CN108373431A - Fluorine-containing chirality allyl compound and its synthetic method - Google Patents

Fluorine-containing chirality allyl compound and its synthetic method Download PDF

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CN108373431A
CN108373431A CN201810129837.4A CN201810129837A CN108373431A CN 108373431 A CN108373431 A CN 108373431A CN 201810129837 A CN201810129837 A CN 201810129837A CN 108373431 A CN108373431 A CN 108373431A
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fluorine
compound
synthetic method
allyl compound
containing chiral
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赵晓明
宋涛
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Tongji University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/24—Sulfones; Sulfoxides having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/14—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom

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Abstract

The present invention provides a kind of synthetic method of fluorine-containing chiral allyl compound, this method is catalyst by transition metal palladium complex, it is reacted by allyl compound and fluorine-containing methylene compound, with high enantioselectivity and high diastereoselective synthesis fluorine-containing chiral allyl compound with optical activation, present invention also provides a kind of fluorine-containing chiral allyl compounds, are the optical pure compound for the formula that has the following structureWherein, * is asymmetric carbon atom, R1Selected from aryl, R2Selected from the aryl for arbitrarily having sulfuryl or carbonyl, R3Selected from ester group or nitro.Compared with prior art, catalyst of the present invention be easy to get, catalytic activity height, mild condition, wide application range of substrates.

Description

Fluorine-containing chirality allyl compound and its synthetic method
Technical field
The present invention relates to a kind of fluorine-containing chiral allyl compounds, more particularly, to a kind of fluorine-containing chiral allyl compound And reacted with fluorine-containing methylene compound by the allyl compound of Metal Palladium complex catalysis, which is to be selected with high mapping Property and non-high enantioselective synthesis have optically active fluorine-containing chirality allyl compound synthetic method.
Background technology
The allylation reaction of palladium chtalyst is important means of the synthesis with optically active fluorine-containing compound.In this background Under, more and more fluorine-containing methylene compounds and fluorine-containing silyl enol ether are widely studied, and are obtained using carbon as chiral centre Allyl, carbon-fluorine compounds.[a)Z.Lu,S.M.Ma,Angew.Chem.Int.Ed.2008,47,258-297；for selected papers,see:b)T.Fukuzumi,N.Shibata,M.Sugiura,H.Yasui,S.Nakamura, T.Toru,Angew.Chem.Int.Ed.2006,45,4973-4977；c)T.Kawasaki,T.Kitazume,Israel J.Chem.1999,39,129-131；d)B.Jiang,Z.G.Huang,K.J.Cheng,Tetrahedron:Asymmetry 2006,17,942-951；e)K.Shibatomi,T.Muto,Y.Sumilkawa,A.Narayama,S.Iwasa,Synlett 2009,241-244；f)S.Goehler,C.B.W.Stark,Org.Biomol.Chem.2007,5,1605-1614；h) J.A.B.Laurenson,J.M.Percy,S.Meiries,R.Roig,Tetrahedron Lett.2009,50,3571- 3573；i)Q.Li,W.Wang,K.B.Berst,A.Laiborne,L.Hasvold,Bioorg.Med.Chem.Lett.1998, 8,1953-1958；j)K.Shibatomi,F.Kobayashi,A.Narayama,I.Fujisawa,S.Iwasa, Chem.Commun.2012,48,413-415；k)J.M.Cox,T.R.Hawkes,P.Bellini,R.M.Ellis, R.Barrett,Pestic.Sci.1997,50,297-311；k)H.Su,Y.Xie,W.Liu,S.You, Bioorg.Med.Chem.Lett.2011,21,3578–3582.].In fluorine-containing nucleopilic reagent, racemic fluorine-containing methylene The less report of compound.Under normal conditions, the fluorine-containing methylene base class compound of racemization can with disubstituted allyl substrate reactions Once to form two chiral centres.Recently, Hou Xuelong groups report under palladium chtalyst, mono-substituted allyl substrate with The allylation reaction of 2- fluoro- 2 (diethoxy phosphoryl) acetate, this reaction are selected with excellent enantioselectivity and diastereomeric Selecting property obtain fluorine-containing allyl based products [l) Y.Huang, Q.S.Zhang, P.Fang, T.G.Chen, J.Zhu, X.L.Hou, Chem.Commun.,2014,50,6751-6753].It is interesting that in clevudine, clofarabine, fluticasone furoate, two Fluorine, which sprinkles, all has fluorine-containing chiral centre in the drugs such as Buddhist nun's ester and liquid crystal material.[m)C.K.Chu,Y.C.Cheng,B.S.Pai, G.Q.Yao,U.S.Patent 5,587,362,1996；n)P.Marcellin,H.Mommeja-Marin,S.L.Sacks, G.K.Lau,D.Sereni,J.P.Bronowicki,E.Mondou,Hepatology.2004,40,140-148；o) J.A.Montgomery,A.T.Shortnacy-Fowler,S.D.Clayton,J.M.Riordan,J.A.J.,III Secrist,J.Med.Chem.1992,35,397-401；q)L.A.Sorbera,N.Serradell,J.Bolos,Drugs Future 2007,32,12-16；r)M.Hird,Chem.Soc.Rev.,2007,36,2070-2095；s)H.Liu, H.Nohira,Liq.Cryst.1996,20,581-586.].In fact, the synthesis of the cis-selectivity of fluorochemical is still With many tera incognitas.
