CN115260069B - 3, 3-difluoroallylium salt compound and preparation method and application thereof - Google Patents

3, 3-difluoroallylium salt compound and preparation method and application thereof Download PDF

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CN115260069B
CN115260069B CN202211043669.XA CN202211043669A CN115260069B CN 115260069 B CN115260069 B CN 115260069B CN 202211043669 A CN202211043669 A CN 202211043669A CN 115260069 B CN115260069 B CN 115260069B
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substituted
salt
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difluoroallylium
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CN115260069A (en
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张新刚
闵巧桥
冯笑甜
高兴
任金秀
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The invention discloses a 3,3-Difluoroallylium salt compounds, and a preparation method and application thereof. The invention provides a 3, 3-difluoroallylium salt shown in a formula C and a preparation method of the substance; the important fluorine-containing reagent is prepared by using cheap industrial raw materials; the method can be used as an alpha, alpha-gem difluoroallylation reagent, provides a more universal and cheap new method for alpha, alpha-gem difluoroallylation, and has high efficiency and better application prospect.

Description

3, 3-difluoroallylium salt compound and preparation method and application thereof
Technical Field
The invention relates to a 3, 3-difluoroallylsulfonium salt compound and a preparation method and application thereof, in particular to a 3, 3-difluoroallylsulfonium salt, selenonium salt and telluronium salt compound and a preparation method and application thereof.
Background
The alpha-aryl, heteroaryl, alkenyl, alkynyl, alkyl-alpha, alpha-difluoroallyl structural compound and the derivative building blocks thereof have wide application in the aspects of biological medicine, pesticide, material science and the like. For example: some important fluorine-containing drugs KAG-308, glecarprevir, taflupirest, etc. contain an alpha, alpha-difluoroallyl structure.
However, conventional methods of synthesizing α -aryl, heteroaryl, alkenyl, alkynyl, alkyl- α, α -difluoroalkyl blocks are generally made from carbonyl groups by DAST or Deoxofluor (e.g., markovsi, l.n.; pahinnik, v.e.; kirsanov, a.v. synthesis 1973,787. (b) Middleton, w.j.j. Org. chem.1975,40,574. (c) Lal, g.s.; pez, g.p.; pesarei, r.j.; prozonic, f.m.; cheng, h.j. Org. Chem.1999,64,7048.). However, these methods generally have disadvantages such as lengthy reaction steps, poor functional group compatibility, and the necessity of using highly toxic fluorinating agents for some reactions.
Transition metal catalyzed block synthesis of alpha-aryl, heteroaryl or alkenyl-alpha, alpha-difluoroalkyl structural compounds and derivatives thereof developed in the last two decades ((a) Schwaebe, m.k.; mcCarthy, J.R., whitten, J.P. tetrahedron Lett.2000,41,791 (b) Feng, Z., chen, F., zhang, X.org. Lett.2012,14,1938 (c) Belhomme, M. -C, poisson, T., pannecouke, X.org. Lett.2013,15,3428 (d) Taguchi, T., kitagawa, O., morikawa, T., nishiwaki, T., uehara, H., endo, H., kobashi, Y.tetrahedron Lett.1986,27,6103 (e) Sato, K., omote, M, A, fldamag, I.J., lett.No. 2013,15,3428 (d) Taguchi, T., kitagawa, O., morikawa, T., U.S. Lemid, U.H., U.S. Endo, K., U.G., U.S. Lett.S. 6,27,6103 (e) Sato the extent of the same kind, A, U.M., bunneco. However, these methods still exist such as: the compatibility of the functional group is poor, the catalyst usage is high, the reaction condition is harsh, and the like.
In 2014, the palladium-catalyzed coupling reaction of nucleophiles with α -bromo- α, α -difluoroallyl reagents (j.am.chem.soc.2014, 136,1230; ZL 2013.1 0658880.0) simplified the synthesis of α -aryl, heteroaryl, alkenyl- α, α -difluoroallyl structures, but the reaction still had the following limitations: 1. the structural diversity of the product is still to be further broken through under the restriction of synthesis of the alpha-bromo-alpha, alpha-difluoroallyl reagent; 2. because the activity of the alpha-bromo-alpha, alpha-difluoroallyl reagent is high, the reaction is only applicable to part of the nucleophile of the Csp2, and is difficult to be applicable to the nucleophile of the Csp and Csp3 carbon type; 3. palladium catalysts are expensive and some cheaper and less toxic catalysts need to be sought.
For alkyl-alpha, alpha-difluoroallyl structural compounds formed by the reaction of alpha, alpha-difluoroallylation with a nucleophile of the Csp3 carbon type, there are currently few suitable reagents and methods that can be efficiently achieved, and only one example of the reaction of an alpha, alpha-difluoroallyl reagent with a very specific structure, highly activated Csp3 carbon nucleophile has been reported (Nature Communication,2021, 12:3257). For other types of α, α -difluoroallylic reagents (synlett. 1996,4,371; chem. Pharm. Bull.1985,33 (11), 5137), the preparation process is often cumbersome and the reactions involved are often regioselective, defluorinated side reactions can occur, reaction conditions are severe, reaction substrates and types are limited, and it is difficult to achieve a broad spectrum, efficient preparation of the desired product structure.
Therefore, the development of a novel, structurally diverse, reaction-adjustable, alpha-gem-difluoroallylation reagent and its application in a novel, more broad-spectrum and inexpensive method for the allylation of alpha, alpha-gem-difluorois of significant significance.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of larger structural limitation, low reaction activity controllability, limited substrate applicability and the like of the alpha, alpha-gem-difluoroallylation reagent in the prior alpha, alpha-gem-difluoroallylation reaction. The invention aims to provide a novel alpha, alpha-gem-difluoroallylation reagent (namely 3, 3-difluoroallylsulfonium salt, selenonium salt, telluronium salt and derivatives thereof) with various structures and adjustable reactivity, and the reagent can be applied to a novel alpha, alpha-gem-difluoroallylation method with wider spectrum and low cost.
The invention solves the technical problems through the following technical proposal.
The invention provides a 3, 3-difluoroallylium salt shown as a formula C,
wherein z=s, se or Te; x is an anion;
R 1 、R 2 、R 3 and R is 4 H, F, cl, br, I, C independently 1 -C 20 Is or are R 5 Substituted C 1 -C 20 Alkyl, C of (2) 1 -C 20 Is optionally substituted by one or more R 6 Substituted C 1 -C 20 Heteroalkyl of (C) 6 -C 20 Is or are R 7 Substituted C 6 -C 20 Or aryl, heteroaryl of 5-20 membered atoms or substituted with one or more R 8 Substituted 5-20 membered heteroaryl; wherein, C is as follows 1 -C 20 The hetero atom or hetero atom group of the hetero alkyl group is selected from C (=O), S (=O) 2 、SO 2 NR 1’ R 2’ 、O、N、Si、P、P(＝O)、PO(OR 3’ ) 2 、PS(OR 3’ ) 2 、B(R 4’ ) 2 And B (OR) 4’ ) 2 The number of heteroatoms and hetero atom groups is 1 or more; the hetero atoms of the 5-20 membered heteroaryl are selected from S, O, N, si, P and B, and the number of the hetero atoms is 1 or more;
alternatively, R 1 And R is 4 Together with the attached Z forms: 5-20 membered heterocycloalkyl, substituted by one or more R 9 Substituted 5-20 membered heterocycloalkyl, 5-20 membered heteroaryl or substituted with one or more R 10 Substituted 5-20 membered heteroaryl; the heteroatom or heteroatom group of the 5-20 membered heterocycloalkyl group is selected from C (=O), S, S (=O) and S (=O) 2 、O、N、Si、P、P(＝O)、PO(OR 3’ ) 2 、PS(OR 3’ ) 2 、B(R 4’ ) 2 And B (OR) 4’ ) 2 The number of heteroatoms and hetero atom groups is 1 or more; the hetero atom or hetero atom group of the 5-20 membered heteroaryl group is selected from C (=O), S, S (=O) and S (=O) 2 、O、N、Si、P、P(＝O)、PO(OR 3’ ) 2 、PS(OR 3’ ) 2 、B(R 4’ ) 2 And B (OR) 4’ ) 2 The number of heteroatoms and hetero atom groups is 1 or more;
each R 5 、R 6 、R 7 、R 8 、R 9 And R is 10 F, cl, br, I, C independently 1 -C 20 Alkyl, C of (2) 3 -C 20 Cycloalkyl, C 6 -C 20 Aryl, C of (2) 2 -C 20 Alkynyl, C 2 -C 20 Alkenyl, C 1 -C 20 Is optionally substituted by one or more R 1a Substituted C 1 -C 20 Is or are R 1b Substituted C 3 -C 20 Is or are R 1c Substituted C 6 -C 20 Aryl, one or more R 1d Substituted C 2 -C 20 Alkynyl of (2), by one or more R 1e Substituted C 1 -C 20 Is optionally substituted by one or more R 1f Substituted C 2 -C 20 Alkenyl of (c); the C is 1 -C 20 The hetero atom or hetero atom group of the hetero alkyl group is selected from C (=O), S (=O) 2 、SO 2 NR 1’ R 2’ 、O、N、Si、P、P(＝O)、PO(OR 3’ ) 2 、PS(OR 3’ ) 2 、B(R 4’ ) 2 And B (OR) 4’ ) 2 The number of heteroatoms and hetero atom groups is 1 or more;
each R 1’ 、R 2’ 、R 3’ And R is 4’ Independently C 1 -C 20 Alkyl, C of (2) 3 -C 20 Cycloalkyl, C 6 -C 20 Is or are R 1a Substituted C 1 -C 20 Is or are R 1b Substituted C 3 -C 20 Is or are R 1c Substituted C 6 -C 20 Aryl of (a);
each R 1a 、R 1b 、R 1c 、R 1d 、R 1f And R is 1e F, cl, br, I, N independently 3 、C 1 -C 20 Alkyl, C of (2) 6 -C 20 Or independently by three C' s 1 -C 4 Alkyl-substituted silyl groups.
In one embodiment of the present invention, a 3, 3-difluoroallylium salt of formula C,
wherein z=s, se or Te; x is an anion;
the R is 1 、R 2 、R 3 And R is 4 H, F, cl, br, I, C independently 1 -C 20 Is or are R 5 Substituted C 1 -C 20 Alkyl, C of (2) 1 -C 20 Is optionally substituted by one or more R 6 Substituted C 1 -C 20 Heteroalkyl of (C) 6 -C 20 Is or are R 7 Substituted C 6 -C 20 Or aryl, heteroaryl of 5-20 membered atoms or substituted with one or more R 8 Substituted 5-20 membered heteroaryl; wherein, C is as follows 1 -C 20 The hetero atom or hetero atom group of the hetero alkyl group is selected from C (=O), S (=O) 2 、SO 2 NR 1’ R 2’ 、O、N、Si、P、P(＝O)、PO(OR 3’ ) 2 、PS(OR 3’ ) 2 、B(R 4’ ) 2 And B (OR) 4’ ) 2 The number of heteroatoms and hetero atom groups is 1 or more; the hetero atoms of the 5-20 membered heteroaryl are selected from S, O, N, si, P and B, and the number of the hetero atoms is 1 or more;
alternatively, R 1 And R is 4 Together with the attached Z forms: 5-20 membered heterocycloalkyl, substituted by one or more R 9 Substituted 5-20 membered heterocycloalkyl, 5-20 membered heteroaryl or substituted with one or more R 10 Substituted 5-20 membered heteroaryl; the heteroatom or heteroatom group of the 5-20 membered heterocycloalkyl group is selected from C (=O), S, S (=O) and S (=O) 2 、O、N、Si、P、P(＝O)、PO(OR 3’ ) 2 、PS(OR 3’ ) 2 、B(R 4’ ) 2 And B (OR) 4’ ) 2 The number of heteroatoms and hetero atom groups is 1 or more; the hetero atom or hetero atom group of the 5-20 membered heteroaryl group is selected from C (=O), S, S (=O) and S (=O) 2 、O、N、Si、P、P(＝O)、PO(OR 3’ ) 2 、PS(OR 3’ ) 2 、B(R 4’ ) 2 And B (OR) 4’ ) 2 The number of heteroatoms and hetero atom groups is 1 or more;
the R is 5 、R 6 、R 7 、R 8 、R 9 And R is 10 F, cl, br, I, C independently 1 -C 20 Alkyl, C of (2) 3 -C 20 Cycloalkyl, C 6 -C 20 Aryl, C of (2) 2 -C 20 Alkynyl, C 1 -C 20 Is optionally substituted by one or more R 1a Substituted C 1 -C 20 Is or are R 1b Substituted C 3 -C 20 Is or are R 1c Substituted C 6 -C 20 Aryl, one or more R 1d Substituted C 2 -C 20 Alkynyl of (2), by one or more R 1e Substituted C 1 -C 20 Is a heteroalkyl group; the C is 1 -C 20 The hetero atom or hetero atom group of the hetero alkyl group is selected from C (=O), S (=O) 2 、SO 2 NR 1’ R 2’ 、O、N、Si、P、P(＝O)、PO(OR 3’ ) 2 、PS(OR 3’ ) 2 、B(R 4’ ) 2 And B (OR) 4’ ) 2 The number of heteroatoms and hetero atom groups is 1 or more;
each R 1’ 、R 2’ 、R 3’ And R is 4’ Independently C 1 -C 20 Alkyl, C of (2) 3 -C 20 Cycloalkyl, C 6 -C 20 Is or are R 1a Substituted C 1 -C 20 Is or are R 1b Substituted C 3 -C 20 Is or are R 1c Substituted C 6 -C 20 Aryl of (a);
each R 1a 、R 1b 、R 1c 、R 1d And R is 1e F, cl, br, I, N independently 3 、C 1 -C 20 Is a hydrocarbon group.
In certain preferred embodiments of the present application, certain groups in the 3, 3-difluoroallylium salt of formula C are defined below, and the unrecited groups are as described in any of the embodiments of the present application (hereinafter referred to as "in certain embodiments of the present application"), wherein,
x is a conventional anion, and may be, for example, an organic or inorganic anion common in the art, such as trifluoromethanesulfonic acid anion, fluoroboric acid anion, hexafluorophosphoric acid anion, hexafluoroantimonic acid anion, p-toluenesulfonic acid anion, fluorine anion, chlorine anion, bromine anion, iodine anion, and the like.
X is a conventional anion, and may be, for example, an organic or inorganic anion common in the art, such as tetraphenylboronic acid anion, trifluoromethanesulfonic acid anion, fluoroboric acid anion, hexafluorophosphoric acid anion, hexafluoroantimonic acid anion, p-toluenesulfonic acid anion, fluoro anion, chloro anion, bromo anion, iodo anion, and the like.
In one aspect of the invention, C as described in any one of the above 1 -C 20 Alkyl, substituted C 1 -C 20 C in the alkyl group of (2) 1 -C 20 The alkyl groups of (a) are independently C 1 -C 10 Alkyl radicals of (2), e.g. C 1 -C 6 Alkyl radicals of (2), such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-hexyl radical (n-C) 6 H 13 ) Or tert-butyl.
In one aspect of the invention, C as described in any one of the above 1 -C 20 Alkyl, substituted C 1 -C 20 C in the alkyl group of (2) 1 -C 20 The alkyl groups of (a) are independently C 1 -C 10 Alkyl radicals of (2), e.g. C 1 -C 6 Also, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one aspect of the invention, C as described in any one of the above 2 -C 20 Alkynyl, substituted C 2 -C 20 C in alkynyl group of (C) 2 -C 20 Alkynyl groups of (2) are independently C 2 -C 10 Alkynyl radicals of (2), e.g. C 2 -C 6 Alkynyl radicals of (2), also e.g
In one aspect of the invention, C as described in any one of the above 2 -C 20 Alkenyl, substituted C 2 -C 20 C in alkenyl group (C) 2 -C 20 Alkenyl groups of (2) are independently C 2 -C 10 Alkenyl radicals of (2), e.g. C 2 -C 6 Alkenyl radicals of (2), also e.g
In one aspect of the invention, C as described in any one of the above 1 -C 20 Is substituted C 1 -C 20 C in heteroalkyl (C) 1 -C 20 Is independently-C (=o) O-hybridized C 1 -C 20 Alkyl of (a); for example, -C (=o) OMe.
In one aspect of the invention, C as described in any one of the above 1 -C 20 Is substituted C 1 -C 20 C in heteroalkyl (C) 1 -C 20 Is independently-C (=o) O-or-O-hybridized C 1 -C 20 Alkyl of (a); for example, -C (=O) OMe, -C (=O) OEt, -OCH 3 。
In one aspect of the invention, C as described in any one of the above 6 -C 20 Aryl, substituted C 6 -C 20 C in aryl of (C) 6 -C 20 Is independently phenyl.
In one aspect of the invention, R as described in any one of the above 1 And R is 4 Together with the attached Z forms: 5-20 membered heterocycloalkyl, 5-20 membered heterocycloalkyl of substituted 5-20 membered heterocycloalkyl being independently 5-10 membered heterocycloalkyl, e.g
In one aspect of the invention, R as described in any one of the above 1 And R is 4 Together with the attached Z forms: the 5-20 membered heteroaryl, the 5-20 membered heteroaryl in the substituted 5-20 membered heteroaryl being independently a 5-10 membered heteroaryl, e.g. benzothiophene
In one aspect of the invention, C as described in any one of the above 3 -C 20 Independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In one aspect of the invention, the R 4 Independently C 1 -C 20 Alkyl of (C) is preferred 1 -C 6 For example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the invention, R 1 、R 2 、R 3 And R is 4 Is independently H, F, cl, br, me, et, phenyl (ph), tolyl (Tol), methoxyphenyl, bromophenyl, tris (methyl) phenyl (e.g., 2,4, 6-trimethylphenyl Mes), tris (isopropyl) phenyl (TIPP), phenylethylene, tert-butylphenyl, n-hexyl, -C (=O) OMe,
in one embodiment of the invention, R 1 、R 2 、R 3 And R is 4 Is independently H, F, cl, br, me, et, phenyl (ph), tolyl (Tol), methoxyphenyl, bromophenyl, tris (methyl) phenyl (e.g., 2,4, 6-trimethylphenyl Mes), tris (isopropyl) phenyl (TIPP), phenylethene, -C (=O) OMe,
In one aspect of the inventionIn the scheme, R 2 Is independently H, me, n-hexyl, -C (=O) OMe,
In one embodiment of the invention, R 2 Is independently H, me, -C (=O) OMe,
In one embodiment of the invention, R 4 And is independently Me or Et.
In one embodiment of the invention, R 3 Is independently H, F, cl, br, -C (=O) OMe, me, phenyl, phenylethene, methoxyphenyl, tert-butylphenyl,
In one embodiment of the invention, R 3 Is independently H, F, cl, br, -C (=O) OMe, me, phenyl, phenylethylene,
In one embodiment of the invention, R 1 And R is 4 One of which is Me or Et and the other is phenyl, tolyl, methoxyphenyl, bromophenyl, tri (methyl) phenyl, tri (isopropyl) phenyl, phenylethene.
In one embodiment of the invention, R 1 And R is 4 Together with the attached Z forms: alkyls are independently C as described 1 -C 20 Is or are R 5 Substituted C 1 -C 20 Alkyl of (a); for example->
In one embodiment of the present invention, the 3, 3-difluoroallylium salt represented by formula C has any one of the following structures:
wherein X is as defined above; x is F, cl, br, BF 4 、OTf、BPh 4 、PF 6 、TeF 6 Or SbF 6 TIPP is tri (isopropyl) phenyl, mes is 2,4, 6-trimethylphenyl, tol is tolyl, and Alkyl is independently said C 1 -C 20 Is or are R 5 Substituted C 1 -C 20 Alkyl of (a); ar is independently C as described 6 -C 20 Is or are R 7 Substituted C 6 -C 20 Aryl of (a); r is R 5 And R is R 7 Is defined as in the present invention.
In one embodiment of the present invention, the 3, 3-difluoroallylium salt represented by formula C is any one of the following compounds:
the invention provides a preparation method of a 3, 3-difluoroallylium salt compound shown in a formula C, which comprises the following steps:
in an organic solvent, carrying out alkylation reaction on a compound shown as a formula D and an alkylating reagent to obtain a 3, 3-difluoroallylium salt compound shown as a formula C; the alkylating agent is R 4 X and/or R 4 I and AgX system or R 4 3 OBF 4 ；
Therein, Z, X, R 1 、R 2 、R 3 And R is 4 The definition of (2) is as in any one of the above schemes.
In the alkylation reaction, the alkylating agent can be R 4 X, e.g. MeOTf.
In the alkylation reaction, the alkylating agent may be (R 4 ) 3 OBF 4 For example (Et) 3 OBF 4 。
The operation and conditions of the alkylation reaction are those conventional in the art; in the present invention, it is preferable that,
in the alkylation reaction, the organic solvent may be an aprotic solvent such as DCM, THF, DMF or DMSO.
In the alkylation reaction, the amount of the organic solvent is not particularly limited, so that the reaction is not affected; in the present invention, the mass volume ratio of the compound represented by the formula D to the organic solvent is preferably 0.01mol/L to 2mol/L (for example, 0.7mol/L to 1 mol/L).
In the alkylation reaction, the molar ratio of the compound of formula D to the alkylating agent may be from 1:0.8 to 1:1.5, for example 1:0.9, 1:1, 1.12: 1. 1.15:1, 1:0.933 or 1:1.1.
in the alkylation reaction, the molar ratio of the compound of formula D to the alkylating agent may be 1:0.9 to 1:1.5, e.g., 1:1, 1.15:1.
The alkylation reaction is preferably carried out under argon or nitrogen.
The alkylation reaction is preferably carried out at 0 ℃ to 140 ℃, for example 10 to 30 ℃.
In the alkylation reaction, the progress of the reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or NMR), typically by taking the compound of formula D as the end point of the reaction when it is lost or no longer reacted.
In one embodiment, the preparation method further comprises a preparation method of the compound shown in the formula D, which comprises the following steps: in an organic solvent, carrying out substitution reaction on a compound shown in a formula A and a compound shown in a formula B to obtain a compound shown in a formula D;
therein, Z, R 1 、R 2 And R is 3 Is defined as in any one of the above schemes;
X 1 f, cl or Br; m is M 1 Is an alkali metal.
In one embodiment, M in the substitution reaction 1 Na, K or Li.
In the substitution reaction, the operation and conditions of the substitution reaction may be those conventional in the art; in the present invention, it is preferable that,
in the substitution reaction, the organic solvent may be an aprotic solvent such as one or more of dioxane (dioxane), tetrahydrofuran (THF), N-Dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).
In the substitution reaction, the amount of the organic solvent may be not particularly limited so as not to affect the reaction; in the present invention, the mass volume ratio of the compound represented by the formula B to the organic solvent is preferably 0.01mol/L to 2mol/L (for example, 0.7mol/L to 1 mol/L).
In the substitution reaction, the compound of the formula B may be added in the form of a conventional solution, for example, in a THF solution, for example, in a 1.2M THF solution.
In the substitution reaction, the molar ratio of the compound shown in the formula A to the compound shown in the formula B may be 1:1 to 1:3, for example, 1:1.2, 1:1.25, 1:2, 1:1.67, 1:1.335.
In the substitution reaction, the molar ratio of the compound shown in the formula A to the compound shown in the formula B may be 1:1 to 1:3, for example, 1:1.2, 1:1.25, 1:2.
The substitution reaction is preferably carried out under argon or nitrogen.
The substitution reaction is preferably carried out at room temperature to 140 ℃, preferably 50 ℃ to 140 ℃, for example 100±10 ℃.
In the substitution reaction, the progress of the reaction may be monitored by conventional monitoring methods in the art (e.g., TLC or NMR), typically by taking the compound of formula A as the end point of the reaction when it is lost or no longer reacted.
The invention also provides application of the 3, 3-difluoroallylium salt compound shown in the formula C as an alpha, alpha-gem difluoroallylation reagent.
In the present invention, R in the 3, 3-difluoroallylium salt compound represented by the formula C 1 Or R is 4 The steric and electrical effects of (a) can adjust the reaction selectivity.
In one aspect, the application includes the steps of:
in a solvent, carrying out a coupling reaction between a 3, 3-difluoroallylium salt compound shown in a formula C and a zinc reagent to obtain an alpha, alpha-gem-difluoroallylic compound shown in a formula E;
therein, Z, X, R 1 、R 2 、R 3 And R is 4 Is defined as in any one of the above schemes;
[C]representing the combination of Csp1, csp2 or Csp3 with [ Zn ]]A connected portion; [ Zn ] ]Representing ZnX 2 、Zn·LiX 2 、ZnX 2 ·LiX 2 ；X 2 Independently bromine or chlorine.
In one embodiment, in the coupling reaction, the [ Zn ] is ZnBr, znCl, zn LiCl, znCl LiCl, znBr LiCl.
The operation and conditions of the coupling reaction may be those conventional in the art. The following may be preferred in the present invention:
in the coupling reaction, the solvent can be an ether solvent; the ether solvent is tetrahydrofuran.
