CN107400079B - A kind of Regioselective synthesis of 2,5- disubstituted pyrroles - Google Patents
A kind of Regioselective synthesis of 2,5- disubstituted pyrroles Download PDFInfo
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Abstract
The invention discloses the Regioselective synthesis of one kind 2,5- disubstituted pyrroles, belong to the field of chemical synthesis.This method is using simple pyrroles as starting material, using substep iodo and coupling reaction, synthesizes a series of 2,5- disubstituted pyrroles for being connected with different substituents by the reaction of 6 steps, 60% or more, structure passes through yield1H NMR、13C NMR and HRMS are confirmed.The present invention is compared with Paal-Knorr synthetic method traditional before, it does not need to construct building block molecule in advance, it is raw material with cheap and easily-available pyrroles, simplify synthesis process, it can be the 2 of pyrroles, 5 neatly introduce different substituent groups, lay the foundation for compounds such as synthetic drug, molecular wire and high molecular polymers.
Description
Technical field
The invention belongs to the field of chemical synthesis, and in particular to the regio-selective synthesis side of one kind 2,5- disubstituted pyrroles
Method.
Background technique
2,5- disubstituted pyrroles are a kind of important polysubstituted pyrrole compounds, have good bioactivity or photo electric
Can, it is prevalent in biologically active natural products or unnatural products, is many drugs, porphyrin analog, high score
The essential building blocks of sub- polymer, alkaloid and amino acid.2,5- disubstituted pyrroles have a good application prospect, synthesis
Research causes people and more and more pays close attention to.
Currently, the synthetic method of 2,5- disubstituted pyrroles is broadly divided into two classes, the i.e. cyclization and pyrrole ring of chain compound
Function dough.Currently, chain compound cyclization using more, such as traditional Paal-Knorr synthetic method, while also having one
A little novel synthetic methods, such as by the condensation reaction of 1,3- diine and primary amine, metal catalytic synthetic method, pivaloyl azide
Cyclisation and isomerization, α-nitro ketal with the cyclisation of α-acylamino- sulfone and aromatisation and ring expansion method synthesize 2,5- disubstituted pyrroles
Deng.But in the synthetic method of these pyrroles, the substituent group on the upper position 2,5- of pyrroles is introduced before constituting pyrrole ring, this
So that the introducing of substituent group is restricted, while the higher cost of these synthetic routes, raw material is unstable or has hypertoxicity, produces
Species are more complex, and applicable is limited in scope.Therefore, exploring the method that one can introduce substituent group flexible and changeablely has ten
Divide important meaning.
Summary of the invention
It is an object of the invention to design one to synthesize 2,5- disubstituted pyrroles with the method for coupling by substep iodo
Route.Using the pyrroles of cheap and simple as raw material, by the halogenating reaction in situ using trimethyl silicon substrate and more mature palladium is studied
The coupling reaction of catalysis devises the synthetic route of 2, a 5- disubstituted pyrroles, and the method makes the transformation of substituent group cleverer
Work is changeable, and reaction condition is milder, and product is more easily separated, has in the synthesis of many functional compounds and applies valence well
Value.
Technical solution of the present invention:
The Regioselective synthesis of one kind 2,5- disubstituted pyrroles synthesizes the reaction equation of 2,5- disubstituted pyrroles are as follows:
Synthesis 2,5- disubstituted pyrroles specific steps include:
The first step synthesizes compound 2
Under inert gas protection, NaH organic solution, pyrroles's organic solution are prepared；It is under ice bath stirring that pyrroles is organic
Solution is added dropwise in NaH organic solution, is reacted 1-3 hours, forms solution A, wherein the molar ratio of NaH and pyrroles are in solution A
1:1-3；N, N- dimethylsulphamoyl chloride (ClSO are added dropwise into solution A2NMe2), at 0 DEG C to 2-5h is reacted at room temperature, obtain solution
B；Solution B is extracted with ether, collects organic phase, and uses water and saturated common salt water washing organic phase respectively, then uses nothing
Water Na2SO4Dry, column separation after solvent removed by evaporation at reduced pressure obtains compound 2.
N in the solution B, N- dimethylsulphamoyl chloride (ClSO2NMe2) it with the molar ratio of pyrroles is 1-2:1.
Second step synthesizes compound 3
Under inert gas protection, compound 2 is that 1:2-4 is mixed with n-BuLi in molar ratio, is subzero 50- in temperature
1-3h is reacted at subzero 90 DEG C, is completed hydrogen lithium exchange reactions, is obtained solution C；Solution C is mixed with trim,ethylchlorosilane, wherein
Compound 2 in solution C and trim,ethylchlorosilane molar concentration rate are 1:2-5, and being raised to after room temperature that the reaction was continued naturally, 2-5 is small
When, substitution reaction is completed, mix products A is obtained；Suitable water is added in mix products A, is extracted with ether, collects organic
Phase uses saturated sodium bicarbonate, water, saturated common salt water washing organic phase respectively, then uses anhydrous Na2SO4It is dry, it is evaporated under reduced pressure and removes
Column separation after solvent obtains compound 3.
Third step synthesizes compound 4
Under inert gas protection, by compound 3 and N- N-iodosuccinimide (NIS) in AgNO3Catalysis is lower to occur iodine
Generation reaction, obtains mix products B, wherein compound 3, NIS and AgNO3Molar ratio be 1:(1-2): (0.1-0.3), room temperature
Under, after reaction 6-10 hours, saturated aqueous sodium thiosulfate is added, is extracted with ether, collects organic phase, use water respectively
With saturated common salt water washing organic phase, then anhydrous Na is used2SO4Dry, column separation after solvent removed by evaporation at reduced pressure obtains chemical combination
Object 4.
4th step synthesizes compound 5a-5d
Under inert gas protection, it using compound 4, aryl boric acid as raw material, is dissolved in reaction dissolvent, adds alkali and four
Triphenylphosphine palladium occurs Suzuki coupling reaction, obtains mix products C, instead in alkaline environment under the catalysis of tetra-triphenylphosphine palladium
Answering temperature is 80-110 DEG C, and the reaction time is 3-5 hours；Water is added into mix products C, is extracted with ether, collection has
Machine phase uses water and saturated common salt water washing organic phase respectively, then uses anhydrous Na2SO4It is dry, column is crossed after solvent removed by evaporation at reduced pressure
Separation, respectively obtains compound 5a-5d.
