Application of PNP type Pincer manganese catalyst in catalysis of synthesis of thiophene substituted ketone derivatives

Abstract

The invention belongs to the field of synthetic chemistry, and particularly relates to application of a PNP type Pincer manganese catalyst in catalysis of synthesis of thiophene substituted ketone derivatives. The PNP type Pincer manganese catalyst can be used for catalyzing the synthesis of thiophene substituted ketone derivatives; the PNP type Pincer manganese catalyst is PNP (iPr)-Mn (CO) 2Br, PNP (Cy)-Mn (CO) 2Br or PNP (Ph)-Mn (CO) 2Br. The preparation method of the thiophene substituted ketone derivative comprises the following steps: taking 2-thiophenemethanol and a carbonyl-containing compound as reaction raw materials, adding alkali and a PNP type Pincer manganese catalyst, and carrying out dehydrogenation coupling reaction to obtain the thiophene substituted ketone derivative. The synthesis of the thiophene substituted ketone derivative is catalyzed by the PNP type Pincer manganese catalyst, and the catalyst has the advantages of wide substrate applicability, high reaction efficiency and the like; the PNP type Pincer manganese catalyst is adopted to catalyze the synthesis of the thiophene substituted ketone derivative, so that the method has the advantages of low cost, good biocompatibility, wide raw material source, good atom economy and the like.

Description

Technical Field

[0001] The invention belongs to the field of synthetic chemistry, and particularly relates to application of a PNP type Pincer manganese catalyst in catalyzing the synthesis of thiophene substituted ketone derivatives. Background Art

[0002] Thiophene derivatives are common natural ingredients that are widely found in various foods, including coffee, beef, pork, shrimp, papaya and whiskey, and play a dominant role in the overall flavor impression of foods. Thiophene compounds are added to foods as flavor ingredients at low dosages and low usage levels, usually imparting strong nutty, earthy, meaty and grassy characteristic aromas, such as burnt caramel, roasted coffee and roasted. They also have the potential to play an important role in flavor chemistry and the preparation of various flavors. Ketone odorants and flavors occupy an important position in the flavor industry, with ketone compounds accounting for more than 15% of flavor compounds. Low-order aliphatic ketones can be used in synthetic flavors, and odd-numbered methyl ketones C7, C9 and C11 have a unique nutty aroma. Terpenes, aromatic ketones and alicyclic ketones are commercially important flavor and fragrance compounds. Thioketone compounds usually have a strong aromatic odor. Despite the importance of thioketones and thiophenes in flavor and fragrance applications and industry, there are limited reports on thiophenone flavor compounds.

[0003] The traditional method for synthesizing thiophenones is the Friedel–Crafts reaction of thiophene with anhydrides, acyl halides or carboxylic acids. In fact, thiophenones can also be prepared by Cu-catalyzed aldol condensation chemistry. However, the traditional synthesis method has the disadvantages of using halogenated substrates that are harmful to the environment and hazardous chemicals that produce waste. At present, there are few reports on catalytic systems (especially manganese-based catalytic systems) for synthesizing thiophene-substituted ketones using 2-thiophene methanol as a starting material. Direct use of alcohols as cheap and green reagents plays a vital role in the construction of CC bonds. Forming CC bonds through hydrogen borrowing reactions is a powerful strategy for synthesizing ketones. Some noble metal-based catalysts such as Pd, Ir, Os, Rh and Ru have been developed for this reaction, but the catalysts reported in the prior art have problems such as high cost and difficulty in obtaining. Summary of the invention

[0004] In order to solve the shortcomings and deficiencies of the prior art, the object of the present invention is to provide an application of a PNP-type Pincer manganese catalyst in catalyzing the synthesis of thiophene-substituted ketone derivatives. The PNP-type Pincer manganese catalyst can be used to catalyze the dehydrogenation coupling reaction of 2-thiophene methanol and a carbonyl-containing compound to generate thiophene-substituted ketone derivatives, which can reduce the cost of the reaction and improve the efficiency of the reaction.

[0005] In order to achieve the above object, the present invention adopts the following technical solution:

[0006] Application of a PNP-type Pincer manganese catalyst in catalyzing the synthesis of thiophene-substituted ketone derivatives. The PNP-type Pincer manganese catalyst can be used to catalyze the dehydrogenation coupling reaction of 2-thiophene methanol and a carbonyl-containing compound to generate thiophene-substituted ketone derivatives; the PNP-type Pincer manganese catalyst is PNP( i Pr)-Mn(CO)2Br, PNP(Cy)-Mn(CO)2Br or PNP(Ph)-Mn(CO)2Br; the PNP( i The structural formula of Pr)-Mn(CO)2Br is shown in Formula I; the structural formula of PNP(Cy)-Mn(CO)2Br is shown in Formula II; the structural formula of PNP(Ph)-Mn(CO)2Br is shown in Formula III;

[0007]

[0008] Furthermore, the preparation method of the thiophene substituted ketone derivative comprises the following steps:

[0009] 2-thiophene methanol and a carbonyl-containing compound are used as reaction raw materials, a base and a PNP-type Pincer manganese catalyst are added, and a dehydrogenation coupling reaction is carried out to obtain a thiophene substituted ketone derivative; the carbonyl-containing compound is a compound represented by formula IV or a compound represented by formula VI;

[0010] When the carbonyl-containing compound is a compound of formula IV, a thiophene-substituted ketone derivative of formula V is obtained, and the reaction route is shown in formula (1);

[0011]

[0012] In formula (1), R 1 is an alkyl group, an aryl group or a substituted aryl group; the substituent of the substituted aryl group is an alkyl group or a hydroxyl group.

