CN115322128B - Synthesis of C (sp) based on alkyl halides3) Organic sulfur compound with S bond, and preparation method and application thereof - Google Patents

Synthesis of C (sp) based on alkyl halides3) Organic sulfur compound with S bond, and preparation method and application thereof Download PDF

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CN115322128B
CN115322128B CN202210938986.1A CN202210938986A CN115322128B CN 115322128 B CN115322128 B CN 115322128B CN 202210938986 A CN202210938986 A CN 202210938986A CN 115322128 B CN115322128 B CN 115322128B
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陈良安
裴盼
赵旻
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Nanjing Normal University
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Abstract

The invention discloses an organic sulfur compound for synthesizing a C (sp 3) -S bond based on alkyl halide, and a preparation method and application thereof. In an organic solvent, sulfur compounds of C (sp 3) -S bonds are constructed by coupling with non-activated halogenated alkanes by taking thioester formate as a sulfur source and a low-cost metal simple substance as a catalyst. The invention develops a sulfur source reagent with low toxicity, low price, stability and high atom economy, and uses the cheap metal with catalytic amount as the catalyst, and the metal catalyst has low price, easy acquisition, high catalytic efficiency and low cost, and is suitable for large-scale production and application; the reaction condition is mild, and the selectivity is high; the substrate functional group has good compatibility and wide application range, and natural products and drug molecules can be compatible, so that the method has important practical application value in the fields of synthetic drugs and industry; under optimized conditions, the yield of organosulfur compounds of the C (sp 3) -S bond is as high as 90%.

Description

Organic sulfur compound for synthesizing C (sp 3) -S bond based on alkyl halide, and preparation method and application thereof
Technical Field
The invention belongs to the fields of catalytic synthesis technology and homogeneous metal catalytic coupling synthesis, and particularly relates to an organic sulfur compound for synthesizing a C (sp 3) -S bond based on alkyl halide, and a preparation method and application thereof.
Background
The C (sp 3) -S bond is a basic structural unit in organic chemistry, is widely applied to natural products, drug molecules and advanced materials, and has high application value. For example: griseoviridin isolated from Streptomyces griseus is a representative member of the Streptogramin antibiotic; viracept are used as anti-HIV agents along with other ingredients; PENICILLIN V (antibiotics), NELFINAVIR (antiviral drugs), CIMETIDINE (digestive system drugs), CELESTICETIN (natural products), etc., thus, constructing the C (sp 3) -S bond is a research hotspot in the field of organic synthesis.
Early C-S bond synthesis was often limited to condensation reactions between metal thiosalts and organic halides, where nucleophilic substitution reactions of alkyl halides with thiols are the most classical method of forming C (sp 3) -S bonds, but such reactions require high temperatures, strong bases; the substrate is mostly limited to primary halides only; the yield is low; thiol smell is unpleasant and has high toxicity and other disadvantages. In addition, in the field of constructing C-S bonds, sulfur sources are mainly sulfur reagents such as thiols, disulfides, sulfonyl chlorides, sulfonyl hydrazides, sodium/potassium sulfides, thiosulfates, and the like. Although these sulfur source agents have been used well, most of these organic/inorganic sulfur source agents reported so far have problems of low activity, pungent odor, high toxicity, poor compatibility of functional groups, and the like. Therefore, finding a sulfur source reagent that is highly reactive, inexpensive, readily available, and easy to handle is considered one of the important developments in the construction of C (sp 3) -S bonds.
The thioester formate is used as a general formylating reagent, has wide application in constructing a C-C bond in a transition metal catalytic reaction, and has the outstanding advantages of being prepared from various cheap and easily available industrial starting materials, being easy to process, high in stability and high in atom economy. However, at present, in the cross-coupling reaction catalyzed by transition metals, thioesters have not been reported as sulfur source reagents for constructing C (sp 3) -S bonds. Therefore, the method is developed into a sulfur source reagent which is environment-friendly, low in cost, easy to obtain and simple and convenient to operate, and has important practical application value in synthesizing sulfur compounds with wide application in medicine and industry.
Through literature investigation, photocatalytic reactions and transition metal catalytic reactions have been the mainstream of many strategies for constructing C-S bonds, mainly developing reactions for constructing C (sp 2) -S bonds, but most reactions require the use of organic metal reagents sensitive to water and air, which can lead to elimination and homodimerization of β -hydrides, making the construction of C (sp 3) -S bonds very difficult; meanwhile, the problems of harsh reaction conditions, excessive use of reducing agent, excessive cost of metal catalyst and the like exist. In addition, in the equivalent inexpensive metal reaction, electrophiles such as CO 2, isocyanate, and acid chloride have been successfully coupled with alkyl halides to give sulfur compounds of C (sp 2) -S bonds, but few reports have been made on the formation of C (sp 3) -S bonds by the inexpensive metal-catalyzed coupling reaction.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides an organic sulfur compound for synthesizing a C (sp 3) -S bond based on alkyl halide, a preparation method and application thereof, breaks through the use of equivalent metals in the past, and firstly proposes to take a catalytic amount of cheap metal as a catalyst, wherein the catalyst is used for coupling non-activated primary/secondary halogenated hydrocarbon with another newly developed sulfur source reagent to construct the C (sp 3) -S bond. Solves the problems of harsh reaction conditions, lower reaction yield and poor functional group compatibility of the existing sulfur compounds with C (sp 3) -S bonds; the sulfur source reagent has high toxicity and pungent smell, and the use of noble metal catalysts; is not environment-friendly, unsafe and uneconomic. The synthesis method has low cost and high catalytic efficiency, and provides a good supplementary method for synthesizing the organic sulfur compound with the existing C (sp 3) -S bond.
In order to solve the problems in the prior art, the invention adopts the technical proposal that
A method for synthesizing an organic sulfur compound of C (sp 3) -S bond based on an alkyl halide, comprising the steps of: under N 2 atmosphere, with a thioester formateIs sulfur source, low-cost metal simple substance is metal catalyst, non-activated halogenated alkane/>Reacting for 8-24 hours at 30-100 ℃ in an organic solvent to obtain the sulfur compound with C (sp 3) -S bond through quenching, extracting, decompressing, distilling, separating and purifying, wherein R is selected from C1-C20 straight-chain alkyl, C3-C20 cycloalkyl, substituted or unsubstituted phenyl, biphenyl, naphthyl, shallot or phenanthryl.
