CN106608859A - Synthetic method of 1,2,5-thiazolinone-1,1-dioxide and 2,3-dihydro-1,2,5-thiadiazole-1,1-dioxide containing quaternary carbon chiral centers - Google Patents

Synthetic method of 1,2,5-thiazolinone-1,1-dioxide and 2,3-dihydro-1,2,5-thiadiazole-1,1-dioxide containing quaternary carbon chiral centers Download PDF

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CN106608859A
CN106608859A CN201510688829.XA CN201510688829A CN106608859A CN 106608859 A CN106608859 A CN 106608859A CN 201510688829 A CN201510688829 A CN 201510688829A CN 106608859 A CN106608859 A CN 106608859A
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CN106608859B (en
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徐明华
李翼
于月娜
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Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/34—Other additions, e.g. Monsanto-type carbonylations, addition to 1,2-C=X or 1,2-C-X triplebonds, additions to 1,4-C=C-C=X or 1,4-C=-C-X triple bonds with X, e.g. O, S, NH/N
    • B01J2231/341—1,2-additions, e.g. aldol or Knoevenagel condensations
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/822—Rhodium

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Abstract

The invention provides a synthetic method of 1,2,5-thiazolinone-1,1-dioxide and 2,3-dihydro-1,2,5-thiadiazole-1,1-dioxide containing quaternary carbon chiral centers. Specifically, according to the method, a monovalent rhodium metal compound together with a chiral phosphorene ligand forms a complex to catalyze an organoboron reagent, so that a 4-substitued-3-carbonyl-1,2,5-thiadiazole substrate and a derivative thereof undergo an asymmetric addition reaction to obtain a corresponding compound containing a quaternary carbon chiral center. The method is good in selectivity, the product can be used for synthesis of multiple crucial chiral compounds, such as alpha, alpha-diaryl amino amide, through further functional group conversion, and has bright industrial production and application prospects.

Description

One kind is containing quaternary carbon chirality 1,2,5- thiazolinone -1,1- dioxide and 2,3- dihydro -1,2,5- thiadiazoles -1,1- dioxies The synthetic method of compound
Technical field
The invention belongs to chemical field, and in particular to the organoboron reagent of monovalence rhodium metal catalysis is to 4- replacement -3- The asymmetric 1,2- additive reaction of carbonyl -1,2,5- thiadiazoles substrate and its derivant is built containing in quaternary carbon chirality 1,2,5- thiazolinone -1,1- the dioxide of the heart and the side of 2,3- dihydro -1,2,5- thiadiazoles -1,1- dioxide Method.
Background technology
Sultam is the very important compound of a class, and it is in organic chemistry, pharmaceutical chemistry and material science In suffer from widely application.Always change accordingly, with respect to the study on the synthesis of sultam class compound Learn the forward position of research field.An important class in as sultam, 1,2,5- thiazolinone -1,1- dioxide With 2,3- dihydro -1,2,5- thiadiazoles -1,1- dioxide changed because of its pharmacodynamics and the peculiar property in structure Scholar and the concern of Pharmaceutical Chemists, therefore realize 1,2,5- thiazolinone -1,1- dioxide and derivant Efficiently asymmetric synthesis will be helpful to further promote this kind of compound in the applied research of association area.
At present, chiral 1,2,5- thiazolinone -1,1- dioxide and 2,3- dihydro -1,2,5- thiophenes two are obtained both at home and abroad Azoles -1, the method for 1- dioxide is mainly by chiral separation or chiral source synthesis two ways, these sides Method is existed, such as：Split the problems such as inefficient, chiral source is not easy to obtain, synthesis step is relatively complicated, tool There is larger limitation.
In recent years, the asymmetric addition construction of strategy official using transition metal-catalyzed organoboron reagent to imines The chiral aminated compoundss of energy dough are the research directions that chemists pay close attention to.The strategy is used for corresponding 1,2,5- thiazolinone -1,1- dioxide and 2,3- dihydro -1,2,5- thiadiazoles -1,1- dioxide efficiently not Symmetrical synthesis, does not there is in the world at present successfully report.Hayashi etc. adopts compound with rhodium/chiral diene Thing has attempted 4- methylphenylboronic acids ester to 4- phenyl -3- oxo -1 as catalyst, 2,5- thiadiazoles it is asymmetric 1,2- additive reaction, due to react enantioselectivity it is unsatisfactory, only construct two products (Nishimura, T.；Ebe,Y.；Fujimoto,H.；Hayashi,T.Chem.Commun.2013,49,5504.).Therefore, send out Zhan Xin, highly effective catalyst system and catalyzing catalysis organoboron reagent replaces -3- carbonyl -1,2,5- thiadiazoles to 4- Asymmetric 1, the 2- additions of substrate and its derivant, to realize the 1 of high optical activity, 2,5- thiazolinone -1,1- bis- The synthesis of oxide and 2,3- dihydro -1,2,5- thiadiazoles -1,1- dioxide is still that the field is in the urgent need to address Problem.
The content of the invention
It is an object of the invention to provide a kind of high selectivity prepare 1,2,5- thiazolinone -1,1- dioxide and The method of 2,3- dihydro -1,2,5- thiadiazoles -1,1- dioxide.
A first aspect of the present invention, there is provided shown in a kind of formula 3 and/or formula ent-3 containing quaternary carbon chirality in The method of the compound of the heart, methods described includes step：
Under oxygen free condition, in organic solvent, match somebody with somebody with chiral phosphorus alkene in additive and monovalence rhodium metal compound In the presence of the composition catalyst that body is formed, asymmetric adding is carried out with the organoboron reagent and the substrate of formula 2 of formula 1 Into reaction, formula 3 and/or the compound containing quaternary carbon chiral centre shown in formula ent-3 are obtained：
In formula,
R1It is selected from the group：Substituted or unsubstituted C6-30Aryl, substituted or unsubstituted C4-12Heteroaryl, its In, described replacement refers to that the hydrogen atom on group is replaced by one or more (such as 1-5) substituent groups, described The hetero atom that contains of heteroaryl be oxygen or sulfur；
Described substituent group is selected from the group：Halogen, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl, C1-6 Halogenated alkoxy, benzyloxy, unsubstituted or substituted C6-10Aryl or its combination；The halogen be F, Cl, Br or I；
R2It is nothing, or C1-6Alkyl；
R3It is selected from the group：Substituted or unsubstituted C6-30Aryl, substituted or unsubstituted C4-12Heteroaryl, its In, described replacement refers to that the hydrogen atom on group is replaced by one or more (such as 1-5) substituent groups, described The hetero atom that contains of heteroaryl be oxygen or sulfur；
Described substituent group is selected from the group：Halogen, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl, C1-6 Halogenated alkoxy, benzyloxy, unsubstituted or substituted C6-10Aryl or its combination；The halogen be F, Cl, Br or I；
R4It is nothing or C1-3Straight or branched alkyl；
[B] is selected from the group：B(OR)2Or (BO)3, wherein R is H or C1-3Straight or branched alkyl；
Dotted line represents chemical bond or does not exist.
In another preference, described reaction equation is as follows：
Wherein, each group is as defined above.
In another preference, described reaction equation is as follows：
Wherein, each group is as defined above.
In another preference, described R1For substituted or unsubstituted phenyl, naphthyl or C4-12Heteroaryl Base, wherein hetero atom are oxygen or sulfur.
In another preference, described R2For C1-6Straight or branched alkyl, for example, methyl.
In another preference, described R3For substituted or unsubstituted phenyl.
In another preference, described R4For C1-3Straight or branched alkyl, for example, ethyl.
In another preference, described [B] is B (OH)2。
In another preference, by compound 4- -3- oxo -1 is replaced, the use gauge of 2,5- thiadiazole substrates 2, Described monovalence rhodium metal catalyst consumption is 1～30mol%；And/or described chiral phosphorus alkene part consumption is 1～30mol%.
In another preference, described chiral phosphorus alkene part has following structural formula (preferably, described formula I and Formula II enantiomer each other)：
In formula,
R6And R7Connection forms substituted or unsubstituted-(CH2)n-, wherein, n is 3 or 4, or coupled Carbon atom connect to form substituted or unsubstituted phenyl, wherein, described replacement refers to that hydrogen on group is former Son is replaced by one or more (such as 1-5) substituent groups, and described substituent group is selected from the group：It is halogen, unsubstituted Or C by one or more halogen substiuteds1-6Alkyl, or it is unsubstituted or by one or more halogen substiuteds C1-6Alkoxyl；
R8For H or substituted or unsubstituted C6-30Aryl, wherein, described replacement is the hydrogen atom on group Replaced by one or more (such as 1-5) substituent groups, described substituent group is selected from the group：It is halogen, unsubstituted Or by the C of one or more halogen substiuteds1-6Alkyl, or it is unsubstituted or by one or more halogen substiuteds C1-6Alkoxyl；
R9It is the group being selected from the group on phenyl ring optional position：It is hydrogen, halogen, unsubstituted or by one The C of individual or multiple halogen substiuteds1-6Alkyl, or C unsubstituted or by one or more halogen substiuteds1-6Alcoxyl Base；
R5It is selected from the group：Hydrogen, halogen, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Alkane Epoxide, substituted or unsubstituted phenyl, naphthyl or other aryl, wherein, described replacement is referred on group Hydrogen atom replaced by one or more (such as 1-5) substituent groups, described substituent group is selected from the group：Halogen, C unsubstituted or by one or more halogen substiuteds1-6Alkyl is unsubstituted or by one or more halogens Substituted C1-6Alkoxyl.
In another preference, described R6And R7Connection forms substituted or unsubstituted-(CH2)n-, wherein, N is 4.
In another preference, described R8For C6-30Aryl.
In another preference, described R9For hydrogen, halogen, C1-6Alkyl or C1-6Alkoxyl.
In another preference, described R5For hydrogen, halogen, C1-6Alkyl or substituted or unsubstituted benzene Base.
In another preference, described chiral phosphorus alkene part is selected from the group：
In another preference, described monovalence rhodium metal compound is selected from the group：[Rh(C2H4)2Cl]2、 [Rh(C2H4)2OH]2、[Rh(COE)2Cl]2、[Rh(COE)2OH]2, or its combination.
In another preference, in the described organoboron reagent of formula 1, [B] is B (OR)2Or (BO)3, wherein R For H or C1-3Straight or branched alkyl；
In another preference, described method also has one or more features being selected from the group：
(1) additive for reacting used is that concentration is the water-soluble of the salt being selected from the group of 0.5mol/L～5mol/L Liquid：KF、KOH、K2CO3、Na2CO3、K3PO4、K2HPO4；
(2) consumption of reaction additives is 50mol%～500mol%；
(3) react organic solvent used to be selected from the group：Dichloromethane (CH2Cl2), toluene (Toluene), chlorine Imitative (CHCl3), Isosorbide-5-Nitrae-dioxane (Dioxane), tetrahydrofuran (THF), or its combination；
(4) temperature of reaction is 0～100 DEG C；
(5) response time is 3～12 hours.
A second aspect of the present invention, there is provided the compound shown in a kind of structural formula 3 or ent-3, described change Compound has following structural formula：
Wherein, R1、R2、R3、R4Definition as described in first aspect present invention.
In another preference, ee value >=84% of the formula 3 or ent-3 compounds, preferably >=90%, more preferably Ground >=95%.
In another preference, described R1、R2、R3、R4It is respectively in embodiment Deng group and respectively embodies Corresponding group in compound.
In another preference, described compound is compound prepared in embodiment.