Invention content
It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide a kind of fluorine-containing chiral allyls Based compound and its synthetic method.
The purpose of the present invention can be achieved through the following technical solutions：
A kind of fluorine-containing chiral allyl compound, is the optical pure compound with such as structure formula (I)：
Wherein, * is asymmetric carbon atom, R1Selected from aryl, R2Selected from the aryl for arbitrarily having sulfuryl or carbonyl, R3Selected from ester group Or nitro.
Preferably, the R1Selected from phenyl, substituted-phenyl or how one kind in base.
The aryl refers to unsubstituted aryl or the aryl with substituent group；Phenyl refers to-C6H5, substituted benzene Base refers to the group obtained after hydrogen atom on phenyl is substituted, Nai Ji refer to 2- how base.
The synthetic method of the fluorine-containing chiral allyl compound, with allylic compound and fluorine-containing methylene base class Conjunction object is raw material, with [Pd (C3H3)Cl]2The palladium complex generated with ligand effect is as catalyst, under the action of additive It is reacted, the fluorine-containing chiral allyl compound is made.
Preferably, the structural formula of the allylic compound isThe fluorine-containing methylene base class Close object structural formula be
Wherein, R1Selected from aryl, preferably phenyl, substituted-phenyl or how base, R2Selected from the aryl for arbitrarily having sulfuryl or carbonyl, R3Selected from ester group or nitro, LG is leaving group.
Preferably, the LG is acetoxyl group, at this point, the structural formula of the allylic compound is
Preferably, the ligand is (S, S)-L1Trost, S-L2PHOX, (R)-L3BINAP or (R)-L4, structural formula It is as follows respectively：
It is further preferred that the ligand is the optically pure ligand for the formula that has the following structure：
Preferably：
The organic solvent is toluene, dichloromethane, tetrahydrofuran or N,N-dimethylformamide；
The additive is potassium phosphate, sodium phosphate, potassium carbonate, cesium carbonate or cesium fluoride.
Preferably, the allylic compound, fluorine-containing methylene base class compound, [Pd (C3H3)Cl]2, ligand, addition The molar ratio of agent is 1:2:0.05:0.1:3；Reaction temperature is -20 DEG C, and the reaction time is 48 hours.
The synthetic method of fluorine-containing chirality allyl compound can be represented by the formula：
Wherein Ligand is chiral ligand, and Add. is various additives mentioned above and combination, and Sol. is to be previously mentioned Various solvents, LG is leaving group, be acetoxyl group.
Preferably, products therefrom is by recrystallization, thin-layer chromatography and column chromatography for separation.
It is further preferred that the method for thin-layer chromatography and column chromatography, solvent used is nonpolar solvent and polar solvent Mixed solvent.It can be the mixed solvents such as petroleum ether-dichloromethane, petroleum ether-ethyl acetate, petroleum ether-ether to recommend solvent, Its volume ratio can be respectively：Nonpolar solvent：Polar solvent=20-2：1.Such as：Petrol ether/ethyl acetate=20-2/1, Petroleum ether/dichloromethane=20-2/1.
In the present invention, we have invented one kind under palladium chtalyst, disubstituted allyl substrate and fluorine-containing active methylene The allylation reaction of based compound, this reaction are once obtained with high enantioselectivity and high cis-selectivity in two chiralitys The heart.And catalyst is easy to get, catalytic activity height, mild condition, wide application range of substrates.
The synthetic method of fluorine-containing chiral allyl compound provided by the invention can become synthesize fluorine-containing chiral drug and The effective means of liquid crystal material.
Compared with prior art, the present invention provides one kind effectively using chiral palladium complex as catalyst, by fluorine-containing Methylene base class compound and the reaction of allylic compound, with high enantioselectivity and the fluorine-containing chirality of high diastereoselective synthesis The method of allyl compound.This method is applicable to different types of fluorine-containing methylene base class compound and allylic chemical combination Object, reaction condition is mild, easy to operate.In addition the yield reacted also preferably (is generally 70-91%), enantioselectivity height (one As be 78-99), cis-selectivity height (highest 17/1).
Specific implementation mode
With reference to specific embodiment, the present invention is described in detail, but the implementation of the present invention is without being limited thereto.
A kind of fluorine-containing chiral allyl compound, is the optical pure compound with such as structure formula (I)：
Wherein, * is asymmetric carbon atom, R1Selected from aryl, preferably phenyl, substituted-phenyl or how base, R2Selected from arbitrarily having sulfuryl Or the aryl of base, R3Selected from ester group or nitro.
The synthetic method of above-mentioned fluorine-containing chiral allyl compound, with allylic compound and fluorine-containing methylene base class chemical combination Object is raw material, with [Pd (C3H3)Cl]2With ligand effect generate palladium complex as catalyst, under the action of additive into The fluorine-containing chiral allyl compound is made in row reaction.
The structural formula of above-mentioned allylic compound isThe structural formula of fluorine-containing methylene base class compound isWherein, R1Selected from aryl, preferably phenyl, substituted-phenyl or how base, R2Selected from the aryl for arbitrarily having sulfuryl or carbonyl, R3 Selected from ester group or nitro, LG is leaving group.
The aryl refers to unsubstituted aryl or the aryl with substituent group；Phenyl refers to-C6H5, substituted benzene Base refers to the group obtained after hydrogen atom on phenyl is substituted, Nai Ji refer to 2- how base.
