CN103265545B - Method for preparing parazole iso-indole compound - Google Patents
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- QYLGINFSKQDGEL-UHFFFAOYSA-N C(C(c1ccccc1-c1c2)[n]1nc2-c1ccc[o]1)c1ccccc1 Chemical compound C(C(c1ccccc1-c1c2)[n]1nc2-c1ccc[o]1)c1ccccc1 QYLGINFSKQDGEL-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to a method for preparing a parazole iso-indole compound. According to the technical scheme, the method comprises the following steps of: preparing an ortho-alkynyl benzaldehyde derivative through Sonogashira reaction by taking an ortho-bromobenzene formaldehyde derivative and an acetenyl compound as the raw materials; and further taking the ortho-alkynyl benzaldehyde derivative as the raw material, adding methanol as the solvent, subsequently adding a ketone compound, hydrochloric acid hydrazine and alkali, uniformly stirring, and further preparing the parazole iso-indole compound under temperature raising and backflow condition in one step. The method has easily-accessible raw materials, is short in synthesis route, simple to react and operate, rapid in reaction speed, easy in aftertreatment, high in yield and small in environmental pollution, has objective economic practical values and at the same time has wide application prospects in the field of medicine synthesis.
Description
Technical field
The present invention relates to a kind of method preparing parazole iso-indole compound, belong to technical field of medicine synthesis.
Background technology
Parazole iso-indole compound as the important one of nitrogen-containing heterocycle compound, due to its medicine, agricultural chemicals extensive use received much concern in recent years.Therefore, the efficient synthesis of this compounds is of great significance for the research and development tool of further genralrlization pyrazoles isoindoles related drugs.
The synthetic method of the parazole iso-indole compound reported at present mainly contains following several:
Method 1: 2000 year, Sosnicki describes the method being carried out synthesizing pyrazole isoindoles compound 4 by substrate 1-ethanoyl methylene radical-3,3-dimethyl-1,3-dihydroisobenzofuran 1, but productive rate only has 5%.
Method two: 2005, Voitenko group proposes the method for another kind of synthesizing pyrazole isoindoles compound, select phthalic acid derivatives 5 for raw material, obtain pyrazoles isoindole derivatives through the condensation of addition, hydrazine, intramolecular cycloaddition reaction and reduction reaction.
Method 3: 2008 years, Moyano utilizes diazonium salt to attempt the novel method of parazole iso-indole compound as raw material.But because in diazotization reaction, side reaction is many, make the productive rate of target product very low.
Method 4: 2011 years,
o-toluylene-methylene radical-the sydnone 21 using multistep synthesis is core intermediate, and under the effect of light, oxidation obtains target compound further.The committed step of this method is 1,3-Dipolar Cycloaddition.It should be noted that compound 21 two chromophoric group toluylene, sydnone has methylene radical separately, to be conducive in different polynuclear planes and molecule 1, the generation of 3-Dipolar Cycloaddition, but also Just because of this, sydnone 21 exists a variety of resonant, thus greatly reduces reaction efficiency.
Method five: prepare parazole iso-indole compound with metal catalytic generation molecule inner ring condensation
2010, Choi and its co-worker adopted the c h bond priming reaction one-step synthesis parazole iso-indole compound of palladium chtalyst in molecule first, and productive rate is up to 87%.Research finds, by the generation regulating the consumption of additive and lithium chloride effectively can avoid by product 25.
There is the shortcomings such as raw material preparation is complicated, synthetic route is long, use transition metal, severe reaction conditions, productive rate are lower in existing literature method, does not meet the requirement that " Green Chemistry " develops mostly.
Summary of the invention
Problem to be solved by this invention is to provide the preparation method of the parazole iso-indole compound that a kind of synthetic route is short, productive rate is high.
Technical scheme provided by the invention is:
With o-bromobenzaldehye derivative and acetylene compound for raw material, prepare adjacent alkynyl benzaldehyde derivative by Sonogashira reaction; Again with adjacent alkynyl benzaldehyde derivative for raw material, add methyl alcohol as solvent, then add ketone compounds, hydrazine hydrochloride and alkali, stir, under temperature rising reflux condition, prepare parazole iso-indole compound.
Described ketone compounds is aliphatic ketone or aromatic ketone.
Described alkali is organic bases or mineral alkali.
Described organic bases is triethylamine, and described mineral alkali is sodium methylate, potassium tert.-butoxide or salt of wormwood.