In another preference, the compound is selected from the group：
A third aspect of the present invention, there is provided shown in a kind of formula 3 or ent-3 as described in respect of the second aspect of the invention Compound purposes, be used for：
A () carries out open loop to the compound of formula 3, remove sulfonyl, so as to form the α, α-two of optical activity holding Arylamino amide 4；
B () carries out open loop to the compound of formula 3, so as to form α, α-ammonia diaryl base amide 4, subsequently cyclisation is formed 5,5-Diphenyl-2,4-imidazolidinedione analog 5, compound 5 again through thio and ammonification two-step reaction, so as to form the compound of formula 7；
It is above-mentioned it is various in, R1, R2, R3It is defined as above.
In another preference, the described compound of formula 3 is formula 3aa compound, and described formula 3aa chemical combination Thing is used for：
(a-1) in tetrahydrofuran solvent, formula 3aa compound is used into tetrahydrochysene under the conditions of backflow (preferably 70 DEG C) The process of aluminum lithium, obtains the α that corresponding optical activity keeps, α-ammonia diaryl base acid amide 4a.
In another preference, the described compound of formula 3 is formula 3ia compound, and described formula 3ia compound For：
(b-1) formula 3ia compound Jing tetrahydrochysene lithium aluminiums are processed and obtain formula 4b compound；Formula 4b compound triphosgene Process, obtain corresponding 5,5-Diphenyl-2,4-imidazolidinedione analog formula 5a compound；Formula 5a compound is reacted by Lawson, is obtained Thio product formula 6a compound；Thio product formula 6a compound is coupled and ammonification two-step reaction by Suzuki, Prepare BACE-1 inhibitor.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and below (such as embodiment) Can be combined with each other between each technical characteristic of middle specific descriptions, so as to constitute new or preferred technical side Case.As space is limited, here is no longer tired out one by one and is stated.
Specific embodiment
The present inventor has found first, using monovalence rhodium/chiral phosphorus alkene coordination compound through extensively in-depth study Used as catalyst, catalysis organoboron reagent replaces -3- carbonyl -1,2,5- thiadiazole substrates and its derivant to 4- Asymmetric 1,2- additive reaction, can efficiently prepare the thiazole of high optical activity 1,2,5- containing quaternary carbon chiral centre Quinoline ketone -1,1- dioxide and 2,3- dihydro -1,2,5- thiadiazoles -1,1- dioxide.Additionally, different by selecting The chiral phosphorus alkene part of configuration, the inventive method can obtain contrary thiazolinone -1 of chirality 1,2,5- of configuration, 1- Dioxide and 2,3- dihydro -1,2,5- thiadiazoles -1,1- dioxide.The present invention is completed on this basis.
Term
As used herein, term " alkyl " refers to straight or branched alkyl, preferably C1-6Alkyl, this In invention, alkyl also includes that one or more H on alkyl are selected from the group that the substituent group of the following group is replaced： Halogen, substituted or unsubstituted phenyl, C unsubstituted or by one or more halogen substiuteds1-6Alkyl. It should be understood that the term also includes C3-10Substituted or unsubstituted cycloalkyl.
As used herein, term " alkoxyl " refers to C1-6Straight or branched alkoxyl, in the present invention, Alkoxyl also includes that one or more H on alkyl are selected from the group that the substituent group of the following group is replaced：Halogen, Substituted or unsubstituted phenyl, C unsubstituted or by one or more halogen substiuteds1-6Alkyl.
As used herein, term " aryl " or " Ar " refer to C6-30Aryl, representational example be phenyl, Naphthyl, anthryl, phenanthryl.In the present invention, aryl also includes that one or more H on aryl are selected from down The group that the substituent group of group is replaced：It is halogen, phenyl, unsubstituted or by one or more halogen substiuteds C1-6Alkyl, C unsubstituted or by one or more halogen substiuteds1-6Alkoxyl.
As used herein, term " heteroaryl " refers to C4-12Heteroaryl, wherein hetero atom is oxygen or sulfur, generation The example of table is furyl, thienyl, benzofuranyl, benzothienyl.In the present invention, heteroaryl Base also includes that one or more H on aryl are selected from the group that the substituent group of the following group is replaced：Halogen, benzene Base, C unsubstituted or by one or more halogen substiuteds1-6It is alkyl, unsubstituted or by one or more The C of halogen substiuted1-6Alkoxyl.
As used herein, term " one or more " is often referred to 1-6, preferably 1-5, more preferably 1-3 It is individual.
As used herein, term " Ph " represents phenyl.
As used herein, term " RT " expression room temperature, such as 10～40 DEG C.
Preparation method
The synthetic method of the present invention can be represented by following type reaction formulas:
Reaction substrate 1 is organoboron reagent, wherein, R1For substituted or unsubstituted C6-30Aryl or C4-12Heteroaryl Base, wherein described replacement refers to that, with one or more (such as 1-5) substituent groups, hetero atom is oxygen or sulfur, Described substituent group is selected from the group：Halogen, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl, C1-6Halo Alkoxyl, benzyloxy, unsubstituted or substituted C6-10Aryl or its combination；The halogen be F, Cl, Br or I；[B] is B (OR)2Or (BO)3, wherein R is H or C1-3Straight or branched alkyl；
Reaction substrate 2 is that 4- replaces -3- oxo -1,2,5- thiadiazoles, wherein, R2It is nothing or C1-6Straight chain Or the alkyl of side chain；R3For substituted or unsubstituted C6-30Aryl or C4-12Heteroaryl, wherein described replacement Refer to that hetero atom is oxygen or sulfur, and described substituent group is selected from down with one or more (such as 1-5) substituent groups Group：Halogen, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl, C1-6Halogenated alkoxy, benzyloxy, not The C for replacing or replacing6-10Aryl or its combination；The halogen is F, Cl, Br or I；R4Be without or C1-3Straight or branched alkyl；Dotted line represents chemical bond or does not exist.
[Rh (I)] refers to monovalence rhodium metal catalyst, and representational example includes (but being not limited to)； [Rh(C2H4)2Cl]2、[Rh(C2H4)2OH]2、[Rh(COE)2Cl]2、[Rh(COE)2OH]2Or its combination.
In the present invention, representational chiral phosphorus alkene part has following structural formula：
In formula,
R6And R7Connection forms substituted or unsubstituted-(CH2)n-, wherein, n is 3 or 4, or coupled Carbon atom connect to form substituted or unsubstituted phenyl, wherein, described replacement is referred to one or many Individual (such as 1-5) substituent group, described substituent group is selected from the group：It is halogen, unsubstituted or by one or more The C of halogen substiuted1-6Alkyl or C unsubstituted or by one or more halogen substiuteds1-6Alkoxyl；
R8For substituted or unsubstituted phenyl, naphthyl or other aryl, wherein, described replacement refers to have One or more (such as 1-5) substituent groups, described substituent group is selected from the group：It is halogen, unsubstituted or by one The C of individual or multiple halogen substiuteds1-6Alkyl or C unsubstituted or by one or more halogen substiuteds1-6Alcoxyl Base；
R9For hydrogen, halogen, C unsubstituted or by one or more halogen substiuteds1-6Alkyl is unsubstituted Or by the C of one or more halogen substiuteds1-6Alkoxyl；
R5For hydrogen, halogen, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Alkoxyl, take Generation or unsubstituted phenyl, naphthyl or other aryl, wherein, described replacement is referred to one or more (such as 1-5) substituent group, described substituent group is selected from the group：It is halogen, unsubstituted or by one or more halogen The C that element replaces1-6Alkyl or C unsubstituted or by one or more halogen substiuteds1-6Alkoxyl.
In the present invention, the structural formula of the typical compound of chiral phosphorus alkene part includes (but being not limited to)：
In the present invention, described additive can be concentration be the KF of 0.5mol/L～5mol/L, KOH, K2CO3、Na2CO3、K3PO4、K2HPO4Deng aqueous solution；
In the present invention, the consumption of described additive can be 50mol%～500mol%；
In the present invention, described organic solvent can be dichloromethane (CH2Cl2), toluene (Toluene), Chloroform (CHCl3), 1,4- dioxane (Dioxane) or tetrahydrofuran (THF) etc.；
In the present invention, reaction temperature is not particularly limited, can be 0～100 DEG C, preferably 10～60 DEG C, it is more preferably 25～40 DEG C.
In the present invention, the response time be not particularly limited, can be 3～12 hours, preferably 6-12 Hour.
In a preference of the present invention, representational synthetic method can be described as follows：
Under oxygen free condition, monovalence rhodium catalyst, chiral phosphorus alkene part, organoboron reagent, 4- are replaced into -3- oxygen In generation, -1,2,5- thiadiazoles were dissolved in organic solvent, at room temperature complexation reaction 30 minutes, subsequently, added addition Agent simultaneously continues to react 3-12 hours, it is possible to obtain high-optical-purity of the present invention is containing quaternary carbon chirality 1,2,5- thiazolinone -1,1- dioxide and 2,3- dihydro -1,2,5- thiadiazoles -1,1- dioxide.In the reaction In, additive can be KF, KOH, K that concentration is 0.5mol/L～5mol/L2CO3、Na2CO3、 K3PO4、K2HPO4Deng aqueous solution, preferred 2.5mol/L K3PO4Aqueous solution；The consumption of additive can be 50mol%～500mol%, preferred 100mol%；Organic solvent can be dichloromethane (CH2Cl2), first Benzene (Toluene), chloroform (CHCl3), Isosorbide-5-Nitrae-dioxane (Dioxane) or tetrahydrofuran (THF) etc., preferably Toluene (Toluene)；Monovalence rhodium metal catalyst can be [Rh (C2H4)2Cl]2、[Rh(C2H4)2OH]2、 [Rh(COE)2Cl]2、[Rh(COE)2OH]2Or its combination, preferably [Rh (COE)2Cl]2；Monovalence rhodium metal Catalyst amount is 1～30mol%, preferred 3mol%；Chiral phosphorus alkene part consumption is 1～30mol%, excellent Select 3mol%；Organoboron reagent 1 can be boric acid, borate, boric anhydride, Potassium borofluoride, four aryl boron sodium Deng preferred boric acid；It is (1-3) that organoboron reagent 1 and 4- replace the mol ratio of -3- oxo -1,2,5- thiadiazoles 2： 1, preferably 2：1；Reaction temperature is 25～60 DEG C, preferably 25 DEG C.
1,2,5- thiazolinone -1,1- the dioxide containing quaternary carbon chiral centre of high-optical-purity and 2,3- dihydros - 1,2,5- thiadiazoles -1,1- dioxide
By the method for the present invention, containing quaternary carbon chiral centre the 1 of high-optical-purity can be efficiently prepared, 2,5- thiazoles Quinoline ketone -1,1- dioxide and 2,3- dihydro -1,2,5- thiadiazoles -1,1- dioxide.
In the present invention, some representational containing quaternary carbon chiral centre 1,2,5- thiazolinone -1,1- dioxide It is listed in Tables 1 and 2 with 2,3- dihydro -1,2,5- thiadiazoles -1,1- dioxide.
Using toluene as solvent, the concentration of 1 equivalent (100mol%) is the K of 2.5mol/L3PO4Aqueous solution is made For additive, monovalence rhodium [Rh (COE)2Cl]2The complex formed with chiral phosphorus alkene part (R) -4t is used as catalysis As a example by agent, catalysis organic boronic 1 to 4- aryl -3- carbonyl -1, asymmetric the 1,2- of 2,5- thiadiazole substrate 2a-d Additive reaction, can efficiently be obtained required product, and yield (yield) is good, and enantioselectivity (ee) is outstanding, Highest can reach 98% ee values.
