A type of alkyl zinc reagent and its preparation method and application

Abstract

The present invention discloses a class of alkyl zinc reagents and a preparation method and application thereof, belonging to the technical field of synthetic organic chemistry. The general structural formula of the alkyl zinc reagent of the present invention is: R‑znOPiv·Mg(OPiv)Br, wherein R is selected from a chain alkyl, a cyclic alkyl or a substituted alkyl. The present invention completes the preparation of a Grignard reagent by lithium salt catalysis or iodine element catalysis, and then completes the preparation of a zinc reagent by transmetallation and an inorganic salt activation strategy to synthesize an alkyl-substituted alkyl difluoro reagent, and the general structural formula of the alkyl-substituted alkyl difluoro reagent is: #imgabs0# wherein R1 is selected from an ester group, an alkyl group, an alkynyl group, an amide, a benzoxazole, diethyl phosphate or a perfluoro-substituted alkyl group; R is selected from a chain alkyl group, a cyclic alkyl group or a substituted alkyl group; R2, R3 are independently selected from a substituted alkyl group; and R4 is selected from an ester group. The alkyl zinc reagent is applied to the bifunctional reaction of olefins, and the alkyl-substituted alkyl difluoro reagent is applied in click chemistry reactions.

Description

Technical Field

[0001] The invention belongs to the technical field of synthetic organic chemistry, in particular to an alkyl zinc reagent and a preparation method and application thereof. Background Art

[0002] The selective installation of fluorine atoms or fluorine-containing groups into biologically active molecules has the potential to uniquely modulate solubility, metabolic stability, and bioavailability. For example, the CF2 group is a very important structural motif in a variety of compounds with activities relevant to agrochemistry and medicinal chemistry. Therefore, there is a strong need for methods that can effectively introduce CF2. In recent years, the selective dicarbon functionalization of olefins via consecutive C-C bonds has received extensive attention. However, dual Csp3-Csp3 cross-couplings to form two new Csp3 moieties between olefins have been difficult to achieve to date, which can be attributed to (1) the hindered oxidative addition of transition metal species to the alkyl-X bond; (2) the tendency of the β-H of the newly formed Csp3-[M] intermediate to be easily eliminated; and (3) the control of regio- and site-selectivity.

[0003] The present invention completes the preparation of the alkyl zinc reagent through the strategy of inorganic salt activation. Due to the excellent reaction activity of this type of alkyl zinc reagent, it is applied to the difunctionalization reaction of olefins to efficiently realize the synthesis of the alkyl substituted alkyl difluoro reagent. Summary of the invention

[0004] In order to solve the above technical problems, the present invention provides an alkyl zinc reagent and a preparation method and application thereof. The present invention completes the preparation of the Grignard reagent by lithium salt catalysis or iodine element catalysis, and then completes the preparation of the zinc reagent and synthesizes the alkyl substituted alkyl difluoro reagent by transmetallation and inorganic salt activation strategy. The present invention designs a new alkyl zinc reagent by anion regulation strategy, which opens up a prospect for new organic zinc reagents.

[0005] The present invention is achieved through the following technical solutions:

[0006] The first object of the present invention is to provide an alkyl zinc reagent having a general structural formula of R-ZnOPiv·Mg(OPiv)Br, wherein R is selected from one or more of a chain alkyl, a cyclic alkyl and a substituted alkyl.

[0007] In one embodiment of the present invention, the alkyl zinc reagent is selected from one of the following compounds:

[0008]

[0009] The second object of the present invention is to provide a method for preparing the alkyl zinc reagent, comprising the following steps:

[0010] (1) In an organic solvent, an alkyl bromide, magnesium and a catalyst are mixed and reacted to obtain a Grignard reagent;

[0011] (2) adding zinc pivalate to the Grignard reagent obtained in step (1) to react with each other to obtain the alkyl zinc reagent; wherein the structural formula of Zn(OPiv)2 is

[0012] In one embodiment of the present invention, the alkyl bromide is selected from one or more of chain alkyl bromides, cyclic alkyl bromides and substituted alkyl bromides.

[0013] In one embodiment of the present invention, the catalyst is iodine and / or lithium salt.

[0014] In one embodiment of the present invention, the iodine is in the form of iodine grains; the number of the iodine grains is 1-2 grains.

[0015] In one embodiment of the present invention, the organic solvent is selected from one or more of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane and N-methylpyrrolidone.

[0016] In one embodiment of the present invention, the molar ratio of the Grignard reagent to zinc pivalate is 1:1.2-1:1.5.

[0017] In one embodiment of the present invention, in step (1), the mixed reaction conditions are: reaction time 0.5h-2h, reaction temperature 23°C-60°C.

[0018] In one embodiment of the present invention, in step (2), the mixed reaction conditions are: reaction time 10 min-30 min, reaction temperature 0°C-40°C.

[0019] The third object of the present invention is to provide the use of the alkyl zinc reagent in the difunctionalization reaction of olefins.

[0020] The fourth object of the present invention is to provide the use of the alkyl zinc reagent in the preparation of alkyl substituted alkyl difluoro reagents.

[0021] In one embodiment of the present invention, the preparation of the alkyl-substituted alkyl difluoro reagent comprises the following steps:

[0022] In an organic solvent, Mixing and reacting with R-ZnOPiv·Mg(OPiv)Br under the action of a catalyst to obtain the alkyl-substituted alkyl difluoro reagent, wherein X=Br, I;

[0023] Wherein, R1 is selected from one or more of ester group, alkyl group, alkynyl group, amide, benzoxazole, diethyl phosphate and perfluorosubstituted alkyl group; R is selected from one or more of chain alkyl group, cyclic alkyl group and substituted alkyl group; R2 and R3 are independently selected from substituted alkyl group; R4 is selected from ester group.

[0024] In one embodiment of the present invention, the The molar ratio of R-ZnOPiv·Mg(OPiv)Br is 1:1:1.5-1:2:3, wherein X=Br, I.

[0025] In one embodiment of the present invention, the catalyst is selected from one or more of Co, Fe, Cr, Ni and Cu.

[0026] In one embodiment of the present invention, the conditions of the mixed reaction are: reaction temperature is 0°C-23°C, and reaction time is 1h-16h.

[0027] In one embodiment of the present invention, the alkyl-substituted alkyl difluoro reagent is selected from one of the following compounds:

[0028]

[0029]

[0030] A fifth object of the present invention is to provide the use of the alkyl-substituted alkyl difluoro reagent in a click reaction.

[0031] The technical solution of the present invention has the following advantages over the prior art:

[0032] The preparation method of the novel OPiv-supported alkyl zinc reagent described in the present invention is reported for the first time. The reagent shows unique reactivity in the difluoroalkylation reaction catalyzed by cobalt without directing groups, thereby realizing modular installation of CF2 and Csp3 groups on double bonds by cascading Csp3-Csp3 / Csp3-Csp3 bonds, while completing stereo configuration maintenance. Particularly noteworthy is the significant OPiv regulation effect on the alkyl zinc reagent, which leads to excellent reactivity in other halide-supported organozincs. The alkyl zinc reagent prepared by the present invention is a solid reagent. Compared with traditional liquid reagents (unstable), the alkyl zinc reagent prepared by the present invention has higher stability and is easy to use. In addition, the synthetic simplicity and practicality of 1,2-selective dicarbon functionalization to complete the simple modification of drug-like molecules and natural products and the later derivatization of fluorinated products are well illustrated. The present invention designs novel alkyl zinc reagents through anion regulation strategy, opening up a prospect for novel organozinc reagents. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] In order to make the content of the present invention more clearly understood, the present invention is further described in detail below according to specific embodiments of the present invention in conjunction with the accompanying drawings, wherein:

[0034] Figure 1 It is a feasibility description of the preparation of the alkyl-substituted alkyl difluoro reagent in Examples 1 and 2 of the present invention;

[0035] Figure 2 is an outline diagram of the alkyl zinc reagent in Example 1 of the present invention;

[0036] Figure 3 The invention provides a method for preparing the alkyl zinc reagent and the alkyl substituted alkyl difluoro reagent in Examples 1 and 2 of the present invention;

[0037] Figure 4 is the reactivity of the alkyl zinc reagent and the alkyl substituted alkyl difluoro reagent of the present invention;

[0038] Figure 5 is the reactivity of the alkyl zinc reagent and the alkyl substituted alkyl difluoro reagent of the present invention;

[0039] Figure 6 This is a synthetic application example of the alkyl-substituted alkyl difluoro reagent in the application example of the present invention in subsequent structural modification and click reaction. DETAILED DESCRIPTION

[0040] The present invention is further described below in conjunction with the accompanying drawings and specific embodiments so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

[0041] Example 1 Synthesis of alkyl zinc reagent R-ZnOPiv·Mg(OPiv)Br

[0042] This embodiment provides a method for synthesizing an alkyl zinc reagent, which is as follows:

[0043] Mg (182 mg, 1.5 eq), a pellet of I2 and ultra-dry THF (5 mL) were added to a 25 mL dry reaction tube filled with inert gas (N2), (substituted) alkyl bromide (5 mmol, 1.0 eq) was added dropwise under slightly boiling conditions, and then stirred in an oil bath at 60 ° C for 1 h to obtain the corresponding Grignard reagent. According to the Kofron method, the Grignard reagent was titrated with iodine and the concentration was calculated. Zn (OPiv) 2 was added at 1.2 times the concentration of the Grignard reagent, and the reaction mixture was stirred at room temperature for 15 min to obtain the corresponding alkyl zinc reagent, such as Figure 3 3a-1. wherein the structural formula of the alkyl bromide is:

[0044]

[0045] Example 2-14 Synthesis of Alkyl Zinc Reagent R-ZnOPiv·Mg(OPiv)Br

[0046] This embodiment provides a method for synthesizing an alkyl zinc reagent, which is as follows:

[0047] Mg (182 mg, 1.5 eq), a pellet of I2 and ultra-dry THF (5 mL) were added to a 25 mL dry reaction tube filled with inert gas (N2), (substituted) alkyl bromide (5 mmol, 1.0 eq) was added dropwise under slightly boiling conditions, and then stirred in an oil bath at 60°C for 1 h to obtain the corresponding Grignard reagent. According to the Kofron method, the Grignard reagent was titrated with iodine and the concentration was calculated. Zn (OPiv) 2 was added at 1.2 times the concentration of the Grignard reagent, and the reaction mixture was stirred at room temperature for 15 min to obtain the corresponding alkyl zinc reagent. The structural formula of the alkyl bromide is:

[0048] Me-Br, Among them, alkyl bromide Preparation of the resulting alkyl zinc reagent (Abbreviated in the accompanying drawings as )like Figure 2 As shown. Figure 2 It can be seen that the alkyl zinc reagent prepared by the present invention is solid.