[0013] When the carbonyl-containing compound is a compound represented by formula VI, a thiophene-substituted ketone derivative represented by formula VII is obtained, and the reaction route is shown in formula (2);

[0014]

[0015] In formula (2), R 2 When R is an alkyl group, an aryl group, a substituted aryl group or a heteroaryl group, 3 is alkyl, hydrogen; or, R 2 and R 3 Formation of cyclic alkanes.

[0016] Furthermore, the substituent of the substituted aryl group is an alkyl group or a hydroxyl group.

[0017] Furthermore, the PNP(i The preparation method of Pr)-Mn(CO)2Br comprises the following steps: using Mn(CO)5Br and PNP- i Pr is the reaction raw material, toluene is added, and the reaction is carried out under heating conditions to obtain the PNP ( i Pr)-Mn(CO)2Br; the PNP- i The structural formula of Pr is shown in Formula VIII, and the PNP ( i The structural formula of Pr)-Mn(CO)2Br is shown in Formula IX; the reaction route is shown in Formula (2):

[0018]

[0019] Furthermore, the Mn(CO)5Br, PNP- i The molar volume ratio of Pr and toluene is 0.44mmol:0.48mmol:10.00mL; the reaction temperature is 110°C and the reaction time is 4h; after the reaction is completed, the reaction solution is filtered and dried to obtain the PNP ( i Pr)-Mn(CO)2Br.

[0020] Furthermore, the temperature of the dehydrogenation coupling reaction is 140-165°C.

[0021] Furthermore, the dehydrogenation coupling reaction is carried out under inert gas conditions.

[0022] Further, the reaction time at 140-165° C. is at least 6 hours;

[0023] Preferably, the reaction time is 16 h.

[0024] Furthermore, the base is at least one of an alkali metal hydroxide, an alkali metal alkoxide and an alkali metal carbonate.

[0025] Furthermore, the alkali metal hydroxide is at least one of sodium hydroxide and potassium hydroxide; the alkali metal alkoxide is sodium ethoxide (EtONa) and potassium tert-butoxide ( t The alkali metal carbonate is at least one of potassium carbonate (K2CO3), sodium carbonate (Na2CO3) and cesium carbonate (Cs2CO3).

[0026] Furthermore, the organic solvent is at least one of dioxane, toluene and tetrahydrofuran (THF).

[0027] Further, the molar volume ratio of the 2-thiophene methanol, the carbonyl compound, the base, the catalyst and the organic solvent is 0.5000mmol:(0.5000-1.0000)mmol:(0.00625-0.0375)mmol:0.0050mmol:(0.5000-0.6000)mL;

[0028] Preferably, the molar volume ratio of the 2-thiophene methanol, the carbonyl compound, the base, the catalyst and the organic solvent is 0.5000mmol:1.0000mmol:0.0375mmol:0.0050mmol:0.5000mL.

[0029] Furthermore, the structural formula of the carbonyl-containing compound is any one of the following:

[0030]

[0031] Furthermore, after the reaction is completed, the reaction solution needs to be separated by column chromatography.

[0032] Beneficial Effects

[0033] The invention provides an application of a PNP-type Pincer manganese catalyst in catalyzing the dehydrogenation coupling reaction of 2-thiophene methanol and a carbonyl-containing compound to generate thiophene-substituted ketone derivatives; the invention uses the PNP-type Pincer manganese catalyst to catalyze the synthesis of thiophene-substituted ketone derivatives, and the catalyst has the advantages of wide substrate applicability and high reaction efficiency; the synthesis of thiophene-substituted ketone derivatives catalyzed by the PNP-type Pincer manganese catalyst has the advantage of high yield, and the yield of the thiophene-substituted ketone derivatives can be as high as 99%; the synthesis method has the advantages of low cost, good biocompatibility, wide raw material sources and good atom economy. DETAILED DESCRIPTION

[0034] The following description further describes the specific details of the present invention for a full understanding of the present invention. The terms used in the description of the present invention are only used to illustrate the advantages and features of the present invention and are not intended to limit the present invention.

[0035] Unless otherwise defined, all professional and scientific terms used in the present invention have the same meanings as those understood by those skilled in the art of the present invention. Unless otherwise specified, the drugs or reagents used in the present invention are used in accordance with the product instructions or in the conventional methods of use in the relevant field. The process of the present invention is further described based on the instructions and specific embodiments.

[0036] The technical solution of the present invention is further described below in conjunction with specific implementation methods.

[0037] The structures of catalysts [Mn]-1, [Mn]-2 and [Mn]-3 used in the following examples and comparative examples are as follows:

[0038]

[0039] Wherein, the catalyst [Mn]-1 (PNP(Ph)-Mn(CO)2Br catalyst) is prepared by a method comprising the following steps:

[0040] Under argon atmosphere, Mn(CO)5Br (0.44 mmol), PNP- i Pr (0.48 mmol) and degassed toluene (10 mL), the reaction was heated to 110 ° C and stirred for 4 hours. After the reaction was completed, the residue was filtered out, the toluene was dried, 10 mL of degassed n-hexane was added, argon was filtered, and the filter cake was vacuum dried to obtain a light yellow solid (70%). The reaction formula involved is as follows:

[0041]

[0042] NMR: 1 H NMR (400MHz, C6D6) δ3.27(d,J=6.9Hz,2H),2.79(s,1H),2.43(d,J=13.3Hz,2H),2.21(d,J=7.3Hz,2H),1.98–1.84(m,2H),1.64(s,2H) ,1.51(dd,J=15.1,7.3Hz,6H),1.31(dd,J=13.9,6.9Hz,6H),1.21(dd,J=13.1,7.1Hz,6H),1.06(dd,J=10.9,6.9Hz,6H),0.85(s,2H), 13 C NMR (101MHz, C6D6) δ52.33, 26.77 (t, J = 9.3Hz), 25.78 (t, J = 9.3Hz), 24.10 (d, J = 9.5Hz), 19.88 (d, J = 16.5Hz), 18.51, 18.05. 31 P NMR (162MHz, C6D6) δ81.23(s).