The monovalence rhodium catalysis organic boronic 1 of table 1. is asymmetric to 4- aryl -3- carbonyl -1,2,5- thiadiazoles 2a-d's 1,2- additive reaction
Described method can be also used for the expansion of following substrate.Preferably, in the process, with toluene As solvent, the concentration of 1 equivalent (100mol%) for 1.5mol/L KF aqueous solutions as additive, one Valency rhodium [Rh (COE)2Cl]2As a example by the complex formed with chiral phosphorus alkene part (R) -4t is as catalyst, catalysis Organic boronic 1 to 4- aryl -3- ethyoxyl -1, asymmetric 1, the 2- additive reaction of 2,5- thiadiazole substrate 2e-h, Required product can be efficiently obtained, yield (yield) is good, and enantioselectivity (ee) is outstanding, highest can be with Reach 99% ee values.
The monovalence rhodium catalysis organic boronic 1 of table 2. is asymmetric to 4- aryl -3- ethyoxyl -1,2,5- thiadiazoles 2e-h's 1,2- additive reaction
The application of the 1,2,5- thiazolinone -1,1- dioxide containing quaternary carbon chiral centre
Present invention also offers the 1,2,5- thiazolinone -1,1- titanium dioxide containing quaternary carbon chiral centre in the present invention The application of thing, is especially preparing the α with high-optical-purity, α-ammonia diaryl base acid derivative and active ingredient The application in object space face.
In the present invention, a kind of representational purposes is as follows：
In this application, to containing quaternary carbon chiral centre the 1 of the present invention, 2,5- thiazolinone -1,1- dioxide 3 Open loop is carried out, sulfonyl is removed, so as to form the α, α-ammonia diaryl base amide 4 of optical activity holding.
Another kind of representational purposes is as follows：
In this application, to the present invention in containing quaternary carbon chiral centre 1,2,5- thiazolinone -1,1- dioxide 3 carry out open loop, and so as to form α, α-ammonia diaryl base amide 4, subsequently cyclisation forms 5,5-Diphenyl-2,4-imidazolidinedione analog 5, changes Compound 5 through thio and ammonification two-step reaction, so as to form BACE-1 inhibitor 7, can be used for A Erci again The treatment of the silent disease in sea.
It is above-mentioned it is various in, R1, R2, R3It is defined as above.
In another preference, representational purposes is as follows：
- 3- carbonyl -1,2,5- thiadiazoles substrates are replaced to carry out asymmetric reduction reaction institute 4- organoboron reagent The product for obtaining Jing Lithium Aluminium Hydrides under the conditions of backflow (70 DEG C) are processed, and obtain what corresponding optical activity kept α, α-ammonia diaryl base acid amide.
In another preference, representational purposes is as follows：
- 3- carbonyl -1,2,5- thiadiazoles substrates are replaced to carry out asymmetric reduction reaction institute 4- organoboron reagent Successively Jing tetrahydrochysene lithium aluminiums and triphosgene are processed the product for obtaining, and obtain corresponding 5,5-Diphenyl-2,4-imidazolidinedione analog, subsequently, Thio product is obtained by Lawson's reaction, finally, thio product is coupled and ammonification two-step reaction by Suzuki The BACE-1 inhibitor researched and developed by Merck ＆ Co., Inc. is obtained afterwards, can be used for the treatment of Alzheimer.
Main advantages of the present invention include：
(1) complex that the present invention is formed using monovalence rhodium metal with simple chiral phosphorus alkene part is used as catalyst, Realize cheap organoboron reagent and -3- carbonyls -1,2,5- thiadiazoles substrate and its derivant are replaced not to 4- Symmetrical 1,2- additive reaction；
(2) method of the present invention can prepare the various 1,2,5- thiazolinone -1,1- titanium dioxide containing quaternary carbon chiral centre Thing and 2,3- dihydro -1,2,5- thiadiazoles -1,1- dioxide can also further be applied to the important bloom of structure Learn the α of purity, the synthesis of α-ammonia diaryl base acid derivative and reactive compound；
(3) method of the present invention substrate universality is good, for various types of organoboron reagent and 4- take Generation -3- carbonyls -1,2,5- thiadiazoles substrate and its derivant can obtain preferable result；
(4) method of the present invention reaction condition is gentle, easy to operate；
(5) stereo selectivity of product of the invention is high, with prospects for commercial application.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate The present invention rather than restriction the scope of the present invention.The experiment side of unreceipted actual conditions in the following example Method, generally according to normal condition, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise Percentage ratio and number are calculated by weight.
Embodiment 1
The synthesis of compound 3aa：
Under argon protection, by 4- phenyl -3- carbonyl -1,2,5- thiadiazoles substrate 2a (0.25mmol, 100mol%), 4- methylphenylboronic acid 1a (0.5mmol, 200mol%), [Rh (COE)2Cl]2(0.0075mmol,1.5 Mol%), during phosphorus alkene part (R) -4t (0.0075mmol, 3mol%) puts into reaction bulb, toluene (1 is added ML), at room temperature after stirring reaction 30min, the K of 2.5mol/L is added toward system3PO4Aqueous solution (0.1 ML), continue to react.After TLC monitoring reactions completely, reactant liquor is spin-dried for, is separated with silica gel column chromatography It is white solid to product 3aa, 99% yield, 96%ee.
1H NMR(300MHz,CDCl3)δ7.47–7.40(m,2H),7.37–7.31 (m, 3H), 7.28 (d, J=8.3Hz, 2H), 7.14 (d, J=8.4Hz, 2H), 5.40 (s, 1H), 3.11 (s, 3H),2.33(s,3H)；13C NMR(125MHz,CDCl3)δ168.8,139.3,138.2,135.4,129.6, 129.2,128.8,127.7,127.6,75.4,26.2,21.2；HRMS(ESI)for C16H15O3N2S[M-H]- calcd 315.0809,found 315.0816.
Embodiment 2
The synthesis of compound 3ba：
4- methylphenylboronic acid 1a used in embodiment 1 are changed to into 4- chlorophenylboronic acid 1b, remaining experimental implementation is with real Apply example 1.Product 3ba is obtained, is white solid, 95% yield, 96%ee.
1H NMR(300MHz,CDCl3) δ 7.47 (d, J=2.0Hz, 1H), 7.45 (d, J=2.0Hz, 1H), 7.41-7.28 (m, 7H), 5.40 (s, 1H), 3.15 (s, 3H)；13C NMR(125 MHz,CDCl3)δ168.4,138.3,136.2,135.5,129.6,129.23,129.17,129.1,127.6, 75.0,26.4；HRMS(ESI)for C15H12O3N2SCl[M-H]-calcd 335.0263,found 335.0267.
Embodiment 3
The synthesis of compound 3ca：
4- methylphenylboronic acid 1a used in embodiment 1 are changed to into 4- methoxyphenylboronic acid 1c, remaining experimental implementation With embodiment 1.Product 3ca is obtained, is white solid, 99% yield, 92%ee.
1H NMR(300MHz,CDCl3) δ 7.46 (dd, J=6.3,3.3Hz, 2H), 7.36 (dd, J=6.1,2.8Hz, 4H), 7.31 (s, 1H), 6.86 (d, J=8.9Hz, 2H), 5.30 (s, 1H), 3.78(s,3H),3.15(s,3H)；13C NMR(125MHz,CDCl3)δ169.0,160.2,138.3, 130.3,129.2,129.1,128.9,127.7,114.3,75.3,55.5,26.3；HRMS(ESI)for C16H15O4N2S[M-H]-calcd 331.0758,found 331.0762.
Embodiment 4
The synthesis of compound 3ca '：
Phosphorus alkene part (R) -4t used in embodiment 3 is changed to into (S) -4t, remaining experimental implementation is with embodiment 3. Product 3ca ' is obtained, is white solid, 99% yield, -92%ee.
1H NMR(300MHz,CDCl3) δ 7.45 (dd, J=6.3,3.3Hz, 2H), 7.35 (dd, J=6.1,2.8Hz, 4H), 7.29 (s, 1H), 6.85 (d, J=8.9Hz, 2H), 5.32 (s, 1H), 3.77(s,3H),3.14(s,3H)；13C NMR(125MHz,CDCl3)δ169.1,160.3,138.4, 130.3,129.2,129.0,128.9,127.8,114.3,75.4,55.5,26.4；HRMS(ESI)for C16H15O4N2S[M-H]-calcd 331.0758,found 331.0762.
Embodiment 5
The synthesis of compound 3da：
4- methylphenylboronic acid 1a used in embodiment 1 are changed to into 4- fluorobenzoic boric acid 1d, remaining experimental implementation is with real Apply example 1.Product 3da is obtained, is white solid, 94% yield, 94%ee.
1H NMR(300MHz,CDCl3)δ7.54–7.46(m,2H),7.39(s,5H), 7.13–7.00(m,2H),5.46(s,1H),3.17(s,3H)；13C NMR(125MHz,CDCl3)δ 168.6,163.1(d,1JCF=248.8Hz), 138.4,133.7,129.8 (d,3JCF=8.4Hz), 129.5, 129.1,127.6,115.8(d,2JCF=21.3Hz), 75.0,26.3；HRMS(ESI)for C15H12O3N2FS [M-H]-calcd 319.0558,found 319.0560.
Embodiment 6
The synthesis of compound 3ea：
4- methylphenylboronic acid 1a used in embodiment 1 are changed to into 4- bromobenzeneboronic acid 1e, remaining experimental implementation is with real Apply example 1.Product 3ea is obtained, is white solid, 96% yield, 96%ee.
1H NMR(300MHz,CDCl3) δ 7.52 (d, J=2.0Hz, 1H), 7.49 (d, J=2.1Hz, 1H), 7.42 (d, J=2.0Hz, 1H), 7.40-7.29 (m, 6H), 5.34 (s, 1H), 3.16 (s, 3H)；13C NMR(125MHz,CDCl3)δ168.3,138.3,136.7,132.0,129.7,129.5,129.3, 127.6,123.8,75.1,26.4；HRMS(ESI)for C15H12O3N2BrS[M-H]-calcd 378.9757, found 378.9766.
Embodiment 7
The synthesis of compound 3ea '：
Phosphorus alkene part (R) -4t used in embodiment 6 is changed to into (S) -4t, remaining experimental implementation is with embodiment 6. Product 3ea ' is obtained, is white solid, 96% yield, -96%ee.
1H NMR(300MHz,CDCl3) δ 7.53 (d, J=2.0Hz, 1H), 7.50 (d, J=2.1Hz, 1H), 7.41 (d, J=2.0Hz, 1H), 7.40-7.27 (m, 6H), 5.33 (s, 1H), 3.15 (s, 3H)；13C NMR(125MHz,CDCl3)δ168.3,138.5,136.7,132.1,123.0,129.5,129.3, 127.5,123.7,75.2,26.4；HRMS(ESI)for C15H12O3N2BrS[M-H]-calcd 378.9757, found 378.9766.
Embodiment 8
The synthesis of compound 3fa：
4- methylphenylboronic acid 1a used in embodiment 1 are changed to into 4- phenyl phenylboric acid 1f, remaining experimental implementation is same Embodiment 1.Product 3fa is obtained, is white solid, 96% yield, 96%ee.
1H NMR(300MHz,CDCl3) δ 7.54 (dd, J=12.0,5.7Hz, 5H), 7.50–7.40(m,4H),7.40–7.24(M,5H),5.42(s,1H),3.14(s,3H)；13C NMR(100 MHz,CDCl3)δ168.7,142.1,140.0,138.2,137.0,129.4,129.0,128.97,128.1, 127.9,127.7,127.6,127.2,75.4,26.3；HRMS(ESI)for C21H17O3N2S[M-H]-calcd 377.0965,found 377.0973.
Embodiment 9
The synthesis of compound 3fa '：
Phosphorus alkene part (R) -4t used in embodiment 8 is changed to into (S) -4t, remaining experimental implementation is with embodiment 8. Product 3fa ' is obtained, is white solid, 96% yield, -96%ee.
