Method for preparing 2-amino-substituted conjugated diene by means of palladium-catalyzed coupling of secondary propargyl benzoate to sulfonamide

Abstract

Disclosed in the present invention is a palladium-catalyzed coupling reaction of a secondary propargyl benzoate to a sulfonamide, which realizes highly selective synthesis of a 2-amino-substituted conjugated diene. The method is suitable for the coupling of a series of functionalized propargyl benzoates and sulfonamides, and enables late-stage functionalization modification of complex small-molecule drugs, which provides a new method for synthesizing a sulfonamide compound containing a conjugated diene structure, and has significant application prospects.

Description

A method for preparing 2-aminosubstituted conjugated dienes by palladium-catalyzed coupling of secondary propargylic phenylcarboxylate with sulfonamide TECHNICAL FIELD

[0001] The present application belongs to the technical field of chemical synthesis, and relates to a palladium-catalyzed coupling reaction of secondary propargylic phenylcarboxylate with sulfonamide, which realizes the high-selective synthesis of conjugated diene amine. BACKGROUND

[0002] In the past few decades, transition-metal-catalyzed coupling reactions of propargylic alcohol derivatives with nucleophiles have been well developed. Generally, there are three key intermediates in palladium-catalyzed propargylic alcohol coupling reactions. The first one is allylpalladium, which will produce olefin (Ma, S. Eur. J. Org. Chem. 2004, 1175) or diaddition olefin product (Guo, L.-N.; Duan, X.-H.; Liang, Y.-M.; Acc. Chem. Res. 2011, 44, 111) when hard or soft nucleophiles are used, respectively. The second one is η 1 - propargylpalladium, which produces alkyne product through propargyl substitution reaction (Ma, S.; Wang, G. Angew. Chem. Int. Ed. 2003, 42, 4215). However, examples of the third one, η 3 - propargylpalladium intermediate, to form 1,3-diene product are rare. On the other hand, the construction of C–N bond is very important due to its wide presence in natural products and biologically active compounds. In 2001, the first palladium-catalyzed intramolecular propargyl coupling reaction was reported by Mori group, which produced 1,3-diene through intramolecular C–N bond formation (Kozawa, Y.; Mori, M. Tetrahedron Lett. 2001, 42, 4869). In 2020, Guiry group reported the synthesis of conjugated dienes through palladium-catalyzed cross-coupling reaction of propargyl carbonate with amide (O’Broin, C. Q.; Guiry, P. J. Org. Lett. 2020, 22, 879). However, the report described a coupling reaction of secondary propargylic alcohol derivative with secondary amine, which produced 2-amino-1,3-diene with poor stereoselectivity, only 3:1. Considering the importance of conjugated diene amine in organic synthesis reactions, it is still necessary to develop a method for the synthesis of highly stereoselective conjugated diene amine, but there is no report on the preparation of diene amine through palladium-catalyzed coupling of propargylic alcohol derivative with sulfonamide.

[0003] SUMMARY

[0004] The present application overcomes the deficiencies in the prior art and provides a method for preparing 2-aminosubstituted conjugated dienes by palladium-catalyzed coupling of secondary propargylic phenylcarboxylate with sulfonamide, which has mild reaction conditions and is simple to operate.

[0005] The present application overcomes the defects of harsh reaction conditions and poor selectivity in the prior art reaction, and provides a high-selectivity preparation of 2-aminosubstituted conjugated diene compounds by using propargyl phenyl benzoate and sulfonamide which are more cheap and easy to obtain at room temperature.

[0006] The present application provides a method for preparing diene amine by coupling secondary propargyl phenyl benzoate and sulfonamide with palladium as catalyst, which comprises: using secondary propargyl phenyl benzoate and sulfonamide as raw materials, using palladium salt as catalyst, and using organic phosphine as ligand, and under the action of base, the secondary propargyl phenyl benzoate and sulfonamide are directly converted into 2-aminosubstituted conjugated diene compounds, and the reaction process is shown in the following reaction formula (1):

[0007] wherein, R 1 is alkyl, alkyl with functional groups; R 2 is alkyl, alkyl with functional groups, phenyl, aryl or heterocyclic group; R 3 is alkyl, alkyl with functional groups, aryl; Ar is aryl;

[0008] the functional groups in the alkyl with functional groups are halogen, alkenyl, cyano, siloxyl;

