Patent Application
20150191493
The present invention relates to a new process for preparing arylboranes by arylation of organoboron compounds.
Boronic acids and esters are often prepared by a condensation reaction between an organomagnesium or an organolithium compound and a trialkylborate. This reaction requires specific conditions, in particular low temperatures, is not general and often expensive: it is thus difficult to implement it on an industrial scale. They are intermediates in a wide variety of research and industrial applications, for instance, in the synthesis of pharmaceuticals via cross-coupling reactions (N. Miyaura, A. Suzuki, Chem. Rev., 1995, 95, 2457). A simple synthetic methodology allowing for the direct attachment of aromatics to boron is thus an important challenge.
Methods avoiding the use of organometallics have been recently developed, using palladium activation of carbon-halide bond (Miyaura borylation) or iridium activation of Aryl-H (Hartwig borylation). Palladium activation is, for instance, described in: T. Ishiyama, M. Murata, N. Miyaura, J Org Chem 1995, 60, 7508-7510; T. Ishiyama, Y. Itoh, T. Kitano, N. Miyaura, Tetrahedron Letters 1997, 38, 3447-3450; T. Ishiyama, K. Ishida, N. Miyaura, Tetrahedron 2001, 57, 9813-9816; T. Ishiyama, N. Miyaura, Journal of Organometallic Chemistry 2000, 611, 392-402. Iridium activation is, for instance, described in: EP 1 500 659; T. M. Boller, J. M. Murphy, M. Hapke, T. Ishiyama, N. Miyaura, J. F. Hartwig, J. Am. Chem. Soc. 2005, 127, 14263-14278; J. F. Hartwig, K. S. Cook, M. Hapke, C. D. Incarvito, Y. Fan, C. E. Webster, M. B. Hall, J. Am. Chem. Soc. 2005, 127, 2538-2552; J. M. Murphy, X. Liao, J. F. Hartwig, J. Am. Chem. Soc. 2007; J. M. Murphy, C. C. Tzschucke, J. F. Hartwig, Org. Lett. 2007, 9, 757-760; I. A. I. Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy, J. F. Hartwig, Chemical Reviews 2009, 110, 890-931. Both methods use traditional pinacolborane or pinacolatodiboron as boron source, and are tolerant towards functional groups. But it is noteworthy that both methods use rather expensive complexes of transition metals, possibly toxic, half of the boron material being lost in the case of pinacolatodiboron. Their use in the last steps of a pharmaceuticals manufactoring must therefore be avoided.
Aminoboranes such as diisopropylaminoborane iPr2N—BH2 have been used since 2003 as borylation agents in palladium catalysed transformation of aryl bromides, iodides and triflates, by Vaultier et al: U.S. Pat. No. 7,179,940; L. Euzenat, D. Horhant, Y. Ribourdouille, C. Duriez, G. Alcaraz, M. Vaultier, Chem. Commun. 2003, 2280-2281; L. Euzenat, D. Horhant, C. Brielles, G. Alcaraz, M. Vaultier, J. Organomet. Chem. 2005, 690, 2721-2724; L. Marciasini, N. Richy, M. Vaultier, M. Pucheault, Chem. Comm. 2012, 48. Diisopropylaminoborane is stable, easily prepared, handled and stored. Besides, arenediazonium salts, stable in the form of tetrafluoroborates, are easily available from corresponding anilines and have additionally successfully been used for metal-catalysed borylation reaction using pinacolatodiboron as coupling agents (D. M. Willis, R. M. Strongin, Tetrahedron Letters 2000, 41, 8683-8686; J. Zhang, X. Wang, H. Yu, J. Ye, Synlett 2012, 9, 1394-1396).
Up to now, there is no simple process of arylation of a B—H bond involving mild conditions and low cost reagents.
One of the aims of the invention is to provide a new process for the preparation of arylboranes by arylation of a B—H bond.
Another aim of the invention is to provide a new access to aminoarylboranes and to arylboronates under mild conditions.
Another aim of the invention is to provide organoboron compounds which can be used as intermediates for the synthesis of various organoboron compounds by appropriate functionalization.
Another aim of the invention is to provide a process which can be implemented in a flow reactor with good yields.
The invention relates to the use of an arenediazonium salt or a heteroarenediazonium salt, and an organoboron compound containing at least one boron-hydrogen bond, in the absence of base, for the implementation of a process involving an arylation reaction leading to an arylborane compound.
The inventors have unexpectedly found that a B—H bond can be arylated without using any additive. If there is an additive, its amount is less than 5%. The process can be in particular implemented without the presence of a base, and without the presence of an acid, provided that the solvent is appropriate. The term “base” designates a substance, other than an aminoborane, that can accept a proton.
“Arenediazonium salt” designates a compound containing an aromatic ring substituted by a diazonium —N2+ group, in the form of a salt. The aromatic ring may be a heteroaromatic ring. “Organoboron compound” or “organoborane” refers to a compound containing a boron atom. “Arylation reaction” means that the B—H bond of the organoborane is replaced by a B—Ar bond, wherein Ar is the aromatic ring or, possibly, the heteroaromatic ring, brought to the boron by the arenediazonium salt, possibly by the heteroarenediazonium salt. The arylation reaction is thus responsible for the creation of a B—Ar compound, designated by the term “arylborane”.
If the organoboron reagent contains 2 B—H bonds, only one is replaced by an aryl or heteroaryl group.
In this reaction, N2 is a leaving group, which released from the arenediazonium salt, is found to be an accurate measurement of the arylborane formation.
According to an embodiment, the invention relates to the use of an arenediazonium salt or a heteroarenediazonium salt, for the preparation of an arylborane, wherein the aryl group Ar has from 6 to 26 carbon atoms, the aryl group being possibly a heteroaryl group containing one or several heteroatom(s) chosen among O, N or S, and having from 4 to 26 carbon atoms, in particular said arylborane being:
wherein the amino group is a —NR1R2 group, wherein R1 and R2, identical or different, represent:
wherein the alkoxy groups are —OR8 and —OR8a, wherein R8 and R8a, identical or different, represent:
wherein
wherein the amino groups are —NR1R2 and —NR1aR2a groups, R1 and R2 having the above mentioned meanings, R1a being identical or different from R1, and R2a being identical or different from R2, R1a and R2a being identical or different, said arylborane being in particular an aminoarylborane or a cyclic diaminoarylborane. “Aryl group Ar” designates an aromatic group such as a phenyl group, for instance. “Heteroaryl group” means that the aromatic ring contains one or several heteroatom(s) chosen among O, N or S.