In the coupling reaction, the amount of the organic solvent may be not particularly limited so as not to affect the reaction; in the present invention, the mass volume ratio of the compound represented by the formula C to the organic solvent is preferably 0.01mol/L to 2mol/L (e.g., 0.1 mol/L).
In the coupling reaction, the zinc reagent may be added using conventional solution forms, for example, in Dimethylacetamide (DMA) and/or THF solution, and further, for example, 0.1 to 1M DMA and/or THF solution.
In the coupling reaction, the molar ratio of the 3, 3-difluoroallylium salt compound shown in the formula C to the zinc reagent can be 1:1 to 1.5; for example 1:1.1, 1:1.2, 1:1.3.
The coupling reaction is carried out in the presence of a catalyst, which may be a cuprous halide, such as CuBr; the molar ratio of the catalyst to the 3, 3-difluoroallylium salt compound of formula C may be 0.2 to 0.005; for example 0.01, 0.025, 0.05, 0.1.
The coupling reaction may be carried out at a temperature of-78 to 35 ℃, for example at room temperature.
The progress of the reaction may be monitored by conventional monitoring methods in the art (e.g., TLC or NMR), typically at the end of the reaction when the compound of formula C is lost or no longer reacted.
In one embodiment, the 3, 3-difluoroallylium salt compound shown as the formula C is
In one embodiment, the zinc reagent and the corresponding α, α -gem-difluoroallylic compound of formula E are any one of the following groups:
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the onium salts described in this patent can all be reacted with the above-described conventional zinc reagents to produce the desired structure containing alpha, alpha-gem-difluoroallyl groups by copper salt catalysis.
Unless otherwise specified, all technical and scientific terms used herein have the standard meaning of the art to which the claimed subject matter belongs. In case there are multiple definitions for a term, the definitions herein control.
Definition of groups
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be referenced to the descriptions in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato:1999, and "March's Advanced Organic Chemistry" by Michael b.smith and Jerry March, john Wiley & Sons, new york:2007, the entire contents of which are incorporated herein by reference.
In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds. When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left.
Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C 1 -C 6 Alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5 or 6 carbon atoms. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.
In this context, a numerical range as defined in substituents, such as 0 to 4, 1-4, 1 to 3, etc., indicates an integer within the range, such as 1-6 is 1, 2, 3, 4, 5, 6.
In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below, unless otherwise specified.
The term "comprising" is an open-ended expression, i.e. including what is indicated by the application, but not excluding other aspects.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable.
In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. Further, when the group is substituted with 1 or more of the substituents, the substituents are independent of each other, that is, the 1 or more substituents may be different from each other or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. The term "C x -C y Alkyl "refers to a straight or branched chain saturated hydrocarbon containing from x to y carbon atoms. For example, the term "C 1 ～C 6 Alkyl "or" C 1-6 Alkyl "means in particular methyl, ethyl, C independently disclosed 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 An alkyl group; "C 1-4 Alkyl "refers specifically to independently disclosed methyl, ethyl, C 3 Alkyl (i.e. propyl, including n-propyl and isopropyl), C 4 Alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).
The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a particular fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded or attached to a molecule.
When none of the recited substituents indicates through which atom it is attached to a chemical structural formula (including but not specifically mentioned compounds), such substituents may be bonded through any atom thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
When any variable (e.g. R 1a ) In the definition of a compound, the definition of each position of the variable is independent of the definition of the other positions, and the meanings of the variable are independent and do not influence each other. Thus, if a group is substituted with 1, 2 or 3R 1a The radical is substituted, that is to say, it may be substituted by up to 3R 1a Substituted, at position R 1a Definition of (d) and the remaining position R 1a Are defined independently of each other. In addition, combinations of substituents and/or variables are allowed only if the combination yields a stable compound.
Where no substituent is explicitly indicated in a recited group, such a group is merely unsubstituted. For example when "C 1 -C 4 Alkyl "not previously" substituted or unsubstituted "when defined refers only to" C 1 -C 4 Alkyl "as such or" unsubstituted C 1 -C 4 An alkyl group.
In the various parts of the application, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" group, it will be understood that the "alkyl" represents a linked alkylene group.
In some specific structures, when an alkyl group is explicitly represented as a linking group, then the alkyl group represents a linked alkylene group, e.g., the group "halo-C 1 -C 6 C in alkyl' 1 -C 6 Alkyl is understood to mean C 1 -C 6 An alkylene group.
The term "halogen" means fluorine, chlorine, bromine or iodine, in particular F or Cl.
In the present application, as part of a group or other group (e.gAs used in haloalkyl, deuteroalkyl, etc.), the term "alkyl" is meant to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms, consisting only of carbon atoms and hydrogen atoms, and being attached to the remainder of the molecule by a single bond. For example having from 1 to 20 (preferably from 1 to 10, more preferably from 1 to 6, more preferably from 1 to 4) carbon atoms. Wherein propyl is C 3 Alkyl (including isomers such as n-propyl or isopropyl); butyl is C 4 Alkyl (including isomers such as n-butyl, sec-butyl, isobutyl, or tert-butyl); pentyl is C 5 Alkyl (including isomers such as n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, isopentyl, t-pentyl or neopentyl); hexyl is C 6 Alkyl (including isomers such as n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, nonyl, decyl and the like.
In the present application, the term "alkylene" as part of a group or other group means a saturated divalent hydrocarbon group resulting from the removal of two hydrogen atoms from a saturated straight or branched hydrocarbon group; i.e. one hydrogen in the alkyl group is substituted, the definition of alkyl group being as described above. Examples of alkylene groups include methylene (-CH) 2 (-), ethylene { including-CH 2 CH 2 -or-CH (CH) 3 ) - } isopropylidene { including-CH (CH) 3 )CH 2 -or-C (CH) 3 ) 2 - }, and the like.
In the present application, the term "heteroalkyl" as part of a group or other moiety (e.g., as used in haloalkyl, deuterated alkyl, etc.) means that O, S, N (in the form of a tertiary amine moiety) may be present in the alkyl groupA heteroatom or heteroatom group of formula), B, P or Si (e.g. C (=o), S (=o) 2 、P(＝O)、P(＝O) 2 、The a-terminal represents a connection position) to provide a heteroalkyl group (e.g., an alkyl group containing one or more ether, thioether, or amino linkages). Such as alkoxy, alkylthio, and the like; illustrative examples of heteroalkyl groups include-C (=O) OMe and-CH 2 CH 2 OCH 2 CH 3 。
In the present application, the term "alkoxy" as part of a group or other group means an-O-alkyl group, the definition of alkyl being as defined above.
In the present application, the term "alkylthio" as part of a group or other group means-S-alkyl, the definition of alkyl being as defined above.
In the present application, as part of a group or other group, the term "alkenyl" refers to a straight or branched hydrocarbon chain group having at least one double bond, consisting of only carbon and hydrogen atoms, and being attached to the remainder of the molecule by a single bond. For example having from 2 to 20 (preferably from 2 to 10, more preferably from 2 to 6, most preferably from 2 to 4) carbon atoms, including for example, but not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, n-pentenyl, 2-methylbutenyl, 2-dimethylpropenyl, n-hexenyl, heptenyl, 2-methylhexenyl, 3-methylhexenyl, octenyl, nonenyl, decenyl and the like.
In the present application, as part of a group or other group, the term "cycloalkyl" means a saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more bridged, fused or spiro ring system) carbocyclic substituent and which may be attached to the remainder of the molecule by a single bond via any suitable carbon atom. For example, a 3-20 membered cycloalkyl group having 3 to 20 carbon atoms, preferably a 3-10 membered cycloalkyl group having 3 to 10 carbon atoms, more preferably a 3-7 membered cycloalkyl group having 3 to 7 carbon atoms, most preferably a 3-6 membered cycloalkyl group having 3 to 6 carbon atoms. In one embodiment, a typical monocyclic cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
In the present application, the term "heterocycloalkyl" as part of a group or other group means a group having a heteroatom or heteroatom group consisting of carbon atoms and 1 or more heteroatoms selected from O, S, N (in the form of tertiary amine moieties), B, P or Si (e.g., C (=o), S (=o) 2 、P(＝O)、P(＝O) 2 、/>The a-terminal represents the attachment position). For example from 2 to 20 (preferably 2 to 6) carbon atoms and 1 to 6 are selected from C (=o), S, S (=o), S (=o) 2 、O、N、Si、P、P(＝O)、P(＝O) 2 And B is a stable 3 to 26 membered (preferably 3 to 20 membered, more preferably 4 to 10 membered, most preferably 3 to 7 membered) saturated heterocyclic hydrocarbon group consisting of heteroatoms or heteroatom groups; preference is given to heterocyclic hydrocarbon radicals having 1, 2 or 3 ring heteroatoms independently selected from N, O and S, which are saturated, 4-to 10-membered, mono-or polycyclic (e.g. bicyclic, tricyclic or more bridged, fused or spiro ring systems). The ring system of the heterocycloalkyl bicyclic ring may include one or more heteroatoms in one or both rings; and is saturated. In some embodiments, "heterocycloalkyl" is a 5-to 7-membered monocyclic heterocycloalkyl, a 6-to 8-membered ring-attached heterocycloalkyl, a 6-to 8-membered bridged ring-attached heterocycloalkyl, or a 7-to 10-membered spiro-attached heterocycloalkyl.
In the present application, the term "aryl" as part of a group or other group means a conjugated hydrocarbon ring system group that satisfies the 4n+2 rule. For example, a conjugated hydrocarbon ring system group having 6 to 20 carbon atoms (preferably having 6 to 10 carbon atoms) satisfying the 4n+2 rule. For the purposes of the present application, aryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl groups as defined above, provided that the aryl groups are linked to the rest of the molecule via atoms on the aromatic ring by single bonds. In one embodiment, the term "aryl" refers to an aromatic group consisting of carbon atoms, each ring having aromaticity. Examples of aryl groups include, but are not limited to, phenyl, naphthyl.
In the present application, the term "heteroaryl" as part of a group or other group means a heteroatom or heteroatom group (e.g., C (=o), S (=o) having carbon atoms and heteroatoms and heteroatom groups within the ring selected from O, S, N (in the form of tertiary amine moieties), B, P, or Si 2 、P(＝O)、P(＝O) 2 、/>The a-terminal represents the attachment position). For example having 1 to 20 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms and hetero-radicals in the ring selected from C (=o), S, S (=o), S (=o) 2 、O、N、Si、P、P(＝O)、P(＝O) 2 And B is a 5-to 26-membered conjugated ring system group. Unless otherwise specifically indicated in the present specification, heteroaryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl groups as defined above, provided that the heteroaryl groups are connected to the rest of the molecule via an atom on the aromatic ring by a single bond. For the purposes of the present invention, heteroaryl groups preferably comprise from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In one embodiment, the term "heteroaryl" refers to an aromatic group containing a heteroatom, each ring having aromaticity; preference is given to aromatic 5-6-membered monocyclic rings or 9-10-membered bicyclic rings which contain 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
As used herein, the singular forms "a", "an", and "the" are understood to include plural referents unless the context clearly dictates otherwise.
The term "one(s)" or "one(s) or two or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.
Unless otherwise indicated, the present application employs conventional methods of mass spectrometry, elemental analysis, and the various steps and conditions are referred to in the art by conventional procedures and conditions.
The present application employs, unless otherwise indicated, standard nomenclature for analytical chemistry, organic synthetic chemistry and optics, and standard laboratory procedures and techniques. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and light emitting device performance detection.
In addition, unless explicitly indicated otherwise, the description of the application as "…" independently is to be understood broadly as meaning that each individual described may be independent of the other, and may be the same or different. In more detail, the description "… is independently" may mean that specific options expressed between the same symbols in different groups do not affect each other; it may also be expressed that specific options expressed between the same symbols in the same group do not affect each other.
Those skilled in the art will appreciate that, in accordance with the convention used in the art, the present application describes the structural formula of the group usedIs->It means that the corresponding group R is linked to other fragments, groups in the compound through this site.
Those skilled in the art will appreciate that, in accordance with the convention used in the art, the present application describes the structural formula of the group usedRepresents a single bond or a double bond.
Unless otherwise specified, all technical and scientific terms used herein have the standard meaning of the art to which the claimed subject matter belongs. In case there are multiple definitions for a term, the definitions herein control.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present application can be obtained.
The reagents and materials used in the present application are commercially available.
The application has the positive progress effects that: the 3, 3-difluoroallylium salt shown in the formula C can be used as an alpha, alpha-gem-difluoroallylation reagent, provides a novel broad-spectrum and low-cost method for alpha, alpha-gem-difluoroallylation, and has high efficiency and good application prospect.
Detailed Description
The application is further illustrated by means of the following examples, which are not intended to limit the scope of the application. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
In the present application, room temperature (RT or RT means room temperature) means an ambient temperature of 10℃to 35 ℃. Overnight means 8-15 hours. Reflux refers to the reflux temperature of the solvent at atmospheric pressure. The zinc reagent and thioether used in the application can be prepared by adopting a method conventional in the art or can be prepared by adopting the method described in the application. The anhydrous anaerobic conditions according to the application, unless otherwise specified, refer to reactions carried out under protective gas, for example in Argon (Argon or Ar referring to Argon). The temperature in the present application is expressed in degrees celsius (°c), specifically expressed as "°c", "degrees celsius", or "degrees".
Example 1
Sodium hydrogen (130 mmol,5.2 g) was added to a 100mL three-necked flask in the absence of water and oxygen, ar protected250ml of 1, 4-Dioxane (Dioxane means 1, 4-Dioxane or Dioxane) was added, the reaction system was placed in an ice-water bath, thiophenol (100 mmol,12.4 g) was prepared into Dioxane solution, the reaction system (system caking) was slowly added dropwise, then the reaction system was placed in ultrasound for 20min, then placed in an ice-water bath, bromopolypropylene (13.6 ml) was rapidly added, and the reaction was slowly resumed at room temperature for 1h. The reaction mixture was quenched with saturated ammonium chloride, the white solid was added to the reaction mixture to disappear, then dioxane was removed by rotary evaporation, the remaining liquid was extracted three times with diethyl ether, the diethyl ether phases were combined, dried by rotary evaporation, and passed through a column. Pure PE column chromatography gives 16.13g of yellow liquid with a yield of 80.6%. 1 H NMR(400MHz,CDCl3)δ7.29(d,J＝8.2Hz,2H),7.12(d,J＝8.2Hz,2H),4.35(dtd,J＝24.0,8.4,1.6Hz,1H),3.45(dt,J＝8.4,1.6Hz,2H),2.33(s,3H). 19 F NMR(376MHz,CDCl3)δ-86.63(d,J＝38.9Hz,1F),-88.68(ddt,J＝39.0,24.0,1.6Hz,1F). 13 C NMR(126MHz,CDCl3)δ157.1(dd,J＝290.1,288.8Hz),137.2,131.4,130.9,129.7,76.4(dd,J＝24.7,19.0Hz),28.0(d,J＝6.1Hz),21.0.MS(EI):m/z(％)77,123,200(100)([M]+).HRMS(EI)m/z:([M]+)Calculated for C10H10F2S:200.0466；Found:200.0470.
Example 2
Sodium hydroxide (52.5 mmol,2.1 g) was added to a 300mL reaction vessel under anhydrous and anaerobic conditions, thiophenol (50 mmol,6.21 g) was prepared as a dioxane solution, the reaction system was slowly added dropwise, then the reaction system was placed in an ice-water bath, the air was again evacuated, and trifluoropropene was rapidly added under argon (Ar) to form a dioxane solution (1.0M, 150 mL), and the reaction was carried out at 120℃for 15 hours. Adding saturated ammonium chloride for quenching, adding white solid into the reaction system to disappear, then removing dioxane by rotary evaporation, extracting the residual liquid with diethyl ether three times, combining diethyl ether phases, rotary drying, and pure PE column chromatography to obtain 8.18g of product with the purity of 89% and the yield of 72%.
Example 3
To a 100mL round bottom flask was added thioether (100 mmol,20.25g,1.12 equiv) in the absence of water and oxygen, ultra-dry Dichloromethane (DCM) 25mL was added followed by methyl triflate (MeOTf, 9.3mL,89mmol,1.0 equiv) and reacted overnight at room temperature (RT, RT refer to room temperature). Diethyl ether was added dropwise until solid precipitated, diethyl ether was added continuously, stirring, filtration and diethyl ether washing were carried out three times to obtain a product, 31.35g of a white solid, and a yield of 97.4%. 1 H NMR(400MHz,Chloroform-d)δ7.83(d,J＝6.3Hz,2H),7.48(d,J＝7.8Hz,2H),4.67–4.35(m,3H),3.39(s,3H),2.48(s,3H). 13 C NMR(101MHz,Chloroform-d)δ162.55–156.34(m),135.08,131.22,130.85,122.06,68.65(dd,J＝31.8,17.3Hz),42.11(d,J＝8.1Hz),25.21.MS(EI):m/z(％)153.1(100),215.1(M + ).HRMS:Calculated for C 10 H 13 F 2 S:215.0701；Found:215.0702.
Example 4
In a 100mL three-necked flask, diphenyldisulfide (8.8 g,40 mmol) was added under anhydrous and anaerobic conditions, the gas was purged three times, 30mL of ultra-dry n-Hexane (Hexane) was added under argon (Ar), and the flask was placed in a water bath at room temperature (RT indicates room temperature), then n-butyllithium (16.0 mL of a 2.5M solution of n-Hexane, 40 mmol) was added dropwise via syringe, a large amount of white solid was formed, the reaction was exothermic, and the reaction was stopped after the temperature of the flask was lowered to room temperature. At the end of the reaction, diethyl ether was added for dilution, filtered directly in a fume hood, washed three times with diethyl ether, then the solid was transferred to a 100mL schlenk bottle, drained, 20mL tetrahydrofuran (abbreviated as THF) was added, stirred (the solid was completely dissolved), placed in a room temperature water bath, the reaction was stirred overnight with rapid addition of bromodifluoropropene (7.85 g,50 mmol), quenched with water, THF was spun off, extracted three times with diethyl ether, dried and spun dry, column chromatography gave 3.86g as a pale yellow liquid in 52% yield.
Example 5
In a 100mL three-necked flask, diphenyldiselenide (12.49 g,40 mmol) was added under anhydrous and anaerobic conditions, the pumping gas was performed three times, 30mL of ultra-dry n-hexane was added under Ar, and the flask was placed in a Room Temperature (RT) water bath, then n-butyllithium (16.0 mL,2.5M in n-hexane, 40 mmol) was added dropwise to the syringe, a large amount of white solid was formed, the reaction was exothermic, and the reaction was stopped when the temperature of the flask was lowered to room temperature. At the end of the reaction, diethyl ether was added for dilution, filtered directly in a fume hood, washed three times with diethyl ether, then the solid was transferred to a 100mL schlenk bottle, drained, 20mL THF was added, stirred (the solid was completely dissolved), placed in a room temperature water bath, bromodifluoropropene (7.85 g,50 mmol) was rapidly added and stirred for reaction overnight, quenched with water, THF was spun off, extracted three times with diethyl ether, dried and spun dry combined, column chromatography gave 5.0g, 54% yield.
Example 6
In a 100mL three-necked flask, diphenyl ditelluride ether (16.4 g,40 mmol) was added under anhydrous and anaerobic conditions, the pumping gas was performed three times, 30mL of ultra-dry n-hexane was added under Ar, and the flask was placed in a water bath at room temperature, then n-butyllithium (16.0 mL of 2.5M n-hexane solution, 40 mmol) was added dropwise by syringe (a large amount of white solid was formed, the reaction was exothermic, and the reaction was stopped when the temperature of the flask was lowered to room temperature). At the end of the reaction, diethyl ether was added for dilution, filtered directly in a fume hood, washed three times with diethyl ether, then the solid was transferred to a 100mL schlenk bottle, drained, 20mL THF was added, stirred (the solid was completely dissolved), placed in a room temperature water bath, bromopropene (7.85 g,50 mmol) was rapidly added and stirred for reaction overnight, quenched with water, THF was spun off, extracted three times with diethyl ether, dried and spun dry combined, and column chromatography gave 6.54g, 58% yield.
Example 7
In a 100mL three-necked flask, diphenyldiselenide (12.49 g,40 mmol) was added under anhydrous and anaerobic conditions, the pumping gas was performed three times, 30mL of ultra-dry n-hexane was added under Ar, and the flask was placed in a water bath at room temperature, then n-butyllithium (16.0 mL of 2.5M n-hexane solution, 40 mmol) was added dropwise by syringe (a large amount of white solid was formed, the reaction was exothermic, and the reaction was stopped when the temperature of the flask was lowered to room temperature). At the end of the reaction, diethyl ether was added for dilution, filtered directly in a fume hood, washed three times with diethyl ether, then the solid was transferred to a 100mL tube, drained, 20mL dioxane was added, stirred (solid was completely dissolved), placed in a room temperature water bath, and trifluoropropene THF solution (1.2M, 12.5 mL) was added rapidly for reaction at 100℃for five hours. Saturated ammonium chloride is added for quenching, white solid is added to the reaction system to disappear, dioxane is removed by rotary evaporation, the residual liquid is extracted three times by diethyl ether, diethyl ether phases are combined, rotary drying and pure PE column chromatography are carried out to obtain 4.44g of the product, and the yield is 48%.
Example 8
In a 100mL three-necked flask, diphenyl ditelluride ether (16.4 g,40 mmol) was added under anhydrous and anaerobic conditions, the pumping gas was performed three times, 30mL of ultra-dry n-hexane was added under Ar, and the flask was placed in a water bath at room temperature, then n-butyllithium (16.0 mL of 2.5M n-hexane solution, 40 mmol) was added dropwise by syringe (a large amount of white solid was formed, the reaction was exothermic, and the reaction was stopped when the temperature of the flask was lowered to room temperature). At the end of the reaction, diethyl ether was added for dilution, filtered directly in a fume hood, washed three times with diethyl ether, then the solid was transferred to a 100mL tube, drained, 20mL dioxane was added, stirred (solid was completely dissolved), placed in a room temperature water bath, and trifluoropropene THF solution (1.2M, 12.5 mL) was added rapidly for reaction at 100℃for five hours. Saturated ammonium chloride is added for quenching, white solid is added to the reaction system to disappear, dioxane is removed by rotary evaporation, the residual liquid is extracted three times by diethyl ether, diethyl ether phases are combined, rotary drying and pure PE column chromatography are carried out to obtain 5.45g of product, and the yield is 45%.
Example 9
To a 100mL three-necked flask was added thioether (6.7 mmol,1.25g,1.1 equiv) in the absence of water and oxygen, ultra-dry DCM (10 mL) was added, followed by MeOTf (0.62 mL,6.1mmol,1.0 equiv) in an ice-water bath and allowed to react for 12h at room temperature. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the fluorescence of n-hexane layer is extremely weak, spin-drying methanol, and pumping to obtain 1.69g viscous liquid. 1 H NMR(400MHz,Chloroform-d)δ7.96(d,J＝7.9Hz,2H),7.75(t,J＝7.4Hz,1H),7.66(t,J＝7.7Hz,2H),4.60–4.39(m,3H),3.38(s,3H). 19 FNMR(376MHz,Chloroform-d)δ-75.98(d,J＝14.1Hz),-78.56(s),-79.09(dd,J＝20.7,14.2Hz). 13 C NMR(101MHz,Chloroform-d)δ162.55–156.34(m),135.08,131.22,130.85,122.06,68.65(dd,J＝31.8,17.3Hz),42.11(d,J＝8.1Hz),25.21.MS(EI):m/z(％)201.1(100),243.1(M + ).HRMS:Calculated for C 10 H 11 F 2 S:201.0544；Found:201.0544。
Example 10
To a 100mL three-necked flask was added selenoether (7 mmol,1.63g,1.15 equiv) in the absence of water and oxygen, ultra-dry DCM (10 mL) was added, followed by MeOTf (0.62 mL,6.1mmol,1.0 equiv) in an ice-water bath and allowed to spontaneously warm to room temperature for 12h. Spin-drying, adding methanol for dissolution, washing (layering) with n-hexane until the fluorescence of the n-hexane layer is extremely weak, spin-drying the methanol, and pumping to obtain 2.20g of target product.
Example 11
Tellurium ether (7 mmol,1.97g,1.15 equiv) was added to a 100mL three-necked flask in the absence of water and oxygen, ultra-dry DCM (10 mL) was added, and MeOTf (0.62 mL,6.1mmol,1.0 equiv) was then added under an ice-water bath and allowed to spontaneously warm to room temperature for 12h. Spin-drying, adding methanol for dissolution, washing (layering) with n-hexane until the fluorescence of the n-hexane layer is extremely weak, spin-drying the methanol, and pumping to obtain 2.38g of target product.