[0043] High resolution: HR-MS (ESI) called for C 18 H 37 MnNO2P2[M] + :416.1674; found:416.1675.

[0044] Infrared: 3180, 2915, 2870, 1901, 1809, 1458, 1367, 1251, 1054, 956, 827, 653, 626, 599cm -1 .

[0045] The catalysts [Mn]-2 and [Mn]-3 used were synthesized according to the methods in references (Chem. Sci. 2017, 8, 3576; J. Am. Chem. Soc. 2017, 139, 11941; Angew. Chem. Int. Ed. 2018, 57, 13439.).

[0046] The reaction schemes of the following embodiments are:

[0047]

[0048] In formula (1), R 1 is an alkyl group, an aryl group or a substituted aryl group; the substituent of the substituted aryl group is an alkyl group or a hydroxyl group;

[0049] Or:

[0050]

[0051] In formula (2), R 2 is alkyl, aryl, substituted aryl or heteroaryl; R 3 is alkyl, hydrogen; or, R 2 and R 3 To form a cyclic alkane; the substituent of the substituted aryl group is an alkyl group or a hydroxyl group.

[0052] Example 1

[0053] In a glove box, add 2-thiophene methanol (57 mg, 0.5 mmol), compound a (112.2 mg, 1 mmol), cesium carbonate (12.2 mg, 0.0375 mmol), catalyst [Mn]-1 (2.5 mg, 0.005 mmol) and toluene (0.5 mL) to a 15 mL pressure tube with a stirrer. Tighten the bottle cap, put the pressure tube into the metal module and react for 16 hours at 165 ° C. After the reaction is completed, cool in an ice water bath, carefully open the bottle cap, and separate and purify the reaction product by column chromatography to obtain the product with a yield of 99%.

[0054] The structural formula of compound a is:

[0055]

[0056] The structural formula of the product is:

[0057]

[0058] The results of the NMR test are: 1 H NMR (400MHz, CDCl3) δ7.04 (dd, J=5.1, 1.2Hz, 1H), 6.83 (dd, J=5.1, 3.4Hz, 1H), 6.7 2(d,J=3.4Hz,1H),3.05(t,J=7.4Hz,2H),2.76(t,J=7.4Hz,3H),1.74–1.48(m,8H). 13 C NMR(101MHz, CDCl3)δ211.75,144.05,126.81,124.56,123.30,51.54,43.49,28.80,26.00,23.99.HRMS(EI)calcd.for C 12 H 16 OS[M]:208.0922; found:208.0924.

[0059] Example 2

[0060] In a glove box, add 2-thiophene methanol (0.5 mmol), compound b (0.5 mmol), cesium carbonate (12.2 mg, 0.0375 mmol), catalyst [Mn]-1 (2.5 mg, 0.005 mmol) and toluene (0.5 mL) in sequence to a 15 mL pressure tube with a stirrer. Tighten the bottle cap, put the pressure tube into a metal module and react for 16 hours at 165 ° C. After the reaction is completed, cool in an ice water bath, carefully open the bottle cap, and separate and purify the reaction product by column chromatography to obtain the product with a yield of 69%.

[0061] Embodiment 3-8

[0062] Based on Example 2, compound ch was used to replace compound b, and the other steps were the same as Example 2. The products and yields of compound bh used in Example 2-8 are shown in the following table

[0063]

[0064] The nuclear magnetic resonance detection results of the products of Example 2-8 are:

[0065] Example 2 1H NMR (400MHz, CDCl3) δ7.04(dd,J=5.1,1.2Hz,1H),6.83(dd,J=5.1,3.4Hz,1H),6.74–6.69(m,1H),3.04(t ,J=7.5Hz,2H),2.71(t,J=7.4Hz,2H),2.31(t,J=7.3Hz,2H),1.54(q,J=7.4Hz,2H),0.83(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ209.60,143.85,126.82,124.57,123.33,44.95,44.36,23.89,17.23,13.74.

[0066] Example 3 1 H NMR (400MHz, CDCl3) δ7.03 (dd, J=5.1, 1.2Hz, 1H), 6.83 (dd, J=5.1, 3.5Hz, 1H), 6.72 (dt, J=3.4,1.1Hz,1H),3.09–2.98(m,2H),2.71(t,J=7.4Hz,2H),2.33(t,J=7.4Hz,2H),1.53–

[0067] 1.43(m,2H),1.27–1.21(m,2H),0.83(d,J=7.2Hz,3H). 13 C NMR(101MHz, CDCl3)δ209.80,143.85,126.84,124.58,123.34,44.34,42.79,25.88,23.91,22.34,13.89.HRMS(EI)calcd.for C 11 H 16 OS[M]:

[0068] 196.0922; found:196.0919.