Leaving group LG is acetoxyl group, at this point, the structural formula of allylic compound is
Ligand can be (S, S)-L1Trost, S-L2PHOX, (R)-L3BINAP or (R)-L4, and structural formula distinguishes following institute Show：
Ligand is preferably the optically pure ligand for the formula that has the following structure：
Organic solvent is toluene, dichloromethane, tetrahydrofuran or N,N-dimethylformamide；
Additive is potassium phosphate, sodium phosphate, potassium carbonate, cesium carbonate or cesium fluoride.
In above-mentioned reaction, allylic compound, fluorine-containing methylene base class compound, [Pd (C3H3)Cl]2, ligand, additive Molar ratio be 1:2:0.05:0.1:3；Reaction temperature is -20 DEG C, and the reaction time is 48 hours.
The product of gained is by recrystallization, thin-layer chromatography and column chromatography for separation.
Embodiment 1
The additive of allylation reaction of the fluorine-containing methylene compound nucleophilic of palladium complex catalysis, temperature, solvent and The research of ligand
Wherein mol refers to mole, and Add. refers to additive, and Sol. refers to solvent, and T refers to temperature, and Ligand or L refer to chiral ligand.
Concrete outcome is shown in Table 1.
Table 1
In table 1：Solvent DCM is dichloromethane, and Toluene is toluene, and THF is tetrahydrofuran；NR, which refers to, not to react.
L1, L2, L3 and L4 ligand in table is as follows successively respectively：
Embodiment 2
The allyl fluoroalkylation of palladium complex catalysis reacts applied research.
Reaction equation is as follows：
In the reaction tube of the argon gas protection of a drying, [Pd (C are sequentially added3H3)Cl]2(0.005mmol), chiral ligand PHOX (0.01mmol), toluene (2mL) react 30 minutes at -20 DEG C, then allyl compound are added into reaction tube (0.1mmol), the reaction was continued 15 minutes, and fluorine-containing methylene base class compound (0.2mmol), carbonic acid is then added into reaction successively Caesium (0.3mmol) is stirred to react 48 hours at -20 DEG C.After reaction, residue thin-layer chromatography obtains after solvent is removed under reduced pressure Target product (petrol ether/ethyl acetate=10-2：1, v/v).
It the results are shown in Table 2.
Table 2
Embodiment 3
Embodiment 2 is obtained product 3a further to convert, synthesis of chiral 3,4- dihydro-pyrroles type oxide (6a).
In the reaction tube of the argon gas protection of a drying, addition 1.5mL DIBAL-H (1.0M in toluene, 1.5mmol), 10mL toluene is cooled to -75 DEG C.It is slowly added to 3a (0.5mmol) at this temperature, continues to be stirred to react 3 small When.It is quenched successively using saturated ammonium chloride after reaction, ethyl acetate (10mL x3) extraction, anhydrous sodium sulfate drying, filtering And column chromatography after solvent is removed, obtain product 4a.
In the reaction tube of the argon gas protection of a drying, hydroxylamine hydrochloride (0.2mmol), 4a (0.1mmol), three are sequentially added Ethamine (0.3mmol) and dichloroethanes (1mL), be heated to 65 DEG C react 5 hours, make to be quenched with water after reaction, then according to It is secondary using dichloroethanes extraction, anhydrous sodium sulfate is dry, after filtering except solvent and column chromatography obtains product 6a.
Reaction equation is as follows：
Characterization of The Products：
3a：
(2S,3R)-Methyl 3,5-bis(3-chlorophenyl)-2-fluoro-2-(phenylsulfonyl) pent-4-enoate(3a)
Yield:91% (44.7mg)；white solid；M.p.138~143 DEG C [α]D 20=37.5 (c 1.0, EtOAc)；95%ee [Daicel CHIRALCEL AD-H (0.46cm × 25cm)；N-hexane/2-propanol=90/10； Flow rate=0.7mL/min；Detection wavelength=214or 254nm；tR=50.93 (major), 56.04 (minor),57.50(minor),60.46(major)min].1H NMR (400MHz, chloroform-d) δ 7.90 (d, J= 7.8Hz, 2H), 7.69 (t, J=7.5Hz, 1H), 7.48 (t, J=7.7Hz, 2H), 7.36-7.09 (m, 8H), 6.62 (d, J= 15.8Hz, 1H), 6.32 (d, J=9.3Hz, 1H), 4.81 (dd, J=32.1,9.3Hz, 1H), 3.54 (s, 3H)19F NMR (377MHz, chloroform-d) δ=- 161.66 (s), -163.87 (s)13C NMR(101MHz,chloroform-d)13C NMR (101MHz, Chloroform-d) δ 163.12 (d, J=24.9Hz), 138.50,137.99,135.33,134.91, (134.77,134.54,134.21,130.67,130.24,129.78,128.98,128.78 d, J=2.3Hz), 128.44, 128.08,126.74 (d, J=2.2Hz), 126.44,125.10,124.22 (d, J=4.9Hz), 110.18,107.77, (53.44,51.00 d, J=17.1Hz) .HRMS (ESI-TOF):calcd for C24H19Cl2FKO4S[M+K]+:531.0002； Found:530.9997.IR(KBr):νmax(cm-1)=2924,1769,1448,1336,1312,1162,1138,908,731, 584.