Example 12
Sodium hydrogen (26 mmol,1.04g, (60% dispersed in liquid paraffin)) was added to a 100mL three-necked flask without water and oxygen, then ultra-dry n-hexane (about 2.5 mL, after immersing the solid) was added to remove the oil on the sodium hydrogen surface, (stirring for two minutes, standing, syringe drawing off n-hexane, repeating three times, and the last drawing off) the reaction system was placed in an ice-water bath, thiophenol (20 mmol,3.0 g) was prepared as a dioxane solution, the reaction system (system caking) was slowly added dropwise, then the plug was placed in an ultrasonic bath for 20min, then placed in an ice-water bath again, air was pumped again, and trifluoropropene THF solution (1.2M, 33.3 mL) was rapidly added under Ar for reaction at 100℃for five hours. Adding saturated ammonium chloride for quenching, adding white solid into the reaction system to disappear, then removing dioxane by rotary evaporation, extracting the residual liquid with diethyl ether three times, combining diethyl ether phases, rotary drying, and carrying out pure PE column chromatography to obtain the product with the yield of 33.5%. 1 H NMR(400MHz,Chloroform-d)δ6.93(s,2H),4.29(dtd,J＝23.9,8.4,1.5Hz,1H),3.22(dt,J＝8.4,1.6Hz,2H),2.50(s,6H),2.27(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-86.94(d,J＝37.8Hz),-89.68(dd,J＝39.4,24.1Hz). 13 C NMR(101MHz,Chloroform-d)δ155.69(m),143.17,138.57,129.03,128.87,128.63,27.81(d,J＝5.9Hz),21.87,21.41,21.01.MS(EI):m/z(％)151(100),228(M + ).HRMS:Calculated for C 10 H 13 F 2 S:228.0779；Found:215.0785。
Example 13
Under the condition of no water and no oxygen, the direction isA50 mL round bottom flask was charged with thioether (6.7 mmol,1.53 g), ultra-dry DCM (10 mL) was added, then MeOTf (0.64 mL,6.4 mmol) was added under ice-water bath and allowed to spontaneously warm to room temperature for 12h. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the n-hexane layer has extremely weak fluorescence, spin-drying methanol, and pumping to obtain viscous liquid. The resulting product was purified by column chromatography (DCM: meoh=10:1) to give a yellowish oil. 1 H NMR(400MHz,Chloroform-d)δ7.07(s,2H),4.76–4.47(m,3H),3.47(s,3H),2.59(s,6H),2.34(s,3H). 19 F NMR(3＝76MHz,Chloroform-d)δ-76.58(d,J＝16.6Hz),-80.12(dd,J＝22.5,17.1Hz). 13 C NMR(101MHz,Chloroform-d)δ162.70–155.93(m),146.36,132.40,128.92,114.71,69.62(dd,J＝31.6,17.2Hz),38.98(d,J＝8.1Hz),25.68,21.59,21.26,21.23.MS(EI):m/z(％)243.1(100),315.1(M + ).HRMS:Calculated for C 10 H 13 F 2 S:243.1014；Found:243.1015。
Example 14
Sodium hydrogen (13 mmol,0.52g, (60% dispersed in liquid paraffin)) was added to a 100mL three-necked flask without water and oxygen, then ultra-dry n-hexane (about 2.5 mL, after immersing the solid) was added to remove the oil on the sodium hydrogen surface, (stirring for two minutes, standing, syringe drawing off n-hexane, repeating three times, and the last drawing off) the reaction system was placed in an ice-water bath, thiophenol (10 mmol,2.36 g) was formulated as a dioxane solution, slowly added dropwise to the reaction system (system caking), then the plug was placed in an ultrasonic bath for 20min, then placed in an ice-water bath again, and then rapidly added with bromodifluoropropene (2.62 g,16.7 mmol) under Ar for reaction at 100℃for five hours. Adding saturated ammonium chloride for quenching, adding until white solid disappears in the reaction system, then removing dioxane by rotary evaporation, extracting the residual liquid with diethyl ether for three times, combining diethyl ether phases, rotary drying, and performing pure PE column chromatography to obtain the product with the yield of 36%. 1 H NMR(400MHz,Chloroform-d)δ7.01(s,2H),4.33(dt,J＝24.0,8.3Hz,1H),4.00–3.83(m,2H),3.20(d,J＝8.4Hz,2H),2.88(p,J＝7.2Hz,1H),1.24(s,18H). 19 F NMR(376MHz,Chloroform-d)δ-86.62(d,J＝38.8Hz),-89.08(dd,J＝38.7,24.0Hz). 13 C NMR(101MHz,Chloroform-d)δ160.66–153.89(m),153.27,150.02,127.00,121.81,76.15(dd,J＝24.6,19.4Hz),34.28,31.56,30.10(d,J＝5.9Hz),24.39,23.89.
Example 15
Sodium hydrogen (26 mmol,1.04g, (60% dispersed in liquid paraffin)) was added to a 100mL tube sealed under anhydrous and anaerobic conditions, then ultra-dry n-hexane (about 2.5 mL, after flooding the solid) was added to remove the oil on the sodium hydrogen surface, (stirring for two minutes, standing, syringe drawing off n-hexane, repeating three times, and the last pumping) the reaction system was placed in an ice-water bath, thiophenol (20 mmol,2.8 g) was formulated as a dioxane solution, slowly dropped into the reaction system (system caking), then the plug was placed in an ultrasonic bath for 20min, then placed in an ice-water bath again, air was re-pumped, and bromodifluoropropene (4.19 g,26.7 mmol) was rapidly added under Ar for reaction at 100℃for five hours. Saturated ammonium chloride is added for quenching, white solid is added to the reaction system to disappear, dioxane is removed by rotary evaporation, the residual liquid is extracted by diethyl ether for three times, diethyl ether phases are combined, rotary drying and pure PE column chromatography are carried out to obtain 3.45g of the product, and the yield is 80%. 1 H NMR(400MHz,Chloroform-d)δ7.01(s,2H),4.33(dt,J＝24.0,8.3Hz,1H),4.00–3.83(m,2H),3.20(d,J＝8.4Hz,2H),2.88(p,J＝7.2Hz,1H),1.24(s,18H). 19 F NMR(376MHz,Chloroform-d)δ-86.62(d,J＝38.8Hz),-89.08(dd,J＝38.7,24.0Hz). 13 C NMR(101MHz,Chloroform-d)δ160.66–153.89(m),153.27,150.02,127.00,121.81,76.15(dd,J＝24.6,19.4Hz),34.28,31.56,30.10(d,J＝5.9Hz),24.39,23.89.
Example 16
Anhydrous and oxygen-free (e.g. under Argon, argon or Ar referring to ArgonGas), to a 50mL round bottom flask was added thioether (1.5 mmol,0.32 g), ultra-dry DCM (0.5 mL) was added, followed by MeOTf (0.14 mL,1.4 mmol) and the reaction was carried out at room temperature for 12h. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the fluorescence of n-hexane layer is extremely weak, spin-drying methanol, and pumping to obtain 0.45g viscous liquid with 82% yield. 1 H NMR(400MHz,Chloroform-d)δ7.88(d,J＝8.9Hz,2H),7.15(d,J＝9.0Hz,2H),4.69–4.34(m,3H),3.91(s,3H),3.36(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-75.88(d,J＝14.3Hz),-78.94–-79.39(m). 13 C NMR(101MHz,Chloroform-d)δ162.55–156.34(m),135.08,131.22,130.85,122.06,68.65(dd,J＝31.8,17.3Hz),42.11(d,J＝8.1Hz),25.21.MS(EI):m/z(％)231.1(100),233.1(M + ).HRMS:Calculated for C 10 H 13 F 2 S:231.0650；Found:231.0652。
Example 17
Sodium hydrogen (26 mmol,1.04g, (60% dispersed in liquid paraffin)) was added to a 50mL round bottom bottle without water and oxygen, then ultra-dry n-hexane (about 2.5 mL, after flooding the solid) was added to remove the oil on the sodium hydrogen surface, (stirring for two minutes, standing, syringe drawing off n-hexane, repeating three times, and the last pumping out) the reaction system was placed in an ice water bath, thiophenol (20 mmol,2.8 g) was formulated as dioxane solution, slowly dropped into the reaction system (system caking), then the plug was placed in an ultrasonic water bath for 20min, then placed in an ice water bath again, air was re-pumped, and bromodifluoropropene (4.19 g,26.7 mmol) was rapidly added under Ar for reaction at 100 ℃ for five hours. Saturated ammonium chloride is added for quenching, white solid is added to the reaction system to disappear, dioxane is removed by rotary evaporation, the residual liquid is extracted with diethyl ether for three times, diethyl ether phases are combined, rotary drying and pure PE column chromatography are carried out to obtain 3.7g of product, and the yield is 85%. 1 H NMR(400MHz,Chloroform-d)δ7.01(s,2H),4.33(dt,J＝24.0,8.3Hz,1H),4.00–3.83(m,2H),3.20(d,J＝8.4Hz,2H),2.88(p,J＝7.2Hz,1H),1.24(s,18H). 19 F NMR(376MHz,Chloroform-d)δ-86.62(d,J＝38.8Hz),-89.08(dd,J＝38.7,24.0Hz). 13 C NMR(101MHz,Chloroform-d)δ160.66–153.89(m),153.27,150.02,127.00,121.81,76.15(dd,J＝24.6,19.4Hz),34.28,31.56,30.10(d,J＝5.9Hz),24.39,23.89.
Example 18
To a 50mL round bottom flask was added thioether (10.7 mmol,2.32 g) in anhydrous and anaerobic condition, ultra-dry DCM (1.5 mL) was added, followed by MeOTf (1.03 mL,9.75 mmol) and reaction at room temperature for 12h. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the fluorescence of n-hexane layer is extremely weak, spin-drying methanol, and pumping to obtain 3.9g viscous liquid with 92% yield. 1 H NMR(400MHz,Chloroform-d)δ7.86–7.56(m,1H),7.23(t,J＝7.7Hz,1H),7.15(d,J＝8.4Hz,1H),4.68–4.41(m,3H),4.06(s,3H),3.37(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-76.12(d,J＝16.2Hz),-78.48,-80.35(dd,J＝23.7,16.3Hz). 13 C NMR(101MHz,Chloroform-d)δ162.51–156.50(m),159.42,137.24,132.99,122.67,113.07,107.56,68.90(dd,J＝31.4,17.3Hz),56.79,38.84(d,J＝8.1Hz),23.11.MS(EI):m/z(％)153.1(100),215.1(M + ).HRMS:Calculated for C 10 H 13 F 2 S:231.0650；Found:231.0651。
Example 18-1
To a 50mL round bottom flask was added thioether (10 mmol,2.32 g) in anhydrous and anaerobic condition, ultra-dry DCM (15 mL) was added, followed by triethyloxonium tetrafluoroborate (2.09 g,11 mmol) and the reaction was carried out at room temperature for 36h. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the fluorescence of n-hexane layer is extremely weak, spin-drying methanol, and pumping to obtain 1.5g viscous liquid with 45% yield. 1 HNMR(400MHz,Chloroform-d)δ7.80–7.72(m,2H),7.27-7.19(m,2H),4.85–4.65(m,2H),4.07(s,3H),3.99-3.83(m，2H),1.36and 1.21(t,J＝8.0Hz,3H). 19 F NMR(376MHz,Chloroform-d)δ-76.6and 77.0(d,J＝14.9Hz),-80.5and 80.9(dd,J＝23.7,14.9Hz)，-148.5，-151.4.
Example 19
NaH (1.20 g,60%,30 mmol) was added to a 100mL reaction flask in an anhydrous and anaerobic ice-water bath, then the reaction flask was washed three times with n-pentane (60 mL each) to remove kerosene from the sodium hydrogen, then the obtained active sodium hydrogen was suspended in 80mL of ultra-dry dioxane, and then thiophenol (3.79 g,20.0 mmol) was slowly added dropwise under an ice-water bath, and after the completion of the addition, the reaction was stirred at room temperature for 30 minutes. Then cooled in an ice water bath again, bromodifluoropropene (25 mmol,3.98 g) was slowly added, and after the addition was completed, the mixture was naturally warmed to room temperature and stirred for 24 hours. Saturated ammonium chloride is quenched, extracted by EA, dried and concentrated. PE column chromatography gives 4.88g of product with an isolated yield of 92%. 1 H NMR(400MHz,Chloroform-d)δ7.87(d,J＝8.3Hz,2H),7.80(d,J＝8.9Hz,2H),4.59–4.43(m,3H),3.39(d,J＝2.3Hz,3H).19F NMR(376MHz,Chloroform-d)δ-75.27(dd,J＝13.2,9.1Hz),-78.51(ddd,J＝19.1,13.1,6.8Hz). 13 C NMR(101MHz,Chloroform-d)δ163.28–155.65(m),134.51,132.34,130.69,121.02,120.43(q,J＝319.5Hz),68.52(dd,J＝31.7,17.4Hz),42.14(d,J＝8.1Hz),25.34.MS(EI):m/z 279.0(％)(100),351.0(M + ).HRMS:Calculated for C 10 H 10 F 2 SBr:278.9643；Found:278.9649。
Example 20
To a 50mL round bottom flask was added thioether (12.2 mmol,3.24 g) in the absence of water and oxygen, ultra-dry DCM (10 mL) was added, followed by MeOTf (1.2 mL,11.2 mmol) and the reaction was carried out at room temperature for 12h. Spin-drying, dissolving in methanol, washing with n-hexane (layering) until the n-hexane layer has extremely weak fluorescence, spin-drying methanol, and pumping to obtain 4.39g of viscous productLiquid, yield 91.5%. 1 H NMR(400MHz,Chloroform-d)δ7.87(d,J＝8.3Hz,2H),7.80(d,J＝8.9Hz,2H),4.59–4.43(m,3H),3.39(d,J＝2.3Hz,3H).19F NMR(376MHz,Chloroform-d)δ-75.27(dd,J＝13.2,9.1Hz),-78.51(ddd,J＝19.1,13.1,6.8Hz). 13 C NMR(101MHz,Chloroform-d)δ163.28–155.65(m),134.51,132.34,130.69,121.02,120.43(q,J＝319.5Hz),68.52(dd,J＝31.7,17.4Hz),42.14(d,J＝8.1Hz),25.34.MS(EI):m/z 279.0(％)(100),351.0(M + ).HRMS:Calculated for C 10 H 10 F 2 SBr:278.9643；Found:278.9649。
Example 21
NaH (9.0 g,60%,225 mmol) was added to a 1000mL reaction flask in an anhydrous and anaerobic ice-water bath, then the reaction flask was washed three times with n-pentane (60 mL each) to remove kerosene from the sodium hydrogen, then the obtained active sodium hydrogen was suspended in 500mL of ultra-dry dioxane, and then thiophenol (22.4 g,180.0 mmol) was slowly added dropwise under an ice-water bath, and the reaction was stirred at room temperature for 60 minutes after the completion of the addition. Then cooling in ice water bath again, adding bromotrifluoropropene (360 mmol,63 g) slowly, and naturally rising to 25 ℃ after the dripping is finished and stirring for 24h. Saturated ammonium chloride is quenched, extracted by EA, dried and concentrated. PE column chromatography gives 43.1g of product in 82% isolated yield. 1 H NMR(400MHz,CDCl 3 )δ7.36(d,J＝8.0Hz,2H),7.13(d,J＝8.0Hz,2H),3.72–3.69(m,2H),2.34(s,3H). 19 F NMR(376MHz,CDCl 3 )δ-81.91(dt,J＝34.9,2.0Hz,1F),-87.65(dt,J＝34.9,2.7Hz,1F). 13 C NMR(101MHz,CDCl 3 )δ154.1(dd,J＝291.3,287.1Hz),138.3,133.3,129.8,129.5,78.4(dd,J＝37.0,22.1Hz),37.7,21.1.MS(FI):m/z(％)280(100)([M] + ).HRMS(FI)m/z:([M] + )Calculated for C 10 H 9 BrF 2 S:277.9571；Found:277.9575.
Example 22
To a 100mL three-necked flask was added thioether (16.5 mmol,4.6 g) in the absence of water and oxygen, ultra-dry DCM (10 mL) was added, followed by MeOTf (2.5 g,15 mmol) and the reaction was carried out at room temperature for 4h. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the n-hexane layer has extremely weak fluorescence, spin-drying methanol, and recrystallizing with diethyl ether to obtain white solid 5.5g with 83% yield. 1 H NMR(400MHz,CDCl 3 )δ7.90(d,J＝8.4Hz,2H),7.50(d,J＝8.4Hz,2H),5.16(d,J＝14.4Hz,1H),4.92–4.84(m,1H),3.57(s,3H),2.49(s,3H). 19 F NMR(376MHz,CDCl 3 )δ-72.74(dd,J＝11.2,4.4Hz,1F),-77.43(d,J＝11.3Hz,1F),-78.49(s,3F). 13 C NMR(101MHz,CDCl 3 )δ156.3(dd,J＝300.6,292.5Hz),147.2,132.0,131.2,120.5(q,J＝319.8Hz),117.4,68.8(dd,J＝35.7,29.8Hz),49.3,26.3,21.7.MS(ESI):m/z(％)138,153,245,293(100),([M-OTf] + ).HRMS(ESI)m/z:([M-OTf] + )Calculated for C 11 H 12 BrF 2 S:292.9806；Found:292.9798.
Example 23
NaH (0.9 g,60%,22.5 mmol) was added to a 1000mL reaction flask under an anhydrous anaerobic ice water bath, then the kerosene was removed from the sodium hydrogen by washing with n-pentane three times (60 mL each time), then the obtained active sodium hydrogen was suspended in 500mL of ultra-dry 1,4 dioxane, then thiophenol (2.48 g,20.0 mmol) was slowly added dropwise under an ice water bath, and the reaction was stirred at room temperature for 60 minutes after the addition. Then cooling in ice water bath again, slowly adding chlorotrifluoropropene (gas, excessive), naturally raising to 25 ℃ after the dripping is finished, and stirring for 24 hours. Saturated ammonium chloride is quenched, extracted by EA, dried and concentrated. PE column chromatography gives 2.9 g of product, 63% separated. 1 H NMR(400MHz,CDCl3)δ7.34(d,J＝7.6Hz,2H),7.11(d,J＝7.6Hz,2H),3.65–3.58(m,2H),2.32(s,3H). 19 F NMR(376MHz,CDCl3)δ-87.12(d,J＝38.2Hz,1F),-92.61(d,J＝38.3Hz,1F). 13 C NMR(101MHz,CDCl3)δ155.7(dd,J＝289.5Hz,288.3Hz),138.3,133.2,129.8,129.5,90.1(dd,J＝41.1,19.2Hz),36.4(d,J＝2.2Hz),21.1.
Example 24
To a 100mL three-necked flask was added thioether (1.18 g,5.0 mmol) in the absence of water and oxygen, ultra-dry DCM (10 mL) was added, followed by MeOTf (0.72 g,4.3 mmol) and the reaction was carried out at room temperature for 4h. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the n-hexane layer has extremely weak fluorescence, spin-drying methanol, and recrystallizing with diethyl ether to obtain white solid 1.9g with 92% yield. 1 H NMR(400MHz,Chloroform-d) 1 H NMR(400MHz,CDCl3)δ7.90(d,J＝7.8Hz,2H),7.49(d,J＝7.8Hz,2H),5.03(d,J＝14.0Hz,1H),4.90–4.78(m,1H),3.56(s,3H),2.49(s,3H). 19 F NMR(376MHz,CDCl3)δ-77.60(d,J＝14.2Hz),-78.62(s,3F),-82.73(d,J＝13.5Hz). 13 C NMR(101MHz,CDCl3)δ156.7(t,J＝296.7Hz),147.1,132.0,131.1,120.6(q,J＝320.1Hz),117.6,83.0(dd,J＝40.1,26.3Hz),48.1,26.4,21.7.
Example 25
NaH (9.0 g,60%,225 mmol) was added to a 1000mL reaction flask under an anhydrous and anaerobic ice-water bath, then the solution was washed three times with n-pentane (60 mL each) to remove kerosene from the sodium hydrogen, then the obtained active sodium hydrogen was suspended in 500mL of ultra-dry 1,4 dioxane, then thiol (24.9 g,180.0 mmol) was slowly added dropwise under an ice-water bath, and the reaction was stirred at room temperature for 60 minutes after the completion of the addition. Then cooling in ice water bath again, adding bromotrifluoropropene (360 mmol,63 g) slowly, and naturally rising to 25 ℃ after the dripping is finished and stirring for 24h. Saturated ammonium chloride is quenched, extracted by EA, dried and concentrated. PE column chromatography gives 43.1g of product in 82% isolated yield. 1 H NMR(400MHz,CDCl 3 )δ7.32–7.26(m,2H),7.24–7.17(m,3H),3.44(dd,J＝2.8,2.0Hz,2H),2.92–2.85(m,2H),2.78–2.72(m,2H). 19 F NMR(376MHz,CDCl 3 )δ-81.70(dt,J＝37.6,2.6Hz,1F),-87.64(dt,J＝37.6,2.6Hz,1F). 13 C NMR(101MHz,CDCl3)δ153.9(dd,J＝290.3,287.7Hz),140.0,128.5,128.4,126.5,78.9(dd,J＝37.1,21.0Hz),35.8,33.1,32.8.MS(FI):m/z(％)186,294(100)([M] + ).HRMS(FI)m/z:([M] + )Calculated for C 11 H 11 F 2 SBr:291.9727；Found:291.9721.
Example 26
To a 100mL round bottom flask was added thioether (50.4 mmol,14.77 g) in the absence of water and oxygen, ultra-dry diethyl ether (30 mL) was added, followed by MeOTf (8.6 mL,75.6 mmol) and reaction at room temperature for 12h. Filtration gave 21.52g of white solid in 93.4% 1H NMR (400 MHz, chloroform-d) delta 7.33 (dt, J=24.0, 7.3Hz, 5H), 4.64 (d, J=14.4 Hz, 1H), 4.29 (d, J=12.5 Hz, 1H), 3.89 (t, J=7.3 Hz, 2H), 3.19 (t, J=7.2 Hz, 2H), 2.90 (S, 3H) 19F NMR (376 MHz, chloroform-d) delta-71.62 (d, J=12.3 Hz), -76.39 (d, J=12.5 Hz), -78.54.13C NMR (101MHz, chloroform-d) delta 156.14 (dd, J=299.8, 293.0 Hz), 84 (q, J= 319.7 Hz), 68.50 (dd, J=35.9, J=29.2 Hz), 2.34F NMR (376 MHz, chloroform-d) delta-71.62 (d, 35.35 (d, J=12.5 Hz), -78.54.13C NMR (101 MHz), 35.34 F=35 (d) delta 156.14 (dd, j=35.9 Hz), and (f=35.35.3 Hz), 2 F+1F (37.3H); found 306.9964.
Example 27
NaH (1.20 g,60%,30 mmol) was added to a 100mL reaction flask in an anhydrous and anaerobic ice-water bath, then the reaction flask was washed three times with n-pentane (60 mL each) to remove kerosene from the sodium hydrogen, then the obtained active sodium hydrogen was suspended in 80mL of ultra-dry dioxane, and then thiophenol (3.79 g,20.0 mmol) was slowly added dropwise under an ice-water bath, and after the completion of the addition, the reaction was stirred at room temperature for 30 minutes. Then cooled again in an ice water bath, 2-methyl-bromodifluoropropene (25 mmol,4.28 g) was slowly added, and after the addition was completed, the mixture was naturally warmed to room temperature and stirred for 24 hours. Saturated ammonium chloride is quenched, extracted by EA, dried and concentrated. PE column chromatography gives 3.77g of product with an isolated yield of 88%.
Example 28
To a 50mL round bottom flask was added thioether (12.2 mmol,2.62 g) in the absence of water and oxygen, ultra-dry DCM (10 mL) was added, followed by MeOTf (1.2 mL,11.2 mmol) and the reaction was carried out at room temperature for 12h. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the fluorescence of n-hexane layer is extremely weak, spin-drying methanol, and pumping to obtain 3.90g viscous liquid with 92% yield.
Example 29
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NaH (1.20 g,60%,30 mmol) was added to a 100mL reaction flask in an anhydrous and anaerobic ice-water bath, then the reaction flask was washed three times with n-pentane (60 mL each) to remove kerosene from the sodium hydrogen, then the obtained active sodium hydrogen was suspended in 80mL of ultra-dry dioxane, and then thiophenol (3.79 g,20.0 mmol) was slowly added dropwise under an ice-water bath, and after the completion of the addition, the reaction was stirred at room temperature for 30 minutes. Then cooled in an ice water bath again, 2-phenyl-bromodifluoropropene (25 mmol,5.83 g) was slowly added, and after the addition was completed, the mixture was naturally warmed to room temperature and stirred for 24 hours. Saturated ammonium chloride is quenched, extracted by EA, dried and concentrated. PE column chromatography gives 4.97g of product in an isolated yield of 90%.
Example 30
To a 50mL round bottom flask was added thioether (12.2 mmol,3.37 g) in the absence of water and oxygen, ultra-dry DCM (10 mL) was added, followed by MeOTf (1.2 mL,11.2 mmol) and the reaction was carried out at room temperature for 12h. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until n-hexane layer has extremely weak fluorescence, spin-drying methanol, and pumping to obtain 4.44g viscous liquid with 90% yield.