Described return time is generally 12-24h.
Preferred as one, the mol ratio of adjacent alkynyl benzaldehyde derivative, ketone compounds, hydrazine hydrochloride, alkali is: 1: 2: 10: 20.
The synthetic route of the inventive method is as follows:
Wherein, R
1for hydrogen, halogen, alkyl, alkoxyl group, nitro or cyano group, R
2for alkyl or aryl, R
3for alkyl or aryl, R
4for hydrogen or alkyl.
The parazole iso-indole compound that the inventive method prepares, its structure is:
Wherein, R
1for hydrogen, halogen, alkyl, alkoxyl group, nitro or cyano group, R
2for alkyl or aryl, R
3for alkyl or aryl, R
4for hydrogen or alkyl.
The inventive method is simple to operate, and cheaper starting materials is easy to get, and operation is simple, and speed of response is fast, and environmental pollution is little, is a kind of succinct method effectively preparing parazole iso-indole compound.Thus pave the way for the large-scale promotion and application of pyrazoles isoindoles related derivatives.
Embodiment
Below in conjunction with example, a kind of method preparing parazole iso-indole compound of the present invention is described in detail.Ratio in eluent is volume ratio.
The synthesis of embodiment 1 2-phenylacetylene base phenyl aldehyde
Get 25mL bottle with two necks, add magneton, under anhydrous and oxygen-free condition, add 2-bromobenzaldehyde 74.0mg (0.4mmol) successively, triphenylphosphine palladium 14.0mg (0.02mmol), triphenylphosphine 31.5mg (0.12mmol), cuprous iodide 7.6mg (0.04mmol), add dry DMF 1mL, triethylamine 1mL, phenylacetylene 65.4mg (0.64mmol) is added after stirring, 8h is reacted under being placed in 80 DEG C of oil bath conditions, after reaction terminates, add saturated ammonium chloride solution 20mL cancellation reaction, add 25mL extraction into ethyl acetate, organic layer evaporated under reduced pressure, crude product silica gel column chromatography is separated, eluent ratio is sherwood oil: ethyl acetate 10: 1, productive rate 85.1%.
1HNMR(400MHz，CDCl
3)δ10.56(s，1H)，7.88-7.84(m，1H)，7.54(d，J＝7.6Hz，1H)，7.50-7.45(m，3H)，7.35(t，J＝7.5Hz，1H)，7.30-7.27(m，3H).
The synthesis of embodiment 2 2-(4-methyl-phenylacetylene base) phenyl aldehyde
Get 25mL bottle with two necks, add magneton, under anhydrous and oxygen-free condition, add 2-bromobenzaldehyde 74.0mg (0.4mmol) successively, triphenylphosphine palladium 14.0mg (0.02mmol), triphenylphosphine 31.5mg (0.12mmol), cuprous iodide 7.62mg (0.04mmol), add dry DMF 1mL, triethylamine 1mL, 4-methylbenzene acetylene 74.3 (0.64mmol) is added after stirring, 8h is reacted under being placed in 80 DEG C of oil bath conditions, after reaction terminates, add saturated ammonium chloride solution 20mL cancellation reaction, add 25mL extraction into ethyl acetate, organic layer evaporated under reduced pressure, crude product silica gel column chromatography is separated, eluent ratio is sherwood oil: ethyl acetate 10: 1, productive rate 63.3%.
1HNMR(400MHz，CDCl
3)δ10.57(s，1H)，7.86(d，J＝7.8Hz，1H)，7.54(d，J＝7.6Hz，1H)，7.51-7.45(m，1H)，7.38(s，1H)，7.36(s，1H)，7.34(d，J＝7.4Hz，1H)，7.10(d，J＝7.9Hz，2H)，2.30(s，3H).
The synthesis of embodiment 3 2-(the fluoro-phenylacetylene base of 4-)-phenyl aldehyde
Get 25mL bottle with two necks, add magneton, under anhydrous and oxygen-free condition, add 2-bromobenzaldehyde 74.0mg (0.4mmol) successively, triphenylphosphine palladium 14.0mg (0.02mmol), triphenylphosphine 31.5mg (0.12mmol), cuprous iodide 7.62mg (0.04mmol), add dry DMF 1mL, triethylamine 1mL, 4-fluorobenzene acetylene 76.9mg (0.64mmol) is added after stirring, 8h is reacted under being placed in 80 DEG C of oil bath conditions, after reaction terminates, add saturated ammonium chloride solution 20mL cancellation reaction, add 25mL extraction into ethyl acetate, organic layer evaporated under reduced pressure, crude product silica gel column chromatography is separated, eluent ratio is sherwood oil: ethyl acetate 10: 1, productive rate 73.0%.