[0049] Example 15 Synthesis of Alkyl Zinc Reagent R-ZnOPiv·Mg(OPiv)Br

[0050] Mg (2.4 eq), dry LiCl (1.25 eq), Zn (OPiv) 2 (1.1 eq) and ultra-dry THF (1 mol / mL is equivalent to the bromide used) were added to a 25 mL dry reaction tube filled with inert gas (N2), and the corresponding bromide (1.0 eq) was added to the above solution at 0°C, and then the reaction solution was stirred at room temperature for 5 hours to obtain the corresponding alkyl zinc reagent. The structural formula of the alkyl bromide is:

[0051] Comparative Example 1

[0052] This comparative example provides a method for synthesizing an alkyl zinc reagent, and the specific method is as follows:

[0053] In a 25 mL dry reaction tube filled with inert gas (N2), 1.2 eq of 1 M ZnCl2 solution was added, 1 mL of THF was added, and then 1.0 eq of Grignard reagent prepared by the same method as in Example 1 was added. After stirring for 15 min, the corresponding compound was obtained. Figure 3 Shown as 3a-II.

[0054] Comparative Example 2

[0055] This comparative example provides a method for synthesizing an alkyl zinc reagent, and the specific method is as follows:

[0056] In a 25 mL dry reaction tube filled with inert gas (N2), 1.2 eq of dry ZnBr2 solid was added, 1 mL of THF was added, and then 1.0 eq of Grignard reagent prepared by the same method as in Example 1 was added. After stirring for 15 min, the corresponding compound was obtained. Figure 2 3a-III is shown.

[0057] Comparative Example 3

[0058] This comparative example provides a method for synthesizing an alkyl zinc reagent, and the specific method is as follows:

[0059] In a 25 mL dry reaction tube filled with inert gas (N2), 1.2 eq of dry ZnI2 solid was added, 1 mL of THF was added, and then 1.0 eq of Grignard reagent prepared by the same method as in Example 1 was added. After stirring for 15 min, the corresponding compound was obtained. Figure 3 3a-IV shown.

[0060] Comparative Example 4

[0061] In a 25 mL dry reaction tube filled with inert gas (N2), 0.5 eq of Zn(OPiv)2 solid was added, 1 mL of THF was added, and then 1.0 eq of the Grignard reagent prepared in the same manner as in Example 1 was added. After stirring for 15 min, the corresponding compound was obtained. Figure 3 3a-VI shown.

[0062] Comparative Example 5

[0063] In a 25 mL dry reaction tube filled with inert gas (N2), 0.5 eq of ZnCl2 solid was added, 1 mL of THF was added, and then 1.0 eq of Grignard reagent prepared by the same method as in Example 1 was added. After stirring for 15 min, the corresponding compound was obtained. Figure 3 3a-V shown.

[0064] Application Example Synthesis of Alkyl Substituted Alkyl Difluoro Reagent Compounds

[0065] The R-ZnOPiv·Mg(OPiv)Br (abbreviated as R-ZnOPiv in the figures) obtained in Examples 1-15 were respectively mixed with The reaction mixture is obtained Wherein, X=Br, I, the specific reaction conditions are shown in Figure 3-Figure 5 , R is selected from chain alkyl, cyclic alkyl or substituted alkyl; R1 is selected from ester, alkyl, alkynyl, amide, benzoxazole, diethyl phosphate or perfluoro substituted alkyl; R is selected from chain alkyl, cyclic alkyl or substituted alkyl; R2, R3 are independently selected from substituted alkyl; R4 is selected from ester. The product obtained by the reaction is shown in Figure 4 and Figure 5 ,Depend on Figure 4 and Figure 5 It can be seen that the use of the alkyl zinc reagent obtained in the present invention in the difunctionalization reaction of olefins catalyzed by transition metal cobalt can produce a product with a higher yield.

[0066] Test Case

[0067] The different alkyl zinc reagents prepared in Example 1 and Comparative Examples 1-5 were used to prepare alkyl-substituted alkyl difluoro reagents by difunctionalization of olefins under the same conditions. The product yields obtained by gas chromatography internal standard method were 78%, 16%, 11%, 20%, 37% and 15%, respectively. Figure 3 shown.

[0068] It can be seen that Example 1 has the best effect, that is, this type of alkyl zinc reagent has better reactivity. The molar ratio of Zn salt to Grignard reagent added in Comparative Examples 4 and 5 is 1:2, which is different from the molar ratio added in Example 1 and Comparative Example 1. The structures of the generated compounds are shown in 3a-V and 3a-VI. The reactivity of this type of diploid structure is not as good as 3a-I.

[0069] In order to further test the reactivity of the above alkyl zinc reagent, the difunctionalization reaction of olefins catalyzed by the alkyl zinc reagent of the present invention under the transition metal cobalt was designed. After screening the reaction conditions of the catalytic system and conducting systematic reaction kinetic monitoring, the experimental results showed that this type of alkyl zinc reagent showed obvious superiority in reactivity and obtained the target product with a high conversion rate. Figure 3 The NMR characterization results of the obtained compounds 4-49 are shown below.

[0070] NMR characterization data of compound 4-compound 49:

[0071] Ethyl

[0072] 2-(1-ethoxy-2,2-difluoro-7-methyl-1-oxooctan-4-yl)cyclohex-1-ene-1-carboxylate(4)

[0073] 1 H-NMR (400MHz, CDCl3): δ = 4.30 (q, J = 7.1, 2H), 4.17 (qd, J = 7.1, 2.0, 2H), 3.50-3.4 1(m,1H),2.32-2.24(m,2H),2.23-1.91(m,4H),1.64-1.56(m,4H),1.49(dt,J=13. 1,6.6,1H),1.44-1.37(m,2H),1.35(t,J=7.2,3H),1.29(t,J=7.1,3H),1.16(ddt, J=12.4,10.6,6.3,1H),1.04(tdd,J=13.2,8.7,6.0,1H),0.86(dd,J=6.6,2.2,6H). 13 C-NMR (100MHz, CDCl3): δ=169.5,164.2(t, 2 J C-F =32.7),145.1,127.5,116.2(t, 1 J C-F =251.0),62.8,60.1,37.6(t, 2 J C-F =22.1),36.2,35.5(t, 3 J C-F =3.2),31.1,28.0,27.2,23.9,22.7,22.4,22.2,22.0,14.2,13.9. 19F-NMR(376MHz,CDCl3):δ=-103.22(d,J=262.5),-104.09(d,J=262.4).HR-MS(EI)m / z calcd for C 20 H 32 F2O4[M+H + ]375.2341,found 375.2345.

[0074] Ethyl

[0075] 8-(1-ethoxy-2,2-difluoro-7-methyl-1-oxooctan-4-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-car boxylate(5)

[0076] 1 H-NMR(400MHz,CDCl3):δ=4.33-4.26(m,2H),4.17(tt,J=7.2,3.6,2H),4.02-3.93(m,4H),3.76-3.68(m,1H),2.52(q,J=17.7,2H),2.33-2.04(m,4H),1.72(t,J=6.5,2H),1.57-1.37(m,3H),1.34(t,J=7.2,3H),1.28(t,J=7.1,3H),1.21-1.11(m,1H),1.11-1.00(m,1H),0.86(d,J=6.6,6H). 13 C-NMR(100MHz,CDCl3):δ=168.0,164.3(t, 2 J C-F =32.8),146.7,124.9,116.2(t, 1 J C-F =251.1),107.4,64.6,64.6,62.9,60.4,37.8(t, 2 J C-F =22.3),37.4,36.2,34.9(t, 3 J C-F =3.3),31.3,30.7,28.1,23.8,22.8,22.5,14.3,14.0. 19 F-NMR(376MHz,CDCl3):δ=-103.13(d,J=262.6),-103.97(d,J=263.0).HR-MS(EI)m / zcalcd for C 22 H34 F2O6[M+H + ]433.2396,found433.2399.

[0077] Ethyl

[0078] 2-(1-ethoxy-2,2-difluoro-7-methyl-1-oxooctan-4-yl)-5,5-difluorocyclohex-1-ene-1-carbo xylate(6)

[0079] 1 H-NMR(400MHz,CDCl3):δ=4.30(qd,J=7.1,1.6,2H),4.19(q,J=7.1,2H),3.90-3.80(m,1H),2.89-2.72(m,2H),2.43-2.12(m,4H),2.10-1.90(m,2H),1.54-1.37(m,3H),1.34(t,J=7.2,3H),1.30(t,J=7.1,3H),1.22-1.12(m,1H),1.06-0.95(m,1H),0.86(dd,J=6.6,1.6,6H). 13 C-NMR(100MHz,CDCl3):δ=167.0,164.1(t, 2 J C-F =32.7),147.1,123.1(dd, 3 J C-F =6.3,4.4),122.3(t, 1 J C-F =238.9),116.0(t, 1 J C-F =251.2),63.0,60.8,37.6(t, 2 J C-F =22.3),36.3(t, 2 J C-F =28.0),36.1,34.6,31.4,29.8(t, 2 J C-F =24.3),28.1,22.8,22.5,14.2,14.0. 19F-NMR(376MHz,CDCl3):δ=-95.45(d,J=235.9),-97.01(d,J=235.9),-103.09(d,J=264.7),-104.20(d,J=264.6).HR-MS(EI)m / z calcd forC 20 H 30 F4O4[M+H + ]411.2153,found411.2157.