[0009] the aryl is phenyl with electron-donating group or electron-withdrawing substituent at ortho, meta or para position; wherein, the electron-donating group is methyl, methoxy, amino; the electron-withdrawing substituent is halogen, ester group, phenyl;

[0010] the heterocyclic group is pyrazole, isoxazole;

[0011] Preferably,

[0012] the R 1 is C1-C10 alkyl, C1-C10 alkyl with functional groups; R 2 is C1-C10 alkyl, C1-C10 alkyl with functional groups, phenyl, aryl; R 3 is C1-C10 alkyl, C1-C10 alkyl with functional groups, aryl; Ar is aryl;

[0013] the functional groups in the alkyl with functional groups are chlorine, alkenyl, cyano, siloxyl;

[0014] the aryl is phenyl with electron-donating group or electron-withdrawing substituent at ortho, meta or para position; wherein, the electron-donating group is methyl, methoxy, amino; the electron-withdrawing substituent is halogen, ester group, phenyl;

[0015] the heterocyclic group is pyrazole, isoxazole;

[0016] Further preferably,

[0017] the R 1 is ethyl, propyl, butyl; R 2 is methyl, phenyl, p-tolyl; R 3 is methyl, butyl; Ar is aryl;

[0018] the functional group in the functional group-containing alkyl group is chlorine, alkenyl, cyano, siloxy;

[0019] the aryl group is a phenyl group with an electron-withdrawing or electron-donating substituent at the ortho, meta or para position; wherein the electron-donating group is methyl, methoxy, amino; and the electron-withdrawing group is halogen, ester group, phenyl;

[0020] the heterocyclic group is pyrazole, isoxazole.

[0021] In the present application, the palladium catalyst is selected from one or a mixture of two or more of bis(allyl palladium chloride), tetrakis(triphenylphosphine) palladium, tris(dibenzylideneacetone) dipalladium, bis(cinnamyl palladium chloride), bis(dibenzylideneacetone) palladium, palladium chloride, palladium acetate, bis(triphenylphosphine) palladium chloride, bis(acetonitrile) palladium chloride, etc.; preferably, bis(allyl palladium chloride).

[0022] In the present application, the phosphine ligand is selected from one or a mixture of 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (BINAP) and 2,2'-bis(diphenylphosphine) biphenyl (BIPHEP), etc.; preferably, 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (BINAP).

[0023] In the present application, the base is selected from one or a mixture of two or more of potassium carbonate, cesium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 4-dimethylaminopyridine (DMAP), etc.; preferably, potassium carbonate.

[0024] In the present application, the organic solvent is selected from one or a mixture of two or more of acetonitrile, tetrahydrofuran, dichloromethane, toluene, etc.; preferably, acetonitrile.

[0025] In the present application, the molar ratio of the raw material secondary propargyl alcohol benzoate, sulfonamide, palladium catalyst, phosphine ligand, base is 1.0:(1.0-3.0):(0.05-0.15):(0.05-0.30):(1.0-3.0); preferably, 1.0:2.0:0.05:0.12:2.0.

[0026] In the present application, the temperature of the reaction is 10-50 degrees Celsius; preferably, it is room temperature, 25 degrees Celsius.

[0027] The possible mechanism of the present application is as follows: the metal palladium catalyst and propargyl alcohol derivative 1 undergo oxidative addition to form intermediate Int.I, which reacts with amine to form tetra-cyclic palladium intermediate Int.II. The tetra-cyclic palladium intermediate Int.II then undergoes protonolysis to form Int.III, and then undergoes β-H elimination under the action of base to form conjugated diene product to complete the catalytic cycle, and the reaction mechanism is shown in the following formula (2):

[0028] The substantial innovation of the present application is that a simple, direct and efficient catalytic system is developed, which utilizes palladium catalysis to couple secondary propargyl alcohol benzoate and sulfonamide to prepare 2-amine substituted conjugated diene with high selectivity.

[0029] The beneficial effects of the present application include: the present application proposes that under the condition of room temperature, in an organic solvent, using propargyl alcohol benzoate and sulfonamide as raw materials, and using palladium salt as catalyst, the propargyl alcohol benzoate and sulfonamide are converted into 2-amine substituted conjugated diene compounds with high selectivity. The substrate of the present application is widely applicable, and has high yield. The cheap and readily available propargyl alcohol benzoate and sulfonamide are used as starting materials, which effectively solves the problems of harsh reaction conditions and poor selectivity in current methods. The present application is simple to operate, the raw materials are cheap and readily available, the reaction conditions are mild, the yield is excellent, the substrate functional group compatibility is good, and the reaction process is environmentally friendly. The present application method can be used for small-scale laboratory synthesis and large-scale industrial production. DETAILED DESCRIPTION

[0030] The present application will be further described in combination with the following specific examples. The process, conditions, experimental methods, etc. for implementing the present application are the general knowledge and common sense in the art, and the present application does not have special limitations.

