NZ502612A - Synthesis of aryl boronic acids - Google Patents
Synthesis of aryl boronic acidsInfo
- Publication number
- NZ502612A NZ502612A NZ502612A NZ50261299A NZ502612A NZ 502612 A NZ502612 A NZ 502612A NZ 502612 A NZ502612 A NZ 502612A NZ 50261299 A NZ50261299 A NZ 50261299A NZ 502612 A NZ502612 A NZ 502612A
- Authority
- NZ
- New Zealand
- Prior art keywords
- aryl
- boronic acid
- reaction mixture
- aryl boronic
- borate
- Prior art date
Links
- 150000001543 aryl boronic acids Chemical class 0.000 title claims abstract description 31
- 230000015572 biosynthetic process Effects 0.000 title description 9
- 238000003786 synthesis reaction Methods 0.000 title description 9
- -1 aryl Grignard reagent Chemical class 0.000 claims abstract description 55
- 239000011541 reaction mixture Substances 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 25
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 18
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims abstract description 16
- LBUNNMJLXWQQBY-UHFFFAOYSA-N 4-fluorophenylboronic acid Chemical compound OB(O)C1=CC=C(F)C=C1 LBUNNMJLXWQQBY-UHFFFAOYSA-N 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 15
- 238000006460 hydrolysis reaction Methods 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 238000003747 Grignard reaction Methods 0.000 claims description 7
- 150000004792 aryl magnesium halides Chemical class 0.000 claims description 7
- 230000002452 interceptive effect Effects 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 239000010410 layer Substances 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 238000011065 in-situ storage Methods 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 3
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical group Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 claims description 2
- 229910001623 magnesium bromide Inorganic materials 0.000 claims 3
- 230000003301 hydrolyzing effect Effects 0.000 claims 2
- XCNQSMOOHQLJID-UHFFFAOYSA-N C[O-].[Mg+]c1ccccc1 Chemical compound C[O-].[Mg+]c1ccccc1 XCNQSMOOHQLJID-UHFFFAOYSA-N 0.000 claims 1
- CDEMHJCJMMOFMB-UHFFFAOYSA-M ClC1=CC=C([Mg]Br)C=C1 Chemical compound ClC1=CC=C([Mg]Br)C=C1 CDEMHJCJMMOFMB-UHFFFAOYSA-M 0.000 claims 1
- MLSKXPOBNQFGHW-UHFFFAOYSA-N methoxy(dioxido)borane Chemical compound COB([O-])[O-] MLSKXPOBNQFGHW-UHFFFAOYSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 description 8
- 235000011468 Albizia julibrissin Nutrition 0.000 description 7
- 241001070944 Mimosa Species 0.000 description 7
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 4
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- QBLFZIBJXUQVRF-UHFFFAOYSA-N (4-bromophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Br)C=C1 QBLFZIBJXUQVRF-UHFFFAOYSA-N 0.000 description 2
- CAYQIZIAYYNFCS-UHFFFAOYSA-N (4-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Cl)C=C1 CAYQIZIAYYNFCS-UHFFFAOYSA-N 0.000 description 2
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 description 2
- BIWQNIMLAISTBV-UHFFFAOYSA-N (4-methylphenyl)boronic acid Chemical compound CC1=CC=C(B(O)O)C=C1 BIWQNIMLAISTBV-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- HUMMCEUVDBVXTQ-UHFFFAOYSA-N naphthalen-1-ylboronic acid Chemical compound C1=CC=C2C(B(O)O)=CC=CC2=C1 HUMMCEUVDBVXTQ-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 244000105975 Antidesma platyphyllum Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 235000009424 haa Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910052755 nonmetal Inorganic materials 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 238000010651 palladium-catalyzed cross coupling reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
A process for producing an aryl boronic acid which comprises: (i) directly combining an aryl Grignard reagent with a trialkyl borate at a temperature of -10º C to 0º C in a reaction vessel, wherein the mole ratio of the trialkyl borate to the aryl Grignard reagent is about 1.2, and wherein a reaction mixture containing an aryl boronic acid alkyl diester is produced; and (ii) subjecting the reaction mixture in to conditions effective to hydrolyze the aryl boronic acid alkyl diester to yield the aryl boronic acid. The aryl boronic acid is preferably, phenyl boronic acid or 4-fluorophenyl boronic acid
Description
WO 99/64428 PCT/US99/13105
SYNTHESIS OF ARYL BORONIC ACIDS This application is a continuation of United States application Serial No. 09/094,511 filed 10 5 June 1998.