1H NMR(300MHz,CDCl3) δ 7.55 (dd, J=12.0,5.7Hz, 5H), 7.51–7.41(m,4H),7.41–7.23(M,5H),5.43(s,1H),3.15(s,3H)；13C NMR(100 MHz,CDCl3)δ168.8,142.1,140.2,138.1,137.1,129.4,129.2,128.9,128.1,127.9, 127.7,127.5,127.4,75.4,26.3；HRMS(ESI)for C21H17O3N2S[M-H]-calcd 377.0965,found 377.0973.
Embodiment 10
The synthesis of compound 3ga：
4- methylphenylboronic acid 1a used in embodiment 1 are changed to into 3- fluorobenzoic boric acid 1g, remaining experimental implementation is with real Apply example 1.Product 3ga is obtained, is white solid, 91% yield, 95%ee.
1H NMR(300MHz,CDCl3)δ7.45–7.30(m,7H),7.29–7.20(m, 1H),7.12–7.00(m,1H),5.39(s,1H),3.17(s,3H)；13C NMR(125MHz,CDCl3)δ 168.2,162.8(d,1JCF=246.3Hz), 140.1 (d,3JCF=7.2Hz), 138.2,130.5 (d,3JCF= 8.2Hz),129.6,129.2,127.6,123.4(d,4JCF=2.9Hz), 116.4 (d,2JCF=20.0Hz), 115.2(d,2JCF=23.8Hz), 75.0,26.4；HRMS(ESI)for C15H12O3N2FS[M-H]-calcd 319.0558,found 319.0562.
Embodiment 11
The synthesis of compound 3ga '：
Phosphorus alkene part (R) -4t used in embodiment 10 is changed to into (S) -4t, remaining experimental implementation is with embodiment 10. Product 3ga ' is obtained, is white solid, 90% yield, -95%ee.
1H NMR(300MHz,CDCl3)δ7.45–7.32(m,7H),7.30–7.21(m, 1H),7.12–7.01(m,1H),5.40(s,1H),3.16(s,3H)；13C NMR(125MHz,CDCl3)δ 168.3,162.9(d,1JCF=246.3Hz), 140.0 (d,3JCF=7.2Hz), 138.3,130.6 (d,3JCF= 8.2Hz),130.0,129.2,127.6,123.5(d,4JCF=2.9Hz), 116.5 (d,2JCF=20.0Hz), 115.2(d,2JCF=23.8Hz), 75.1,26.4；HRMS(ESI)for C15H12O3N2FS[M-H]-calcd 319.0558,found 319.0562.
Embodiment 12
The synthesis of compound 3ha：
4- methylphenylboronic acid 1a used in embodiment 1 are changed to into 3- methylphenylboronic acid 1h, remaining experimental implementation is same Embodiment 1.Product 3ha is obtained, is white solid, 96% yield, 94%ee.
1H NMR(300MHz,CDCl3)δ7.54–7.43(m,2H),7.40–7.33(m, 3H),7.27–7.13(m,4H),5.17(s,1H),3.17(s,3H),2.33(s,3H)；13C NMR(100 MHz,CDCl3)δ168.7,138.9,138.3,138.1,130.2,129.3,128.9,128.1,127.7,124.8, 75.6,26.3,21.6；HRMS(ESI)for C16H15O3N2S[M-H]-calcd 315.0809,found 315.0817.
Embodiment 13
The synthesis of compound 3ha '：
Phosphorus alkene part (R) -4t used in embodiment 12 is changed to into (S) -4t, remaining experimental implementation is with embodiment 12. Product 3ha ' is obtained, is white solid, 97% yield, -94%ee.
1H NMR(300MHz,CDCl3)δ7.55–7.43(m,2H),7.41–7.32(m, 3H),7.28–7.13(m,4H),5.20(s,1H),3.16(s,3H),2.34(s,3H)；13C NMR(100 MHz,CDCl3)δ168.8,139.0,138.4,138.0,130.1,129.4,128.9,128.1,127.8,124.8, 75.7,26.2,21.5；HRMS(ESI)for C16H15O3N2S[M-H]-calcd 315.0809,found 315.0817.
Embodiment 14
The synthesis of compound 3ia：
4- methylphenylboronic acid 1a used in embodiment 1 are changed to into 3- bromobenzeneboronic acid 1i, remaining experimental implementation is with real Apply example 1.Product 3ia is obtained, is white solid, 98% yield, 93%ee.
1H NMR(300MHz,CDCl3) δ 7.70 (s, 1H), 7.51 (t, J=8.4Hz, 2H), 7.44-7.32 (m, 5H), 7.26 (t, J=8.0Hz, 1H), 5.21 (s, 1H), 3.19 (s, 3H)；13C NMR(125MHz,CDCl3)δ168.1,139.9,138.2,132.5,130.7,130.4,129.7,129.3, 127.6,126.4,123.1,74.9,26.5；HRMS(ESI)for C15H13O3N2BrSNa[M+Na]+calcd 402.9722,found 402.9729.
Embodiment 15
The synthesis of compound 3ja：
4- methylphenylboronic acid 1a used in embodiment 1 are changed to into 2- naphthyl phenylboric acid 1j, remaining experimental implementation is same Embodiment 1.Product 3ja is obtained, is white solid, 98% yield, 94%ee.
1H NMR(300MHz,CDCl3) 8.03 (d, J=1.8Hz, 1H), 7.85- 7.74 (m, 3H), 7.55-7.47 (m, 2H), 7.47-7.39 (m, 3H), 7.35 (dt, J=4.9,2.6Hz, 3H),5.44(s,1H),3.13(s,3H)；13C NMR(125MHz,CDCl3)δ168.6,138.2,135.2, 133.3,132.8,129.4,129.04,129.01,128.7,127.8,127.7,127.3,127.1,126.9,124.8, 75.7,26.3；HRMS(ESI)for C19H15O3N2S[M-H]-calcd 351.0809,found 351.0814.
Embodiment 16
The synthesis of compound 3ka：
4- methylphenylboronic acid 1a used in embodiment 1 are changed to into 1- naphthyl phenylboric acid 1k, remaining experimental implementation is same Embodiment 1.Product 3ka is obtained, is white solid, 93% yield, 84%ee.
1H NMR(300MHz,CDCl3) δ 7.90 (d, J=8.0Hz, 1H), 7.85 (d, J =8.0Hz, 1H), 7.78 (d, J=7.0Hz, 1H), 7.66-7.46 (m, 4H), 7.44-7.21 (m, 5H), 5.60(s,1H),3.13(s,3H)；13C NMR(125MHz,CDCl3)δ167.7,138.5,135.3, 133.4,131.1,129.6,129.0,128.9,127.0,126.8,126.2,125.3,125.0,76.6,26.3； HRMS HRMS(ESI)for C19H15O3N2S[M-H]-calcd 351.0809,found 351.0811.
Embodiment 17
The synthesis of compound 3la：
4- methylphenylboronic acid 1a used in embodiment 1 are changed to into 2- methylphenylboronic acid 1l, remaining experimental implementation is same Embodiment 1.Product 3la is obtained, is white solid, 90% yield, 85%ee.
1H NMR(300MHz,CDCl3) δ 7.54 (dd, J=6.3,2.6Hz, 2H), 7.42 - 7.30 (m, 3H), 7.27 (d, J=7.6Hz, 2H), 7.17 (t, J=6.7Hz, 2H), 5.43 (s, 1H), 3.10 (s,3H),2.00(s,3H)；13C NMR(100MHz,CDCl3)δ168.3,137.6,137.1,136.8, 133.3,129.8,128.82,128.78,128.7,127.3,126.4,76.2,26.2,21.0；HRMS(ESI) for C16H15O3N2S[M-H]-calcd 315.0809,found 315.0815.
Embodiment 18
The synthesis of compound 3ma：
4- methylphenylboronic acid 1a used in embodiment 1 are changed to into 3 thienylboronic acid 1m, remaining experimental implementation is same Embodiment 1.Product 3ma is obtained, is white solid, 45% yield, 98%ee.
1H NMR(300MHz,CDCl3)δ7.71–7.57(m,2H),7.40–7.27(m, 4H), 6.29 (d, J=3.1Hz, 1H), 6.21 (d, J=3.3Hz, 1H), 5.53 (s, 1H), 3.09 (s, 3H)；13C NMR(125MHz,CDCl3)δ167.8,141.4,137.9,129.8,129.1,128.2,127.8, 127.4,127.1,72.7,26.5；HRMS(ESI)for C13H11O3N2S2[M-H]-calcd 307.0217, found 307.0222.
Embodiment 19
The synthesis of compound 3na：
4- methylphenylboronic acid 1a used in embodiment 1 are changed to into 3- furan boronic acid 1n, remaining experimental implementation is with real Apply example 1.Product 3na is obtained, is white solid, 72% yield, 98%ee.
1H NMR(300MHz,CDCl3)δ7.71–7.57(m,2H),7.40–7.27(m, 4H), 6.29 (d, J=3.1Hz, 1H), 6.21 (d, J=3.3Hz, 1H), 5.53 (s, 1H), 3.09 (s, 3H)；13C NMR(125MHz,CDCl3)δ166.2,149.5,144.4,134.5,129.6,128.8,127.1, 112.5,111.1,70.9,26.3；HRMS(ESI)for C13H11O4N2S[M-H]-calcd 291.0445, found 291.0451.
Embodiment 20
The synthesis of compound 3ob：
Under argon protection, by 4- (4- aminomethyl phenyls) -3- carbonyl -1,2,5- thiadiazoles substrate 2b (0.25mmol, 100 Mol%), phenylboric acid 1o (0.5mmol, 200mol%), [Rh (COE)2Cl]2(0.0075mmol,1.5 Mol%), during phosphorus alkene part (R) -4t (0.0075mmol, 3mol%) puts into reaction bulb, toluene (1 is added ML), at room temperature after stirring reaction 30min, the K of 2.5mol/L is added toward system3PO4Aqueous solution (0.1 ML), continue to react.After TLC monitoring reactions completely, reactant liquor is spin-dried for, is separated with silica gel column chromatography It is white solid to product 3ob, 96% yield, 94%ee.
1H NMR(300MHz,CDCl3)δ7.53–7.44(m,2H),7.41–7.35(m, 3H), 7.32 (d, J=8.3Hz, 2H), 7.18 (d, J=8.0Hz, 2H), 5.06 (s, 1H), 3.19 (s, 3H), 2.35(s,3H)；13C NMR(125MHz,CDCl3)δ168.9,139.5,138.2,135.5,129.8, 129.3,129.0,127.7,127.6,75.6,26.4,21.3；HRMS(ESI)for C16H17N2O3S[M+H]+ calcd 317.0954,found 317.0959.
Embodiment 21
The synthesis of compound 3bb：
Under argon protection, by 4- (4- aminomethyl phenyls) -3- carbonyl -1,2,5- thiadiazoles substrate 2b (0.25mmol, 100 Mol%), 4- chlorophenylboronic acids 1b (0.5mmol, 200mol%), [Rh (COE)2Cl]2(0.0075mmol,1.5 Mol%), during phosphorus alkene part (R) -4t (0.0075mmol, 3mol%) puts into reaction bulb, toluene (1 is added ML), at room temperature after stirring reaction 30min, the K of 2.5mol/L is added toward system3PO4Aqueous solution (0.1 ML), continue to react.After TLC monitoring reactions completely, reactant liquor is spin-dried for, is separated with silica gel column chromatography It is white solid to product 3bb, 95% yield, 95%ee.