[0080] Ethyl

[0081] 2-(1-ethoxy-2,2-difluoro-7-methyl-1-oxooctan-4-yl)-5,5-dimethylcyclohex-1-ene-1-carb oxylate(7)

[0082] 1 H-NMR(400MHz,CDCl3):δ=4.30(qd,J=7.1,1.2,2H),4.16(qd,J=7.1,1.9,2H),3.53-3.44(m,1H),2.30-2.15(m,1H),2.15-1.96(m,5H),1.53-1.39(m,3H),1.38-1.32(m,5H),1.29(t,J=7.1,3H),1.17(ddt,J=12.3,10.5,6.2,1H),1.10-0.96(m,1H),0.92(d,J=10.4,6H),0.85(dd,J=6.6,2.2,6H). 13 C-NMR(100MHz,CDCl3):δ=169.7,164.4(t, 2 J C-F =32.7),143.7,126.9,116.3(t, 1 J C-F =251.1),62.9,60.2,41.0,37.9(t, 2 J C-F =22.1),36.46,35.3(t, 3 J C-F =3.0),34.9,31.4,28.8,28.6,28.1,27.7,22.9,22.5,21.8,14.3,14.0. 19F-NMR(376MHz,CDCl3)δ=-103.39(d,J=262.6),-104.21(d,J=262.6).HR-MS(EI)m / z calcd for C 22 H 36 F2O4[M+H + ]403.2654,found 403.2657.

[0083] Ethyl

[0084] 4-(1-ethoxy-2,2-difluoro-7-methyl-1-oxooctan-4-yl)-4'-methoxy-1,2,5,6-tetrahydro-[1,1'-biphenyl]-3-carboxylate(8)

[0085] 1 H-NMR(400 MHz,CDCl3):δ=7.15(d,J=8.6,2H),6.86(dd,J=8.7,2.8,2H),4.32(q,J=7.2,2H),4.17(qdd,J=7.1,3.5,1.5,2H),3.79(d,J=1.4,3H),3.62-3.49(m,1H),2.84-2.50(m,2H),2.42-2.04(m,5H),1.95(d,J=12.6,1H),1.74-1.62(m,1H),1.57-1.39(m,3H),1.36(t,J=7.1,3H),1.27(td,J=7.1,2.9,3H),1.23-0.96(m,2H),0.91-0.82(m,6H). 13 C-NMR(100 MHz,CDCl3):δ=169.2,169.2,164.4(t, 2 J C-F =32.8),164.3(t, 2 J C-F =32.7),158.2,158.1,145.6,145.0,138.4,138.2,127.9,127.8,127.6,127.3,116.3(t, 1 J C-F =251.8),116.3(t, 1 J C-F =250.8),114.0,62.9,60.4,55.4,39.2,38.6,38.0(t, 2 J C-F=22.2),37.5(t, 2 J C-F =22.2),36.4,36.4,35.8,35.5(t, 3 J C-F =3.3),35.3(t, 3 J C-F =3.2),35.1,31.8,30.9,29.4,29.2,28.2,28.2,25.0,24.3,22.9,22.9,22.6,14.4,14.3,14.1. 19 F-NMR(376 MHz,CDCl3):δ=-103.10(d,J=262.5),-103.65(s),-104.07(d,J=262.7).HR-MS(EI)m / z calcd for C 27 H 38 F2O5[M+H + ]481.2760,found 481.2764.

[0086] Ethyl

[0087] 2-(1-ethoxy-2,2-difluoro-7-methyl-1-oxooctan-4-yl)cyclopent-1-ene-1-carboxylate(9)

[0088] 1 H-NMR(400 MHz,CDCl3):δ=4.27(q,J=7.1,2H),4.18(q,J=7.1,2H),3.92-3.83(m,1H),2.60(t,J=7.3,2H),2.51-2.30(m,2H),2.29-2.11(m,2H),1.86-1.73(m,2H),1.56-1.36(m,3H),1.34(dd,J=9.2,5.1,3H),1.29(t,J=7.1,3H),1.15(ddd,J=16.8,12.4,5.9,1H),1.05-0.95(m,1H),0.85(d,J=6.6,6H). 13 C-NMR(100 MHz,CDCl3):δ=166.0,164.2(t, 2 J C-F =32.7),158.6,129.9,116.1(t, 1 J C-F =251.0),62.9,59.9,38.1(t, 2J C-F =22.4),36.3,33.9,32.9,32.4(t, 3 J C-F =3.7),31.9,28.0,22.8,22.5,21.7,14.4,14.0. 19 F-NMR(376 MHz,CDCl3):δ=-103.35(s),-103.38(s).HR-MS(EI)m / z calcd forC 19 H 30 F2O4[M+H + ]361.2185,found361.2188.

[0089] Methyl

[0090] 2-(1-ethoxy-2,2-difluoro-7-methyl-1-oxooctan-4-yl)cyclohept-1-ene-1-carboxylate(10)

[0091] 1 H-NMR(400 MHz,CDCl3):δ=4.34-4.26(m,2H),3.70(s,3H),3.36-3.27(m,1H),2.49-2.34(m,2H),2.22-2.03(m,4H),1.82-1.69(m,2H),1.61-1.38(m,7H),1.35(t,J=7.1,3H),1.21-1.02(m,2H),0.86(dd,J=6.6,2.5,6H). 13 C-NMR(100 MHz,CDCl3):δ=170.7,164.3(t, 2 J C-F =32.9),151.3,133.2,116.3(t, 1 J C-F =251.2),62.9,51.4,37.5(t, 2 J C-F =22.1),36.7(t, 3 J C-F =3.4),36.5,32.6,31.1,28.9,28.1,26.4,26.3,22.8,22.6,14.0. 19F-NMR(376MHz,CDCl3):δ=-102.77(d,J=262.6),-103.60(d,J=262.8).HR-MS(EI)m / z calcd forC 20 H 32 F2O4[M+H + ]375.2341,found 375.2339.

[0092] Diethyl(Z)-2-butyl-6,6-difluoro-4-isopentyl-3-methylhept-2-enedioate(11)

[0093] 1 H-NMR(400 MHz,CDCl3):δ=4.29(q,J=7.1,2H),4.23-4.12(m,2H),3.25(tt,J=8.5,5.7,1H),2.29-2.01(m,4H),1.62(s,3H),1.46(ddd,J=17.4,12.1,6.1,2H),1.39-1.31(m,7H),1.29(t,J=7.1,4H),1.15(ddd,J=16.9,12.5,5.9,1H),1.01(tdd,J=11.0,7.5,3.4,1H),0.89(t,J=7.1,3H),0.85(dd,J=6.6,2.4,6H). 13 C-NMR(100 MHz,CDCl3):δ=170.0,164.3(t, 2 J C-F =32.7),141.5,131.5,116.2(t, 1 J C-F =251.0),62.9,60.2,37.8(t, 2 J C-F =22.2),36.7(t, 3 J C-F =3.3),36.3,31.2,30.6,30.2,28.1,22.8,22.6,22.5,14.3,14.0,14.0,12.9. 19 F-NMR(376 MHz,CDCl3):δ=-103.14(d,J=263.5),-103.98(d,J=263.1).HR-MS(EI)m / z calcd for C 21 H 36 F2O4[M+H +]391.2654,found 391.2650.

[0094] Diethyl

[0095] (Z)-2-((R)-3,7-dimethyloct-6-en-1-yl)-6,6-difluoro-4-isopentyl-3-methylhept-2-enedioate(12)

[0096] 1 H-NMR(400 MHz,CDCl3):δ=5.09(t,J=7.1,1H),4.29(q,J=7.1,2H),4.22-4.12(m,2H),3.28(ddd,J=14.1,8.4,5.7,1H),2.33-2.13(m,3H),2.13-1.88(m,3H),1.68(s,3H),1.63(s,3H),1.60(s,3H),1.52-1.37(m,4H),1.34(t,J=7.2,4H),1.28(t,J=7.1,4H),1.23-1.10(m,3H),1.06-0.96(m,1H),0.89(d,J=6.4,3H),0.85(dd,J=6.6,2.3,6H). 13 C-NMR(100 MHz,CDCl3):δ=169.9,169.9,164.3(t, 2 J C-F =33.1),141.7,141.7,131.5,131.2,125.0,116.2(t, 1 J C-F =251.2),62.9,60.2,37.8(t, 2 J C-F =22.3),37.0,37.0,36.6(t, 3 J C-F =2.8),36.3,35.4,35.4,32.6,31.2,28.1,28.1,25.9,25.7,22.9,22.5,19.6,19.6,17.8,14.4,14.0,12.9. 19 F-NMR(376 MHz,CDCl3):δ=-103.14(d,J=263.4),-103.15(d,J=263.3),-103.89(d,J=263.1),-103.91(d,J=263.6).HR-MS(EI)m / z calcd forC 27 H46 F2O4[M+H + ]473.3437,found473.3440.

[0097] Diethyl

[0098] (Z)-6,6-difluoro-4-isopentyl-3-methyl-2-(2-(thiophen-3-yl)ethyl)hept-2-enedioate(13)

[0099] 1 H-NMR(400 MHz,CDCl3):δ=7.22(dd,J=4.7,3.1,1H),6.97-6.90(m,2H),4.34-4.25(m,2H),4.22-4.13(m,2H),3.34(tt,J=8.4,5.7,1H),2.76-2.68(m,2H),2.60-2.53(m,2H),2.24-2.03(m,2H),1.54(s,3H),1.47(dd,J=13.2,6.5,1H),1.43-1.37(m,1H),1.34(dd,J=8.7,5.6,4H),1.30(t,J=7.1,3H),1.20-1.10(m,1H),1.03-0.94(m,1H),0.86(dd,J=6.6,4.0,6H). 13 C-NMR(100 MHz,CDCl3):δ=169.6,164.3(t, 2 J C-F =32.8),143.6,142.0,130.1,128.5,125.3,120.6,116.2(t, 1 J C-F =251.1),62.9,60.4,37.7(t, 2 J C-F =22.2),36.2,36.6(t, 3 J C-F =3.2),31.7,31.2,29.0,28.1,22.8,22.5,14.3,14.0,13.0. 19 F-NMR(376 MHz,CDCl3):δ=-103.58(s),-103.60(s).HR-MS(EI)m / z calcd for C 23 H 34 F2O4S[M+H +]445.2219,found445.2222.

