Embodiment
The object of the invention is for providing a kind of secondary alcohol preparation method; Comprise an organic boronic compound and an aldehyde compound are reacted in a reaction reagent to obtain the secondary alcohol compound, wherein reaction reagent comprise cobalt ion and with cobalt ion bonded bidentate ligand with as catalyzer.
Organic boronic compound of the present invention can comprise alkylboronic acids and/or aryl boric acid.Wherein, the organic boronic compound is preferably aryl boric acid, particularly phenylo boric acid.Phenylo boric acid has following general formula (1):
R wherein
1Be to be selected from down group: hydrogen, halogen, cyanic acid, fluoroform alkyl, amido, C
1-C
10Alkyl, C
2-C
10Thiazolinyl, C
2-C
10Alkynyl, C
3-C
20Naphthenic base, C
3-C
20Cycloalkenyl group, C
1-C
20Heterocyclylalkyl, C
1-C
20Heterocycloalkenyl, aryl and heteroaryl.
Aldehyde compound of the present invention has following general formula (2):
R wherein
2Be to be selected from down group: C
1-C
10Alkyl, C
2-C
10Thiazolinyl, C
2-C
10Alkynyl, C
3-C
20Naphthenic base, C
3-C
20Cycloalkenyl group, C
1-C
20Heterocyclylalkyl, C
1-C
20Heterocycloalkenyl, aryl and heteroaryl.
What should indicate at this is that alkyl, thiazolinyl, alkynyl, naphthenic base, cycloalkenyl group, Heterocyclylalkyl, heterocycloalkenyl, aryl and heteroaryl can comprise through replacing and without substituted group.
The substituting group that possibly be replaced in naphthenic base, cycloalkenyl group, Heterocyclylalkyl, heterocycloalkenyl, aryl and heteroaryl comprises but is not subject to C
1-C
10Alkyl, C
2-C
10Thiazolinyl, C
2-C
10Alkynyl, C
3-C
20Naphthenic base, C
3-C
20Cycloalkenyl group, C
1-C
20Heterocyclylalkyl, C
1-C
20Heterocycloalkenyl, C
1-C
10Alkoxyl group, aryl, aryloxy, heteroaryl, heteroaryloxy, amido, C
1-C
10Alkylamino radical, C
1-C
20Di alkylamino group, aryl amine, diaryl-amine base, C
1-C
10Alkyl sulfamoyl (C
1-C
10Alkylsulfonamino), aryl sulfonamide (arylsulfonamino), C
1-C
10Alkyl imines (C
1-C
10Alkylimino), aryl imine (arylimino), C
1-C
10Alkyl sulphur imines (C
1-C
10Alkylsulfonimino), aryl sulphur imines (arylsulfonimino), hydroxy, halogen, thio group (thio), C
1-C
10Alkylthio, arylthio, C
1-C
10Alkane alkylsulfonyl (alkylsulfonyl), arylsulfonyl (arylsulfonyl), acyl amine (acylamino), amido acyl (aminoacyl), amido sulfonyl (aminothioacyl), carboxamido-group (amido), amidino groups (amidino), guanidine radicals (guanidine), urea groups (ureido), thioureido (thioureido), itrile group, nitro, nitroso-group, repeatedly nitrogen base (azido), acyl group, sulfonyl, acyloxy (acyloxy), carboxyl, and carboxylicesters etc.The substituting group that on the other hand, possibly be replaced in alkyl, thiazolinyl or alkynyl comprises except that C
1-C
10Above-mentioned all substituting groups that alkyl is outer.Naphthenic base, cycloalkenyl group, Heterocyclylalkyl, heterocycloalkenyl, aryl and heteroaryl also can condense (fused) mutually.
Wherein, in one embodiment, reactant is that aryl boric acid and aryl aldehydes are to obtain diarylcarbinols (diaryl methanol).
Cobalt ion can be divalence or trivalent among the present invention, and wherein the preferably is a divalence.Wherein cobalt ion is by Co (acac)
2, CoI
2, CoBr
2Or CoCl
2Institute provides.
Bidentate ligand of the present invention can combine with cobalt ion with as catalyzer, and for example, bidentate ligand has phosphorus, nitrogen or oxygen.