3b：
(2S,3R)-Methyl 3,5-bis(3-bromophenyl)-2-fluoro-2-(phenylsulfonyl) pent-4-enoate(3b)
Yield:73% (42.5 mg)；white solid；M.p.122~130 DEG C [α]D 20=25.2 (c 1.0, EtOAc)；98%ee [Daicel CHIRALCEL IC (cm of 0.46 cm × 25)；N-hexane/2-propanol=90/10； Flow rate=0.8 mL/min；254 nm of detection wavelength=214 or；tR=19.10 (major), 25.36(minor),27.92(major),30.25(minor)min].1H NMR(400 MHz,chloroform-d)δ7.89 (d, J=8.4Hz, 2H), 7.69 (t, J=7.5Hz, 1H), 7.57-7.31 (m, 6H), 7.21 (tdd, J=9.8,8.1, 4.5Hz, 4H), 6.72-6.38 (m, 1H), 6.28 (dd, J=15.7,9.3Hz, 1H), 4.73 (ddd, J=48.9,31.8, 9.4Hz,1H),3.55(s,3H).19F NMR(377 MHz,chloroform-d)δ-161.67,-163.85.13C NMR(101 MHz, chloroform-d) δ 163.09 (d, J=24.9Hz), 138.75,138.26,135.32,134.92,134.15, 131.66 (d, J=2.2Hz), 131.30 (d, J=14.5Hz), 131.01,130.68,130.52,130.11 (d, J= 10.9Hz), 129.33,128.99,127.18 (d, J=2.2Hz), 125.59,125.33,124.23 (d, J=4.8Hz), 122.89,122.73,110.19,107.78,53.45,50.97 (d, J=17.0Hz) .HRMS (ESI-TOF):calcd for C24H19Br2FKO4S[M+K]+:618.8992；Found:618.8986.IR(KBr):νmax(cm-1)=2954,2158,1977, 1769,1746,1474,1335,1265,1180,1161,1083,735,580.
3c：
(2S,3R)-Methyl 2-fluoro-3,5-bis(3-fluorophenyl)-2-(phenylsulfonyl) pent-4-enoate(3c)
Yield:70% (32.5 mg)；white solid；M.p.115~119 DEG C [α]D 20=27.6 (c 1.0, EtOAc)；78%ee [Daicel CHIRALCEL AD-H (0.46cm × 25cm)；N-hexane/2-propanol=90/10； Flow rate=0.8mL/min；Detection wavelength=214 or 254nm；tR=53.2 (major), 74.3 (minor),83.3(minor),99.3(major)min].1H NMR (400MHz, chloroform-d) δ 7.90 (d, J= 7.9Hz, 2H), 7.67 (t, J=7.5Hz, 1H), 7.47 (s, 2H), 7.28 (m, 2H), 6.97 (d, J=8.9Hz, 6H), 6.66 (d, J=15.7Hz, 1H), 6.31 (dd, J=15.8,9.3Hz, 1H), 4.84 (dd, J=32.1,9.3Hz, 1H), 3.53 (s, 3H).19F NMR(377MHz,chloroform-d)δ-111.49,-112.27,-113.11,-113.40,-161.91,- 164.03.13C NMR (101MHz, chloroform-d) δ 164.11 (d, J=22.8Hz), 163.18 (d, J=24.9Hz), 161.66 (d, J=24.8Hz), 138.86 (d, J=7.1Hz), 138.50 (d, J=7.7Hz), 135.29,134.91, 134.35 (d, J=2.6Hz), 130.66,130.53 (d, J=8.2Hz), 130.02 (d, J=8.4Hz), 128.97,124.29 (t, J=2.6Hz), 124.16 (d, J=4.8Hz), 122.69 (d, J=2.7Hz), 115.81 (d, J=2.5Hz), 115.59 (d, J=2.5Hz), 115.24 (d, J=21.0Hz), 114.95 (d, J=21.3Hz), 113.07 (d, J=22.0Hz), 110.20,107.80,53.42,50.91 (d, J=1.8Hz) .HRMS (ESI-TOF):calcd for C24H19F3KO4S[M+K ]+:499.0593；Found:499.0588.IR(KBr):νmax(cm-1)=2955,1768,1584,1448,1335,1273, 1252,1162,1146,754,716,685,597.
3d：
(2S,3R)-Methyl 2-fluoro-3,5-diphenyl-2-(phenylsulfonyl)pent-4-enoate (3d)
Yield:78% (33.1mg)；white solid；m.p.89-90℃.[α]D 20=15.8 (c 1.0, EtOAc)； 94%ee [Daicel CHIRALCEL AD-H (0.46cm × 25cm)；N-hexane/2-propanol=80/20；flow Rate=0.8mL/min；Detection wavelength=214 or 254nm；tR=20.09 (major), 26.15 (minor),30.80(minor),32.88(major)min].1H NMR (400MHz, chloroform-d) δ 7.91 (d, J= 7.9Hz, 2H), 7.63 (t, J=7.5Hz, 1H), 7.43 (t, J=7.7Hz, 2H), 7.34-7.20 (m, 10H), 6.69 (d, J= 15.7Hz, 1H), 6.32 (dd, J=15.8,9.3Hz, 1H), 4.84 (dd, J=32.8,9.3Hz, 1H), 3.53 (s, 3H)19F NMR(376MHz,chloroform-d)δ-161.81,-163.74.13CNMR(101MHz,chloroform-d)δ163.38(d, ), J=25.2Hz 136.94,136.41,135.56,135.13,134.66,130.81 (d, J=1.7Hz), 128.87 (d, J= 10.6Hz), 128.62 (d, J=2.1Hz), 128.47,128.01 (d, J=9.7Hz), 126.67,123.32 (d, J= 4.9Hz), 110.82,108.42,53.26,51.64 (d, J=16.9Hz) .HRMS (ESI-TOF):calcd for C24H21FKO4S[M+K]+:463.0782；Found:463.0776.IR(KBr):νmax(cm-1)=2955,2253,1769, 1448,1333,1264,1163,905,727,649,566.