[0100] Diethyl

[0101] (Z)-6,6-difluoro-4-isopentyl-2-(3-(4-methoxyphenoxy)propyl)-3-methylhept-2-enedioate(14)

[0102] 1 H-NMR(400 MHz,CDCl3):δ=6.82(s,4H),4.33-4.23(m,2H),4.22-4.11(m,2H),3.94-3.84(m,2H),3.76(s,3H),3.31(tt,J=8.7,5.7,1H),2.48(dd,J=10.5,5.0,2H),2.25-2.00(m,2H),1.91-1.79(m,2H),1.64(s,3H),1.44(ddd,J=17.6,12.2,6.1,2H),1.38-1.30(m,4H),1.28(t,J=7.1,3H),1.20-1.09(m,1H),1.03-0.92(m,1H),0.83(t,J=6.6,6H). 13 C-NMR(100 MHz,CDCl3):δ=169.7,164.3(t, 2 J C-F =32.7),153.8,153.3,143.2,130.2,116.2(t, 1 J C-F =251.1),115.4,114.7,67.4,62.9,60.4,55.9,37.8(t, 2 J C-F =22.1),36.3,31.2,28.1,28.1,26.7,22.8,22.4,14.3,14.0,13.0. 19 F-NMR(376 MHz,CDCl3):δ=-102.67--104.38(m,2F).HR-MS(EI)m / z calcd for C 27 H 40 F2O6[M+H + ]499.2866,found499.2869.

[0103] Diethyl

[0104] (Z)-2-(4-(4-chloro-3-methylphenoxy)butyl)-6,6-difluoro-4-isopentyl-3-methylhept-2-enedioate(15)

[0105] 1 H-NMR(400 MHz,CDCl3):δ=7.20(d,J=8.7,1H),6.75(d,J=2.9,1H),6.65(dd,J=8.7,3.0,1H),4.34-4.25(m,2H),4.23-4.12(m,2H),3.90(t,J=6.4,2H),3.29(tt,J=8.6,5.7,1H),2.36-2.30(m,5H),2.27-2.02(m,2H),1.81-1.72(m,2H),1.64(s,3H),1.60-1.36(m,5H),1.34(t,J=7.2,3H),1.28(t,J=7.1,3H),1.20-1.10(m,1H),1.00(tdd,J=11.8,8.5,4.9,1H),0.86(d,J=2.0,3H),0.84(d,J=1.9,3H). 13 C-NMR(100 MHz,CDCl3):δ=-169.8,164.3(t, 2 J C-F =32.3),157.8,142.4,137.0,130.9,129.7,125.7,117.2,116.2(t, 1 J C-F =251.3),113.2,68.0,62.9,60.3,37.7(t, 2 J C-F =22.2),36.7,36.3,31.2,30.1,29.0,28.1,24.9,22.8,22.5,20.4,14.3,14.0,13.1. 19 F-NMR(376 MHz,CDCl3):δ=-103.59(d,J=6.4).HR-MS(EI)m / z calcdfor C 28 H 41 ClF2O5[M+H + ]531.2683,found 531.2680.

[0106] Diethyl(Z)-2-benzyl-6,6-difluoro-4-isopentyl-3-methylhept-2-enedioate(16)

[0107] 1 H-NMR(400 MHz,CDCl3):δ=7.27-7.22(m,2H),7.19-7.13(m,3H),4.34-4.22(m,2H),4.14-4.04(m,2H),3.74-3.62(m,2H),3.55(tt,J=8.8,5.6,1H),2.34-2.05(m,2H),1.68(s,3H),1.44(tdd,J=14.4,11.0,5.2,3H),1.34(t,J=7.2,3H),1.27-1.18(m,1H),1.16(t,J=7.1,3H),1.05(tdd,J=12.3,7.0,5.2,1H),0.86(dd,J=6.6,4.9,6H). 13 C-NMR(100 MHz,CDCl3):δ=169.1,164.3(t, 2 J C-F =32.7),145.7,139.5,129.5,128.4,128.3,126.1,116.2(t, 1 J C-F =251.2),62.9,60.3,37.7(t, 2 J C-F =22.2),36.4,36.1,31.5,28.1,22.8,22.5,14.2,14.0,13.9. 19 F-NMR(376 MHz,CDCl3):δ=-102.90(d,J=263.6),-103.82(d,J=263.7).HR-MS(EI)m / z calcd for C 24 H 34 F2O4[M+H + ]425.2498,found425.2501.

[0108] Diethyl(Z)-2-(4-chlorobenzyl)-6,6-difluoro-4-isopentyl-3-methylhept-2-enedioate(17)

[0109] 1H-NMR(400 MHz,CDCl3):δ=7.22(d,J=8.4,2H),7.10(d,J=8.5,2H),4.33-4.24(m,2H),4.13-4.05(m,2H),3.66(d,J=17.0,2H),3.56(tt,J=8.8,5.4,1H),2.31-2.04(m,2H),1.67(s,3H),1.45(qdd,J=13.4,8.9,5.5,3H),1.34(t,J=7.2,3H),1.23-1.13(m,4H),1.09-0.97(m,1H),0.86(dd,J=6.6,4.1,6H). 13 C-NMR(100 MHz,CDCl3):δ=168.9,164.2(t, 2 J C-F =32.7),146.3,138.0,131.8,129.7,129.1,128.5,116.2(t, 1 J C-F =251.1),62.9,60.4,37.7(t, 2 J C-F =22.2),36.4,35.5,31.5,28.1,22.8,22.5,14.2,14.0,13.9. 19 F-NMR(376 MHz,CDCl3):δ=-102.66(d,J=264.5),-104.17(d,J=263.7).HR-MS(EI)m / zcalcd for C 24 H 33 ClF2O4[M+H + ]459.2108,found 459.2114.

[0110] Diethyl(Z)-2-(4-bromobenzyl)-6,6-difluoro-4-isopentyl-3-methylhept-2-enedioate(18)

[0111] 1H-NMR(400 MHz,CDCl3):δ=7.37(d,J=8.4,2H),7.05(d,J=8.4,2H),4.33-4.24(m,2H),4.14-4.05(m,2H),3.71-3.51(m,3H),2.33-2.04(m,2H),1.67(d,J=6.0,3H),1.54-1.36(m,3H),1.34(t,J=7.2,3H),1.26-1.15(m,4H),1.09-0.97(m,1H),0.86(dd,J=6.6,4.1,6H). 13 C-NMR(100 MHz,CDCl3):δ=168.71,164.08(t, 2 J C-F =32.7),146.34,138.41,131.33,129.98,128.83,119.74,116.03(t, 1 J C-F =251.1),62.81,60.32,37.55(t, 2 J C-F =22.2),36.24,35.46,31.39,27.94,22.69,22.41,14.09,13.90,13.83. 19 F-NMR(376MHz,CDCl3):δ=-102.64(d,J=263.9),-104.17(d,J=264.0).HR-MS(EI)m / z calcd forC 24 H 33 BrF2O4[M+H + ]503.1603,found 503.1598.

[0112] Ethyl

[0113] 2-(5-ethoxy-4,4-difluoro-5-oxopentan-2-yl)-5,5-dimethylcyclohex-1-ene-1-carboxylate(19)

[0114] 1H-NMR(400 MHz,CDCl3):δ=4.31(q,J=7.1,2H),4.22-4.12(m,2H),3.59(m,1H),2.34-2.18(m,1H),2.16-1.96(m,5H),1.38-1.32(m,5H),1.32-1.27(m,3H),1.11(d,J=6.9,3H),0.91(d,J=3.2,6H). 13 C-NMR(100 MHz,CDCl3):δ=169.6,164.4(t, 2 J C-F =32.8),145.6,125.1,116.3(t, 1 J C-F =251.3),62.9,60.3,40.7,38.8(t, 2 J C-F =22.2),34.9,30.4,28.5,28.1,21.9,19.7,14.3,14.0. 19 F-NMR(376 MHz,CDCl3)δ=-104.03(d,J=261.7),-104.80(d,J=260.9).HR-MS(EI)m / z calcd for C 18 H 28 F2O4[M+H + ]347.2028,found347.2023.

[0115] Ethyl 2-(6-ethoxy-5,5-difluoro-6-oxohexan-3-yl)cyclohex-1-ene-1-carboxylate(20)

[0116] 1 H-NMR(400 MHz,CDCl3):δ=4.33-4.26(m,2H),4.22-4.13(m,2H),3.40(tt,J=8.8,5.7,1H),2.35-1.90(m,6H),1.65-1.56(m,4H),1.53-1.38(m,2H),1.35(t,J=7.2,3H),1.29(t,J=7.1,3H),0.84(t,J=7.4,3H). 13 C-NMR(100 MHz,CDCl3):δ=169.7,164.4(t, 2 J C-F =32.8),144.7,128.0,116.3(t,1 J C-F =251.0),62.9,60.2,37.5(t, 2 J C-F =22.2),37.0(t, 3 J C-F =3.3),27.3,26.4,23.9,22.4,22.2,14.3,14.0,11.8. 19 F-NMR(376 MHz,CDCl3):δ=-103.22(d,J=263.1),-104.23(d,J=262.2).HR-MS(EI)m / z calcd forC 17 H 26 F2O4[M+H + ]333.1872,found333.1877.

[0117] Ethyl 8-(9-cyano-5,5-difluorononan-3-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(21)

[0118] 1 H-NMR(400 MHz,CDCl3):δ=4.22-4.13(m,2H),4.04-3.94(m,4H),3.60-3.51(m,1H),2.54(s,2H),2.37(t,J=7.0,2H),2.25(qd,J=17.7,8.8,2H),2.08-1.80(m,4H),1.72(dd,J=13.4,6.7,4H),1.66-1.58(m,2H),1.55-1.37(m,2H),1.29(t,J=7.1,3H),0.83(t,J=7.4,3H). 13 C-NMR(100 MHz,CDCl3):δ=168.5,146.7,125.0,124.8(t, 1 J C-F =241.5),119.6,107.4,64.6,60.5,39.7(t, 2 J C-F =24.6),37.4,37.1(t, 3 J C-F =4.0),35.2(t, 2 J C-F =25.4),30.7,27.0,25.3,23.5,21.6(t, 3 JC-F =4.6),17.1,14.3,11.8. 19 F-NMR(376 MHz,CDCl3)δ=-94.30(d,J=242.7),-95.83(d,J=242.7).HR-MS(EI)m / z calcd forC 21 H 31 F2NO4[M+H + ]400.2294,found400.2297.

