indoles -1-) thiazole -5-) p-methylphenyl ketone (I-19)
Yellow solid, yield 45%, 156-158 DEG C of of fusing point1H NMR(400MHz,CDCl3) δ 8.23 (d, J=8.4Hz,
1H), 8.11 (s, 1H), 7.76 (d, J=8.0Hz, 2H), 7.65 (d, J=7.6Hz, 1H), 7.58-7.54 (m, 2H), 7.39-
7.35(m, 1H),7.34–7.28(m,5H),6.80(s,1H),2.46(s,3H).13C NMR(100MHz,CDCl3)δ186.7,
164.2, 146.2,143.9,139.0,138.3,137.5,134.7,132.0,131.2,130.0,129.5,129.2,
129.0,124.8,123.5, 123.4,120.9,113.4,109.8,21.7.HRMS(ESI)calcd for C25H18BrN2OS
[M+H]+473.0318, found473.0320.
(2- (2- cyclopropyl -1H- indoles -1-) thiazole -5-) phenyl ketone (I-20)
Yellow solid, yield 66%, 87-89 DEG C of of fusing point1H NMR(400MHz,CDCl3) δ 8.47 (d, J=8.4Hz,
1H), 8.16 (s, 1H), 7.96-7.87 (m, 2H), 7.65 (t, J=7.2Hz, 1H), 7.56 (t, J=7.6Hz, 2H), 7.51
(d, J=7.6 Hz, 1H), 7.30 (td, J=8.0,0.8Hz, 1H), 7.22 (d, J=7.2Hz, 1H), 6.43 (s, 1H),
2.25–2.15(m,1H), 1.24–1.17(m,2H),0.97–0.91(m,2H).13C NMR(100MHz,CDCl3)δ187.6,
164.6,147.1,142.3, 137.7,137.3,134.9,132.8,129.0,128.8,123.9,123.1,120.2,
114.4,106.3,9.5,9.3.HRMS(ESI) calcd for C21H17N2OS[M+H]+345.1056,found345.1048
2- (2- phenyl -1H- indoles -1-) thiazole -5- formaldehyde (I-21)
Yellow oil, yield 20%.1H NMR(400MHz,CDCl3) δ 9.83 (s, 1H), 8.41 (d, J=8.4Hz,
1H), 8.17 (s, 1H), 7.61 (d, J=7.2Hz, 1H), 7.45-7.39 (m, 5H), 7.38-7.34 (m, 1H), 7.32-7.27
(m,1H), 6.76(s,1H).13C NMR(100MHz,CDCl3)δ182.0,166.0,149.3,140.0,138.1,136.2,
130.7,130.3, 129.5,129.3,128.9,124.8,123.7,120.9,114.3,110.4.HRMS(ESI)calcd
for C18H13N2OS[M+H]+ 305.0743,found305.0761。
Claims (10)
1. a kind of N-5- carbonyl thiazole indole derivatives, which is characterized in that the N-5- carbonyl thiazole indole derivatives are formula (I) institute
The compound shown:
Wherein, R1For hydrogen, hydroxyl, halogen, cyano, nitro, ester group, trifluoromethyl, trifluoromethoxy, amide groups, C1-C6 hydrocarbon
One of carbonyloxy group for replacing of alkoxy of base, the alkoxy of C1-C6, the alkyl-substituted carbonyloxy group of C1-C4 and C1-C4 or
It is a variety of；
R2For the alkyl of C1-C12, the naphthenic base of C3-C6, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene,
Substituted or unsubstituted benzyl, substituted or unsubstituted phenethyl, substituted or unsubstituted phenylpropyl, replace or not
Substituted benzene butyl, the oxygen heterocycle containing 1-10 carbon atom, contains 1-10 at the nitrogen-containing heterocycle containing 1-10 carbon atom
The sulfur heterocyclic ring of carbon atom；The substituted phenyl, substituted naphthalene, substituted benzyl, substituted phenethyl, substituted phenylpropyl alcohol
The substituent group of base and substituted benzene butyl is each independently selected from hydroxyl, halogen, cyano, nitro, ester group, trifluoromethyl, trifluoro
Methoxyl group, amide groups, the alkyl of C1-C6, the alkoxy of C1-C6, the alkyl-substituted carbonyloxy group of C1-C4 and the alcoxyl of C1-C4
One of carbonyloxy group that base replaces is a variety of；
R3For hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene；The substituted phenyl, substituted naphthalene
Substituent group be each independently selected from hydroxyl, halogen, cyano, nitro, ester group, trifluoromethyl, trifluoromethoxy, amide groups, C1-
The alkyl of C6, the alkoxy of C1-C6, the alkyl-substituted carbonyloxy group of C1-C4 and C1-C4 the carbonyloxy group that replaces of alkoxy in
It is one or more；
R4For hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene；The substituted phenyl, substituted naphthalene
Substituent group be each independently selected from hydroxyl, halogen, cyano, nitro, ester group, trifluoromethyl, trifluoromethoxy, amide groups, C1-
The alkyl of C6, the alkoxy of C1-C6, the alkyl-substituted carbonyloxy group of C1-C4 and C1-C4 the carbonyloxy group that replaces of alkoxy in
It is one or more.