FIELD OF THE INVENTION This invention relates to the synthesis of aryl boronic acids.
BACKGROUND OF THE INVENTION 10 The use and effectiveness of Grignard reagents in etlSerS^l Solvents to alkylate or arylate non-metal compounds was established in the first half of the Twentieth Century. See, Kharasch, M.S., Reinmuth, O., "Grignard Reactions of Nonmetallic Substances", 15 Prentice-Hall, New York (1954).
Known aryl boronic acid synthesis typically entails concurrent or dual addition of substantially equimolar amounts of a trialkyl borate ester and an aromatic Grignard reagent to a reaction vessel at a 20 temperature of less than -60°C, wherein a reaction mixture containing an aryl boronic acid ester is produced in a 30% to 50% yield. The ester is separated and hydx^yjiid to provide the desired aryl boronic acid.
Aryl boronic acids are now in substantial commercial use to synthesize biaryl compounds by the palladium catalyzed cross-coupling "Suzuki" reaction. See, e.g., A. Suzuki, et al., Svn.Commun. (1981) 513-
Printed from Mimosa
50 2 61
519; Y. Young, et al. , Acta Chem.Scand. (1939) 47:221-230; G.B. Smith, et al. , J.Org.Chem. (1994) 598:8151-8156; S. Sengupta, et al. , J. Org. Chem. (1997) 62:3405-3406. Accordingly, there is a need for an improved 5 aryl boronic acid synthesis.
SUMMARY OF THE INVENTION It has been found, contrary to the prior art, that neither temperatures below -60°C nor control of reactant mole ratio is necessary during the synthesis 10 of the aryl borate alkyl diesters. Pursuant to this invention, the synthesis of aryl borate diesters is accomplished at a temperature of from about -10° to 0°C by direct addition of the Grignard to the trialkyl borate or conversely in any desired mole ratio. 15 Hydrolysis of the aryl borate diesters may be accomplished in situ in synthesis reaction mixture with an aqueous mineral, preferably, aqueous sulfuric acid, in known manner. This invention typically provides aryl boronic yields approximately 20-40% greater than 20 those achieved by the prior art. More specifically,
the invention may provide aryl boronic acid yields of from about 50% to about 70% based on the trialkyl borate reactant.
i ' ~zvj/ i property c. ■ of n z.
2 0 2uG0
^ A r- H 'r n
L J. , * -mJ • 6 W tea ILJ ;-2 a- '4t, r\ ^ A ;h> i ^ ;4 ;^ ^ I ,< ;The invention provides a process for producing an aryl boronic acid which comprises: ;(1) directly combining an aryl Grignard reagent with a 5 trialkyl borate at a temperature of -10°C to 0°C m a reaction vessel, ;wherein the mole ratio of trialkyl borate to said aryl Grignard reagent is about 1.5, ;10 ;wherein a reaction mixture containing an aryl boronic acid alkyl diester is produced; and ;(ii) subjecting said reaction mixture m said reaction 15 vessel to conditions effective to hydrolyze said aryl boronic acid alkyl diester contained m said reaction mixture, ;wherein said hydrolysis yields said aryl boronic 20 acid. ;The invention further provides a process for producing an aryl boronic acid which comprises: ;25 (i) providing a reaction vessel containing a non-interfering solvent solution of a trialkyl borate; ;30 ;(ii) adjusting the temperature of said step (i) reaction vessel and its contents to a range of -10°C to 0°C; ;(iii) combining the contents of said reaction vessel at a temperature of -10°C to 0°C with an aryl Grignard reagent, ;35 ;wherein said combining provides a mole ratio of said aryl Grignard reagent to said trialkyl borate which is greater than stoichiometric, ;wherein a first reaction mixture containing an aryl borate diester is produced in said reaction vessel; ;, ,-ci i pr.or::r;TY ;orXE OF ilZ. ;2 0 L'iO 2003 ;received ;502612 ;(iv) hydrolyzmg said step (1) aryl borate diester in situ m said step (1) reaction vessel, ;wherein a second reaction mixture is produced in said 5 reaction vessel, ;wherein said second reaction mixture contains an aryl boronic acid; and ;10 (v) recovering said aryl boronic acid from said second hydrolysis reaction mixture. ;In another aspect the invention provides a process for producing an aryl boronic acid which comprises: ;15 ;(i) directly combining an aryl Grignard reagent with a trialkyl borate at a temperature of -10 °C to 0°C m a reaction vessel, ;20 wherein the mole ratio of said trialkyl borate to said aryl Grignard reagent is from 1.1 to 2.0, and wherein a reaction mixture containing an aryl boronic acid alkyl diester is produced; and ;25 ;(ii) subjecting said reaction mixture m said reaction vessel to conditions effective to hydrolyze said aryl boronic acid alkyl diester contained in said reaction mixture, ;30 ;wherein said hydrolysis yields said aryl boronic acid. ;Additionally, the invention provides a process for 35 producing an aryl boronic acid which comprises: ;(i) providing a solution of a boronic acid alkyl triester in a non-interfering solvent; ;lntel actual property o;tice of n z. 2 0 lv. C 2C00 ;-2c- ;-fs, 'i ' ;(ii) directing combining an aryl magnesium halide with said step (i) solution wherein said boronic acid alkyl triester in said step 5 (1) solution reacts with said aryl magnesium halide of step (11) to produce a first, Grignard reaction mixture comprising an aryl boronic acid alkyl diester m solution in said non-interfering solvent; ;10 wherein said directly combining step (ii) is conducted at a temperature of -10°C to 0°C; and wherein the mole ratio of said boronic acid alkyl triester to said aryl magnesium halide m said 15 directly combining step (ii) is from 1.1 to 2.0; ;(in) subjecting said first, Grignard reaction mixture produced in step (ii) to conditions effective to hydrolyze said aryl boronic acid alkyl diester, ;20 ;wherein a second reaction mixture containing said aryl boronic acid is produced; and ;(iv) separating said aryl boronic acid from said second 25 reaction mixture. ;DETAILED DESCRIPTION OF THE INVENTION The invention may, but need not be, practiced as a one pot method. A Grignard reagent is prepared in known manner in em appropriate ethereal solvent, ;preferably at the greatest concentration resulting in a cr" I p^OT-niY ;or icl. cf ir. ;1 o D.:c 2303 ;Li kl "w k— a u i.*
solution. Any ethereal solvent compatible with Grignard formation may be used. Useful solvents may be ethers which are cyclic, e.g., tetrahydrofuran, or which have the formula ROR, in which R is an alkyl 5 group preferably having 2 to 6 carbon atoms.
Pursuant to the invention, an aryl boronic acid triester is synthesized at a temperature of -10°C to 0°C as illustrated by equation 1:
T -10°C to 0°C
ArMgX+B (OR) 3 —ArB (OR) 2+ROMgX (1)
Yield = 50-70%.
The Grignard aryl (Ar) groups may be substituted at one, some, or all available positions by any halogen 15 (chlorine, bromine, fluorine or iodine), or by any straight or branched chain, substituted or unsubstituted alkyl group, or by any functional group compatible with or protected by standard methods to be compatible with the Grignard function. Phenyl, 20 4-£luorophenyl and naphthyl groups are typical Grignard aryl groups.
The alkyl borate reactant (B(OR3)) is preferably used in an amount greater than stoichiometric with respect to the ArMgX reagent. For example, from about 25 1.1 to 2.0, preferably about 1.5 moles, of B(0R3) may be used for each mole of ArMgX.
Each of the R groups may be any alkyl group. Appropriate R groups have one to ten carbon atoms. R is preferably methyl.
Printed from Mimosa
The hydrolysis of the aryl boronic acid diester (equation 2) may be performed in known manner, e.g., by combining a mineral acid, preferably aqueous H2S04, directly with the Grignard reaction mixture:
ArB(0R)2+H2S04„q) > ArB (OH) 2+2ROH (2)
EXAMPLE 1 (General Example)
The Grignard reagent is prepared in known manner in an appropriate ethereal solvent, preferably at the 10 greatest concentration resulting in a solution.