1H NMR(300MHz,CDCl3) δ 7.51 (d, J=8.8Hz, 2H), 7.39- 7.32 (m, 2H), 7.19 (d, J=3.3Hz, 4H), 5.06 (s, 1H), 3.19 (s, 3H), 2.35 (s, 3H)；13C NMR(125MHz,CDCl3)δ168.6,139.9,136.2,135.6,135.5,130.0,129.2,129.1, 127.5,75.0,26.5,21.3；HRMS(ESI)for C16H16O3N2ClS[M+H]+calcd 351.0565, found 351.0558.
Embodiment 22
The synthesis of compound 3db：
Under argon protection, by 4- (4- aminomethyl phenyls) -3- carbonyl -1,2,5- thiadiazoles substrate 2b (0.25mmol, 100 Mol%), 4- fluorobenzoic boric acids 1d (0.5mmol, 200mol%), [Rh (COE)2Cl]2(0.0075mmol,1.5 Mol%), during phosphorus alkene part (R) -4t (0.0075mmol, 3mol%) puts into reaction bulb, toluene (1 is added ML), at room temperature after stirring reaction 30min, the K of 2.5mol/L is added toward system3PO4Aqueous solution (0.1 ML), continue to react.After TLC monitoring reactions completely, reactant liquor is spin-dried for, is separated with silica gel column chromatography It is white solid to product 3db, 94% yield, 94%ee.
1H NMR(300MHz,CDCl3) δ 7.53 (dd, J=8.7,5.2Hz, 2H), 7.24 (d, J=8.3Hz, 2H), 7.18 (d, J=8.2Hz, 2H), 7.07 (t, J=8.6Hz, 2H), 5.06 (s, 1H),3.19(s,3H),2.36(s,3H)；13C NMR(125MHz,CDCl3)δ168.8,163.2(d,1JCF =248.8Hz), 139.8,135.7,133.7,130.0,129.8 (d,3JCF=8.8Hz), 127.5,115.9 (d,2JCF=22.5Hz), 115.8,75.1,26.4,21.3；HRMS(ESI)for C16H16O3N2FS[M+H]+ calcd 335.0860,found 335.0856.
Embodiment 23
The synthesis of compound 3oc：
Under argon protection, by 4- (4- chlorphenyls) -3- carbonyl -1,2,5- thiadiazoles substrate 2c (0.25mmol, 100 Mol%), phenylboric acid 1o (0.5mmol, 200mol%), [Rh (COE)2Cl]2(0.0075mmol,1.5 Mol%), during phosphorus alkene part (R) -4t (0.0075mmol, 3mol%) puts into reaction bulb, toluene (1 is added ML), at room temperature after stirring reaction 30min, the K of 2.5mol/L is added toward system3PO4Aqueous solution (0.1 ML), continue to react.After TLC monitoring reactions completely, reactant liquor is spin-dried for, is separated with silica gel column chromatography It is white solid to product 3oc, 98% yield, 96%ee.
1H NMR(300MHz,CDCl3) δ 7.49 (d, J=8.7Hz, 2H), 7.44- 7.30(m,7H),5.13(s,1H),3.19(s,3H)；13C NMR(125MHz,CDCl3)δ168.4, 138.4,136.2,135.6,129.7,129.3,129.2,129.1,127.6,75.1,26.5；HRMS(ESI)for C15H14O3N2ClS[M+H]+calcd 337.0408,found 337.0404.
Embodiment 24
The synthesis of compound 3ac：
Under argon protection, by 4- (4- chlorphenyls) -3- carbonyl -1,2,5- thiadiazoles substrate 2c (0.25mmol, 100 Mol%), 4- methylphenylboronic acids 1a (0.5mmol, 200mol%), [Rh (COE)2Cl]2(0.0075mmol,1.5 Mol%), during phosphorus alkene part (R) -4t (0.0075mmol, 3mol%) puts into reaction bulb, toluene (1 is added ML), at room temperature after stirring reaction 30min, the K of 2.5mol/L is added toward system3PO4Aqueous solution (0.1 ML), continue to react.After TLC monitoring reactions completely, reactant liquor is spin-dried for, is separated with silica gel column chromatography It is white solid to product 3ac, 98% yield, 96%ee.
1H NMR(300MHz,CDCl3) δ 7.51 (d, J=8.8Hz, 2H), 7.39- 7.33 (m, 2H), 7.20 (d, J=3.3Hz, 4H), 5.07 (s, 1H), 3.19 (s, 3H), 2.36 (s, 3H)；13C NMR(100MHz,CDCl3)δ168.6,139.9,136.2,135.6,135.5,130.0,129.2,129.1, 127.5,75.0,26.5,21.3；HRMS(ESI)for C16H16O3N2ClS[M+H]+calcd 351.0565, found 351.0561.
Embodiment 25
The synthesis of compound 3od：
Under argon protection, by 4- (4- fluorophenyls) -3- carbonyl -1,2,5- thiadiazoles substrate 2d (0.25mmol, 100 Mol%), phenylboric acid 1o (0.5mmol, 200mol%), [Rh (COE)2Cl]2(0.0075mmol,1.5 Mol%), during phosphorus alkene part (R) -4t (0.0075mmol, 3mol%) puts into reaction bulb, toluene (1 is added ML), at room temperature after stirring reaction 30min, the K of 2.5mol/L is added toward system3PO4Aqueous solution (0.1 ML), continue to react.After TLC monitoring reactions completely, reactant liquor is spin-dried for, is separated with silica gel column chromatography It is white solid to product 3od, 94% yield, 97%ee.
1H NMR(300MHz,CDCl3) δ 7.51 (dd, J=9.1,5.1Hz, 2H), 7.38 (s, 5H), 7.07 (t, J=8.7Hz, 2H), 5.11 (s, 1H), 3.20 (s, 3H)；13C NMR(125MHz, CDCl3)δ168.6,163.2(d,1JCF=248.8Hz), 138.5,133.7,129.8 (d,3JCF=8.4Hz), 129.7,129.3,127.6,116.0(d,2JCF=21.3Hz), 75.1,26.5；HRMS(ESI)for C15H14O3N2FS[M+H]+calcd 321.0704,found 321.0706.
Embodiment 26
The synthesis of compound 3bd：
Under argon protection, by 4- (4- fluorophenyls) -3- carbonyl -1,2,5- thiadiazoles substrate 2d (0.25mmol, 100 Mol%), 4- chlorophenylboronic acids 1b (0.5mmol, 200mol%), [Rh (COE)2Cl]2(0.0075mmol,1.5 Mol%), during phosphorus alkene part (R) -4t (0.0075mmol, 3mol%) puts into reaction bulb, toluene (1 is added ML), at room temperature after stirring reaction 30min, the K of 2.5mol/L is added toward system3PO4Aqueous solution (0.1 ML), continue to react.After TLC monitoring reactions completely, reactant liquor is spin-dried for, is separated with silica gel column chromatography It is white solid to product 3bd, 95% yield, 96%ee.
1H NMR(300MHz,CDCl3) δ 7.48-7.32 (m, 6H), 7.08 (t, J= 8.6Hz,2H),5.12(s,1H),3.20(s,3H)；13C NMR(125MHz,CDCl3)δ168.3,163.3 (d,1JCF=250.0Hz), 136.4,135.9,133.8,129.8 (d,3JCF=8.5Hz), 129.3,129.1, 116.3(d,2JCF=21.3Hz), 74.5,26.5；HRMS(ESI)for C15H12O3N2ClFSNa[M+Na]+ calcd 377.0133,found 377.0141.
Embodiment 27
The synthesis of compound 3ad：
Under argon protection, by 4- (4- fluorophenyls) -3- carbonyl -1,2,5- thiadiazoles substrate 2d (0.25mmol, 100 Mol%), 4- methylphenylboronic acids 1a (0.5mmol, 200mol%), [Rh (COE)2Cl]2(0.0075mmol,1.5 Mol%), during phosphorus alkene part (R) -4t (0.0075mmol, 3mol%) puts into reaction bulb, toluene (1 is added ML), at room temperature after stirring reaction 30min, the K of 2.5mol/L is added toward system3PO4Aqueous solution (0.1 ML), continue to react.After TLC monitoring reactions completely, reactant liquor is spin-dried for, is separated with silica gel column chromatography It is white solid to product 3ad, 95% yield, 96%ee.
1H NMR(300MHz,CDCl3) δ 7.58-7.46 (m, 2H), 7.24 (d, J= 8.2Hz, 2H), 7.18 (d, J=8.4Hz, 2H), 7.12-6.99 (m, 2H), 5.05 (s, 1H), 3.19 (q, J =1.1Hz, 3H), 2.35 (s, 3H)；13C NMR(125MHz,CDCl3)δ168.8,163.2(d,1JCF= 247.5Hz),139.8,135.7,133.7,130.0,129.8(d,3JCF=8.8Hz), 127.5,115.9 (d,2JCF=21.3Hz), 115.8,75.1,26.4,21.3；HRMS(ESI)for C16H16O3N2FS[M+H]+ calcd 335.0860,found 335.0858.
Embodiment 28
The synthesis of compound 3ae：
Under argon protection, by 4- phenyl -3- ethyoxyl -1,2,5- thiadiazoles substrate 2e (0.25mmol, 100 Mol%), 4- methylphenylboronic acids 1a (0.5mmol, 200mol%), [Rh (COE)2Cl]2(0.0075mmol,1.5 Mol%), during phosphorus alkene part (R) -4t (0.0075mmol, 3mol%) puts into reaction bulb, toluene (1 is added ML), at room temperature after stirring reaction 30min, the KF aqueous solutions (0.167 of 1.5mol/L are added toward system ML), continue to react.After TLC monitoring reactions completely, reactant liquor is spin-dried for, is separated with silica gel column chromatography It is white solid to product 3ae, 95% yield, 99%ee.
1H NMR(300MHz,CDCl3) δ 7.40 (dt, J=4.6,1.9Hz, 5H), 7.25 (d, J=5.9Hz, 2H), 7.18 (d, J=8.1Hz, 2H), 4.87 (s, 1H), 4.51 (q, J=7.1Hz, 2H), 2.37 (s, 3H), 1.37 (t, J=7.1Hz, 3H)；13C NMR(100MHz,CDCl3)δ177.3, 139.4,138.2,135.4,129.7,129.3,128.9,127.9,127.8,70.1,21.3,13.9；HRMS (ESI)for C17H18O3N2NaS[M+Na]+calcd 353.0936,found 353.0927.
Embodiment 29
The synthesis of compound 3ae '：
Phosphorus alkene part (R) -4t used in embodiment 28 is changed to into (S) -4t, remaining experimental implementation is with embodiment 28. Product 3ae ' is obtained, is white solid, 95% yield, -98%ee.
1H NMR(300MHz,CDCl3) δ 7.41 (dt, J=4.6,1.9Hz, 5H), 7.24 (d, J=5.9Hz, 2H), 7.20 (d, J=8.1Hz, 2H), 4.88 (s, 1H), 4.50 (q, J=7.1Hz, 2H), 2.38 (s, 3H), 1.37 (t, J=7.1Hz, 3H)；13C NMR(100MHz,CDCl3)δ177.4, 139.4,138.3,135.3,129.8,129.4,129.0,127.9,127.9,70.2,21.4,13.9；HRMS (ESI)for C17H18O3N2NaS[M+Na]+calcd 353.0936,found 353.0927.
Embodiment 30
The synthesis of compound 3be：
4- methylphenylboronic acid 1a used in embodiment 28 are changed to into 4- chlorophenylboronic acid 1b, remaining experimental implementation is same Embodiment 28.Product 3be is obtained, is white solid, 95% yield, 98%ee.
1H NMR(300MHz,CDCl3)δ7.52–7.32(m,7H),7.32–7.24 (m, 2H), 5.14 (s, 1H), 4.51 (qd, J=7.0,3.3Hz, 2H), 1.37 (t, J=7.1Hz, 3H).13C NMR(100MHz,CDCl3)δ176.6,138.3,136.2,135.5,129.7,129.5,129.3,129.1, 127.7,70.4,13.9；HRMS(ESI)for C16H15O3N2NaSCl[M+Na]+calcd 373.0390, found 373.0400.