2. N-5- carbonyl thiazole indole derivatives according to claim 1, which is characterized in that R1For hydrogen, hydroxyl, F, Cl,
Br, I, cyano, nitro ,-COOCH3、-COOCH2CH3, trifluoromethyl, trifluoromethoxy ,-NH-CO-CH3、-NH-CO-CH2CH3、
Methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, methoxyl group, ethyoxyl, positive third
Oxygroup, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy-O-CO-CH3、-O-CO-
CH2CH3、-O-CO-O-CH3With-O-CO-O-CH2CH3One of or it is a variety of；
R2For the alkyl of C1-C8, the naphthenic base of C3-C6, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene, take
Generation or unsubstituted benzyl, substituted or unsubstituted phenethyl, substituted or unsubstituted phenylpropyl, replace or do not take
The benzene butyl in generation, the oxygen heterocycle containing 2-8 carbon atom, contains 2-8 carbon original at the nitrogen-containing heterocycle containing 2-8 carbon atom
The sulfur heterocyclic ring of son；The substituted phenyl, substituted naphthalene, substituted benzyl, substituted phenethyl, substituted phenylpropyl and
The substituent group of substituted benzene butyl is each independently selected from hydroxyl, F, Cl, Br, I, cyano, nitro ,-COOCH3、-COOCH2CH3、
Trifluoromethyl, trifluoromethoxy ,-NH-CO-CH3、-NH-CO-CH2CH3, it is methyl, ethyl, n-propyl, isopropyl, normal-butyl, different
Butyl, sec-butyl, tert-butyl, n-pentyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy,
Sec-butoxy, tert-butoxy, n-pentyloxy ,-O-CO-CH3、-O-CO-CH2CH3、-O-CO-O-CH3With-O-CO-O-CH2CH3In
It is one or more；
R3For hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene；The substituted phenyl, substituted naphthalene
Substituent group be each independently selected from hydroxyl, F, Cl, Br, I, cyano, nitro ,-COOCH3、-COOCH2CH3, trifluoromethyl, three
Fluorine methoxyl group ,-NH-CO-CH3、-NH-CO-CH2CH3, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, Zhong Ding
Base, tert-butyl, n-pentyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,
Tert-butoxy, n-pentyloxy ,-O-CO-CH3、-O-CO-CH2CH3、-O-CO-O-CH3With-O-CO-O-CH2CH3One of or
It is a variety of；
R4Hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene；The substituted phenyl, substituted naphthalene
Substituent group is each independently selected from hydroxyl, F, Cl, Br, I, cyano, nitro ,-COOCH3、-COOCH2CH3, trifluoromethyl, trifluoro
Methoxyl group ,-NH-CO-CH3、-NH-CO-CH2CH3, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl,
Tert-butyl, n-pentyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tertiary fourth
Oxygroup, n-pentyloxy ,-O-CO-CH3、-O-CO-CH2CH3、-O-CO-O-CH3With-O-CO-O-CH2CH3One of or it is a variety of.
3. N-5- carbonyl thiazole indole derivatives according to claim 1 or 2, which is characterized in that chemical combination shown in formula (I)
Object is selected from one of compound shown in following formula:
Phenyl (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-1)；
(2- (2- phenyl -1H- indoles -1-) thiazole -5-) p-methylphenyl ketone (I-2)；
(4- fluorophenyl) (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-3)；
(4- chlorphenyl) (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-4)；
(4- bromophenyl) (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-5)；
(2- (2- phenyl -1H- indoles -1-) thiazole -5-) (tolyl) ketone (I-6)；
Naphthalene -1- base (2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-7)；
Phenyl (4- phenyl -2- (2- phenyl -1H- indoles -1-) thiazole -5-) ketone (I-8)；
(2- (the chloro- 2- phenyl -1H- indoles -1- of 5-) thiazole -5-) (p-methylphenyl) ketone (I-9)；
(2- (5- methyl -2- phenyl -1H- indoles -1-) thiazole -5-) (p-methylphenyl) ketone (I-10)；
(2- (the fluoro- 2- phenyl -1H- indoles -1- of 5-) thiazole -5-) (aminomethyl phenyl) ketone (I-11)；
(2- (the bromo- 2- phenyl -1H- indoles -1- of 5-) thiazole -5-) (aminomethyl phenyl) ketone (I-12)；
(2- (6- methyl -2- phenyl -1H- indoles -1-) thiazole -5-) (aminomethyl phenyl) ketone (I-13)；
(2- (the chloro- 2- phenyl -1H- indoles -1- of 6-) thiazole -5-) (aminomethyl phenyl) ketone (I-14)；
P-methylphenyl (2- (2- (aminomethyl phenyl) -1H- indoles -1-) thiazole -5-) ketone (I-15)；
P-methylphenyl (2- (2- (p-methylphenyl) -1H- indoles -1-) thiazole -5-) ketone (I-16)；
(2- (2- (4- fluorophenyl) -1H- indoles -1-) thiazole -5-) p-methylphenyl ketone (I-17)；
(2- (2- (4- chlorphenyl) -1H- indoles -1-) thiazole -5-) p-methylphenyl ketone (I-18)；
(2- (2- (4- bromophenyl) -1H- indoles -1-) thiazole -5-) p-methylphenyl ketone (I-19)；
(2- (2- cyclopropyl -1H- indoles -1-) thiazole -5-) phenyl ketone (I-20)；
2- (2- phenyl -1H- indoles -1-) thiazole -5- formaldehyde (I-21).