3e：
(2S,3R)-Methyl 2-fluoro-3,5-di(naphthalen-2-yl)-2-(phenylsulfonyl) pent-4-enoate(3e)
Yield:85% (44.6mg)；white solid；m.p.101-105℃.[α]D 20=13.0 (c1.0, EtOAc)； 92%ee [Daicel CHIRALCEL AD-H (0.46cm × 25cm)；N-hexane/2-propanol=90/10；flow Rate=0.8mL/min；Detection wavelength=214 or 254nm；tR=69.78 (major), 75.65 (minor),98.28(major),112.42(minor)min].1H NMR(400MHz,chloroform-d)δ8.02–7.60 (m, 10H), 7.60-7.34 (m, 7H), 7.01 (t, J=7.8Hz, 2H), 6.80 (d, J=15.6Hz, 1H), 6.56 (dd, J= 15.6,9.4Hz, 1H), 4.95 (dd, J=32.5,9.4Hz, 1H), 3.89 (s, 3H)19F NMR(376MHz,chloroform- d)δ-161.58.13C NMR (101MHz, chloroform-d) δ 163.83 (d, J=25.1Hz), 135.19,134.78, 133.96,133.63,133.40,133.30,133.21,132.93,132.43,130.08–129.80(m),129.58– 129.27 (m), 128.23 (d, J=3.3Hz), 128.14,128.00,127.63,127.43,126.79,126.45-126.25 (m), 126.16,123.48,119.10,53.84,52.23 (d, J=16.7Hz) .HRMS (ESI-TOF):calcd for C32H25FKO4S[M+K]+:563.1095；Found:563.1089.IR(KBr):νmax(cm-1)=2924,2361,1769, 1507,1312,1263,1155,966,907,735,507,453.
3f：
(2S,3R)-Methyl 2-fluoro-2-(phenylsulfonyl)-3,5-di-m-tolylpent-4- enoate(3f)
Yield:62% (28mg)；white solid；m.p.123-133℃.[α]D 20=56.5 (c1.0, EtOAc)； 97%ee [Daicel CHIRALCEL AD-H (0.46cm × 25cm)；N-hexane/2-propanol=90/10；flow Rate=0.8mL/min；Detection wavelength=214 or 254nm；tR=20.01 (major), 22.61 (minor),30.90(minor),34.45(major)min].1H NMR (400MHz, chloroform-d) δ 7.91 (d, J= 7.8Hz, 2H), 7.64 (t, J=7.2Hz, 1H), 7.43 (t, J=7.7Hz, 2H), 7.38-6.90 (m, 8H), 6.60 (dd, J= 36.3,15.7Hz, 1H), 6.43-6.10 (m, 1H), 4.96-4.49 (m, 1H), 3.55 (s, 2H), 2.33 (d, J=9.5Hz, 6H).19F NMR(376MHz,chloroform-d)δ-161.73,-163.63.13C NMR(101MHz,chloroform-d)δ 163.40 (d, J=25.2Hz), 138.54,138.14 (d, J=2.8Hz), 137.95,136.87,136.36,135.62, (135.11,134.55,134.38,134.03,130.86,129.26 d, J=2.3Hz), 128.80,128.71 (d, J= 3.5Hz), 128.34,127.26,125.60 (d, J=2.0Hz), 123.94,123.12 (d, J=4.9Hz), 110.93, (108.53,60.39,53.75,53.24,52.02 d, J=16.9Hz), 51.61 (d, J=16.9Hz) .HRMS (ESI-TOF): calcd for C26H25FKO4S[M+K]+:491.1095；Found:491.1089.IR(KBr):νmax(cm-1)=2954, 1768,1747,1333,1275,1158,737,716,582,554.