Embodiment 31
The synthesis of compound 3be '：
Phosphorus alkene part (R) -4t used in embodiment 30 is changed to into (S) -4t, remaining experimental implementation is with embodiment 30. Product 3be ' is obtained, is white solid, 95% yield, -98%ee.
1H NMR(300MHz,CDCl3)δ7.53–7.32(m,7H),7.31–7.24 (m, 2H), 5.15 (s, 1H), 4.50 (qd, J=7.0,3.3Hz, 2H), 1.37 (t, J=7.1Hz, 3H).13C NMR(100MHz,CDCl3)δ176.8,138.4,136.3,135.6,129.6,129.5,129.3,129.1, 127.8,70.5,13.9；HRMS(ESI)for C16H15O3N2NaSCl[M+Na]+calcd 373.0390, found 373.0400.
Embodiment 32
The synthesis of compound 3ce：
4- methylphenylboronic acid 1a used in embodiment 28 are changed to into 4- methoxyphenylboronic acid 1c, remaining experiment behaviour Make with embodiment 28.Product 3ce is obtained, is white solid, 97% yield, 98%ee.
1H NMR(300MHz,CDCl3) δ 7.39 (t, J=3.4Hz, 5H), 7.29 (d, J=8.8Hz, 2H), 6.88 (d, J=8.8Hz, 2H), 5.03 (s, 1H), 4.50 (q, J=7.1Hz, 2H), 3.81 (s, 3H), 1.36 (t, J=7.1Hz, 3H)；13C NMR(150MHz,CDCl3)δ177.4,160.3, 138.4,130.2,129.30,129.25,129.0,127.9,114.3,70.1,55.5,13.9；HRMS(ESI) for C17H18O4N2NaS[M+Na]+calcd 369.0885,found 369.0888.
Embodiment 33
The synthesis of compound 3ce '：
Phosphorus alkene part (R) -4t used in embodiment 32 is changed to into (S) -4t, remaining experimental implementation is with embodiment 32. Product 3ce ' is obtained, is white solid, 98% yield, -98%ee.
1H NMR(300MHz,CDCl3) δ 7.40 (t, J=3.4Hz, 5H), 7.30 (d, J=8.8Hz, 2H), 6.87 (d, J=8.8Hz, 2H), 5.05 (s, 1H), 4.51 (q, J=7.1Hz, 2H), 3.81 (s, 3H), 1.37 (t, J=7.1Hz, 3H)；13C NMR(150MHz,CDCl3)δ177.5,160.3, 138.4,130.3,129.3,129.2,129.0,128.0,114.3,70.2,55.6,13.9；HRMS(ESI)for C17H18O4N2NaS[M+Na]+calcd 369.0885,found 369.0888.
Embodiment 34
The synthesis of compound 3ge：
4- methylphenylboronic acid 1a used in embodiment 28 are changed to into 3- fluorobenzoic boric acid 1g, remaining experimental implementation is same Embodiment 28.Product 3ge is obtained, is white solid, 93% yield, 94%ee.
1H NMR(300MHz,CDCl3)δ7.47–7.35(m,4H),7.35–7.26 (m, 3H), 7.18 (d, J=10.0Hz, 1H), 7.10 (t, J=8.1Hz, 1H), 4.95 (s, 1H), 4.53 (qd, J=7.1,2.1Hz, 2H), 1.39 (t, J=7.1Hz, 3H)；13C NMR(150MHz,CDCl3)δ176.5, 162.8(d,1JCF=246.0Hz), 140.2 (d,3JCF=7.2Hz), 138.2,130.5 (d,3), J=8.2Hz 129.7,129.3,127.7,123.7(d,4J=2.9Hz), 116.4 (d,2JCF=21.0Hz), 115.5 (d,2JCF =24.0Hz), 70.4,13.9；HRMS(ESI)for C16H15O3N2NaSF[M+Na]+calcd 357.0685, found 357.0687.
Embodiment 35
The synthesis of compound 3ge '：
Phosphorus alkene part (R) -4t used in embodiment 34 is changed to into (S) -4t, remaining experimental implementation is with embodiment 34. Product 3ge ' is obtained, is white solid, 95% yield, -94%ee.
1H NMR(300MHz,CDCl3)δ7.46–7.36(m,4H),7.37–7.25 (m, 3H), 7.20 (d, J=10.0Hz, 1H), 7.11 (t, J=8.1Hz, 1H), 4.97 (s, 1H), 4.53 (qd, J=7.1,2.1Hz, 2H), 1.39 (t, J=7.1Hz, 3H)；13C NMR(150MHz,CDCl3)δ176.6, 162.8(d,1JCF=246.0Hz), 140.3 (d,3JCF=7.2Hz), 138.2,130.6 (d,3), J=8.2Hz 129.7,129.43,127.8,123.7(d,4J=2.9Hz), 116.5 (d,2JCF=21.0Hz), 115.5 (d,2JCF=24.0Hz), 70.5,13.9；HRMS(ESI)for C16H15O3N2NaSF[M+Na]+calcd 357.0685,found 357.0687.
Embodiment 36
The synthesis of compound 3he：
4- methylphenylboronic acid 1a used in embodiment 28 are changed to into 3- methylphenylboronic acid 1h, remaining experimental implementation With embodiment 28.Product 3he is obtained, is white solid, 92% yield, 98%ee.
1H NMR(300MHz,CDCl3) δ 7.40 (dd, J=10.7,5.0Hz, 5H), 7.26 (dd, J=9.0,5.9Hz, 1H), 7.16 (dd, J=16.0,9.2Hz, 3H), 4.88 (s, 1H), 4.51 (q, J=7.1Hz, 2H), 2.34 (s, 3H), 1.37 (t, J=7.1Hz, 3H)；13C NMR(125MHz,CDCl3) δ177.2,139.0,138.3,138.1,130.1,129.3,128.9,128.3,127.9,125.0,70.1,21.7, 13.9；HRMS(ESI)for C17H18O3N2NaS[M+Na]+calcd 353.0936,found 353.0927.
Embodiment 37
The synthesis of compound 3je：
4- methylphenylboronic acid 1a used in embodiment 28 are changed to into 2- naphthalene boronic acids 1j, remaining experimental implementation is with real Apply example 28.Product 3je is obtained, is white solid, 72% yield, 96%ee.
1H NMR(300MHz,CDCl3) δ 8.00 (s, 1H), 7.84 (d, J=8.4Hz, 3H), 7.54 (dd, J=9.1,5.3Hz, 2H), 7.45-7.32 (m, 6H), 5.01 (s, 1H), 4.54 (q, J= 7.1Hz, 2H), 1.38 (t, J=7.1Hz, 3H)；13C NMR(150MHz,CDCl3)δ177.1,138.3, 135.2,133.4,132.9,129.5,129.1,128.9,128.8,127.9,127.7,127.6,127.4,127.0, 125.1,70.3,13.9；HRMS(ESI)for C20H18O3N2NaS[M+Na]+calcd 389.0936,found 389.0938.
Embodiment 38
The synthesis of compound 3me：
4- methylphenylboronic acid 1a used in embodiment 28 are changed to into 3 thienylboronic acid 1m, remaining experimental implementation is same Embodiment 28.Product 3me is obtained, is white solid, 87% yield, 98%ee.
1H NMR(300MHz,CDCl3)δ7.50–7.44(m,1H),7.44–7.30(m, 6H), 6.99 (dd, J=5.0,0.9Hz, 1H), 5.01 (s, 1H), 4.51 (q, J=7.1Hz, 2H), 1.38 (t, J =7.1Hz, 3H)；13C NMR(125MHz,CDCl3)δ176.7,138.5,138.1,129.6,129.2, 127.4,127.3,126.8,125.7,74.9,70.2,13.9；HRMS(ESI)for C14H14O3N2NaS2 [M+Na]+calcd 345.0344,found 345.0338.
Embodiment 39
The synthesis of compound 3ne：
4- methylphenylboronic acid 1a used in embodiment 28 are changed to into 3- furan boronic acid 1n, remaining experimental implementation is same Embodiment 28.Product 3ne is obtained, is white solid, 50% yield, 84%ee.
1H NMR(300MHz,CDCl3)δ7.58–7.59(m,1H),7.47–7.48(m, 1H),7.41-7.43(m,5H),6.36-6.37(m,1H),4.99(s,1H),4.47-4.57(m,2H),1.39(t, J=7.2Hz, 3H)；13C NMR(125MHz,CDCl3)δ176.7,144.4,142.4,137.4,129.7, 129.3,127.1,124.0,109.7,72.1,70.2,13.9.
Embodiment 40
The synthesis of compound 3pe：
4- methylphenylboronic acid 1a used in embodiment 28 are changed to into 2- benzofuran boronic acids 1p, remaining experiment behaviour Make with embodiment 28.Product 3pe is obtained, is white solid, 80% yield, 89%ee.
1H NMR(300MHz,CDCl3)δ7.79(s,1H),7.48–7.55(m,3H), 7.35-7.43 (m, 3H), 7.31 (t, J=6.9Hz, 1H), 7.14-7.22 (m, 2H), 5.12 (s, 1H), 4.47-4.55 (m, 2H), 1.33 (t, J=7.5Hz, 3H)；13C NMR(125MHz,CDCl3)δ176.5, 156.3,145.5,136.1,129.8,129.3,127.3,125.4,124.8,123.4,121.2,118.9,112.2, 72.3,70.4,13.9.
Embodiment 41
The synthesis of compound 3cf：
Under argon protection, by 4- (4- methyl) -3- ethyoxyl -1,2,5- thiadiazoles substrate 2f (0.25mmol, 100 Mol%), 4- methoxyphenylboronic acids 1c (0.5mmol, 200mol%), [Rh (COE)2Cl]2(0.0075mmol, 1.5mol%), during phosphorus alkene part (R) -4t (0.0075mmol, 3mol%) puts into reaction bulb, toluene is added (1mL), at room temperature after stirring reaction 30min, the KF aqueous solutions (0.167 of 1.5mol/L are added toward system ML), continue to react.After TLC monitoring reactions completely, reactant liquor is spin-dried for, is separated with silica gel column chromatography It is white solid to product 3cf, 93% yield, 98%ee.
1H NMR(300MHz,CDCl3)δ7.39–7.23(m,4H),7.18(d,J =8.1Hz, 2H), 6.88 (d, J=8.9Hz, 2H), 4.98 (s, 1H), 4.49 (q, J=7.1Hz, 2H), 3.80 (s, 3H), 2.36 (s, 3H), 1.36 (t, J=7.1Hz, 3H)；13C NMR(150MHz,CDCl3)δ177.6, 160.2,139.4,135.6,130.2,129.7,129.3,127.7,114.2,70.0,55.5,21.2,13.9； HRMS(ESI)for C18H20O4N2NaS[M+Na]+calcd 383.1041,found 383.1050.
Embodiment 42
The synthesis of compound 3df：
Under argon protection, by 4- (4- methyl) -3- ethyoxyl -1,2,5- thiadiazoles substrate 2f (0.25mmol, 100 Mol%), 4- fluorobenzoic boric acids 1d (0.5mmol, 200mol%), [Rh (COE)2Cl]2(0.0075mmol,1.5 Mol%), during phosphorus alkene part (R) -4t (0.0075mmol, 3mol%) puts into reaction bulb, toluene (1 is added ML), at room temperature after stirring reaction 30min, the KF aqueous solutions (0.167 of 1.5mol/L are added toward system ML), continue to react.After TLC monitoring reactions completely, reactant liquor is spin-dried for, is separated with silica gel column chromatography It is white solid to product 3df, 92% yield, 96%ee.