The arylation reaction, performed in the invention, provides access to several categories of arylboranes.
The preferred arylboranes reagents are aminoarylboranes wherein the nitrogen of the amino group is hindered at its a position, the amino group having the meanings mentioned above and being in particular a group chosen among:
In the formula:
“the alkoxy groups —OR8 and —OR8a being in particular connected by a 2 to 4 carbons chain and possibly forming a 5 or 6 membered ring including the boron atom and the two oxygen atoms” corresponds to an advantageous case, illustrated in particular by the boronate groups of formulae:
respectively derivated from pinacol, 2,2-dimethylpropane-1,4-diol, or catechol.
According to an embodiment, the invention relates to the use of activating means or not, wherein the activating means are chosen among activating agents, preferably a complex of a transition metal or a salt of a transition metal or a salt of a transition metal complex or radical generating means, preferably by light irradiation or a radical initiator.
The arylation reaction occurs with activating means, but also without activating means, which was unexpected.
“Activating means” designates activation by means of a chemical species or a physical parameter, such as exposure to light, in particular to UV-light.
“Activating agent” designates a chemical species able to catalyse the arylation reaction or able to be modified in the reaction medium to give in situ the catalyst of the arylation reaction. This activating agent can be considered as an additive. Its molar percentage is less than 5%. The activating agents used in the process of the invention generally contain a transition metal. They are provided in the form of a complex wherein ligands and/or anions are bound to the metal.
The use of an activating agent is not absolutely necessary in most cases, but it increases the yield in arylborane.
The invention relates to the use of an aprotic polar solvent, in particular chosen among acetonitrile, propionitrile, butyronitrile, ethylacetate, isopropylacetate, dioxane, dimethylacetamide (DMAc), acetone, N-methyl-2-pyrrolidone (NMP), 2-methoxy-2-methylpropane (MTBE) or tetrahydrofuran (THF), or a mixture thereof, in particular acetonitrile.
The arylation reaction is advantageously performed in an aprotic polar solvent due to the high solubility of the arenediazonium salts in such a solvent. The arylation reaction proceeds faster than the competitive reduction of the arenediazonium salts into the corresponding anilines. Aprotic polar solvents such as acetonitrile, propionitrile, butyronitrile, ethylacetate, isopropylacetate, dioxane, dimethylacetamide (DMAc), acetone, N-methyl-2-pyrrolidone (NMP), 2-methoxy-2-methylpropane (MTBE) or tetrahydrofuran (THF), or a mixture thereof, are therefore preferred, in particular acetonitrile.
The reaction is unsuccessful in an apolar solvent such as toluene or heptane, most likely due to the poor solubility of the arenediazonium salts in such a solvent.
According to a particular embodiment, the invention relates to the use of an arenediazonium salt or a heteroarenediazonium salt of the formula Ar—N2A, wherein
wherein
R18 and R18a, identical or different, represent:
The preferred anion is the tetrafluoroborate anion. Arenediazonium tetrafluoroborate salts are either synthesized in situ from cheap and readily available anilines, or they can be isolated and stored. The aromatic ring can be mono, di or trisubstituted, in ortho, meta or para position(s). The arylation reaction works with arenediazonium salts wherein aryl group bears donating groups and with arenediazonium salts wherein aryl group bears withdrawing groups. Thus, the following arenediazonium salts have been used:
The aromatic ring can possibly be substituted by a borylated group, wherein boron is a B(III) or a B(IV).
respectively derivated from pinacol, 2,2-dimethylpropane-1,4-diol, or catechol.
derived from 1,2,3-propane triol (glycerol), or
derived from 2-(hydroxymethyl)-2-methyl-1,3-propanediol,
According to a particular embodiment, the invention relates to the use of an organoboron compound to be arylated containing at least one boron-hydrogen bond and being an organoborane of the general following formula I
wherein
According to a particular embodiment, the invention relates to the use of an organoboron compound of type I containing two boron-hydrogen bonds and being an aminoborane of general formula II
wherein
R1 and R2 have the above mentioned meanings.
According to a particular advantageous embodiment, the invention relates to the use of the organoboron compound of type I containing one boron-hydrogen bond and being a dialkoxyborane (boronic ester) of general formula III
wherein
R8 and R8a have the above mentioned meanings.
According to a particular embodiment, the invention relates to the use of an activating agent to perform the arylation reaction,
the activating agent containing a transition metal belonging, in particular, to the group IV, VIII, IX, X or XI, being in particular a metallocene or a salt thereof chosen among:
A “metallocene” is a compound containing a metal center in the oxidation state (II), and typically two cyclopentadienyl anions (Cp−, C5H5−), the resulting formula being (C5H5)2M.
A metallocene forms a sandwich structure as represented in the scheme below:
In this scheme, the two pentagons are the cyclopentadienyl anions with circles inside them indicating they are aromatically stabilized.
By substituting the cyclopentadienyl group, this parent metallocene gives rise to analogues. For instance, Cp may be replaced by Cp*, which is 1,2,3,4,5-pentamethylcyclopentadienyl group.
The complex of a transition metal is preferably an iron, titanium or zirconium compound stabilized by ligands, preferably Cp or a derivative of Cp, such as Cp*, mentioned above. The metallocenes preferably used are: Cp2Fe, Cp2TiCl2 or Cp2ZrHCl.
The Cp group may be substituted by one or several alkyl groups, such as methyl, n-Butyl, by an acetyl group or by a vinyl group, for instance.
The present invention relates to a new process for the preparation of an arylborane compound containing at least one B—H bond, by arylation of a B—H bond, which comprises:
The term “base” does not include “aminoborane”.
The “reaction medium” designates the mixture containing the arenediazonium or heteroarenediazonium salt, the organoboron compound and the solvent. The organoboron compound contains one or two B—H bond(s). One hydrogen bound to the boron is replaced by the aryl or heteroaryl group. This is represented in the equation below:
B—H→B—Ar
After arylation reaction, there is a “possible step of recovery” which means that, depending on the nature of the obtained product at the step (1), the product can be isolated or purified, or can be modified i.e, refunctionalized at the boron atom, to give a more stable compound.
According to an embodiment, the process for the preparation of an arylborane compound containing at least one B—H bond, by arylation of a B—H bond, comprises:
In the reaction medium mentioned above, there is possibly an activating agent, preferably a metallocene, as mentioned above.