The compound 5a is 2- phenyl -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles；5b is
2- (4- methoxyphenyl) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles；5c is 2- (4- chlorphenyl) -5-
(trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles；5d is 2- (4- acetylphenyl) -5- (trimethyl silicon substrate) -1-
(N, N- dimethyl methyl acyl group) pyrroles.
The compound 4, aryl boric acid, alkali, tetra-triphenylphosphine palladium molar ratio be 1:(1-2): (3-5): (0.05-
0.2).The alkali is sodium carbonate.The aryl boric acid be phenyl boric acid, to methoxyphenylboronic acid, to chlorophenylboronic acid or to second
Acyl group phenyl boric acid etc..The reaction dissolvent is toluene and methanol is 1:(1-3 by volume) mixed solution；Every 0.1mmol
Compound 4 corresponds to 3-7mL reaction dissolvent.
5th step synthesizes compound 6a-6c under inert gas protection, the compound 5a- chromatographed by the 4th step column
5c is raw material, and iodide reaction occurs in organic solvent under silver nitrate catalysis with N- N-iodosuccinimide (NIS), is mixed
Product D, reaction temperature are 20-45 DEG C, and the reaction time is 1-5 hours；It is water-soluble that saturated sodium thiosulfate is added into mix products D
Liquid is extracted with ether, collects organic phase, uses water and saturated common salt water washing organic phase, then anhydrous Na respectively2SO4It is dry,
Column separation after solvent removed by evaporation at reduced pressure respectively obtains compound 6a-6c.
The compound 6a is the iodo- 5- phenyl -1- of 2- (N, N- dimethyl methyl acyl group) pyrroles, and 6b is the iodo- 5- (4- of 2-
Methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles, 6c is the iodo- 5- of 2- (4- chlorphenyl) -1- (N, N- dimethyl sulphonyl
Base) pyrroles.
The compound 5a-5c:N- N-iodosuccinimide: the molar ratio of silver nitrate is 1:(1-2): (0.01-
0.5)。
The reaction dissolvent is ethyl alcohol, acetonitrile, N,N-Dimethylformamide；The corresponding 3-7mL of every 0.1mmol compound 4
Reaction dissolvent.
6th step synthesizes compound 7a-7d
Under inert gas protection, respectively with compound 6b and to methoxyphenylboronic acid, compound 6b and para hydroxybenzene boron
Acid, compound 6c and to methoxyphenylboronic acid, compound 6b and to chlorophenylboronic acid be raw material, add the raw material into organic solvent
In, and Pd (PPh is added3)4And alkali, in Pd (PPh3)4Catalysis under, Suzuki coupling reaction occurs in alkaline environment, is mixed
Product E, reaction temperature are 80-110 DEG C, and the reaction time is 1-8 hours；Water is added into mix products E, is extracted with ether
It takes, collects organic phase, use water and saturated common salt water washing organic phase, then anhydrous Na respectively2SO4It is dry, solvent removed by evaporation at reduced pressure
Column separation afterwards respectively obtains compound 7a-7d.
The compound 7a is 2,5- bis- (4- methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles, compound
7b is 2- (4- hydroxy phenyl) -5- (4- methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles, and compound 7c is 2,5-
Two (4- chlorphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles, compound 7d are 2- (4- chlorphenyl) -5- (4- methoxybenzene
Base) -1- (N, N- dimethyl methyl acyl group) pyrroles.
The compound 6b, to methoxyphenylboronic acid or para hydroxybenzene boric acid, Pd (PPh3)4, alkali molar ratio be 1:
(1-3): (0.05-0.1): compound 6c described in (3-6), to methoxyphenylboronic acid or to chlorophenylboronic acid, Pd (PPh3)4, alkali
Molar ratio is 1:(1-3): (0.05-0.1): (3-6).The alkali is sodium carbonate, potassium carbonate or potassium phosphate.The aryl boron
Acid be phenyl boric acid, to methoxyphenylboronic acid, to chlorophenylboronic acid or para hydroxybenzene boric acid.
The reaction dissolvent is toluene and methanol is 1:(1-3 by volume) mixed solution；Every 0.1mmol chemical combination
Object 4 corresponds to 3-7mL reaction dissolvent.
The invention has the benefit that
(1) it compared with Paal-Knorr synthetic method traditional before, does not need to construct building block molecule in advance, use is cheap and easily-available
Pyrroles be raw material, simplify synthesis process.
(2) direct function dough is carried out to pyrrole ring, is difficult 2 that introduce substituent group in pyrroles and 5 property selected introduces
Substituent group.
(3) good for the universality of the substituent group of introducing, the introducing of the various substituent groups of realization of high yield.
Specific embodiment
Below in conjunction with technical solution, a specific embodiment of the invention is further illustrated.
Embodiment 1
The first step, the synthesis of compound 2
Under nitrogen protection, NaH (1.73g, 43.2mmol) is added in bis- mouthfuls of flasks of 250mL, DMF (50 mL)；100mL
Pyrroles (2.42g, 36mmol) and DMF (20mL) are added in two mouthfuls of flasks, it is washed to be added dropwise to n-hexane under ice bath stirring
NaH DMF solution in, stir 1h；ClSO is added dropwise2NMe2(3.9mL, 36mmol) reacts 2h at 0 DEG C.Into two mouthfuls of bottles
Suitable ice water is added, is extracted with ether, organic phase is collected, uses water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry
Dry, column separation after solvent removed by evaporation at reduced pressure, solvent is n-hexane: ether (10:1) obtains white solid 4.39g, yield
70.0%.mp:61-62℃；1H NMR(500MHz,CDCl3) δ 2.79 (s, 6H), 6.31 (t, 1H, J=2 Hz), 7.09 (t,
1H, J=2Hz)；13C NMR(125MHz,CDCl3)δ38.3,111.7,120.9.HRMS (ESI-TOF)for C6H10N2O2S[M
+H]+:calcd,175.0536.found 175.0536.