[0031] Note: In the reaction formula of the following examples, mol represents mole; [Pd(allyl)Cl]2 represents di(allyl palladium chloride); BINAP represents 1,1'-binaphthalene-2,2'-bis(diphenylphosphine); MeCN represents acetonitrile; K2CO3 represents potassium carbonate.

[0032] The application provides a palladium-catalyzed coupling reaction of secondary propargyl alcohol benzoate and sulfonamide, which realizes high-selective synthesis of 2-amine-substituted conjugated diene, the method is suitable for coupling of a series of functionalized propargyl alcohol benzoate and sulfonamide, and can realize late functional group modification of complex small molecule drugs, which provides a new method for synthesizing sulfonamide compounds containing conjugated diene structure, and has important application prospect.

[0033] Example 1

[0034] Step I: A dry 10 mL vial was charged with 2a (370.6 mg, 2.0 mmol), [Pd(allyl)Cl]2(18.2 mg, 0.05 mmol), rac-BINAP (74.6 mg, 0.12 mmol), and K2CO3(276.0 mg, 2.0 mmol) was introduced into the glove box. 1a (293.2 mg, 1.0 mmol) and MeCN (10 mL) were added in the glove box. The glove box was taken out, and the reaction was carried out at room temperature for 15 h. After the reaction was completed, a short silica gel column (2-3 cm, 300-400 mesh) was used to extract and quench, and the product 3aa (242.2 mg, 68%) was obtained in the form of an oily liquid after washing with ethyl acetate (10 mL x 3) and removing the solvent under reduced pressure, and silica gel column chromatography separation [eluent: petroleum ether / ethyl acetate = 50 / 1 (306 mL), 30 / 1 (620 mL)].

[0035] 1 H NMR (400 MHz, CDCl3) δ = 7.60 (d, J = 8.4 Hz, 2H, ArH), 7.49-7.39 (m, 2H, ArH), 7.28-7.13 (m, 5H, ArH), 6.43 (s, 1H, CH), 5.90 (d, J = 16.0 Hz, 1H, CH), 5.51-4.88 (m, 1H, CH), 3.11 (s, 3H, CH3), 2.39 (s, 3H, CH3), 2.05-1.95 (m, 2H, CH2), 1.37-1.24 (m, 2H, CH2), 0.86 (t, J = 7.4 Hz, 3H, CH3); 13 C NMR (100 MHz, CDCl3) δ 143.0, 137.6, 137.5, 134.9, 133.6, 130.1, 129.2, 128.9, 128.4, 128.3, 127.8, 127.6, 36.4, 34.6, 22.1, 21.4, 13.7; IR (neat, cm -1): v = 2958, 2918, 2858, 1596, 1445, 1343, 1151, 1088; MS (ESI) m / z (%): 356 [C 21 H 26 O2NS] + ; HRMS calcd m / z for C 21 H 26 O2NS[M+H + ]: 356.1679, found 356.1674.

[0036] Example 2

[0037] The procedure was the same as Example 1, Step I, 1c (306.6 mg, 1.0 mmol), 2a (370.2 mg, 2.0 mmol), [Pd(allyl)Cl]2(18.1 mg, 0.05 mmol), rac-BINAP (74.9 mg, 0.12 mmol), K2CO3(276.5 mg, 2.0 mmol), MeCN (10 mL) to give solid product 3ca (248.1 mg, 67%) [eluent: petroleum ether / ethyl acetate = 50 / 1 (510 mL), 30 / 1 (310 mL)]