[0119] Ethyl

[0120] 8-(1-cyano-5,5-difluoro-10,12,12-trimethyltridecan-7-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(22)

[0121] 1 H-NMR(400 MHz,CDCl3):δ=4.21-4.10(m,2H),4.02-3.91(m,4H),3.66-3.52(m,1H),2.57-2.45(m,2H),2.35(t,J=7.1,2H),2.31-2.18(m,2H),2.07-1.77(m,4H),1.74-1.57(m,6H),1.48-1.30(m,3H),1.27(t,J=7.1,3H),1.21-0.95(m,4H),0.86(t,J=4.4,12H). 13 C-NMR(100 MHz,CDCl3):δ=168.4,168.3,147.4,147.1,124.8(t, 1 J C-F =241.6),124.7,124.6,119.6,107.4,107.4,64.6,64.6,60.4,51.5,51.2,40.1(t, 2 J C-F =24.4),39.9(t, 2 J C-F =24.6),37.4,36.9,36.7,35.7(t, 3 J C-F =3.8),35.3(t, 2 J C-F =25.5),35.2(t, 2 J C-F=25.5),31.8,31.6,31.2,31.2,30.8,30.1,29.5,29.3,25.3,23.7,22.8,22.5,21.6(t, 3 J C-F =4.6),17.1,14.4. 19 F-NMR(376 MHz,CDCl3):δ=-95.02(ddd,J=284.4,242.6,27.5).HR-MS(EI)m / z calcdfor C 28 H 45 F2NO4[M+H + ]498.3389,found 498.3382.

[0122] Ethyl

[0123] 8-(9-cyano-1-cyclohexyl-5,5-difluorononan-3-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(23)

[0124] 1 H-NMR(400 MHz,CDCl3):δ=4.21-4.12(m,2H),4.03-3.93(m,4H),3.63-3.54(m,1H),2.59-2.45(m,2H),2.41-2.33(m,2H),2.32-2.17(m,2H),2.06-1.80(m,4H),1.74-1.58(m,11H),1.49-1.33(m,2H),1.28(t,J=7.1,3H),1.22-1.00(m,6H),0.90-0.80(m,2H). 13 C-NMR(100 MHz,CDCl3):δ=168.4,147.3,124.9(t, 1 J C-F =241.6),124.5,119.6,107.4,64.6,64.6,60.5,39.9(t, 2 J C-F =24.6),37.8,37.4,35.8(t, 3 J C-F =3.9),35.2(t, 2 J C-F =25.5),34.9,33.6,33.3,31.4,30.8,26.8,26.5,26.5,25.3,23.7,21.6(t,3 J C-F =4.6),17.1,14.4. 19 F-NMR(376MHz,CDCl3):δ=-94.18(d,J=242.6),-95.76(d,J=242.4).HR-MS(EI)m / z calcd forC 27 H 41 F2NO4[M+H + ]482.3076,found482.3080.

[0125] Ethyl

[0126] 8-(9-cyano-5,5-difluoro-1-(4-fluorophenyl)nonan-3-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(24)

[0127] 1 H-NMR(400 MHz,):δ=7.13-7.06(m,2H),6.97-6.89(m,2H),4.15(q,J=7.1,2H),4.04-3.94(m,4H),3.78-3.68(m,1H),2.60-2.43(m,4H),2.39-2.27(m,4H),2.11-1.81(m,4H),1.80-1.61(m,8H),1.28(t,J=7.1,3H). 13 C-NMR(100 MHz,CDCl3):δ=168.3,162.6,160.1,146.6,137.8,129.8,129.7,125.3,124.7(t, 1 J C-F =241.8),119.6,115.2,115.0,107.3,64.7,64.6,60.6,39.9(t, 2 J C-F =24.6),37.4,35.8,35.4(t, 2 J C-F =25.4),32.8,30.7,27.2,25.3,23.8,21.6(t, 3 J C-F =4.6),17.1,14.3. 19F-NMR(376 MHz,CDCl3):δ=-95.21(dd,J=662.5,243.0),-117.83(s).HR-MS(EI)m / z calcd for C 27 H 34 F3NO4[M+H + ]494.2513,found494.2517.

[0128] Ethyl

[0129] 2-(1-((5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-6-ethoxy-5,5-difluoro-6-oxohexan-3-yl)-5,5-dimethylcyclohex-1-ene-1-carboxylate(25)

[0130] 1 H-NMR(400 MHz,CDCl3):δ=5.15(s,1H),4.30(dd,J=14.2,7.1,2H),4.22-4.12(m,2H),3.51(s,1H),2.43-1.66(m,16H),1.56-1.41(m,2H),1.37-1.27(m,9H),0.92(d,J=8.9,6H),0.80(s,3H). 13 C-NMR(100 MHz,CDCl3):δ=169.5,169.4,164.2(t, 2 J C-F =32.7),148.1,148.0,143.4,143.2,127.1,127.1,116.1(t, 1 J C-F =251.1),115.9,115.8,62.8,60.2,45.9,45.8,40.9,37.9,37.8(t, 2 J C-F =22.2),35.1,34.7,31.7,31.6,31.2,31.1,28.7,28.6,28.4,27.7,27.6,26.3,21.2,14.2,13.9. 19 F-NMR(376 MHz,CDCl3):δ=-96.91--109.40(m,).HR-MS(EI)m / z calcd for C 28 H 42 F2O4[M+H +]481.3124,found481.3128.

[0131] Ethyl

[0132] 8-(12-cyano-8,8-difluorododec-1-en-6-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(26)

[0133] 1 H-NMR(400 MHz,CDCl3):δ=5.77(ddt,J=16.9,10.2,6.7,1H),5.04-4.90(m,2H),4.23-4.12(m,2H),4.04-3.92(m,4H),3.71-3.61(m,1H),2.59-2.47(m,2H),2.36(t,J=7.1,2H),2.24(ddt,J=17.7,12.8,6.6,2H),2.08-1.80(m,6H),1.75-1.67(m,4H),1.62(dt,J=8.8,2.8,2H),1.50-1.31(m,3H),1.31-1.26(m,4H). 13 C-NMR(100 MHz,CDCl3):δ=168.4,147.0,138.8,124.8(t, 1 J C-F =241.6),124.8,119.6,114.8,107.4,64.6,60.5,39.9(t, 2 J C-F =24.6),37.4,35.4(t, 3 J C-F =3.9),35.3(t, 2 J C-F =25.4),33.8,33.4,30.7,26.5,25.3,23.7,21.6(t, 3 J C-F =4.6),17.1,14.4. 19 F-NMR(376 MHz,CDCl3):δ=-94.33(d,J=242.8),-95.85(d,J=242.7).HR-MS(EI)m / z calcd for C 24 H 35 F2NO4[M+H + ]440.2607,found 440.2611.

[0134] Ethyl

[0135] 8-(8-chloro-1-ethoxy-2,2-difluoro-1-oxooctan-4-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(27)

[0136] 1 H-NMR(400 MHz,CDCl3):δ=4.34-4.25(m,2H),4.20-4.13(m,2H),4.02-3.93(m,4H),3.79(dd,J=13.3,7.1,1H),3.51(t,J=6.8,2H),2.52(q,J=17.8,2H),2.33-2.08(m,4H),1.82-1.69(m,4H),1.52-1.37(m,3H),1.34(t,J=7.2,4H),1.29(t,J=7.1,3H). 13 C-NMR(100 MHz,CDCl3):δ=167.9,164.2(t, 2 J C-F =32.7),146.2,125.4,116.1(t, 1 J C-F =251.2),107.3,64.6,64.6,63.0,60.5,44.9,37.8(t, 2 J C-F =22.4),37.4,34.4(t, 3 J C-F =3.2),32.7,32.5,30.7,24.3,23.8,14.3,14.0. 19 F-NMR(376 MHz,CDCl3):δ=-103.08(d,J=263.3),-104.15(d,J=263.0).HR-MS(EI)m / z calcd for C 21 H 31 ClF2O6[M+H + ]453.1850,found453.1855.

[0137] Ethyl

[0138] 2-(9-cyano-1-(1,3-dioxan-2-yl)-5,5-difluorononan-3-yl)cyclohex-1-ene-1-carboxylate(28)

[0139] 1 H-NMR(400 MHz,CDCl3):δ=4.49(t,J=4.6,1H),4.16(qd,J=7.1,1.2,2H),4.08(dd,J=11.5,4.0,2H),3.80-3.68(m,2H),3.43(dd,J=8.1,5.2,1H),2.36(t,J=7.0,2H),2.27(s,2H),2.12-1.94(m,4H),1.94-1.78(m,3H),1.70(dd,J=14.6,7.4,2H),1.66-1.56(m,7H),1.56-1.42(m,4H),1.28(t,J=7.1,3H). 13 C-NMR(100 MHz,CDCl3):δ=169.8,145.3,127.6,124.9(t, 1 J C-F =241.6),119.6,102.2,67.0,60.3,39.9(t, 2 J C-F =24.4),35.9(t, 3 J C-F =3.8),35.3(t, 2 J C-F =25.5),32.9,27.8,27.3,25.9,25.3,23.8,22.3,22.1,21.6(t, 3 J C-F =4.6),17.1,14.4. 19 F-NMR(376 MHz,CDCl3):δ=-94.67(d,J=242.7),-95.40(d,J=242.6).HR-MS(EI)m / zcalcd for C 23 H 35 F2NO4[M+H + ]428.2607,found 428.2612.

