CN112876344B - Chemical selectivity and enantioselectivity intramolecular Heck reaction catalyzed by palladium - Google Patents
Chemical selectivity and enantioselectivity intramolecular Heck reaction catalyzed by palladium Download PDFInfo
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Abstract
The invention provides a palladium-catalyzed intramolecular Heck reaction with chemoselectivity and enantioselectivity, belonging to the field of organic synthesis. Because the invention proposes to use the compound
PMP (pentamethylpiperidine) is used as alkali, p-xylene is used as solvent, palladium acetate is used as catalyst, and
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to palladium-catalyzed chemoselective and enantioselective intramolecular Heck reaction.
Background
The Heck reaction is that aryl, alkenyl halide or alkenyl triflate compound generates an olefination reaction under the catalysis of Pd (0) complex in the presence of alkali to form a new C-C bond. From the analysis of elementary reaction, the mechanism is as follows: the halogenated alkane and zero-valent palladium are subjected to oxidation addition to produce a carbon-palladium intermediate, a carbon-carbon double bond and the formed carbon-palladium intermediate are subjected to cis-coplanar insertion of a carbon-palladium bond to form a carbon-carbon single bond and a new carbon-palladium bond intermediate, and then cis-coplanar beta-H elimination is carried out to generate new substituted olefin. In recent years, due to better understanding and understanding of the Heck reaction, which is widely used in key synthetic steps for many natural products, there has been more intensive research and development in selecting appropriate reactants, solvents, bases, additives, and catalyst, precursor, and ligand conditions needed for optimal reactions.
As early as over 150 years ago, the phenomena of universe and life asymmetry have been recognized. The fundamental life phenomena and the related laws of nature are all generated by chirality, which is a fundamental property of nature. Chiral compounds refer to compounds with the same molecular weight and molecular structure, as our left and right hands, two enantiomers are mirror images of each other and cannot completely coincide. Chiral compounds are found everywhere in nature, and in our usual life, for example, drugs that we eat while ill often have one or more chiral centers. In addition, different configurations of chiral compounds often have different effects. The tragedy most well known to the audience, in the last 50 to 60 centuries, thalidomide (thalidomide) was widely used to treat early vomiting of thousands of pregnant women, as well as fetal abnormalities, with approximately 1 million "seal-malformed infants" born worldwide. The latter study shows that the anti-reactionary drug contains two forms of compounds, wherein the S form has teratogenic effect. Chiral synthetic chemistry and industry are also closely related, and the 'chiral drug' engineering which grows up after the 20 th century is a good example; furthermore, there is likewise a requirement for "chirality" in fragrances, food additives, pesticides and the like. Therefore, it is very interesting to synthesize a single optically pure chiral molecule. At present, three approaches are mainly used for obtaining optical pure compounds, namely enantiomer resolution, chiral compound conversion and asymmetric catalytic synthesis. Among them, asymmetric catalysis has been a focus and a leading edge of research because a small amount of catalyst can be used to obtain a desired optically active product.
Asymmetric Heck reaction is an efficient method (up to 99% ee) for synthesizing chiral centers of tertiary carbon and quaternary carbon, and many carbocyclic and heterocyclic ring structures can be constructed by Heck reaction, including compounds with spiro structures and the like. The reaction range is relative to products, the isomerization of olefin is a kind of problems existing in the reaction process, and is influenced by regioselectivity and chemoselectivity, products are often accompanied with the appearance of different products with chemoselectivity in the Heck reaction, however, the problems can be overcome, the stereoselectivity and regioselectivity of the reaction can be improved by developing a novel chiral ligand to enable the chiral ligand to be dissociated in the products more quickly, and the problem that by-products are caused by the existence of chemoselectivity is solved. The preparation of a variety of chiral compounds using asymmetric Heck reactions has been successfully used for enantioselective synthesis of complex natural products.
Disclosure of Invention
The present invention has been made to solve the above problems, and an object of the present invention is to provide a palladium-catalyzed chemoselective and enantioselective intramolecular Heck reaction.