The general reaction formula is shown as follows: 1 DEG and2 DEG ALKYL HALIDES
Preferably, when the non-activated haloalkane isWhen the non-activated halogenated alkane is used as an electrophile, the molar ratio of the non-activated halogenated alkane to the formic acid thioester to the metal catalyst is 1 (1-2) (0.1-0.9).
Preferably, the concentration of the organic solvent is 0.2 to 1M.
Preferably, the temperature of the reaction is 60-100 ℃.
As an improvement, the non-activated halogenated alkaneR 1 in (2) is selected from hydrogen; r 2 and R 3 may be the same or different, and when R 2 is the same as R 3, R 2 and R 3 may be independently any alkyl group selected from C1-C20 straight chain alkyl, C1-C20 halo substituted alkyl, C1-C20 alkyl borate, C1-C20 alkylcarbonyl, nitro, hydroxy, ester, carboxyl or cyano, C1-C20 alkylaminocarbonyl, C3-C20 heteroatom-containing cycloalkyl, steroid, sugar or nucleoside, wherein the heteroatom is N, O or S; when R 2 is different from R 3, R 2 is selected from hydrogen, R 3 is optionally selected from C1-C20 straight-chain alkyl, C1-C20 halo-substituted alkyl, C1-C20 alkyl borate, C1-C20 alkylcarbonyl, nitro, hydroxy, ester, carboxyl or cyano, C1-C20 alkylaminocarbonyl; x is Cl, br or I.
Preferably, the metal catalyst is selected from one of manganese powder, zinc powder, iron powder, copper powder or bis- (1, 5-cyclooctadiene) nickel.
Preferably, the organic solvent is selected from one of dichloromethane, 1, 2-dichloroethane, dimethyl sulfoxide, N-dimethylformamide, N-diacetamide, ethyl acetate, N-dimethylpropylurea, N-methylpyrrolidone, cyclopentyldimethyl ether, and 1, 3-dimethyl-2-imidazolidinone.
An organic sulfur compound of C (sp 3) -S bond prepared by any one of the above methods.
The application of any of the organic sulfur compounds with C (sp 3) -S bonds in the preparation of emerging medicines or modification of bioactive molecules and natural products.
The beneficial effects are that:
Compared with the prior art, the organic sulfur compound for synthesizing the C (sp 3) -S bond based on the alkyl halide, the preparation method and the application thereof firstly propose to use a catalytic amount of cheap metal catalyst, and the catalyst has the characteristics of high catalytic efficiency, environmental friendliness, low cost and the like, and the metal catalyst can lead the region of the C-S bond of the thioester formate to be selectively broken to generate sulfur free radicals, and then lead the sulfur free radicals to be subjected to coupling reaction with non-activated halogenated alkane to synthesize the organic sulfide of the C (sp 3) -S bond. Has the following advantages:
(1) The invention only needs one-step reaction, under the optimized reaction condition, the yield of the separated target product can reach more than 90 percent, the defect that the substitution reaction of the alkyl halide and the mercaptan is limited to the primary halide in the past is overcome, the compatibility of the substrate functional group is good, and the invention is applicable to the modification of complex drug molecules;
(2) The invention breaks through the use of equivalent metals in the past, and firstly proposes that the construction of C (sp 3) -S bonds is realized by taking catalytic amount of cheap metals as catalysts, thereby being a more efficient and economical method for synthesizing organic sulfides;
(3) The invention provides a thioformate Can be prepared from various cheap and easily available starting reagents, and has wide sources, easy processing, high stability and high atom economy. To date, thioesters have not been reported as sulfur source reagents for the construction of C (sp 3) -S bonds in transition metal catalyzed cross-coupling reactions. According to the invention, through selectively breaking the C-S bond, the novel sulfur source reagent which is low in cost, easy to obtain and environment-friendly is developed for the first time, and a good supplementing method is provided for the construction of the existing C (sp 3) -S bond;
(4) The organic sulfide of C (sp 3) -S bond synthesized by the method is an important organic intermediate and is widely applied to the fields of medical intermediates and biology.
Detailed Description
The invention will be better understood from the following examples. However, it will be readily appreciated by those skilled in the art that the description of the embodiments is provided for illustration only and should not limit the invention as described in detail in the claims.
The experimental methods described in the examples, unless otherwise specified, are all conventional; the reagents and materials, unless otherwise specified, are readily prepared commercially or by the prior art.
Example 1
A10 mL reaction flask was charged with manganese powder (0.15 mmol), secondary haloalkyl 1a (0.3 mmol), arylthio formate 2a (0.36 mmol) and 1, 3-dimethyl-2-imidazolidinone (0.9 mL) under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 70℃for 16 hours. After the reaction was completed, it was quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether) to give the corresponding product 1,1H NMR(400MHz,CDCl3):δ7.41–7.35(m,2H),7.32–7.27(m,2H),7.25–7.15(m,3H),6.91–6.84(m,2H),3.81(s,3H),3.12–3.03(m,2H),2.91–2.84(m,2H).13C NMR(100MHz,CDCl3):δ159.06,140.50,133.40,128.64,128.59,126.47,126.41,114.72,55.48,37.38,36.04. in 94% yield.
Example 2
Zinc powder (0.15 mmol), primary haloalkane 1b (0.3 mmol), arylthio formate 2a (0.38 mmol) and 1, 3-dimethyl-2-imidazolidinone (0.9 mL) were added sequentially to a 10mL reaction flask under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 65℃for 12 hours. After the reaction was completed, it was quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether) to give the corresponding product 2,1H NMR(400MHz,CDCl3):δ7.41–7.35(m,2H),7.32–7.27(m,2H),7.25–7.15(m,3H),6.91–6.84(m,2H),3.81(s,3H),3.12–3.03(m,2H),2.91–2.84(m,2H).13C NMR(100MHz,CDCl3):δ159.06,140.50,133.40,128.64,128.59,126.47,126.41,114.72,55.48,37.38,36.04. in 90% yield.