[0069] Example 4 1 H NMR (400MHz, CDCl3) δ7.03 (dd, J=5.1, 1.2Hz,

[0070] 1H NMR (400 MHz, CDCl3) δ 7.03 (dd, J = 5.2, 1.2 Hz, 1H), 6.83 (dd, J = 5.1, 3.4 Hz, 1H), 6.74–6.70 (m, 1H), 3.04 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.4 Hz, 2H), 2.21 (d, J = 6.9 Hz, 2H), 2.07 (dt, J = 13.5, 6.7 Hz, 1H), 0.83 (d, J = 6.6 Hz, 6H). 13 13C NMR (101 MHz, CDCl3) δ 209.29, 143.85, 126.81, 124.58, 123.32, 52.03, 44.88, 24.62, 23.83, 22.58. HRMS (EI) calcd. for C 11 H 16 OS [M]: 196.0922; found: 196.0919.

[0071] Example 5 1 1H NMR (400 MHz, CDCl3) δ 7.03 (dd, J = 5.2, 1.2 Hz,

[0072] 1H), 6.82 (dd, J = 5.1, 3.4 Hz, 1H), 6.75–6.69 (m, 1H), 3.03 (t, J = 7.4 Hz, 2H), 2.74 (td, J = 7.2, 3.1 Hz, 2H), 2.37 (d, J = 6.9 Hz, 1H), 1.59 (dd, J = 14.0, 7.0 Hz, 1H), 1.31 (dt, J = 14.1, 7.1 Hz, 1H), 0.98 (d, J = 6.9 Hz, 3H), 0.78 (t, J = 7.4 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 213.11,

[0073] 143.99, 126.79, 124.59, 123.29, 48.01, 42.87, 25.87, 23.85, 15.76, 11.65. HRMS (EI) calcd. for C 11 H 16 OS [M]: 196.0922; found: 196.0919.

[0074] Example 6 11H NMR (400 MHz, CDCl3) δ 7.03 (d, J = 5.1 Hz, 1H), 6.83 (dd, J = 5.1, 3.5 Hz, 1H), 6.72 (d, J = 3.4 Hz, 1H), 3.04 (t, J = 7.4 Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 2.36–2.28 (m, 2H), 1.46 (dd, J = 13.1, 6.5 Hz, 1H), 1.43–1.37 (m, 2H), 0.80 (d, J = 6.3 Hz, 6H). 13 13C NMR (101 MHz, CDCl3) δ 209.84, 143.84, 126.83, 124.58, 123.33, 44.32, 41.10, 32.56, 27.69, 23.95, 22.34. HRMS (EI) calcd. for C 12 H 18 OS [M]: 210.1078; found: 210.1075.

[0075] Example 7 1 1H NMR (400 MHz, CDCl3) δ 7.93–7.82 (m, 2H), 7.50–7.43 (m, 1H), 7.36 (dd, J = 8.4, 6.9 Hz, 2H), 7.03 (dd, J = 5.1, 1.3 Hz, 1H), 6.83 (dd, J = 5.2, 3.4 Hz, 1H), 6.77 (dd, J = 3.3, 1.3 Hz, 1H), 3.32–3.24 (m, 2H), 3.23–3.15 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ 198.66, 143.93, 136.73, 133.25, 128.69, 128.08, 126.91, 124.74, 123.45, 40.58, 24.21.

[0076] Example 8 1 1H NMR (400 MHz, CDCl3) δ 12.24 (s, 1H), 7.81–7.69 (m, 1H), 7.51–7.41 (m, 1H), 7.14 (d, J = 5.1 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.95–6.83 (m, 3H), 3.39 (t, J = 7.3 Hz, 2H), 3.29 (t, J = 7.2 Hz, 2H). 13C NMR (101MHz, CDCl3) δ204.68,162.44,143.31,136.51,129.82,126.98,124.90,123.64,119.27,119.05,118.61,40.15,24.02.

[0077] Example 9

[0078] In a glove box, add 2-thiophene methanol (0.5 mmol), compound i (0.5 mmol), cesium carbonate (12.2 mg, 0.0375 mmol), catalyst [Mn]-1 (2.5 mg, 0.005 mmol) and toluene (0.5 mL) to a 15 mL pressure tube with a stirrer. Tighten the bottle cap, put the pressure tube into the metal module and react for 16 hours at 165 ° C. After the reaction is completed, cool in an ice water bath, carefully open the bottle cap, and separate and purify the reaction product by column chromatography to obtain the product with a yield of 73%.

[0079] Examples 10-23

[0080] On the basis of Example 9, Compound jw was used to replace Compound i, and the other steps were the same as Example 9. The compounds, products and yields used in Examples 9 to 23 are shown in the following table:

[0081]

[0082] The nuclear magnetic resonance detection results of the product of Example 9-23 are:

[0083] Example 9 1 H NMR (400MHz,CDCl3) 1 H NMR(400MHz,Chloroform-d)δ7.63(s,1H),7.46(d,J=5.1Hz,1H),7.25(d,J=3 .6Hz,1H),7.07(s,1H),3.46–3.32(m,1H),2.10(s,3H),1.09(d,J=7.0Hz,6H). 13 C NMR(101MHz, CDCl3)δ205.81,139.68,132.87,131.87,131.00,129.67,127.49,33.91,19.77,13.60.HRMS(EI)calcd.for C 11 H 14 OS[M]:194.0765; found:194.0761.

[0084] Example 101 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.42 (d, J = 5.1 Hz, 1H), 7.23–7.17 (m, 1H), 7.05 (d, J = 5.0 Hz, 1H), 3.46–3.25 (m, 1H), 2.69–2.52 (m, 2H), 1.39 (q, J = 7.9 Hz, 2H), 1.07 (d, J = 6.8 Hz, 6H), 0.95 (t, J = 7.5 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 205.94, 138.92, 138.12, 132.09, 130.53, 129.37, 127.35, 33.95, 29.30, 21.71, 19.73, 14.41. HRMS (EI) calcd. for C 13 H 18 OS [M]: 222.1078; found: 222.1082.