The invention provides a palladium-catalyzed chemoselective and enantioselective intramolecular Heck reaction, which is characterized by the following reaction formula:
Wherein, in the compound I, m is 0 or 1, n is 1 or 2; x is C, CH 2 Or C (CH) 3 ) 2 Any one of the above; r is selected from hydrogen and C 1 ～C 12 Alkyl of (A), C 1 ～C 10 Alkoxy group of,
Any one of the above; r 1 、R 2 Each independently selected from hydrogen, halogen, C 1 ～C 12 Alkyl of (A), C 1 ～C 10 Alkoxy group of (C) 1 ～C 10 Silicon base, C 1 ～C 10 Alkanoyl of (2), C 1 ～C 10 Any one of the ester groups of (a); the ligand is
Wherein Ar is 3,5-Me 2 C 6 H 3 。
The palladium-catalyzed chemo-selective and enantioselective intramolecular Heck reaction provided by the invention is also characterized in that the reaction steps are as follows: step 1, under the protection of inert gas, stirring a palladium catalyst and a ligand and a solvent to obtain a mixed solution A; and 2, adding the compound I and alkali into the mixed solution A, reacting for a certain time at a certain temperature, and purifying after the reaction is finished to obtain a target product II.
The palladium-catalyzed chemoselective and enantioselective intramolecular Heck reaction provided by the invention also has the following characteristics: wherein, the certain temperature in the step 2 is 40-60 ℃, and preferably 50 ℃.
The palladium-catalyzed chemoselective and enantioselective intramolecular Heck reaction provided by the invention also has the following characteristics: wherein the certain time in the step 2 is 50-70 h, preferably 60 h.
The palladium-catalyzed chemoselective and enantioselective intramolecular Heck reaction provided by the invention also has the following characteristics: wherein the mol ratio of the compound I, alkali, palladium catalyst and ligand is 1: (1.8-2.2): (0.8-1.2): (0.1-0.3).
The palladium-catalyzed chemoselective and enantioselective intramolecular Heck reaction provided by the invention is also characterized in that the palladium catalyst is palladium acetate.
The palladium catalyzed chemoselective and enantioselective intramolecular Heck reaction provided by the invention is also characterized in that the solvent is p-xylene.
The palladium catalyzed chemoselective and enantioselective intramolecular Heck reaction provided by the invention is also characterized in that the base is pentamethylpiperidine.
Action and Effect of the invention
According to the invention, palladium-catalyzed chemoselective and enantioselective intramolecular Heck reactions are concerned, since the invention proposes to use compounds
PMP (pentamethylpiperidine) is used as alkali, p-xylene is used as solvent, palladium acetate is used as catalyst, and
Detailed Description
In order to make the technical means, the creation features, the achievement purposes and the effects of the invention easy to understand, the invention is specifically described with the embodiment below.
The apparatus used in the examples described below was a BrukeraV-400 nuclear magnetic resonance apparatus (Germany).
The solvents used in the following examples were commercially available.
The following examples use starting materials according to reference DOI, 10.1021/ol2003308 synthesis.
The ligands in the following examples are derived from patent CN 110615811.
The yields in the following examples are isolated yields.
Liquid phase conditions in the following examples: HPLC with a Chiralpak IE column (n-hexane: isopropanol: 95:5,0.8mL/min)
< example 1>
A compound 2a is prepared according to the following reaction formula:
the synthesis procedure for compound 2a is as follows:
step 1, adding palladium acetate (10 mmol%, 4.5mg), chiral ligand L (20 mmol%, 23.6mg) and 3mL of p-xylene into a 10mL reaction tube under argon atmosphere, and stirring for 1 hour at room temperature;
and 2, sequentially adding the compound 1a (0.2mmol,77.7mg) and PMP (1,2,2,6, 6-pentamethylpiperidine, 0.4mmol and 72.4 mu L) into a pre-stirred reaction tube under an argon atmosphere, stirring at 50 ℃ for 60 hours, detecting the reaction through a TLC plate, passing through a column (column chromatography silica gel filled column) until the reaction is completely carried out, eluting with an eluent (petroleum ether is used for elution, and then petroleum ether/ethyl acetate with the volume ratio of 30/1) and spin-drying the solvent to obtain a product 2a which is yellow oily matter, wherein the yield is 96 percent and the ee value is-91 percent.
The nuclear magnetic data and characteristic data for compound 2a are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.40–7.30(m,5H),5.39(d,J＝0.7Hz,1H),4.97(s,1H),3.93–3.81(m,1H),2.64–2.54(m,2H),2.46–2.24(m,5H),2.10–1.99(m,2H),1.90–1.82(m,1H)；
13 C NMR(101MHz,CDCl 3 )δ198.05,166.03,149.17,141.0,138.91,128.29,127.52,126.20,113.42,55.06,37.75,30.12,27.90,25.33,23.58.