Second step, the synthesis of compound 3
Under nitrogen protection, THF (60mL) is added in bis- mouthfuls of flasks of 250mL, TMP (2,2,6,6- tetramethyl piperidine)
N-BuLi (18.5mL/2.5M, 46.8 mmol) are slowly added dropwise in (8.05mL, 47.4mmol) at -78 DEG C, are lower than -65 DEG C of temperature
Degree is lower to react 1h, and pyrroles 2 (3.14g, 18mmol) is dissolved in THF (20mL), is slowly dropped into syringe to two mouthfuls of flasks
In, 1.5h is stirred under the conditions of -78 DEG C, then by Me3SiCl (6mL, 46.8mmol) is dissolved in THF (20mL), with injection
Device is slowly dropped into reaction solution, and low temperature stirs 0.5h, and when temperature is slowly warmed to room temperature, reaction 2h stops reaction.To reaction
Suitable water is added in resulting mix products, is extracted with ether, organic phase is collected, uses saturated sodium bicarbonate, water respectively
With saturated common salt water washing, anhydrous Na2SO4Dry, column separation after solvent removed by evaporation at reduced pressure, solvent is n-hexane: ether
(20:1) obtains white solid 5.62g, yield 98.0%.mp:81-83℃；1H NMR (500MHz,CDCl3)δ0.30(s,
18H),2.62(s,6H),6.56(s,2H)；13C NMR(125MHz, CDCl3)δ0.6,37.7,125.2,142.8.HRMS
(ESI-TOF)for C12H26N2O2SSi2[M+H]+: calcd,319.1326.found 319.1326.
Third step, the synthesis of compound 4
Under nitrogen protection, compound 3 (160mg, 0.5mmol) is added in bis- mouthfuls of flasks of 100mL, NIS (138mg,
0.6mmol), AgNO3(15mg, 0.09mmol) and CH2Cl2(20mL) stirs 8h at room temperature, stops reaction.To reaction
Suitable sodium thiosulfate solution is added in resulting mix products, is extracted with ether, collects organic phase, uses water respectively
With saturated common salt water washing, anhydrous Na2SO4Dry, column separation after solvent removed by evaporation at reduced pressure, solvent is n-hexane: ether
(30:1) obtains Bluish white solid 156mg, yield 84.0%.mp:48-49℃；1H NMR(500MHz,CDCl3)δ0.30(s,
9H), 2.88 (s, 6H), 6.42 (d, 1H, J=3.5Hz), 6.60 (d, 1H, J=3.5Hz)；13C NMR(125 MHz,CDCl3)δ
0.6,37.9,125.2,126.3,144.5.HRMS(ESI-TOF)for C9H17IN2O2SSi [M+H]+:calcd,
372.9897.found 372.9893.
4th step, the synthesis of compound 5a-5d
Under nitrogen protection, compound 4a (37mg, 0.1mmol) is added in bis- mouthfuls of flasks of 50mL, phenyl boric acid
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
It is stirred to react 4h under the conditions of DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether
It takes, collects organic phase, use water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- phenyl -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5a)
White solid 27mg, yield 84%；mp:74-75℃；1H NMR(500MHz,(CD3)2CO)δ0.33(s,9H),
2.29 (s, 6H), 6.26 (d, J=3.5Hz, 1H), 6.53 (d, J=3Hz, 1H), 7.43 (tdd, J=8.0Hz, J=5.0Hz,
J=3.0Hz, 3H), 7.49 (dt, J=5Hz, J=2Hz, 2H)；13C NMR (125MHz,(CD3)2CO)δ0.9,36.5,
115.9,122.9,123.0,128.4,129.0,131.2,133.4, 139.6,139.9.HRMS(ESI-TOF)for
C15H22N2O2SSi[M+H]+:calcd,323.1244.found 323.1240.
Under nitrogen protection, compound 4b (37mg, 0.1mmol) is added in bis- mouthfuls of flasks of 50mL, phenyl boric acid
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
It is stirred to react 5h under the conditions of DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether
It takes, collects organic phase, use water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- (4- methoxyphenyl) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5b)
White solid 27mg, yield 78%；mp:169-170℃；1H NMR(500MHz,CDCl3)δ0.34 (s,9H),
2.30 (s, 6H), 3.83 (s, 3H), 6.19 (d, J=3Hz, 1H), 6.47 (d, J=3Hz, 1H), 6.91 (d, J=9Hz, 1H),
7.41 (d, J=9Hz, 1H)；13C NMR(125MHz,CDCl3)δ0.7,36.5, 55.3,113.0,115.1,122.0,
124.9,131.9,138.4,139.8,159.6.HRMS(ESI-TOF)for C16H24N2O3SSi[M+H]+:calcd,
353.1350.found353.1351.
Under nitrogen protection, compound 4c (37mg, 0.1mmol) is added in bis- mouthfuls of flasks of 50mL, phenyl boric acid
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
It is stirred to react 3h under the conditions of DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether
It takes, collects organic phase, use water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- (4- chlorphenyl) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5c)
White solid 26mg, yield 73%；mp:169-170℃；1H NMR(500MHz,CDCl3)δ0.34(s,9H),
2.32 (s, 6H), 6.23 (d, J=3.5Hz, 1H), 6.49 (d, J=3.5Hz, 1H), 7.36 (d, J=8.5Hz, 1H), 7.43
(d, J=8.5Hz, 1H)；13C NMR(125MHz,(CD3)2CO)δ0.9, 36.7,116.5,123.1,128.5,132.1,
132.8,134.6,138.3,140.6.HRMS(ESI-TOF)for C15H21ClN2O2SSi[M+H]+:calcd,
357.0854.found357.0853.
Under nitrogen protection, compound 4d (37mg, 0.1mmol) is added in bis- mouthfuls of flasks of 50mL, phenyl boric acid
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
It is stirred to react 4h under the conditions of DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether
It takes, collects organic phase, use water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- (4- acetylphenyl) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5d)
White solid 27mg, yield 75%；mp:114-115℃；1H NMR(500MHz,CDCl3)δ0.36 (s,9H),
2.29 (s, 6H), 2.63 (s, 3H), 6.30 (d, J=3.5Hz, 1H), 6.51 (d, J=3.5Hz, 1H), 7.61 (d, J=
8.5Hz, 1H), 7.98 (d, J=8.5Hz, 1H)；13C NMR(125MHz,CDCl3)δ0.7, 26.7,36.7,116.2,
122.4,127.6,130.5,136.4,137.4,137.7,141.5,197.6.HRMS (ESI-TOF)for C17H24N2O3SSi
[M+H]+:calcd,365.1350.found365.1352.
5th step, the synthesis of compound 6a-6d
Under nitrogen protection, compound 5a (0.16mmol) is added in bis- mouthfuls of flasks of 50mL, NIS (44mg,
0.20mmol), AgNO3(8mg, 0.05mmol) and anhydrous acetonitrile (5mL) is stirred to react 1h under the conditions of 35 DEG C, stops reaction.To
It reacts and suitable sodium thiosulfate solution is added in resulting mix products, extracted with ether, collect organic phase, respectively
With water and saturated common salt water washing, anhydrous Na2SO4It is dry, column separation after solvent removed by evaporation at reduced pressure, solvent be n-hexane/
Ether obtains required compound.