For example, phosphorous bidentate ligand can comprise:
DPPE (1,2-bis (diphenylphosphino) ethane, 1, two (diphenylphosphine) ethane of 2-), (R)-Prophos ((R)-(+)-1,2-bis (diphenylphophino) propane; (R)-(+)-1, two (diphenylphosphine) propane of 2-), (R)-Tol-BINAP ((R)-(+)-2,2-Bis (di-p-tolylphosphino)-1,1-binaphthyl, (R)-(+)-2; Two (two-p-methylphenyl phosphines)-1 of 2-, 1-dinaphthalene), (S)-BINAP ((S)-(-)-2,2-Bis (diphenylphosphino)-1,1-binaphthyl, (S)-(-)-2; Two (diphenylphosphine)-1 of 2-, the 1-dinaphthalene), (S, S)-Chiraphos ((2S, 3S)-(-)-bis (diphenylphophino) butane, (2S; 3S)-(-)-two (diphenylphosphine) butane), (R, R)-BDPP ((2R, 4R)-(+)-2,4-bis (diphenylphophino) pentane), (2R; 4R)-(+)-2, two (diphenylphosphine) pentanes of 4-), (S, S)-BDPP ((2S, 4S)-(+)-2,4-bis (diphenylphophino) pentane); (2S, 4S)-(+)-2, two (diphenylphosphine) pentanes of 4-), (R, R)-Ph-BPE ((-)-1,2-Bis ((2R; 5R)-2,5-diphenylphospholano) ethane, (-)-1,2-pair ((2R, 5R)-2; The 5-diphenylphosphine) ethane), (R)-Quinap (isoquinoline of (R)-(+)-1-(2-diphenylphosphino-1-naphthyl), (R)-(+)-1-(2-diphenylphosphine-1-naphthyl) isoquinoline 99.9), (R)-MOP ((R)-(+)-2-(diphenylphosphino)-2-methoxy-1,1-binaphthyl, (R)-(+)-2-(diphenylphosphine)-2-methoxyl group-1; The 1-dinaphthalene), (S, S)-DIPAMP ((S, S)-1,2-Bis [(2-methoxyphenyl) (phenylphosphino)] ethane; (S, S)-1, two [(2-methoxyphenyl) (the Phenylphosphine)] ethane of 2-), ((R)-(-)-(3,5-Dioxa-4-phospha-cyclohepta [2 for (R)-Monophos; 1-a:3,4-a '] dinaphthalen-4-yl) dimethylamine, (R)-(-)-(3,5-dioxygen-4-phosphorus-ring heptan [2; 1-a:3,4-a '] two naphthalenes-4-yl) n n dimetylaniline), and (S, S)-DIOP ((4S, 5S)-(+)-4; 5-Bis (diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxolane, (4S; 5S)-(+)-4, two (the dimethyl phosphine methyl)-2 of 5-, 2-dimethyl--1,3-dioxolanes).
For example, nitrogenous bidentate ligand can comprise:
3,5-dimethyl-bispyrazolylmethane (3,5-dimethyl--two pyrazoles methane), 2,2 '-bipyridine (2; 2 '-two pyridines), and 1,1-bis [4,4-dimethyl-1,3-oxazolin-2-yl] ethane (1; Two [4, the 4-dimethyl--1,3-oxazoles-2-yl] ethane of 1-).
For example, containing the oxygen bidentate ligand can comprise:
(S)-BINOL ((S)-(-)-1,1 '-Bi (2-naphthol), (S)-(-)-1,1 '-two (beta naphthals)).
In addition, in one embodiment, reaction reagent preferably of the present invention is an alkalescence, and wherein preferably's alkalescence source is to be provided by salt of wormwood, but should be not as limit.
Please with reference to table 1 and following reaction formula, among one embodiment of the invention, the organic boronic compound is an aryl boric acid 1, and it can react with aldehyde compound 2, to obtain secondary alcohol 3 under cobalt ion and bidentate ligand existence.
The addition reaction result [a] of table 1, aryl boric acid and aldehydes
[a] is only if represent that especially the condition of carrying out that is responded is aryl boric acid 1 (1.20mmol), aldehydes 2 (1.00mmol), Co (acac)
2(5mol%), dppe (5mol%) and THF/CH
3CN (volume ratio 1: 1) was in 80 ℃ of reactions 12 hours.
[b] isolated yield.
Embodiment 3aa to 3as
Among above-mentioned reaction conditions, phenylo boric acid (1a) with have various substituent aromatic aldehydes, heterocycle aldehydes and fatty aldehydes and react the generation secondary alcohol.The phenyl aldehyde that wherein has electron-withdrawing group (for example has 4-NO
2Substituting group (2b), have 4-CHO substituting group (2c), have 4-CO
2Me substituting group (2d) and have 4-CF
3Substituting group (2e)) can produce diarylcarbinols 3ab-3ae, and have good yield (89-97%; Table 1 numbering 2-5).
Benzaldehyde derivative with halogenic substituent also is applicable to catalyzed reaction of the present invention.For example substituting group 4-F (2f), 3-F (2g), 2-F (2h), 4-Cl (2i) and 4-Br (2j) can react to generate relative diarylcarbinols 3af-3aj, the productive rate (please with reference to table 1 numbering 6-10) that its tool is good or excellent with phenylo boric acid (1a) effectively.