[0038] m.p. 76.4-77.2 °C (ethyl acetate); 1 H NMR (400 MHz, CDC13) δ = 7.58 (d, J = 8.4 Hz, 2H, ArH), 7.23 (d, J = 8.0 Hz, 2H, ArH), 7.19-7.09 (m, 4H, ArH), 7.00 (d, J = 7.2 Hz, 2H, ArH), 6.40 (s, 1H, CH), 5.92 (d, J = 15.6 Hz, 1H, CH), 5.05-4.95 (m, 1H, CH), 3.11 (s, 3H, CH3), 2.38 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.06-1.95 (m, 2H, CH2), 1.38-1.28 (m, 2H, CH2), 0.87 (t, J = 7.4 Hz, 3H, CH3); 13 C NMR (100 MHz, CDC13) δ 142.9, 137.7, 137.5, 134.7, 133.4, 130.1, 129.5, 129.2, 128.5, 28.48, 128.2, 127.5, 126.0, 36.4, 34.6, 22.1, 21.4, 21.3, 13.7; IR (neat, cm -1): v = 3028, 2957, 2922, 2870, 1597, 1493, 1456, 1342, 1152, 1086; MS (ESI) m / z (%): [C 22 H 28 NO2S] + ,370; HRMS calcd m / z for [C 22 H 28 O2NS] + : 370.1835, found 370.1829.

[0039] Example 3

[0040] The procedure was the same as Example 1, Step I, 1e (310.3 mg, 1.0 mmol), 2a (370.2 mg, 2.0 mmol), [Pd(allyl)Cl]2(18.4 mg, 0.05 mmol), rac-BINAP (74.9 mg, 0.12 mmol), K2CO3(276.2 mg, 2.0 mmol), MeCN (10 mL) to give solid product 3ea (288.8 mg, 77%) [eluent: petroleum ether / ethyl acetate = 30 / 1 (465 mL)].

[0041] m.p. 63.1-63.7 °C (petroleum ether); 1 H NMR (400 MHz, CDC13) δ = 7.60 (d, J = 8.0 Hz, 2H, ArH), 7.42 (q, J = 5.6 Hz, 2H, ArH), 7.19 (d, J = 8.0 Hz, 2H, ArH), 6.92 (t, J = 8.8 Hz, 2H, ArH), 6.39 (s, 1H, CH), 5.86 (d, J = 15.6 Hz, 1H, CH), 5.47-5.34 (m, 1H, CH), 3.11 (s, 3H, CH3), 2.41 (s, 3H, CH3), 1.98 (q, J = 7.2 Hz, 2H, CH2), 1.36-1.22 (m, 2H, CH2), 0.85 (t, J = 7.2 Hz, 3H, CH3); 13 C NMR (100 MHz, CDC13) δ 162.2 (d, J = 247.3 Hz), 143.2, 137.5, 137.3 (d, J = 1.6 Hz), 133.7, 131.1 (d, J = 3.2 Hz), 130.6 (d, J = 7.9 Hz), 129.3, 128.9, 128.0, 127.6, 115.3 (d, J = 21.3 Hz), 36.4, 34.6, 22.1, 21.4, 13.7; 19F NMR (376 MHz, CDC13) δ = -113.7; IR (neat, cm -1 ): v = 2957, 2930, 2872, 1641, 1597, 1506, 1456, 1346, 1229, 1153, 1088; MS (ESI) m / z (%): [C 21 H 25 FNO2S] + ,374;Anal.Calcd.for C 21 H 24 FNO2S:C 67.53,H 6.48;found C 67.42,H 6.20.

[0042] Example 4

[0043] The procedure was the same as Example 1, Step I, 1f (327.2 mg, 1.0 mmol), 2a (370.0 mg, 2.0 mmol), [Pd(allyl)Cl]2(18.2 mg, 0.05 mmol), rac-BINAP (74.9 mg, 0.12 mmol), K2CO3(276.0 mg, 2.0 mmol), MeCN (10 mL) to give solid product 3fa (268.8 mg, 69%) [eluent: petroleum ether / ethyl acetate = 40 / 1 (410 mL), 30 / 1 (310 mL)].

[0044] m.p. 88.1-89.0 °C (ethyl acetate); 1 H NMR (400 MHz, CDC13) δ = 7.56 (d, J = 8.0 Hz, 2H, ArH), 7.33 (d, J = 8.4 Hz, 2H, ArH), 7.20-7.13 (m, 4H, ArH), 6.37 (s, 1H, CH), 5.87 (d, J = 15.2 Hz, 1H, CH), 5.50-5.39 (m, 1H, CH), 3.11 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.03-1.91 (m, 2H, CH2), 1.36-1.22 (m, 2H, CH2), 0.85 (t, J = 7.4 Hz, 3H, CH3); 13 C NMR (100 MHz, CDC13) δ 143.2, 138.2, 137.4, 134.2, 133.4, 130.0, 129.2, 128.6, 128.4, 127.9, 127.4, 36.5, 34.5, 22.0, 21.4, 13.6; IR (neat, cm -1): v = 2955, 2924, 2872, 1639, 1597, 1489, 1335, 1155, 1088; MS (ESI) m / z (%): [C 21 H 25 35 ClO2NS] + ,390;Anal.Calcd.for C 21 H 24 ClNO2S:C 64.68,H 6.20;found C 64.31,H 6.09.