The iodo- 5- phenyl -1- of 2- (N, N- dimethyl methyl acyl group) pyrroles (6a)
White solid 43mg, yield 71%；mp:86-87℃；1H NMR(500MHz,CDCl3)δ2.62(s, 6H),6.16
(d, J=3.5Hz, 1H), 6.65 (d, J=3.5Hz, 1H), 7.36 (dd, J=7Hz, J=1.5Hz, 3H), 7.40 (d, J=
2Hz,2H)；13C NMR(125MHz,CDCl3)δ37.9,116.9,125.9,127.5, 128.2,130.2,133.4,
141.6.HRMS(ESI-TOF)for C12H13IN2O2S[M+H]+:calcd, 376.9815.found376.9823.
Under nitrogen protection, compound 5b (0.16mmol) is added in bis- mouthfuls of flasks of 50mL, NIS (44mg,
0.20mmol), AgNO3(8mg, 0.05mmol) and anhydrous acetonitrile (5mL) is stirred to react 5h under the conditions of 35 DEG C, stops reaction.To
It reacts and suitable sodium thiosulfate solution is added in resulting mix products, extracted with ether, collect organic phase, respectively
With water and saturated common salt water washing, anhydrous Na2SO4It is dry, column separation after solvent removed by evaporation at reduced pressure, solvent be n-hexane/
Ether obtains required compound.
The iodo- 5- of 2- (4- methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles (6b)
White solid 35mg, yield 86%；mp:199-200℃；1H NMR(500MHz,CDCl3)δ 2.62(s,6H),
3.83 (s, 3H), 6.12 (d, J=3.5Hz, 1H), 6.63 (d, J=3.5Hz, 1H), 6.89 (d, J=8.5Hz, 2H), 7.33
(d, J=8.5Hz, 2H)；13C NMR(125MHz,CDCl3)δ37.9,55.3, 112.9,116.6,125.9,131.6,
141.4,159.6.HRMS(ESI-TOF)for C13H15IN2O3S [M+H]+:calcd,406.9921.found406.9911.
Under nitrogen protection, compound 5c (0.16mmol) is added in bis- mouthfuls of flasks of 50mL, NIS (44mg,
0.20mmol), AgNO3(8mg, 0.05mmol) and anhydrous acetonitrile (5mL) is stirred to react 1h under the conditions of 35 DEG C, stops reaction.To
It reacts and suitable sodium thiosulfate solution is added in resulting mix products, extracted with ether, collect organic phase, respectively
With water and saturated common salt water washing, anhydrous Na2SO4It is dry, column separation after solvent removed by evaporation at reduced pressure, solvent be n-hexane/
Ether obtains required compound.
The iodo- 5- of 2- (4- chlorphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles (6c)
White solid 42mg, yield 84%；mp:111-112℃；1H NMR(500MHz,CDCl3)δ2.67 (s,6H),
6.16 (d, J=3.5Hz, 1H), 6.65 (d, J=3.5Hz, 1H), 7.33 (s, 4H)；13C NMR (125MHz,CDCl3)δ
38.1,117.2,126.1,127.7,131.4,131.9,134.3,140.5.HRMS (ESI-TOF)for C12H12ClIN2O2S
[M+H]+:calcd,410.9425.found 410.9422.
6th step, the synthesis of compound 7a-7d
Under nitrogen protection, compound 6b (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, to methoxyphenylboronic acid
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL),
It is stirred to react 1h at 100 DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether,
Organic phase is collected, uses water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column separation after solvent removed by evaporation at reduced pressure,
Solvent is n-hexane: ether, obtains required compound.
2,5- bis- (4- methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles (7a)
White solid, yield 83%；mp:192-193℃；1H NMR(500MHz,CDCl3)δ2.33(s, 6H),3.84
(s, 6H), 6.21 (s, 2H), 6.93 (d, J=9Hz, 4H), 7.48 (d, J=9Hz, 4H)；13C NMR(125MHz,CDCl3)δ
37.2,55.2,113.2,113.8,126.4,130.5,139.2,159.2. HRMS(ESI-TOF)for C20H22N2O4S[M+
H]+:calcd,387.1373.found387.1372.
Under nitrogen protection, compound 6b (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, para hydroxybenzene boric acid
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
It is stirred to react 8h at DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether, receives
Collect organic phase, uses water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column separation after solvent removed by evaporation at reduced pressure, exhibition
Opening agent is n-hexane: ether obtains required compound.
2- (4- hydroxy phenyl) -5- (4- methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles (7b)
White solid, yield 84%；mp:233-234℃；1H NMR(500MHz,CDCl3)δ2.33(s, 6H),3.84
(s, 3H), 6.21 (s, 2H), 6.85 (d, J=8.5Hz, 2H), 6.93 (d, J=8.5Hz, 2H), 7.43 (d, J=8.5Hz,
2H), 7.48 (d, J=8.5Hz, 2H)；13C NMR(125MHz,CDCl3)δ 37.2,55.3,113.2,113.8,114.7,
126.4,126.5,130.5,130.7,139.2,139.2,155.3,159.2. HRMS(ESI-TOF)for C19H20N2O4S[M
+H]+:calcd,373.1217.found373.1229.
Under nitrogen protection, compound 6c (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, to chlorophenylboronic acid
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL),
It is stirred to react 1h at 100 DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether,
Organic phase is collected, uses water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane: ether obtains required compound.
2,5- bis- (4- chlorphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles (7c)
White solid, yield 81%；mp:126-127℃；1H NMR(500MHz,CDCl3)δ2.34(s, 6H),6.30
(s, 2H), 7.37 (d, J=8.5Hz, 4H), 7.49 (d, J=8.5Hz, 4H)；13C NMR(125 MHz,CDCl3)δ37.2,
114.9,128.0,130.4,131.9,133.8,139.1.HRMS(ESI-TOF)for C18H16Cl2N2O2S[M+H]+:calcd,
395.0382.found395.0382.
Under nitrogen protection, compound 6b (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, to chlorophenylboronic acid
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL),
It is stirred to react 1.5h at 100 DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether
It takes, collects organic phase, use water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane: ether obtains required compound.