The invention relates to the preparation of an arylborane compound, wherein the aryl group Ar has from 6 to 26 carbon atoms,
the aryl group being possibly a heteroaryl group containing one or several heteroatom(s) chosen among O, N or S, and having from 4 to 26 carbon atoms,
in particular said arylborane being:
wherein the amino group is a —NR1R2 group, wherein R1 and R2, identical or different, represent:
wherein the alkoxy groups are —OR8 and —OR8a, wherein R8 and R8a, identical or different, represent:
wherein
wherein the amino groups are —NR1R2 and —NR1aR2a groups, R1 and R2 having the above mentioned meanings, R1a being identical or different from R1, and R2a being identical or different from R2, R1a and R2a being identical or different, said arylborane being in particular an aminoarylborane or a cyclic diaminoarylborane.
The process of the present invention comprises a step of contacting an arenediazonium salt or a heteroarenediazonium salt of formula Ar—N2A,
wherein
wherein
R18 and R18a, identical or different, represent:
wherein
R1 and R2 possibly forming an alkylene group corresponding to the formula —CR3R4—(CH2)n—CR5R6, in which n is ranging from 0 to 4, and the R3 to R6 substituents are chosen, independently of one another, among hydrogen and alkyl groups having from 1 to 20 carbon atoms in particular said alkylene being 1,1,5,5-tetramethylpentylene,
R1a and R2a possibly forming an alkylene group corresponding to the formula —CR3aR4a—(CH2)n—CR5aR6a, in which n is ranging from 0 to 4, and the R1a to R6a substituents are chosen, independently of one another, among hydrogen and alkyl groups having from 1 to 20 carbon atoms in particular said alkylene being 1,1,5,5-tetramethylpentylene,
X and Y being independently chosen, provided that if X═H then Y#H, and if X═—OR8 and Y═-OR8a, then the alkoxy groups —OR8 and —OR8a are in particular connected by a 2 to 4 carbons chain and possibly form a ring including the boron atom and the two oxygen atoms, the ring being therefore a 5 to 7 membered ring originated from a diol chosen among ethane-1,2-diol, propane-1,3-diol, 2,3-dimethylbutane-2,3-diol (pinacol), pinanediol, 2-methylbutane-2,3-diol, 1,2-diphenylethane-1,2-diol, 2-methylpentane-2,4-diol, 1,2-dihydroxybenzene (catechol), in particular pinacol or pinanediol,
for the preparation of an arylborane or a heteroarylborane of following formula IV
wherein
X, Y and Ar have the above mentioned meanings.
The 4 following equations represent the preparation of the 4 types of arylboranes available by the process of the invention:
A has the above mentioned meanings.
The process particularly relates to the preparation of an aminoarylborane compound and comprises:
wherein R1 and R2, identical or different, have the above mentioned meanings, in a reaction medium containing a solvent, in the absence of base, for the preparation of an aminoarylborane compound of formula V,
wherein Ar, R1 and R2 have the above mentioned meanings, R1 and R2 being preferably isopropyl groups,
The aminoarylboranes of formula V correspond to the preferred type of arylboranes available using the process of the invention. Their general preparation is represented in the above equation 1.
Compounds of formula II are easily available. An amine R′R2NH is reacted with NaBH4 in an acidic medium, under an inert atmosphere, to give an amine-borane complex of formula R1R2NH.BH3, subsequently concentrated under vacuum and isolated. The aminoborane R1R2N—BH2 is then obtained by heating the amine-borane complex, which results in a deshydrogenation, and the crude amonborane obtained is distilled to give the pure aminoborane which can be stored under an inert atmosphere of nitrogen or argon.
The aminoboranes thus obtained are represented below.
prepared from diisopropylamine,
prepared from N,N-dicyclo hexylamine,
prepared from 2,2,6,6-tetramethylpiperidine,
prepared from (methylbenzyl)(isopropyl)amine. In that case, the aminoborane can be optically active when the amine is chiral.
The yield in aminoboranes is at least of 90%.
Compounds IIA, IIB, IIC and IID can then undergo an arylation reaction with an arenediazonium salt or a heteroarenediazonium salt, in a reaction medium containing a solvent, preferably acetonitrile, at room temperature, in the absence of base, with or without an activating means. The following equations describe the preparation of the aminoarylboranes of the general formula V, the aryl group having the above mentioned meanings.
Compound VD can be chiral when the (methylbenzyl)(isopropyl)amine used to prepare IID is in its chiral form.
A has the above mentioned meanings.
According to a particularly advantageous embodiment, the process of the present invention relates to the preparation of a diisopropylaminoarylborane compound and comprises:
in a reaction medium containing a solvent, in the absence of base, for the preparation of a diisopropylaminoarylborane compound of formula VA,
wherein Ar has the above mentioned meanings,
The effect of the relative hindrance at the nitrogen atom in compounds II and therefore close to the boron atom, is to increase the chemioselectivity in favour of the arylation reaction. The yields are higher with hindered amines.
The compound IIA is advantageously used in the process.
According to a particularly advantageous embodiment, the process of the present invention relates to the preparation of a diisopropylaminoarylborane compound which comprises:
in a reaction medium containing a solvent, in the absence of base, in the presence of an activating agent preferably chosen among metallocenes, in particular ferrocenes, titanocenes, or zirconocenes, preferably Cp2Fe, Cp2TiCl2 or Cp2ZrHCl, for the preparation of a diisopropylaminoarylborane compound of formula VA,
wherein Ar has the above mentioned meanings,
The arylation reaction is carried out under mild conditions, even without any activating agent.
However, the use of a small amount of activating agent (1% or even less than 1%), might increase the yield in aminoarylboranes.
The scheme below represents the reaction between diisopropylaminoborane and 4-methoxybenzenediazonium tetrafluoroborate,
The yields are indicated.
“RT” means “room temperature” i.e. 18-20° C.
The product is isolated and purified or is submitted to a further reaction, step (2) involving a functional change at the boron atom.
According to another embodiment, the process of the present invention relates to the preparation of a dialkoxyarylborane compound and comprises:
(1) a step of contacting an arenediazonium salt or a heteroarenediazonium salt with a dialkoxyborane of following formula III
wherein R8 and R8a, identical or different, have the above mentioned meanings, in a reaction medium containing a solvent, in the absence of base, for the preparation of a dialkoxyarylborane compound of formula VI,
wherein
R8, R8′ and Ar have the above mentioned meanings,
Boronic esters are extensively used as chemical building blocks and as intermediates, particularly in the Suzuki coupling. They are thus interesting compounds.
The compounds of formula III
wherein “the alkoxy groups —OR8 and —OR8a are in particular connected by a 2 to 4 carbons chain and possibly form a 5 or 6 membered ring including the boron atom and the two oxygen atoms” are advantageous because of their availability and relative stability.
