CN103804385B - The method of 1,3,4-tri-substituted azole derivatives - Google Patents
The method of 1,3,4-tri-substituted azole derivatives Download PDFInfo
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- CN103804385B CN103804385B CN201210439635.2A CN201210439635A CN103804385B CN 103804385 B CN103804385 B CN 103804385B CN 201210439635 A CN201210439635 A CN 201210439635A CN 103804385 B CN103804385 B CN 103804385B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
Abstract
The present invention relates to the method that one prepares 1,3,4-tri-substituted azole derivatives, specifically prepare the novel method of 1,3,4-tri-substituted azole derivatives by simple 1,6 diine and amine by cyclization isomerization.Set out with the starting raw material that business is cheap and easy to get, use transition metal as oxygenant, the method through one pot of two step obtains 1,3,4-tri-substituted azole derivatives.
Description
Technical field
The present invention relates to the method that one prepares 1,3,4-tri-substituted azole derivatives, specifically by 1,6 diines, amine prepare the novel method of 1,3,4-tri-substituted azole derivatives by cyclization isomerization.
Background technology
Its analogue of 1,3,4-tri-substituted azole is an important heterogeneous ring compound, because pyrrole unit is extensively present in natural protoheme and chlorophyll, and the critical segment of requisite two kinds of structures in life.The pyrroles of functionalization can through converting useful pharmaceutical intermediate and the skeleton of material to.
(document 1:(a) Berlinck, R.G.S.; Britton, R.; Piers, E.; Lim, L.; Roberge, M.; Da, Rocha, R.M.; Andersen, R.J.J.Org.Chem.1998,63,9850. (b) O ' Malley, D.P.; Li, K.; Maue, M.; Zografos, A.L.; Baran, P.S.J.Am.Chem.Soc.2007,129,4762. (c) Hughes, C.C.; Prieto-Davo, A.; Jensen, P.R.Fenical, W.Org.Lett.2008,10,629. (d) Chen, Y.; Zeng, D.; Xie, N.; Dang, Y.J.Org.Chem.2005,70,5001).Thus this compounds is studied (document 2:(a) Yamamoto, Y.Chem.Rev.2008 widely, 108,3199. (b)
-Corral, M.;
-Dorado, M.; Rodr í guez-Garc í a, I.Chem.Rev.2008,108,3174. (c) Weibel, J.-M.; Blanc, A.; Pale, P.Chem.Rev.2008,108,3149. (d) Zhang, X.; Liu, B.Q.; Shu, X.; Gao, Y.; Lv, H.P.; Zhu, J.J.Org.Chem.2012,77,501. (e) Verniest, G.; Padwa, A.Org.Lett.2008,10,4379. (f) Deng, L.C.; Li, J.H.Org.Lett.2007,9,5111. (g) Yan, R.-L.; Luo, J.; Wang, C.-X.; Ma, C.-W.; Huang, G.-S.; Liang, Y.-M.J.Org.Chem.2010,75,5395. (h) Mart í n, R.; Rivero, M.R.; Buchwald, S.L.Angew.Chem., Int.Ed.2006,45,7079. (i) Liu, W.B; Jiang, H.F.; Huang, L.B.Org.Lett.2010,12,312.Contrary, by 1, the research novel method that successfully relatively less (document 3:Yamamoto, Y.Chem.Rev.2008,108,3199.) thus develop synthesis 1,3,4-tri-substituted azole that 6 diines directly synthesize corresponding pyrroles has great significance.Along with being on the increase of substituting group pattern of this compounds, their physiologically active by studied, thus give this compounds as medicine provide more may.We have developed one by 1, and 6 diines and amine prepare the novel method of 1,3,4-tri-substituted azole (2) by cyclization isomerization.The method raw material is simple, only the simple material such as applied metal Silver Nitrate and alkali Potassium ethanoate as just can high yield obtain 1,3,4-tri-substituted azole derivatives product.The method has atom economy, synthetic method green high-efficient.
Summary of the invention
The present invention relates to the novel method that one prepares 1,3,4-tri-substituted azole derivatives.