< example 2>
A compound 2b is prepared according to the following reaction scheme:
the synthetic procedure for compound 2b was similar to that of example 1, except that compound 1a was replaced with compound 1 b. Compound 2b was a yellow oil in 70% yield and-77% ee.
The nuclear magnetic data and characteristic data for compound 2b are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.27(td,J＝8.1,1.7Hz,1H),7.11(dd,J＝7.4,1.7Hz,1H),6.91(ddd,J＝13.6,10.0,4.6Hz,2H),5.12(d,J＝1.3Hz,1H),5.00(d,J＝0.8Hz,1H),3.81(s,4H),2.54–2.45(m,3H),2.42–2.38(m,2H),2.26–2.13(m,2H),2.06–1.98(m,2H),1.86–1.78(m,1H)；
13 C NMR(101MHz,CDCl 3 )δ198.42,167.22,156.37,149.92,138.42,132.18,129.87,128.73,120.50,114.68,110.61,55.24,37.86,30.46,27.73,25.36,23.70.
< example 3>
A compound 2c is prepared according to the following reaction scheme:
the synthetic procedure for compound 2c was similar to that of example 1, except that compound 1a was replaced with compound 1 c. Compound 2c is a yellow oil in 96% yield with an ee of-89%.
The nuclear magnetic data and characteristic data for compound 2c are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.28–7.12(m,4H),5.38(s,1H),4.95(s,1H),3.92–3.89(m,1H),2.66–2.49(m,2H),2.47–2.42(m,3H),2.38(s,3H),2.34–2.21(m,2H),2.13–1.99(m,2H),1.90–1.820(m,1H)；
13 C NMR(101MHz,CDCl 3 )δ198.19,166.28,149.35,141.14,138.91,137.88,128.31,128.21,127.03,123.28,113.16,55.02,37.78,30.30,27.89,25.38,23.62,21.46.
< example 4>
A compound 2d is prepared according to the following reaction scheme:
the synthetic procedure for compound 2d was similar to that of example 1, except that compound 1a was replaced with compound 1 d. Compound 2d is a yellow solid in 89% yield with an ee of-91%.
The nuclear magnetic data and characteristic data for compound 2d are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.60–7.58(m,3H),7.54–7.52(m,1H),7.48–7.34(m,5H),5.45(d,J＝0.5Hz,1H),5.01(s,1H),3.97–3.93(m,1H),2.65–2.52(m,2H),2.48–2.36(m,3H),2.36–2.27(m,2H),2.12–1.98(m,2H),1.94–1.86(m,1H)；
13 C NMR(101MHz,CDCl 3 )δ198.13,166.06,149.22,141.63,141.35,140.94,139.02,128.77,128.75,127.38,127.07,126.41,125.20,125.14,113.74,55.14,37.77,30.23,27.95,25.40,23.61.
< example 5>
A compound 2e is prepared according to the following reaction scheme:
the synthetic procedure for compound 2e was similar to that of example 1, except that compound 1a was replaced with compound 1 e. Compound 2e was a yellow oil in 90% yield and-90% ee.
The nuclear magnetic data and characteristic data for compound 2e are as follows:
1 H NMR(400MHz,CDCl 3 )δ6.99(s,2H),6.94(s,1H),5.35(s,1H),4.89(s,1H),3.89–3.85(m,1H),2.64–2.52(m,2H),2.44–2.36(m,3H),2.32(s,6H),2.30–2.16(m,2H),2.12–1.95(m,2H),1.88–1.80(m,1H)；
13 C NMR(101MHz,CDCl 3 )δ198.13,166.32,149.56,141.29,138.90,137.76,129.20,124.11,112.84,54.96,37.80,30.48,27.88,25.40,23.65,21.32.
< example 6>
A compound 2f is prepared according to the following reaction:
the synthetic procedure for compound 2f was similar to that of example 1, except that compound 1a was replaced with compound 1 f. Compound 2f was a yellow oil in 87% yield with an ee of-91%.