[0140] Ethyl

[0141] 2-(9-cyano-1-(1,3-dioxan-2-yl)-5,5-difluorononan-3-yl)-5,5-dimethylcyclohex-1-ene-1-carboxylate(29)

[0142] 1H-NMR(400 MHz,CDCl3):δ=4.49(t,J=4.7,1H),4.20-4.12(m,2H),4.11-4.04(m,2H),3.79-3.68(m,2H),3.44(dd,J=8.7,5.0,1H),2.36(t,J=7.0,2H),2.11-1.98(m,6H),1.95-1.79(m,3H),1.75-1.66(m,2H),1.60(ddd,J=11.2,10.1,6.1,3H),1.56-1.42(m,4H),1.34(dd,J=7.4,5.2,2H),1.28(t,J=7.1,3H),0.91(d,J=9.5,6H). 13 C-NMR(100MHz,CDCl3):δ=169.8,143.9,126.9,124.9(t, 1 J C-F =241.6),119.6,102.2,67.0,60.3,41.0,40.0(t, 2 J C-F =24.5),35.7(t, 3 J C-F =3.9),35.3(t, 2 J C-F =25.5),34.9,33.0,28.8,28.6,28.2,27.8,25.9,25.3,21.6,17.1,14.4. 19 F-NMR(376 MHz,CDCl3):δ=-95.14(d,J=3.8).HR-MS(EI)m / zcalcd for C 25 H 39 F2NO4[M+H + ]456.2920,found 456.2926.

[0143] Ethyl 8-[1-(4-chlorophenoxy)-11-cyano-7,7-difluoroundecan-5-yl]-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(30)

[0144] 1H-NMR(400 MHz,CDCl3):δ=7.24-7.18(m,2H),6.82-6.76(m,2H),4.16(q,J=7.1Hz,2H),4.02-3.93(m,4H),3.90(t,J=6.5 Hz,2H),3.79-3.61(m,1H),2.53(s,2H),2.36(t,J=7.0 Hz,2H),2.33-2.16(m,2H),2.09-1.81(m,4H),1.78-1.66(m,6H),1.66-1.59(m,2H),1.49(dt,J=16.6,7.4 Hz,2H),1.43-1.33(m,2H),1.26(d,J=7.1 Hz,3H). 13 C-NMR(100 MHz,CDCl3):δ=168.4,157.8,147.0,129.4,127.2,125.4,124.8(t, 1 J C-F =241.6 Hz),119.6,115.9,107.4,68.1,64.7,64.6,60.6,39.9(t, 2 J C-F =24.7 Hz),37.4,35.4(t, 2 J C-F =25.5 Hz),33.7,30.7,29.2,25.3,23.7,23.6,21.6(t, 3 J C-F =4.6 Hz),17.1,14.4. 19 F-NMR(376 MHz,CDCl3):δ=-94.47(d,J=242.8 Hz),-96.07(d,J=242.9 Hz).HR-MS(EI)m / z calcd for C 29 H 38 ClF2NO5,[M+H + ]554.2479 found 554.2476.

[0145] Ethyl

[0146] 8-(1-(4-chloro-3-methylphenoxy)-11-cyano-7,7-difluoroundecan-5-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(31)

[0147] 1H-NMR(400 MHz,CDCl3):δ=7.20(dd,J=8.7,5.0,1H),6.76(dd,J=8.1,2.9,1H),6.65(td,J=8.3,3.0,1H),4.21-4.11(m,2H),4.04-3.93(m,4H),3.92-3.84(m,2H),3.76-3.65(m,1H),2.53(s,2H),2.36(t,J=7.0,2H),2.33(s,3H),2.27(dd,J=15.0,6.7,2H),2.08-1.31(m,16H),1.28(td,J=7.1,4.6,3H). 13 C-NMR(100 MHz,CDCl3):δ=168.3,157.7,147.0,137.0,129.6,125.7,124.9,124.8(t, 2 J C-F =241.6),119.6,117.2,113.2,107.4,68.0,64.6,64.6,60.5,39.9(t, 2 J C-F =24.6),37.4,35.4(t, 2 J C-F =25.5),33.7,30.7,29.6,29.3,25.9,25.3,23.7,21.6(t, 3 J C-F =4.7),20.4,17.1,14.4. 19 F-NMR(376MHz,CDCl3):δ=-94.45(d,J=242.8),-96.05(d,J=242.9).HR-MS(EI)m / z calcd forC 30 H 40 ClF2NO5[M+H + ]568.2636,found568.2640.

[0148] Ethyl 8-[1-(2-chloro-4-methoxyphenoxy)-11-cyano-7,7-difluoroundecan-5-yl]-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(32)

[0149] 1H-NMR(400 MHz,CDCl3):δ=6.93(d,J=3.0 Hz,1H),6.85(d,J=9.0 Hz,1H),6.73(dd,J=9.0,3.0 Hz,1H),4.17(q,J=7.1 Hz,2H),4.01-3.92(m,6H),3.75(s,3H),3.71(dd,J=10.2,4.3 Hz,1H),2.53(s,2H),2.36(t,J=7.0 Hz,2H),2.31-2.20(m,2H),2.00-1.89(m,2H),1.86-1.68(m,8H),1.65-1.60(m,2H),1.56-1.46(m,2H),1.42(dd,J=14.2,6.9 Hz,2H),1.26(d,J=7.1 Hz,3H). 13 C-NMR(100 MHz,CDCl3):δ=168.3,153.8,148.9,146.9,124.7,124.7(t, 1 J C-F =241.7 Hz),123.7,119.5,115.9,115.0,112.9,107.3,69.8,64.5,60.4,55.9,39.8(t, 2 J C-F =24.6 Hz),37.3,35.3(t, 4 J C-F =3.8 Hz),35.2(t, 2 J C-F =25.4 Hz),33.6,30.6,29.2,27.0,25.2,23.6,21.5(t, 3 J C-F =4.6 Hz),17.0,14.2. 19 F-NMR(376 MHz,CDCl3):δ=-94.62(d,J=243.7 Hz),-96.13(d,J=241.8 Hz).HR-MS(EI)m / z calcd for C 30 H 40 ClF2NO6[M+H + ]584.2585,found 584.2588.

[0150] Ethyl

[0151] 8-(7-cyano-1-cyclopropyl-3,3-difluoroheptyl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(33)

[0152] 1 H-NMR(400 MHz,CDCl3):δ=4.18-4.09(m,2H),3.99(pd,J=7.8,4.3,4H),2.90(td,J=9.2,5.3,1H),2.54(s,2H),2.51-2.40(m,2H),2.36(t,J=7.0,2H),2.23-2.02(m,2H),1.96-1.80(m,2H),1.76(t,J=6.5,2H),1.73-1.67(m,2H),1.66-1.59(m,2H),1.26(t,J=7.1,3H),0.85-0.74(m,1H),0.65-0.51(m,1H),0.44-0.34(m,1H),0.32-0.15(m,2H). 13 C-NMR(100 MHz,CDCl3):δ=168.2,148.1,124.5(t, 1 J C-F =241.1),123.2,119.6,107.4,64.6,64.6,60.4,40.8,39.7(t, 2 J C-F =24.9),37.3,35.3(t, 2 J C-F =25.6),30.8,25.2,24.7,21.6,17.0,15.7,14.3,6.4,3.9. 19 F-NMR(376 MHz,CDCl3):δ=-94.67(d,J=242.8),-96.03(d,J=242.7).HR-MS(EI)m / z calcd for C 22 H 31 F2NO4[M+H + ]412.2294,found412.2299.

[0153] Ethyl

[0154] 8-(7-cyano-1-cyclobutyl-3,3-difluoroheptyl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(34)

[0155] 1 H-NMR(400 MHz,CDCl3):δ=4.26-4.17(m,2H),4.05-3.91(m,4H),3.63(t,J=9.1,1H),2.53(s,2H),2.37(t,J=7.1,2H),2.33-2.02(m,4H),1.94-1.57(m,15H),1.31(t,J=7.1,3H). 13 C-NMR(100 MHz,CDCl3):δ=168.6,145.7,125.0,124.7(t, 1 J C-F =241.3),119.6,107.4,64.6,64.6,60.5,39.1,37.4,36.5(t, 2 J C-F =25.0),34.9(t, 2 J C-F =25.4),30.7,28.0,27.1,25.7,25.3,21.5(t, 3 J C-F =4.7),17.3,17.0,14.4. 19 F-NMR(376 MHz,CDCl3):δ=-94.38(d,J=242.6),-95.37(d,J=242.6).HR-MS(EI)m / z calcd forC 23 H 33 F2NO4[M+H + ]426.2450,found426.2448.

[0156] Ethyl

[0157] 8-(1-cyclopropyl-4-(diethylamino)-3,3-difluoro-4-oxobutyl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(35)

[0158] 1H-NMR(400 MHz,CDCl3):δ=4.11(q,J=7.1,2H),4.01-3.91(m,4H),3.60-3.21(m,4H),3.03(dd,J=15.4,8.4,1H),2.56-2.35(m,6H),1.74(t,J=6.9,2H),1.23(t,J=7.1,3H),1.14(dt,J=14.0,7.0,6H),0.87-0.78(m,1H),0.56-0.47(m,1H),0.42-0.32(m,1H),0.31-0.22(m,2H). 13 C-NMR(100 MHz,CDCl3):δ=168.2,163.0(t, 2 J C-F =29.3),148.4,122.8,119.4(t, 1 J C-F =255.5),107.5,64.6,64.5,60.2,41.9(t, 3 J C-F =6.3),41.6,40.2,37.7(t, 2 J C-F =22.6),37.3,30.8,24.9,15.2,14.3,14.2,12.4,6.3,3.8. 19 F-NMR(376 MHz,CDCl3):δ=-98.26(d,J=280.2),-99.70(d,J=280.2).HR-MS(EI)m / z calcd forC 22 H 33 F2NO5[M+H + ]430.2400,found430.2405.

[0159] Ethyl

[0160] 8-(1-cyclopropyl-3,3-difluoro-4-morpholino-4-oxobutyl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(36)

[0161] 1H-NMR(400 MHz,CDCl3):δ=4.17-4.07(m,2H),4.03-3.94(m,4H),3.76-3.59(m,8H),3.05(dd,J=16.6,7.1,1H),2.59-2.37(m,6H),1.82-1.69(m,2H),1.27-1.23(t,J=7.06,3H),0.92-0.74(m,1H),0.60-0.36(m,2H),0.32-0.21(m,2H). 13 C-NMR(100 MHz,CDCl3):δ=168.1,162.3(t, 2 J C-F =29.5),148.2,122.9,119.2(t, 1 J C-F =255.4),107.5,66.9,66.8,64.6,64.6,60.3,46.6(t, 3 J C-F =6.4),43.5,40.1,37.5(t, 2 J C-F =22),37.3,30.8,24.9,15.3,14.3,6.3,3.9. 19 F-NMR(376 MHz,CDCl3):δ=-97.89(d,J=282.0),-98.74(d,J=282.0).HR-MS(EI)m / z calcd for C 22 H 30 F2NO6[M+H + ]444.2192,found444.2199.