1HNMR(400MHz，CDCl
3)δ10.54(s，1H)，7.86(d，J＝7.8Hz，1H)，7.57-7.45(m，4H)，7.38(t，J＝7.4Hz，1H)，7.00(t，J＝8.7Hz，2H).
The synthesis of embodiment 4 2-(2-thienyl acetylene)-phenyl aldehyde
Get 25mL bottle with two necks, add magneton, under anhydrous and oxygen-free condition, add 2-bromobenzaldehyde 74.0mg (0.4mmol) successively, triphenylphosphine palladium 14.0mg (0.02mmol), triphenylphosphine 31.5mg (0.12mmol), cuprous iodide 7.62mg (0.04mmol), add dry DMF 1mL, triethylamine 1mL, 2-thiophene acetylene 69.2mg (0.64mmol) is added after stirring, 8h is reacted under being placed in 80 DEG C of oil bath conditions, after reaction terminates, add saturated ammonium chloride solution 20mL cancellation reaction, add 25mL extraction into ethyl acetate, organic layer evaporated under reduced pressure, crude product silica gel column chromatography is separated, eluent ratio is sherwood oil: ethyl acetate 10: 1, productive rate 65.0%.
1H NMR(400MHz，CDCl
3)δ10.50(s，1H)，7.86(d，J＝7.9Hz，1H)，7.50(ddd，J＝11.1，8.8，4.4Hz，2H)，7.36(t，J＝7.5Hz，1H)，7.24(d，J＝1.3Hz，2H)，6.96(dd，J＝5.0，3.8Hz，1H).
The synthesis of embodiment 5 4-methyl-2-(2-thienyl acetylene)-phenyl aldehyde
Get 25mL bottle with two necks, add magneton, under anhydrous and oxygen-free condition, add 2-bromo-4-tolyl aldehyde 79.6mg (0.4mmol) successively, triphenylphosphine palladium 14.0mg (0.02mmol), triphenylphosphine 31.5mg (0.12mmol), cuprous iodide 7.62mg (0.04mmol), add dry DMF 1mL, triethylamine 1mL, 2-thiophene acetylene 69.2mg (0.64mmol) is added after stirring, 8h is reacted under being placed in 80 DEG C of oil bath conditions, after reaction terminates, add saturated ammonium chloride solution 20mL cancellation reaction, add 25mL extraction into ethyl acetate, organic layer evaporated under reduced pressure, crude product silica gel column chromatography is separated, eluent ratio is sherwood oil: ethyl acetate 10: 1, productive rate 59.3%.
1H NMR(400MHz，CDCl
3)δ10.52(s，1H)，7.84(d，J＝8.0Hz，1H)，7.43(s，1H)，7.34(t，J＝4.6Hz，2H)，7.25(d，J＝7.3Hz，1H)，7.04(t，J＝4.4Hz，1H)，2.41(s，3H).
The synthesis of embodiment 6 8-phenyl-2-methyl-8H-pyrazoles [5,1-a] isoindole
In the 25mL tri-neck round-bottomed flask that reflux condensing tube is housed, add 2-phenylacetylene base phenyl aldehyde 82.4mg (0.4mmol), hydrazine hydrochloride (419.9mg successively, 4mmol), acetone (46.5mg, 0.8mmol), anhydrous methanol 5ml, triethylamine (1.1ml is added after stirring, 8mmol), system reflux, reaction process TLC detects, after question response terminates, steaming desolventizes and obtains crude product, column chromatography for separation, and eluent ratio is petrol ether/ethyl acetate=6/1; Productive rate: 85%;
1h NMR (400MHz, CDCl
3) δ 7.31 (d, J=7.5Hz, 1H), 7.17 (dd, J=9.9,5.1Hz, 1H), 7.08 (dd, J=5.3,1.7Hz, 3H), 7.03 (m, J=7.6,1.0Hz, 1H), 6.93 (dd, J=7.0,2.2Hz, 2H), 6.77 (d, J=7.6Hz, 1H), 5.98 (s, 1H), 5.20 (dd, J=8.4,3.9Hz, 1H), 3.63 (dd, J=13.6,4.0Hz, 1H), 2.97 (dd, J=13.6,8.5Hz, 1H), 2.32 (s, 3H).