A flask of appropriate size to accommodate the reaction volume as well as the volume of the aqueous acid hydrolysis solution is set up under a sweep of inert atmosphere and equipped for reflux and cooling. 15 Trialkyl borate, e.g., trimethyl borate diluted with an equal weight of an ethereal solvent, preferably THF, is charged to the flask in an amount to provide a mole ratio of ArMgX:B (0CH3) 3 of 1:1.5. The flask is cooled with dry ice:acetone to -10°C and addition of Grignard 20 reagent begun, wherein a reaction mixture containing an aryl borate dialkyl ester is produced.
Upon completion of the Grignard addition, the reaction mixture is stirred to room temperature (1-2 hours). The dialkyl ester is hydrolyzed in situ by 25 directly adding a 10% w/v H2S04 aqueous solution in an amount equal to 2 mole H2S04 with vigorous stirring for 30 minutes. The reaction mixture is then allowed to settle for 30 minutes. The hydrolysis reaction mixture
Printed from Mimosa
PCT/US99/13I05
forms an upper organic layer and a lower aqueous layer. The organic layer is separated, and then dried over sodium sulfate. Solvent is distilled until solids begin to precipitate. Hexanes are added, and the 5 precipitated product collected by filtration.
The method described by this general example has yielded the results reported in Table 1.
TABLE 1
Grignard Name
Grignard Concentration
Solvent
Product Hame(s)
Quantity
Reacted
(Mole)
yield of
Product
(Mole)
%
Yield
Phenyl
2M
THF
Phenyl
2
67
MgCl
boronic
acid;
Benzene
boronic
acid
Phenyl MgBr
3M
Ether
Phenyl boronic acid;
Benzene boronic acid
3
1.9
65
Printed from Mimosa
4-Fluoro
1.5M
THF
4-Fluoro
3
1.65
55
phenyl
phenyl
MgBr
boronic acid; 4-
Fluoro-
benzene boronic acid
4-Fluoro
2M
Ether
4-Fluoro
3
1.71
57
phenyl
phenyl
MgBr
acid; 4-
Fluoro-
benzene boronic acid
4-Methyl
2M
THF
4-Methyl
3
1.65
55
phenyl
phenyl
MgCl
boronic acid; 4-
Methyl benzene boronic acid
4-Methyl
2M
Ether
4-Methyl
3
1.62
54
phenyl
phenyl
MgBr
boronic acid; 4-
Methyl benzene boronic acid
Printed from Mimosa
Naphthyl MgBr
1M
THF
1-
Naphthyl boronic acid
28.9
14
7
51
4-Chloro phenyl
MgBr
2M
Ether
4-Chloro phenyl boronic acid; 4-
Chloro-
benzene boronic acid
2
1
24
62
4-Bromo phanyl
MgBr
2M
Ether
4-Bromo phenyl boronic acid; 4-
Bromo-
benzene boronic acid
2
1
12
56
4-
Mathoxy phenyl
MgBr
1.2M
THF
4-
Methoxy benzene boronic acid
3
1
65
55
4-
Mathoxy phenyl
MgBr
2M
Ether
4-
Methoxy benzene boronic acid
3
1
8
60
Printed from Mimosa
The results reported in Table 1 were obtained in the laboratory with the exception that the synthesis of 1-naphthyl boronic acid was achieved in a pilot plant.
EXAMPLE 2 (Phenyl Boronic Acid)
A reaction flask was charged with trimethyl borate (1.5 moles, 155.7g) and tetrahydrofuran (300g). The mixture was cooled to a temperature of -5°C to 0°C.
One mole of phenyl magnesium bromide was added slowly with maintenance of the temperature between -5°C and 0°C. The reaction mixture was stirred for thirty minutes.
Ten percent (10%) aqueous sulfuric acid was directly added to the Grignard reaction mixture which contained the methyl ester of phenyl boronic acid. The resulting hydrolysis reaction mixture was stirred for thirty minutes and then allowed to settle for thirty minutes. The mixture separated into an upper layer and a lower layer. The upper layer was separated, dried over sodium sulfate (lOg), and filtered. The volume of the filtrate was reduced by distillation of THF, 300 ml of hexane was added, and the distillation continued until most of the THF was removed. The remainder of the reaction mixture was cooled and filtered to recover solids which dried in vacuum. Yield—65% to 70% phenyl boronic acid.