[0045] Example 5

[0046] The procedure was the same as Example 1, Step I, 1j (350.6 mg, 1.0 mmol), 2a (370.4 mg, 2.0 mmol), [Pd(allyl)Cl]2(18.4 mg, 0.05 mmol), rac-BINAP (74.9 mg, 0.12 mmol), K2CO3(276.5 mg, 2.0 mmol), MeCN (10 mL) to give liquid product 3ja (279.4 mg, 68%) [eluent: petroleum ether / ethyl acetate = 20 / 1 (315 mL), 10 / 1 (660 mL).

[0047] 1 H NMR (400 MHz, CDC13) δ = 7.90 (s, 1H, ArH), 7.83 (d, J = 8.0 Hz, 2H, ArH), 7.64 (d, J = 8.0 Hz, 1H, ArH), 7.51 (d, J = 8.4 Hz, 2H, ArH), 7.31 (t, J = 7.6 Hz, 1H, ArH), 7.08 (d, J = 8.0 Hz, 2H, ArH), 6.46 (s, 1H, CH), 5.94 (d, J = 15.6 Hz, 1H, CH), 5.68-5.54 (m, 1H, CH), 3.88 (s, 3H, CH3), 3.17 (s, 3H, CH3), 2.35 (s, 3H, CH3), 2.04 (q, J = 7.2 Hz, 2H, CH2), 1.40-1.28 (m, 2H, CH2), 0.88 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDC13) δ 166.7, 143.0, 138.8, 137.5, 135.2, 134.7, 132.8, 130.2, 130.1, 129.7, 129.1, 128.8, 128.5, 128.4, 128.0, 127.4, 52.0, 36.7, 34.6, 22.1, 21.4, 13.7; IR (neat, cm -1 ): v = 2953, 2925, 2870, 1716, 1596, 1435, 1338, 1281, 1153, 1111, 1087; MS (ESI) m / z (%): [C 23 H 28 NO4S] + ,414; HRMS calcd m / z for [C 23 H 28 NO4S] + : 414.1734, found 414.1725.

[0048] Example 6

[0049] The procedure was the same as Example 1, Step I of this invention, 1 m (326.4 mg, 1.0 mmol), 2a (370.5 mg, 2.0 mmol), [Pd(allyl)Cl]2(18.1 mg, 0.05 mmol), rac-BINAP (74.9 mg, 0.12 mmol), K2CO3(276.5 mg, 2.0 mmol), MeCN (10 mL) to give solid product 3ma (266.9 mg, 69%) [eluent: petroleum ether / ethyl acetate = 30 / 1 (465 mL)].

[0050] m.p. 111.4-112.1 °C (ethyl acetate); 1 H NMR (400 MHz, CDC13) δ = 7.59 (d, J = 8.0 Hz, 2H, ArH), 7.46-7.34 (m, 2H, ArH), 7.29-7.11 (m, 5H, ArH), 6.45 (s, 1H, CH), 5.97 (d, J = 15.6 Hz, 1H, CH), 5.48-5.34 (m, 1H, CH), 3.48 (t, J = 6.6 Hz, 2H, CH2), 3.11 (s, 3H, CH3), 2.39 (s, 3H, CH3), 2.23-2.11 (m, 2H, CH2), 1.80-1.68 (m, 2H, CH2); 13C NMR (100 MHz, CDC13) δ 143.1, 137.4, 137.2, 134.6, 131.1, 130.8, 129.6, 129.2, 128.9, 128.4, 127.9, 127.5, 44.1, 36.4, 31.6, 29.5, 21.4; IR (neat, cm -1 ): v = 2970, 2901, 1595, 1445, 1366, 1341 1287, 1229, 1150, 1086; MS (ESI) m / z (%): [C 21 H 25 35 ClO2NS] + ,390;Anal.Calcd.for C 21 H 24 ClNO2S:C 64.68,H 6.20;found C 64.82,H 6.15.