13c NMR (100MHz, CDCl
3) δ 151.93,144.70,142.86,134.55,129.62,128.67,127.13,127.07,125.70,125.47,122.77,119.12,94.82,62.20,38.95,13.42.
The synthesis of embodiment 7 8-(4-fluorophenyl)-2-methyl-8H-pyrazoles [5,1-a] isoindole
In the 25mL tri-neck round-bottomed flask that reflux condensing tube is housed, add 2-(4-F-phenyl) ethynyl successively) phenyl aldehyde 89.6mg (0.4mmol), hydrazine hydrochloride (419.9mg, 4mmol), acetone (46.5mg, 0.8mmol), anhydrous methanol 5ml, triethylamine (1.1ml is added after stirring, 8mmol), system reflux, reaction process TLC detects, after question response terminates, steaming desolventizes and obtains crude product, column chromatography for separation, and eluent ratio is petrol ether/ethyl acetate=6/1; Productive rate: 79%;
1hNMR (400MHz, CDCl
3) δ 7.28 (d, J=7.3Hz, 1H), 7.17 (t, J=7.2Hz, 1H), 7.07 (t, J=7.3 Hz, 1H), 6.91 (d, J=7.3Hz, 1H), 6.85-6.59 (m, 4H), 5.95 (s, 1H), 5.18 (d, J=2.4Hz, 1H), 3.49 (d, J=11.5Hz, 1H), 3.12 (dd, J=13.7,7.4Hz, 1H), 2.30 (s, 3H).
13c NMR (100MHz, CDCl
3) δ 162.96,160.52,153.09,145.96,143.64,131.21,131.13,128.23,126.63,123.59,120.28,114.99,114.78,95.94,63.15,38.89,14.45.
The synthesis of embodiment 82,6-dimethyl-8-(4-aminomethyl phenyl)-8H-pyrazoles [5,1-a] isoindole
In the 25mL tri-neck round-bottomed flask that reflux condensing tube is housed, add 4-methyl-2-phenylacetylene base phenyl aldehyde 93.6mg (0.4mmol), hydrazine hydrochloride (419.9mg successively, 4mmol), acetone (46.5mg, 0.8mmol), anhydrous methanol 5ml, triethylamine (1.1ml is added after stirring, 8mmol), system reflux, reaction process TLC detects, after question response terminates, steaming desolventizes and obtains crude product, column chromatography for separation, and eluent is petrol ether/ethyl acetate=6/1; Productive rate: 72%;
1h NMR (400MHz, CDCl
3) δ 7.20 (d, J=7.7Hz, 1H), 6.98 (d, J=7.7Hz, 1H), 6.91 (d, J=7.8Hz, 2H), 6.83 (d, J=7.9Hz, 2H), 6.62 (s, 1H), 5.93 (s, 1H), 5.13 (dd, J=8.4,3.9Hz, 1H), 3.56 (dd, J=13.7,3.9Hz, 1H), 2.93 (dd, J=13.7,8.4Hz, 1H), 2.30 (s, 3H), 2.18 (d, J=5.6Hz, 6H).
13c NMR (100MHz, CDCl
3) δ 152.84,145.90,144.47,136.49,136.22,132.71,129.65,128.88,128.72,128.10,124.64,119.90,95.42,63.35,39.69,21.63,21.09,14.47.
The synthesis of the fluoro-2-methyl of embodiment 9 6--8-(thiophene-2-ylmethyl)-8H-pyrazoles [5,1-a] isoindole
In the 25mL tri-neck round-bottomed flask that reflux condensing tube is housed, add 4-F-2-(thiophene-2-ethynyl) phenyl aldehyde 92.0mg (0.4mmol), hydrazine hydrochloride (419.9mg successively, 4mmol), acetone (46.5mg, 0.8mmol), anhydrous methanol 5ml, triethylamine (1.1ml is added after stirring, 8mmol), system reflux, reaction process TLC detects, after question response terminates, steaming desolventizes and obtains crude product, column chromatography for separation, and eluent is petrol ether/ethyl acetate=6/1; Productive rate: 78%;
1h NMR (400MHz, CDCl
3) δ 7.37 (dd, J=8.3,4.9Hz, 1H), 7.04 (dd, J=18.0,3.6Hz, 2H), 6.81 (dd, J=8.6,3.4Hz, 2H), 6.59 (d, J=3.2Hz, 1H), 6.05 (s, 1H), 5.31 (dd, J=7.4,3.6Hz, 1H), 3.81 (dd, J=14.9,3.6Hz, 1H), 3.51 (dd, J=14.9,7.5Hz, 1H), 2.40 (s, 3H).