(1) reference literature, by hydroamination reaction one-step synthesis enamine intermediates: 1,6 diines and amine react in ether generate enamine (document 4:
(a)
t.E; Hultzsch, K.C; Yus, M; Foubelo, F.; Tada, MChem.Rev.2008,108,3795. (b) Sirijindalert, T.; HansuthirakulK.; Rashatasakhon, P.; SukwattanasinittM.; Ajavakom, A.Tetrahedron2010,66,5161. (c) Patil, N.T.; Singh, VOrganomet.Chem.2011,696,419. (d) Liu, X.Y.; Ding, P.; Huang, J.S.; Che, C.M.Org.Lett.2007,9,2645. (e) Ramanathan, B.; Keith, A.J.; Armstrong, D.; Odem, A.L.Org.Lett.2004,6,2957) (see formula 1);
The synthesis step of formula 1. enamine intermediates
(2) 1,3,4-tri-substituted azole derivatives is prepared by enamine intermediates
Concrete operation step is shown in (formula 2):
The synthesis of formula 2.1,3,4-tri-substituted azole derivatives
Reaction equation is shown in formula 2, reacts in reactor, adds oxygenant in reactor, alkali, vacuumizes rear logical argon replaces three times, adds rear 1ml solvent, drips raw material enamine intermediates, reacts 1 day-2 days under 65 DEG C of-80 ° of C.Revolve after reaction terminates after evaporating solvent, solid carries out silica gel column chromatography, obtains, 1,3,4-tri-substituted azole.
The present invention has following advantage:
1. reactant enamine is obtained through simple reaction step by raw material alkynes cheap and easy to get and amine.
2. the operation of 1,3,4-tri-substituted azole generated is simple; Reactant atom economy.
Accompanying drawing explanation
Fig. 1 is compound 3aa's
1hNMR spectrogram (R substituent is benzylamine);
Fig. 2 is compound 3aa's
13cNMR spectrogram (R substituent is benzylamine);
Fig. 3 is compound 3ag's
1hNMR spectrogram (R substituent is 4-Methoxybenzylamine);
Fig. 4 is compound 3ag's
13cNMR spectrogram (R substituent is 4-Methoxybenzylamine);
Fig. 5 is the Advances in crystal X-ray diffraction structure iron (R substituent is 4-Methoxybenzylamine) of compound 3ag.
Embodiment
Embodiment 1
(preparation 3a):
React in reactor, after reactor vacuumizes rear logical argon replaces three times, under ice-water bath, add the diine 1a of 0.5mmol, add the ether that 1ml newly steams, then drip benzylamine 2a and the ether mixing solutions of 0.5mmol, be naturally warming up to stirring at normal temperature 1-2 days.After reaction terminates, revolve solvent evaporated, 1ml anhydrous acetonitrile dissolves, and is added drop-wise in the Silver Nitrate of 1.1mmol and the Potassium ethanoate mixing solutions of 1.1mmol, react after 1-2 days hours, revolve solvent evaporated, methylene dichloride dissolves, and loading carries out silica gel column chromatography, eluent is sherwood oil: ethyl acetate=20:1 is to sherwood oil: the mixed solvent of ethyl acetate=4:1, obtain 1,3,4-tri-substituted azole 3aa.Be benzylamine for R substituent, separation yield is 80%.