The nuclear magnetic data and characteristic data for compound 2f are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.31–7.29(m,2H),6.87–6.85(m,2H),5.30(d,J＝0.6Hz,1H),4.86(s,1H),3.88–3.85(m,1H),3.81(s,3H),2.63–2.49(m,2H),2.46–2.34(m,3H),2.31–2.18(m,2H),2.10–1.95(m,2H),1.88–1.79(m,1H)；
13 C NMR(101MHz,CDCl 3 )δ198.23,166.42,159.14,148.38,138.87,133.38,127.36,113.68,111.97,55.23,55.16,37.79,30.06,27.94,25.39,23.62.
< example 7>
A preparation of 2g of compound is shown below:
the procedure for the synthesis of compound 2g was similar to that of example 1, except that compound 1a was replaced with compound 1 g. Compound 2g was a yellow oil in 91% yield with an ee of-90%.
The nuclear magnetic data and characteristic data of compound 2g are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.40–7.33(m,4H),5.41(s,1H),4.93(s,1H),3.94–3.90(m,1H),2.67–2.50(m,2H),2.48–2.38(m,3H),2.33–2.21(m,2H),2.10–2.01(m,2H),1.92–1.83(m,1H),1.35(s,9H)；
13 C NMR(101MHz,CDCl 3 )δ198.22,166.45,150.64,148.76,138.92,137.94,125.84,125.26,112.76,55.00,37.81,34.46,31.24,30.27,27.95,25.36,23.64.
< example 8>
A compound 2h is prepared according to the following reaction formula:
the synthetic procedure for compound 2h was similar to example 1, except that compound 1a was replaced with compound 1 h. Compound 2h was a yellow oil in 88% yield with an ee of-91%.
The nuclear magnetic data and characteristic data for compound 2h are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.99–7.96(m,2H),7.42–7.39(m,2H),5.44(s,1H),5.03(s,1H),3.89(s,4H),2.60–2.49(m,2H),2.46–2.35(m,3H),2.32–2.21(m,2H),2.08–1.93(m,2H),1.84–1.76(m,1H)；
13 C NMR(101MHz,CDCl 3 )δ198.01,166.66,165.43,148.43,145.55,139.14,129.63,129.14,126.18,54.75,52.03,37.70,30.11,27.86,25.30,23.54.
< example 9>
A compound 2i is prepared according to the following reaction formula:
the synthetic procedure for compound 2i was similar to that of example 1, except that compound 1a was replaced with compound 1 i. Compound 2i was a yellow oil in 94% yield and-93% ee.
The nuclear magnetic data and characteristic data for compound 2i are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.92–7.90(m,2H),7.46–7.43(m,2H),5.46(s,1H),5.05(s,1H),3.919–3.88(m,1H),2.59(s,3H),2.58–2.52(m,2H),2.44–2.38(m,3H),2.37–2.23(m,2H),2.01–1.976(m,2H),1.85–1.77(m,1H)；
13 C NMR(101MHz,CDCl 3 )δ198.07,197.53,165.42,148.38,145.73,139.21,136.11,128.48,126.43,115.41,54.82,37.74,30.10,27.92,26.56,25.34,23.58.
< example 10>
A compound 2j is prepared according to the following reaction:
the synthetic procedure for compound 2j was similar to that of example 1, except that compound 1a was replaced with compound 1 j. Compound 2j is a yellow solid with a yield of 93% and an ee of-91%.
The nuclear magnetic data and characteristic data for compound 2j are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.65–7.59(m,4H),7.50–7.46m,4H),5.49(s,1H),5.01(s,1H),3.98–3.95(m,1H),2.71–2.59(m,2H),2.50–2.40(m,3H),2.38–2.24(m,2H),2.16–1.99(m,2H),1.96–1.88(m,1H)；
13 C NMR(101MHz,CDCl 3 )δ198.18,166.14,148.63,140.39,139.86,139.00,128.75,127.79,127.35,127.02,126.89,126.62,113.43,54.98,37.79,30.22,27.96,25.38,23.62.
< example 11>
A compound 2k is prepared according to the following reaction scheme:
the synthetic procedure for compound 2k is similar to that of example 1, except that compound 1a is replaced with compound 1 k. The obtained product is a mixture of a compound 2k and a compound 2a, wherein the mass ratio of the compound 2k to the compound 2a is 3:2, the mixture cannot calculate the total yield, a single product cannot be purified, and the raw materials react 100%. The ee value of compound 2k was-90% and that of compound 2a was-88%.