Compounds IIIA, IIIB and IIIC can be submitted to an arylation reaction with an arenediazonium salt or a heteroarenediazonium salt, in a reaction medium containing a solvent, preferably acetonitrile, at room temperature, in the absence of base, preferably with an activating means.
The following equations described the preparation of the dialkoxyarylboranes (boronic esters) of the general formula VI, the aryl group having the above mentioned meanings; the reagents IIIA (pinacolborane), IIIB and IIIC (catecholborane) are commercially available or easy to prepare.
According to a particular embodiment, the process of the present invention relates to the preparation of an arylpinacolborane compound and comprises:
in a reaction medium containing a solvent, in the absence of base, for the preparation of an arylpinacolborane compound of formula VIA,
wherein Ar has the above mentioned meanings,
According to a particularly advantageous embodiment, the process of the present invention relates to the preparation of an arylpinacolborane compound and comprises:
in a reaction medium containing a solvent, in the absence of base, in the presence of an activating agent preferably chosen among metallocenes, in particular ferrocenes, titanocenes, or zirconocenes, preferably Cp2Fe, Cp2TiCl2 or Cp2ZrHCl, for the preparation of an arylpinacolborance compound of formula VIA,
wherein Ar has the above mentioned meanings,
The use of an activating agent might increase the yield.
According to a particular embodiment, the activation means are radical generating means, in particular light irradiation, preferably ultraviolet light irradiation(UV), at a wavelength comprised from 180 nm to 400 nm, preferably comprised from 200 nm to 400 nm, in particular equal to about 254 nm,
or a radical initiator, chosen among azobisisobutyronitrile (AIBN), 1,1′-azobiscyclohexanecarbonitrile (ABCN), dilauroyl peroxide (DLP).
According to a particular embodiment, the solvent is aprotic and polar, in particular chosen among acetonitrile, propionitrile, butyronitrile, ethylacetate, isopropylacetate, dioxane, dimethylacetamide (DMAc), acetone, N-methyl-2-pyrrolidone (NMP), 2-methoxy-2-methylpropane (MTBE) or tetrahydrofuran (THF), or a mixture thereof, in particular acetonitrile.
For instance, the arylation reaction of diisopropylaminoborane with 4-methoxybenzenediazonium tetrafluoroborate, in the presence of Cp2Fe, gives 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane with a 22% yield in THF. The yield is 87% if the solvent is acetonitrile. But there is no arylborane obtained in an apolar solvent, such as toluene.
The mixture can be acetonitrile/NMP 95/5, THF/NMP 95/5.
For instance, the arylation reaction of diisopropylaminoborane with 4-methylbenzenediazonium tetrafluoroborate, in the presence of Cp*2TiCl2, gives 2-(4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane with a 50% yield in THF. The yield increases to 74% in a mixture of THF+5% NMP.
Particularly, the step of contacting an arenediazonium salt or a heteroarenediazonium salt with an aminoborane is performed in an aprotic polar solvent, preferably acetonitrile, at a temperature comprised from 10° C. to 60° C., in particular comprised from 18° C. to 30° C., preferably equal to about 20° C., during a time ranging from 1 h to 3 h, preferably 2.5 h, for the preparation of an aminoarylborane.
An advantage of the process of the invention is that it is carried out at room temperature, in very mild conditions.
Advantageously, the step of mixing an arenediazonium salt or a heteroareneazonium salt with an aminoborane is performed in an aprotic polar solvent, preferably acetonitrile, in the presence of an activating agent containing a transition metal, said activating agent being preferably chosen among metallocenes, in particular ferrocenes, titanocenes, or zirconocenes, preferably Cp2Fe, Cp2TiCl2 or Cp2ZrHCl,
with a molar percentage relative to the metal comprised from 0.001% to 5%, in particular comprised from 0.001% to 1%, preferably equal to about 0.001%, or about 0.01%, or about 0.1% or about 1%,
at a temperature comprised between 10° C. to 60° C., in particular comprised between 18° C. to 30° C., preferably equal to about 20° C., during a time ranging from 1 h to 3 h, preferably 2.5 h,
for the preparation of an aminoarylborane compound.
Another embodiment of the process relates to a step of contacting an arenediazonium salt or a heteroarenediazonium salt with a dialkoxyborane performed in an aprotic polar solvent, preferably acetonitrile,
at a temperature comprised between 20° C. to 50° C., in particular comprised between 20° C. to 30° C., preferably equal to about 25° C., during a time ranging from 2 h to 4 h, preferably 2.5 h,
for the preparation of an dialkoxyarylborane.
According to a particularly advantageous embodiment, the step of mixing an arenediazonium salt or a heteroareneazonium salt with an alkoxyborane is performed in an aprotic polar solvent, preferably acetonitrile,
in the presence of an activating agent containing a transition metal, said activating agent being chosen among metallocenes, in particular ferrocenes, titanocenes, or zirconocenes, preferably Cp2Fe, Cp2TiCl2 or Cp2ZrHCl, with a molar percentage relative to the metal comprised from 0.001% to 5%, in particular comprised from 0.001% to 1%, preferably equal to about 0.001%, or about 0.01%, or about 0.1% or about 1%,
at a temperature comprised between 20° C. to 50° C., in particular comprised between 20° C. to 30° C., preferably equal to about 25° C., during a time ranging from 2 h to 4 h, preferably 2.5 h,
for the preparation of a dialkoxyarylborane compound.
According to a particular embodiment, the process of the invention comprises a step of preparation of an arenediazonium salt or of a heteroarenediazonium salt of formula Ar—N2A, in situ.
The anilines are commercially available. The choice of an arenediazonium salt is thus very large. The following equation represents the oxidation reaction of an aniline with an alkylnitrite, preferably isoamylnitrite in the presence of trifluoroborane etherate, i,e, Et2O—BF3, to give a suspension or a solution of an arenediazonium tetrafluoroborate which can be used directly in the arylation reaction in the presence or not in presence of an activating agent:
The aryl group is substituted or not, as mentioned above.
If the arenediazonium salt is isolated, the reaction is performed with NaNO2 and HBF4.
According to a particular embodiment, the process of the invention comprises a step (2) of recovery and purification of the amino arylborane obtained at step (1).
The aminoarylborane can be isolated and purified by a bulb to bulb distillation.