[0085] Example 11 1 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 5.1 Hz, 1H), 7.33 (dd, J = 3.7, 1.1 Hz, 1H), 7.15 (dd, J = 5.1, 3.7 Hz, 1H), 3.20–3.11 (m, 1H), 2.16 (d, J = 1.2 Hz, 3H), 1.86–1.77 (m, 4H), 1.53–1.15 (m, 6H). 13 13C NMR (101 MHz, CDCl3) δ 205.19, 139.69, 132.99, 131.88, 130.82, 129.66, 127.48, 44.42, 29.97, 25.96, 13.61. HRMS (EI) calcd. for C 14 H 18 OS [M]: 234.1078; found: 234.1076.

[0086] Example 12 1 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 5.1 Hz, 2H), 7.30 (s, 1H), 7.18 (d, J = 7.9 Hz, 2H), 7.14 (d, J = 3.7 Hz, 1H), 7.04 (dd, J = 5.1, 3.7 Hz, 1H), 2.35 (s, 3H), 2.25 (s, 3H). 13C NMR(101MHz, CDCl3)δ205.19,139.69,132.99,131.88,130.82,129.66,127.48,44.42,29.97,25.96,13.61.HRMS(EI)calcd.for C 15 H 14 OS[M]:242.0765; found:242.0768.

[0087] Embodiment 13 1 H NMR (400MHz, CDCl3) δ7.08–7.05(m,1H),6.85(dd,J=5.1,3.5Hz,1H),6.73(dd,J=3.3,1.2Hz,1H),3.24(dd,J=15.1,4 .1Hz,1H),2.78(dd,J=15.0,8.9Hz,1H),2.35-2.25(m,2H),2.22-2.11(m,1H),2.09-1.99(m,1H),1.95–1.85(m,1H). 13 C NMR (101MHz, CDCl3) δ205.77(s),152.01(s),144.18(s),132.78(s),125.23(s),114.98(s),112.33(s),33.81(s),19.74(s),13.42(s).

[0088] Embodiment 14 1 H NMR (400MHz, CDCl3) δ7.12(dd,J=5.2,1.2Hz,1H),6.91(dd,J=5.2,3.3Hz,1H),6.79(d,J=3.4Hz,1H),3.35(d,J=5.0Hz,1 H),2.78–2.66(m,1H),2.65–2.52(m,1H),2.48–2.29(m,2H),2.20–2.04(m,2H),1.65(dd,J=8.6,2.8Hz,2H),1.25(s,2H). 13 CNMR(101MHz, CDCl3)δ212.10,142.76,126.76,125.59,123.53,52.73,42.17,33.57,29.59,28.03,25.14.

[0089] Example 15a 11H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.37 (d, J = 5.1 Hz, 1H), 7.20 (d, J = 4.0 Hz, 1H), 7.01 (dd, J = 5.1, 3.7 Hz, 1H), 2.83–2.70 (m, 2H), 2.68–2.58 (m, 2H), 1.77–1.63 (m, 6H). 13 13C NMR (101 MHz, CDCl3) δ 204.90, 138.68, 137.87, 132.69, 128.71, 128.09, 127.39, 43.18, 31.25, 28.98, 28.61, 25.13. HRMS (EI) calcd. for C 12 H 14 OS [M]: 206.0765; found: 206.0767.

[0090] Example 15b 1 1H NMR (400 MHz, CDCl3) δ 7.04 (dd, J = 5.2, 1.2 Hz, 1H), 6.83 (dd, J = 5.2, 3.4 Hz, 1H), 6.70 (d, J = 3.4 Hz, 1H), 3.23–3.13 (m, 1H), 2.85–2.70 (m, 2H), 2.49–2.31 (m, 2H), 1.85–1.71 (m, 4H), 1.43–1.11 (m, 4H). 13 13C NMR (101 MHz, CDCl3) δ 215.06, 142.72, 126.77, 125.59, 123.55, 53.72, 43.50, 31.86, 30.74, 29.15, 29.00, 23.90. HRMS (EI) calcd. for C 12 H 16 OS [M]: 208.0922; found: 208.0919.

[0091] Example 16a 1 1H NMR (400 MHz, CDCl3) δ 7.19 (s, 1H), 7.09–7.00 (m, 1H), 6.84 (dd, J = 5.1, 3.4 Hz, 1H), 6.72 (d, J = 3.4 Hz, 1H), 2.87–2.69 (m, 1H), 2.20–1.99 (m, 2H), 1.49 (s, 2H), 1.18 (s, 2H), 0.89–0.82 (m, 3H). 13 13C NMR (101 MHz, CDCl3) 1313C NMR (101 MHz, Chloroform-d) δ 210.15, 155.72, 147.23, 141.90, 126.78, 125.42, 123.66, 47.02, 32.87, 31.22, 18.22, 11.97. HRMS (EI) calcd. for C 12 H 14 OS [M]: 206.0765; found: 206.0767.

[0092] Example 16b 1 1H NMR (400 MHz, CDCl3) 1 1H NMR δ 7.04 (d, J = 4.6 Hz, 1H), 6.83 (t, J = 4.3 Hz, 1H), 6.71 (d, J = 3.4 Hz, 1H), 3.19 (ddd, J = 43.8, 15.0, 4.1 Hz, 1H), 2.80 (dd, J = 15.0, 8.6 Hz, 1H), 2.31–2.05 (m, 2H), 2.02–1.68 (m, 2H), 1.64–1.11 (m, 4H), 0.85 (t, J = 7.5 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 214.91, 154.03, 141.12, 110.17, 106.37, 50.64, 43.26, 30.68, 30.06, 29.25, 28.90, 23.98. HRMS (EI) calcd. for C 12 H 16 OS [M]: 208.0922; found: 208.0919.