2- (4- chlorphenyl) -5- (4- methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles (7d)
White solid, yield 75%；mp:211-212℃；1H NMR(500MHz,CDCl3)δ2.33(s, 6H),3.85
(s, 3H), 6.24 (d, J=1.5Hz, 1H), 6.27 (d, J=1.5Hz, 1H), 6.94 (d, J=9Hz, 2H), 7.36 (d, J=
8.5Hz, 2H), 7.49 (dd, J=8.5Hz, J=5Hz, 4H)；13C NMR(125 MHz,CDCl3)δ37.2,55.3,113.3,
113.9,114.8,125.8,127.9,130.3,130.7,132.4, 133.4,138.5,139.9,159.4.HRMS(ESI-
TOF)for C19H19ClN2O3S[M+H]+:calcd, 391.0878.found391.0878.
Embodiment 2
The first step, the synthesis of compound 2
Under nitrogen protection, NaH (1.44g, 36mmol) is added in bis- mouthfuls of flasks of 250mL, DMF (50 mL)；100mL bis-
Pyrroles (2.42g, 36mmol) and DMF (20mL) are added in mouth flask, it is washed to be added dropwise to n-hexane under ice bath stirring
In the DMF solution of NaH, 1h is stirred；ClSO is added dropwise2NMe2(3.9mL, 36mmol) reacts 2h at 0 DEG C.Add into two mouthfuls of bottles
Enter suitable ice water, extracted with ether, collect organic phase, uses water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry
Dry, column separation after solvent removed by evaporation at reduced pressure, solvent is n-hexane: ether (10:1) obtains white solid 4.39g, yield
80%.
Second step, the synthesis of compound 3
Under nitrogen protection, THF (60mL) is added in bis- mouthfuls of flasks of 250mL, TMP (2,2,6,6- tetramethyl piperidine)
N-BuLi (14.2mL/2.5M, 36mmol) is slowly added dropwise in (8.05mL, 47.4mmol) at -90 DEG C, is lower than at a temperature of -65 DEG C
1h is reacted, pyrroles 2 (3.14g, 18mmol) is dissolved in THF (20mL), is slowly dropped into syringe into two mouthfuls of flasks ,-
1.5h is stirred under the conditions of 90 DEG C, then by Me3SiCl (4.6mL, 36mmol) is dissolved in THF (20mL), slow with syringe
It is added dropwise in reaction solution, low temperature stirs 0.5h, and when temperature is slowly warmed to room temperature, reaction 2h stops reaction.It is resulting to reacting
Suitable water is added in mix products, is extracted with ether, organic phase is collected, uses saturated sodium bicarbonate, water and saturation respectively
Brine It, anhydrous Na2SO4Dry, column separation after solvent removed by evaporation at reduced pressure, solvent is n-hexane: ether (20:
1) white solid 5.62g, yield 99%, are obtained.
Third step, the synthesis of compound 4
Under nitrogen protection, compound 3 (160mg, 0.5mmol) is added in bis- mouthfuls of flasks of 100mL, NIS (115mg,
0.5mmol), AgNO3(8.33mg, 0.05mmol) and CH2Cl2(20mL) stirs 6h at room temperature, stops reaction.To anti-
It answers and suitable sodium thiosulfate solution is added in resulting mix products, extracted with ether, collect organic phase, use respectively
Water and saturated common salt water washing, anhydrous Na2SO4Dry, column separation after solvent removed by evaporation at reduced pressure, solvent is n-hexane: second
Ether (30:1) obtains Bluish white solid 156mg, yield 93%..
4th step, the synthesis of compound 5a-5d
Under nitrogen protection, compound 4a (37mg, 0.1mmol) is added in bis- mouthfuls of flasks of 50mL, phenyl boric acid
(0.1mmol), 2M Na2CO3(0.3mL), Pd (PPh3)4(6mg, 0.005mmol) and toluene and methanol (1:1) (3mL), 80 DEG C
Under the conditions of be stirred to react 3h, stop reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether,
Organic phase is collected, uses water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column separation after solvent removed by evaporation at reduced pressure,
Solvent is n-hexane/ether, obtains required compound.5a-5d
2- phenyl -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5a), white solid 25mg, yield
79%；
Under nitrogen protection, compound 4b (37mg, 0.1mmol) is added in bis- mouthfuls of flasks of 50mL, phenyl boric acid
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
It is stirred to react 5h under the conditions of DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether
It takes, collects organic phase, use water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- (4- methoxyphenyl) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5b), white solid
25mg, yield 73%；
Under nitrogen protection, compound 4c (37mg, 0.1mmol) is added in bis- mouthfuls of flasks of 50mL, phenyl boric acid
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
It is stirred to react 3h under the conditions of DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether
It takes, collects organic phase, use water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- (4- chlorphenyl) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5c), white solid 24
Mg, yield 68%；
Under nitrogen protection, compound 4d (37mg, 0.1mmol) is added in bis- mouthfuls of flasks of 50mL, phenyl boric acid
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
It is stirred to react 4h under the conditions of DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether
It takes, collects organic phase, use water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- (4- acetylphenyl) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5d), white solid
25mg, yield 70%；
5th step, the synthesis of compound 6a-6c
Under nitrogen protection, compound 5a (0.16mmol) is added in bis- mouthfuls of flasks of 50mL, NIS (35.2mg,
0.16mmol), AgNO3(2mg, 0.016mmol) and dehydrated alcohol (3mL) is stirred to react 1h under the conditions of 20 DEG C, stops reaction.
Suitable saturated aqueous sodium thiosulfate is added to reacting in resulting mix products, is extracted with ether, collects organic
Phase uses water and saturated common salt water washing, anhydrous Na respectively2SO4It dries, column separation after solvent removed by evaporation at reduced pressure, solvent is
N-hexane/ether obtains required compound 6a-6c.
The iodo- 5- phenyl -1- of 2- (N, N- dimethyl methyl acyl group) pyrroles (6a), white solid 42mg, yield 76%；
Under nitrogen protection, compound 5b (0.16mmol) is added in bis- mouthfuls of flasks of 50mL, NIS (44mg,
0.20mmol), AgNO3(8mg, 0.05mmol) and anhydrous acetonitrile (5mL) is stirred to react 5h under the conditions of 35 DEG C, stops reaction.To
It reacts and suitable sodium thiosulfate solution is added in resulting mix products, extracted with ether, collect organic phase, respectively
With water and saturated common salt water washing, anhydrous Na2SO4It is dry, column separation after solvent removed by evaporation at reduced pressure, solvent be n-hexane/
Ether obtains required compound.