1., when R group is benzyl, product 5-benzyl-3,5-dihydro-1H-furo [3,4-c] pyrrol-1-one3aa characterization data is as follows:
1hNMR (400MHz, Acetone) δ 7.39 (d, J=1.6Hz, 1H), 7.37 (s, 1H), 7.36 (s, 1H), 7.32 (t, J=3.1Hz, 2H), 7.31 (s, 1H), 6.80 (d, J=1.3Hz, 1H), 5.30 (s, 2H), 5.12 (d, J=1.1Hz, 2H) .(spectrogram is shown in Figure of description 1)
13cNMR (100MHz, Acetone) δ 167.46,138.64,134.05,129.64,128.80,128.41,118.74,116.04,113.39,66.78,54.60.(spectrogram is shown in Figure of description 2)
2. when R group is methoxy-benzyl, product
5-(4-methoxybenzyl)-3,5-dihydro-1H-furo [3,4-c] pyrrol-1-one3ag characterization data is as follows:
1hNMR (400MHz, Acetone) δ 7.35 (s, 1H), 7.28 (d, J=8.6Hz, 2H), 6.92 (d, J=8.7Hz, 2H), 6.76 (s, 1H), 5.20 (s, 2H), 5.10 (s, 2H), 3.78 (s, 3H) .(spectrogram is shown in Figure of description 3)
13cNMR (100MHz, Acetone) δ 167.12,160.57,130.40,118.42,114.89,113.33 – 113.13,66.71,55.56,54.11.(spectrogram is shown in Figure of description 4)
3. when R group be base time, product
5-ethyl-3,5-dihydro-1H-furo[3,4-c]pyrrol-1-one(3ab),oil,yield:56%;
1HNMR(400MHz,Acetone)δ7.28(s,1H),6.76(s,1H),5.11(s,2H),4.12(q,J=7.3Hz,2H),1.45(t,J=7.3Hz,3H);
13CNMR(101MHz,Acetone)δ167,133.7,117.8,115.4,112.5,66.6,45.8,17.0.
4. when R group is propyl group, product
5-propyl-3,5-dihydro-1H-furo[3,4-c]pyrrol-1-one(3ac),oil;yield:71%;
1HNMR(400MHz,Acetone)δ7.27(s,1H),6.75(s,1H),5.12(d,J=1.1Hz,2H),4.03(t,J=7.1Hz,2H),1.84(t,J=10.8Hz,2H),0.89(t,J=7.4Hz,3H);
13CNMR(101MHz,Acetone)δ167.1,133.6,118.6,115.4,113.0,66.7,52.8,25.6,11.21.
5. when R group is butyl, product
5-butyl-3,5-dihydo-1H-fuo[3,4-c]pyrrol-1-one(3ad),oil;yield:86%;
1HNMR(400MHz,Acetone)δ7.27(s,1H),6.75(s,1H),5.11(d,J=1.1Hz,2H),4.08(t,J=7.1Hz,2H),1.80(dt,J=14.8,7.4Hz,2H),1.31(dq,J=14.8,7.4Hz,2H),0.92(t,J=7.4Hz,3H);
13CNMR(101MHz,Acetone)δ167.1,133.5,118.3,115.6,112.8,66.3,50.5,34.1,20.3,13.6.
6. when R group is cyclohexyl, product
5-cyclohexyl-3,5-dihydro-1H-furo[3,4-c]pyrrol-1-one(3ae),whitesolid,yield:73%;
1HNMR(400MHz,Acetone)δ7.32(s,1H),6.82(s,1H),5.10(s,2H),4.06(tt,J=11.9,3.8Hz,1H),2.09(d,J=12.5Hz,2H),1.87(d,J=13.5Hz,2H),1.77-1.66(m,2H),1.52-1.38(m,2H),1.29(tt,J=13.0,3.5Hz,2H);
13CNMR(101MHz,Acetone)δ167.2,133.2,116.3,115.1,111.1,66.7,60.5,35.2,26.22,25.8.
7. when R group is 2 methyl-benzyl, product
5-(2-methylbenzyl)-3,5-dihydro-1H-furo[3,4-c]pyrrol-1-one(3af),whitesolid,yield:80%;
1HNMR(400MHz,Acetone)δ7.28(d,J=1.4Hz,1H),7.26–7.16(m，3H),7.03(d,J=7.4Hz,1H),6.71(s,1H),5.32(s,2H),5.12(s,2H),2.30(s,3H);
13CNMR(101MHz,Acetone)δ166.5,137.0,136.2,133.8,131.3,129.0,127.2,118.8,113.5,66.8,52.6,18.9.
8. when R group is 2-chlorobenzyl, product
5-(2-chlorobenzyl)-3,5-dihydro-1H-furo[3,4-c]pyrrol-1-one(3ah),whitesolid,yield:42%;
1HNMR(400MHz,Acetone)δ7.47(t,J=6.1Hz,1H),7.41–7.29(m,3H),7.13(s,1H),6.82(d,J=6.0Hz,1H),5.41(d,J=7.1Hz,2H),5.13(d,J=7.1Hz,2H);
13CNMR(101MHz,Acetone)δ166.8,136.1,133.9,133.5,130.4,130.3,130.3,128.5,118.9,116.1,113.4,66.7,51.9.