[0093] Example 17 1 1H NMR (400 MHz, CDCl3) δ 7.04 (d, J = 5.1 Hz, 1H), 6.83 (dd, J = 5.4, 3.1 Hz, 1H), 6.72 (d, J = 3.4 Hz, 1H), 3.21 (dd, J = 14.9, 4.1 Hz, 1H), 2.81 (dd, J = 15.0, 8.8 Hz, 1H), 2.41 (dd, J = 8.1, 3.4 Hz, 1H), 2.11–1.94 (m, 1H), 1.72–1.52 (m, 3H), 1.01 (s, 3H), 0.82 (s, 3H). 1313C NMR (101 MHz, CDCl3) δ 211.94, 154.12, 141.02, 110.20, 106.30, 49.79, 42.11, 33.71, 28.02, 27.81, 25.12. HRMS (EI) calcd. for C 12 H 16 OS [M]: 208.0922; found: 208.0919.

[0094] Example 18 1 1H NMR (400 MHz, Chloroform-d) δ 7.12 (dd, J = 5.1, 1.3 Hz, 1H), 6.92 (dd, J = 5.1, 3.4 Hz, 1H), 6.80 (dd, J = 3.4, 1.1 Hz, 1H), 6.67 (t, J = 1.3 Hz, 1H), 3.72 (dd, J = 6.1, 1.4 Hz, 2H), 2.45–2.36 (m, 3H), 2.08–2.01 (m, 1H), 1.78–1.69 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 201.43, 145.77, 142.37, 138.19, 126.87, 125.58, 123.79, 41.76, 31.01, 29.82, 25.39, 15.22. HRMS (EI) calcd. for C 12 H 14 OS [M]: 206.0765; found: 206.0767.

[0095] Example 19 1 1H NMR (400 MHz, CDCl3) δ 7.04 (d, J = 5.1 Hz, 1H), 6.84 (s, 1H), 6.72 (d, J = 3.4 Hz, 1H), 6.57 (s, 2H), 2.48–2.09 (m, 3H), 2.05–1.57 (m, 4H), 1.28 (dd, J = 13.1, 6.9 Hz, 4H), 0.84 (t, J = 6.8 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 201.10, 145.38, 142.44, 138.29, 126.84, 125.53, 123.77, 46.44, 31.37, 29.88, 27.82, 24.91, 20.20, 14.19. HRMS (EI) calcd. for C 14 H 20OS[M]:236.1235; found:236.1238.

[0096] Embodiment 20 1 H NMR (400MHz, CDCl3) δ7.07(dd,J=5.1,1.2Hz,1H),6.97(d,J=7.7Hz,1H),6.84(dd,J=5.1,3.4Hz,1H),6.7 6(dd,J=3.4,1.2Hz,1H),6.64(dd,J=7.7,1.6Hz,1H),4.66(s,1H),4.05(s,2H),2.21(s,3H),1.18(s,1H). 13 C NMR(101MHz, CDCl3)δ153.42,143.39,138.33,130.33,126.88,125.11,124.21,121.80,116.62,30.43,21.07.HRMS(EI)calcd.for C 12 H 12 OS[M]:204.0609; found:204.0613.

[0097] Embodiment 21 1 H NMR (400MHz, CDCl3) δ7.08–7.02(m,1H),6.89(d,J=2.2Hz,1H),6.86–6.80( m,2H),6.78–6.72(m,1H),6.60(d,J=8.1Hz,1H),4.04(s,3H),2.17(s,3H). 13 CNMR(101MHz,CDCl3)151.39,143.35,131.10,130.22,128.60,126.92,125.19,124.20,115.77,30.72,20.58.HRMS(EI)calcd.for C 12 H 12 OS[M]:204.0609; found:202.0455.

[0098] Embodiment 22 1 H NMR(400MHz, CDCl3)δ7.50(d,J=5.1Hz,1H),7.30(d,J=3.7Hz,1H),7.19–7.03(m,2H),5.99(ddd ,J=99.6,5.5,2.4Hz,2H),4.39–3.73(m,2H),2.86–2.71(m,1H),2.63–2.51(m,1H),1.25(s,1H).13 C NMR(101MHz, CDCl3)δ203.15,147.31,138.37,133.32,132.85,130.03,128.71,128.20,117.44,59.84,49.10,34.48.HRMS(EI)calcd.forC 12 H 10 OS[M]:202.0452; found:202.0455.

[0099] Embodiment 23 1 H NMR(400MHz, CDCl3)δ8.81(s,1H),8.17(d,J=7.7Hz,1H),7.86(s,1H),7.62–7.50(m,2H),7.20 –7.17(m,1H),7.13(dd,J=5.0,3.8Hz,1H),6.98(td,J=7.7,1.1Hz,1H),6.89(d,J=7.8Hz,1H). 13 C NMR (101MHz, CDCl3) δ170.98,141.36,137.86,134.82,130.77,129.65,128.79,128.19,123.75,121.97,121.59,110.24.

[0100] Embodiment 24

[0101] In a glove box, add 2-thiophene methanol (57 mg, 0.5 mmol), compound a (112.2 mg, 1 mmol), cesium carbonate (4.07 mg, 0.0125 mmol), catalyst [Mn]-1 (2.5 mg, 0.005 mmol) and toluene (0.5 mL) to a 15 mL pressure tube with a stirrer. Tighten the bottle cap, put the pressure tube into the metal module and react for 16 hours at 140 ° C. After the reaction is completed, cool in an ice water bath, carefully open the bottle cap, and separate and purify the reaction product by column chromatography to obtain the product with a yield of 60%.