Example 3
Copper powder (0.15 mmol), primary haloalkane 1c (0.3 mmol), arylthio formate 2a (0.4 mmol) and N, N-diacetamide (0.9 mL) were added sequentially to a 10mL reaction flask under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 80℃for 13 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=300:1) to give the corresponding product 3,1H NMR(400MHz,CDCl3):δ7.40–7.33(m,2H),7.28(dd,J＝7.3,6.1Hz,2H),6.94(s,1H),6.90–6.81(m,4H),4.05(t,J＝6.1Hz,2H),3.79(s,3H),3.01(t,J＝7.1Hz,2H),2.09–2.00(m,2H).13C NMR(100MHz,CDCl3):δ159.05,158.93,133.37,129.56,126.24,120.82,114.72,114.60,66.02,55.47,32.49,29.17. in 89% yield.
Example 4
Manganese powder (0.18 mmol), primary haloalkane 1d (0.3 mmol), arylthio formate 2a (0.38 mmol) and N, N-dimethylpropenyl urea (0.9 mL) were added sequentially to a 10mL reaction flask under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 90℃for 16 hours. After the reaction was completed, it was quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether) to give the corresponding product 4,1H NMR(400MHz,CDCl3):δ7.38–7.31(m,2H),6.88–6.81(m,2H),4.48(t,J＝6.1Hz,1H),4.36(t,J＝6.0Hz,1H),3.80(s,3H),2.87–2.78(m,2H),1.75–1.64(m,2H),1.63–1.56(m,2H),1.56–1.47(m,2H).13C NMR(100MHz,CDCl3):δ158.96,133.27,126.65,114.65,84.86,83.22,55.47,35.81,30.20,30.00,29.04,24.45,24.39.19F NMR(376MHz,CDCl3):δ-218.33. in 85% yield.
Example 5
Manganese powder (0.20 mmol), primary haloalkane 1e (0.3 mmol), arylthio formate 2a (0.4 mmol) and dimethyl sulfoxide (0.9 mL) were added sequentially to a 10mL reaction flask under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 100℃for 18 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=100:1) to give the corresponding product 5,1H NMR(400MHz,CDCl3):δ7.37–7.29(m,2H),6.87–6.80(m,2H),4.11(q,J＝7.1Hz,2H),3.79(s,3H),2.85–2.78(m,2H),2.27(t,J＝7.5Hz,2H),1.66–1.60(m,2H),1.59–1.54(m,2H),1.49–1.38(m,2H),1.25(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3):δ173.77,158.94,133.24,126.75,114.65,60.38,55.47,35.78,34.33,29.10,28.26,24.66,14.39. in 90% yield.
Example 6
Zinc powder (0.18 mmol), primary haloalkane 1f (0.3 mmol), arylthio formate 2a (0.35 mmol) and 1, 3-dimethyl-2-imidazolidinone (0.9 mL) were added sequentially to a 10mL reaction flask under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 70℃for 18 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=100:1) to give the corresponding product 6,1H NMR(400MHz,CDCl3):δ7.38–7.30(m,2H),6.88–6.81(m,2H),3.79(s,3H),2.83(t,J＝6.8Hz,2H),2.33(t,J＝6.9Hz,2H),1.83–1.67(m,4H).13C NMR(100MHz,CDCl3):δ159.21,133.66,125.81,119.50,114.75,77.48,77.16,76.84,55.44,35.13,28.18,24.22,16.90. in 63% yield.
Example 7
Manganese powder (0.20 mmol), primary haloalkane 1g (0.3 mmol), arylthio formate 2a (0.4 mmol) and N, N-dimethylpropenyl urea (0.9 mL) were added sequentially to a 10mL reaction flask under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 80℃for 13 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=100:1) to give the corresponding product 7,1H NMR(400MHz,CDCl3):δ8.11(d,J＝2.3Hz,1H),7.89(dd,J＝7.7,1.2Hz,1H),7.56(td,J＝7.4,1.4Hz,1H),7.50–7.40(m,2H),7.39–7.29(m,3H),7.02(t,J＝7.7Hz,1H),6.86–6.81(m,2H),5.18(s,2H),4.08(t,J＝6.7Hz,2H),3.79(s,3H),3.63(s,2H),2.82–2.76(m,2H),1.65–1.59(m,2H),1.58–1.52(m,2H),1.44–1.36(m,2H),1.35–1.27(m,2H).13C NMR(100MHz,CDCl3):δ191.00,171.63,160.58,158.88,140.59,136.48,135.67,133.13,132.91,132.56,129.61,129.41,128.06,127.95,126.85,125.23,121.16,114.63,73.77,65.11,55.47,40.42,35.81,29.31,28.57,28.36,25.60. in 70% yield.
Example 8
A10 mL reaction flask was charged with bis- (1, 5-cyclooctadiene) nickel (0.24 mmol), primary haloalkane 1h (0.3 mmol), arylthio formate 2a (0.38 mmol) and N, N-dimethylpropylurea (0.9 mL) in sequence under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 90℃for 13 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=10:1) to give the corresponding product 8,1H NMR(400MHz,CDCl3):δ7.38–7.30(m,2H),6.88–6.81(m,2H),3.79(s,3H),2.83(t,J＝6.8Hz,2H),2.33(t,J＝6.9Hz,2H),1.83–1.67(m,4H).13C NMR(100MHz,CDCl3):δ159.21,133.66,125.81,119.50,114.75,77.48,77.16,76.84,55.44,35.13,28.18,24.22,16.90. in 40% yield.