The nuclear magnetic data and the characteristic data of mixture 2k +2a are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.53–7.51(m,2H),7.40–7.30(m,5H),5.42(dd,J＝11.7,0.7Hz,2H),4.98(s,2H),3.94–3.90(m,2H),2.63–2.55(m,3H),2.49–2.38(m,5H),2.33–2.21(m,3H),2.14–1.97(m,3H),1.91–1.83(m,2H),0.30(s,9H)；
13 C NMR(101MHz,CDCl 3 )δ198.09,166.17,166.09,149.13,149.05,141.26,141.00,139.79,138.89,133.35,128.29,127.52,126.19,125.45,113.54,113.42,55.04,54.94,37.74,30.17,30.10,27.90,27.89,25.32,25.29,23.57,-1.24.
< example 12>
A compound 2l is prepared according to the following reaction scheme:
the synthetic procedure for compound 2l was similar to that of example 1, except that compound 1a was replaced with compound 1 l. Compound 2l was a yellow oil in 87% yield with an ee of-91%.
The nuclear magnetic data and characteristic data for compound 2l are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.60(d,J＝8.2Hz,2H),7.48(d,J＝8.1Hz,2H),5.45(s,1H),5.07(s,1H),3.92–3.89(m,1H),2.65–2.50(m,2H),2.49–2.35(m,3H),2.33–2.21(m,2H),2.16–1.97(m,2H),1.88–1.78(m,1H)；
13 C NMR(101MHz,CDCl 3 )δ198.11,165.33,148.26,144.73,139.33,128.64,127.76,126.67,125.39(q,J＝3.7Hz),115.45,54.98,37.81,30.12,27.99,25.39,23.65.
< example 13>
A compound 2m is prepared according to the following reaction formula:
the synthetic procedure for compound 2m was similar to that of example 1, except that compound 1a was replaced with compound 1 m. Compound 2m was a yellow oil in 73% yield and-80% ee.
The nuclear magnetic data and characteristic data for compound 2m are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.03–8.01(m,1H),7.89–7.85(m,1H),7.82–7.76(m,1H),7.53–7.46(m,2H),7.46–7.41(m,1H),7.26–7.22(m,1H),5.30(d,J＝0.4Hz,1H),5.22(d,J＝1.4Hz,1H),3.82(dd,J＝8.6,4.3Hz,1H),2.69–2.59(m,2H),2.51–2.43(m,3H),2.40–2.31(m,2H),2.22–2.04(m,2H),1.94–1.85(m,1H)；
13 C NMR(101MHz,CDCl 3 )δ198.21,165.38,148.78,140.42,139.22,133.69,131.28,128.39,127.57,125.93,125.71,125.37,125.10,125.07,116.25,57.13,37.81,29.67,27.72,25.57,23.64.
< example 14>
A compound 2n is prepared according to the following reaction formula:
the synthetic procedure for compound 2n is similar to that of example 1, except that compound 1a is replaced with compound 1 n. Compound 2n was a yellow oil in 81% yield and-88% ee.
The nuclear magnetic data and characteristic data for compound 2n are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.40–7.31(m,5H),5.43(s,1H),5.06(s,1H),4.44–4.31(m,2H),4.19–4.09(m,2H),4.05–4.02(m,1H),2.78–2.59(m,2H),2.44–2.34(m,1H),2.00–1.92(m,1H)；
13 C NMR(101MHz,CDCl 3 )δ193.64,164.08,148.43,140.53,137.08,128.50,127.87,126.20,113.80,71.62,65.37,52.52,30.53,27.44.
< example 15>
A compound 2o is prepared according to the following reaction:
the synthetic procedure for compound 2o is similar to that of example 1, except that compound 1a is replaced with compound 1 o. Compound 2o was a yellow oil in 87% yield with-82% ee.
The nuclear magnetic data and characteristic data for compound 2o are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.39–7.30(m,5H),5.40(s,1H),4.97(s,1H),3.87–3.83(m,1H),2.69–2.44(m,3H),2.39–2.28(m,2H),2.14–2.07(m,2H),1.94–1.87(m,1H),1.04(d,J＝4.7Hz,6H)；
13 C NMR(101MHz,CDCl 3 )δ198.04,163.98,149.44,141.18,137.61,128.34,127.57,126.18,113.68,54.98,51.79,39.41,34.95,30.82,30.82,28.79,28.16,27.79.