According to a particular embodiment, the process of the invention comprises after step (1) or (2), a step (3) of treatment of the arylborane obtained at step (1) or (2), into an arylborane which is different from the one obtained at step (1) or (2), said treatment being in particular an alcoholysis, preferably with a first alcohol, in particular methanol, said alcoholysis possibly followed
wherein R8, R8a and Ar have the above mentioned meanings,
in particular for the preparation of a cyclic aryldialkoxyborane,
preferably for the preparation of an arylpinacolborane of the following formula VIA
wherein Ar has the above mentioned meanings,
wherein Ar has the above mentioned meanings.
Thus, the boronic esters are prepared according to a tandem arylation/functional modification on the boron atom, this treatment consisting in a methanolysis followed by a trans esterification.
The boronic acids are prepared by the same way as the boronic esters replacing the transesterification by an hydrolysis.
The boronic esters can be prepared in one step, by arylation of a boronate, or in two steps, via an aminoarylborane, the latter way being preferred.
The process of the present invention relates particularly to the preparation of the diisopropylaminoarylboranes of formulas represented below,
said diisopropylaminoboranes being isolated and purified, or not:
In another embodiment, the process of the present invention relates to the preparation of the arylpinacolboranes of following formula VIA
wherein Ar has the above mentioned meanings,
said arylpinacolboranes being recovered and purified, and being in particular
whererin —B(pin) represents:
In a particular embodiment, the process of the invention comprises:
in a reaction medium containing a solvent, in the absence of base, in the presence of 0.1% Cp2Fe as activating agent,
for the preparation of a diisopropylaminoarylborane compound of formula VA,
wherein compound VA has the above mentioned meanings,
wherein —B(pin) represents:
A two step procedure, step (1) being the arylation reaction followed by a step (2) of methanolysis with further transesterification, leads to stable arylboronates, with most yields comprised in the 65-90% yield range with an activating agent containing iron. No real trend could be determined between electron donating or withdrawing groups. Methyl and methoxy groups (compounds VIA1 to VIA5) led to 47 to 87% isolated yield whereas reaction on arenediazonium salts bearing electron withdrawing groups afforded the corresponding arylboronates in 55-91% yield (compounds VIA6 to VIA10). Fluorine and chlorine substituted arylboronates were obtained in 61-71% yield (compounds VIA12 to VIA19). One advantage of this method is the compatibility with bromides and iodides. Few methods allow to synthesize selectively bromine or iodine substituted boron derivatives. In the process of the invention, the selectivity is very good as no reaction is observed when iodobenzene or bromobenzene are placed in the same reaction conditions. Hence, bromo- and iodo-substituted pinacol benzeneboronate were isolated in 65-74% yield (compounds VIA21 to VIA24). But the reaction on 4-benzoyl substituted arenediazonium salts lead to benzophenone resulting from the competitive direct reduction of the C—N into C—H bond (compound VIA21). Bis boronates were also synthesized in good yield considering that the resulting product arose from 6 consecutive reactions with an average of 91% yield per transformation (compound VIA26).
In a particular embodiment, the process of the invention comprises:
In a particularly advantageous embodiment, the process of the invention comprises:
Using a tubular reactor is particularly advantageous because the method can be used on industrial scale (FIGURE I). One of the advantages is to work with low concentrations of reagents, thus decreasing the undesirable side reactions, and resulting in a constant final product quality and a low cost of working.
According to an embodiment, the process comprises a step of detection of an aniline possibly substituted by the same substituents as the ones of the arenediazonium salt.
Beside the arylation reaction, a competitive reaction of reduction of the arenediazonium or heteroarenediazonium salt may occur, resulting in the formation of the corresponding aniline, in a molar percentage varying from 0 to 3 percent.
FIGURE I represents a flow arylation reaction between diisopropylaminoborane and an aryldiazonium salt catalysed by ferrocene on a scheme showing the tubular system used in the process (see example 1).
R1 represents a pre-reactor, R2 represents a reactor, T represents a T device and “d” represents a syringe.
GC-MS analysis were performed with a HP 6890 series GC-system equipped with a J&W Scientific DB-1701 capillary column, a HP 5973 mass selective detector (EI) using the following method: 70° C. for 1 min then 20° C.·min−1 until 230° C. then 6 min at 230° C. 1H, 11B, 13C, 19F and 31P NMR were recorded on 300 MHz Avance I and 400 MHz Avance II spectrometers. The chemical shifts (6) and coupling constants (J) are expressed in ppm and Hertz respectively.
Pinacol and pinacolborane were purchased from Sigma-Aldrich. Pinacol was distilled before use. Anilines were used without further purification. Diisopropylaminoborane was prepared as described in literature. All catalytic reactions were carried out under argon atmosphere unless specified. All chemicals were stored under argon. Acetonitrile was distilled over CaH2. Silica gel (230-400 mesh) purchased from Merck was used for flash chromatography. Analytical TLC silica gel 60 F254 were used.
Ferrocene is Cp2Fe.
NMR: nuclear magnetic resonance, and to describe the multiplicities: s=singlet, d=doublet,
m=multiplet.
TLC: thin layer chromatography
GC-MS: gas chromatography—mass spectrum
tR: retention time
wt: weight
PTFE: polytetrafluoroethylene
i.d.: internal diameter
M: mol/L
DMAc: dimethylacetamide
NMP: N-methyl-2-pyrrolidone
Cp*: 1,2,3,4,5-pentamethylcyclopentadienyl group.
General Procedure A: Synthesis of Aryldiazonium Salt or Heteroaryl Diazonium Salt, Isolated from the Reaction Medium
To a suspension of aniline in water is added, at 0° C., HBF4 (50% wt in water) and the mixture is stirred 10 min at 0° C. A saturated solution of NaNO2 in water is then slowly added and the resulting mixture is stirred for 1 h at 0° C. The precipitate is collected by filtration, washed successively with cold water, cold Et2O/MeOH 70/30 and Et2O. The crude diazonium salt is purified by Et2O precipitation from a saturated acetone solution, the solid is then triturated with Et2O and dried under vacuum to afford pure arene diazonium salt or heteroarenediazonium salt.
General Procedure B: Tandem Diazotation/Borylation Sequence of Aniline to Aryl Boronate
To a solution of aniline (1 mmol) in 3 ml of distillated acetonitrile, at 0° C., is added boron trifluoride etherate (1.5 mmol 0.4 ml) and the solution is stirred for 5 minutes. Isoamyl nitrite (1.2 mmol, 0.2 ml) is then slowly added and the solution is stirred for 15 minutes. Diisopropylamino borane (4 mmol, 0.6 ml) is then slowly added and the mixture is allowed to be stirred at room temperature for 3 hours. The reaction is then quenched, at 0° C., by the slow addition of 2 ml of distillated methanol and stirred 1 hour at room temperature. The mixture is concentrated under vacuum and a solution of pinacol (1.3 mmol, 153 mg) in 2 ml of diethyl ether is added and the mixture is stirred 4 hours at room temperature. 10 ml of diethyl ether is then added and the crude is washed three time with 6 ml of a aqueous solution of copper chloride (50 g/L). The organic phase is then filtered and died over Na2SO4 and concentrated under vacuum to afford pure aryl boronate.