Example 9
Zinc powder (0.18 mmol), primary haloalkane 1i (0.3 mmol), arylthio formate 2a (0.3 mmol) and N-methylpyrrolidone (0.9 mL) were added in sequence to a10 mL reaction flask under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 90℃for 13 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=100:1) to give the corresponding product 9,1H NMR(400MHz,CDCl3):δ7.37–7.29(m,2H),6.88–6.79(m,2H),3.79(s,3H),3.61(t,J＝6.4Hz,2H),2.85–2.79(m,2H),1.63–1.52(m,4H),1.51–1.42(m,3H).13C NMR(100MHz,CDCl3):δ158.89,133.14,126.76,114.63,62.84,55.44,35.86,32.35,29.18,24.92. in 85% yield.
Example 10
A10 mL reaction flask was charged with bis- (1, 5-cyclooctadiene) nickel (0.20 mmol), secondary haloalkane 1j (0.3 mmol), arylthio formate 2a (0.30 mmol) and N, N-dimethylpropylurea (0.9 mL) in sequence under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 60℃for 15 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=200:1) to give the corresponding product 10,1H NMR(400MHz,CDCl3):δ7.39–7.34(m,2H),7.31–7.25(m,2H),7.21–7.14(m,3H),6.85–6.79(m,2H),3.80(s,3H),2.99–2.88(m,1H),2.82(dt,J＝8.8,4.2Hz,1H),2.72(ddd,J＝13.7,9.9,6.6Hz,1H),1.98–1.87(m,2H),1.81–1.69(m,1H),1.01(d,J＝6.8Hz,3H),0.95(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3):δ159.10,142.24,134.84,128.60,128.47,126.99,125.93,114.56,57.86,55.45,33.89,33.41,31.63,19.56,19.20. in 60% yield.
Example 11
Manganese powder (0.27 mmol), secondary haloalkane 1k (0.3 mmol), arylthio formate 2a (0.4 mmol) and N, N-dimethylformamide (0.9 mL) were added in this order to a10 mL reaction flask under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 90℃for 15 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=100:1) to give the corresponding product 11,1H NMR(400MHz,CDCl3):δ7.40–7.34(m,2H),7.30–7.24(m,2H),7.21–7.14(m,3H),6.86–6.82(m,2H),3.81(s,3H),2.92–2.76(m,3H),1.86–1.77(m,2H),1.56–1.46(m,4H),0.89(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3):δ159.44,142.19,135.79,128.58,128.47,125.91,125.03,114.48,55.44,49.57,36.78,36.14,33.05,20.13,14.10. in 65% yield.
Example 12
Manganese powder (0.20 mmol), primary haloalkane 1l (0.3 mmol), arylthio formate 2a (0.4 mmol) and N, N-dimethylformamide (0.9 mL) were added in sequence to a 10mL reaction flask under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 90℃for 13 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=100:1) to give the corresponding product 12,1H NMR(400MHz,CDCl3):δ7.41–7.34(m,2H),7.30–7.25(m,2H),7.21–7.14(m,3H),6.87–6.79(m,2H),3.81(s,3H),2.91–2.73(m,3H),1.86–1.76(m,2H),1.58–1.51(m,2H),1.50–1.39(m,2H),1.34–1.23(m,2H),0.89(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3):δ159.43,142.19,135.80,128.58,128.47,125.91,125.02,114.47,55.45,49.82,36.11,34.23,33.06,29.08,22.74,14.21. in 85% yield.
Example 13
A10 mL reaction flask was charged with manganese powder (0.15 mmol), secondary haloalkyl 1m (0.3 mmol), arylthio formate 2a (0.4 mmol) and 1, 3-dimethyl-2-imidazolidinone (0.9 mL) under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 90℃for 18 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=100:1) to give the corresponding product 13,1H NMR(400MHz,CDCl3):δ7.39–7.34(m,2H),7.29–7.26(m,1H),7.25–7.21(m,3H),7.21–7.13(m,2H),7.13–7.05(m,4H),6.87–6.81(m,2H),3.81(s,3H),3.19–3.10(m,1H),3.01–2.86(m,2H),2.81–2.70(m,2H),1.93–1.81(m,1H),1.79–1.67(m,1H).13C NMR(100MHz,CDCl3):δ159.56,141.86,139.50,135.84,129.32,128.56,128.44,128.43,126.43,125.94,124.88,114.59,55.47,51.06,41.66,34.88,32.97. in 85% yield.
Example 14
A10 mL reaction flask was charged with manganese powder (0.20 mmol), secondary haloalkyl 1n (0.3 mmol), arylthio formate 2a (0.4 mmol) and 1, 3-dimethyl-2-imidazolidinone (0.9 mL) under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 70℃for 15 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=200:1) to give the corresponding product 14,1H NMR(400MHz,CDCl3):δ7.41–7.34(m,2H),7.30–7.25(m,2H),7.21–7.14(m,3H),6.87–6.79(m,2H),3.81(s,3H),2.91–2.73(m,3H),1.86–1.76(m,2H),1.58–1.51(m,2H),1.50–1.39(m,2H),1.34–1.23(m,2H),0.89(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3):δ159.43,142.19,135.80,128.58,128.47,125.91,125.02,114.47,55.45,49.82,36.11,34.23,33.06,29.08,22.74,14.21. in 80% yield.
Example 15
Zinc powder (0.20 mmol), secondary haloalkane 1o (0.3 mmol), arylthio formate 2a (0.4 mmol) and N, N-dimethylformamide (0.9 mL) were added in sequence to a 10mL reaction flask under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 100℃for 9 hours. After the reaction was completed, it was quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether) to give the corresponding product 15,1H NMR(400MHz,CDCl3):δ7.42–7.35(m,2H),6.88–6.80(m,2H),3.80(s,3H),2.98–2.82(m,1H),1.98–1.86(m,2H),1.80–1.72(m,2H),1.63–1.57(m,1H),1.38–1.14(m,6H).13C NMR(100MHz,CDCl3):δ159.42,135.73,125.09,114.40,55.44,48.06,33.51,26.27,25.91. in 10% yield.