3g：
(2S,3R)-Methyl 2-benzoyl-3,5-bis(3-chlorophenyl)-2-fluoropent-4- enoate(3g)
Yield:90% (42.4mg)；colorless oil.[α]D 20=39.1 (c 1.0, EtOAc)；96%ee [Daicel CHIRALCEL AD-H(0.46cm×25cm)；N-hexane/2-propanol=80/20；Flow rate= 0.8mL/min；Detection wavelength=214 or 254nm；tR=7.91 (major), 8.48 (minor), 12.33(minor),13.73(major)min].1H NMR (400MHz, chloroform-d) δ 8.07 (t, J=8.4Hz, 1H), 7.88 (d, J=7.8Hz, 1H), 7.75-7.09 (m, 11H), 6.72-6.18 (m, 2H), 4.86 (ddd, J=40.4, 32.3,8.3Hz, 1H), 4.46-3.91 (m, 2H), 1.26 (p, J=9.5,8.8Hz, 3H)19F NMR(376MHz, chloroform-d)δ-160.25,-168.79.13C NMR (101MHz, chloroform-d) δ 191.68 (d, J= 26.6Hz), 165.84 (d, J=25.9Hz), 165.46 (d, J=26.0Hz), 139.20,139.11,138.41,138.19, (137.81,134.62,134.44 d, J=3.6Hz), 134.35 (t, J=4.1Hz), 134.25,133.98,133.80, (133.62,133.02,131.64,129.95,129.90,129.83 d, J=2.4Hz), 129.70 (d, J=2.0Hz), (129.58,129.51,128.59,128.47,128.02 d, J=3.1Hz), 127.90 (d, J=2.8Hz), 127.74, 127.64,127.55 (d, J=2.6Hz), 126.60,126.53,126.43,126.33,125.09 (d, J=16.6Hz), 124.77 (d, J=3.5Hz), 103.61 (d, J=5.2Hz), 101.53 (d, J=3.8Hz), 75.10,63.03 (d, J= 25.4Hz), 52.98 (d, J=18.5Hz) .HRMS (ESI-TOF):calcd for C26H21Cl2FKO3[M+K]+: 509.0489；Found:509.0483.IR(KBr):νmax(cm-1)=2981,1750,1692,1594,1475,1231,1027, 965,780,736,692.
3h：
(2S,3R)-Methyl 2-benzoyl-3,5-bis(3-bromophenyl)-2-fluoropent-4-enoate (3h)
Yield:75% (42.0mg)；colorless oil.[α]D 20=33.0 (c 1.0, EtOAc)；97%ee [Daicel CHIRALCEL AD-H(0.46cm×25cm)；N-hexane/2-propanol=90/10；Flow rate= 0.8mL/min；Detection wavelength=214 or 254nm；tR=10.12 (major), 11.03 (minor), 15.92(minor),21.02(major)min].1H NMR (400MHz, Chloroform-d) δ 8.05 (dd, J=7.8, 2.0Hz, 1H), 7.87 (dd, J=7.7,2.0Hz, 1H), 7.73-7.02 (m, 11H), 6.76-6.14 (m, 2H), 4.84 (ddd, J=40.7,32.3,8.2Hz, 1H), 4.54-3.94 (m, 2H), 1.26 (t, J=7.1Hz, 3H)19F NMR(376MHz, chloroform-d)δ-168.80.13C NMR (101MHz, chloroform-d) δ 191.66 (d, J=26.5Hz), 165.82 (d, J=26.0Hz), 165.44 (d, J=25.9Hz), 139.46,139.37,138.69,138.46,134.36 (d, J= 3.9Hz), 133.99,133.80,133.54,132.94,132.71 (d, J=2.9Hz), 132.47 (d, J=2.5Hz), 130.95 (d, J=4.0Hz), 130.67,130.58,130.25,130.12,129.98 (d, J=3.7Hz), 129.87 (d, J =6.5Hz), 129.55 (d, J=6.4Hz), 129.30 (d, J=9.5Hz), 128.59,128.47,128.33 (d, J= 2.9Hz), 127.99 (d, J=2.6Hz), 126.58 (d, J=6.1Hz), 126.38 (d, J=3.7Hz), 125.23 (d, J= 3.6Hz), 122.65 (d, J=34.4Hz), 122.64 (d, J=9.0Hz), 103.59 (d, J=3.2Hz), 101.52 (d, J= 2.0Hz), 63.04 (d, J=23.5Hz), 52.93 (d, J=18.6Hz), 52.72 (d, J=19.1Hz) .HRMS (ESI- TOF):calcd for C26H21Br2FKO3[M+K]+:596.9479；Found:596.9473.IR(KBr):νmax(cm-1)= 2980,2926,1750,1691,1592,1565,1474,1230,1072,1035,778,691.
3i：
(2S,3R)-Methyl 2-benzoyl-2-fluoro-3,5-diphenylpent-4-enoate(3i)
Yield:76% (30.6mg)；white solid；m.p.115-116℃.[α]D 20=20.8 (c 1.0, EtOAc)；99%ee [Daicel CHIRALCEL AD-H (0.46cm × 25cm)；N-hexane/2-propanol=80/20； Flow rate=0.8mL/min；Detection wavelength=214 or 254nm；tR=12.77 (minor), 14.88(major),24.64(minor),26.86(major)min].1H NMR(400MHz,chloroform-d)δ8.05 (d, J=7.8Hz, 1H), 7.82 (d, J=7.7Hz, 1H), 7.71-7.09 (m, 12H), 6.72-6.30 (m, 2H), 4.89 (td, J=33.6,8.6Hz, 1H), 4.51-3.90 (m, 2H), 1.28 (q, J=6.9Hz, 3H)19F NMR(376MHz, chloroform-d)δ-169.12.13C NMR (101MHz, chloroform-d) δ 192.43 (d, J=27.0Hz), 166.11 (d, J=25.9Hz), 165.76 (d, J=26.1Hz), 137.46,136.86,136.65,134.79 (d, J=3.7Hz), 134.70 (d, J=3.1Hz), 134.38,133.88,133.70,133.44,129.84,129.74 (d, J=2.7Hz), (129.46,129.40,128.59,128.53,128.41 d, J=1.6Hz), 128.31,127.81,127.69,127.58, (127.27,126.52,126.44,125.77 d, J=6.0Hz), 125.45 (d, J=3.8Hz), 104.11 (d, J= 8.0Hz), 102.07,62.98,62.65,60.38,53.59 (d, J=18.5Hz), 53.32 (d, J=18.5Hz) .HRMS (ESI-TOF):calcd for C26H23FNaO3[M+Na]+:425.1529；Found:425.1523.IR(KBr):νmax(cm-1) =2984,2159,1977,1750,1691,1448,1259,1233,907,729,691,649.