113 mg of 2-(4-methoxy-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure B using 123 mg of 4-methoxyaniline as a pale yellow oil, yield: 52.5%.
1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=8.7 Hz, 2H) 6.90 (d, J=8.7 Hz, 2H) 3.83 (s, 3H) 1.33 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 31.05
13C NMR (75 MHz, CDCl3) δ
MS (EI) tR=9.05 min; m/z: 234 (M+., 100%)
Procedure C: Synthesis of Diisopropylaminoborane
To a stirred solution of diisopropylamine (70.6 mL, 0.5 mol, 1 eq) in THF (200 mL) were added at 0° C. 20.4 mL of H2SO4 (0.75 mol, 0.5 eq). A white precipitate appears immediately. After 15 min at 0° C., were carefully added 28.4 g of NaBH4 (0.75 mol, 1.1 eq) in powder. The mixture was allowed to warm to room temperature and stirred for 3 h. The crude was concentrated under vacuum and the residue was taken with toluene, washed with water (4×100 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give the amine-borane complex as a colorless oil. The amine-borane complex was refluxed at 210° C. with a sand bath in the presence of a bubbling device to observe the formation of hydrogen. After the completion of the dehydrogenation (about 1 h 30), a distillation apparatus was installed and the aminoborane was distillated under argon to give a 51 g of colorless liquid (90% yield).
A 10 m segment of PTFE tubing (0.81 mm i.d., 5 ml total volume) was wrapped in a circular-like form to favoring mixing and reactor heat (R2, see
In a dried tube reactor under argon as described in example 2, the arenediazonium salt (1 mmol) and the ferrocene (10 μmol, 1.8 mg) were dissolved in 2 mL of anhydrous CH3CN. Diisopropylaminoborane (2 mmol, 226 mg) was then added to the solution and the mixture was stirred for 2 h 30 at room temperature. The reaction mixture was quenched by a slow addition of anhydrous MeOH at 0° C. (2 mL) and stirred for an additional hour at room temperature. After removal of all the volatiles, 1.3 eq of pinacol was added in Et2O (2 mL), the mixture was stirred 4 h at room temperature. The crude mixture was washed with a 50 g/L CuCl2 solution (2×5 mL). The organic layer were separated, dried over Na2SO4, filtered and concentrated to dryness. The resulted oil was dissolved with CH2Cl2 and filtered of a pad of silica gel, eluting with CH2Cl2 to afford the corresponding boronate.
175 mg of 2-(4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 206 mg of 4-methylbenzenediazonium tetrafluoroborate as a pale yellow oil, with an 80% isolated yield.
1H NMR (300 MHz, CDCl3): δ 7.71 (d, J=7.9 Hz, 2H) 7.19 (d, J=7.6 Hz, 2H) 2.37 (s, 3H) 1.34 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 31.39
13C NMR (75 MHz, CDCl3) δ 141.55; 134.94; 128.66; 83.76; 24.99; 21.88
MS (EI) tR=7.95 min; m/z: 218 (M+., 100%)
161 mg of 2-(1-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 222 mg of 2-methoxybenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 69%.
1H NMR (300 MHz, CDCl3) δ 7.67 (dd, J=7.3, 1.8 Hz, 1H), 7.39 (ddd, J=8.5, 7.5, 1.9 Hz, 1H), 6.94 (t, J=7.3 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 3.83 (s, 3H), 1.36 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 31.09
13C NMR (75 MHz, CDCl3) δ 136.69, 132.43, 120.21, 110.51, 83.45, 55.84, 24.84
134 mg of 2-(3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 222 mg of 3-methoxybenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 57%.
1H NMR (300 MHz, CDCl3) δ 7.40 (d, J=7.2 Hz, 1H) 7.36-7.31 (m, 1H) 7.28 (d, J=7.3 Hz, 1H) 7.01 (ddd, J=8.2, 2.8, 1.1 Hz, 1H) 3.83 (s, 3H) 1.35 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 31.37
13C NMR (75 MHz, CDCl3) δ 159.20, 129.07, 127.33, 118.88, 118.05, 83.97, 55.39, 25.00. MS (EI) tR=8.90 min; m/z: 234 (M+., 100%)
204 mg of 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 222 mg of 4-methoxybenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 87%.
1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=8.7 Hz, 2H) 6.90 (d, J=8.7 Hz, 2H) 3.83 (s, 3H) 1.33 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 31.05
13C NMR (75 MHz, CDCl3) δ
MS (EI) tR=9.05 min; m/z: 234 (M+., 100%)
139 mg of 2-(3,4,5-trimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 284 mg of 3,4,5-trimethoxybenzenediazonium tetrafluoroborate as a pale yellow oil with an isolated yield of 47%.
1H NMR (300 MHz, CDCl3) δ 7.04 (s, 2H) 3.90 (s, 6H) 3.87 (s, 3H) 1.34 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 32.00
13C NMR (75 MHz, CDCl3) δ 153.07; 141.08; 111.52; 84.02; 60.93; 56.32; 25.00
MS (EI) tR=11.65 min; m/z: 296 (M+., 100%)
176 mg of 2-(3-iodophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 237 mg of 4-nitrobenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 71%.
1H NMR (300 MHz, CDCl3) δ 8.19 (d, J=8.7 Hz, 2H) 7.96 (d, J=8.7 Hz, 2H) 1.37 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 30.87
13C NMR (75 MHz, CDCl3) δ 135.80; 122.56; 84.78; 25.02
MS (EI) tR=10.31 min; m/z: 249 (M+., 100%)
171 mg of 2-(3-trifluoromethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 260 mg of 3-trifluoromethylbenzenediazonium tetrafluoroborate as a pale yellow oil.
1H NMR (300 MHz, CDCl3) δ 7.97 (d, J=7.4 Hz, 1H) 7.70 (d, J=7.9 Hz, 1H) 7.48 (t, J=7.6 Hz, 1H) 1.36 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 30.48
13C NMR (75 MHz, CDCl3) δ 138.12; 128.16; 127.94; 118.30; 84.43; 25.02
MS (EI) tR=7.02 min; m/z: 272 (M+., 100%)
127 mg of 2-(4-cyanophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 217 mg of 4-cyanobenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield 55%.