[0051] Example 7

[0052] The procedure was the same as Example 1, Step I, 1q (303.5 mg, 1.0 mmol), 2a (370.2 mg, 2.0 mmol), [Pd(allyl)Cl]2(18.1 mg, 0.05 mmol), rac-BINAP (74.5 mg, 0.12 mmol), K2CO3(276.0 mg, 2.0 mmol), MeCN (10 mL) to give solid product 3qa (229.7 mg, 63%) [eluent: petroleum ether / ethyl acetate = 10 / 1 (330 mL), 3 / 1 (400 mL), 2 / 1 (300 mL)].

[0053] m.p. 111.1-112.1 °C (ethyl acetate); 1 H NMR (400 MHz, CDC13) δ = 7.58 (d, J = 8.4 Hz, 2H, ArH), 7.43-7.33 (m, 2H, ArH), 7.25-7.12 (m, 5H, ArH), 6.51 (s, 1H, CH), 6.08 (d, J = 15.6 Hz, 1H, CH), 5.52-5.39 (m, 1H, CH), 3.12 (s, 3H, CH3), 2.50-2.27 (m, 7H, 2 x CH2 with CH3); 13C NMR (100 MHz, CDC13) δ 143.3, 137.3, 136.6, 134.3, 132.3, 131.4, 129.3, 129.0, 128.4, 128.2, 127.8, 127.6, 118.9, 36.4, 28.2, 21.4, 17.1; IR (neat, cm -1 ): v = 3053, 3025, 2927, 2359, 2342, 2246, 1596, 1491, 1423, 1337, 1149; MS (ESI) m / z (%): [C 21 H 23 N2O2S] + ,367; Anal. Calcd. for C 21 H 22 N2O2S: C 68.83, H 6.05; found C 68.80, H 6.03.

[0054] Example 8

[0055] The procedure was the same as Example 1, Step I of this invention, 1a (292.4 mg, 1.0 mmol), 2b (343.1 mg, 2.0 mmol), [Pd(cinnamyl)Cl]2(25.7 mg, 0.05 mmol), rac-BINAP (74.8 mg, 0.12 mmol), K2CO3(276.9 mg, 2.0 mmol), MeCN (10 mL) to give solid product 3ab (229.4 mg, 67%) [eluent: petroleum ether / ethyl acetate = 50 / 1 (510 mL), 30 / 1 (465 mL)].

[0056] m.p. 76.2-77.3 °C; 1 H NMR (400 MHz, CDC13) δ = 7.78-7.69 (m, 2H, ArH), 7.51 (t, J = 1.2 Hz, 1H, ArH), 7.46-7.40 (m, 2H, ArH), 7.38 (t, J = 7.6 Hz, 2H, ArH), 7.27-7.15 (m, 3H, ArH), 6.44 (s, 1H, CH), 5.90 (d, J = 15.6 Hz, 1H, CH), 5.45-5.35 (m, 1H, CH), 3.13 (s, 3H, CH3), 1.97 (q, J = 7.2 Hz, 2H, CH2), 1.35-1.23 (m, 2H, CH2), 0.85 (t, J = 7.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDC13) δ 140.4, 137.4, 134.7, 133.6, 132.3, 130.2, 128.8, 128.6, 128.4, 128.2, 127.9, 127.5, 36.5, 34.5, 22.0, 13.7; IR (neat, cm -1 ): v = 2963, 2919, 2873, 2855, 1639, 1444, 1343, 1151, 1088; MS (ESI) m / z (%): [C 20 H 24 NO2S] + ,342;Anal.Calcd.for C 20 H 23 NO2S:C 70.35,H 6.79;found C 70.31,H 6.78.

[0057] Example 9

[0058] The reaction was carried out as in Example 1, Step I, 1a (292.0 mg, 1.0 mmol), 2c (218.3 mg, 2.0 mmol), [Pd(cinnamyl)Cl]2(25.8 mg, 0.05 mmol), rac-BINAP (74.9 mg, 0.12 mmol), K2CO3(276.5 mg, 2.0 mmol), MeCN (10 mL) to give solid product 3ac (142.3 mg, 51%) [eluent: petroleum ether / ethyl acetate = 30 / 1 (930 mL)].