< example 16>
A compound 2p is prepared according to the following reaction:
the synthetic procedure for compound 2p is similar to that of example 1, except that compound 1a is replaced with compound 1 p. Compound 2p was a yellow oil in 90% yield and-86% ee.
The nuclear magnetic data and characteristic data for compound 2p are as follows:
1 H NMR(400MHz,CDCl 3 )δ4.78–4.77(m,1H),4.73(d,J＝0.6Hz,1H),3.44–3.41(m,1H),2.57–2.43(m,2H),2.38–2.34(m,2H),2.23–2.16(m,2H),2.14–1.95(m,3H),1.80–1.71(m,1H),1.60(s,3H)；
13 C NMR(101MHz,CDCl 3 )δ198.26,165.88,145.43,138.60,112.30,57.68,37.76,28.35,27.71,25.04,23.53,19.11.
< example 17>
A compound 2q is prepared according to the following reaction:
the synthetic procedure for compound 2q was similar to that of example 1, except that compound 1a was replaced with compound 1 q. Compound 2q is a yellow solid in 92% yield and ee-85%.
The nuclear magnetic data and characteristic data for compound 2q are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.30–7.28(m,2H),7.17–7.15(m,2H),5.37(s,1H),4.93(s,1H),3.92–3.88(m,1H),2.68–2.52(m,2H),2.48–2.42(m,3H),2.37(s,3H),2.32–2.24(m,2H),2.15–1.96(m,2H),1.91–1.82(m,1H)；
13 C NMR(101MHz,CDCl 3 )δ198.26,166.40,148.95,138.91,137.42,129.47,129.05,126.14,112.74,55.14,37.81,30.14,27.95,25.40,23.64,21.04.
< example 18>
A compound 2r is prepared according to the following reaction formula:
the synthetic procedure for compound 2r was similar to that of example 1, except that compound 1a was replaced with compound 1 r. Compound 2r is a yellow oil in 54% yield and-65% ee.
The nuclear magnetic data and characteristic data for compound 2r are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.42–7.35(m,5H),5.41(s,1H),5.02(s,1H),3.99(dd,J＝8.6,6.3Hz,1H),2.77–2.71(m,2H),2.54–2.49(m,2H),2.43–2.38(m,2H),2.34–2.29(m,2H)；
13 C NMR(101MHz,CDCl 3 )δ187.38,148.86,143.97,128.37,128.01,127.79,127.11,126.25,113.13,49.41,40.92,36.38,26.67,24.68.
< example 19>
A compound 2s is prepared according to the following reaction formula:
the synthetic procedure for compound 2s was similar to that of example 1, except that compound 1a was replaced with compound 1 s. The product was obtained as a mixture of compound 2s and compound 2t in the form of a yellow oil with a yield of 84% and an ee value of-25%.
The nuclear magnetic data and the characteristic data of the mixture 2s +2t are as follows:
1 H NMR(400MHz,CDCl 3 )δ4.90(s,1H),4.65(s,1H),2.84–2.74(m,2H),2.61–2.58(m,2H),2.48–2.39(m,5H),2.35–2.20(m,7H),2.03–1.91(m,8H),1.82(s,3H),1.73(s,3H),1.69–1.60(m,4H)；
13 C NMR(101MHz,CDCl 3 )δ199.46,157.29,155.43,146.02,134.13,133.79,132.50,127.04,123.66,113.32,48.62,38.30,38.02,32.42,29.82,28.61,26.87,24.41,24.30,23.17,22.66,22.61,22.49,22.27,21.17,18.82.
< example 20>
A compound 2u is prepared according to the following reaction scheme:
the synthetic procedure for compound 2u was similar to that of example 1, except that compound 1a was replaced with compound 1 u. Compound 2u is a yellow oil in 82% yield and-5% ee.
The nuclear magnetic data and characteristic data for compound 2u are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.45–7.31(m,5H),5.45(d,J＝1.1Hz,1H),4.89(s,1H),3.45(s,1H),2.55–2.46(m,3H),2.42–2.23(m,3H),2.10–1.89(m,2H),1.68–1.58(m,4H)；
13 C NMR(101MHz,CDCl 3 )δ199.45,157.32,149.48,141.29,134.26,128.38,127.58,126.34,115.04,45.84,38.16,30.36,27.02,22.78,22.24,17.53.