9. when R group is naphthyl, product
5-(naphthalen-2-ylmethyl)-3,5-dihydro-1H-fuo[3,4-c]pyrrol-1-one,whitesolid,yield:58%;
1HNMR(400MHz,Acetone)δ8.14(d,J=9.0Hz,1H),7.98(d,J=7.1Hz,1H),7.93(d,J=8.3Hz,1H),7.57(dd,J=7.5,2.3Hz,2H),7.52–7.47(m,1H),7.43(s,1H),7.30(d,J=7.0Hz,1H),6.80(s,1H),5.80(s,2H),5.11(s,2H);
13CNMR(101MHz,Acetone)δ166.8,134.7,133.8,131.8,129.7,129.6,127.5,127.1,126.9,126.4,123.8,119.0,115.8,113.4,66.7,52.2.
Monocrystalline 3agX-ray diffraction structures figure is shown in Figure of description 5.
Claims (4)
1. prepare the method for 1,3,4-tri-substituted azole derivatives for one kind, it is characterized in that:
With 1 shown in following formula, 6 diines (1), primary amine (2) generate 1,3,4-tri-substituted azole derivatives (3) for raw material passes through cyclization isomerization,
Reaction formula is as follows:
Wherein primary amine is benzylamine, ethamine, Tri N-Propyl Amine, n-Butyl Amine 99, hexahydroaniline, adjacent methylbenzylamine, 4-Methoxybenzylamine, o-chlorine benzylamine, or naphthylamines.
2. in accordance with the method for claim 1, it is characterized in that:
Concrete operation step is as follows:
React in reactor, reactor vacuumizes rear logical argon replaces, under-4 to 4 degrees Celsius, to 1, in 6 diines (1), drip the diethyl ether solution of primary amine (2), reaction 1-2 days, after reaction terminates, take out solvent with under decompression, acetonitrile dissolves, be added drop-wise in the mixing solutions of metal nitrate silver and alkali Potassium ethanoate, 65 DEG C-80 DEG C are reacted after 1-2 days, stopped reaction, drain solvent, methylene dichloride dissolves loading and carries out silica gel column chromatography, obtains product to 1,3,4-tri-substituted azole.
3. in accordance with the method for claim 2, it is characterized in that: by simple raw material one-step synthesis complex compound; Solvent load is every mmole 1,6 diine solvent 2 – 5 milliliters.
4. in accordance with the method for claim 2, it is characterized in that:
1,6 diines are 1 to 1 with primary amine consumption mol ratio;
The molar concentration rate of the diethyl ether solution of primary amine is 0.5mol/mL;
The molar concentration rate of the acetonitrile solution of metal nitrate silver and alkali Potassium ethanoate is 1.1mol/mL.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101948463A (en) * | 2010-01-19 | 2011-01-19 | 清华大学 | Method for synthesizing substituted pyrrole by cycloaddition reaction of 1, 3-diyne and primary amine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101948463A (en) * | 2010-01-19 | 2011-01-19 | 清华大学 | Method for synthesizing substituted pyrrole by cycloaddition reaction of 1, 3-diyne and primary amine |
Non-Patent Citations (3)
| Title |
|---|
| A Powerful New Strategy for Diversity-Oriented Synthesis of Pyrroles from Donor-Acceptor Cyclopropanes and Nitriles;Ming Yu，et al.,;《Organic Letters》;20031203;第5卷(第26期);第5099-5101页 * |
| Gold- and Silver-Mediated Cycloisomerizations of N-Propargylamides;Guido Verniest,et al.,;《Organic Letters》;20080903;第10卷(第19期);第4379-4382页 * |
| Hydroamination: Direct Addition of Amines to Alkenes and Alkynes;Thomas E. Muller,et al.,;《Chemical Reviews》;20080826;第108卷(第9期);第3795-3892页 * |
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