[0102] Examples 25-26

[0103] On the basis of Example 24, the type of catalyst was changed. The catalyst used in Example 25 was [Mn]-2, and the catalyst used in Example 26 was [Mn]-3. The yields of the products of Example 25 and Example 26 were 56% and 58%, respectively.

[0104] Embodiment 27

[0105] In a glove box, add 2-thiophene methanol (57 mg, 0.5 mmol), compound a (112.2 mg, 1 mmol), cesium carbonate (4.07 mg, 0.0125 mmol), catalyst [Mn]-1 (2.5 mg, 0.005 mmol) and toluene (0.5 mL) to a 15 mL pressure tube with a stirrer. Tighten the bottle cap, put the pressure tube into the metal module and react for 16 hours at 165 ° C. After the reaction is completed, cool in an ice water bath, carefully open the bottle cap, and separate and purify the reaction product by column chromatography to obtain the product with a yield of 88%.

[0106] Embodiment 28

[0107] In a glove box, add 2-thiophene methanol (57 mg, 0.5 mmol), compound a (112.2 mg, 1 mmol), cesium carbonate (8.15 mg, 0.025 mmol), catalyst [Mn]-1 (2.5 mg, 0.005 mmol) and toluene (0.5 mL) to a 15 mL pressure tube with a stirrer. Tighten the bottle cap, put the pressure tube into the metal module and react for 16 hours at 165 ° C. After the reaction is completed, cool in an ice water bath, carefully open the bottle cap, and separate and purify the reaction product by column chromatography to obtain the product with a yield of 97%.

[0108] Embodiment 29

[0109] In a glove box, add 2-thiophene methanol (57 mg, 0.5 mmol), compound a (0.75 mmol), cesium carbonate (12.2 mg, 0.0375 mmol), catalyst [Mn]-1 (2.5 mg, 0.005 mmol) and toluene (0.5 mL) to a 15 mL pressure tube with a stirrer. Tighten the bottle cap, put the pressure tube into the metal module and react for 16 hours at 165 ° C. After the reaction is completed, cool in an ice water bath, carefully open the bottle cap, and separate and purify the reaction product by column chromatography to obtain the product with a yield of 96%.

[0110] Embodiment 30

[0111] In a glove box, add 2-thiophene methanol (57 mg, 0.5 mmol), compound a (0.5 mmol), cesium carbonate (12.2 mg, 0.0375 mmol), catalyst [Mn]-1 (2.5 mg, 0.005 mmol) and toluene (0.5 mL) to a 15 mL pressure tube with a stirrer. Tighten the bottle cap, put the pressure tube into the metal module and react for 16 hours at 165 ° C. After the reaction is completed, cool in an ice water bath, carefully open the bottle cap, and separate and purify the reaction product by column chromatography to obtain the product with a yield of 97%.

[0112] Comparative Example 1

[0113] In a glove box, 2-thiophene methanol (57 mg, 0.5 mmol), compound a (112.2 mg, 1 mmol) were added in sequence to a 15 mL pressure tube with a stirrer. t BuOK (1.4 mg, 0.0125 mmol), catalyst [Mn]-1 (2.5 mg, 0.005 mmol) and toluene (0.5 mL). Tighten the bottle cap, put the pressure tube into the metal module and react for 16 hours at 140°C. After the reaction, cool in an ice water bath, carefully open the bottle cap, and separate and purify the reaction product by column chromatography, but no product was obtained.

[0114] Comparative Examples 2-5

[0115] The base was replaced on the basis of Comparative Example 1. The bases used in Comparative Examples 2-4 were Na2CO3, EtONa and K2CO3 respectively. No base was added in Example 5. The other steps were the same as those in Comparative Example 1. No product was obtained in Comparative Examples 2-5.

[0116] Comparative Example 6

[0117] On the basis of Comparative Example 1, the base was replaced with the same molar amount of Cs2CO3, the organic solvent was replaced with dioxane, and the other steps were the same as those in Comparative Example 1, and no product was obtained.

[0118] Comparative Example 7

[0119] On the basis of Comparative Example 1, the base was replaced with the same molar amount of Cs2CO3, the reaction temperature was changed to 115°C, and the other steps were the same as Comparative Example 1, and no product was obtained.

[0120] Comparative Example 8

[0121] On the basis of Comparative Example 1, the base was replaced with Cs2CO3, the amount of the base was changed to 0.00625 mmol, the temperature was changed to 165°C, and the other steps were the same as Comparative Example 1, and no product was obtained.

[0122] Comparative Example 9

[0123] On the basis of Comparative Example 8, the amount of base was changed to 0.0375 mmol, no catalyst was added, and the other steps were the same as Comparative Example 1, but no product was obtained.

[0124] Performance Testing

[0125] All samples were evaluated by a panel of 12 experts. All samples were evaluated three times in parallel in the evaluation room. The number of samples evaluated at one time did not exceed 15. The next evaluation was conducted after a 10-minute break between evaluations. The compounds were identified by olfactory aroma. The description of aroma characteristics was based on the GB / T 14454.2-2008 method for evaluating aroma of spices. The specific evaluation indicators are shown in Table 1. The aroma and aroma intensity scoring scales are shown in Table 2.

[0126] During the sniffing process, the odor characteristics and aroma intensity of each sample were recorded one by one, and the sample aroma scale value was filled in according to the actual experience. After the sniffing evaluation, the expert group discussed and agreed on the aroma intensity and aroma characteristics of the sample.