Example 16
A10 mL reaction flask was charged with manganese powder (0.15 mmol), secondary haloalkyl 1p (0.3 mmol), arylthio formate 2a (0.4 mmol) and 1, 3-dimethyl-2-imidazolidinone (0.9 mL) under nitrogen. After mixing at room temperature, the reaction mixture was reacted at 70℃for 17 hours. After the reaction was completed, it was quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether) to give the corresponding product 16,1H NMR(400MHz,CDCl3):δ7.40–7.34(m,2H),6.87–6.80(m,2H),3.80(s,3H),3.49–3.37(m,1H),2.03–1.88(m,2H),1.83–1.67(m,2H),1.62–1.54(m,4H).13C NMR(100MHz,CDCl3):δ159.08,134.26,127.06,114.48,55.45,48.10,33.52,24.77. in 40% yield.
Example 17
Zinc powder (0.15 mmol), secondary haloalkane 1q (0.3 mmol), arylthio formate 2a (0.4 mmol) and dimethyl sulfoxide (0.9 mL) were added sequentially to a 10mL reaction flask under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 100℃for 17 hours. After the reaction was completed, it was quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether) to give the corresponding product 17,1H NMR(400MHz,CDCl3):δ7.43–7.37(m,2H),6.88–6.83(m,2H),3.95(dt,J＝11.7,3.7Hz,2H),3.80(s,3H),3.38(td,J＝11.4,2.3Hz,2H),3.11–3.01(m,1H),1.84(dd,J＝12.2,1.5Hz,2H),1.65(dd,J＝10.9,4.3Hz,1H),1.59(dd,J＝10.2,3.5Hz,1H).13C NMR(100MHz,CDCl3):δ159.83,136.28,123.71,114.57,67.56,55.47,44.69,33.31. in 30% yield.
Example 18
Zinc powder (0.20 mmol), secondary haloalkane 1r (0.3 mmol), arylthio formate 2a (0.36 mmol) and dimethyl sulfoxide (0.9 mL) were added sequentially to a 10mL reaction flask under nitrogen. After mixing at room temperature, the reaction mixture was reacted at 70℃for 17 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=20:1) to give the corresponding product 18,1H NMR(400MHz,CDCl3):δ7.38(d,J＝8.5Hz,2H),6.84(d,J＝8.6Hz,2H),3.96(d,J＝6.1Hz,2H),3.79(s,3H),3.04–2.95(m,1H),2.84(t,J＝11.4Hz,2H),1.85(dd,J＝13.1,2.9Hz,2H),1.43(s,9H).13C NMR(100MHz,CDCl3):δ159.79,154.77,136.22,123.79,114.56,79.62,55.41,45.73,32.21,28.52. in 30% yield.
Example 19
A10 mL reaction flask was charged with manganese powder (0.20 mmol), secondary haloalkyl 1s (0.3 mmol), arylthio formate 2a (0.36 mmol) and 1, 3-dimethyl-2-imidazolidinone (0.9 mL) under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 100℃for 8 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=50:1) to give the corresponding product 19,1H NMR(400MHz,CDCl3):δ8.22(d,J＝8.6Hz,1H),7.78(d,J＝8.7Hz,2H),7.57(ddd,J＝8.4,6.9,1.1Hz,1H),7.43–7.36(m,3H),7.22(d,J＝9.0Hz,1H),6.81–6.72(m,2H),4.37(dt,J＝9.4,6.3Hz,1H),4.30(dt,J＝9.4,5.8Hz,1H),3.71(s,3H),3.55–3.45(m,1H),2.13–2.03(m,2H),1.36(t,J＝6.4Hz,3H).13C NMR(100MHz,CDCl3):δ159.47,153.21,135.63,133.25,130.00,128.98,128.17,127.80,126.31,124.60,124.48,115.14,114.49,109.54,67.64,55.35,41.36,36.54,21.66. in 70% yield.
Example 20
Zinc powder (0.18 mmol), secondary haloalkane 1t (0.3 mmol), arylthio formate 2a (0.30 mmol) and 1, 3-dimethyl-2-imidazolidinone (0.9 mL) were added sequentially to a 10mL reaction flask under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 90℃for 20 hours. After the reaction was completed, it was quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether) to give the corresponding product 20,1H NMR(400MHz,CDCl3):δ7.41–7.35(m,2H),6.86–6.81(m,2H),3.80(s,3H),2.92–2.81(m,1H),1.99–1.90(m,1H),1.84–0.91(m,31H),0.91–0.78(m,11H),0.75(s,3H),0.66–0.56(m,4H).13C NMR(100MHz,CDCl3):δ159.38,135.70,125.07,114.39,56.62,56.38,55.44,54.51,48.22,47.16,42.71,40.14,39.65,38.97,36.30,35.93,35.86,35.58,32.16,29.36,28.81,28.38,28.16,24.32,23.96,22.98,22.71,21.16,18.80,12.43,12.20. in 50% yield.
Example 21
A10 mL reaction flask was charged with manganese powder (0.20 mmol), secondary haloalkyl 1u (0.3 mmol), arylthio formate 2a (0.4 mmol) and 1, 3-dimethyl-2-imidazolidinone (0.9 mL) under nitrogen. After mixing at room temperature, the reaction mixture was reacted at 70℃for 17 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=1:1) to give the corresponding product 21,1H NMR(400MHz,CDCl3):δ7.50–7.43(m,2H),6.86(t,J＝5.9Hz,2H),5.39(d,J＝2.8Hz,1H),5.17(t,J＝9.9Hz,1H),5.02(dd,J＝10.0,3.3Hz,1H),4.56(d,J＝9.9Hz,1H),4.18(dd,J＝11.3,6.8Hz,1H),4.09(dd,J＝11.3,6.5Hz,1H),3.88(t,J＝6.6Hz,1H),3.81(s,3H),2.10(d,J＝7.9Hz,6H),2.04(s,3H),1.97(s,3H).13C NMR(100MHz,CDCl3):δ170.54,170.35,170.25,169.59,160.35,136.03,122.13,114.46,87.12,74.39,72.18,67.39,67.31,61.64,55.47,21.05,20.84,20.78,20.75. in 55% yield.