Example 31
NaH (1.20 g,60%,30 mmol) was added to a 100mL reaction flask in an anhydrous and anaerobic ice-water bath, then the reaction flask was washed three times with n-pentane (60 mL each) to remove kerosene from the sodium hydrogen, then the obtained active sodium hydrogen was suspended in 80mL of ultra-dry dioxane, and then thiophenol (3.79 g,20.0 mmol) was slowly added dropwise under an ice-water bath, and after the completion of the addition, the reaction was stirred at room temperature for 30 minutes. Then cooled in an ice water bath again, 2-phenethyl-bromodifluoropropene (25 mmol,6.53 g) was slowly added, and after the addition was completed, the mixture was naturally warmed to room temperature and stirred for 24 hours. Saturated ammonium chloride is quenched, extracted by EA, dried and concentrated. PE column chromatography gives 5.60g of product with an isolated yield of 92%.
Example 32
To a 50mL round bottom flask was added thioether (12.2 mmol,3.72 g) and super dry DCM (10 mL) followed by MeOTf (1.2 mL,11.2 mmol) and reacted at room temperature for 12h under anhydrous and anaerobic conditions. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the fluorescence of n-hexane layer is extremely weak, spin-drying methanol, and pumping to obtain 4.62g viscous liquid with 88% yield.
Example 33
NaH (1.20 g,60%,30 mmol) was added to a 100mL reaction flask in an anhydrous and anaerobic ice-water bath, then the reaction flask was washed three times with n-pentane (60 mL each) to remove kerosene from the sodium hydrogen, then the obtained active sodium hydrogen was suspended in 80mL of ultra-dry dioxane, and then thiophenol (3.79 g,20.0 mmol) was slowly added dropwise under an ice-water bath, and after the completion of the addition, the reaction was stirred at room temperature for 30 minutes. Then cooled again in an ice water bath, 2-methyl p-formate phenyl-bromodifluoropropene (25 mmol,7.28 g) was slowly added, and after the addition was completed, the mixture was naturally warmed to room temperature and stirred for 24 hours. Saturated ammonium chloride is quenched, extracted by EA, dried and concentrated. PE column chromatography gives 6.29g of product with an isolated yield of 94%.
Example 34
To a 50mL round bottom flask was added thioether (12.2 mmol,4.08 g) and super dry DCM (10 mL) followed by MeOTf (1.2 mL,11.2 mmol) and reacted at room temperature for 12h under anhydrous and anaerobic conditions. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the fluorescence of n-hexane layer is extremely weak, spin-drying methanol, and pumping to obtain 4.86g viscous liquid with 87% yield.
Example 35
NaH (1.20 g,60%,30 mmol) was added to a 100mL reaction flask in an anhydrous and anaerobic ice-water bath, then the reaction flask was washed three times with n-pentane (60 mL each) to remove kerosene from the sodium hydrogen, then the obtained active sodium hydrogen was suspended in 80mL of ultra-dry dioxane, and then thiophenol (3.79 g,20.0 mmol) was slowly added dropwise under an ice-water bath, and after the completion of the addition, the reaction was stirred at room temperature for 30 minutes. Then cooled in an ice water bath again, 2-p-ethynylphenyl-bromodifluoropropene (25 mmol,6.43 g) was slowly added, and after the addition was completed, the mixture was naturally warmed to room temperature and stirred for 24 hours. Saturated ammonium chloride is quenched, extracted by EA, dried and concentrated. PE column chromatography gave 4.21g of the product in 70% isolated yield.
Example 36
To a 50mL round bottom flask was added thioether (12.2 mmol,3.67 g) and super dry DCM (10 mL) was added, followed by MeOTf (1.2 mL,11.2 mmol) and reacted at room temperature for 12h under anhydrous and anaerobic conditions. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the fluorescence of n-hexane layer is extremely weak, spin-drying methanol, and pumping to obtain 4.37g viscous liquid with 84% yield.
Example 37
NaH (1.20 g,60%,30 mmol) was added to a 100mL reaction flask in an anhydrous and anaerobic ice-water bath, then the reaction flask was washed three times with n-pentane (60 mL each) to remove kerosene from the sodium hydrogen, then the obtained active sodium hydrogen was suspended in 80mL of ultra-dry dioxane, and then thiophenol (3.79 g,20.0 mmol) was slowly added dropwise under an ice-water bath, and after the completion of the addition, the reaction was stirred at room temperature for 30 minutes. Then cooled in an ice water bath again, 2-azidobenzyl-bromodifluoropropene (25 mmol,7.20 g) was slowly added, and after the addition was completed, the mixture was naturally warmed to room temperature and stirred for 24 hours. Saturated ammonium chloride is quenched, extracted by EA, dried and concentrated. PE column chromatography gives 5.17g of product in a yield of 78%.
Example 38
To a 50mL round bottom flask was added thioether (12.2 mmol,4.04 g) in the absence of water and oxygen, ultra-dry DCM (10 mL) was added, followed by MeOTf (1.2 mL,11.2 mmol) and reaction at room temperature for 12h. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the fluorescence of n-hexane layer is extremely weak, spin-drying methanol, and pumping to obtain 4.72g viscous liquid with 85% yield.
Example 39
NaH (1.20 g,60%,30 mmol) was added to a 100mL reaction flask in an anhydrous and anaerobic ice-water bath, then the reaction flask was washed three times with n-pentane (60 mL each) to remove kerosene from the sodium hydrogen, then the obtained active sodium hydrogen was suspended in 80mL of ultra-dry dioxane, and then thiophenol (3.79 g,20.0 mmol) was slowly added dropwise under an ice-water bath, and after the completion of the addition, the reaction was stirred at room temperature for 30 minutes. Then cooled in an ice water bath again, 2-butynyl-bromodifluoropropene (25 mmol,5.23 g) was slowly added, and after the completion of the dropwise addition, the mixture was naturally warmed to room temperature and stirred for 24 hours. Saturated ammonium chloride is quenched, extracted by EA, dried and concentrated. PE column chromatography gives 4.44g of product in 88% isolated yield.
Example 40
To a 50mL round bottom flask was added thioether (12.2 mmol,3.08 g) in the absence of water and oxygen, ultra-dry DCM (10 mL) was added, followed by MeOTf (1.2 mL,11.2 mmol) and reaction at room temperature for 12h. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the fluorescence of n-hexane layer is extremely weak, spin-drying methanol, and pumping to obtain 3.69g viscous liquid with 79% yield.
Example 41
NaH (1.20 g,60%,30 mmol) was added to a 100mL reaction flask in an anhydrous and anaerobic ice-water bath, then the reaction flask was washed three times with n-pentane (60 mL each) to remove kerosene from the sodium hydrogen, then the obtained active sodium hydrogen was suspended in 80mL of ultra-dry dioxane, and then thiophenol (3.79 g,20.0 mmol) was slowly added dropwise under an ice-water bath, and after the completion of the addition, the reaction was stirred at room temperature for 30 minutes. Then cooled in an ice water bath again, bromodifluorobutene (25 mmol,4.28 g) was slowly added, and after the addition was completed, the mixture was naturally warmed to room temperature and stirred for 24 hours. Saturated ammonium chloride is quenched, extracted by EA, dried and concentrated. PE column chromatography gives 3.40g of product with an isolated yield of 80%.
Example 42
To a 50mL round bottom flask was added thioether (12.2 mmol,2.62 g) in the absence of water and oxygen, ultra-dry DCM (10 mL) was added, followed by MeOTf (1.2 mL,11.2 mmol) and the reaction was carried out at room temperature for 12h. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the fluorescence of n-hexane layer is extremely weak, spin-drying methanol, and pumping to obtain 3.74g viscous liquid with 88% yield. 1 H NMR(400MHz,CDCl 3 )δ7.83(d,J＝8.0Hz,2H),7.46(d,J＝8.0Hz,2H),4.56(d,J＝12.8Hz,1H),4.52–4.44(m,1H),3.44(s,3H),2.47(s,3H),1.69(t,J＝3.2Hz,3H). 19 F NMR(376MHz,CDCl 3 )δ-78.52(s,3F),-84.44–-84.71(m,1F),-85.24–-85.44(m,1F).
Example 43
NaH (1.20 g,60%,30 mmol) was added to a 100mL reaction flask in an anhydrous and anaerobic ice-water bath, then the reaction flask was washed three times with n-pentane (60 mL each) to remove kerosene from the sodium hydrogen, then the obtained active sodium hydrogen was suspended in 80mL of ultra-dry dioxane, and then thiophenol (3.79 g,20.0 mmol) was slowly added dropwise under an ice-water bath, and after the completion of the addition, the reaction was stirred at room temperature for 30 minutes. Then cooled in an ice water bath again, bromodifluoropropene (25 mmol,5.23 g) was slowly added, and after the addition was completed, the mixture was naturally warmed to room temperature and stirred for 24 hours. Saturated ammonium chloride is quenched, extracted by EA, dried and concentrated. PE column chromatography gives 3.89g of product in 77% isolated yield.
Example 44
To a 50mL round bottom flask was added thioether (12.2 mmol,3.09 g) under anhydrous and anaerobic conditions, ultra-dry DCM (10 mL) was added, followed by MeOTf (1.2 mL,11.2 mmol) and reaction at room temperature for 12h. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the fluorescence of n-hexane layer is extremely weak, spin-drying methanol, and pumping to obtain 4.10g viscous liquid with 88% yield.
Example 45
NaH (1.20 g,60%,30 mmol) was added to a 100mL reaction flask in an anhydrous and anaerobic ice-water bath, then the reaction flask was washed three times with n-pentane (60 mL each) to remove kerosene from the sodium hydrogen, then the obtained active sodium hydrogen was suspended in 80mL of ultra-dry dioxane, and then thiophenol (3.79 g,20.0 mmol) was slowly added dropwise under an ice-water bath, and after the completion of the addition, the reaction was stirred at room temperature for 30 minutes. Then cooled again in an ice water bath, methyl bromodifluoroacrylate (25 mmol,5.38 g) was slowly added, and after the addition was completed, the mixture was naturally warmed to room temperature and stirred for 24 hours. Saturated ammonium chloride is quenched, extracted by EA, dried and concentrated. PE column chromatography gives 4.49g of product in an isolated yield of 87%.
Example 46
To a 50mL round bottom flask was added thioether (12.2 mmol,3.15 g) in the absence of water and oxygen, ultra-dry DCM (10 mL) was added, followed by MeOTf (1.2 mL,11.2 mmol) and the reaction was carried out at room temperature for 12h. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the fluorescence of n-hexane layer is extremely weak, spin-drying methanol, and pumping to obtain 3.74g viscous liquid with 79% yield.
Example 47
NaH (1.20 g,60%,30 mmol) was added to a 100mL reaction flask in an anhydrous and anaerobic ice-water bath, then the reaction flask was washed three times with n-pentane (60 mL each) to remove kerosene from the sodium hydrogen, then the obtained active sodium hydrogen was suspended in 80mL of ultra-dry dioxane, and then thiophenol (3.79 g,20.0 mmol) was slowly added dropwise under an ice-water bath, and after the completion of the addition, the reaction was stirred at room temperature for 30 minutes. Then cooled again in an ice water bath, bromodifluorobutenol benzyl ether (25 mmol,6.93 g) was slowly added, and after the addition was completed, the mixture was naturally warmed to room temperature and stirred for 24 hours. Saturated ammonium chloride is quenched, extracted by EA, dried and concentrated. PE column chromatography gives 5.64g of product in 88% isolated yield.
Example 48
To a 50mL round bottom flask was added thioether (12.2 mmol,3.91 g) in the absence of water and oxygen, ultra-dry DCM (10 mL) was added, followed by MeOTf (1.2 mL,11.2 mmol) and the reaction was carried out at room temperature for 12h. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the fluorescence of n-hexane layer is extremely weak, spin-drying methanol, and pumping to obtain 4.29g viscous liquid with 79% yield.
Example 49
NaH (1.20 g,60%,30 mmol) was added to a 100mL reaction flask in an anhydrous and anaerobic ice-water bath, then the reaction flask was washed three times with n-pentane (60 mL each) to remove kerosene from the sodium hydrogen, then the obtained active sodium hydrogen was suspended in 80mL of ultra-dry dioxane, and then thiophenol (3.79 g,20.0 mmol) was slowly added dropwise under an ice-water bath, and after the completion of the addition, the reaction was stirred at room temperature for 30 minutes. Then cooled in an ice water bath again, bromodifluoropropene (25 mmol,7.20 g) was slowly added, and after the addition was completed, the mixture was naturally warmed to room temperature and stirred for 24 hours. Saturated ammonium chloride is quenched, extracted by EA, dried and concentrated. PE column chromatography gives 5.64g of product with an isolated yield of 85%.
Example 50
To a 50mL round bottom flask was added thioether (12.2 mmol,4.05 g) in the absence of water and oxygen, ultra-dry DCM (10 mL) was added, followed by MeOTf (1.2 mL,11.2 mmol) and the reaction was carried out at room temperature for 12h. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the n-hexane layer has extremely weak fluorescence, spin-drying methanol, and pumping to obtain 4.22g viscous liquid with 76% yield.
Example 51
NaH (1.20 g,60%,30 mmol) was added to a 100mL reaction flask in an anhydrous and anaerobic ice-water bath, then the reaction flask was washed three times with n-pentane (60 mL each) to remove kerosene from the sodium hydrogen, then the obtained active sodium hydrogen was suspended in 80mL of ultra-dry dioxane, and then thiophenol (3.79 g,20.0 mmol) was slowly added dropwise under an ice-water bath, and after the completion of the addition, the reaction was stirred at room temperature for 30 minutes. Then cooled in an ice water bath again, bromodifluoropropene (25 mmol,4.88 g) was slowly added, and after the addition was completed, the mixture was naturally warmed to room temperature and stirred for 24 hours. Saturated ammonium chloride is quenched, extracted by EA, dried and concentrated. PE column chromatography gives 4.24g of product with an isolated yield of 89%.
Example 52
To a 50mL round bottom flask was added thioether (12.2 mmol,2.91 g) in the absence of water and oxygen, ultra-dry DCM (10 mL) was added, followed by MeOTf (1.2 mL,11.2 mmol) and the reaction was carried out at room temperature for 12h. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the fluorescence of n-hexane layer is extremely weak, spin-drying methanol, and pumping to obtain 3.52g viscous liquid with 78% yield.
Example 53
Pd (PPh) was weighed into a reaction vessel 3 ) 2 Cl 2 (0.05 equiv) and t-BuDavePhos (0.1)equiv), the prepared zinc reagent (1.5 equiv, tetrahydrofuran solution) and thioether (1.0 equiv) starting materials were added under argon protection, and finally MeCN (MeCN: thf=1: 1, molar volume ratio of MeCN to zinc reagent 0.5 mol/L), and reacting for 12 hours at room temperature. Wherein, the preparation of the zinc reagent can be carried out by adopting a preparation method conventional in the field, and the method provided by the invention can be used for preparing the following compounds by referring to the preparation scheme unless otherwise specified.
The product is:
104mg, colorless liquid, 36% yield, PE column chromatography. 1 H NMR(400MHz,CDCl 3 )δ7.43–7.34(m,4H),7.32–7.24(m,3H),7.24–7.18(m,1H),7.18–7.12(m,2H),3.56–3.51(m,2H),2.94–2.83(m,2H),2.81–2.66(m,2H). 19 F NMR(376MHz,CDCl 3 )δ-88.76(d,J＝37.1Hz,1F),-88.96(d,J＝37.0Hz,1F). 13 C NMR(101MHz,CDCl 3 )δ154.4(dd,J＝293.3,289.7Hz),140.3,132.4(t,J＝3.1Hz),128.5,128.4,128.3(t,J＝3.2Hz),127.8,126.4,90.5(dd,J＝19.4,14.8Hz),36.0,33.0,29.9(d,J＝2.8Hz).
The product is:
0.9g, yellow liquid, yield 28%. 1 H NMR(400MHz,CDCl 3 )δ7.33–7.25(m,4H),7.24–7.19(m,1H),7.18–7.14(m,2H),6.93–6.87(m,2H),3.80(s,3H),3.51(t,J＝2.2Hz,2H),2.91–2.82(m,2H),2.76–2.68(m,2H). 19 F NMR(376MHz,CDCl 3 )δ-89.66(d,J＝39.7Hz,1F),-89.97(d,J＝39.6Hz,1F). 13 C NMR(101MHz,CDCl 3 )δ159.0,155.7(dd,J＝292.3Hz,J＝292.5Hz),140.3,133.1,129.5(t,J＝3.2Hz),128.5,126.3,124.5(t,J＝3.4Hz),113.9,89.9(dd,J＝19.8,15.0Hz),55.2,36.0,33.0,30.0(d,J＝2.7Hz).
The product is:
78mg, colorless liquid, yield 28%, silica gel column chromatography (petroleum ether/ethyl acetate=100:1). 1 H NMR(400MHz,CDCl 3 )δ 1 H NMR(400MHz,CDCl 3 )δ7.39(d,J＝8.0Hz,2H),7.35–7.24(m,4H),7.21(dd,J＝8.6,6.8Hz,1H),7.17–7.10(m,2H),3.55(s,2H),2.86(dd,J＝9.7,6.2Hz,2H),2.73(dd,J＝9.7,6.1Hz,2H),1.32(s,9H). 19 F NMR(376MHz,CDCl 3 )δ-88.68(d,J＝37.9Hz),-88.81(d,J＝37.8Hz). 19 F NMR(376MHz,CDCl 3 )δ-88.89(d,J＝37.5Hz,1F),-89.02(d,J＝37.9Hz,1F). 13 C NMR(101MHz,CDCl 3 )δ154.4(dd,J＝292.7,290.2Hz),150.6,140.3,129.3,128.4,127.9(t,J＝3.1Hz),126.3,125.4,90.3(dd,J＝18.7,15.3Hz),36.1,34.5,33.0,31.2,29.7.
The product is:
79mg, colorless oily liquid, yield 22%, silica gel column chromatography (petroleum ether/ethyl acetate=80:1). 1 H NMR(400MHz,CDCl 3 )δ8.04(d,J＝8.0Hz,2H),7.46(d,J＝8.0Hz,2H),7.35–7.18(m,3H),7.16(d,J＝7.2Hz,2H),4.38(q,J＝7.2Hz,2H),3.5(s,2H),2.97–2.83(m,2H),2.79–2.64(m,2H),1.39(t,J＝7.2Hz,3H). 19 F NMR(376MHz,CDCl 3 )δ-86.48(d,J＝32.6Hz,1F),-86.61(d,J＝32.6Hz,1F). 13 C NMR(101MHz,CDCl 3 )δ166.1,154.6(dd,J＝295.0,291.3Hz),140.1,137.0(d,J＝2.7Hz),129.7,129.6,128.5,128.4,128.2(t,J＝3.1Hz),126.4,90.3(dd,J＝19.8,14.4Hz),61.0,35.9,33.1,29.5,14.3.MS(FI):m/z(％)362(100).([M] + )；HRMS(FI)m/z:([M] + )Calculated for C 20 H 20 F 2 O 2 S:362.1147；Found:362.1151.
Under anhydrous and anaerobic condition (Ar), the raw material A is treated in LiAlH 4 After the ester group is reduced, quenching is carried outAfter workup by solvent extraction, 1.2 equivalents of DPPA and 1.2 equivalents of DBU were added to give 656mg of product as a colorless oily liquid, 38% yield, and column chromatography on silica gel (petroleum ether/ethyl acetate=80:1). 19 F NMR(376MHz,CDCl 3 )δ-88.1(d,J＝35.7Hz,1F),-88.2(d,J＝43.6Hz,1F). 1 H NMR(400MHz,CDCl 3 )δ7.40(d,J＝8.4Hz,2H),7.32-7.28(m,4H),7.24-7.21(m,1H),7.20-7.15(m,2H),4.35(s,2H),3.54(t,J＝2.0Hz,2H),2.89–2.85(m,2H),2.76–2.72(m,2H).
The product is:
1.1g, yellow liquid, 34% yield. 1 H NMR(400MHz,Chloroform-d)δ7.42–7.10(m,6H),6.96(d,J＝9.5Hz,2H),6.85(d,J＝8.5Hz,1H),3.80(s,3H),3.53(s,2H),2.87(t,J＝7.8Hz,2H),2.74(dd,J＝9.3,6.4Hz,2H). 19 F NMR(376MHz,Acetonitrile-d3)δ-93.35(d,J＝36.5Hz,1F),-93.91(d,J＝36.5Hz,1F). 13 C NMR(101MHz,Chloroform-d)δ159.55,158.05–150.55(m),140.32,133.78(t,J＝4.0Hz),129.46,128.47,128.44,126.36,120.71(t,J＝3.2Hz),114.35(t,J＝3.6Hz),113.08,90.50(dd,J＝20.0,13.7Hz),55.21,36.03,33.09,29.92,29.89。
The product is:
0.88g, pale yellow liquid, 46% yield. 1 H NMR(400MHz,Chloroform-d)δ7.48(d,J＝7.7Hz,2H),7.32(dd,J＝12.0,7.5Hz,4H),7.24(d,J＝14.6Hz,1H),7.24(s,1H),7.18(d,J＝7.1Hz,2H),3.53(s,2H),2.96–2.80(m,2H),2.80–2.59(m,2H),0.27(s,9H). 19 F NMR(376MHz,Chloroform-d)δ-87.39(d,J＝34.3Hz),-87.60(d,J＝34.4Hz). 13 C NMR(126MHz,Chloroform-d)δ158.18–150.25(m),140.21,132.54,132.01,131.80,131.48,128.49,128.46,128.06(t,J＝3.4Hz),126.41,122.52,104.61,95.01,92.11–88.53(m),35.97,33.10,29.54,-0.08。
EXAMPLE 54 preparation of 3, 3-difluoroallylonium salt
Under anhydrous and anaerobic conditions, at 0deg.C, a methylene chloride solution of thioether was obtained in example 53 (1.05 equiv,0.5M CH 2 Cl 2 Solution) was slowly added dropwise methyl triflate (1.0 equiv) and stirred overnight at room temperature. And after the reaction is finished, diethyl ether is added into the system in a dropwise manner, and a product can be separated out. The following sulfur salts were prepared in this way, unless otherwise specified.
The product is:
1.8g, white solid, 79% yield. m.p.48.7-51.5 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.47–7.33(m,3H),7.35–7.23(m,5H),7.17(d,J＝6.8Hz,2H),4.61(d,J＝14.0Hz,1H),4.40(d,J＝14.0Hz,1H),3.74(t,J＝7.2Hz,2H),3.49(s,3H),3.16–3.00(m,2H),2.73(s,3H). 19 F NMR(376MHz,CDCl 3 )δ-78.39(s,3F),-79.54(d,J＝15.2Hz,1F),-79.77(d,J＝15.2Hz,1F). 13 C NMR(126MHz,CDCl 3 )δ156.0(t,J＝299.2Hz),135.7,129.4,129.2,129.1,128.8(t,J＝2.6Hz),128.6,128.2(t,J＝2.5Hz),127.9,120.4(q,J＝319.6Hz),84.4(dd,J＝21.3,18.4Hz),43.4,41.1(d,J＝4.3Hz),30.7,22.5.MS(ESI):m/z(％)105,305(100).([M-OTf] + )；HRMS(ESI)m/z:([M-OTf] + )Calculated for C 18 H 19 F 2 S:305.1170；Found:305.1162.
The product is:
730mg, viscous liquid, 73% yield. 1 H NMR(400MHz,CDCl 3 )δ7.37–7.21(m,5H),7.18(d,J＝7.3Hz,2H),6.92(d,J＝8.3Hz,2H),4.56(d,J＝13.9Hz,1H),4.38(d,J＝13.8Hz,1H),3.80(s,3H),3.71(t,J＝7.4Hz,2H),3.16–2.95(m,2H),2.73(s,3H). 19 F NMR(400MHz,CDCl 3 )δ-78.41(s,3F),-81.16(d,J＝19.0Hz,1F),-81.30(d,J＝19.0Hz,1F). 13 C NMR(101MHz,CDCl 3 )δ159.9,155.6(t,J＝297.1Hz),135.7,129.4,129.0,128.5,127.6,120.53(q,J＝320.5Hz),120.49,114.6,83.8(t,J＝19.8Hz),55.1,43.0,41.1,30.3,22.2.MS(ESI):m/z(％)145.1,335.1(100),([M-OTf] + ).HRMS(ESI)m/z:([M-OTf] + )Calculated for C 19 H 21 OF 2 S:335.1276；Found:335.1276.
The product is:/>
370mg, white solid, 43% yield. m.p.86.3-87.4 ℃;1H NMR (400 mhz, cdcl 3) delta 7.43 (d, j=7.6 Hz, 2H), 7.34-7.22 (M, 5H), 7.16 (d, j=6.8 Hz, 2H), 4.61 (d, j=13.8 Hz, 1H), 4.42 (d, j=13.8 Hz, 1H), 3.73 (t, j=7.2 Hz, 2H), 3.20-2.95 (M, 2H), 2.76 (S, 3H), 1.31 (S, 9H) 19F NMR (400 mhz, cdcl 3) delta-83.65 (S, 3F), 85.20 (d, j=16.4 Hz, 1F), 85.49 (d, j=16.4 Hz, 1F) 13C NMR (126 mhz, cdcl 3) delta 156.0 (dd=299.1, 7 Hz), 152.6,135.7,129.2,128.6,127.84,127.77 (t, j=2.5 Hz), 1.31 (S, 9H), 19F NMR (400 mhz, cdcl 3) delta-83.65 (S, 3F), 85.20 (d, j=16.4 Hz, 1F), 85.49 (d, j=16.156.0 (dd, 39.7 Hz), and (38.34.34 Hz). M/z (%) 215.1,361.2 (100), ([ M-OTf ] +) HRMS (ESI) M/z: ([ M-OTf ] +) Calculated for C22H27F2S 361.1796; found 361.1799.