1H NMR(300MHz,CDCl3)δ7.45–7.50(m,2H),7.15-7.21 (m,4H),7.04-7.10(m,2H),4.89(s,1H),4.47-4.55(m,2H),2.37(s,3H),1.37(t,J =7.5Hz, 3H)；13C NMR(150MHz,CDCl3) δ 177.1,163.2 (J=247.5Hz), 139.7, (J=2.5Hz), 135.6,133.6 130.1,129.9 (J=10Hz), 127.6,115.8 (J=21.25Hz), 70.2,21.2,13.9.
Embodiment 43
The synthesis of compound 3og：
Under argon protection, by 4- (4- chlorine) -3- ethyoxyl -1,2,5- thiadiazoles substrate 2g (0.25mmol, 100 Mol%), phenylboric acid 1o (0.5mmol, 200mol%), [Rh (COE)2Cl]2(0.0075mmol,1.5 Mol%), during phosphorus alkene part (R) -4t (0.0075mmol, 3mol%) puts into reaction bulb, toluene (1 is added ML), at room temperature after stirring reaction 30min, the KF aqueous solutions (0.167 of 1.5mol/L are added toward system ML), continue to react.After TLC monitoring reactions completely, reactant liquor is spin-dried for, is separated with silica gel column chromatography It is white solid to product 3og, 98% yield, 94%ee.
1H NMR(300MHz,CDCl3)δ7.27–7.31(m,2H),7.35-7.45(m, 7H), 4.94 (s, 1H), 4.47-4.58 (m, 2H), 1.38 (t, J=7.2Hz, 3H)；13C NMR(150MHz, CDCl3)δ176.7,138.3,136.3,135.5,129.7,129.5,129.3,129.1,127.7,77.0,70.4, 13.9.
Embodiment 44
The synthesis of compound 3cg：
Under argon protection, by 4- (4- chlorine) -3- ethyoxyl -1,2,5- thiadiazoles substrate 2g (0.25mmol, 100 Mol%), 4- methoxyphenylboronic acids 1c (0.5mmol, 200mol%), [Rh (COE)2Cl]2(0.0075mmol, 1.5mol%), during phosphorus alkene part (R) -4t (0.0075mmol, 3mol%) puts into reaction bulb, toluene is added (1mL), at room temperature after stirring reaction 30min, the KF aqueous solutions (0.167 of 1.5mol/L are added toward system ML), continue to react.After TLC monitoring reactions completely, reactant liquor is spin-dried for, is separated with silica gel column chromatography It is white solid to product 3cg, 94% yield, 98%ee.
1H NMR(300MHz,CDCl3) δ 7.44 (d, J=8.8Hz, 2H), 7.36 (d, J=8.8Hz, 2H), 7.19 (d, J=8.9Hz, 2H), 6.89 (d, J=8.9Hz, 2H), 5.05 (s, 1H), 4.51 (pd, J=7.5,3.3Hz, 2H), 3.82 (s, 3H), 1.37 (t, J=7.1Hz, 3H)；13C NMR(150 MHz,CDCl3)δ176.9,160.4,136.4,135.4,130.3,129.5,129.1,129.0,114.6,70.3, 55.6,13.9；HRMS(ESI)for C17H17O4N2NaSCl[M+Na]+calcd 403.0495,found 403.0496.
Embodiment 45
The synthesis of compound 3dg：
Under argon protection, by 4- (4- chlorine) -3- ethyoxyl -1,2,5- thiadiazoles substrate 2g (0.25mmol, 100 Mol%), 4- fluorobenzoic boric acids 1d (0.5mmol, 200mol%), [Rh (COE)2Cl]2(0.0075mmol,1.5 Mol%), during phosphorus alkene part (R) -4t (0.0075mmol, 3mol%) puts into reaction bulb, toluene (1 is added ML), at room temperature after stirring reaction 30min, the KF aqueous solutions (0.167 of 1.5mol/L are added toward system ML), continue to react.After TLC monitoring reactions completely, reactant liquor is spin-dried for, is separated with silica gel column chromatography It is white solid to product 3dg, 95% yield, 98%ee.
1H NMR(300MHz,CDCl3) δ 7.46-7.21 (m, 6H), 7.08 (t, J= 8.6Hz, 2H), 5.28 (s, 1H), 4.52 (q, J=7.1Hz, 2H), 1.38 (t, J=7.1Hz, 3H)；13C NMR(125MHz,CDCl3)δ176.4,163.3(d,1JCF=248.8Hz), 136.4,135.8,133.8, 129.9(d,3J=8.5Hz), 129.3 (d,4J=1.8Hz), 116.2 (d,2JCF=21.3Hz), 70.5,13.9； HRMS(ESI)for C16H14O3N2NaSClF[M+Na]+calcd 391.0295,found 391.0292.
Embodiment 46
The synthesis of compound 3ch：
Under argon protection, by 4- (3- chlorine) -3- ethyoxyl -1,2,5- thiadiazoles substrate 2h (0.25mmol, 100 Mol%), 4- methoxyphenylboronic acids 1c (0.5mmol, 200mol%), [Rh (COE)2Cl]2(0.0075mmol, 1.5mol%), during phosphorus alkene part (R) -4t (0.0075mmol, 3mol%) puts into reaction bulb, toluene is added (1mL), at room temperature after stirring reaction 30min, the KF aqueous solutions (0.167 of 1.5mol/L are added toward system ML), continue to react.After TLC monitoring reactions completely, reactant liquor is spin-dried for, is separated with silica gel column chromatography It is white solid to product 3ch, 96% yield, 97%ee.
1H NMR(300MHz,CDCl3)δ7.58–7.29(m,4H),7.20(d,J =8.5Hz, 2H), 6.89 (d, J=8.5Hz, 2H), 5.05 (s, 1H), 4.52 (dt, J=6.3,4.8Hz, 2H), 3.82 (s, 3H), 1.38 (t, J=7.0Hz, 3H)；13C NMR(150MHz,CDCl3)δ176.7,160.5, 139.9,134.9,130.1,129.5,129.1,128.3,126.2,114.6,70.4,55.6,13.9；HRMS (ESI)for C17H17O4N2NaSCl[M+Na]+calcd 403.0495,found 403.0496.
Embodiment 47
The synthesis of compound 3dh：
Under argon protection, by 4- (3- chlorine) -3- ethyoxyl -1,2,5- thiadiazoles substrate 2h (0.25mmol, 100 Mol%), 4- fluorobenzoic boric acids 1d (0.5mmol, 200mol%), [Rh (COE)2Cl]2(0.0075mmol,1.5 Mol%), during phosphorus alkene part (R) -4t (0.0075mmol, 3mol%) puts into reaction bulb, toluene (1 is added ML), at room temperature after stirring reaction 30min, the KF aqueous solutions (0.167 of 1.5mol/L are added toward system ML), continue to react.After TLC monitoring reactions completely, reactant liquor is spin-dried for, is separated with silica gel column chromatography It is white solid to product 3dh, 98% yield, 97%ee.
1H NMR(300MHz,CDCl3) δ 7.48-7.27 (m, 6H), 7.09 (t, J= 8.6Hz, 2H), 4.94 (s, 1H), 4.54 (q, J=7.1Hz, 2H), 1.39 (t, J=7.1Hz, 3H)；13C NMR(150MHz,CDCl3)δ176.2,163.3(d,1JCF=249.0Hz), 139.9,135.2,133.6 (d,4), J=3.1Hz 130.4,129.9 (d,3), J=6.6Hz 128.1,126.0,116.3 (d,2JCF=21.0Hz), 70.6,13.9；HRMS(ESI)for C16H14O3N2NaSClF[M+Na]+calcd 391.0295,found 391.0301.
Embodiment 48
The synthesis of compound 4a：
Under argon protection, Lithium Aluminium Hydride (0.4mmol, 200mol%) and tetrahydrofuran (2mL) are added into reaction In bottle, it is placed at 0 DEG C, during compound 3aa (0.2mmol, 100mol%) is added to into system, then heats (70 DEG C) of backflow is reacted three hours.After TLC monitoring reactions completely, reaction bulb is placed under ice bath, successively Reaction is quenched with water, 10% sodium hydroxide solution, aqueous layer with ethyl acetate is extracted three times, merges organic faciess, Anhydrous sodium sulfate drying, pressurization removes solvent, and the isolated product 4a of Jing silica gel column chromatographies, is white solid, 88% yield, 96%ee.
1H NMR(300MHz,CDCl3) δ 7.36 (d, J=7.9Hz, 2H), 7.34- 7.17 (m, 5H), 7.12 (d, J=8.0Hz, 2H), 2.84 (d, J=4.9Hz, 3H), 2.33 (s, 3H), 2.16 (s,2H)；13C NMR(100MHz,CDCl3)174.5,145.5,142.3,137.3,129.1,128.4, 127.6,127.5,127.4,68.0,26.7,21.2；HRMS(ESI)for C16H19ON2[M+H]+calcd 255.1492,found 255.1490.
Embodiment 49
The synthesis of compound 4b：
Compound 3aa used in embodiment 48 is changed to into compound 3ia, remaining experimental implementation is with embodiment 48. Product 4b is obtained, is white solid, 86% yield.
1H NMR(300MHz,CDCl3) δ 7.56 (s, 1H), 7.42 (d, J=7.7Hz, 1H), 7.38-7.27 (m, 6H), 7.19 (t, J=7.8Hz, 1H), 2.85 (d, J=4.9Hz, 3H), 2.04 (s, 3H)；13C NMR(125MHz,CDCl3)δ173.7,147.6,144.5,130.7,130.6,130.0,128.6, 127.8,127.5,126.7,122.6,67.9,26.7；HRMS(ESI)for C15H16ON2Br[M+H]+calcd 319.0441,found 319.0436.
Embodiment 50
The synthesis of compound 5a：
Under nitrogen protection, compound 4b (0.2mmol, 100mol%) is dissolved in tetrahydrofuran (2mL), Be placed at 0 DEG C, be slowly added to successively triphosgene (0.2mmol, 100mol%) and triethylamine (1.0mmol, 500mol%), it is warming up under room temperature and reacts 12 hours.After TLC monitoring reactions completely, to reaction system Middle addition frozen water is quenched reaction, and aqueous layer with ethyl acetate is extracted three times, merges organic faciess, and anhydrous sodium sulfate is done Dry, pressurization removes solvent, and the isolated product 5a of Jing silica gel column chromatographies is white solid, 71% yield.
1H NMR(300MHz,CDCl3) δ 7.57 (d, J=1.4Hz, 1H), 7.49 (d, J=7.8Hz, 1H), 7.44-7.30 (m, 6H), 7.23 (d, J=7.8Hz, 1H), 6.70 (s, 1H), 3.10 (s, 3H)；13C NMR(125MHz,CDCl3)δ173.0,156.7,141.3,138.7,132.0,130.5,130.0, 129.2,129.0,126.8,125.9,123.1,69.9,25.3；HRMS(ESI)for C16H14O2N2Br [M+H]+calcd 345.0233,found 345.0229.
Embodiment 51
The synthesis of compound 6a：
Under nitrogen protection, by compound 5a (0.2mmol, 100mol%) and Lawesson reagents (0.4mmol, In 200mol%) being dissolved in toluene (5mL), it is heated to reflux (110 DEG C) and reacts 12 hours.TLC monitoring reactions After completely, removal of solvent under reduced pressure, the isolated product 6a of Jing silica gel column chromatographies is white solid, 95% Yield, 93%ee.