The iodo- 5- of 2- (4- methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles (6b), white solid 37mg, yield
91%；
Under nitrogen protection, compound 5c (0.16mmol) is added in bis- mouthfuls of flasks of 50mL, NIS (44mg,
0.20mmol), AgNO3(8mg, 0.05mmol) and anhydrous acetonitrile (5mL) is stirred to react 1h under the conditions of 35 DEG C, stops reaction.To
It reacts and suitable sodium thiosulfate solution is added in resulting mix products, extracted with ether, collect organic phase, respectively
With water and saturated common salt water washing, anhydrous Na2SO4It is dry, column separation after solvent removed by evaporation at reduced pressure, solvent be n-hexane/
Ether obtains required compound.
The iodo- 5- of 2- (4- chlorphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles (6c), white solid 44mg, yield 89%；
6th step, the synthesis of compound 7a-7d
Under nitrogen protection, compound 6b (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, to methoxyphenylboronic acid
(0.15mmo1), 2M Na2CO3(0.15mL), Pd (PPh3)4(9mg, 0.0075mmol) and toluene and methanol (1:1) (3mL),
It is stirred to react 1h at 80 DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether,
Organic phase is collected, uses water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column separation after solvent removed by evaporation at reduced pressure,
Solvent is n-hexane: ether, obtains required compound.7a-7d
2,5- bis- (4- methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles (7a), white solid, yield 78%；
Under nitrogen protection, compound 6b (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, para hydroxybenzene boric acid
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL),
It is stirred to react 8h at 100 DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether,
Organic phase is collected, uses water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column separation after solvent removed by evaporation at reduced pressure,
Solvent is n-hexane: ether, obtains required compound.
2- (4- hydroxy phenyl) -5- (4- methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles (7b), white are solid
Body, yield 79%；
Under nitrogen protection, compound 6c (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, to chlorophenylboronic acid
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL),
It is stirred to react 1h at 100 DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether,
Organic phase is collected, uses water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane: ether obtains required compound.
2,5- bis- (4- chlorphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles (7c), white solid, yield 75%；
Under nitrogen protection, compound 6b (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, to chlorophenylboronic acid
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL),
It is stirred to react 1.5h at 100 DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether
It takes, collects organic phase, use water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column is crossed after solvent removed by evaporation at reduced pressure
Separation, solvent is n-hexane: ether obtains required compound.
2- (4- chlorphenyl) -5- (4- methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles (7d), white solid,
Yield 70%；
Embodiment 3
The first step, the synthesis of compound 2
Under nitrogen protection, NaH (4.32g, 108mmol) is added in bis- mouthfuls of flasks of 250mL, DMF (50 mL)；100mL bis-
Pyrroles (2.42g, 36mmol) and DMF (20mL) are added in mouth flask, it is washed to be added dropwise to n-hexane under ice bath stirring
In the DMF solution of NaH, 3h is stirred；ClSO is added dropwise2NMe2(7.8mL, 72mmol), reacts 5h at room temperature.Add into two mouthfuls of bottles
Enter suitable ice water, extracted with ether, collect organic phase, uses water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry
Dry, column separation after solvent removed by evaporation at reduced pressure, solvent is n-hexane: ether (10:1) obtains white solid 4.39g, yield
70%.
Second step, the synthesis of compound 3
Under nitrogen protection, THF (60mL) is added in bis- mouthfuls of flasks of 250mL, TMP (2,2,6,6- tetramethyl piperidine)
N-BuLi (28.5mL/2.5M, 72mmol) is slowly added dropwise in (8.05mL, 47.4mmol) at -78 DEG C, is lower than at a temperature of -50 DEG C
1h is reacted, pyrroles 2 (3.14g, 18mmol) is dissolved in THF (20mL), is slowly dropped into syringe into two mouthfuls of flasks ,-
1.5h is stirred under the conditions of 50 DEG C, then by Me3SiCl (11.5mL, 90mmol) is dissolved in THF (20mL), slow with syringe
Slowly it is added dropwise in reaction solution, low temperature stirs 0.5h, and when temperature is slowly warmed to room temperature, reaction 5h stops reaction.To reaction gained
Mix products in suitable water is added, extracted with ether, collect organic phase, respectively with saturated sodium bicarbonate, water and full
And brine It, anhydrous Na2SO4Dry, column separation after solvent removed by evaporation at reduced pressure, solvent is n-hexane: ether
(20:1) obtains white solid 5.62g, yield 94%.
Third step, the synthesis of compound 4
Under nitrogen protection, compound 3 (160mg, 0.5mmol) is added in bis- mouthfuls of flasks of 100mL, NIS (230mg,
1mmol), AgNO3(25mg, 0.15mmol) and CH2Cl2(20mL) stirs 10h at room temperature, stops reaction.To reaction
Suitable sodium thiosulfate solution is added in resulting mix products, is extracted with ether, collects organic phase, uses water respectively
With saturated common salt water washing, anhydrous Na2SO4Dry, column separation after solvent removed by evaporation at reduced pressure, solvent is n-hexane: ether
(30:1) obtains Bluish white solid 156mg, yield 83%..
4th step, the synthesis of compound 5a-5d
Under nitrogen protection, compound 4a (37mg, 0.1mmol) is added in bis- mouthfuls of flasks of 50mL, phenyl boric acid
(0.2mmol), 2M Na2CO3(0.5mL), Pd (PPh3)4(24mg, 0.02mmol) and toluene and methanol (1:3) (7mL), 100
It is stirred to react 5h under the conditions of DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether
It takes, collects organic phase, use water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.5a-5d
2- phenyl -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5a), white solid 25mg, yield
79%；
Under nitrogen protection, compound 4b (37mg, 0.1mmol) is added in bis- mouthfuls of flasks of 50mL, phenyl boric acid
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
It is stirred to react 5h under the conditions of DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether
It takes, collects organic phase, use water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- (4- methoxyphenyl) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5b), white solid
25mg, yield 73%；
Under nitrogen protection, compound 4c (37mg, 0.1mmol) is added in bis- mouthfuls of flasks of 50mL, phenyl boric acid
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
It is stirred to react 3h under the conditions of DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether
It takes, collects organic phase, use water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- (4- chlorphenyl) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5c), white solid 24
Mg, yield 68%；
Under nitrogen protection, compound 4d (37mg, 0.1mmol) is added in bis- mouthfuls of flasks of 50mL, phenyl boric acid
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
It is stirred to react 4h under the conditions of DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether
It takes, collects organic phase, use water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- (4- acetylphenyl) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5d), white solid
25mg, yield 70%；
5th step, the synthesis of compound 6a-6c
Under nitrogen protection, compound 5a (0.16mmol) is added in bis- mouthfuls of flasks of 50mL, NIS (71mg,
0.32mmol), AgNO3(13.6mg, 0.08mmol) and anhydrous N,N-Dimethylformamide (11mL) stirs under the conditions of 45 DEG C anti-
5h is answered, reaction is stopped.Suitable sodium thiosulfate solution is added to reacting in resulting mix products, is extracted with ether
It takes, collects organic phase, use water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column is crossed after solvent removed by evaporation at reduced pressure
Separation, solvent are n-hexane/ether, obtain required compound 6a-6c.