Identical ground; Phenyl aldehyde (2k), 1-naphthaldehyde (1-napthaldehyde; (2-napthaldehyde 2m) also can carry out addition reaction to generate product 3ak-3am and to have good yield (please with reference to table 1 numbering 11-13) with phenylo boric acid (1a) 2l), to reach the 2-naphthaldehyde.
Phenyl aldehyde (for example 4-Me (2n) and 4-OMe (2o)) with electron donating group also can carry out addition reaction and produce product 3an and 3ao, and its productive rate is moderate (please with reference to table 1 numbering 14 and 15).
The heterocycle aldehydes; Comprise 4-formylpyridine (4-formylpyridine; 2p), 2-formyl furans (2-formylfuran, 2q) and 2-formyl thiophene (2-formylthiophene, but 2r) also effecting reaction to obtain becoming to add product 3ap to 3ar; Its productive rate is respectively 76,69 and 78% (please with reference to table 1 numbering 16-18).
The fat aldehydes, for example (cyclohexanecarbaldehyde 2s), also can carry out addition reaction to obtain product 3as to cyclohexyl formaldehyde effectively, and its productive rate is 79% (please with reference to table 1 numbering 19).
Embodiment 3bd-3id
In addition, have among the present invention that various substituent aryl boric acids can (methyl 4-formylbenzoate 2d) reacts with the 4-acyl radical methyl benzoate.Its substituting group of aryl boric acid comprises that 4-Br (1b), 4-F (1c), 4-CHO (1d), 4-Me (1e), 4-OMe (1f), 2-OMe (1g) and 4-vinyl (1h) can react with generation with 2d and have substituent diarylcarbinols 3bd-3hd; Its productive rate is respectively 93; 93,84,92; 97,96 and 75% (with reference to table 1 numbering 20-26).
Learnt that by The above results addition reaction of the present invention is for various functional groups, for example Br, F, CHO, Me and OMe etc. all can be suitable for widely.
In addition, this catalyzed reaction also is applicable to the phenylo boric acid that has thiazolinyl.Wherein ((E)-styrylboronic acid 1i) obtains the allylic secondary alcohol of tool with the 2d reaction to (E)-styryl boric acid, and its productive rate is 78% (please with reference to table 1 numbering 27).
Embodiment: use different catalysts
At Co (acac)
2(5mol%), dppe (5mol%) is dissolved in THF/CH
3Among the CN (1: 1), phenylboronic acid (1a) and 4-cyanobenzaldehyde (2a) are in 80 ℃ of reactions of carrying out 12 hours, and to obtain adduct 3aa, productive rate is 96%.
In this reaction, need not add extra alkali, only need use the organic boronic of 1.2mmol.
Above-mentioned catalyzed reaction also can be used CoI
2Or CoCl
2(5mol%) and dppe (5mol%) as catalyzer, and use THF as solvent to obtain 3aa, its productive rate is 9697%, yet needs adding alkali K this moment
2CO
3(1.5 equivalent) is with activation boric acid.
The secondary alcohol that mapping is selected
Please with reference to table 2 and following reaction formula; Another object of the present invention provides a kind of enantioselectivity preparation method of secondary alcohol; It is by an organic boronic compound 1 and an aldehyde compound 2 are reacted in an organic solution to obtain the secondary alcohol compound 3 that mapping is selected, and wherein this organic solution comprises a cobalt ion and a chirality bidentate ligand.
Addition reaction result [a] is selected in the mapping of table 2, aryl boric acid and aldehydes
[a] except special expression, the condition of carrying out that is responded is aryl boric acid 1 (1.50mmol), aldehydes 2 (1.00mmol), CoI
2(5mol%), (R, R)-BDPP (5mol%), K
2CO
3(1.5 equivalent) and THF (2.0ml) were in 80 ℃ of reactions 12 hours.
[b] isolated yield.
[c] use (S, S)-BDPP.
Embodiment: the selection of ligand and cobalt ion
The applicable the present invention of the chiral ligand of numerous species, and test, comprise (R)-Prophos, (R)-Tol-BINAP, (S)-BINAP, (S; S)-Chiraphos, (S)-BINOL, (R; R)-Ph-BPE, (R)-Quinap, (R)-MOP, (S, S)-DIPAMP, (R)-Monophos, (R, R)-BDPP, (S; S)-BDPP and (S, S)-DIOP.The reaction conditions of test is that reactant is 1a and 2d, and cobalt ion is CoI
2(5mol%), two bud chiral ligands (5mol%) and K
2CO
3(1.5 equivalent), and solvent is THF.Among the ligand of test, (R, R)-the BDPP effect is best, and the diarylcarbinols (table 2 numbering 3) of (S) formula of 98% productive rate and 94%ee value can be provided; The productive rate that other ligand produces 3ad is 44-86%, and the ee value is 10-67%.