1H NMR(300MHz,CDCl3)δ8.25(s,1H),7.59–7.45(m,2H), 7.42–7.34(M,3H),7.33–7.20(m,4H),3.33(s,3H)；13C NMR(125MHz,CDCl3) δ183.0,173.1,140.0,137.5,132.3,130.6,130.0,129.4,126.9,125.8,123.2,71.9, 28.3；HRMS(ESI)for C16H14ON2BrS[M+H]+calcd 361.0005found 360.9999.
Embodiment 52
The synthesis of compound 7a：
Under nitrogen protection, by compound 6a (0.2mmol, 100mol%), 3- methoxyphenylboronic acids (0.3mmol, 150mol%) it is dissolved in toluene (5mL) and ethanol (1mL) with tetra-triphenylphosphine palladium (0.02mmol, 10mol%) In, the aqueous sodium carbonate (0.2mL, 200mol%) of 2mol/L is subsequently added, heat (80 DEG C) reactions 5 little When.After TLC monitoring reactions completely, add water and reaction is quenched, aqueous layer with ethyl acetate is extracted three times (3 × 20 ML), organic faciess are merged, Jing after anhydrous sodium sulfate drying, removal of solvent under reduced pressure, silica gel column chromatography is separated It is white solid to product 7a, 92% yield, 93%ee.
1H NMR(300MHz,CDCl3)δ8.08-8.13(m,1H),7.53-7.58 (m, 2H), 7.29-7.46 (m, 7H), 7.08 (d, J=7.5Hz, 1H), 7.03 (s, 1H), 6.88 (d, J=8.1 Hz,1H),5.30(s,1H),3.83(s,3H),3.34(s,3H)；HRMS(ESI)for C23H21O2N2S [M+H]+calcd 389.1324found 389.1329.
Embodiment 53
The synthesis of BACE-1 inhibitor：
Under nitrogen protection, compound 7a (0.2mmol, 100mol%) is dissolved in methanol (2mL), then according to Secondary addition t-butylperoxy alcohol (1mL) and ammonia (1mL), heat (50 DEG C) and react 12 hours.TLC is monitored After reaction completely, add water and reaction is quenched, water layer extracts three times (3 × 20mL) with dichloromethane, merge organic Phase, Jing after anhydrous sodium sulfate drying, removal of solvent under reduced pressure, the isolated product BACE-1 of silica gel column chromatography Inhibitor, is white solid, 81% yield.
1H NMR(300MHz,CDCl3)δ7.70(s,1H),7.44-7.49(m,4H), 7.29-7.40 (m, 5H), 7.13 (d, J=8.1Hz, 1H), 7.08 (s, 1H), 6.87 (d, J=8.1Hz, 1H), 3.83(s,3H),3.60(s,2H),3.11(s,3H)；HRMS(ESI)for C23H22O2N3[M+H]+calcd 372.1712found 372.1709.
The all documents referred in the present invention are all incorporated as in this application reference, just as each document It is individually recited as with reference to such.In addition, it is to be understood that after the above-mentioned teachings for having read the present invention, Those skilled in the art can make various changes or modifications to the present invention, and these equivalent form of values equally fall within this Shen Please appended claims limited range.

Claims (10)

1. the method for a kind of formula 3 and/or the compound containing quaternary carbon chiral centre shown in formula ent-3, it is special Levy and be, including step：
Under oxygen free condition, in organic solvent, match somebody with somebody with chiral phosphorus alkene in additive and monovalence rhodium metal compound In the presence of the composition catalyst that body is formed, asymmetric adding is carried out with the organoboron reagent and the substrate of formula 2 of formula 1 Into reaction, formula 3 and/or the compound containing quaternary carbon chiral centre shown in formula ent-3 are obtained：
In formula,
R1It is selected from the group：Substituted or unsubstituted C6-30Aryl, substituted or unsubstituted C4-12Heteroaryl, its In, described replacement refers to that the hydrogen atom on group is replaced by one or more (such as 1-5) substituent groups, described The hetero atom that contains of heteroaryl be oxygen or sulfur；
Described substituent group is selected from the group：Halogen, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl, C1-6 Halogenated alkoxy, benzyloxy, unsubstituted or substituted C6-10Aryl or its combination；The halogen be F, Cl, Br or I；
R2It is nothing, or C1-6Alkyl；
R3It is selected from the group：Substituted or unsubstituted C6-30Aryl, substituted or unsubstituted C4-12Heteroaryl, its In, described replacement refers to that the hydrogen atom on group is replaced by one or more (such as 1-5) substituent groups, described The hetero atom that contains of heteroaryl be oxygen or sulfur；
Described substituent group is selected from the group：Halogen, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl, C1-6 Halogenated alkoxy, benzyloxy, unsubstituted or substituted C6-10Aryl or its combination；The halogen be F, Cl, Br or I；
R4It is nothing or C1-3Straight or branched alkyl；
[B] is selected from the group：B(OR)2Or (BO)3, wherein R is H or C1-3Straight or branched alkyl；
Dotted line represents chemical bond or does not exist.
2. the method for claim 1, it is characterised in that replace -3- oxo -1 by compound 4-, 2,5- The use gauge of thiadiazole substrate 2, described monovalence rhodium metal catalyst consumption is 1～30mol%；And/or Described chiral phosphorus alkene part consumption is 1～30mol%.
3. the method for claim 1, it is characterised in that described chiral phosphorus alkene part has as follows Structural formula (preferably, described Formulas I and Formula II each other enantiomer)：
In formula,
R6And R7Connection forms substituted or unsubstituted-(CH2)n-, wherein, n is 3 or 4, or coupled Carbon atom connect to form substituted or unsubstituted phenyl, wherein, described replacement refers to that hydrogen on group is former Son is replaced by one or more (such as 1-5) substituent groups, and described substituent group is selected from the group：It is halogen, unsubstituted Or C by one or more halogen substiuteds1-6Alkyl, or it is unsubstituted or by one or more halogen substiuteds C1-6Alkoxyl；
R8For H or substituted or unsubstituted C6-30Aryl, wherein, described replacement is the hydrogen atom on group Replaced by one or more (such as 1-5) substituent groups, described substituent group is selected from the group：It is halogen, unsubstituted Or by the C of one or more halogen substiuteds1-6Alkyl, or it is unsubstituted or by one or more halogen substiuteds C1-6Alkoxyl；
R9It is the group being selected from the group on phenyl ring optional position：It is hydrogen, halogen, unsubstituted or by one The C of individual or multiple halogen substiuteds1-6Alkyl, or C unsubstituted or by one or more halogen substiuteds1-6Alcoxyl Base；
R5It is selected from the group：Hydrogen, halogen, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Alkane Epoxide, substituted or unsubstituted phenyl, naphthyl or other aryl, wherein, described replacement is referred on group Hydrogen atom replaced by one or more (such as 1-5) substituent groups, described substituent group is selected from the group：Halogen, C unsubstituted or by one or more halogen substiuteds1-6Alkyl is unsubstituted or by one or more halogens Substituted C1-6Alkoxyl.
4. the method for claim 1, it is characterised in that described chiral phosphorus alkene part is selected from the group：
5. the method for claim 1, it is characterised in that described monovalence rhodium metal compound is selected from The following group：[Rh(C2H4)2Cl]2、[Rh(C2H4)2OH]2、[Rh(COE)2Cl]2、[Rh(COE)2OH]2, or Its combination.
6. the method for claim 1, it is characterised in that in the described organoboron reagent of formula 1, [B] For B (OR)2Or (BO)3, wherein R is H or C1-3Straight or branched alkyl.
7. the method for claim 1, it is characterised in that described method also has what is be selected from the group One or more features：
(1) additive for reacting used is that concentration is the water-soluble of the salt being selected from the group of 0.5mol/L～5mol/L Liquid：KF、KOH、K2CO3、Na2CO3、K3PO4、K2HPO4；
(2) consumption of reaction additives is 50mol%～500mol%；
(3) react organic solvent used to be selected from the group：Dichloromethane (CH2Cl2), toluene (Toluene), chlorine Imitative (CHCl3), Isosorbide-5-Nitrae-dioxane (Dioxane), tetrahydrofuran (THF), or its combination；
(4) temperature of reaction is 0～100 DEG C；
(5) response time is 3～12 hours.
8. a kind of structural formula 3 or the compound shown in ent-3, it is characterised in that described compound has such as Lower structural formula：
Wherein, R1、R2、R3、R4Definition as described in the appended claim 1.
9. compound as claimed in claim 8, it is characterised in that the compound is selected from the group：
10. the purposes of formula as claimed in claim 83 or the compound shown in ent-3, it is characterised in that use In：
A () carries out open loop to the compound of formula 3, remove sulfonyl, so as to form the α, α-two of optical activity holding Arylamino amide 4；
B () carries out open loop to the compound of formula 3, so as to form α, α-ammonia diaryl base amide 4, subsequently cyclisation is formed 5,5-Diphenyl-2,4-imidazolidinedione analog 5, compound 5 again through thio and ammonification two-step reaction, so as to form the compound of formula 7；
It is above-mentioned it is various in, R1, R2, R3It is defined as above.
CN201510688829.XA 2015-10-21 2015-10-21 Synthetic method of chiral 1,2, 5-thiazolinone-1, 1-dioxide and 2, 3-dihydro-1, 2, 5-thiadiazole-1, 1-dioxide containing quaternary carbon Active CN106608859B (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1347412A (en) * 1999-04-22 2002-05-01 拜尔公司 O-aryl dithiazole dioxides
CN101003533A (en) * 2007-01-12 2007-07-25 南开大学 Derivative of thiadiazoles containing cyclo oxdiazole, synthetic method, and biological activity
WO2011162514A2 (en) * 2010-06-21 2011-12-29 한국화학연구원 Method for preparing [1,2,3]-oxathiazolidine-2,2-dioxide or [1,2,5]-thiadiazolidine-1,1-dioxide derivatives
CN104744514A (en) * 2013-12-27 2015-07-01 中国科学院上海药物研究所 Chiral phosphorus alkene ligand, synthesis method and application thereof in asymmetric reaction

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1347412A (en) * 1999-04-22 2002-05-01 拜尔公司 O-aryl dithiazole dioxides
CN101003533A (en) * 2007-01-12 2007-07-25 南开大学 Derivative of thiadiazoles containing cyclo oxdiazole, synthetic method, and biological activity
WO2011162514A2 (en) * 2010-06-21 2011-12-29 한국화학연구원 Method for preparing [1,2,3]-oxathiazolidine-2,2-dioxide or [1,2,5]-thiadiazolidine-1,1-dioxide derivatives
CN104744514A (en) * 2013-12-27 2015-07-01 中国科学院上海药物研究所 Chiral phosphorus alkene ligand, synthesis method and application thereof in asymmetric reaction

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
HUI WANG等: "Rhodium-Catalyzed Highly Enantioselective Arylation of Cyclic Diketimines: Efficient Synthesis of Chiral Tetrasubstituted 1,2,5-Thiadiazoline 1,1-Dioxides", 《ORG. LETT.》 *
SUN AH LEE等: "Highly enantioselective synthesis of cyclic sulfamidates and sulfamides via rhodium-catalyzed transfer hydrogenation", 《CHEM. COMMUN.》 *
TAKAHIRO NISHIMURA等: "Asymmetric synthesis of gem-diaryl substituted cyclic sulfamidates and sulfamides by rhodium-catalyzed arylation of cyclic ketimines", 《CHEM. COMMUN.》 *
ZEJUN XIAO等: "An improved procedure for the synthesis of 4,4-disubstituted 3-oxo-1,2,5-thiadiazolidine 1,1-dioxides", 《JOURNAL OF HETEROCYCLIC CHEMISTRY》 *
于月娜等: "手性膦烯配体在铑催化的芳基硼酸对β-芳基-α,β-不饱和磺酸酯不对称共轭加成反应中的应用", 《化学学报》 *

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