The iodo- 5- phenyl -1- of 2- (N, N- dimethyl methyl acyl group) pyrroles (6a), white solid 42mg, yield 86%；
Under nitrogen protection, compound 5b (0.16mmol) is added in bis- mouthfuls of flasks of 50mL, NIS (44mg,
0.20mmol), AgNO3(8mg, 0.05mmol) and anhydrous acetonitrile (5mL) is stirred to react 5h under the conditions of 35 DEG C, stops reaction.To
It reacts and suitable sodium thiosulfate solution is added in resulting mix products, extracted with ether, collect organic phase, respectively
With water and saturated common salt water washing, anhydrous Na2SO4It is dry, column separation after solvent removed by evaporation at reduced pressure, solvent be n-hexane/
Ether obtains required compound.
The iodo- 5- of 2- (4- methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles (6b), white solid 37mg, yield
91%；
Under nitrogen protection, compound 5c (0.16mmol) is added in bis- mouthfuls of flasks of 50mL, NIS (44mg, 0.20mmol),
AgNO3(8mg, 0.05mmol) and anhydrous acetonitrile (5mL) is stirred to react 1h under the conditions of 35 DEG C, stops reaction.It is resulting to reacting
Suitable sodium thiosulfate solution is added in mix products, is extracted with ether, organic phase is collected, uses water and saturation respectively
Brine It, anhydrous Na2SO4Dry, column separation after solvent removed by evaporation at reduced pressure, solvent is n-hexane/ether, is obtained
Required compound.
The iodo- 5- of 2- (4- chlorphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles (6c), white solid 44mg, yield
89%；
6th step, the synthesis of compound 7a-7d
Under nitrogen protection, compound 6b (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, to methoxyphenylboronic acid
(0.45mmo1), 2M Na2CO3(0.6mL), Pd (PPh3)4(18mg, 0.01mmol) and toluene and methanol (1:3) (11mL),
It is stirred to react 8h at 110 DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether,
Organic phase is collected, uses water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane: ether obtains required compound.7a-7d
2,5- bis- (4- methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles (7a), white solid, yield 88%；
Under nitrogen protection, compound 6b (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, para hydroxybenzene boric acid
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL),
It is stirred to react 8h at 100 DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether,
Organic phase is collected, uses water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column separation after solvent removed by evaporation at reduced pressure,
Solvent is n-hexane: ether, obtains required compound.
2- (4- hydroxy phenyl) -5- (4- methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles (7b), white are solid
Body, yield 89%；
Under nitrogen protection, compound 6c (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, to chlorophenylboronic acid
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL),
It is stirred to react 1h at 100 DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether,
Organic phase is collected, uses water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane: ether obtains required compound.
2,5- bis- (4- chlorphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles (7c), white solid, yield 85%；
Under nitrogen protection, compound 6b (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, to chlorophenylboronic acid
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL),
It is stirred to react 1.5h at 100 DEG C, stops reaction.Suitable water is added to reacting in resulting mix products, is extracted with ether
It takes, collects organic phase, use water and saturated common salt water washing, anhydrous Na respectively2SO4It is dry, column is crossed after solvent removed by evaporation at reduced pressure
Separation, solvent is n-hexane: ether obtains required compound.
2- (4- chlorphenyl) -5- (4- methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles (7d), white solid,
Yield 80%.
Claims (10)
1. one kind 2, the Regioselective synthesis of 5- disubstituted pyrroles, it is characterised in that:
The reaction equation of the Regioselective synthesis of the 2,5- disubstituted pyrroles are as follows:
Synthesize 2,5- disubstituted pyrroles method the following steps are included:
The first step synthesizes compound 2
Under inert gas protection, NaH organic solution, pyrroles's organic solution are prepared；By pyrroles's organic solution under ice bath stirring
It is added dropwise in NaH organic solution, reaction 1-3 hours, formation solution A, the molar ratio of NaH and pyrroles are 1:1-3；Into solution A
N, N- dimethylsulphamoyl chloride ClSO is added dropwise2NMe2, at 0 DEG C to 2-5h is reacted at room temperature, obtain solution B；With ether to solution B into
Row extraction, collects organic phase, and uses water and saturated common salt water washing organic phase respectively, then uses anhydrous Na2SO4Dry, decompression is steamed
Hair removes column separation after solvent, obtains compound 2；
N, N- dimethylsulphamoyl chloride ClSO2NMe2Molar ratio with pyrroles is 1-2:1；Second step synthesizes compound 3
Under inert gas protection, compound 2 is that 1:2-4 is mixed with n-BuLi in molar ratio, is that subzero 50- is subzero in temperature
1-3h is reacted at 90 DEG C, is completed hydrogen lithium exchange reactions, is obtained solution C；Solution C is mixed with trim,ethylchlorosilane, compound 2 with
Trim,ethylchlorosilane molar concentration rate is 1:2-5, is raised to after room temperature that the reaction was continued 2-5 hour naturally, and completion substitution reaction obtains
Mix products A；Suitable water is added in mix products A, is extracted with ether, organic phase is collected, uses unsaturated carbonate hydrogen respectively
Sodium, water, saturated common salt water washing organic phase, then use anhydrous Na2SO4Dry, column separation after solvent removed by evaporation at reduced pressure obtains
Compound 3；
Third step synthesizes compound 4
Under inert gas protection, by compound 3 and N- N-iodosuccinimide (NIS) in AgNO3The lower generation iodo of catalysis is anti-
It answers, obtains mix products B, wherein compound 3, NIS and AgNO3Molar ratio be 1:1-2:0.1-0.3, at room temperature, react 6-