[0127] Table 1 Fragrance raw material quality evaluation table

[0128]

[0129]

[0130] Table 2 Rating scale for aroma and aroma intensity

[0131]

[0132] The olfactory identification test of the compounds prepared in the examples showed that Example 1 mainly had fruity and clove aromas, Example 2 had sweet and mellow aromas, Example 3 had nutty and sweet aromas, Example 4 had a similar smell to Example 2, with jasmine, wine and sweet aromas, Example 5 had amber and spicy aromas, and Example 6 had spicy, wine and sweet aromas. Example 9 had woody, floral and burnt aromas; Example 11 had sweet and fruity aromas; Example 18 had sweetness, grass and slight roasted aromas; Example 16a had fruity and wine aromas; Example 23 had sweet and bean aromas; the above compounds all had excellent fragrance retention effects, showing aromas that were significantly different from the raw materials, as shown in Table 3 for details.

[0133] Table 3 Olfactory identification of compounds

[0134]

[0135]

[0136] The compound prepared in the embodiment of the present invention was used to carry out a cigarette flavoring application experiment. The results showed that the addition of the compound prepared in the present invention had a certain degree of influence on the aroma characteristics, smoke characteristics and taste characteristics of the single-material cigarette, and could effectively improve the delicate and soft degree of the smoke, making the smoke soft and mellow. It had a significant effect on reducing irritation, reducing dryness, increasing sweetness, and making the aftertaste clean and comfortable.

Claims

1. Application of a PNP-type Pincer manganese catalyst in catalyzing the synthesis of thiophene-substituted ketone derivatives, characterized in that: The PNP-type Pincer manganese catalyst can be used to catalyze the dehydrogenation coupling reaction of 2-thiophene methanol and carbonyl-containing compounds to generate thiophene substituted ketone derivatives; The PNP type Pincer manganese catalyst is PNP ( i Pr)-Mn(CO)2Br, PNP(Cy)-Mn(CO)2Br or PNP(Ph)-Mn(CO)2Br; the PNP( i The structural formula of Pr)-Mn(CO)2Br is shown in Formula I; the structural formula of PNP(Cy)-Mn(CO)2Br is shown in Formula II; the structural formula of PNP(Ph)-Mn(CO)2Br is shown in Formula III; 2. The use according to claim 1, characterized in that: The preparation method of the thiophene substituted ketone derivative comprises the following steps: using 2-thiophene methanol and a carbonyl-containing compound as reaction raw materials, adding a base and a PNP type Pincer manganese catalyst, and performing a dehydrogenation coupling reaction to obtain the thiophene substituted ketone derivative.

3. The use according to claim 2, characterized in that: When the carbonyl-containing compound is a compound of formula IV, a thiophene-substituted ketone derivative of formula V is obtained, and the reaction route is shown in formula (1): In formula (1), R 1 is an alkyl group, an aryl group or a substituted aryl group, and the substituent of the substituted aryl group is an alkyl group or a hydroxyl group.

4. The use according to claim 2, characterized in that: When the carbonyl-containing compound is a compound represented by Formula VI, a thiophene-substituted ketone derivative represented by Formula VII is obtained, and the reaction route is shown in Formula (2): In formula (2), R 2 When R is an alkyl group, an aryl group, a substituted aryl group or a heteroaryl group, 3 is alkyl or hydrogen; or, R 2 and R 3 Formation of cyclic alkanes.

5. The use according to claim 4, characterized in that: The substituent of the substituted aryl group is an alkyl group or a hydroxyl group.

6. The use according to claim 2, characterized in that: The structural formula of the carbonyl-containing compound is any one of the following:

7. The use according to claim 1, characterized in that: The PNP( i The preparation method of Pr)-Mn(CO)2Br comprises the following steps: using Mn(CO)5Br and PNP- i Pr is the reaction raw material, toluene is added, and the reaction is carried out under heating conditions to obtain the PNP ( i Pr)-Mn(CO)2Br; the reaction route is shown in formula (3):

8. The use according to claim 7, characterized in that: The Mn(CO)5Br,PNP- i The molar volume ratio of Pr and toluene is 0.44mmol:0.48mmol:10mL; the reaction temperature is 110°C and the reaction time is 4h; after the reaction is completed, the reaction solution is filtered and dried to obtain the PNP ( i Pr)-Mn(CO)2Br.

9. The use according to claim 1, characterized in that: The dehydrogenation coupling reaction is carried out at a temperature of 140-165°C and for 16 hours; The dehydrogenation coupling reaction is carried out under inert gas conditions; After the reaction is completed, the reaction solution needs to be separated by column chromatography; The base is at least one of an alkali metal hydroxide, an alkali metal alkoxide and an alkali metal carbonate; The organic solvent is at least one of dioxane, toluene and tetrahydrofuran; The molar volume ratio of the 2-thiophene methanol, the carbonyl compound, the base, the catalyst and the organic solvent is 0.5000mmol: (0.5000-1.0000)mmol: (0.0625-0.0375)mmol: 0.0050mmol: (0.5000-0.6000)mL.

10. The use according to claim 9, characterized in that: The alkali metal hydroxide is at least one of sodium hydroxide and potassium hydroxide; the alkali metal alkoxide is at least one of sodium ethoxide and potassium tert-butoxide; the alkali metal carbonate is at least one of potassium carbonate, sodium carbonate and cesium carbonate; The molar volume ratio of the 2-thiophene methanol, the carbonyl compound, the base, the catalyst and the organic solvent is 0.5000mmol:1.0000mmol:0.0375mmol:0.0050mmol:0.5000mL.

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