4. the preparation method of N-5- carbonyl thiazole indole derivatives, this method described in a kind of any one of claim 1-3
Include the following steps: in the presence of a catalyst, in the presence of additive, under Oxygen Condition, in organic solvent, by formula (II)
Shown in propargylamine shown in alkynyl isothiocyanates and formula (III) carry out tandem reaction, obtain formula (I) compound represented；
5. the preparation method according to claim 4, which is characterized in that alkynyl isothiocyanates and formula shown in formula (II)
(III) molar ratio of the dosage of propargylamine class compound shown in is 1:0.8-2.0, preferably 1:1-1.5.
6. the preparation method according to claim 4, which is characterized in that the catalyst is stannous chloride, cuprous bromide, iodine
Change cuprous, hydration trifluoracetic acid copper, copper chloride, copper bromide, one of dimethyl sulphide cuprous bromide or a variety of；
The molar ratio of the dosage of alkynyl isothiocyanates shown in formula (II) and catalyst is 1:0.1-0.3.
7. the preparation method according to claim 4, which is characterized in that the organic solvent is acetonitrile, methylene chloride, dichloro
Ethane, toluene, one of dimethylformamide and dimethyl acetamide or a variety of；
The dosage of the organic solvent makes the concentration of alkynyl isothiocyanates shown in formula (II) be 0.05-0.5mmol/mL.
8. the preparation method according to claim 4, which is characterized in that the additive is water.
Wherein, the molar ratio of the dosage of the additive is rubbing for the dosage of alkynyl isothiocyanates described in 1:3-7 and additive
You are than being 1:1-10, preferably 1:3-7.
9. according to the described in any item preparation methods of claim 4-9, which is characterized in that the condition of the tandem reaction includes:
Temperature is 95-120 DEG C, time 10-24h.
10. the purposes of N-5- carbonyl thiazole indole derivatives, is used to prepare small described in a kind of any one of claim 1-3
Molecular drug.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008006793A1 (en) * | 2006-07-14 | 2008-01-17 | Glaxo Group Limited | Indole compounds |
| WO2008006790A1 (en) * | 2006-07-14 | 2008-01-17 | Glaxo Group Limited | Indole compounds |
| CN105669698A (en) * | 2016-02-25 | 2016-06-15 | 青岛科技大学 | Preparation method of polysubstituted thiapyran diindyl derivative |
| CN105820174A (en) * | 2016-04-08 | 2016-08-03 | 青岛科技大学 | Polysubstituted thienoindole derivative and preparation method thereof |
-
2018
- 2018-08-09 CN CN201810904660.0A patent/CN108947997A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008006793A1 (en) * | 2006-07-14 | 2008-01-17 | Glaxo Group Limited | Indole compounds |
| WO2008006790A1 (en) * | 2006-07-14 | 2008-01-17 | Glaxo Group Limited | Indole compounds |
| CN105669698A (en) * | 2016-02-25 | 2016-06-15 | 青岛科技大学 | Preparation method of polysubstituted thiapyran diindyl derivative |
| CN105820174A (en) * | 2016-04-08 | 2016-08-03 | 青岛科技大学 | Polysubstituted thienoindole derivative and preparation method thereof |
Non-Patent Citations (4)
| Title |
|---|
| ANJU MODI，等: "Base-Promoted Synthesis of Quinoline-4(1H)-thiones from o-Alkynylanilines and Aroyl Isothiocyanates", 《ORGANIC LETTERS》 * |
| CHUN ZHANG，等: "Dioxygen Activation under Ambient Conditions: Cu-Catalyzed Oxidative Amidation−Diketonization of Terminal Alkynes Leading to α-Ketoamides", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| WENYAN HAO，等: "The copper(i)-catalyzed tandem reaction of o-alkynylphenyl isothiocyanates with isocyanides: a rapid synthesis of 5H-benzo[d]imidazo[5,1-b][1,3]thiazines", 《CHEMICAL COMMUNICATIONS》 * |
| YOSHIRO ODA，等: "Synthesis of N-Azolylindoles by Copper-Catalyzed C–H/N–H Coupling–Annulation Sequence of o-Alkynylanilines", 《ORGANIC LETTERS》 * |
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