1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=8.1 Hz, 1H) 7.64 (d, J=8.2 Hz, 1H) 1.35 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 30.37
13C NMR (75 MHz, CDCl3) δ
MS (EI) tR=9.52 min; m/z: 229 (M+., 100%)
220 mg of 2-(3,5-ditrifluoromethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 328 mg of 3-5-ditrifluoromethylbenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 65%.
1H NMR (300 MHz, CDCl3) δ 8.23 (s, 2H) 7.94 (s, 1H) 1.37 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 30.21
13C NMR (75 MHz, CDCl3) δ 134.79; 131.29; 130.85; 125.47; 124.87; 121.85; 85.01; 25.01
MS (EI) tR=6.33 min; m/z: 340 (M+., 100%)
214 mg of 2-(2-methyl-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 251 mg of 2-methyl-3-nitrobenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 91%.
1H NMR (300 MHz, CDCl3) δ 7.94 (dd, J=7.4, 1.2 Hz, 1H), 7.80 (dd, J=8.1, 1.3 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 2.67 (s, 3H), 1.36 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 31.55
13C NMR (75 MHz, CDCl3) δ 139.77, 138.27, 126.26, 125.88, 84.38, 24.99, 18.01.
MS (EI) tR=10.99 min; m/z: 263 (M+., 100%)
127 mg of phenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 192 mg of benzenedizaonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 62%.
1H NMR (300 MHz, CDCl3) δ 7.81 (dd, J=8.0, 1.4 Hz, 2H) 7.49 (m, 2H) 7.39 (m, 2H)
11B NMR (100 MHz, CDCl3) δ 31.10
13C NMR (75 MHz, CDCl3) δ 134.86; 131.39; 127.84; 83.90; 25.01
MS (EI) tR=7.22 min; m/z: 204 (M+., 100%)
135 mg of 2-(2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 210 mg of 2-fluorobenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 61%.
1H NMR (300 MHz, CDCl3) δ 7.78-7.70 (m, 1H), 7.49-7.38 (m, 1H), 7.14 (t, J=7.4 Hz, 1H), 7.03 (t, J=8.9 Hz, 1H)
11B NMR (100 MHz, CDCl3) δ 29.92
13C NMR (75 MHz, CDCl3) δ 169.01, 165.68, 137.01, 136.90, 133.44, 133.32, 123.73, 123.69, 115.54, 115.23, 84.03, 24.97
156 mg of 2-(3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 210 mg of 3-fluorobenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 70%.
1H NMR (300 MHz, CDCl3) δ 7.57 (d, J=7.3 Hz, 1H) 7.48 (dd, J=9.2, 2.7 Hz, 1H) 7.40-7.29 (m, 1H) 7.13 (dddd, J=9.2, 8.3, 2.8, 1.1 Hz, 1H) 1.35 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 30.83
13C NMR (75 MHz, CDCl3) δ 130.45; 129.64; 129.55; 121.24; 120.98; 118.43; 118.15; 84.24; 25.01
MS (EI) tR=7.17 min; m/z: 222 (M+., 100%)
135 mg of 2-(3-iodophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 210 mg of 4-fluorobenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 61%.
1H NMR (300 MHz, CDCl3) δ 7.80 (dd, J=8.6, 6.3 Hz, 1H), 7.09-6.99 (m, 1H), 1.34 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 30.26
13C NMR (75 MHz, CDCl3) δ 166.91, 163.59, 137.18, 137.07, 115.11, 114.84, 84.05, 25.01.
MS (EI) tR=7.07 min; m/z: 222 (M+., 100%)
118 mg of 2-(2-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 226 mg of 2-chlorobenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 49%.
1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=6.9 Hz, 1H) 7.39 (m, 2H) 7.28 (m, 1H) 1.4 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 31.17
13C NMR (75 MHz, CDCl3) δ 139.68; 136.54; 131.97; 129.52; 125.94; 84.28; 24.94
MS (EI) tR=8.56 min; m/z: 238.5 (M+., 100%)
143 mg of 2-(3-iodophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 226 mg of 3-chlorobenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 70%.
1H NMR (300 MHz, CDCl3) δ 7.78 (s, 1H) 7.67 (d, J=7.3 Hz, 1H) 7.42 (d, J=8.1 Hz, 1H) 7.30 (t, J=7.7 Hz, 1H)
11B NMR (100 MHz, CDCl3) δ 30.40
13C NMR (75 MHz, CDCl3) δ 134.7; 134.18; 132.79; 131.40; 129.32; 84.29; 25
MS (EI) tR=8.43 min; m/z: 238.5 (M+., 100%)
170 mg of 2-(3-iodophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 226 mg of 4-chlorobenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 71%.
1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=8.4 Hz, 2H) 7.34 (d, J=8.4 Hz, 2H) 1.34 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 30.93
13C NMR (75 MHz, CDCl3) δ 136.27; 128.16; 84.17; 25.02
MS (EI) tR=8.37 min; m/z: 338.5 (M+., 100%)
179 mg of 2-(3,5-dichlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 261 mg of 3,5-dichlorobenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 66%.
1H NMR (300 MHz, CDCl3) δ 7.25 (s, 2H) 7.44 (s, 1H) 1.34 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 29.94
13C NMR (75 MHz, CDCl3) δ 134.88; 132.85; 131.23; 84.67; 24.99
MS (EI) tR=9.27 min; m/z: 273 (M+., 100%)
187 mg of 2-(3,4-dichlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 261 mg of 3,4-dichlorobenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 68%.
1H NMR (300 MHz, CDCl3) δ 7.68 (d, J=6.9 Hz, 1H) 7.35 (m, 2H) 7.23 (m, 1H) 1.37 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 31.17
13C NMR (75 MHz, CDCl3) δ 136.71; 135.66; 133.90; 132.43; 130.16; 84.5; 25
MS (EI) tR=9.57 min; m/z: 273 (M+., 100%)
210 mg of 2-(3-iodophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 271 mg of 2-bromobenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 74%.
1H NMR (300 MHz, CDCl3) δ 7.61 (dd, J=6.8, 2.3 Hz, 1H) 7.54 (dd, J=7.1, 1.9 Hz, 1H) 7.26 (m, 2H) 1.38 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 31.23
13C NMR (75 MHz, CDCl3) δ 136.36, 132.63, 131.82, 128.02, 126.26, 84.30, 24.81.