After 10 hours, saturated aqueous sodium thiosulfate is added, is extracted with ether, collect organic phase, respectively with water and saturation food
Salt water washing organic phase, then use anhydrous Na2SO4Dry, column separation after solvent removed by evaporation at reduced pressure obtains compound 4；
4th step synthesizes compound 5b-5c
Under inert gas protection, it using compound 4, aryl boric acid as raw material, is dissolved in reaction dissolvent, adds alkali and four triphens
In alkaline environment under the catalysis of tetra-triphenylphosphine palladium Suzuki coupling reaction occurs for base phosphine palladium, obtains mix products C, reaction temperature
Degree is 80-110 DEG C, and the reaction time is 3-5 hours；Water is added into mix products C, is extracted with ether, organic phase is collected,
Water and saturated common salt water washing organic phase are used respectively, then use anhydrous Na2SO4It is dry, column separation after solvent removed by evaporation at reduced pressure,
Respectively obtain compound 5b-5c；
The compound 5b is 2- (4- methoxyphenyl) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles；
5c is 2- (4- chlorphenyl) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles；The compound 4, aryl boron
Acid, alkali, tetra-triphenylphosphine palladium molar ratio be 1:1-2:3-5:0.05-0.2；
5th step synthesizes compound 6b-6c
It is raw material by the compound 5b-5c that the 4th step column chromatographs, with N- N-iodosuccinimide under inert gas shielding
In organic solvent iodide reaction occurs for NIS under silver nitrate catalysis, obtains mix products D, and reaction temperature is 20-45 DEG C, reaction
Time is 1-5 hours；Saturated aqueous sodium thiosulfate is added into mix products D, is extracted with ether, collects organic
Phase uses water and saturated common salt water washing organic phase, then anhydrous Na respectively2SO4It is dry, column separation after solvent removed by evaporation at reduced pressure,
Respectively obtain compound 6b-6c；
The compound 6b is the iodo- 5- of 2- (4- methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles, and 6c is that 2- is iodo-
5- (4- chlorphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles；The compound 5b-5c:N- N-iodosuccinimide: nitric acid
The molar ratio of silver is 1:1-2:0.01-0.5；
6th step synthesizes compound 7a-7d
Under inert gas protection, respectively with compound 6b and to methoxyphenylboronic acid, compound 6b and para hydroxybenzene boric acid, change
Close object 6c and to chlorophenylboronic acid, compound 6b and to chlorophenylboronic acid be raw material, add the raw material into organic solvent, and Pd is added
(PPh3)4And alkali, in Pd (PPh3)4Catalysis under Suzuki coupling reaction occurs, obtain mix products E, reaction temperature 80-110
DEG C, the reaction time is 1-8 hours；Water is added into mix products E, is extracted with ether, organic phase is collected, respectively with water and
Saturated common salt water washing organic phase, then anhydrous Na2SO4Dry, column separation after solvent removed by evaporation at reduced pressure respectively obtains chemical combination
Object 7a-7d；
The compound 7a is 2,5- bis- (4- methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles, and compound 7b is
2- (4- hydroxy phenyl) -5- (4- methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles, compound 7c are 2,5-, bis- (4-
Chlorphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles, compound 7d is 2- (4- chlorphenyl) -5- (4- methoxyphenyl) -1-
(N, N- dimethyl methyl acyl group) pyrroles；
The compound 6b, to methoxyphenylboronic acid or para hydroxybenzene boric acid, Pd (PPh3)4, alkali molar ratio be 1:1-3:
0.05-0.1:3-6；The compound 6c, to chlorophenylboronic acid, Pd (PPh3)4, alkali molar ratio be 1:1-3:0.05-0.1:3-
6。
2. a kind of Regioselective synthesis of 2,5- disubstituted pyrroles according to claim 1, it is characterised in that: the
Aryl boric acid described in four steps is to methoxyphenylboronic acid, to chlorophenylboronic acid.
3. a kind of Regioselective synthesis of 2,5- disubstituted pyrroles according to claim 1 or 2, feature exist
In: reaction dissolvent described in the 4th step is the mixed solution that toluene and methanol are 1:1-3 by volume, every 0.1mmol chemical combination
Object 4 corresponds to 3-7mL reaction dissolvent.
4. a kind of Regioselective synthesis of 2,5- disubstituted pyrroles according to claim 1 or 2, feature exist
In: organic solvent described in the 5th step is ethyl alcohol, acetonitrile, N,N-Dimethylformamide.
5. a kind of Regioselective synthesis of 2,5- disubstituted pyrroles according to claim 3, it is characterised in that: the
Organic solvent described in five steps is ethyl alcohol, acetonitrile, N,N-Dimethylformamide.
6. one kind 2 described according to claim 1 or 2 or 5, the Regioselective synthesis of 5- disubstituted pyrroles, feature
Be: organic solvent described in the 6th step is the mixed solution that toluene and methanol are 1:1-3 by volume.
7. a kind of Regioselective synthesis of 2,5- disubstituted pyrroles according to claim 3, it is characterised in that: the
Organic solvent described in six steps is the mixed solution that toluene and methanol are 1:1-3 by volume；.
8. one kind 2 described according to claim 1 or 2 or 5 or 7, the Regioselective synthesis of 5- disubstituted pyrroles is special
Sign is: the alkali in the 4th step is sodium carbonate；Alkali in 6th step is sodium carbonate, potassium carbonate or potassium phosphate.
9. a kind of Regioselective synthesis of 2,5- disubstituted pyrroles according to claim 3, it is characterised in that: the
Alkali in four steps is sodium carbonate；Alkali in 6th step is sodium carbonate, potassium carbonate or potassium phosphate.
10. a kind of Regioselective synthesis of 2,5- disubstituted pyrroles according to claim 6, it is characterised in that:
Alkali in 4th step is sodium carbonate；Alkali in 6th step is sodium carbonate, potassium carbonate or potassium phosphate.
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| Highly Regioselective Synthesis of 3,4-Disubstituted 1H-Pyrrole;Jian-Hui Liu et al.;《J. Org. Chem.》;20000429;第65卷(第11期);3274-3283 |
| 分步碘代与偶联：2,4-二取代吡咯的合成;宋珠草;《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》;20150715;B014-149 |
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