[0162] Ethyl

[0163] 2-(1-cyclopropyl-3,3-difluoro-4-oxo-4-(pyrrolidin-1-yl)butyl)cyclohept-1-ene-1-carboxylate(37)

[0164] 1H-NMR(400 MHz,CDCl3):δ=3.63(d,J=9.3,5H),3.48(t,J=6.9,2H),2.56(td,J=9.1,5.2,1H),2.48-2.23(m,6H),1.96-1.88(m,2H),1.87-1.77(m,3H),1.74-1.37(m,5H),1.22(s,2H),0.85-0.74(m,1H),0.55-0.32(m,2H),0.31-0.22(m,2H). 13 C-NMR(100MHz,CDCl3):δ=170.9,162.5(t, 2 J C-F =30.1),152.8,131.3,118.9(t, 1 J C-F =252.1),51.3,47.6,46.8(t, 3 J C-F =6.8),42.1(t, 4 J C-F =3.3),37.0(t, 2 J C-F =22.4),32.6,30.9,29.8,27.2,26.7,26.6,26.2,23.4,14.8,6.1,4.3. 19 F-NMR(376 MHz,CDCl3):δ=-100.18(d,J=277.2),-101.98(d,J=277.3).HR-MS(EI)m / z calcd for C 21 H 31 F2NO3[M+H + ]384.2345,found 384.2347.

[0165] Ethyl(Z)-4-cyclopropyl-6,6-difluoro-3-methyl-7-oxo-7-(piperidin-1-yl)-2-(2-(thiophen-2-yl)ethyl)hept-2-enoate(38)

[0166] 1H-NMR(400 MHz,CDCl3):δ=7.22(dd,J=4.8,3.0 Hz,1H),6.96(d,J=4.9 Hz,2H),4.17-4.09(m,2H),3.61(dd,J=10.6,5.0 Hz,2H),3.54(dd,J=10.6,5.0 Hz,2H),2.73(t,J=7.7 Hz,2H),2.68-2.62(m,1H),2.61-2.51(m,2H),2.41(ddd,J=22.7,13.8,6.9 Hz,2H),1.68(s,3H),1.65(dd,J=6.6,3.2 Hz,2H),1.61-1.56(m,4H),1.27(d,J=7.1Hz,3H),0.83-0.76(m,1H),0.58-0.50(m,1H),0.40-0.29(m,2H),0.26(dt,J=8.9,4.3 Hz,1H). 13 C-NMR(100 MHz,CDCl3):δ=169.9,162.1(t, 2 J C-F =29.0 Hz),145.0,142.1,128.5,128.1,125.2,120.6,119.4(t, 1 J C-F =255.5 Hz),60.2,47.0(t, 3 J C-F =6.7 Hz),44.6,41.8(t, 4 J C-F =2.7 Hz),37.7(t, 2 J C-F =22.4 Hz),31.6,29.1,26.7,25.7,24.7,15.4,14.3,14.1,6.2,3.9. 19 F-NMR(376 MHz,CDCl3):δ=-97.83(d,J=280.1 Hz),-99.13(d,J=280.1Hz).HR-MS(EI)m / z calcd forC 24 H 33 F2NO3S[M+H + ]454.2222,found 454.2227.

[0167] Ethyl

[0168] 8-(2,2-difluoro-1-(indolin-1-yl)-7-methyl-1-oxooctan-4-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(39)

[0169] 1 H-NMR(400 MHz,CDCl3):δ=8.19(d,J=8.3,1H),7.21(t,J=6.9,2H),7.08(t,J=7.1,1H),4.38-4.24(m,2H),4.10(qq,J=10.8,7.1,2H),4.00-3.90(m,4H),3.83-3.74(m,1H),3.17(t,J=8.3,2H),2.58-2.23(m,6H),1.78-1.69(m,2H),1.56-1.40(m,3H),1.26-1.19(m,4H),1.14-1.04(m,1H),0.87(d,J=6.6,6H). 13 C-NMR(100 MHz,CDCl3):δ=168.4,161.6(t, 2 J C-F =30.3),147.2,142.9,131.8,127.6,125.1,124.7,124.4,119.3(t, 1 J C-F =255.4),118.0,107.5,64.6,64.6,60.3,48.1(t, 3 J C-F =8.0),37.4,37.3(t, 2 J C-F =22.0),36.3,35.0,31.7,30.8,28.8,28.2,23.9,22.8,22.6,14.3. 19 F-NMR(376 MHz,CDCl3):δ=-101.27(d,J=281.1),-102.05(d,J=280.9).HR-MS(EI)m / z calcd forC 28 H 37 F2NO5[M+H + ]506.2713,found506.2717.

[0170] Ethyl 2-{1-[3,4-dihydroquinolin-1(2H)-yl]-1,1-difluoro-6-methylheptan-3-yl}-5,5-dimethylcyclohex-1-ene-1-carboxylate(40)

[0171] 1 H-NMR(400 MHz,CDCl3):δ=6.93(d,J=3.0 Hz,1H),6.85(d,J=9.0 Hz,1H),6.73(dd,J=9.0,3.0 Hz,1H),4.17(q,J=7.1 Hz,2H),4.01-3.92(m,6H),3.75(s,3H),3.71(dd,J=10.2,4.3 Hz,1H),2.53(s,2H),2.36(t,J=7.0 Hz,2H),2.31-2.20(m,2H),2.00-1.89(m,2H),1.86-1.68(m,8H),1.65-1.60(m,2H),1.56-1.46(m,2H),1.42(dd,J=14.2,6.9 Hz,2H),1.26(d,J=7.1 Hz,3H). 13 C-NMR(100 MHz,CDCl3):δ=184.5,170.1,162.9(t, 2 J C-F =29.7 Hz),144.3,134.5,134.2,132.9,132.5,128.8,128.7,127.1,126.8,126.7,126.7,126.6,126.3,126.2,119.6(t, 1 J C-F =255.2 Hz),60.2,47.3(t, 3 J C-F =7.5Hz),45.7,43.5(t, 3 J C-F =7.0Hz),41.8,41.0,38.6,37.7(td, 3 J C-F =21.9,7.2 Hz),36.6,35.2,35.0,31.9,29.6,28.6,28.4,28.2,28.1,28.0,22.9,22.6,21.8,14.4,14.4. 19F-NMR(376 MHz,CDCl3):δ=-99.04(dd,J=279.3,11.9 Hz),-100.02(dd,J=279.3,120.4 Hz).HR-MS(EI)m / z calcd for C 28 H 41 F2NO2[M+H + ]462.3178,found 462.3175.

[0172] Ethyl

[0173] 2-(3,3-difluoro-8-methyl-1-(triisopropylsilyl)non-1-yn-5-yl)cyclohex-1-ene-1-carboxylate(41)

[0174] 1 H-NMR(400 MHz,CDCl3):δ=4.16(qd,J=7.1,0.9,2H),3.50-3.30(m,1H),2.32-1.93(m,5H),1.66-1.32(m,8H),1.28(t,J=7.1,3H),1.08(d,J=2.1,23H),0.85(dd,J=6.6,2.5,6H). 13 C-NMR(100 MHz,CDCl3):δ=169.9,145.0,127.4,113.8(t, 1 J C-F =233.6),99.8(t, 2 J C-F =38.8),89.5(t, 3 J C-F =5.4),60.2,42.8(t, 2 J C-F =25.4),37.0,36.6,30.7,28.3,27.3,24.5,23.0,22.5,22.4,22.3,18.6,14.4,11.1. 19 F-NMR(376 MHz,CDCl3):δ=-78.99(d,J=272.0),-82.30(d,J=272.0).HR-MS(EI)m / z calcd for C 28 H 48 F2O2Si[M+H + ]483.3464,found483.3461.

[0175] Ethyl

[0176] 2-(3,3-difluoro-8-methylnon-1-yn-5-yl)-5,5-dimethylcyclohex-1-ene-1-carboxylate(42)

[0177] 1 H-NMR(400 MHz,CDCl3):δ=4.22-4.10(m,2H),3.60-3.43(m,1H),2.73(t,J=5.0,1H),2.31-1.95(m,6H),1.53-1.40(m,2H),1.35(t,J=6.5,2H),1.29(t,J=7.1,3H),1.25-0.98(m,3H),0.92(d,J=5.8,6H),0.86(dd,J=6.6,2.6,6H). 13 C-NMR(100 MHz,CDCl3):δ=169.9,143.3,127.0,114.1(t, 1 J C-F =233.9),76.9(t, 2 J C-F =40.5),75.3(t, 3 J C-F =6.8),60.2,42.5(t, 2 J C-F =24.7),41.0,36.5,34.9,31.3,28.7,28.6,28.2,27.8,22.9,22.6,21.8,14.4. 19 F-NMR(376 MHz,CDCl3):δ=-80.89(d,J=275.6),-82.17(d,J=275.0).HR-MS(EI)m / z calcd forC 21 H 32 F2O2[M+H + ]355.2443,found 355.2447.

[0178] Ethyl

[0179] 2-(1-(1,3-dioxan-2-yl)-5,5-difluoro-7-(triisopropylsilyl)hept-6-yn-3-yl)cyclohex-1-ene-1-carboxylate(43)

[0180] 1H-NMR(400 MHz,CDCl3):δ=4.48(t,J=4.9,1H),4.18-4.11(m,2H),4.10-4.01(m,2H),3.72(td,J=12.2,2.5,2H),3.57-3.46(m,1H),2.35-1.96(m,7H),1.70-1.42(m,9H),1.26(t,J=7.1,3H),1.10-1.05(m,21H). 13 C-NMR(100 MHz,CDCl3):δ=169.6,144.7,127.7,113.5(t, 1 J C-F =233.7),102.3,99.8(t, 2 J C-F =38.8),89.5(t, 3 J C-F =5.5),67.0,60.2,42.8(t, 2 J C-F =25.6),36.2,33.1,27.2,27.1,26.0,24.3,22.3,22.2,18.6,14.4,11.0. 19 F-NMR(376 MHz,CDCl3):δ=-79.98(d,J=272.1),-82.83(d,J=272.1).HR-MS(EI)m / z calcd for C 29 H 48 F2O4Si[M+H + ]527.3363,found 527.3366.