Example 22
A10 mL reaction flask was charged with manganese powder (0.20 mmol), secondary haloalkyl 1v (0.3 mmol), arylthio formate 2a (0.36 mmol) and 1, 3-dimethyl-2-imidazolidinone (0.9 mL) under nitrogen. After mixing at room temperature, the reaction mixture was reacted at 70℃for 17 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=100:1) to give the corresponding product 22,1H NMR(400MHz,CDCl3):δ7.39(d,J＝8.4Hz,2H),6.84(t,J＝7.0Hz,2H),3.79(s,3H),3.67–3.42(m,3H),3.39–3.19(m,2H),2.18–2.05(m,1H),1.90–1.75(m,1H),1.44(s,9H).13C NMR(100MHz,CDCl3):δ159.86,154.46,135.71,135.61,124.43,124.32,114.72,79.45,55.44,51.73,51.64,46.74,46.05,45.01,44.60,31.98,31.42,28.60. in 90% yield.
Example 23
A10 mL reaction flask was charged with manganese powder (0.21 mmol), secondary haloalkyl 1v (0.3 mmol), arylthio formate 2b (0.4 mmol) and 1, 3-dimethyl-2-imidazolidinone (0.9 mL) under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 70℃for 16 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=100:1) to give the corresponding product 23,1H NMR(400MHz,CDCl3):δ7.32(d,J＝8.1Hz,2H),7.12(t,J＝7.3Hz,2H),3.74–3.44(m,3H),3.42–3.23(m,2H),2.33(s,3H),2.23–2.11(m,1H),1.95–1.81(m,1H),1.45(s,9H).13C NMR(100MHz,CDCl3):δ154.47,137.72,132.81,132.66,130.75,130.60,129.94,79.53,77.48,77.16,76.84,51.90,51.78,45.90,45.23,45.00,44.63,32.11,31.55,28.62,21.23. in 90% yield.
Example 24
Zinc powder (0.20 mmol), secondary haloalkane 1v (0.3 mmol), arylthio formate 2c (0.4 mmol) and N, N-dimethylformamide (0.9 mL) were added in sequence to a 10mL reaction flask under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 70℃for 11 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=20:1) to give the corresponding product 24,1H NMR(400MHz,CDCl3):δ7.34(d,J＝8.2Hz,2H),7.16(t,J＝7.4Hz,2H),3.76–3.44(m,3H),3.44–3.24(m,2H),2.97–2.80(m,1H),2.25–2.11(m,1H),1.96–1.81(m,1H),1.44(d,J＝7.6Hz,9H),1.24(d,J＝5.6Hz,6H).13C NMR(100MHz,CDCl3):δ154.36,148.46,132.62,132.40,131.08,130.89,127.22,79.37,51.84,51.79,45.69,45.03,44.93,44.52,33.78,32.02,31.53,29.72,28.52,23.91. in 88% yield.
Example 25
A10 mL reaction flask was charged with bis- (1, 5-cyclooctadiene) nickel (0.20 mmol), secondary haloalkane 1v (0.3 mmol), arylthio formate 2c (0.4 mmol) and N, N-dimethylpropylurea (0.9 mL) in sequence under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 90℃for 12 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=15:1) to give the corresponding product 25,1H NMR(400MHz,CDCl3):δ7.38–7.28(m,4H),3.75–3.46(m,3H),3.45–3.23(m,2H),2.26–2.12(m,1H),1.96–1.82(m,1H),1.44(s,9H),1.30(s,9H).13C NMR(100MHz,CDCl3):δ154.41,150.70,132.24,131.98,130.95,130.73,126.17,79.42,51.92,51.88,45.61,44.97,44.58,34.62,32.08,31.61,31.33,28.58. in 90% yield.
Example 26
Manganese powder (0.20 mmol), secondary haloalkane 1v (0.3 mmol), arylthio formate 2d (0.4 mmol) and N-methylpyrrolidone (0.9 mL) were added in this order to a 10mL reaction flask under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 60℃for 11 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=15:1) to give the corresponding product 26,1H NMR(400MHz,CDCl3):δ7.47–7.35(m,2H),6.99(d,J＝6.4Hz,2H),3.76–3.43(m,3H),3.43–3.21(m,2H),2.16(dt,J＝12.5,6.2Hz,1H),1.85(dt,J＝12.4,6.1Hz,1H),1.43(s,9H).13C NMR(100MHz,CDCl3):δ163.83,161.36,154.39,135.08,134.99,134.88,129.38,129.28,116.38,116.16,79.54,51.74,51.67,46.33,45.63,44.91,44.53,32.00,31.44,28.57.19F NMR(376MHz,CDCl3):δ-113.65. in 90% yield.
Example 27
Under the protection of nitrogen, 0.20mmol of manganese powder, 1v (0.3 mmol) of secondary halogenated alkane, 2e (0.4 mmol) of formic acid aryl thioester and 0.9mL of N-methylpyrrolidone are added in sequence to a 10mL reaction flask. After mixing uniformly at room temperature, the reaction mixture was reacted at 80℃for 12 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=10:1) to give the corresponding product 27,1H NMR(400MHz,CDCl3):δ7.36–7.29(m,2H),7.29–7.23(m,2H),3.74–3.43(m,3H),3.43–3.20(m,2H),2.26–2.13(m,1H),1.92–1.81(m,1H),1.44(s,9H).13C NMR(101MHz,CDCl3):δ154.39,133.51,133.17,133.05,129.32,79.63,51.84,51.73,45.61,44.91,44.56,32.09,31.50,28.60. in 90% yield.
Example 28
Manganese powder (0.27 mmol), secondary haloalkane 1v (0.3 mmol), arylthio formate 2f (0.36 mmol) and N, N-dimethylpropenyl urea (0.9 mL) were added sequentially to a 10mL reaction flask under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 70℃for 12 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=20:1) to give the corresponding product 28,1H NMR(400MHz,CDCl3):δ7.40(d,J＝5.2Hz,2H),7.27–7.22(m,2H),3.74–3.43(m,3H),3.43–3.21(m,2H),2.29–2.13(m,1H),1.95–1.82(m,1H),1.44(s,9H).13C NMR(100MHz,CDCl3):δ154.38,133.98,133.24,133.11,132.25,121.41,79.63,51.85,51.73,45.43,44.89,44.75,44.56,32.09,31.50,28.60. in 80% yield.