13c NMR (100MHz, CDCl
3) δ 153.82,146.39,142.49,136.75,130.88,130.46,129.94,128.68,127.02,123.11,121.73,120.45,96.18,62.37,38.98,14.16.
The synthesis of embodiment 10 8-(3,5-bis-(trifluoromethyl) phenyl) the fluoro-2-methyl of-6--8H-pyrazoles [5,1-a] isoindole
In the 25mL tri-neck round-bottomed flask that reflux condensing tube is housed, add 2-((3 successively, 5-bis-(trifluoromethyl) phenyl) ethynyl)-4-F-phenyl aldehyde 144mg (0.4mmol), hydrazine hydrochloride (419.9mg, 4mmol), acetone (46.5mg, 0.8mmol), anhydrous methanol 5ml, triethylamine (1.1ml is added after stirring, 8mmol), system reflux, reaction process TLC detects, and after question response terminates, steaming desolventizes and obtains crude product, column chromatography for separation, eluent is petrol ether/ethyl acetate=6/1; Productive rate: 82%;
1h NMR (400MHz, CDCl
3) δ 7.52 (s, 1H), 7.41-7.28 (m, 4H), 7.10 (s, 2H), 5.95 (s, 1H), 5.55-5.39 (m, 1H), 3.78 (dd, J=13.8,5.3Hz, 1H), 3.50 (dd, J=13.8,3.3Hz, 1H), 2.39 (s, 3H).
13c NMR (100MHz, CDCl
3) δ 153.82,146.39,142.49,136.75,130.88,130.46,129.96,128.68,127.02,124.44,123.11,121.73,120.45,96.18,62.37,38.98,29.71.
The synthesis of embodiment 11 8-phenyl-2-ethyl-8H-pyrazoles [5,1-a] isoindole
In the 25mL tri-neck round-bottomed flask that reflux condensing tube is housed, add 2-phenylacetylene base phenyl aldehyde 82.4mg (0.4mmol), hydrazine hydrochloride (419.9mg successively, 4mmol), butanone (57.7mg, 0.8mmol), anhydrous methanol 5ml, triethylamine (1.1ml is added after stirring, 8mmol), system reflux, reaction process TLC detects, after question response terminates, steaming desolventizes and obtains crude product, column chromatography for separation, and eluent is petrol ether/ethyl acetate=6/1; Productive rate: 74%;
1h NMR (400MHz, CDCl
3) δ 7.42 (d, J=7.5Hz, 1H), 7.29 (t, J=7.5Hz, 1H), 7.24-7.16 (m, 3H), 7.14 (d, J=7.6Hz, 1H), 7.01 (dd, J=6.4,2.8Hz, 2H), 6.90 (d, J=7.6Hz, 1H), 6.11 (s, 1H), 5.34 (dd, J=8.4,3.9Hz, 1H), 3.73 (dd, J=13.6,3.9Hz, 1H), 3.11 (dd, J=13.6,8.4Hz, 1H), 2.78 (q, J=7.6Hz, 2H), 1.34 (t, J=7.6Hz, 3H).
13c NMR (100MHz, CDCl
3) δ 159.44,145.64,143.94,135.56,129.76,128.14,126.73,126.52,123.82,120.15,94.36,63.26,40.01,22.38,14.38.