[0059] m.p. 69.1-69.8 °C; 1 H NMR (400 MHz, CDC13) δ = 7.44 (d, J = 7.2 Hz, 2H, ArH), 7.35 (t, J = 7.2 Hz, 2H, ArH), 7.26 (t, J = 7.6 Hz, 2H, ArH), 6.51 (s, 1H, CH), 6.08 (d, J = 7.6 Hz, 1H, CH), 6.02-5.92 (m, 1H, CH), 3.15 (s, 3H, CH3), 2.61 (s, 3H, CH3), 2.18 (q, J = 7.2 Hz, 2H, CH2), 1.55-1.42 (m, 2H, CH2), 0.95 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDC13) δ = 138.0, 135.2, 133.9, 130.0, 128.7, 128.5, 128.3, 128.0, 40.1, 36.8, 34.6, 22.3, 13.7; IR (neat, cm -1 ): v = 2956, 2929, 2868, 1618, 1447, 1333, 1320, 1134; MS (ESI) m / z (%): [C 15 H 22 NO2S] + ,280;Anal. Calcd. for C 15 H 21 NO2S:C 64.48, H 7.58; found C 64.37, H 7.53.

[0060] Example 10

[0061] Procedure as Example 1, Step I, 1a (293.7 mg, 1.0 mmol), 2d (582.6 mg, 2.0 mmol), [Pd(cinnamyl)Cl]2(25.8 mg, 0.05 mmol), rac-BINAP (74.9 mg, 0.12 mmol), K2CO3(276.5 mg, 2.0 mmol), MeCN (10 mL) gave liquid product 3ad (339.8 mg, 85%) [eluent: petroleum ether / ethyl acetate = 50 / 1 (510 mL), 40 / 1 (410 mL)].

[0062] 1 H NMR (400 MHz, CDC13) δ = 7.70 (d, J = 8.4 Hz, 2H, ArH), 7.61 (d, J = 7.2 Hz, 2H, ArH), 7.30-7.18 (m, 6H, ArH), 6.53 (s, 1H, CH), 5.78 (d, J = 15.2 Hz, 1H, CH), 5.46-5.33 (m, 1H, CH), 3.45-3.31 (m, 2H, CH2), 2.41 (s, 3H, CH3), 1.94 (q, J = 7.2 Hz, 2H, CH2), 1.55-1.45 (m, 2H, CH2), 1.27 (q, J = 7.6 Hz, 2H, CH2), 1.23-1.14 (m, 2H, CH2), 0.84 (t, J = 7.2 Hz, 3H, CH3), 0.80 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDC13) δ 143.1, 137.8, 135.2, 134.8, 133.7, 131.0, 129.4, 129.3, 129.1, 128.2, 127.93, 127.88, 49.2, 34.6, 30.4, 22.1, 21.4, 20.2, 13.7, 13.6; IR (neat, cm -1 ): v = 3028, 2958, 2931, 2872, 1737, 1598, 1494, 1344, 1160, 1088; MS (ESI) m / z (%): [C 24 H 32 NO2S] + ,398;Anal. Calcd. for C 24 H 31 NO2S:C 72.51, H 7.86; found C 72.44, H 7.78.

[0063] Example 11

[0064] The reaction was carried out as in Example 1, Step I, 1a (58.9 mg, 0.2 mmol), 2e (158.4 mg, 0.4 mmol), [Pd((cinnamyl)Cl]2(5.2 mg, 0.01 mmol), rac-BINAP (14.9 mg, 0.024 mmol), K2CO3(55.6 mg, 2.0 mmol), MeCN (2 mL) to give liquid product 3ae (68.5 mg, 60%) [eluent: petroleum ether / ethyl acetate = 10 / 1 (440 mL)].