Example 29
A10 mL reaction flask was charged with manganese powder (0.20 mmol), secondary haloalkyl 1v (0.3 mmol), arylthio formate 2g (0.4 mmol) and 1, 3-dimethyl-2-imidazolidinone (0.9 mL) under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 70℃for 11 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=20:1) to give the corresponding product 29,1H NMR(400MHz,CDCl3):δ7.35(dd,J＝7.6,1.1Hz,1H),7.29–7.21(m,1H),6.90(dt,J＝13.2,7.4Hz,2H),3.89(s,3H),3.87–3.77(m,1H),3.74–3.47(m,2H),3.43–3.23(m,2H),2.27–2.13(m,1H),1.95–1.82(m,1H),1.44(s,9H).13C NMR(100MHz,CDCl3):δ158.47,154.48,132.84,132.78,128.82,122.59,121.16,110.88,79.47,55.91,52.06,51.88,44.99,44.60,43.50,42.76,32.06,31.49,28.63. in 85% yield.
Example 30
Under the protection of nitrogen, 0.20mmol of manganese powder, 1v (0.3 mmol) of secondary halogenated alkane, 2h (0.4 mmol) of formic acid aryl thioester and 0.9mL of N, N-dimethylformamide are added to a 10mL reaction flask in sequence. After mixing uniformly at room temperature, the reaction mixture was reacted at 60℃for 11 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=20:1) to give the corresponding product 30,1H NMR(400MHz,CDCl3):δ7.42(t,J＝7.4Hz,1H),7.27(d,J＝5.1Hz,1H),7.09(d,J＝6.7Hz,2H),3.83–3.74(m,1H),3.71–3.46(m,2H),3.43–3.23(m,2H),2.27–2.09(m,1H),1.92–1.78(m,1H),1.44(s,9H).13C NMR(100MHz,CDCl3):δ163.56,161.11,154.43,134.83,129.91,124.69,124.65,121.22,116.16,115.93,79.56,77.48,77.16,76.84,51.90,51.79,44.87,44.47,44.04,32.11,31.56,28.59.19F NMR(376MHz,CDCl3):δ-107.76. in 70% yield.
Example 31
Zinc powder (0.24 mmol), secondary haloalkane 1v (0.3 mmol), arylthio formate 2i (0.4 mmol) and N, N-diacetamide (0.9 mL) were added sequentially to a10 mL reaction flask under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 70℃for 11 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=100:1) to give the corresponding product 31,1H NMR(400MHz,CDCl3):δ7.12(t,J＝11.9Hz,3H),3.66–3.30(m,4H),3.28–3.16(m,1H),2.52(s,6H),2.18–2.04(m,1H),1.92–1.78(m,1H),1.44(s,9H).13C NMR(101MHz,CDCl3):δ154.44,143.50,143.44,132.29,132.18,128.68,128.29,79.39,51.63,51.53,45.80,45.01,44.60,32.38,31.68,28.58,22.23. in 80% yield.
Example 32
A10 mL reaction flask was charged with bis- (1, 5-cyclooctadiene) nickel (0.21 mmol), secondary haloalkane 1v (0.3 mmol), arylthio formate 2j (0.4 mmol) and N, N-dimethylformamide (0.9 mL) in sequence under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 70℃for 15 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=20:1) to give the corresponding product 31,1H NMR(400MHz,CDCl3):δ7.19(t,J＝11.6Hz,3H),7.06(s,1H),3.70(dt,J＝14.5,9.8Hz,2H),3.62–3.45(m,1H),3.45–3.23(m,2H),2.33(d,J＝4.1Hz,3H),2.20(dd,J＝11.7,5.9Hz,1H),1.89(dd,J＝12.3,6.3Hz,1H),1.45(s,9H).13C NMR(100MHz,CDCl3):δ154.35,138.87,134.35,134.20,132.33,132.24,128.89,128.71,128.56,128.07,79.45,51.88,51.82,45.24,44.90,44.54,32.07,31.53,28.52,21.34. in 80% yield.
Example 33
A10 mL reaction flask was charged with manganese powder (0.20 mmol), secondary haloalkyl 1w (0.3 mmol), alkylthioester formate 2k (0.4 mmol) and 1, 3-dimethyl-2-imidazolidinone (0.9 mL) in sequence under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 70℃for 18 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=100:1) to give the corresponding product 33,1H NMR(400MHz,CDCl3):δ7.73–7.64(m,3H),7.41(dd,J＝8.5,1.5Hz,1H),7.30(t,J＝7.4Hz,2H),7.21(dd,J＝12.9,7.2Hz,3H),7.16–7.09(m,2H),4.07(t,J＝6.4Hz,2H),3.90(s,3H),3.84(q,J＝7.1Hz,1H),2.84(dd,J＝9.1,6.5Hz,2H),2.70(dd,J＝9.2,6.4Hz,2H),2.39(t,J＝7.3Hz,2H),1.59–1.54(m,5H),1.54–1.46(m,2H),1.34–1.26(m,2H).13C NMR(100MHz,CDCl3):δ174.84,157.72,140.75,135.91,133.77,129.39,129.02,128.59,127.22,126.45,126.38,126.06,119.10,105.66,64.70,55.43,45.64,36.46,33.76,32.13,29.23,28.30,25.22,18.59. in 45% yield.
Example 34
Manganese powder (0.18 mmol), primary haloalkane 1w (0.3 mmol), alkylthioester formate 2l (0.4 mmol) and N, N-dimethylformamide (0.9 mL) were added sequentially to a 10mL reaction flask under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 80℃for 18 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=10:1) to give the corresponding product 34,1H NMR(400MHz,CDCl3):δ7.75–7.67(m,3H),7.43(dd,J＝8.5,1.5Hz,1H),7.19–7.11(m,2H),4.09(t,J＝6.6Hz,2H),3.94(s,3H),3.86(q,J＝7.1Hz,1H),2.64–2.55(m,1H),2.42(t,J＝7.4Hz,2H),1.99–1.89(m,2H),1.82-1.72(d,J＝22.2Hz,2H),1.62–1.58(m,5H),1.51(dd,J＝15.1,7.5Hz,2H),1.38–1.22(m,8H).13C NMR(100MHz,CDCl3):δ174.85,157.71,135.91,133.77,129.39,129.03,127.22,126.39,126.05,119.08,105.66,64.76,55.44,45.64,43.60,33.85,29.98,29.68,28.32,26.27,26.00,25.38,18.60. in 55% yield.