The synthesis of embodiment 12 8-phenyl-2-phenyl-8H-pyrazoles [5,1-a] isoindole
In the 25mL tri-neck round-bottomed flask that reflux condensing tube is housed, add 2-phenylacetylene base phenyl aldehyde 82.4mg (0.4mmol), hydrazine hydrochloride (419.9mg successively, 4mmol), methyl phenyl ketone (96.1mg, 0.8mmol), anhydrous methanol 5ml, triethylamine (1.1ml is added after stirring, 8mmol), system reflux, reaction process TLC detects, after question response terminates, steaming desolventizes and obtains crude product, column chromatography for separation, and eluent is petrol ether/ethyl acetate=6/1; Productive rate: 75%;
1h NMR (400MHz, CDCl
3) δ 7.83 (d, J=7.7Hz, 2H), 7.43-7.34 (m, 3H), 7.25 (dd, J=13.8,7.3Hz, 3H), 7.15-7.06 (m, 4H), 7.00-6.93 (m, 2H), 6.90 (d, J=7.6Hz, 1H), 6.52 (s, 1H), 5.38 (dd, J=7.9,4.1Hz, 1H), 3.68 (dd, J=13.7,4.0Hz, 1H), 3.16 (dd, J=13.7,8.0Hz, 1H).
13c NMR (100MHz, CDCl
3) δ 155.93,146.39,143.83,135.39,134.26,130.52,129.82,128.70,128.32,128.21,127.69,126.89,126.82,125.66,123.88,120.42,93.49,63.71,40.03.
The synthesis of embodiment 13 8-phenyl-2-(4-aminomethyl phenyl)-8H-pyrazoles [5,1-a] isoindole
In the 25mL tri-neck round-bottomed flask that reflux condensing tube is housed, add 2-phenylacetylene base phenyl aldehyde 82.4mg (0.4mmol), hydrazine hydrochloride (419.9mg successively, 4mmol), 4-methyl acetophenone (107.2mg, 0.8mmol), anhydrous methanol 5ml, triethylamine (1.1ml is added after stirring, 8mmol), system reflux, reaction process TLC detects, after question response terminates, steaming desolventizes and obtains crude product, column chromatography for separation, and eluent is petrol ether/ethyl acetate=6/1; Productive rate: 68%;
1h NMR (400MHz, CDCl
3) δ 7.80 (d, J=8.1Hz, 2H), 7.48 (d, J=7.7Hz, 1H), 7.36-7.29 (m, 2H), 7.26 (s, 1H), 7.18-7.10 (m, 4H), 7.03 (dd, J=6.3,3.0Hz, 2H), 6.97 (d, J=7.6Hz, 1H), 6.57 (s, 1H), 5.45 (dd, J=8.0,4.0Hz, 1H), 3.76 (dd, J=13.7,4.0Hz, 1H), 3.23 (dd, J=13.7,8.1Hz, 1H), 2.40 (s, 3H).
13c NMR (100MHz, CDCl
3) δ 156.02,146.31,143.86,137.44,135.42,131.60,131.46,130.58,129.82,129.38,128.49,128.28,128.19,126.96,126.82,125.56,123.85,120.37,93.26,63.66,40.02,21.33.
The synthesis of embodiment 14 8-phenyl-2-(4-fluorophenyl)-8H-pyrazoles [5,1-a] isoindole
In the 25mL tri-neck round-bottomed flask that reflux condensing tube is housed, add 2-phenylacetylene base phenyl aldehyde 82.4mg (0.4mmol), hydrazine hydrochloride (419.9mg successively, 4mmol), 4-fluoro acetophenone (110.4mg, 0.8mmol), anhydrous methanol 5ml, triethylamine (1.1ml is added after stirring, 8mmol), system reflux, reaction process TLC detects, after question response terminates, steaming desolventizes and obtains crude product, column chromatography for separation, and eluent is petrol ether/ethyl acetate=6/1, productive rate: 71%,
1h NMR (400MHz, CDCl
3) δ 7.86 (dd, J=8.2, 5.6Hz, 2H), 7.48 (d, J=7.1Hz, 1H), 7.35 (dd, J=7.0, 2.8Hz, 1H), 7.31 (d, J=7.6Hz, 1H), 7.22-7.15 (m, 4H), 7.12 (t, J=8.6Hz, 2H), 7.07-7.02 (m, 2H), 6.97 (d, J=7.6Hz, 1H), 6.54 (s, 1H), 5.44 (dd, J=8.0, 4.1Hz, 1H), 4.77-4.60 (m, 0H), 3.75 (dd, J=13.7, 4.1Hz, 1H), 3.21 (dd, J=13.7, 8.1Hz, 1H).
13c NMR (100MHz, CDCl
3) δ 155.01,146.50,143.83,135.37,133.09,131.55,130.40,129.79,129.04,128.96,128.58,128.35,128.24,127.32,127.24,126.97,126.86,123.89,120.44,115.68,115.46,93.29,63.72,40.03.