The product is:
840mg, white solid, 84% yield. m.p.104.8-105.6 ℃; 1 H NMR(400MHz,CDCl 3 )δ8.08(d,J＝7.6Hz,2H),7.44(d,J＝7.6Hz,2H),7.36–7.23(m,3H),7.19(d,J＝6.4Hz,2H),4.72(d,J＝14.0Hz,1H),4.48(d,J＝14.0Hz,1H),4.39(q,J＝6.8Hz,2H),3.81(t,J＝6.8Hz,2H),3.15–3.00(m,2H),2.74(s,3H),1.40(t,J＝7.0Hz,3H). 19 F NMR(376MHz,CDCl 3 )δ-77.38(d,J＝10.8Hz,1F),-77.70(d,J＝10.8Hz,1F),-78.48(s,3F). 13 C NMR(126MHz,CDCl 3 )δ165.7,156.3(dd,J＝300.5,299.6Hz),135.7,133.3(t,J＝3.2Hz),131.1,130.4,129.3,128.6,128.3(t,J＝3.2Hz),128.0,84.3(t,J＝19.7Hz),61.4,43.6,40.8,30.8,22.6,14.3.MS(ESI):m/z(％)356,377(100)([M-OTf] + ).HRMS(ESI)m/z:([M-OTf] + )Calculated for C 21 H 23 F 2 O 2 S:377.1381；Found:377.1380.
the product is:
880mg, white solid, 91% yield. 19 F NMR(376MHz,CDCl 3 )δ-78.5(s,3F),-78.9(d,J＝16.1Hz,1F),-79.2(d,J＝15.0Hz,1F). 1 H NMR(400MHz,CDCl 3 )δ7.37(s,3H),7.34-7.25(m,4H),7.19-7.16(m,2H),4.65(d,J＝13.2Hz,1H),4.44(d,J＝14.4Hz,1H),4.36(s,2H),3.76(t,J＝7.6Hz,2H),3.15–3.05(m,2H),2.74(s,3H).
The product is:
660mg, viscous liquid, 68%. 1 H NMR(400MHz,Chloroform-d)δ7.38–7.13(m,6H),6.98–6.85(m,3H),4.61(d,J＝14.0Hz,1H),4.40(d,J＝14.1Hz,1H),3.83(s,3H),3.74(t,J＝7.3Hz,2H),3.09(q,J＝6.8Hz,2H),2.74(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-78.38(s,3F),-79.22(d,J＝14.7Hz,1F),-79.42(d,J＝14.6Hz,1F). 13 C NMR(126MHz,Chloroform-d)δ160.26,158.87–153.36(m),135.73,130.57,130.19(t,J＝2.6Hz),129.34,128.66,127.94,120.43,115.25,113.65(t,J＝2.9Hz),84.49(dd,J＝21.5,18.2Hz),55.50,43.48,41.16(d,J＝4.4Hz),30.79,22.56.
The product is:
773mg, white solid, 61% yield. 1 H NMR(400MHz,Chloroform-d)δ7.51(d,J＝7.2Hz,2H),7.40–7.24(m,5H),7.19(d,J＝7.0Hz,2H),4.66(s,1H),4.44(s,1H),3.80(s,2H),3.11(s,2H),2.71(s,3H),0.26(s,9H). 19 F NMR(376MHz,Chloroform-d)δ-78.21(d,J＝12.6Hz),-78.49.
Example 55
NaH (1.20 g,60%,30 mmol) was added to a 100mL reaction flask in an anhydrous and anaerobic ice-water bath, then the reaction flask was washed three times with n-pentane (60 mL each) to remove kerosene from the sodium hydrogen, then the obtained active sodium hydrogen was suspended in 80mL of ultra-dry dioxane, and then thiophenol (3.79 g,20.0 mmol) was slowly added dropwise under an ice-water bath, and after the completion of the addition, the reaction was stirred at room temperature for 30 minutes. Then cooled again in an ice water bath, 2-butenyldifluoropropene (25 mmol,5.24 g) was slowly added, and after the addition was completed, the mixture was naturally warmed to room temperature and stirred for 24 hours. Saturated ammonium chloride is quenched, extracted by EA, dried and concentrated. PE column chromatography gives 4.0g of product in an isolated yield of 79%.
Example 56
To a 50mL round bottom flask was added thioether (12.2 mmol,3.10 g) in the absence of water and oxygen, ultra-dry DCM (10 mL) was added, followed by MeOTf (1.2 mL,11.2 mmol) and the reaction was carried out at room temperature for 12h. Spin-drying, dissolving in methanol, washing with n-hexane (layering), washing until the fluorescence of n-hexane layer is extremely weak, spin-drying methanol, and pumping to obtain 2.80g viscous liquid with 60% yield. 1 H NMR(400MHz,CDCl 3 )δ7.83(d,J＝7.8Hz,2H),7.45(d,J＝7.8Hz,2H),5.76–5.59(m,1H),5.02(d,J＝17.2Hz,1H),4.98(d,J＝10.0Hz,1H),4.53(d,J＝13.2Hz,1H),4.48–4.39(m,1H),3.43(s,3H),2.45(s,3H),2.31–2.00(m,4H). 19 F NMR(376MHz,CDCl 3 )δ-78.30(s,3F),-82.92(d,J＝25.1Hz,1F),-83.73(d,J＝25.1Hz,1F).
Example 57
To a methanol solution of potassium carbonate (2.0 equiv.) under argon protection, the product of the previous step and phenethyl mercaptan (1.0 equiv.) were added and stirred overnight at room temperature. The reaction system was filtered, spin-dried, and column-chromatographed to give the objective compound, by which the following compound was prepared.
The product is:
4.6g, yellow liquid, 52%. 19 F NMR(376MHz,CDCl 3 )δ-87.53(d,J＝44.3Hz),-89.74(dd,J＝44.1,24.3Hz). 1 H NMR(400MHz,CDCl 3 )δ7.38–7.26(m,4H),7.25–7.14(m,5H),4.15(ddd,J＝24.3,10.8,1.8Hz,1H),2.96–2.81(m,4H),2.81–2.65(m,4H),2.52(t,J＝7.2Hz,2H),1.71–1.42(m,7H).
The product is:
466mg, yellow liquid, 13%. 19 F NMR(376MHz,CDCl 3 )δ-87.32(d,J＝43.8Hz),-89.60(dd,J＝43.8,24.2Hz). 1 H NMR(400MHz,CDCl 3 )δ7.31(t,J＝7.1Hz,2H),7.26–7.10(m,3H),4.16(dd,J＝24.7,11.4Hz,1H),3.68–3.42(m,1H),3.27(t,J＝6.6Hz,2H),2.94–2.80(m,2H),2.79–2.62(m,2H),1.75–1.37(m,6H).
The product is:
4.5g, yellow liquid, 58%. 19 F NMR(376MHz,CDCl 3 )δ-87.84(d,J＝44.8Hz),-90.08(dd,J＝44.7,24.4Hz). 1 H NMR(400MHz,CDCl 3 )δ7.30(t,J＝7.5Hz,2H),7.21(dd,J＝14.6,7.2Hz,3H),4.23–4.05(m,1H),3.67(s,3H),3.55–3.41(m,1H),2.98–2.80(m,2H),2.79–2.63(m,2H),2.30(t,J＝7.5Hz,2H),1.70–1.19(m,14H).
Example 58
Into a 250mL three-necked flask (5.53 g,40mmol,2.0 equiv), difluoroallyl compound (20 mmol,1.0 equiv) and methanol (MeOH, 60 mL) were added, thiol (20 mmol,1.0 equiv) was added dropwise and stirred overnight at room temperature, filtered, washed three times with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, concentrated after drying, and purified by petroleum ether column chromatography to give the product (3.46 g,72% yieldd) as a colorless oil. 1 H NMR(400MHz,CDCl 3 )δ7.31(t,J＝7.2Hz,2H),7.25–7.17(m,3H),4.15(ddd,J＝24.4,10.9,2.0Hz,1H),3.54–3.42(m,1H),3.01–2.59(m,4H),1.77–1.58(m,1H),1.55–1.43(m,1H),1.41–1.33(m,2H),1.32–1.24(m,6H),0.89(t,J＝6.8Hz,3H). 19 F NMR(376MHz,CDCl 3 )δ-87.90(dd,J＝45.0,2.0Hz),-90.12(dd,J＝45.0,24.5Hz). 13 C NMR(101MHz,CDCl 3 )δ157.3(t,J＝288.9Hz),140.4,128.4,126.3,82.0(t,J＝19.6Hz),38.8,38.7,36.2,35.1,32.3,31.6,28.8,27.1,22.5,14.0.MS(FI):m/z(％)298(100)([M] + ).HRMS(FI)m/z:([M] + )Calculated for C 17 H 24 F 2 S:298.1561；Found:298.1567.
Thioether (1.4 g,4.7mmol,1.05 equiv) was added to a 100mL Schlemen tube without water and oxygen, ultra-dry DCM (10 mL) was added, meOTf ((4.5 mmol,1.0 equiv)) was added to an ice-water bath, and the reaction was stirred at room temperature overnight. 1 H NMR(400MHz,CD 2 Cl 2 ) Diastereomer mixtures delta 7.35-7.19 (m, 5H), 4.51-4.35 (m, 1H), 4.34-4.23 (m, 0.45H), 4.18-4.07 (m, 0.55H), 3.49-3.37 (m, 2H), 3.18-3.02 (m, 2H), 2.77 (s, 1.7H) (2.74 (s, 1.3H)), 1.85-1.61 (m, 2H), 1.32-1.15 (m, 8H), 0.81 (t, J=6.6 Hz, 3H). 19 F NMR(376MHz,CD 2 Cl 2 ) Diastereomer mixtures delta-75.34 (d, j=16.6 hz, 0.56F), -75.52 (d, j=15.8 hz, 0.44F), -77.14-77.34 (M, 1F), -78.96 (s, 3F). MS (ESI): M/z (%) 153,167,181,313 (100), ([ M-OTf)] + ).HRMS(ESI)m/z:([M-OTf] + )Calculated for C 18 H 27 F 2 S:313.1796；Found:313.1794.
The following examples are the use of 3, 3-difluoroallylsulfonium salts, selenonium salts, telluronium salts and derivatives thereof in synthetic chemistry.
Application example pre-experiment:
optimization of the reaction solvent
In the absence of water and oxygen, a magneton, a sulfate (72.9 mg,0.2 mmol) and CuBr (2.8 mg,0.02 mmol) were added to the reaction tube, the air was exchanged three times, 2mL of the solvent described in the following table, which was ultra-dry and anhydrous, were added under Ar, followed by stirring uniformly, and zinc reagent SM2 (0.464M) was slowly added dropwise at room temperature, and after the completion of the dropwise addition, the reaction was stirred at room temperature for 3 hours. The reaction results are shown in the following table:
note that: weighing the catalyst under the air; the target compound represents a target compound; SM1 represents a starting material which is a starting material, 19 f% refers to fluorobenzene as an internal standard 19 FNMR measurement yield; ND indicates undetected.
The temperature of the coupling reaction in this step is not particularly limited and may be carried out in the range of-78 to 35 ℃.
Optimization of the amount of zinc reagents [ C ] - [ Zn):
experimental operation see the optimization experiments of the reaction solvents, the conditions of the zinc reagents are described in the following table:
examples [Ar-ZnCl-LiCl] Target compound [ ] 19 F％) SM1( 19 F％)
1 1.1equiv >99 ND
2 1.2equiv 95 ND
3 1.3equiv 94 ND
4 1.5equiv 96 ND
Note that: ND indicates undetected.
Catalyst type optimization:
experimental operation: 1a (0.2 mmol,1.0 equiv), 4a (1.2 equiv), THF (2 mL), procedure see reaction solvent optimization experiments, catalyst types are shown in the following table:
note that: 19 f% refers to fluorobenzene as an internal standard 19 F NMR measurement of yield; ND indicates undetected. c CuCl (99.999%) was used.
Considering that CuBr is low in cost and easy to operate, the following experiment is optimized by using CuBr as a catalyst.
Optimizing the catalyst dosage:
the catalyst amounts are shown in the following table:
note that: trace represents trace amounts.
Comparative examples 1 to 6:
the operating conditions are described in the above-described optimization examples, and the comparative conditions are shown in the following table, unless otherwise specified:
preparation of zinc reagent:
general procedure for aryl zinc reagent:
1) Grignard reagent conversion method:
50ml Shi Laike bottle, weigh magnesium chip, the glove box weighs lithium chloride, in the state of pumping, roast the gun until lithium chloride does not wall up, naturally restore to room temperature, add THF, place in ice water bath, add DIBAL-H, stir until no bubble is generated in the reaction, then add aryl bromide raw material rapidly, stir for 10min in ice bath, restore to room temperature, stir and react for 4H, titration concentration. Filtering by a filter head, quantitatively adding zinc chloride solution, stirring and reacting for 1h, and titrating the concentration.
Preparation examples 1 to 3
2) Iodine magnesium exchange method: (functional group-containing Zinc reagent)
50 ml of Schlemk bottle, adding magneton, pumping and ventilating three times, adding a THF solution of i-Pr-MgCl-LiCl under Ar, placing at a corresponding cold bath temperature, keeping the temperature and stirring for 5min, then adding a corresponding aryl iodide reagent (solid batch addition and liquid drop addition), and monitoring whether the raw materials are completely converted by GC. After complete conversion, the concentration of the Grignard reagent is titrated, and zinc chloride solution is added according to the concentration and the volume of the Grignard reagent and stirred for 20min at room temperature. The concentration was titrated again.
Preparation examples 4 to 8:
preparation of alkyl zinc reagent:
zinc powder insertion method:
preparation examples 9 to 16:
zinc powder and lithium chloride are weighed into a sealed tube, after air exchange is carried out for three times, the air exchange is carried out, the baking gun is used for baking for 5-10min under the air extraction state, the room temperature is restored, THF is added for stirring, 1, 2-dibromoethane is added, the temperature is 60 ℃ for heating to bubbling, cooling is carried out to the room temperature, then iodine and TMSCl are added, the temperature is 60 ℃ for heating and stirring for reacting for 20min, then the temperature is cooled to the room temperature again, raw materials are added, and the temperature is 50-80 ℃ for stirring for reacting for 18h. (the above-mentioned C represents the concentration of the zinc reagent product)
Application example 1
Wherein by means ofThe reaction with a zinc reagent is exemplified by,
unless otherwise indicated, the reaction operations and conditions were carried out with reference to the above examples (application example preliminary experiments), the zinc reagents shown in the following tables were reacted, and the reaction results are shown in the following tables.
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And (3) injection: to be used for 19 F NMR measurement of yield.
Application examples
See application examples section, the zinc reagents shown in the following table were reacted with the results shown in the following table:
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note that: to be used for 19 F NMR measurement of yield.
Application example 2
2.5mol% of CuBr was added to a 25mL Schlenk flask, and difluoroallylium salt (0.5 mmol,1.0 equiv) of formula C was added thereto, and the flask was evacuated and Ar was filled three times. 2.0mL of THF was added and formula [ C]-[Zn]The zinc reagent (1.2 equiv) was stirred at room temperature for 3 hours to effect a reaction. The fluorobenzene is taken as an internal standard reagent 19 F NMR determination of product yield, NH 4 The reaction was quenched with Cl and diluted with EtOAc, the aqueous phase was washed with ethyl acetate (3X 10 mL) and the organic phase was Na 2 SO 4 Drying, filtering and collecting. Purifying the filtrate by column chromatography or preparative reverse phase HPLC to obtain the target compound.
The reaction results are shown below:
the product is:
the amount of the yellow oily liquid, 114mg,>99％yield，α/γ>99:1 19 f NMR determination, purification using FP ECOFLEX C18 (mobile phase: meCN: H) 2 O＝7:3) 1 H NMR(400MHz,CDCl 3 )δ7.66(d,J＝8.4Hz,2H),7.63–7.57(m,4H),7.47(t,J＝7.6Hz,2H),7.39(t,J＝7.6Hz,1H),6.30–6.10(m,1H),5.63(dt,J＝17.4,2.8Hz,1H),5.52(d,J＝10.8Hz,1H). 19 F NMR(376MHz,CDCl 3 )δ-93.37(d,J＝9.5Hz,2F). 13 C NMR(101MHz,CDCl 3 )δ142.9,140.2,135.1(t,J＝27.7Hz),133.7(t,J＝30.1Hz),128.9,127.8,127.21,127.15,126.0(t,J＝5.6Hz),119.8(t,J＝9.1Hz),119.3(t,J＝238.3Hz).MS(EI):m/z(％)152,203,230([M] + ).HRMS(EI)m/z:([M] + )Calculated for C 15 H 12 F 2 :230.0906；Found:230.0902.
The product is:
colorless oily liquid, 120.4mg,91% yield, alpha/gamma>99:1 19 F NMR measurement. 1 H NMR(400MHz,CDCl 3 )δ7.69-7.68(m,2H),7.64–7.61(m,4H),7.50-7.46(m,2H),7.42-7.39(m,1H),6.30–6.10(m,1H),5.90-5.89(m,1H),5.71-5.70(m,1H). 19 F NMR(376MHz,CDCl 3 )δ-95.52(s,2F). 13 C NMR(101MHz,CDCl 3 )δ143.5,140.02,136.2(t,J＝34.3Hz),132.9(t,J＝27.2Hz),128.9,127.9,127.22,127.16,126.4(t,J＝5.7Hz),117.54(t,J＝5.3Hz),117.46(t,J＝244.2Hz).
The product is:/>
colorless oil, 76mg,83% yield, silica gel chromatography (DCM: PE=5:95) 1 H NMR(400MHz,CDCl 3 )δ7.34(t,J＝7.8Hz,1H),7.09(d,J＝7.8Hz,1H),7.04(s,1H),6.97(d,J＝8.0Hz,1H),6.22-6.04(m,1H),5.66–5.54(m,1H),5.48(d,J＝10.8Hz,1H),3.83(s,3H). 19 F NMR(376MHz,CDCl 3 )δ-93.64(d,J＝10.0Hz，2F). 13 C NMR(101MHz,CDCl 3 )δ159.6,137.7(t,J＝27.5Hz),133.7(t,J＝30.0Hz),129.6,119.8(t,J＝9.1Hz),119.1(t,J＝238.7Hz),117.8(t,J＝5.7Hz),115.6(t,J＝1.5Hz),111.0(t,J＝5.9Hz),55.3.MS(FI):m/z(％)91,138,184(100)([M] + ).HRMS(FI)m/z:([M] + )Calculated for C 10 H 10 F 2 O:184.0694；Found:184.0692.
The product is:
colorless oil, 69mg,65% yield, alpha/gamma >99:1 19 F NMR measurement, silica gel chromatographic purification and separation, low boiling point, 1 H NMR(400MHz,CDCl 3 )δ7.44(s,4H),6.38–5.96(m,1H),5.60(dt,J＝17.2,2.8Hz,1H),5.47(d,J＝10.8Hz,1H),1.34(s,9H). 19 F NMR(376MHz,CDCl3)δ-93.12(dd,J＝9.6,2.7Hz,2F). 13 C NMR(126MHz,CDCl3)δ159.6,137.7(t,J＝27.5Hz),133.7(t,J＝30.0Hz),129.6,119.8(t,J＝9.1Hz),119.1(t,J＝238.7Hz),117.8(t,J＝5.7Hz),115.6(t,J＝1.5Hz),111.0(t,J＝5.9Hz),55.3.
the product is:
yellowish oily substance, 107mg,95% yield, alpha/gamma>99:1 19 F NMR measurement, silica gel chromatography purification (petroleum ether/ethyl acetate=100:1), FP ECOFLEX C18 (20 g) purification isolation (MeCN: H 2 O＝7:3)， 1 H NMR(400MHz,CDCl 3 )δ8.10(d,J＝8.8Hz,2H),7.57(d,J＝8.8Hz,2H),6.15(ddt,J＝17.2,10.8,9.6Hz,1H),5.57(dt,J＝17.2,2.8Hz,1H),5.51(d,J＝10.8,1H),4.40(q,J＝7.2Hz,2H),1.41(t,J＝7.2Hz,3H). 19 F NMR(376MHz,CDCl 3 )δ-94.43(dd,J＝9.5,2.8Hz,2F). 13 C NMR(126MHz,CDCl 3 )δ165.8,140.4(t,J＝27.7Hz),133.3(t,J＝29.7Hz),131.9,129.6,125.5(t,J＝5.7Hz),120.3(t,J＝9.2Hz),118.9(t,J＝239.0Hz),61.2,14.2.MS(EI):m/z(％)133,153,181(100),198,226([M] + ).HRMS(EI)m/z:([M] + )Calculated for C 12 H 12 O 2 F 2 :226.0800；Found:226.0804.
The product is:
the yellow oil, (93.0 mg,62% yield) was chromatographed on silica gel (petroleum ether), 1 H NMR(400MHz,CDCl 3 )δ7.57–7.53(m，2H)，7.44–7.41(m，1H)，7.42–7.32(m，1H)，6.20–6.04(m，1H)，5.60(d，J＝17.6，2.8Hz，1H)，5.55(d,J＝11.0Hz,1H). 19 F NMR(376MHz,CDCl 3 )δ-72.81(s,3F),-93.87(dd,J＝9.8,2.9Hz,2F). 13 C NMR(126MHz,CDCl 3 )δ149.4,139.0(t,J＝28.7Hz),132.8(t,J＝29.6Hz),130.6,125.6(t,J＝5.5Hz),122.9,120.8(t,J＝9.2Hz),118.9(t,J＝5.9Hz),118.7(q,J＝320.7Hz).118.1(t,J＝239.6Hz).MS(FI):m/z(％)61(100),70,88,302([M] + ).HRMS(EI)m/z:([M] + )Calculated for C 10 H 7 O 3 F 5 s302.0031; found 302.0027. Product:
butter-like object, 66mg,74%, alpha/gamma>50:1 19 F NMR determination, purification of silica gel chromatography FP ECOFLEX C18 (20 g) (MeCN: H 2 O＝7:3) 1 H NMR(400MHz,CDCl 3 )δ7.73(d,J＝8.0Hz,2H),7.62(d,J＝8.0Hz,2H),6.18–6.05(m,1H),5.62–5.52(m,2H). 19 F NMR(376MHz,CDCl 3 )δ-95.04(d,J＝9.7Hz,2F). 13 C NMR(101MHz,CDCl 3 )δ140.7(t,J＝28.3Hz),132.7(t,J＝29.5Hz),132.3,126.3(t,J＝5.6Hz),120.8(t,J＝9.3Hz),118.3(t,J＝239.8Hz),118.0,114.0(t,J＝1.7Hz).MS(EI):m/z(％)75,102,152(100),179([M] + ).HRMS(EI)m/z:([M] + )Calculated for C 10 H 7 NF 2 :179.0541；Found:179.0543.
0.1mol% of CuBr was added to a 50mL Schlenk flask, and difluoroallylium salt (6 mmol,1.0 equiv) of formula C was added thereto, and the flask was evacuated and Ar was filled three times. 10.0mL of THF was added and formula [ C]-[Zn]The zinc reagent (1.2 equiv) was stirred at room temperature for 16 hours to effect a reaction. With fluorobenzene as an internal standard reagent (first from 19 F NMR measurement α/γ=25: 1) By using 19 F NMR determination of product yield, NH 4 The reaction was quenched with Cl and diluted with EtOAc, the aqueous phase was washed with ethyl acetate (3X 10 mL) and the organic phase was Na 2 SO 4 Drying, filtering and collecting. Purification of FP ECOFLEX C18 (20 g) by silica gel chromatography (MeCN: H 2 O=7:3) product:827mg,77％yield,α/γ＝25:1 19 f NMR measurement.
The product is:
yellowish oil, 79mg,88% yield, alpha/gamma>99:1 19 F NMR determination, purification of silica gel chromatography FP ECOFLEX C18 (20 g) (MeCN: H 2 O＝7:3) 1 H NMR(400MHz,CDCl 3 )δ7.80(s,1H),7.74(d,J＝8.0Hz,2H),7.57(t,J＝7.8Hz,1H),6.20–6.04(m,1H),5.72–5.45(m,2H). 19 F NMR(376MHz,CDCl 3 )δ-94.37(d,J＝9.8Hz,2F). 13 C NMR(126MHz,CDCl 3 )δ137.8(t,J＝28.8Hz),133.5(t,J＝1.6Hz),132.7(t,J＝29.4Hz),129.8(t,J＝5.4Hz),129.5,129.3(t,J＝5.9Hz),120.9(t,J＝9.2Hz),118.1(t,J＝239.6Hz),117.9,112.9.MS(EI):m/z(％)77,102,129,152(100),179([M] + ).HRMS(FI)m/z:([M] + )Calculated for C 10 H 7 NF 2 :179.0545；Found:179.0541.