[0181] tert-Butyl4-(benzyloxy)-4-(5-(2-(ethoxycarbonyl)-4,4-dimethylcyclohex-1-en-1-yl)-3,3-difluorohept-1-yn-1-yl)piperidine-1-carboxylate(44)

[0182] 1H-NMR(400 MHz,CDCl3):δ=7.37-7.29(m,5H),4.64(s,2H),4.13(dtt,J=10.8,7.3,3.7,2H),3.47(dddd,J=24.9,12.6,10.5,3.5,5H),2.29-1.96(m,9H),1.92-1.81(m,2H),1.56(dd,J=14.0,6.5,1H),1.46(s,9H),1.36(t,J=5.6,2H),1.25(t,J=7.1,3H),0.92(s,6H),0.83(t,J=7.4,3H). 13 C-NMR(100 MHz,CDCl3):δ=169.6,154.7,143.8,138.3,128.5,127.8,127.8,126.9,114.5(t, 1 J C-F =234.1),86.9(t, 3 J C-F =6.5),80.7(t, 2 J C-F =40.7),79.9,72.1,66.3,60.2,42.5(t, 2 J C-F =25.1),40.9,37.9,34.9,28.6,28.4,28.1,26.3,22.1,14.4,12.0. 19 F-NMR(376 MHz,CDCl3):δ=-79.06(d,J=272.8),-81.94(d,J=272.8).HR-MS(EI)m / z calcd forC 35 H 49 F2NO5[M+H + ]602.3652,found 602.3657.

[0183] Ethyl

[0184] 2-(2,2-difluoro-7-methyl-1-(tosyloxy)octan-4-yl)cyclopent-1-ene-1-carboxylate(45)

[0185] 1H-NMR(400 MHz,CDCl3):δ=7.79(d,J=8.3,2H),7.35(d,J=8.1,2H),4.23-4.09(m,4H),3.85-3.69(m,1H),2.64-2.53(m,2H),2.45(s,3H),2.43-2.27(m,2H),2.13-1.92(m,2H),1.82-1.73(m,2H),1.51-1.31(m,3H),1.27(t,J=7.1,3H),1.13-0.90(m,2H),0.83(dd,J=6.6,0.8,6H). 13 C-NMR(100 MHz,CDCl3):δ=166.2,159.1,145.4,132.4,130.1,129.7,128.2,120.8(t, 1 J C-F =244.1),68.1(t, 2 J C-F =35.1),59.9,37.2(t, 2 J C-F =22.5),36.3,33.8,32.7,32.5(t, 3 J C-F =3.7),32.3,27.9,22.8,22.4,21.8,21.7,14.4. 19 F-NMR(376 MHz,CDCl3):δ=-101.96(d,J=257.8),-103.27(d,J=257.8).HR-MS(EI)m / z calcdfor C 24 H 34 F2O5S[M+H + ]473.2168,found 473.2172.

[0186] Ethyl

[0187] 8-(1-cyclopropyl-3-(diethoxyphosphoryl)-3,3-difluoropropyl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(46)

[0188] 1H-NMR(400 MHz,CDCl3):δ=4.30-4.19(m,4H),4.12(q,J=7.1,2H),4.03-3.92(m,4H),3.10(dd,J=16.5,7.2,1H),2.62-2.14(m,6H),1.79-1.68(m,2H),1.36(t,J=7.1,6H),1.26-1.22(m,3H),0.89-0.74(m,1H),0.62-0.34(m,2H),0.28(pd,J=9.2,5.0,2H).

[0189] 13 C-NMR(100 MHz,CDCl3):δ=168.1,147.9,123.1,119.6(t, 1 J C-F =261.1),107.5,64.6,64.6,60.4,39.5,39.4,37.3,36.6(t, 2 J C-F =20.0),36.4(t, 2 J C-F =20.1),30.9,27.2,24.9,16.6,16.5,15.2,14.3,6.6,4.0. 19 F-NMR(376 MHz,CDCl3):δ=-112.54(qd,J=296.5,108.5,2F).HR-MS(EI)m / z calcd for C 21 H 33 F2O7P[M+H + ]467.2005,found467.2008.

[0190] Ethyl

[0191] 8-(1-(benzo[d]oxazol-2-yl)-1,1-difluoro-6-methylheptan-3-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(47)

[0192] 1H-NMR(400MHz,CDCl3):δ=7.79(d,J=7.4,1H),7.59(d,J=7.6,1H),7.47-7.37(m,2H),4.03-3.83(m,7H),2.73-2.43(m,2H),2.42-2.20(m,4H),1.72-1.63(m,2H),1.55-1.40(m,3H),1.22-1.15(m,4H),1.07(ddd,J=18.2,12.5,6.0,1H),0.85(dd,J=6.6,0.7,6H). 13 C-NMR(100MHz,CDCl3):δ=168.0,158.3(t, 2 J C-F =33.6),150.7,146.5,140.2,126.8,125.3,124.9,121.3,116.8(t, 1 J C-F =242.7),111.5,107.3,64.6,64.5,60.3,39.3(t, 2 J C-F =22.8),37.3,36.2,35.1,31.6,30.7,28.2,23.9,22.8,22.6,14.2. 19 F-NMR(376MHz,CDCl3):δ=-96.70(d,J=275.2),-98.46(d,J=275.2).HR-MS(EI)m / z calcdfor C 26 H 33 F2NO5[M+H + ]478.2400,found478.2404.

[0193] Ethyl 2-[1-(1,3-dioxan-2-yl)-5,5,6,6,7,7,8,8,8-nonafluorooctan-3-yl]-5,5-dimethylcyclohex-1-ene-1-carboxylate(48)

[0194] 1H-NMR(400MHz,CDCl3):δ=4.51(t,J=3.4Hz,1H),4.17(q,J=7.1Hz,2H),4.08(dd,J=11.3,3.8Hz,2H),3.74(td,J=12.1,2.3Hz,2H),3.69-3.60(m,1H),2.33-2.16(m,1H),2.16-1.96(m,6H),1.68-1.47(m,4H),1.40-1.33(m,2H),1.32-1.29(m,1H),1.27(t,J=7.1Hz,3H),0.92(s,3H),0.91(s,3H). 13 C-NMR(100MHz,CDCl3):δ=169.5,142.2,127.8,102.0,67.0,67.0,60.4,40.9,34.9,34.0,33.6(t, 2 J C-F =21.2Hz),32.8,28.5,28.4,28.1,27.8,25.9,21.6,14.3. 19 F-NMR(376MHz,CDCl3):δ=-81.06(ddd,J=13.6,6.8,3.5Hz),-111.18--118.07(m),-124.59(dd,J=20.2,10.0Hz),-125.88(ddd,J=24.5,15.3,6.5Hz).HR-MS(EI)m / z calcd for C 23 H 31 F9O4[M+H + ]543.2151,found 543.2148.

[0195] Ethyl(Z)-4-[2-(1,3-dioxan-2-yl)ethyl]-6,6,7,7,8,8,9,9,9-nonafluoro-3-methyl-2-[2-(thiophen-2-yl)ethyl]non-2-enoate(49)

[0196] 1H-NMR (400MHz, CDCl3): δ = 7.25-7.16 (m, 1H), 6.94 (d, J = 4.1Hz, 2H), 4.51 (t, J = 4 .6Hz,1H),4.18(q,J=7.1Hz,2H),4.08(dd,J=11.2,4.5Hz,2H),3.74(td,J=12.2, 2.3Hz,2H),3.64-3.44(m,1H),2.78-2.68(m,2H),2.62-2.53(m,2H),2.24-1.89( m,3H),1.64-1.57(m,2H),1.55(s,3H),1.53-1.32(m,3H),1.28(t,J=7.1Hz,3H). 13 C-NMR (100MHz, CDCl3): δ=169.5,142.0,141.9,131.0,128.5,125.4,120.7,102.0,67.0,67.0,60.5,35.3,33.7(t, 2 J C-F =21.2Hz),32.7,31.7,29.0,27.4,25.9,14.3,12.7. 19 F-NMR (376MHz, CDCl3): δ = -81.06 (ddd, J = 9.9, 8.7, 3.0Hz), -107.27--117.07 (m) ,-124.60(dd,J=20.4,10.0Hz),-125.88(ddd,J=20.9,9.5,5.0Hz).HR-MS(EI)m / z calcd for C 24 H 29 F9O4S[M+H + ]585.1716,found585.1708.

[0197] The present invention studies the substrate applicability and functional group compatibility of a new type of alkyl zinc reagent in the difunctionalization reaction of olefins. In this reaction system, it shows a wide range of substrate applicability and excellent functional group compatibility, and the reaction can be smoothly scaled up to the gram scale, and the reaction efficiency remains basically unchanged. The alkyl zinc reagent has good chemical reactivity through the inorganic salt activation strategy. The reagent can be further applied to the structural modification of natural products with pharmacological activity and drug molecules, which further illustrates that this type of alkyl zinc reagent and the synthetic methodology have potential application value in the fields of organic chemistry, biochemistry, and medicinal chemistry. Specific reaction results are as follows: Figure 4-Figure 6 shown.

[0198] Obviously, the above embodiments are merely examples for clear explanation and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the protection scope of the invention.

Claims

1. The use of an alkyl zinc reagent in the preparation of an alkyl substituted alkyl difluoro reagent, characterized in that: The preparation of the alkyl-substituted alkyl difluoro reagent comprises the following steps: In an organic solvent, Mixed reaction with R-ZnOPiv·Mg(OPiv)Br under the action of catalyst to obtain the alkyl substituted alkyl difluoro reagent Wherein X=Br, I; the alkyl-substituted alkyl difluoro reagent is: The catalyst is selected from Co and / or Ni.

2. The use according to claim 1, characterized in that: Said The molar ratio of R-ZnOPiv·Mg(OPiv)Br is 1:1:1.5 or 1:2:3, wherein X=Br, I.

Images