Embodiment 15 8-phenyl-2-(furans-2-base)-8H-pyrroles [5,1-a] isoindole
In the 25mL tri-neck round-bottomed flask that reflux condensing tube is housed, add 2-phenylacetylene base phenyl aldehyde 82.4mg (0.4mmol), hydrazine hydrochloride (419.9mg successively, 4mmol), 2-furans ethyl ketone (88.9mg, 0.8mmol), anhydrous methanol 5ml, sodium methylate (524.4mg is added after stirring, 8mmol), system reflux, reaction process TLC detects, after question response terminates, steaming desolventizes and obtains crude product, column chromatography for separation, and eluent is petrol ether/ethyl acetate=6/1; Productive rate: 68%,
1h NMR (400MHz, CDCl
3) δ 7.43 (t, J=10.6Hz, 2H), 7.25 (t, J=7.6Hz, 1H), 7.20-7.08 (m, 4H), 7.01-6.81 (m, 3H), 6.66 (d, J=3.3Hz, 1H), 6.51-6.30 (m, 2H), 5.36 (dd, J=8.3,3.9Hz, 1H), 3.73 (dd, J=13.7,3.9Hz, 1H), 3.11 (dd, J=13.7,8.3Hz, 1H).
13c NMR (101MHz, CDCl
3) δ 149.37,148.04,146.15,143.92,141.75,135.30,130.15,129.79,128.34,128.25,127.05,126.85,123.92,120.51,111.32,105.58,93.29,63.75,39.91.
Embodiment 16 8-phenyl-2-(thiophene-2-base)-8H-pyrroles [5,1-a] isoindole
In the 25mL tri-neck round-bottomed flask that reflux condensing tube is housed, add 2-phenylacetylene base phenyl aldehyde 82.4mg (0.4mmol), hydrazine hydrochloride (419.9mg successively, 4mmol), 2-thiophene ethyl ketone (109.4mg, 0.8mmol), anhydrous methanol 5ml, salt of wormwood (1105.6mg is added after stirring, 8mmol), system reflux, reaction process TLC detects, after question response terminates, steaming desolventizes and obtains crude product, column chromatography for separation, and eluent is petrol ether/ethyl acetate=6/1; Productive rate: 70%,
1h NMR (400MHz, CDCl
3) δ 7.38 (d, J=7.5Hz, 1H), 7.31 (d, J=3.5Hz, 1H), 7.23 (t, J=7.5Hz, 1H), 7.20-7.15 (m, 1H), 7.15-7.06 (m, 4H), 7.04-6.98 (m, 1H), 6.98-6.91 (m, 2H), 6.86 (d, J=7.6Hz, 1H), 6.42 (s, 1H), 5.35 (dd, J=8.1,4.0Hz, 1H), 3.68 (dd, J=13.7,4.0Hz, 1H), 3.11 (dd, J=13.7,8.2Hz, 1H).
13c NMR (101MHz, CDCl
3) δ 150.92,146.45,143.86,137.54,135.30,130.23,129.81,128.35,128.23,127.51,127.03,126.85,124.30,123.90,123.47,120.47,93.52,63.73,39.98.
Claims (6)
1. prepare a method for parazole iso-indole compound, it is characterized in that:
With o-bromobenzaldehye derivative
and acetylene compound
for raw material, prepare adjacent alkynyl benzaldehyde derivative by Sonogashira reaction
again with adjacent alkynyl benzaldehyde derivative
for raw material, add methyl alcohol as solvent, then add ketone compounds
hydrazine hydrochloride and alkali, stir, temperature rising reflux condition next step prepare parazole iso-indole compound
described R1 is hydrogen or alkyl, described R
2for aryl, described R
3for alkyl or aryl, described R
4for hydrogen.
2. method according to claim 1, is characterized in that, described alkali is organic bases or mineral alkali.
3. method according to claim 2, is characterized in that, described organic bases is triethylamine.
4. method according to claim 2, is characterized in that, described mineral alkali is sodium methylate, potassium tert.-butoxide or salt of wormwood.
5. method according to claim 1, is characterized in that, described return time is 12-24h.
6. method according to claim 1, is characterized in that, the mol ratio of adjacent alkynyl benzaldehyde derivative, ketone compounds, hydrazine hydrochloride, alkali is: 1:2:10:20.
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