< comparative example 1>
A compound 2v is prepared according to the following reaction:
the synthetic procedure for compound 2v was similar to that of example 1, except that compound 1a was replaced with compound 1 v. Compound 2v was a yellow oil in 85% yield.
The nuclear magnetic data and characteristic data for compound 2v are as follows:
1 H NMR(400MHz,CDCl 3 )δ5.80–5.73(m,1H),2.54(dt,J＝5.7,5.0Hz,4H),2.42–2.39(m,2H),2.34–2.32(m,2H),2.05–1.99(m,2H),1.76(d,J＝7.1Hz,3H)；
13 C NMR(101MHz,CDCl 3 )δ198.56,159.62,147.42,140.66,120.98,38.12,26.65,25.86,23.11,22.39,15.11.
< comparative example 2>
A compound 2w is prepared according to the following reaction formula:
the synthetic procedure for compound 2w is similar to example 1, except that compound 1a is replaced with compound 1 w. Compound 2w was a yellow oil in 93% yield.
The nuclear magnetic data and characteristic data for compound 2w are as follows:
1 H NMR(400MHz,CDCl 3 )δ6.02(q,J＝7.0Hz,1H),2.48–2.45(m,2H),2.40–2.37(m,2H),2.31–2.28(m,4H),1.98–1.92(m,2H),1.77(d,J＝7.1Hz,3H),1.66–1.60(m,2H)；
13 C NMR(101MHz,CDCl 3 )δ199.90,150.30,136.71,132.49,125.56,37.57,25.49,25.48,22.84,22.11,21.44,14.25.
effects and effects of the embodiments
According to the bookThe examples relate to palladium-catalysed chemoselective and enantioselective intramolecular Heck reactions, since this example proposes the use of compounds
PMP (pentamethylpiperidine) is used as alkali, p-xylene is used as solvent, palladium acetate is used as catalyst, and
the palladium-catalyzed chemical selectivity and enantioselective intramolecular Heck reaction provided by the embodiment prepares the hexa-penta-and hexa-chiral bicyclic compound with high stereoselectivity, which is an important structural unit in a steroid skeleton compound and has wide application value.
The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.
Claims (7)
1. A palladium-catalyzed chemoselective and enantioselective intramolecular Heck reaction, characterized by the following formula:
the reaction steps are as follows:
step 1, under the protection of inert gas, stirring a palladium catalyst and a ligand and a solvent to obtain a mixed solution A;
step 2, adding the compound I and alkali into the mixed solution A, reacting for a certain time at a certain temperature, after the reaction is finished, purifying to obtain a target product II,
wherein, in the compound I, m is 0 or 1, n is 1 or 2; x is C, CH 2 Or C (CH) 3 ) 2 Any one of the above; r is selected from hydrogen and C 1 ～C 12 Alkyl of (A), C 1 ～C 10 Alkoxy group of,
Any one of the above; r 1 、R 2 Each independently selected from hydrogen, halogen, C 1 ～C 12 Alkyl of (A), C 1 ～C 10 Alkoxy group of (C) 1 ～C 10 Silicon base, C 1 ～C 10 Alkanoyl of (2), C 1 ～C 10 Any one of the ester groups of (a);
the ligand is
Wherein Ar is 3,5-Me 2 C 6 H 3 。
2. The palladium catalyzed chemo-and enantioselective intramolecular Heck reaction according to claim 1, characterized in that:
wherein the certain temperature is 40-60 ℃.
3. The palladium catalyzed chemo-and enantioselective intramolecular Heck reaction according to claim 1, characterized in that:
Wherein the certain time is 50-70 h.
4. The palladium catalyzed chemo-and enantioselective intramolecular Heck reaction according to claim 1, characterized in that:
wherein the molar ratio of the compound I, the base, the palladium catalyst and the ligand is 1: (1.8-2.2): (0.8-1.2): (0.1-0.3).
5. The palladium catalyzed chemo-and enantioselective intramolecular Heck reaction according to claim 1,
wherein the palladium catalyst is palladium acetate.
6. The palladium catalyzed chemo-and enantioselective intramolecular Heck reaction according to claim 1,
wherein the solvent is p-xylene.
7. The palladium catalyzed chemo-and enantioselective intramolecular Heck reaction according to claim 1,
wherein the base is pentamethylpiperidine.
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