The product is:/>
yellow oil, 110.4mg,97% yield, alpha/gamma>99:1 19 F NMR determination, purification of silica gel chromatography FP ECOFLEX C18 (20 g) (MeCN: H 2 O＝7:3) 1 H NMR(400MHz,CDCl 3 )δ8.18(s,1H),8.12(d,J＝7.8Hz,1H),7.70(d,J＝7.8Hz,1H),7.52(t,J＝7.8Hz,1H),6.25–6.07(m,1H),5.59(dt,J＝17.2,2.8Hz,1H),5.52(d,J＝10.8Hz,1H),4.40(q,J＝7.2Hz,2H),1.41(t,J＝7.2Hz,3H). 19 F NMR(376MHz,CDCl 3 )δ-93.73(dd,J＝9.8,2.8Hz,2F). 13 C NMR(101MHz,CDCl 3 )δ165.9,136.7(t,J＝28.1Hz),133.3(t,J＝29.9Hz),131.0,130.9,129.8(t,J＝5.5Hz),128.6,126.7(t,J＝5.8Hz),120.3(t,J＝9.2Hz),118.6(t,J＝239.8Hz),61.3,14.3.MS(EI):m/z(％)133,153,181(100),226([M] + ).HRMS(EI)m/z:([M] + )Calculated for C 12 H 12 O 2 F 2 :226.0800；Found:226.0806.
The product is:
1.5 molar equivalents of difluoroallylium salt of formula C, 1 molar equivalent of zinc reagent, gave 113mg,87% yield, alpha/gamma>99:1 19 F NMR measurement, silica gel chromatography purification separation (petroleum ether/ethyl acetate=100:1) 1 H NMR(400MHz,CDCl 3 )δ8.46–8.13(m,1H),7.70(dd,J＝8.6,2.6Hz,1H),7.49–7.44(m,2H),7.43–7.36(m,2H),7.37–7.32(m,1H),6.98–6.80(m,1H),6.24–6.09(m,1H),5.61(dt,J＝17.2,2.8Hz,1H),5.54(d,J＝10.8Hz,1H),5.42(s,2H). 19 F NMR(376MHz,CDCl 3 )δ-92.13(dd,J＝9.7,2.9Hz,2F). 13 C NMR(101MHz,CDCl 3 )δ164.6,144.8(t,J＝6.4Hz),136.9,136.3(t,J＝4.7Hz),133.3(t,J＝30.0Hz),128.5,128.0,128.0,125.4(t,J＝28.5Hz),120.3(t,J＝9.0Hz),118.8(t,J＝237.7Hz),111.1,68.0.MS(EI):m/z(％)65,91(100),138,185,265([M] + ).HRMS(EI)m/z:([M] + )Calculated for C 15 H 13 F 2 ON:261.0960；Found:261.0956.
The product is:
brown solid, 133.4mg,95%, alpha/gamma>99:1 19 F NMR measurement, silica gel chromatography purification separation (petroleum ether/ethyl acetate=10:1) mp:51.2-53.5 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.23(d,J＝8.0Hz,1H),7.22–7.15(m,2H),7.01(t,J＝7.4Hz,1H),5.91(dq,J＝17.2,11.2Hz,1H),5.70–5.49(m,1H),5.41(d,J＝11.2,1H)4.05(t,J＝8.4Hz,2H),3.20(t,J＝8.2Hz,2H),2.44(t,J＝7.4Hz,2H),2.09–1.88(m,2H),1.85–1.73(m,2H),1.66–1.50(m,2H). 19 F NMR(376MHz,CDCl 3 )δ-97.67–-98.06(m,2F). 13 C NMR(101MHz,CDCl 3 )δ170.6,142.9,132.9(t,J＝27.5Hz),131.0,127.3,124.4,123.4,121.1(t,J＝238.4Hz),119.0(t,J＝9.5Hz),116.7,47.7,36.8(t,J＝26.5Hz),35.4,27.8,24.0,22.0(t,J＝4.3Hz).MS(EI):m/z(％)119(100),279([M] + ).HRMS(EI)m/z:([M] + )Calculated for C 16 H 19 NOF 2 ([M] + ):279.1429；Found:279.1430.
The product is:
colorless oil, 124mg,97% yield, alpha/gamma>99:1 19 F NMR measurement, silica gel chromatography purification separation (petroleum ether/ethyl acetate=100:1) 1 H NMR(400MHz,CDCl 3 )δ6.70(d,J＝8.4Hz,1H),6.48(d,J＝2.4Hz,1H),6.30(dd,J＝8.4,2.4Hz,1H),6.03–5.84(m,3H),5.64(d,J＝17.2Hz,1H),5.44(d,J＝10.8Hz,1H),3.92(t,J＝6.2Hz,2H),2.21–2.02(m,2H),1.97–1.88(m,2H). 19 F NMR(376MHz,CDCl 3 )δ-93.10–-103.05(m,2F). 13 C NMR(101MHz,CDCl 3 )δ154.3,148.2,141.7,132.9(t,J＝27.6Hz),121.2(t,J＝238.4Hz),119.3(t,J＝9.5Hz),107.9,105.6,101.1,98.0,67.9,33.7(t,J＝26.8Hz),22.5(t,J＝4.2Hz).MS(DART):m/z(％)138(100),256([M] + ).HRMS(DART)m/z:([M+H] + )Calculated for C 13 H 15 F 2 O 3 :257.0984；Found:257.0983.
The product is as follows:
brown oil, 78.2mg,73% yield, α/γ>99:1 19 F NMR measurement, silica gel chromatography purification separation (petroleum ether/ethyl acetate=100:1) 1 H NMR(400MHz,CDCl 3 )δ5.97–5.81(m,1H),5.78(s,2H),5.68–5.53(m,1H),5.44(d,J＝10.8Hz,1H),3.79(t,J＝7.8Hz,2H),2.22(s,6H),2.02–1.86(m,2H),1.87–1.77(m,2H). 19 F NMR(376MHz,CDCl 3 )δ-97.55–-98.25(m,2F). 13 C NMR(126MHz,CDCl 3 )δ132.6(t,J＝27.5Hz),127.2,120.9(t,J＝239.3Hz),119.5(t,J＝9.4Hz),105.3,42.8,34.1(t,J＝27.0Hz),23.8(t,J＝3.7Hz),12.4.MS(EI):m/z(％)108(100),213([M] + ).HRMS(EI)m/z:([M] + )Calculated for C 12 H 17 F 2 N is 213.1324; found 213.1330. Product:
colorless oil, 80mg,90% yield, alpha/gamma>99:1 19 F NMR measurement, silica gel chromatography purification separation (petroleum ether/ethyl acetate=100:1) 1 H NMR(400MHz,CDCl 3 )δ7.68(d,J＝7.6Hz,2H),7.18(d,J＝7.6Hz,2H),5.75(dq,J＝17.4,11.2Hz,1H),5.51–5.34(m,1H),5.27(d,J＝11.2Hz,1H),3.14(t,J＝15.6Hz,2H),1.26(s,12H). 19 F NMR(376MHz,CDCl 3 )δ-96.39–-96.58(m,2F). 13 C NMR(126MHz,CDCl 3 )δ135.8(t,J＝4.4Hz),134.7,132.4(t,J＝26.9Hz),129.9,120.0(t,J＝240.6Hz),119.5(t,J＝9.2Hz),83.8,44.1(t,J＝27.5Hz),24.8.MS(FI):m/z(％)85,117,148,195(100),217,294([M] + ).HRMS(FI)m/z:([M] + )Calculated for C 16 H 21 F 2 O 2 10 B:293.1633；Found:293.1638.
The product is as follows:
colorless oil, 66.0mg,90% yield, α/γ=15:1 19 F NMR measurement, silica gel chromatography purification separation (Petroleum ether) 1 H NMR(500MHz,CDCl 3 )δ7.47(d,J＝7.5Hz,4H),7.37(t,J＝7.5Hz,4H),7.31(t,J＝7.5Hz,2H),5.96(dq,J＝17.2,11.1Hz,1H),5.75–5.63(m,1H),5.42(d,J＝11.1Hz,1H),4.45(t,J＝16.5Hz,1H). 19 F NMR(376MHz,CDCl 3 )δ-94.60–-108.06(m,2F). 13 C NMR(126MHz,CDCl 3 )δ137.5(t,J＝2.2Hz),132.7(t,J＝26.4Hz),129.6,128.4,127.3,120.6(t,J＝244.8Hz),120.0(t,J＝9.1Hz),58.8(t,J＝25.1Hz).MS(EI):m/z(％)152,167(100),244([M] + ).HRMS(EI)m/z:([M] + )Calculated for C 16 H 14 F 2 244.1058; found 244.1063. Product:
colorless oil, 51.0mg,80% yield, α/γ >99:1 19 F NMR determination, reversed-phase preparative HPLC purification (MeCN: H 2 O＝9:1) 1 H NMR(400MHz,CDCl 3 )δ7.33–7.27(m 2H),7.23–7.16(m,3H),5.86(dq,J＝17.2,11.2Hz,1H),5.68–5.56(m,1H),5.44(d,J＝11.2Hz,1H),2.81–2.75(m,1H),2.60–2.53(m,1H),2.06–1.87(m,2H),1.52–1.42(m,1H),1.07(d,J＝6.8Hz,3H). 19 F NMR(376MHz,CDCl 3 )δ-104.12(t,J＝12.5Hz,2F). 13 C NMR(101MHz,CDCl 3 )δ141.8,131.6(t,J＝27.3Hz),128.4,128.3,125.9,122.9(t,J＝241.8Hz),119.8(t,J＝9.6Hz),39.7(t,J＝24.8Hz),33.3,31.7(t,J＝3.6Hz),13.0(t,J＝4.8Hz).MS(EI):m/z(％)91(100),131,210([M] + ).HRMS(EI)m/z:([M] + )Calculated for C 13 H 16 F 2 :210.1220；Found:210.1215.
The product is as follows:
yellow oil, 112.3mg,79% yield, α/γ>99:1 19 F NMR determination, reversed phase preparative HPLC (MeCN: H 2 O＝6:4) 1 H NMR(400MHz,CDCl 3 )δ7.98(d,J＝8.8Hz,2H),6.92(d,J＝8.8Hz,2H),5.89(dq,J＝17.4,11.3Hz,1H),5.71–5.61(m,1H),5.48(d,J＝11.3Hz,1H),4.50–4.23(m,2H),2.26–2.06(m,2H),1.64–1.52(m,1H),1.09(d,J＝6.8Hz,3H). 19 F NMR(376MHz,CDCl 3 )δ-103.74(dt,J＝241.3,11.6Hz,1F),-105.56(dt,J＝241.3,13.0Hz,1F). 13 C NMR(101MHz,CDCl 3 )δ166.2,163.4,131.5,131.3(t,J＝27.2Hz),122.6,122.5(t,J＝242.0Hz),120.2(t,J＝9.5Hz),113.6,62.3,55.4,37.4(t,J＝25.4Hz),29.2(t,J＝4.1Hz),13.1(t,J＝4.7Hz).MS(EI):m/z(％)135(100),152,284([M] + ).HRMS(EI)m/z:([M] + )Calculated for C 13 H 16 F 2 :284.1219；Found:284.1225.
The product is as follows:
yellow oil, 83mg,60% yield, alpha/gamma>99:1 19 F NMR measurement, silica gel chromatography purification separation (petroleum ether: ethyl acetate=1:1) 1 H NMR(400MHz,CDCl 3 )diastereomer mixtures: 1 H NMR(400MHz,CDCl3)δ5.84(m,1H),5.64–5.54(m,1H),5.45–5.38(m,1H),4.46–4.40(m,0.86H)(4.38(dd,J＝8.4,2.7Hz,0.14H)),3.67(s,3H),3.65–3.54(m,1H),3.54–3.43(m,1H),2.68–2.53(m,2H),2.22–2.08(m,2H),2.00–1.87(m,2H),1.02(t,J＝6.7Hz,3H). 19 F NMR(376MHz,CDCl 3 ) Diastereomeric mixtures δ -103.76 (dtd, j=240.6, 11.0,2.6hz, 0.46F)), -103.42 (dtd, j=240.8, 11.0,2.6hz, 0.07F), -104.22 (dtd, j=240.7, 11.7,2.6hz, 0.39F)), -104.49 (dtd, j=241.5, 12.2,2.4hz, 0.07F), -107.36-108.84 (m, 0.85F) (-107.50-109.05 (m, 0.15F)). 13 C NMR(126MHz,CDCl 3 ) Diastereomer mixtures delta 172.64 (172.62), 169.8 (169.6), 131.6 (t, j=27.1 Hz) (131.5 (t, j=27.1 Hz)), 122.21 (t, j= 241.9 Hz) (122.16 (t, j=242.0 Hz)), 120.0 (t, j=9.6 Hz) (119.9 (t, j=9.6 Hz)), 58.64 (58.59), 52.0,47.0 (46.9), 36.9 (t, j=25.2 Hz) (36.5 (t, j=25.2 Hz)), 34.6 (t, j=3.7 Hz) (34.4 (t, j=3.8 Hz)), 29.07 (28.99), 24.61 (24.58), 13.51 (t, j=3.9 Hz) (13.48 (t, j=3.9 Hz)), MS (EI): M/z 70 (100), 216,275 ([ M)] + ).HRMS(EI)m/z:([M] + )Calculated for C 13 H 19 O 3 NF 2 275.1328; found 275.1331. Product:
yellowish oil, 110.9mg,85% yield, alpha/gamma>99:1 19 F NMR measurement, silica gel chromatography purification separation (petroleum ether/ethyl acetate=10:1) 1 H NMR(400MHz,CDCl 3 )δ5.81(dq,J＝17.2,11.2Hz,1H),5.57(dt,J＝17.2,2.6Hz,1H),5.43(d,J＝11.2Hz,1H),4.26–3.95(m,2H),2.71–2.47(m,2H),1.99–1.80(m,1H),1.77–1.67(m,2H),1.41(s,9H),1.36–1.24(m,2H). 19 F NMR(376MHz,CDCl 3 )δ-104.5--107.2(m,2F). 13 C NMR(126MHz,CDCl 3 )δ154.5,131.2(t,J＝27.2Hz),121.5(t,J＝241.4Hz),120.1(t,J＝9.5Hz),79.5,43.1(t,J＝25.8Hz),28.3,24.9.MS(ESI):m/z(％)162(100),284([M+Na] + ).HRMS(ESI)m/z:([M+Na] + )Calculated for C 13 H 21 O 2 NF 2 Na:284.1433；Found:284.1428.
The product is as follows:
colorless oil, 56mg,74% yield, α/γ>50:1 19 F NMR measurement, silica gel chromatography purification and separation (Petroleum ether 100%) 1 H NMR(500MHz,CDCl 3 )δ7.32(d,J＝8.5Hz,2H),7.24(d,J＝8.5Hz,2H),5.59(dq,J＝17.3,10.5Hz,1H),5.45–5.37(m,1H),5.23(d,J＝11.0Hz,1H),2.37(dd,J＝16.5,9.0Hz,1H),1.75–1.63(m,1H),1.47–1.36(m,1H),1.34(s,9H),1.21–1.13(m,1H). 19 F NMR(376MHz,CDCl 3 )δ-90.04(dt,J＝251.0,10.2Hz),-95.59(dt,J＝251.4,12.4Hz). 13 C NMR(126MHz,CDCl 3 )δ149.2,133.3,133.0(t,J＝28.7Hz),129.3(t,J＝1.6Hz),124.7,120.5(dd,J＝239.0,236.9Hz),118.4(t,J＝9.3Hz),34.4,31.4,23.6(dd,J＝32.1,30.3Hz),20.3(dd,J＝3.9,1.9Hz),5.7(dd,J＝4.9,2.6Hz).MS(EI):m/z(％)45,70(100),159,250([M] + ).HRMS(EI)m/z:([M] + )Calculated for C 16 H 20 F 2 :250.1528；Found:250.1534.
The product is as follows:
1 H NMR(600MHz,DMSO-d6)δ5.78(dq,J＝17.4,11.9Hz,1H),5.33(ddt,J＝17.3,2.5,1.3Hz,1H),5.22(d,J＝11.1Hz,1H),0.78(s,9H). 19 F NMR(565MHz,DMSO-d 6 )δ-112.20(d,J＝12.0Hz,2F).MS(FI):m/z(％)134(100)([M] + )；HRMS(FI)m/z:([M] + )Calculated for C 7 H 12 F 2 134.0902; found 134.0903. Product:
yellow liquid, 131mg,85% yield，α/γ>11:1， 19 F NMR measurement, silica gel chromatography purification and separation (Petroleum ether 100%) 1 H NMR(400MHz,CDCl 3 )δ7.68(d,J＝8.4Hz,2H),7.66–7.60(m,4H),7.53–7.45(m,2H),7.44–7.37(m,1H),6.28–6.24(m,1H),5.97–5.92(m,1H). 19 F NMR(376MHz,CDCl 3 )δ-93.08(s,2F). 13 C NMR(126MHz,CDCl 3 )δ143.4,140.0,132.9(t,J＝27.4Hz),128.9,127.9,127.2,127.1,126.9(t,J＝34.7Hz),126.4(t,J＝5.5Hz)，122.5(t，J＝5.9Hz)，117.7(t，J＝243.8Hz).MS(EI):m/z(％)152，203(100)，308([M] + ).HRMS(EI)m/z:([M] + )Calculated for C 15 H 11 F 2 Br:308.0007；Found:308.0013.
The product is as follows:
a yellowish oil, 97mg,63% yield, α/γ=3: 1 is composed of 19 FNMR measurement, when 0.6-fold equivalent of catalyst was used, 140mg of product, 92% yield, α/γ=50: 1, silica gel chromatography (petroleum ether/ethyl acetate=100:1) 1 H NMR(400MHz,CDCl 3 )δ7.43–7.28(m,5H),6.27–6.25(m,1H),5.86–5.85(m,1H),4.53(s,2H),3.54(t,J＝6.4Hz,2H),2.34–2.16(m,2H),1.91–1.74(m,2H). 19 F NMR(376MHz,CDCl 3 )δ-98.22(t,J＝16.3Hz,2F). 13 C NMR(101MHz,CDCl 3 )δ138.2,128.4,127.58,127.56,125.5(t,J＝31.7Hz),121.1(t,J＝6.6Hz),120.1(t,J＝244.6Hz),72.8,69.0,32.1(t,J＝25.9Hz),22.6(t,J＝4.1Hz).MS(FI):m/z(％)187(100),304([M] + ).HRMS(FI)m/z:([M] + )Calculated for C 13 H 15 F 2 OBr:304.0269；Found:304.0273.
The product is as follows:
a yellowish oil, 76.5mg,98% yield, α/γ=50 when 0.6-fold equivalent of catalyst is used: 1 is composed of 19 F NMR measurement. 1 H NMR(400MHz,CDCl 3 )δ7.39–7.28(m,5H),5.84–5.83(m,1H),5.61–5.60(m,1H),4.53(s,2H),3.53(t,J＝6.3Hz,2H),2.27–2.15(m,2H),1.82–1.75(m,2H). 19 F NMR(376MHz,CDCl 3 )δ-99.9(t,J＝16.4Hz,2F). 13 C NMR(101MHz,CDCl 3 )δ138.3,135.0(t,J＝32.1Hz),128.4,127.60,127.59,120.0(t,J＝244.4Hz),116.4(t,J＝5.9Hz),72.9,69.0,31.7(t,J＝25.8Hz),22.6(t,J＝4.2Hz).
The product is as follows:
colorless oil, 160.9mg,96% yield, α/γ>99:1 silica gel chromatography purification separation (Petroleum ether/ethyl acetate=100:1) 1 H NMR(400MHz,CDCl 3 )δ6.70(d,J＝8.4Hz,1H),6.49(d,J＝2.4Hz,1H),6.31(dd,J＝8.4,2.4Hz,1H),6.29–6.26(m,1H),5.91(s,2H),5.88–5.85(m,1H),3.93(t,J＝6.2Hz,2H),2.38–2.22(m,2H),1.97–1.86(m,2H). 19 F NMR(376MHz,CDCl 3 )δ-98.34(t,J＝16.2Hz,2F). 13 C NMR(101MHz,CDCl 3 )δ154.2,148.2,141.7,125.4(t,J＝31.5Hz),121.2(t,J＝6.6Hz),120.0(t,J＝244.8Hz),107.9,105.6,101.1,98.1,67.6,32.0(t,J＝26.1Hz),22.3(t,J＝4.1Hz).MS(EI):m/z(％)138(100),334([M] + ).HRMS(EI)m/z:([M] + )Calculated for C 13 H 13 F 2 O 3 Br:334.0011；Found:334.0008.
The product is as follows:
colorless oil, 100mg,90% yield, α/γ>99：1 19 FNMR determination, silica gel chromatography purification separation (petroleum ether/ethyl acetate=100:1), use 0.6-fold equivalent of catalyst CuBr, 1 H NMR(400MHz,CDCl 3 )δ6.29–6.25(m,1H),5.90–5.85(m,1H),2.44(t,J＝7.2Hz,2H),2.34–2.17(m,2H),1.85(p,J＝7.2Hz,2H). 19 F NMR(376MHz,CDCl 3 )δ-98.65(t,J＝16.0Hz). 13 C NMR(101MHzCDCl 3 )δ124.7(t,J＝31.2Hz)121.6(tJ＝6.7Hz)119.3(tJ＝245.4Hz),118.6,34.0(t,J＝26.3Hz),18.5(t,J＝4.3Hz),16.7.MS(FI):m/z(％)144,223(100)([M] + ).HRMS(FI)m/z:([M] + )Calculated for C 7 H 8 F 2 NBr:222.9803；Found:222.9805.
the product is as follows:
yellowish oil, 71mg,97% yield, alpha/gamma>99：1 19 F NMR measurement, silica gel chromatography purification isolation (petroleum ether/dcm=20:1), 1 H NMR(400MHz,CDCl 3 )δ7.46–7.40(m,2H),7.39–7.33(m,3H),5.76(s,1H),5.50(s,1H),3.48(t,J＝6.8Hz,2H),2.02–1.85(m,2H),1.74(p,J＝6.8Hz,2H),1.65–1.54(m,2H). 19 F NMR(376MHz,CDCl 3 )δ-95.99(t,J＝16.2Hz,2F). 13 C NMR(101MHz,CDCl 3 )144.6(t,J＝22.8Hz),136.9,128.4,128.2,128.1,122.3(t,J＝243.1Hz),118.2(t,J＝9.0Hz),44.4,35.4(t,J＝26.4Hz),31.9,19.7(t,J＝4.3Hz).MS(FI):m/z(％)194,244(100)([M] + ).HRMS(EI)m/z:([M] + )Calculated for C 13 H 15 F 2 Cl:244.0825；Found:244.0828.
the product is as follows:
yellow oil, 89mg,99% yield, alpha/gamma>99：1 19 F NMR measurement, silica gel chromatography purification separation (petroleum ether), 1 H NMR(400MHz,CDCl 3 )δ7.37(d,J＝8.8Hz,2H),7.34(d,J＝8.8Hz,2H),5.70(s,1H),5.48(s,1H),3.48(t,J＝6.6Hz,2H),2.00–1.86(m,2H),1.80–1.70(m,2H),1.64–1.52(m,2H),1.34(s,9H). 19 F NMR(376MHz,CDCl 3 )δ-95.97(t,J＝16.3Hz,2F). 13 C NMR(101MHz,CDCl 3 )δ151.3,144.4(t,J＝23.1Hz),133.9,127.7,125.3,122.5(t,J＝243.1Hz),117.6(t,J＝9.0Hz),44.5,35.5(t,J＝26.5Hz),34.5,31.9,31.3,19.8(t,J＝4.3Hz).MS(FI):m/z(％)57,128,285(100),300([M + ]).HRMS(FI)m/z:([M] + )Calculated for C 17 H 23 F 2 Cl([M + ]):300.1451；Found:300.1450.