Example 35
Manganese powder (0.20 mmol), primary haloalkane 1w (0.3 mmol), alkylthioester formate 2a (0.4 mmol) and N, N-dimethylpropylurea (0.9 mL) were added sequentially to a 10mL reaction flask under nitrogen. After mixing uniformly at room temperature, the reaction mixture was reacted at 70℃for 19 hours. After the reaction was completed, quenched with water (6 mL), extracted with ethyl acetate (3×5 mL), the organic phases were combined, washed with brine (3×5 mL), filtered, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by a silica gel plate (petroleum ether/ethyl acetate=100:1) to give the corresponding product 35,1H NMR(400MHz,CDCl3):δ7.70(dd,J＝12.3,5.3Hz,3H),7.41(dd,J＝8.5,1.3Hz,1H),7.23–7.08(m,4H),6.84(d,J＝8.5Hz,2H),4.09–4.03(m,2H),3.91(s,3H),3.85(q,J＝7.1Hz,1H),3.79(s,3H),3.60(s,2H),2.29(t,J＝7.3Hz,2H),1.58–1.43(m,6H),1.33–1.24(m,3H).13C NMR(100MHz,CDCl3):δ174.84,158.63,157.71,135.89,133.77,130.60,129.96,129.38,129.02,127.22,126.37,126.04,119.09,113.95,105.66,64.70,55.43,55.40,45.62,35.73,31.13,28.85,28.27,25.20,18.60. in 40% yield.
Example 36
The procedure of example 1 was followed except that the catalyst was changed and zinc powder was used as the catalyst to give a1 yield of 70%.
Example 37
The procedure of example 1 was followed except that the solvent was changed and dimethyl sulfoxide was used as the solvent, to obtain a yield of 1 of 74%.
Example 38
Application (gram-scale reaction) of the organic sulfur compound prepared by example 1:
The procedure of example 1 was followed except that the molar amount of 1v was changed and was enlarged from 0.3mmol scale to 4.5mmol scale to give more than 1g (1.21 g, 92% yield) of sulfur-containing compound 23.
Note that: the primary/Zhong Lu generations of examples 7, 20, 21, 33, 34 and 35 were each synthesized starting from a drug molecule and completed in the corresponding procedure to give sulfur-containing drug molecules.
The cheap metal catalyst and the non-activated halogenated alkane are subjected to oxidative addition to form high-activity metal species, and the C-S bond region of various substituted formate thioesters can be selectively broken to generate sulfur free radicals, so that the catalyst is used as an effective sulfur source reagent, and the smooth reaction is further facilitated; the transition metal catalyzed cross-coupling reaction is utilized to obtain the product. Wherein the influence on various substituents on the thioester formate and the non-activated halogenated alkane is the integral electron cloud density and the steric hindrance during the reaction, namely the modification of the substituents only influences the reaction to a certain extent and does not play a decisive role in the occurrence of the reaction.

Claims (5)

1. A process for synthesizing organic sulfur compounds with C (sp 3) -S bond based on alkyl halides, characterized in that under N 2 atmosphere, the organic sulfur compounds are synthesized with a thioester formateIs sulfur source, bis- (1, 5-cyclooctadiene) nickel or cheap metal simple substance as metal catalyst, non-activated halogenated alkane/>Reacting in organic solvent at 30-100deg.C for 8-24 hr to obtain sulfur compound with C (sp 3) -S bond, quenching, extracting, distilling under reduced pressure, separating and purifyingWherein R is selected from C1-C20 linear alkyl, C3-C20 cycloalkyl, substituted or unsubstituted phenyl, biphenyl, naphthyl, shallot or phenanthryl, and the low-cost metal simple substance is selected from manganese powder, zinc powder, iron powder, copper powder or one low-cost metal simple substance; said non-activated haloalkane/>R 1 in (2) is selected from hydrogen; r 2 and R 3 may be the same or different,
When R 2 is the same as R 3, R 2 and R 3 can be independently any heteroatom-containing cycloalkyl or glycosyl group selected from C3-C20 wherein the heteroatom is N, O or S;
When R 2 is different from R 3, R 2 is selected from hydrogen, R 3 is optionally selected from C1-C20 straight-chain alkyl, C1-C20 halo-substituted alkyl, C1-C20 alkyl borate, C1-C20 alkylcarbonyl, nitro, hydroxy, ester, carboxyl or cyano, C1-C20 alkylaminocarbonyl; x is Cl, br or I.
2. The method for synthesizing organic sulfur compounds having C (sp 3) -S bonds based on alkyl halides as claimed in claim 1, wherein when the non-activated haloalkane isWhen the non-activated halogenated alkane is used as an electrophile, the molar ratio of the non-activated halogenated alkane to the formic acid thioester to the metal catalyst is 1 (1-2) (0.1-0.9).
3. The method for synthesizing an organic sulfur compound having a C (sp 3) -S bond based on an alkyl halide as claimed in claim 1, wherein the concentration of the organic solvent is 0.2 to 1M.
4. A method for synthesizing an organic sulfur compound having a C (sp 3) -S bond based on an alkyl halide as claimed in claim 1, wherein the temperature of the reaction is 60-100 ℃.
5. The method for synthesizing an organic sulfur compound having a C (sp 3) -S bond based on an alkyl halide according to claim 1, wherein the organic solvent is one of dichloromethane, 1, 2-dichloroethane, dimethyl sulfoxide, N-dimethylformamide, N-diacetamide, ethyl acetate, N-dimethylpropylurea, N-methylpyrrolidone, cyclopentyldimethyl ether, 1, 3-dimethyl-2-imidazolidinone.
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