MS (EI) tR=9.10 min; m/z: 283 (M+., 100%)
204 mg of 2-(3-iodophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 271 mg of 3-bromobenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 72%.
1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=7.3 Hz, 1H) 7.62 (ddd, J=8.0, 2.0, 1.1 Hz, 1H) 7.27 (d, J=7.7 Hz, 1H) 1.38 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 30.65
13C NMR (75 MHz, CDCl3) δ 137.63, 134.32, 133.23, 129.63, 122.60, 84.31, 25.01.
MS (EI) tR=9.03 min; m/z: 283 (M+., 100%)
184 mg of 2-(3-iodophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 271 mg of 4-bromobenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 65%.
1H NMR (300 MHz, CDCl3) δ 7.66 (d, J=8.2 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 1.34 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 31.04
13C NMR (75 MHz, CDCl3) δ
MS (EI) tR=8.99 min; m/z: 283 (M+., 100%)
230 mg of 2-(3-iodophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 318 mg of 3-iodobenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 70%.
1H NMR (300 MHz, CDCl3) δ 8.14 (s, 1H) 7.74-7.80 (m, 2H) 7.11 (t, J=7.6 Hz, 1H) 1.34 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 30.2
13C NMR (75 MHz, CDCl3) δ 25.0; 31.1; 84.3; 94.4; 129.8; 133.8; 140.2; 143.6
GC-MS (EI) tR=9.80 min; m/z: 330 (M+., 100%)
244 mg of 2-(3-iodophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 318 mg of 4-iodobenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 74%.
1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=8.7 Hz, 1H) 6.90 (d, J=8.7 Hz, 1H) 3.83 (s, 3H) 1.33 (s, 12H)
11B NMR (100 MHz, CDCl3) δ 31.02
13C NMR (75 MHz, CDCl3) δ 139.48; 137.06; 136.42; 98.95; 84.18; 25.00
MS (EI) tR=9.80 min; m/z: 330 (M+., 100%)
234 mg of bis(4′-(3,3,4,4-tetramethyl-2,5,1-dioxaboryl)phenyl)methane were obtained following the general procedure D according to example 3, using 396 mg of bis(4′-benzene)methanediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 56%.
1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=8.0 Hz, 4H) 7.25 (d, J=8.0 Hz, 4H) 4.07 (s, 2H) 1.40 (s, 24H)
11B NMR (100 MHz, CDCl3) δ 31.35
13C NMR (75 MHz, CDCl3) δ 144.24, 135.15, 130.13, 129.05, 128.56, 126.22, 115.49, 83.82, 42.45, 24.99.
2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, Compound VIA4,
was prepared according to example 3 (Cp2Fe), by varying the solvent.
VIA4 was isolated with a:
2-(4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, compound VIA1,
was prepared according to example 3, using Cp2TiCl2 as activating agent, in a solvent containing 5% NMP.
VIA1 was isolated with a:
2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, compound VIA4,
was prepared according to example 3, by varying the activating agent.
VIA4 was isolated with a:
Compound VIA4 was prepared according to example 3, in the absence of ferrocene, or in the presence of various amounts of ferrocene. The isolated yields are:
Compounds VIA1 to VIA22, VIA24 and VIA26 were prepared using the procedure D (example 3), by replacing the ferrocene (1%) by the titanocene Cp2TiCl2 (1%). The yields are shown in the table 1
[a]isolated yield
2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, compound VIA4,
was prepared according to example 33, by varying the activating agent containing titanium.
VIA4 was isolated with a:
Compound VIA4 was prepared according to example 3, in the absence of titanocene, or the presence of various amounts of titanocene Cp2TiCl2. The isolated yields are:
Compounds VIA1 to VIA26 were prepared using the procedure D (example 3), by replacing the ferrocene (1%) by Schwartz's reagent Cp2ZrHCl (1%). Compounds VIA1 to VIA26 were thus prepared. The yields are shown in the table 2.
[a]isolated yield
2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, compound VIA4,
was prepared according to example 3, by varying the activating agent containing zirconium, VIA4 was isolated with a:
2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, compound VIA4,
was prepared according to example 3, by varying the activating agent containing cobalt, nickel or ruthenium, in the amount of 1%.
VIA4 was isolated with a:
Compounds VIA1 to VIA26 were prepared using the procedure D (example 3) without any activating agent. The yields are shown in the table 3.
[a]isolated yield
In a dried tube reactor under argon (see example 2), were dissolved the 4-methoxybenzene diazonium tetrafluoroborate salt (1 mmol, 222 mg) and ferrocene (10 μmol, 1.8 mg) in 2 mL of anhydrous CH3CN. Pinacolborane (2 mmol 256 mg) was then added to the solution and stirred for 2 h 30 at room temperature. The reaction mixture was quenched by a slow addition of anhydrous MeOH at 0° C. (2 mL) and stirred for an additional hour at room temperature. After removal of all the volatiles, the crude mixture was taken in diethyl ether and washed with a 50 g/L CuCl2 solution (2×5 mL). The organic layer were separated, dried over Na2SO4, filtered and concentrated in vacuo. The resulted oil was dissolved with CH2Cl2 and filtered of a pad of silica gel, eluted with CH2Cl2 to afford the corresponding boronate in 3% yield.
To a solution of aniline (1 mmol) in 3 ml of freshly distilled acetonitrile, at 0° C., was added boron trifluoride etherate (1.5 mmol 0.4 ml) and the solution stirred for 5 minutes. Isoamyl nitrite (1.2 mmol, 0.2 ml) was then slowly added and the solution stirred for 15 minutes. Diisopropylaminoborane (4 mmol, 0.6 ml) was then slowly added and the mixture was stirred at room temperature for 3 hours. The reaction was then quenched, at 0° C., by the slow addition of 2 ml of distillated methanol and stirred 1 hour at room temperature. The mixture was concentrated under vacuum and a solution of pinacol (1.3 mmol, 153 mg) in 2 ml of diethyl ether was added and the mixture stirred for 4 hours at room temperature. 10 ml of diethyl ether were then added and the crude washed three times with 6 ml of an aqueous solution of copper chloride CuCl2 (50 g/L). The organic phase was then filtered and dried over Na2SO4 and concentrated under vacuum to afford pure arylboronate.
After reaction, the product was isolated by bulb to bulb distillation.
The anilines have the following formula, wherein the position(s) of the substituent(s) is (are) indicated by a number, reported in the table 4, as well as their nature:
| Number | Date | Country | Kind |
|---|---|---|---|
| 12305854.7 | Jul 2012 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2013/063572 | 6/27/2013 | WO | 00 |