[0065] 1 H NMR (400 MHz, CDC13) δ = 7.64 (d, J = 8.8 Hz, 2H, ArH), 7.37 (d, J = 7.37 Hz, 2H, ArH), 7.31 (d, J = 8.4 Hz, 2H, ArH), 7.25-7.14 (m, 5H, ArH), 7.09 (d, J = 8.0 Hz, 2H, ArH), 6.73 (s, 1H, CH), 6.46 (s, 1H, CH), 5.90 (d, J = 15.6 Hz, 1H, CH), 5.60-5.50 (m, 1H, CH), 3.11 (s, 3H, CH3), 2.37 (s, 3H, CH3), 2.02 (q, J = 7.2 Hz, 2H, CH2), 1.39-1.29 (m, 2H, CH2), 0.88 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100MHz, CDCl3) δ145.1, 143.9 (q, J = 38.7Hz), 142.3, 139.6 (d, J = 3.2Hz), 137.3, 134.6, 133.8, 130.3, 129.7,128.7,128.6,128.57,128.5,128.1,125.7,125.0,106.2,36.6,34.5,22.2,21.2,13.6;IR(neat,cm -1 ):ν=2957,2929,2871,1596,1471,1235,1156,1132; MS(ESI)m / z(%):[C 31 H 30 O2N3F3S] + ,566; HRMS calcd m / z for C 31 H 31 O2N3F3S[M + ]:566.2084,found 566.2080.

[0066] The scope of protection of this invention is not limited to the above embodiments. Any variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of this invention are included in this invention and are protected by the appended claims.

Claims

1. A method for the palladium-catalyzed coupling of secondary propargylic phenyl carboxylate esters with sulfonamides to produce dienamines, characterized in that, In an organic solvent, a secondary propargyl alcohol benzoate and a sulfonamide are used as raw materials, a palladium salt is used as a catalyst, an organic phosphine is used as a ligand, and the secondary propargyl alcohol benzoate and the sulfonamide are directly converted into a 2-aminosubstituted conjugated diene compound under the action of a base, and the reaction process is shown in the following reaction formula (1): wherein R 1 is alkyl, alkyl with functional groups; R 2 is alkyl, alkyl with functional groups, phenyl, aryl or heterocyclic group; R 3 is alkyl, alkyl with functional groups, aryl; Ar is aryl; The functional group in the functional group-containing alkyl group is halogen, alkenyl, cyano, siloxy; The aryl group is a phenyl group with an electron-donating group or an electron-withdrawing substituent at the ortho, meta, or para position; The heterocyclic group is pyrazole, isoxazole.

2. The method of claim 1, wherein, R is C1-C10 alkyl, C1-C10 alkyl with functional groups; R 1 is C1-C10 alkyl, C1-C10 alkyl with functional groups; R 2 is C1-C10 alkyl, C1-C10 alkyl with functional groups, phenyl, aryl; R 3 is C1-C10 alkyl, C1-C10 alkyl with functional groups, aryl; Ar is aryl; The functional group in the functional group-containing alkyl group is halogen, alkenyl, cyano, siloxy; The aryl group is a phenyl group with an electron-donating group or an electron-withdrawing substituent at the ortho, meta, or para position; The heterocyclic group is pyrazole, isoxazole.

3. The method of claim 1, wherein, The R 1 Ethyl, propyl, butyl; R 2 Methyl, phenyl, p-tolyl; R 3 Ar is methyl or butyl; Ar is aryl. The functional group in the functional group-containing alkyl group is halogen, alkenyl, cyano, siloxy; The aryl group is a phenyl group with an electron-donating group or an electron-withdrawing substituent at the ortho, meta, or para position; wherein the electron-donating group is methyl, methoxy, amino; the electron-withdrawing group is halogen, ester group, phenyl; The heterocyclic group is pyrazole, isoxazole.

4. The method of claim 1, wherein, The palladium catalyst is selected from one or a mixture of two or more of bis(allylchloropalladium), tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, bis(cinnamylchloropalladium), bis(dibenzylideneacetone)palladium, palladium chloride, palladium acetate, bis(triphenylphosphine)palladium chloride, bis(acetonitrile)palladium chloride.

5. The method of claim 1, wherein, The phosphine ligand is selected from one or a mixture of 1,1'-binaphthalene-2,2'-bisdiphenylphosphine and 2,2'-bis(diphenylphosphino)binaphthalene.

6. The method of claim 1, wherein, The base is selected from one or a mixture of two or more of potassium carbonate, cesium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 4-dimethylaminopyridine.

7. The method of claim 1, wherein, The organic solvent is selected from one or a mixture of two or more of acetonitrile, tetrahydrofuran, dichloromethane, toluene.

8. The method of claim 1, wherein, The molar ratio of the raw materials secondary propargyl alcohol benzoate, sulfonamide, palladium catalyst, phosphine ligand, base is 1.0:(1.0-3.0):(0.05-0.15):(0.05-0.30):(1.0-3.0).

9. The method of claim 1, wherein, The temperature of the reaction is 10-50 degrees Celsius.

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