3j：
(2S,3R)-methyl 2-benzoyl-2-fluoro-3,5-di(naphthalen-2-yl)pent-4- enoate(3j)
Yield:86% (43.3mg)；white solid；m.p.106-108℃.[α]D 20=35.0 (c 1.0, EtOAc)；93%ee [Daicel CHIRALCEL AD-H (0.46cm × 25cm)；N-hexane/2-propanol=80/20； Flow rate=0.4mL/min；Detection wavelength=214 or 254nm；tR=48.49 (minor), 53.34(major),55.43(major),69.73(minor)min].1H NMR(400MHz,chloroform-d)δ8.15– 7.38 (m, 19H), 6.88-6.48 (m, 2H), 5.30-5.05 (m, 1H), 4.20 (dq, J=38.8,7.3Hz, 2H), 1.29 (t, J=7.1Hz, 3H)19F NMR(376MHz,chloroform-d)δ-160.25,-168.32.13C NMR(101MHz, Chloroform-d) δ 192.23 (d, J=27.5Hz), 165.76 (d, J=26.2Hz), 134.92,134.72,134.48, (134.27,133.74,133.45 d, J=5.3Hz), 132.99,132.84,129.85 (d, J=6.5Hz), 129.52 (d, J =3.6Hz), 128.81,128.51,128.43 (d, J=2.3Hz), 128.31,127.98 (d, J=6.4Hz), 127.60 (d, ), J=5.8Hz 127.34 (d, J=3.0Hz), 126.44,126.16,126.05,125.82,123.58,91.11,89.14, (62.67,53.48 d, J=18.6Hz) .HRMS (ESI-TOF):calcd for C34H27FNaO3[M+Na]+:525.1842； Found:525.1836.IR(KBr):νmax(cm-1)=3056,2363,2159,2025,1977,1734,1262,1235,764, 764,748,477.
3k：
2,2'-((3R,4S)-4-Fluoro-4-nitro-4-(phenylsulfonyl)but-1-ene-1,3-diyl) dinaphthalene(3k)
Yield:52% (26.6mg)；colorless oil.[α]D 20=32.2 (c 1.0, EtOAc)；87%ee [Daicel CHIRALCEL AD-H(0.46cm×25cm)；N-hexane/2-propanol=90/10；Flow rate= 0.8mL/min；Detection wavelength=214 or 254nm；tR=33.34 (minor), 38.18 (minor), 52.28(major),91.86(major)min].1H NMR(400MHz,chloroform-d)δ8.15–7.32(m,19H), 7.11-6.90 (m, 1H), 6.46 (td, J=16.4,8.8Hz, 1H), 5.34 (ddd, J=40.0,30.9,9.4Hz, 1H)19F NMR(376MHz,chloroform-d)δ-126.90,-128.90.13C NMR(101MHz,chloroform-d)δ173.89 (d, J=101.9Hz), 137.21,136.71,135.82,135.09,133.34,133.14 (d, J=4.2Hz), 132.96, 130.65,130.41,129.91,129.32,129.19,128.79,128.65,128.30,128.10,127.69,127.64, (127.54,127.34,127.25,126.86,126.77,126.60 d, J=3.1Hz), 126.45 (d, J=4.6Hz), 125.71,123.47,123.33,121.28,60.37,52.85.HRMS(ESI-TOF):calcd for C30H22FNNaO4S[M +Na]+:534.1151；Found:534.1146.IR(KBr):νmax(cm-1)=2254,2116,1912,1585,1275, 1261,905,730,650,473,442.
4a：
(2S,3R)-3,5-Bis(3-chlorophenyl)-2-fluoro-2-(phenylsulfonyl)pent-4- enal(4a)
Yield:87% (202mg)；pale yellow oil.[α]D 20=56.5 (c 1.0, EtOAc)；96%ee [Daicel CHIRALCEL AD-H(0.46cm×25cm)；N-hexane/2-propanol=90/10；Flow rate= 0.7mL/min；Detection wavelength=214 or 254nm；tR=29.34,60.73min]1H NMR (400MHz, chloroform-d) δ 9.32 (d, J=7.3Hz, 1H), 7.88 (d, J=7.9Hz, 2H), 7.71 (t, J= 7.4Hz, 1H), 7.53 (t, J=7.7Hz, 2H), 7.37-7.10 (m, 8H), 6.70-6.21 (m, 2H), 4.84 (dd, J= 32.4,8.6Hz,1H).19F NMR(376MHz,chloroform-d)δ-171.79.13C NMR(101MHz,chloroform- D) δ 190.42 (d, J=31.2Hz), 137.96,137.34,135.50-134.79 (m), 134.55,134.04,130.82- 130.28 (m), 129.80,129.36,129.13 (d, J=2.5Hz), 128.66,128.12,127.30 (d, J=2.2Hz), (126.44,125.08,124.20 d, J=4.5Hz), 110.39,108.03,49.44 (d, J=17.1Hz) .HRMS (ESI- TOF):calcd for C23H17Cl2FNaO3S[M+Na]+:485.0157；Found:485.0152.IR(KBr):νmax(cm-1) =2926,2254,1741,1332,1158,904,779,725,685,585,549,528.