Among above-mentioned reaction conditions, (S, S)-BDPP can produce the diarylcarbinols 3ad of formula of another kind of enantiomer-(R), and its productive rate is 95%, and the ee value is 93% (table 2 numbering 4).
Other cobalt catalyst, Co (acac)
2/ (R, R)-BDPP, it can be among THF and do not need alkali to act on, and produces chirality (S)-3ad, and productive rate is 95%, and ee value is 93%, so also is an efficient catalyzer.
Embodiment 3aa-3as
Please with reference to table 2 and reaction formula, reaction conditions is CoI
2(5mol%)/(R, R)-BDPP (5mol%) and K
2CO
3(1.5 equivalent) and has various substituent aldehydes and phenylo boric acid (1a) carries out addition reaction among THF solution.
The phenyl aldehyde that wherein has electron-withdrawing group (for example has 4-CN substituting group (2a), has 4-NO
2Substituting group (2b), has 4-CO
2Me substituting group (2d) and have 4-CF
3Substituting group (2e)) can produce the chirality diarylcarbinols 3ab to 3ae of (S) formula, it has good productive rate and is respectively 97,95,98 and 97%; And has good ee value than being respectively 92,93,94 and 92% (please with reference to table 2 numbering 1-3,5).
In addition, if use CoI
2/ (S, S)-BDPP carries out the reaction of 1d and 2d as catalyzer, and then as predictably producing (R)-3ad, its ee value is 93% (please numbering 4 with reference to table 2).
As above-mentioned; Using CoI/ (R; R)-situation of BDPP as catalyzer among; Having substituting group 4-F (2f), 4-Cl (2i) and the substituent phenyl aldehyde of 4-Br (2j) can react to generate relative diarylcarbinols 3af, 3ai and 3aj with phenylo boric acid (1a) effectively, and the good ee value of its tool is respectively 99,93 and 96%.(please with reference to table 2, numbering 6-8).
In like manner; 1-naphthaldehyde (1-napthaldehyde; 2l), the 2-naphthaldehyde (2-napthaldehyde, 2m), (2-formylthiophene 2r) reacts diarylcarbinols 3al, 3am, 3an, 3ao and the 3ar that can obtain (S) formula for 4-Me (2n), 4-OMe (2o) and 2-formyl thiophene; Its productive rate is 77-90%, and the ee value is 86-93% (please with reference to table 2 numbering 9-13).
In addition, cyclohexyl formaldehyde (2s) can produce (R)-3as, and its productive rate is 84%, the ee value is 97% (please with reference to table 2 numbering 14).
Embodiment 3bd, 3ed, 3fd and 3gd:
In addition, have among the present invention that various substituent aryl boric acids can (methyl 4-formylbenzoate 2d) reacts with the 4-acyl radical methyl benzoate.Its substituting group of aryl boric acid comprises that 4-Br (1b), 4-Me (1e), 4-OMe (1f) and 2-OMe (1g) are to produce diarylcarbinols 3bd, 3ed, 3fd and 3gd; And have good productive rate and be respectively 92-99% and high ee value and be respectively 90-94% (please with reference to table 2, numbering 15,19-21).
In addition, to be (R)-3bk the be enantiomer (table 2 numbering 8) of (S)-3aj that should indicate, wherein (S)-3aj's is by phenylo boric acid (1a) and 4-bromobenzaldehyde (2j) and uses identical chirality CoI
2/ (R, R)-BDPP catalyzer gained.Identical also has, (R)-and 3ek (table 2 numbering 17) is the enantiomer of (S)-3an (table 2 numbering 11); And (R)-3fk (table 2 numbering 18) is the enantiomer of (S)-3ao (table 2 numbering 12).
Therefore, the present invention can provide a kind of elastic secondary alcohol preparation method, and it can use identical chiral catalyst and the non-title property addition reaction of catalysis and obtain two kinds of enantiomers.In addition, among asymmetric formula reaction of the present invention, product (S)-3ai and (R)-3ek is the important intermediate of biologically active substance (S)-cetirizine (cetirizine) and (R)-neobenodine.
Comprehensively above-mentioned, the present invention is by using cobalt ion and bidentate ligand catalysis organic boronic and aldehydes to carry out addition reaction obtaining having the secondary alcohol of medicinal use, and has good productive rate and/or ee value.In addition, the present invention can use more cheap cobalt and commercially available chiral ligand (for example (R R)-BDPP) reacts, and therefore the aryl boric acid of numerous species and aldehydes quite have advantage all applicable to secondary alcohol preparation method of the present invention.
Above-described embodiment only is for technological thought of the present invention and characteristics are described; Its purpose makes those skilled in the art can understand content of the present invention and is implementing according to this; When can not with qualification scope of patent protection of the present invention; Equivalent variations or the modification promptly done according to disclosed spirit generally must be encompassed in the scope of patent protection of the present invention.