Printed from Mimosa
Claims (17)
1. A process for producing an aryl boronic acid which comprises: 5 (l) directly combining an aryl Grignard reagent with a trialkyl borate at a temperature of -10 °C to 0°C in a reaction vessel, 10 wherein the mole ratio of trialkyl borate to said aryl Grignard reagent is about 1.5, wherein a reaction mixture containing an aryl boronic acid alkyl diester is produced; and 15 (ii) subjecting said reaction mixture m said reaction vessel to conditions effective to hydrolyze said aryl boronic acid alkyl diester contained m said reaction mixture, 20 wherein said hydrolysis yields said aryl boronic acid.
2. The claim 1 process, wherein said step (i) is accomplished at a temperature of -5°C to 0°C. 25
3. A process for producing an aryl boronic acid which comprises: (i) providing a reaction vessel containing a non-30 interfering solvent solution of a trialkyl borate; (n) adjusting the temperature of said step (i) reaction vessel and its contents to a range of -10°C to 0°C; 35 (in) combining the contents of said reaction vessel at a temperature of -10°C to 0°C with an aryl Grignard reagent, Vw - - - 10 - I , tr> wherein said combining provides a mole ratio of said aryl Grignard reagent to said trialkyl borate which is greater than stoichiometric, 5 wherein a first reaction mixture containing an aryl borate diester is produced in said reaction vessel; (iv) hydrolyzing said step (1) aryl borate diester in situ 10 in said step (i) reaction vessel, wherein a second reaction mixture is produced in said reaction vessel, 15 wherein said second reaction mixture contains an aryl boronic acid; and (v) recovering said aryl boronic acid from said second hydrolysis reaction mixture. 20
4. The claim 3 process wherein the step (i) mole ratio of said trialkyl borate to said aryl Grignard reagent is from about 1.1 to about 2.0. 25 5. The claim 3 or claim 4 process wherein said hydrolyzing step (iv) is accomplished by combining aqueous sulfuric acid with step (iii) aryl borate diester 30 35 wherein said second hydrolysis reaction mixture forms an upper organic layer and a lower aqueous layer, and wherein said claim 2 or claim 3 process further comprises a step (iv)(a): • :t ■ L r.c.^TY o., I-i- cf n z. 2 G -iC 2.30
D - 11 - if ' 3' (iv) (a) separating said upper organic layer from said lower aqueous layer of said hydrolysis reaction mixture.
6. A process for producing an aryl boronic acid which 5 comprises: (i) directly combining an aryl Grignard reagent with a trialkyl borate at a temperature of -10 °C to 0°C in a reaction vessel, 10 wherein the mole ratio of said trialkyl borate to said aryl Grignard reagent is from 1.1 to 2.0, and wherein a reaction mixture containing an aryl boronic 15 acid alkyl diester is produced; and (ii) subjecting said reaction mixture in said reaction vessel to conditions effective to hydrolyze said aryl boronic acid alkyl diester contained m said reaction 20 mixture, wherein said hydrolysis yields said aryl boronic acid.
7. The claim 6 process, wherein said aryl boronic acid is 25 phenyl boronic acid, or 4-fluorophenyl boronic acid.
8. The claim 6 or claim 7 method, wherein said trialkyl borate of step (i) is trimethyl borate. 30
9. A process for producing an aryl boronic acid which comprises: (i) providing a solution of a boronic acid alkyl triester m a non-interfering solvent; 35 _ | r, r L - » i !• i t - 12 - % " N 0 f> rX ^ U > ' y , ^ (ii) directing combining an aryl magnesium halide with said step (i) solution wherein said boronic acid alkyl triester in said step 5 (i) solution reacts with said aryl magnesium halide of step (11) to produce a first, Grignard reaction mixture comprising an aryl boronic acid alkyl diester in solution in said non-interfering solvent; 10 wherein said directly combining step (ii) is conducted at a temperature of -10°C to 0°C; and wherein the mole ratio of said boronic acid alkyl triester to said aryl magnesium halide in said directly 15 combining step (n) is from 1.1 to 2.0; (iii) subjecting said first, Grignard reaction mixture produced in step (ii) to conditions effective to hydrolyze said aryl boronic acid alkyl diester, 20 wherein a second reaction mixture containing said aryl boronic acid is produced; and (iv) separating said aryl boronic acid from said second 25 reaction mixture.