6a：
Fluorinated 4H-1,2-oxazine(6a)
Yield:60% (28.7mg)；pale yellow oil.[α]D 20=-45.8 (c 1.0, EtOAc)；95%ee [Daicel CHIRALCEL AD-H(0.46cm×25cm)；N-hexane/2-propanol=90/10；Flow rate= 0.8mL/min；Detection wavelength=214or 254nm；tR=44.88,53.83min]1H NMR(400MHz, Chloroform-d) δ 7.61 (t, J=7.4Hz, 1H), 7.50 (d, J=8.1Hz, 2H), 7.39 (t, J=7.8Hz, 2H), 7.25-7.05 (m, 6H), 7.03 (s, 1H), 6.90 (d, J=7.2Hz, 1H), 6.86 (s, 1H), 5.14 (dd, J=8.4, 4.6Hz, 1H), 3.80-3.39 (m, 2H), 3.07 (dd, J=14.8,4.4Hz, 1H)19FNMR(376MHz,chloroform- d)δ-119.82,-138.64.13C NMR(101MHz,chloroform-d)δ135.64,135.34,134.81,134.72, (134.61,130.83,130.11,130.02,129.92,129.45 d, J=1.8Hz), 129.23,128.94,128.17, (127.79,127.72,126.29,126.02,111.20,108.89,74.94 d, J=2.1Hz), 60.38,52.41 (d, J= 18.4Hz).HRMS(ESI-TOF):calcd for C23H18Cl2FNNaO3S[M+Na]+:500.0266；Found: 500.0261.IR(KBr):νmax(cm-1)=2924,2159,2025,1977,1559,1325,1275,1150,907,764, 748,685,592.
The above-mentioned description to embodiment is for ease of ordinary skill in the art to understand and use the invention.It is ripe The personnel for knowing art technology obviously easily can make various modifications to these embodiments, and general original described herein It ought to use in other embodiment without having to go through creative labor.Therefore, the present invention is not limited to the above embodiments, this field Technical staff's announcement according to the present invention, improvement and modification made without departing from the scope of the present invention all should be in the guarantors of the present invention Within the scope of shield.

Claims (10)

1. a kind of fluorine-containing chiral allyl compound, which is characterized in that it is the optical pure compound with such as structure formula (I)：
Wherein, * is asymmetric carbon atom, R1Selected from aryl, R2Selected from the aryl for arbitrarily having sulfuryl or carbonyl, R3Selected from ester group or nitre Base.
2. the synthetic method of fluorine-containing chiral allyl compound according to claim 1, which is characterized in that the R1Choosing From phenyl, substituted-phenyl or how one kind in base.
3. the synthetic method of fluorine-containing chiral allyl compound as described in claim 1, which is characterized in that with allylic It is raw material to close object and fluorine-containing methylene base class compound, with [Pd (C3H3)Cl]2The palladium complex generated with ligand effect is as catalysis Agent is reacted under the action of additive, and the fluorine-containing chiral allyl compound is made.
4. the synthetic method of fluorine-containing chiral allyl compound according to claim 3, which is characterized in that the allyl The structural formula of base class compound isThe structural formula of the fluorine-containing methylene base class compound is
Wherein, R1Selected from aryl, preferably phenyl, substituted-phenyl or how base, R2Selected from the aryl for arbitrarily having sulfuryl or carbonyl, R3Choosing From ester group or nitro, LG is leaving group.
5. the synthetic method of fluorine-containing chiral allyl compound according to claim 4, which is characterized in that the LG is Acetoxyl group, at this point, the structural formula of the allylic compound is
6. the synthetic method of fluorine-containing chiral allyl compound according to claim 3, which is characterized in that the ligand For (S, S)-L1Trost, S-L2PHOX, (R)-L3BINAP or (R)-L4, structural formula is distinguished as follows：
7. the synthetic method of fluorine-containing chiral allyl compound according to claim 6, which is characterized in that the ligand To have the following structure the optically pure ligand of formula：
8. the synthetic method of fluorine-containing chiral allyl compound according to claim 3, it is characterised in that：
The organic solvent is toluene, dichloromethane, tetrahydrofuran or N,N-dimethylformamide；
The additive is potassium phosphate, sodium phosphate, potassium carbonate, cesium carbonate or cesium fluoride.
9. according to the synthetic method of any fluorine-containing chiral allyl compound of claim 2~8, which is characterized in that institute The allylic compound stated, fluorine-containing methylene base class compound, [Pd (C3H3)Cl]2, ligand, additive molar ratio be 1:2: 0.05:0.1:3；Reaction temperature is -20 DEG C, and the reaction time is 48 hours.
10. the synthetic method of fluorine-containing chiral allyl compound according to claim 3, which is characterized in that products therefrom By recrystallization, thin-layer chromatography and column chromatography for separation.
CN201810129837.4A 2018-02-08 2018-02-08 Fluorine-containing chirality allyl compound and its synthetic method Pending CN108373431A (en)

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CN101565393A (en) * 2009-06-02 2009-10-28 中国科学院上海有机化学研究所 3-(substituted bisulfonyl fluromethane)-1-propylene compound, synthetic method and applications thereof
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Application publication date: 20180807

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