The product is as follows:
yellowish oil, 90mg,95% yield, alpha/gamma>99：1 19 F NMR measurement, silica gel chromatography purification separation (petroleum ether/ethyl acetate=100:1), 1 H NMR(400MHz,CDCl 3 )δ8.03(d,J＝8.2Hz,2H),7.48(d,J＝8.2Hz,2H),5.82(s,1H),5.55(s,1H),4.39(q,J＝7.2Hz,2H),3.47(t,J＝6.4Hz,2H),1.99–1.82(m,2H),1.78–1.68(m,2H),1.63–1.53(m,2H),1.40(t,J＝7.2Hz,3H). 19 F NMR(376MHz,CDCl 3 )δ-95.84(t,J＝16.1Hz,2F). 13 C NMR(101MHz,CDCl 3 )δ166.2,144.0(t,J＝23.5Hz),141.3,130.3,129.6,128.0,122.0(t,J＝243.2Hz),119.4(t,J＝8.9Hz),61.1,44.4,35.4(t,J＝26.2Hz),31.8,19.7(t,J＝4.3Hz),14.3.MS(FI):m/z(％)133,151,181,198(100),316([M + ]).HRMS(FI)m/z:([M] + )Calculated for C 16 H 19 F 2 O 2 Cl([M + ]) 316.1036; found 316.1033. Product:
yellow oil, 57mg,72% yield, alpha/gamma>99：1 19 F NMR measurement, silica gel chromatography purification separation (petroleum ether/ethyl acetate=50:1), 0.6-fold equivalent CuBr use, 1 H NMR(400MHz，CDCl 3 )δ7.72(d,J＝8.0Hz，2H)，7.60(d，J＝8.0Hz，2H)，6.04–5.91(m,1H),5.82–5.70(m,1H),2.17–2.05(m,2H),1.46–1.34(m,2H),1.35–1.18(m,6H),0.87(t,J＝6.6Hz,3H). 19 F NMR(376MHz,CDCl 3 )(Z)δ-86.40(d,J＝13.6Hz),(E)-91.71(dd,J＝10.0,3.3Hz). 13 CNMR(126MHz,CDCl 3 )δ141.6(t,J＝28.7Hz),138.4(t,J＝8.9Hz),132.2,126.4(t,J＝5.5Hz),125.0(t,J＝28.7Hz),118.7(t,J＝238.6Hz),118.1,113.8,31.8,31.5,28.7,28.2,22.5,14.0.MS(DART):m/z(％)185,264([M+H] + ).HRMS(DART)m/z:([M+H] + ):Calculated for C 16 H 20 F 2 N:264.1558；Found:2641556, product:
yellowish oil, 67mg,65% yield, alpha/gamma>99：1 19 F NMR measurement, silica gel chromatography purification separation (petroleum ether/ethyl acetate=50:1), 0.6-fold equivalent CuBr use, 1 H NMR(400MHz,CDCl 3 )δ6.70(d,J＝8.4Hz,1H),6.48(d,J＝2.4Hz,1H),6.31(dd,J＝8.4,2.4Hz,1H),6.14–6.03(m,0.55H),5.91(s,2H),5.81–5.67(m,0.45H),5.65–5.37(m,1H),3.96–3.88(m,2H),2.34–2.01(m,4H),2.02–1.86(m,2H),1.46–1.36(m,2H),1.36–1.24(m,6H),0.89(t,J＝6.4Hz,3H). 19 F NMR(376MHz,CDCl 3 )δ-91.00(q,J＝15.7Hz,0.9F),-94.84–-95.01(m,1.1F). 13 C NMR(101MHz,CDCl 3 ) δ 154.3,148.2,141.7,138.5 (t, j=6.1 Hz) (136.3 (t, j=9.0 Hz)), 124.9 (t, j=24.5 Hz) (124.4 (t, j=25.1 Hz)), 122.5 (t, j=239.0 Hz) (121.50 (t, j=237.9 Hz)), 107.9,105.6,101.1,98.1,68.0,35.2 (t, j=27.4 Hz) (34.13 (t, j=27.4 Hz)), 31.8,31.62 (31.60), 29.3,28.9 (28.8), 28.3 (28.4), 22.6 (22.5), 14.0 (isomer data in brackets) ·ms (DART): M/z (%) 322 (100), 341 ([ M ] M) + ]).HRMS(DART)m/z:([M+H] + )Calculated for C 19 H 27 F 2 O 3 :341.1923Found:341.1920
The product is as follows:
yellowish oil, 64mg,51% yield, alpha/gamma>99：1 19 F NMR determination, silica gel chromatography purification separation (petroleum ether), 0.6-fold equivalent of CuBr used, 1 H NMR(400MHz,CDCl 3 )δ6.13–5.98(m,0.8H),5.80–5.67(m,0.2H),5.60–5.37(m,1H),3.54(t,J＝6.5Hz,2H),2.30–2.18(m,0.4H),2.14–2.06(m,1.6H),2.00–1.78(m,4H),1.70–1.54(m,2H),1.47–1.34(m,2H),1.34–1.22(m,6H),0.89(t,J＝6.8Hz,3H). 19 F NMR(376MHz,CDCl 3 )δ-90.74(q,J＝14.9Hz,0.4F),-93.83–-95.92(m,1.6F). 13 C NMR(101MHz,CDCl 3 )δ138.5(t,J＝6.1Hz),136.3(t,J＝9.1Hz),124.75(t,J＝26.5Hz)(124.30(t,J＝27.1Hz)),121.4(t,J＝237.9Hz),44.6,36.7(t,J＝27.2Hz),32.1,31.8,31.6,28.8,28.5,22.6,20.0(t,J＝4.3Hz),14.1.MS(FI):m/z(％)232(100),252([M] + ).HRMS(FI)m/z:([M] + )Calculated for C 13 H 23 F 2 Cl:252.1451；Found:252.1454.
the product is as follows:
the yellowish oil (108.6 mg,96% yield) was chromatographed on silica gel (petroleum ether/ethyl acetate=100:1) 1 H NMR(400MHz,Chloroform-d)δ7.40–7.27(m,5H),5.91(dq,J＝17.3,10.9Hz,1H),5.62(dt,J＝17.4,2.7Hz,1H),5.42(d,J＝11.0Hz,1H),4.51(s,2H),3.52(t,J＝6.2Hz,2H),2.12–1.94(m,2H),1.86–1.73(m,H). 19 F NMR(376MHz,Chloroform-d)δ-97.92–-98.22(m,2F). 13 C NMR(126MHz,Chloroform-d)δ138.32,132.93(t,J＝27.5Hz),128.37,127.59,121.30(t,J＝238.4Hz),119.15(t,J＝9.5Hz),72.85,69.33,33.90(t,J＝26.8Hz),22.77(t,J＝4.2Hz).MS(EI):m/z(％)91(100),226(M + ).HRMS:Calculated for C 13 H 16 OF 2 :226.1167；Found:226.1164.
0.5mol% of CuBr was added to a 50mL Schlenk flask, and difluoroallylium salt (4.2 mmol,1.0 equiv) of formula C was added thereto, and the flask was evacuated and Ar was filled three times. 10.0mL of THF was added and formula [ C]-[Zn]The zinc reagent (1.2 equiv) was stirred at room temperature for 16 hours to effect a reaction. With fluorobenzene as an internal standard reagent (first from 19 F NMR measurement α/γ=10: 1) By using 19 F NMR determination of product yield, NH 4 The reaction was quenched with Cl and diluted with EtOAc, the aqueous phase was washed with ethyl acetate (3X 10 mL) and the organic phase was Na 2 SO 4 Drying, filtering and collecting.
The product obtained by gram-scale reaction:the yellowish oil, 676.3mg,81% year, was purified by chromatography on silica gel (DCM: pe=1:5).
The product is as follows:
colorless oil (79.7 mg,90% yield), silica gel chromatography purification separation (petroleum ether/ethyl acetate=100:1) 1 H NMR(400MHz,Chloroform-d)δ7.68(d,J＝7.7Hz,2H),7.18(d,J＝7.7Hz,2H),5.75(dq,J＝17.4,11.1Hz,1H),5.51–5.34(m,1H),5.27(dt,J＝11.0,0.8Hz,1H),3.14(t,J＝15.6Hz,2H),1.26(s,12H). 19 F NMR(376MHz,Chloroform-d)δ-96.49(ddd,J＝16.7,14.0,10.2Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ135.83(t,J＝4.4Hz),134.73,132.36(t,J＝26.9Hz),129.92,120.03(t,J＝240.6Hz),119.54(t,J＝9.2Hz),83.78,44.10(t,J＝27.5Hz),24.84.MS(EI):m/z(％)294(M+).HRMS:Calculated for C16H21F210B:293.1638；Found:293.1633.
The product is as follows:
colorless oil (44.0 mg,90% yield), silica gel chromatography purification separation (petroleum ether) 1 H NMR(400MHz,Chloroform-d)δ7.29(m 2H),7.23–7.16(m,3H),5.86(dq,J＝17.4,11.5Hz,1H),5.68–5.56(m,1H),5.44(d,J＝11.0Hz,1H),2.77(ddd,J＝14.8,10.1,5.3Hz,1H),2.56(ddd,J＝13.8,10.1,6.6Hz,1H),2.06–1.87(m,2H),1.47(ddt,J＝13.5,9.8,4.8Hz,1H),1.07(d,J＝6.8Hz,3H). 19 F NMR(376MHz,Chloroform-d)δ-104.12(t,J＝12.5Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ141.78,131.57(t,J＝27.3Hz),128.41,128.34,125.93,122.88(t,J＝241.8Hz),119.77(t,J＝9.6Hz),39.65(t,J＝24.8Hz),33.27,31.70(t,J＝3.6Hz),13.00(t,J＝4.8Hz).MS(EI):m/z(％)91(100),210(M+).HRMS:Calculated for C 13 H 16 F 2 210.1220; found 210.1215. Product:
orange oil, 48.1mg,82% yield, α/γ=50: 1 is composed of 19 F NMR measurement, silica gel chromatography purification separation (petroleum ether/ethyl acetate=100:1) 1 H NMR(400MHz,Chloroform-d)δ6.27(dd,J＝2.3,1.2Hz,1H),5.87(dd,J＝2.4,1.2Hz,1H),5.80(s,2H),3.94–3.72(m,2H),2.25(s,6H),2.23–2.07(m,2H),1.80(tt,J＝10.5,6.7Hz,2H). 19 F NMR(376MHz,Chloroform-d)δ-98.06(t,J＝16.0Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ127.17,124.95(t,J＝31.4Hz),121.43(t,J＝6.7Hz),119.85(t,J＝245.2Hz),105.37,42.62,32.40(t,J＝26.2Hz),23.74(t,J＝3.7Hz),12.42.MS(FI):m/z(％)138(100),291([M] + ).HRMS:Calculated for C 12 H 16 NF 2 Br([M] + ):291.0431；Found:291.0429.
The above-mentioned productCan be further used for preparing +.>The reaction is as follows:
pd (PPh) 3 ) 4 (8.6 mg,5 mol%) was added to a 25mL Schlemk bottle, formula CuI (2.8 mg,10 mol%) was added, and the vacuum was applied three times. Adding the compound under the protection of argon (45.7 mg,0.15mmol,1.0 equiv.) Dry diisopropylethylamine EtN (i-Pr) 2 (52.2. Mu.L, 0.3mmol,2.0 equiv) and phenylacetylene (16.1. Mu.L, 0.15mmol,1.0 equiv) were added to the reaction mixture, and reacted at 40℃for 24h with stirring. Cooled to room temperature, the extract was separated with ethyl acrylate by adding water, and the organic phase was washed with saturated brine (brine) to remove Na 2 SO 4 Drying, drying by distillation under reduced pressure, and purifying with FP ECOFLEX C18 (20 g) chromatography to obtain compound +.>34mg,70％yield， 1 H NMR(400MHz,CDCl 3 )δ7.50–7.45(m,2H),7.39–7.27(m,8H),5.95–5.90(m,1H),5.82–5.78(m,1H),4.52(s,2H),3.56(t,J＝6.4Hz,2H),2.35–2.19(m,2H),1.91–1.80(m,2H). 19 F NMR(376MHz,CDCl 3 )δ-99.31(t,J＝16.4Hz,2F). 13 C NMR(126MHz,CDCl 3 )δ138.3,131.7,128.8,128.3,128.2,128.1(t,J＝28.8),127.6,127.5,124.1(t,J＝6.9Hz),122.2,120.8(t,J＝244.1Hz),92.1,84.4(t,J＝4.3Hz),72.8,69.3,33.0(t,J＝26.1Hz),22.7(t,J＝4.2Hz).MS(FI):m/z(％)91(100),129,235,326([M] + ).HRMS(FI)m/z:([M] + )Calculated for C 21 H 19 F 2 O:326.1477；Found:326.1475.
The product is as follows:
yellowish oily substance (52.5 mg,83% yield), silica gel chromatography purification separation (petroleum ether 100%) 1 H NMR(400MHz,Chloroform-d)δ7.46(d,J＝8.9Hz,2H),7.41(d,J＝8.5Hz,2H),7.21(t,J＝7.9Hz,1H),6.99–6.92(m,1H),6.90–6.81(m,2H),5.71(td,J＝1.8,1.0Hz,1H),5.65(s,1H),3.74(s,3H),1.33(s,9H). 19 F NMR(376MHz,Chloroform-d)δ-90.08(s,2F). 13 C NMR(101MHz,Chloroform-d)δ159.15,153.04(t,J＝1.7Hz),145.40(t,J＝26.6Hz),137.90,133.40(t,J＝27.6Hz),129.08,125.66(t,J＝5.5Hz),125.21,120.74,120.57(t,J＝241.8Hz)，119.39(t，J＝8.0Hz)，113.85，113.68，55.10，34.71，31.20.MS(FI):m/z(％)316(100)，316([M] + ).HRMS:Calculated for C 20 H 22 F 2 :316.1629；Found:316.1633.
The product is as follows:
yellowish oil, 54.2mg,76% yield, α/γ=25:1, consist of 19 F NMR measurement, silica gel chromatography purification separation (Petroleum ether) 1 H NMR(400MHz,Chloroform-d)δ7.26(t,J＝8.0Hz,1H),7.00(ddd,J＝7.7,1.8,1.0Hz,1H),6.96(t,J＝2.1Hz,1H),6.88(ddd,J＝8.2,2.7,0.9Hz,1H),5.73(dt,J＝1.8,1.0Hz,1H),5.48(q,J＝1.2Hz,1H),3.81(s,3H),3.56(t,J＝6.3Hz,2H),2.09–1.90(m,2H),1.69–1.55(m,2H),0.84(s,9H),-0.01(s,6H). 19 F NMR(376MHz,Chloroform-d)δ-95.65(t,J＝16.6Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ159.38,144.70(t,J＝23.3Hz),138.41,129.31,122.66(t,J＝242.7Hz),120.58,118.03(t,J＝8.9Hz),113.57,62.12,55.19,32.80(t,J＝26.4Hz),25.83,18.19,-5.43.MS(FI):m/z(％)356(100),356(M + ).HRMS:Calculated for C 19 H 30 F 2 O 2 Si:356.1984；Found:356.1978.
The product is as follows:
yellowish oily substance (27.9 mg,73% yield), silica gel chromatography purification separation (petroleum ether) 1 H NMR(400MHz,Chloroform-d)δ7.35(s,4H),5.72–5.62(m,1H),5.46(s,1H),3.56(t,J＝6.2Hz,2H),1.98(tt,J＝16.4,8.2Hz,2H),1.71–1.49(m,2H),1.32(s,9H),0.82(s,9H),-0.02(s,6H). 19 F NMR(376MHz,Chloroform-d)δ-95.71(t,J＝16.6Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ151.12,144.61(t,J＝23.2Hz),134.01,125.21,127.70,128.82–122.39(m),117.37(t,J＝8.9Hz),62.13,34.52,32.86(t,J＝26.4Hz),31.26,25.85,18.20,-0.02,-5.41.MS(FI):m/z(％)325(100),382(M + ).HRMS:Calculated for C 22 H 36 F 2 OSi 382.2504; found 382.2498. Product:
yellowish oily substance (74 mg,90% yield), silica gel chromatography purification separation (petroleum ether) 1 H NMR(400MHz,Chloroform-d)δ7.35(d,J＝8.8Hz,2H),6.88(d,J＝8.8Hz,2H),5.67(s,1H),5.43(s,1H),3.82(s,3H),3.47(t,J＝6.4Hz,2H),2.00–1.83(m,2H),1.79–1.68(m,2H),1.62–1.50(m,2H). 19 F NMR(376MHz,Chloroform-d)δ-95.97(t,J＝16.1Hz,2F). 13 C NMR (101 mhz, chloro form-d) δ 159.6,144.0 (t, j=23.0 Hz), 129.27,129.25,122.5 (t, j= 243.0 Hz), 117.1 (t, j=9.1 Hz), 113.7,55.2,44.5,35.4 (t, j=26.5 Hz), 31.9,19.8 (t, j=4.3 Hz)And (3) products:
yellow oil, 94mg,66% yield, e/z=4.6:1, γ/α>99:1， 19 F NMR measurement, silica gel chromatography purification separation (petroleum ether/ethyl acetate=1:1), 0.6-fold equivalent CuBr use, 1 H NMR(400MHz,CDCl 3 )δ8.07(d,J＝8.4Hz,2H),7.55(d,J＝8.4Hz,0.30H)(7.60(d,J＝8.4Hz,1.70H),6.00–5.87(m,1H),5.86–5.70(m,1H),4.40(t,J＝6.2Hz,2H),2.85(t,J＝6.2Hz,2H),2.63(q,J＝6.8Hz,4H),2.16–2.01(m,2H),1.45–1.32(m,2H),1.31–1.21(m,6H),1.06(t,J＝7.2Hz,6H),0.86(t,J＝6.8Hz,3H). 19 F NMR(376MHz,CDCl 3 )δ-85.78(d,J＝12.7Hz,0.28F),-91.12(d,J＝9.2Hz,1.72F). 13 C NMR(126MHz,CDCl 3 )δ165.9,141.4(t,J＝28.2Hz),137.9(t,J＝8.9Hz),131.4,129.6,125.6(t,J＝5.4Hz),125.5(t,J＝29.0Hz),119.3(t,J＝237.9Hz),63.4,50.9,47.8,31.8,31.5,28.7,28.2,22.5,14.0,11.8.MS(DART):m/z(％)382(100)([M+H] + ).HRMS(DART)m/z:([M+H] + )Calculated for C 19 H 27 F 2 O 3 :382.2552；Found:382.2550.
Application example 3
2.5mol% of CuBr in step (1) was added to a 25mL Schlenk flask, and difluoroallylium salt (0.5 mmol,1.0 equiv) of formula C was added thereto, and the flask was evacuated and Ar was filled three times. 2.0mL of THF was added and formula [ C]-[Zn]The zinc reagent (1.2 equiv) was stirred at room temperature for 3 hours to effect a reaction. The fluorobenzene is taken as an internal standard reagent 19 F NMR determination of product yield, NH 4 The reaction was quenched with Cl and diluted with EtOAc, the aqueous phase was washed with ethyl acetate (3X 10 mL) and the organic phase was Na 2 SO 4 Drying, filtering and collecting. The purified product was used directly in the next step.
Step (2): k was added to a 25mL flask at 25℃ 2 OsO 2 (OH) 4 (9.2 mg,5 mol%) NMO (135 mg,1mmol,2.0 equiv) was stirred with the above obtained compound for 24h, diluted with ethyl acetate, and saturated NaHCO 3 Washing with Na with brine 2 SO 4 Dried, filtered and concentrated. The following products were obtained by silica gel chromatography.
Step (1):
step (2):
the product is as follows:
the product is as follows:/>
viscous yellow oil, 203mg,85% yield, α/γ=99: 1 is composed of 19 F NMR measurement, dr=1:1), silica gel chromatography purification separation (petroleum ether/ethyl acetate=100:1) 1 H NMR(400MHz,CDCl 3 )δ8.08(d,J＝8.2Hz,2H),7.60(d,J＝8.2Hz,2H),5.94(d,J＝3.6Hz,1H),5.50(d,J＝2.8Hz,1H),4.62(d,J＝3.6Hz,1H),4.41–4.27(m,2H),4.17–4.02(m,3H),3.84–3.65(m,2H),3.19(t,J＝6.2Hz,1H),2.22(s,1H),1.55(s,3H),1.41(s,3H),1.32(s,3H),1.26(s,3H). 19 F NMR(376MHz,CDCl 3 )δ-105.10(dd,J＝255.5,8.3Hz,0.5F),-105.23(dd,J＝255.5,8.4Hz,0.5F),-110.67(dd,J＝255.5,13.4Hz,1F). 13 C NMR(101MHz,CDCl 3 )δ164.5,139.2(t,J＝25.7Hz),131.2,129.7,126.1(t,J＝6.4Hz),120.4(t,J＝248.6Hz),112.4,109.5,105.0,83.3,79.8,76.9,73.9(t,J＝29.7Hz),72.5,67.2,60.9,26.8,26.6,26.1,25.1.MS(DART):m/z(％)274,417(100),475([M+H] + ).HRMS(DART)m/z:([M+H] + )Calculated for C 22 H 29 F 2 O 9 :475.1774；Found:475.1771.
The product is as follows:
yellow viscous oil (150 mg,71% yield, two steps,α/γ=99: 1 is composed of 19 F NMR measurement, dr=1:1), silica gel chromatography purification separation (petroleum ether/ethyl acetate=1:1) 1 H NMR(400MHz,CDCl 3 )δ5.85(d,J＝3.6Hz,1H),4.51(d,J＝4.0Hz,1H),4.28(q,J＝6.4Hz,1H),4.11(dd,J＝7.4,3.0Hz,1H),4.05(dd,J＝8.6,6.2Hz,1H),3.96(dd,J＝8.8,6.0Hz,1H),3.83(d,J＝3.2Hz,1H),3.81–3.72(m,3H),3.63–3.55(m,1H),3.54–3.46(m,1H),3.33(s,1H),2.57(s,1H),2.03–1.78(m,2H),1.63–1.49(m,4H),1.47(s,3H),1.43–1.37(m,5H),1.33(s,3H),1.30(s,3H). 19 F NMR(376MHz,CDCl 3 )δ-108.22–-109.84(m,1F),-110.86–-112.38(m,1F). 13 C NMR(126MHz,CDCl 3 )δ123.7(t,J＝244.4Hz),111.7,108.9,105.1,82.3,82.0,81.0,72.6(dd,J＝29.8,27.4Hz),72.4,70.2,67.0,61.0(t,J＝4.0Hz),32.8(t,J＝23.9Hz),29.3,26.7,26.6,26.1,25.8,25.2,21.0(t,J＝4.3Hz).MS(FI):m/z(％)101(100),425([M-CH 3 ] + ).HRMS(FI)m/z:([M+H] + )Calculated for C 20 H 35 F 2 O 8 ([M+H] + ):441.2295；Found:441.2301.
The product is as follows:brown solid, 127mg,60% yield, two steps, α/γ=99: 1 is composed of 19 F NMR measurement, dr=1:1, silica gel chromatography purification separation (petroleum ether/ethyl acetate=1:1) 1 H NMR(400MHz,CDCl 3 )δ7.19(d,J＝8.6Hz,1H),6.70(d,J＝8.6Hz,1H),6.64(s,1H),3.98(t,J＝6.0Hz,2H),3.92–3.76(m,3H),2.98–2.82(m,2H),2.50(dd,J＝18.9,8.6Hz,1H),2.43–2.34(m,1H),2.29–1.89(m,9H),1.67–1.32(m,5H),1.30–1.20(m,1H),0.90(s,3H). 19 F NMR(376MHz,CDCl 3 )δ-107.13–-110.53(m,1F),-111.62--112.72(m,1F). 13 C NMR(101MHz,CDCl 3 )δ221.3,156.8,137.8,132.2,126.3,123.8(t,J＝245.7Hz),114.6,112.1,77.2,72.6(dd,J＝30.3,27.2Hz),67.0,61.0(t,J＝3.9Hz),50.4,48.0,43.9,38.3,35.9,31.5,29.9(t,J＝21.1Hz),29.6,26.5,25.9,21.6,13.8.MS(ESI):m/z(％)55(100),74,185,270,422([M] + ).HRMS(ESI)m/z:([M+Na] + )Calculated for C 24 H 32 F 2 O 4 Na:445.2161；Found:445.2156.
Application example 4
2.5mol% of CuBr was added to a 25mL Schlenk flask, and difluoroallylium salt (0.5 mmol,1.0 equiv) of formula C was added thereto, and the flask was evacuated and Ar was filled three times. 2.0mL of THF was added and formula [ C]-[Zn]The zinc reagent (1.2 equiv) was stirred at room temperature for 3 hours to effect a reaction. The fluorobenzene is taken as an internal standard reagent 19 F NMR determination of product yield, NH 4 The reaction was quenched with Cl and diluted with EtOAc, the aqueous phase was washed with ethyl acetate (3X 10 mL) and the organic phase was Na 2 SO 4 Drying, filtering and collecting. The purified product was directly used in the next step of preparation reaction.
The 25mL Schlemk flask was evacuated and backfilled with Ar (3 times). Cyclohexene (4 mmol,8.0 equiv) was then added. In an ice bath, BH 3. THF (2 mmol,4.0 equiv) was added dropwise at 0deg.C. After stirring for 5 minutes, the reaction mixture was warmed to room temperature and stirred for 1 hour. The above crude product was added. The resulting mixture was stirred at room temperature for 2 hours. Cooled to 0 ℃ and NaOH (7 mmol,14.0equiv,2 m) was added dropwise followed by H 2 O 2 (8 mmol,16.0equiv,30% wt.). After stirring for 15 minutes, the reaction mixture was warmed to room temperature and stirred for 2 hours. The obtained mixture was purified by adding saturated Na 2 O 3 And diluted with EtOAc. The aqueous phase was extracted with ethyl acetate (3X 10 ml). The combined organic layers were treated with Na2SO 4 Drying, filtering and concentrating. The product was purified by silica gel chromatography.