10. The claim 9 process wherein said non-interfering solvent in step (i) is tetrahydrofuran. 30
11. The claim 9 process wherein said boronic acid alkyl diester m step (i) is methyl borate.
12. The claim 9 process wherein said aryl magnesium halide is phenyl magnesium bromide, or naphthyl magnesium bromide, or 4-35 fluorophenyl magnesium bromide, or 4-chlorophenyl magnesium bromide, or methoxyphenyl magnesium bromide. t7t:i' -tj, l f;;cveriy o; rict cf [jz. 2 0 LiC 2.G0 13 -
13. The claim 9 process wherein said step (iii) conditions are produced by 10% aqueous sulfuric acid.
14. A process according to claim 1 substantially as herein described or exemplified.
15. A process according to claim 3 substantially as herein described or exemplified.
16. A process according to claim 6 substantially as herein described or exemplified.
17. A process according described or exemplified. to claim 9 substantially as herein END
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US9451198A | 1998-06-10 | 1998-06-10 | |
| PCT/US1999/013105 WO1999064428A1 (en) | 1998-06-10 | 1999-06-10 | Synthesis of aryl boronic acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ502612A true NZ502612A (en) | 2001-06-29 |
Family
ID=22245595
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ502612A NZ502612A (en) | 1998-06-10 | 1999-06-10 | Synthesis of aryl boronic acids |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1064286A1 (en) |
| JP (1) | JP2002517503A (en) |
| AU (1) | AU4678699A (en) |
| CA (1) | CA2297780A1 (en) |
| NZ (1) | NZ502612A (en) |
| WO (1) | WO1999064428A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10140857A1 (en) * | 2001-08-21 | 2003-03-06 | Clariant Gmbh | Process for the preparation of aryl and alkyl boron compounds in microreactors |
| GB2415193A (en) * | 2004-06-19 | 2005-12-21 | F2 Chemicals Ltd | Fluorinated arylboronic acids |
| EP2018146A2 (en) | 2006-03-07 | 2009-01-28 | The Procter and Gamble Company | Compositions for oxidatively dyeing keratin fibers and methods for using such compositions |
| DE102007003036A1 (en) | 2006-12-20 | 2008-06-26 | Bayer Cropscience Ag | Pyrimidinylpyrazole |
| CA2733958A1 (en) | 2008-08-14 | 2010-02-18 | Bayer Cropscience Ag | Insecticidal 4-phenyl-1h-pyrazoles |
| EP2246335A1 (en) | 2009-02-17 | 2010-11-03 | Bayer CropScience AG | Aminopyridineamides as pesticides |
| EP2266973A1 (en) | 2009-05-29 | 2010-12-29 | Bayer CropScience AG | Pyrazinylpyrazole |
| CN104119367A (en) * | 2014-07-09 | 2014-10-29 | 中国科学技术大学苏州研究院 | Preparation method of aryl boric acid |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2898365A (en) * | 1956-12-05 | 1959-08-04 | American Potash & Chem Corp | Process for manufacture of areneboronic acids |
-
1999
- 1999-06-10 JP JP2000553436A patent/JP2002517503A/en active Pending
- 1999-06-10 EP EP99930198A patent/EP1064286A1/en not_active Withdrawn
- 1999-06-10 WO PCT/US1999/013105 patent/WO1999064428A1/en not_active Application Discontinuation
- 1999-06-10 NZ NZ502612A patent/NZ502612A/en unknown
- 1999-06-10 CA CA002297780A patent/CA2297780A1/en not_active Abandoned
- 1999-06-10 AU AU46786/99A patent/AU4678699A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP1064286A1 (en) | 2001-01-03 |
| AU4678699A (en) | 1999-12-30 |
| CA2297780A1 (en) | 1999-12-16 |
| JP2002517503A (en) | 2002-06-18 |
| WO1999064428A1 (en) | 1999-12-16 |
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