The first step:
and a second step of:
the product is as follows:yellow oil, 136mg,92% yield, three steps, α/γ=45: 1 is composed of 19 F NMR measurement, silica gel chromatography purification separation (petroleum ether/ethyl acetate=3:1) 1 H NMR(400MHz,CDCl 3 )δ3.87(t,J＝6.2Hz,2H),3.67(s,3H),2.30(t,J＝7.6Hz,2H),2.12(tt,J＝17.0,6.1Hz,2H),1.94–1.77(m,2H),1.64–1.57(m,2H),1.52–1.41(m,2H),1.36–1.23(m,12H). 19 F NMR(376MHz,CDCl 3 )δ-97.04(p,J＝17.0Hz,2F). 13 C NMR(101MHz,CDCl 3 )δ174.4,125.1(t,J＝240.3Hz),57.0(t,J＝5.5Hz),51.4,38.9(t,J＝24.5Hz),37.0(t,J＝24.8Hz),34.0,29.25,29.22,29.21,29.1,29.0,24.9,22.2(t,J＝4.7Hz).MS(FI):m/z(％)74(100),87,149,224,294([M] + ).HRMS(FI)m/z:([M] + )Calculated for C 15 H 28 F 2 O 3 :294.2001；Found:294.2003.
The product is as follows:
yellow oil, 68mg,66% yield, three steps, α/γ=48: 1 is composed of 19 F NMR measurement, silica gel chromatography purification separation (petroleum ether/ethyl acetate=5:1) 1 H NMR(400MHz,CDCl 3 )δ3.87(t,J＝6.2Hz,2H),2.12(tt,J＝17.1,6.2Hz,2H),1.96–1.77(m,2H),1.53–1.41(m,2H),1.35–1.27(m,10H),0.88(t,J＝6.8Hz,3H). 19 F NMR(376MHz,CDCl 3 )δ-97.07(p,J＝17.0Hz). 13 C NMR(126MHz,CDCl 3 )δ125.2(dd,J＝241.4,239.3Hz),57.1(t,J＝5.4Hz),38.9(t,J＝24.4Hz),37.0(t,J＝24.8Hz),31.8,29.3,29.1,22.6,22.2(t,J＝4.5Hz),14.1.MS(FI):m/z(％)85(100),124,168,188([M-HF] + ).HRMS(FI)m/z:([M] + )Calculated for C 11 H 22 F 2 O:208.1633；Found:208.1637.
The product is as follows:
yellow oil, 123mg,84% yield, three steps, α/γ=99: 1 is composed of 19 F NMR determination, silica gel chromatography purityChemical separation (Petroleum ether/ethyl acetate=5:1) 1 H NMR(400MHz,CDCl 3 )δ7.41(d,J＝8.4Hz,2H),7.05(d,J＝8.4Hz,2H),3.85(t,J＝6.0Hz,2H),2.62(t,J＝7.2Hz,2H),2.18–2.04(m,2H),1.97–1.74(m,4H),1.65(br,1H). 19 F NMR(376MHz,CDCl 3 )δ-97.30(p,J＝16.8Hz,2F). 13 C NMR(126MHz,CDCl 3 )δ140.3,131.4,130.1,124.78(t,J＝240.6Hz),119.7,56.8(t,J＝5.6Hz),38.9(t,J＝24.4Hz),36.2(t,J＝25.1Hz),34.6,23.6(t,J＝4.6Hz).MS(EI):m/z(％)90,182(100),203,292([M] + ).HRMS(EI)m/z:([M] + )Calculated for C 12 H 15 F 2 OBr:292.0269；Found:292.0272.
Application example 5
0.1mol% of CuBr was added to a 50mL Schlenk flask, and difluoroallylium salt (5 mmol,1.0 equiv) of formula C was added thereto, and the flask was evacuated and Ar was filled three times. 10.0mL of THF was added and formula [ C]-[Zn]The zinc reagent (1.2 equiv) was stirred at room temperature for 10 hours to effect a reaction. The fluorobenzene is taken as an internal standard reagent 19 F NMR determination of product yield, NH 4 The reaction was quenched with Cl and diluted with EtOAc, the aqueous phase was washed with ethyl acetate (3X 10 mL) and the organic phase was Na 2 SO 4 Drying, filtering and collecting. The obtained intermediate reduces double bonds through Pd/C to obtain a target product, and the reduction conditions are as follows: pd/C (21.2 mg, 10%) and 0.2mmol of the above product were added to 2mL of DCM and H was vented at room temperature 2 (1atm)24h。
The product is as follows:
yellow oil, 1.31g,88% yield, α/γ=50: 1 is composed of 19 F NMR determination, FP ECOFLEX C18 (20 g) (MeCN: H 2 O=6:4) and separating and purifying, 1 H NMR(400MHz,CDCl 3 )δ8.09(d,J＝8.0Hz,2H),7.57(d,J＝8.0Hz,2H),6.14(dq,J＝17.4，10.6Hz，1H)，5.57(dt，J＝17.4，2.9Hz，1H)，5.51(d，J＝10.6Hz，1H)，4.42(t，J＝6.2Hz，2H)，2.87(t,J＝6.2Hz,2H),2.65(q,J＝7.2Hz,4H),1.08(t,J＝7.2Hz,6H). 19 F NMR(376MHz,CDCl 3 )δ-94.47(d,J＝9.6Hz,2F). 13 C NMR(101MHz,CDCl 3 )δ165.7,140.4(t,J＝27.4Hz),133.2(t,J＝29.3Hz),131.7,129.6,125.5(t,J＝5.6Hz),120.2(t,J＝9.2Hz),118.7(t,J＝239.1Hz),63.5,50.8,47.6,11.9.MS(DART):m/z(％)86(100),105,181,225,297([M] + ).HRMS(DART)m/z:([M+H] + )Calculated for C 16 H 21 F 2 O 2 N:298.1613；Found:298.1610.
application example 6
2.5mol% of CuBr was added to a 25mL Schlenk flask, and difluoroallylium salt (1 mmol,1.0 equiv) of formula C was added thereto, and the flask was evacuated and Ar was filled three times. 3.0mL of THF was added and formula [ C]-Zn]The zinc reagent (1.2 equiv) was stirred at room temperature for 3 hours to effect a reaction. NH (NH) 4 The reaction was quenched with Cl and diluted with EtOAc, the aqueous phase was washed with ethyl acetate (3X 10 mL) and the organic phase was Na 2 SO 4 Drying, filtering and collecting the product. As shown in the following formula, the obtained difluoro compound can react with 1-octene in DCM under the action of Grubbs II-generation catalyst to obtain a compound 8, and the compound 8 can undergo Pd/C reduction reaction and hydrolysis reaction to obtain a final product compound 9.
The product is as follows:
a yellowish oil, 211mg,90% yield, α/γ=50: 1 is composed of 19 F NMR determination, FP ECOFLEX C18 (20 g) (MeCN: H 2 O=7:3) separation and purification 1 H NMR(400MHz,CDCl 3 )δ5.89(dq,J＝17.4,11.0Hz,1H),5.60(dt,J＝17.4,2.5Hz,1H),5.40(d,J＝11.0Hz,1H),4.12(q,J＝7.2Hz,2H),2.29(t,J＝7.6Hz,2H),1.95–1.82(m,2H),1.68–1.58(m,2H),1.50–1.41(m,2H),1.41–1.27(m,4H),1.25(t,J＝7.2Hz,3H). 19 F NMR(376MHz,CDCl 3 )δ-97.73–-98.06(m,2F). 13 C NMR(101MHz,CDCl 3 )δ173.7,133.1(t,J＝27.7Hz),121.3(t,J＝238.4Hz),118.9(t,J＝9.5Hz),60.1,37.0(t,J＝26.4Hz),34.2,28.9,28.8,24.7,22.1(t,J＝4.3Hz),14.2.MS(EI):m/z(％)88(100),126,234([M] + ).HRMS(EI)m/z:([M] + )Calculated for C 12 H 20 F 2 O 2 :234.1426；Found:234.1430.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (25)

1. A3, 3-difluoroallylonium salt of the formula C,
wherein z=s, se or Te; x is an anion;
R 1 、R 2 、R 3 and R is 4 H, F, cl, br, I, C independently 1 -C 20 Is or are R 5 Substituted C 1 -C 20 Alkyl, C of (2) 1 -C 20 Is optionally substituted by one or more R 6 Substituted C 1 -C 20 Heteroalkyl of (C) 6 -C 20 Is or are R 7 Substituted C 6 -C 20 Or aryl, heteroaryl of 5-20 membered atoms or substituted with one or more R 8 Substituted 5-20 membered heteroaryl; wherein, C is as follows 1 -C 20 The hetero atom or hetero atom group of the hetero alkyl group is selected from C (=O), S (=O) 2 、SO 2 NR 1’ R 2’ 、O、N、Si、P、P(＝O)、PO(OR 3’ ) 2 、PS(OR 3’ ) 2 、B(R 4’ ) 2 And B (OR) 4’ ) 2 The number of heteroatoms and hetero atom groups is 1 or more; the hetero atoms of the 5-20 membered heteroaryl are selected from S, O, N, si, P and B, and the number of the hetero atoms is 1 or more;
alternatively, R 1 And R is 4 Together with the attached Z forms: 5-20 membered heterocycloalkyl, substituted by one or more R 9 Substituted 5-20 membered heterocycloalkyl, 5-20 membered heteroaryl or substituted with one or more R 10 Substituted 5-20 membered heteroaryl; the heteroatom or heteroatom group of the 5-20 membered heterocycloalkyl group is selected from C (=O), S, S (=O) and S (=O) 2 、O、N、Si、P、P(＝O)、PO(OR 3’ ) 2 、PS(OR 3’ ) 2 、B(R 4’ ) 2 And B (OR) 4’ ) 2 The number of heteroatoms and hetero atom groups is 1 or more; the hetero atom or hetero atom group of the 5-20 membered heteroaryl group is selected from C (=O), S, S (=O) and S (=O) 2 、O、N、Si、P、P(＝O)、PO(OR 3’ ) 2 、PS(OR 3’ ) 2 、B(R 4’ ) 2 And B (OR) 4’ ) 2 The number of heteroatoms and hetero atom groups is 1 or more;
each R 5 、R 6 、R 7 、R 8 、R 9 And R is 10 F, cl, br, I, C independently 1 -C 20 Alkyl, C of (2) 3 -C 20 Cycloalkyl, C 6 -C 20 Aryl, C of (2) 2 -C 20 Alkynyl, C 2 -C 20 Alkenyl, C 1 -C 20 Is optionally substituted by one or more R 1a Substituted C 1 -C 20 Is or are R 1b Substituted C 3 -C 20 Is or are R 1c Substituted C 6 -C 20 Aryl, one or more R 1d Substituted C 2 -C 20 Alkynyl of (2), by one or more R 1e Substituted C 1 -C 20 Is optionally substituted by one or more R 1f Substituted C 2 -C 20 Alkenyl of (c); the C is 1 -C 20 The hetero atom or hetero atom group of the hetero alkyl group is selected from C (=O), S (=O) 2 、SO 2 NR 1’ R 2’ 、O、N、Si、P、P(＝O)、PO(OR 3’ ) 2 、PS(OR 3’ ) 2 、B(R 4’ ) 2 And B (OR) 4’ ) 2 The number of heteroatoms and hetero atom groups is 1 or more;
each R 1’ 、R 2’ 、R 3’ And R is 4’ Independently C 1 -C 20 Alkyl, C of (2) 3 -C 20 Cycloalkyl, C 6 -C 20 Is or are R 1a Substituted C 1 -C 20 Is or are R 1b Substituted C 3 -C 20 Is or are R 1c Substituted C 6 -C 20 Aryl of (a);
each R 1a 、R 1b 、R 1c 、R 1d 、R 1e And R is 1f F, cl, br, I, N independently 3 、C 1 -C 20 Alkyl, C of (2) 6 -C 20 Or independently by three C' s 1 -C 4 Alkyl-substituted silyl groups.
2. The 3, 3-difluoroallylium salt of formula C of claim 1, wherein R is 5 、R 6 、R 7 、R 8 、R 9 And R is 10 F, cl, br, I, C independently 1 -C 20 Alkyl, C of (2) 3 -C 20 Cycloalkyl, C 6 -C 20 Aryl, C of (2) 2 -C 20 Alkynyl, C 1 -C 20 Is optionally substituted by one or more R 1a Substituted C 1 -C 20 Is or are R 1b Substituted C 3 -C 20 Is or are R 1c Substituted C 6 -C 20 Aryl group of (1)One or more R 1d Substituted C 2 -C 20 Alkynyl of (2), by one or more R 1e Substituted C 1 -C 20 Is a heteroalkyl group; the C is 1 -C 20 The hetero atom or hetero atom group of the hetero alkyl group is selected from C (=O), S (=O) 2 、SO 2 NR 1’ R 2’ 、O、N、Si、P、P(＝O)、PO(OR 3’ ) 2 、PS(OR 3’ ) 2 、B(R 4’ ) 2 And B (OR) 4’ ) 2 The number of heteroatoms and hetero atom groups is 1 or more;
the R is 1a 、R 1b 、R 1c 、R 1d And R is 1e F, cl, br, I, N independently 3 、C 1 -C 20 Is a hydrocarbon group.
3. The 3, 3-difluoroallylium salt of formula C of claim 1, wherein the 3, 3-difluoroallylium salt of formula C satisfies one or more of the following conditions:
(1) X is an organic or inorganic anion;
(2) The C is 1 -C 20 Alkyl, substituted C 1 -C 20 C in the alkyl group of (2) 1 -C 20 The alkyl groups of (a) are independently C 1 -C 10 Alkyl of (a);
(3) The C is 1 -C 20 Is substituted C 1 -C 20 C in heteroalkyl (C) 1 -C 20 Is independently-C (=o) O-hybridized C 1 -C 20 Alkyl of (a);
(4) The C is 6 -C 20 Aryl, substituted C 6 -C 20 C in aryl of (C) 6 -C 20 Is independently phenyl;
(5) Said R is 1 And R is 4 Together with the attached Z forms: 5-20 membered heterocycloalkyl, 5-20 membered heterocycloalkyl of substituted 5-20 membered heterocycloalkyl being independently 5-10 membered heterocycloalkyl;
(6) Said R is 1 And R is 4 Together with the attached Z forms: a 5-20 membered heteroaryl, a 5-20 membered heteroaryl in a substituted 5-20 membered heteroaryl being independently a 5-10 membered heteroaryl;
(7) The C is 3 -C 20 Independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
(8) The C is 2 -C 20 Alkynyl, substituted C 2 -C 20 C in alkynyl group of (C) 2 -C 20 Alkynyl groups of (2) are independently C 2 -C 10 Is an alkynyl group of (c).
4. A 3, 3-difluoroallylium salt of formula C of claim 3, wherein the 3, 3-difluoroallylium salt of formula C satisfies one or more of the following conditions:
(1) X is trifluoromethanesulfonic acid anion, fluoroboric acid anion, hexafluorophosphoric acid anion, hexafluoroantimonic acid anion, p-toluenesulfonic acid anion, fluorine anion, chlorine anion, bromine anion and iodine anion;
(2) The C is 1 -C 20 Alkyl, substituted C 1 -C 20 C in the alkyl group of (2) 1 -C 20 The alkyl groups of (a) are independently C 1 -C 6 Alkyl of (a);
(3) The C is 1 -C 20 Is substituted C 1 -C 20 C in heteroalkyl (C) 1 -C 20 independently-C (=o) OMe;
(4) Said R is 1 And R is 4 Together with the attached Z forms: 5-20 membered heterocycloalkyl, 5-20 membered heterocycloalkyl of substituted 5-20 membered heterocycloalkyl being independently
(5) Said R is 1 And R is 4 Together with the attached Z forms: the 5-20 membered heteroaryl, the 5-20 membered heteroaryl in the substituted 5-20 membered heteroaryl, is independently benzothiophene;
(6) The C is 2 -C 20 Alkynyl, substituted C 2 -C 20 C in alkynyl group of (C) 2 -C 20 Alkynyl groups of (2) are independently C 2 -C 6 Is an alkynyl group of (c).
5. The 3, 3-difluoroallylium salt of formula C of claim 4, wherein the 3, 3-difluoroallylium salt of formula C satisfies one or more of the following conditions:
(1) The C is 1 -C 20 Alkyl, substituted C 1 -C 20 C in the alkyl group of (2) 1 -C 20 Independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
(2) Said R is 1 And R is 4 Together with the attached Z forms: the 5-20 membered heteroaryl, the 5-20 membered heteroaryl in the substituted 5-20 membered heteroaryl are independently
(3) The C is 2 -C 20 Alkynyl, substituted C 2 -C 20 C in alkynyl group of (C) 2 -C 20 Alkynyl groups of (2) are independently
6. The 3, 3-difluoroallylium salt of formula C of claim 1, wherein the 3, 3-difluoroallylium salt of formula C satisfies one or more of the following conditions:
(1) The C is 1 -C 20 Alkyl, substituted C 1 -C 20 C in the alkyl group of (2) 1 -C 20 Independently of the alkyl groups of (2)The ground is n-hexyl;
(2) The C is 1 -C 20 Is substituted C 1 -C 20 C in heteroalkyl (C) 1 -C 20 Is independently-C (=o) O-or-O-hybridized C 1 -C 20 Alkyl of (a);
(3) The C is 2 -C 20 Alkenyl, substituted C 2 -C 20 C in alkenyl group (C) 2 -C 20 Alkenyl groups of (2) are independently C 2 -C 10 Alkenyl groups of (c).
7. The 3, 3-difluoroallylium salt of formula C of claim 6, wherein the 3, 3-difluoroallylium salt of formula C satisfies one or more of the following conditions:
(1) The C is 1 -C 20 Is substituted C 1 -C 20 C in heteroalkyl (C) 1 -C 20 Is independently-C (=O) OEt, -OCH 3 ；
(2) The C is 2 -C 20 Alkenyl, substituted C 2 -C 20 C in alkenyl group (C) 2 -C 20 Alkenyl groups of (2) are independently C 2 -C 6 Alkenyl groups of (c).
8. The 3, 3-difluoroallylium salt of formula C of claim 7, wherein C 2 -C 20 Alkenyl, substituted C 2 -C 20 C in alkenyl group (C) 2 -C 20 Alkenyl groups of (2) are independently
9. The 3, 3-difluoroallylium salt of formula C of claim 3 or 6, wherein the 3, 3-difluoroallylium salt of formula C satisfies one or more of the following conditions:
(1)R 1 、R 2 、R 3 and R is 4 Independently H, F, cl, br, me, et, phenyl, tolyl, methoxyphenyl, bromophenyl, tris (methyl) phenyl, tris (isopropyl) phenyl, phenylethene, -C (=O) OMe,
(2) Said R is 1 And R is 4 Together with the attached Z forms: wherein Alkyl is independently C 1 -C 20 Is or are R 5 Substituted C 1 -C 20 Is a hydrocarbon group.
10. The 3, 3-difluoroallylonium salt of formula C of claim 9, wherein said salt isIndependently is->
11. The 3, 3-difluoroallylium salt of formula C of claim 3 or 6,
the R is 1 、R 2 、R 3 And R is 4 Independently t-butylphenyl, n-hexyl,
Or said R 1 And R is 4 One of which is Me or Et and the other of which is phenyl, tolyl, methoxyphenyl, bromophenyl, tri (methyl) phenyl, tri (isopropyl) phenyl or phenylethene.
12. The 3, 3-difluoroallylium salt of formula C of claim 1, wherein the 3, 3-difluoroallylium salt of formula C has any one of the following structures:
Wherein X is as defined above; x is F, cl or Br, TIPP is tri (isopropyl) phenyl, mes is 2,4, 6-trimethylphenyl, tol is tolyl, and Alkyl is independently said C 1 -C 20 Is or are R 5 Substituted C 1 -C 20 Alkyl of (a); ar is independently C as described 6 -C 20 Is or are R 7 Substituted C 6 -C 20 Aryl groups of (a).
13. The 3, 3-difluoroallylium salt of formula C of claim 1, wherein the 3, 3-difluoroallylium salt of formula C is any one of the following compounds:
14. a process for the preparation of a 3, 3-difluoroallylium salt of formula C according to any one of claims 1 to 13, comprising the steps of:
in an organic solvent, carrying out alkylation reaction on a compound shown as a formula D and an alkylating reagent to obtain a 3, 3-difluoroallylium salt compound shown as a formula C; the alkylating agent is R 4 X and/or R 4 I is a system of AgX;
therein, Z, X, R 1 、R 2 、R 3 And R is 4 Is defined as in any one of claims 1 to 13.
15. The process for preparing a 3, 3-difluoroallylium salt of formula C of claim 14, wherein one or more of the following conditions are satisfied:
(1) The organic solvent is an aprotic solvent;
(2) The mol ratio of the compound shown in the formula D to the alkylating agent is 1:0.9 to 1:1.5;
(3) The alkylation reaction is carried out under argon or nitrogen;
(4) The alkylation reaction is carried out at 0 ℃ to 140 ℃.
16. The process for preparing a 3, 3-difluoroallylium salt of formula C of claim 15, wherein one or more of the following conditions are satisfied:
(1) The organic solvent is DCM, THF, DMF or DMSO;
(2) The mol ratio of the compound shown in the formula D to the alkylating reagent is 1:1 and 1.15:1;
(3) The alkylation reaction temperature is independently 10 to 30 ℃.
17. The method for preparing a 3, 3-difluoroallylium salt of formula C of claim 14, further comprising the step of preparing the compound of formula D, comprising:
in an organic solvent, carrying out substitution reaction on a compound shown in a formula A and a compound shown in a formula B to obtain a compound shown in a formula D;
therein, Z, R 1 、R 2 And R is 3 Is defined as in claim 14;
X 1 f, cl or Br; m is M 1 Is an alkali metal.
18. The process for preparing a 3, 3-difluoroallylium salt of formula C of claim 17, wherein one or more of the following conditions are satisfied:
(1)M 1 na, K or Li;
(2) The organic solvent is an aprotic solvent;
(3) The molar ratio of the compound shown in the formula A to the compound shown in the formula B is 1:1 to 1:3;
(4) The substitution reaction is carried out under argon or nitrogen;
(5) The substitution reaction is carried out at room temperature to 140 ℃.
19. The process for preparing a 3, 3-difluoroallylium salt of formula C of claim 18, wherein one or more of the following conditions are satisfied:
(1) The organic solvent is one or more of dioxane, THF, DMF and DMSO;
(2) The molar ratio of the compound shown in the formula A to the compound shown in the formula B is 1:1.2, 1:1.25 and 1:2;
(3) The temperature of the substitution reaction is independently 50 ℃ to 140 ℃.
20. The process for preparing a 3, 3-difluoroallylium salt of formula C of claim 19, wherein the temperature of the substitution reaction is 100.+ -. 10 ℃.
21. Use of a 3, 3-difluoroallylium salt compound of formula C according to any one of claims 1 to 13 as an α, α -gem-difluoroallylation reagent.
22. The use of a 3, 3-difluoroallylation salt compound of formula C of claim 21 as an α, α -gem-difluoroallylation reagent, comprising the steps of:
in a solvent, carrying out a coupling reaction between a 3, 3-difluoroallylium salt compound shown in a formula C and a zinc reagent to obtain an alpha, alpha-gem-difluoroallylic compound shown in a formula E;
therein, Z, X, R 1 、R 2 、R 3 And R is 4 Is defined as in any one of claims 1 to 13;
[C]representing the combination of Csp1, csp2 or Csp3 with [ Zn ]]A connected portion; [ Zn ]]Representing ZnX 2 、Zn·LiX 2 、ZnX 2 ·LiX 2 ；X 2 Independently bromine or chlorine.
23. The use of a 3, 3-difluoroallylation salt compound of C as claimed in claim 22 as an α, α -gem-difluoroallylation reagent, wherein [ Zn ] is ZnBr, znCl, zn ·licl, zncl·licl, znbr·licl.
24. Use of a 3, 3-difluoroallylation salt compound of formula C according to claim 21 or 22 as an α, α -gem difluoroallylation reagent, wherein one or more of the following conditions are satisfied:
(1) The molar ratio of the 3, 3-difluoroallylium salt compound shown in the formula C to the zinc reagent is 1:1 to 1.5;
(2) The coupling reaction is carried out in the presence of a catalyst, wherein the catalyst is CuBr; the molar ratio of the catalyst to the 3, 3-difluoroallylium salt compound shown in the formula C is 0.2 to 0.005;
(3) The temperature of the coupling reaction is-78 to 35 ℃;
(4) The solvent is an ether solvent;
(5) When the 3, 3-difluoroallylium salt compound shown as the formula C isWhen the zinc reagent and the corresponding alpha, alpha-gem difluoroallyl compound shown in the formula E are any one of the following groups:
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25. use of a 3, 3-difluoroallylation salt compound of formula C according to claim 24 as an α, α -gem-difluoroallylation reagent, wherein one or more of the following conditions are satisfied:
(1) The molar ratio of the 3, 3-difluoroallylium salt compound shown in the formula C to the zinc reagent is 1:1.1, 1:1.2 and 1:1.3;
(2) The molar ratio of the catalyst to the 3, 3-difluoroallylium salt compound shown in the formula C is 0.01, 0.025, 0.05 and 0.1;
(3) The temperature of the coupling reaction is room temperature;
(4) The ether solvent is tetrahydrofuran.
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