WO2017044043A1

WO2017044043A1 - Process for direct amidation of amines via rh(i)-catalyzed addition of boroxines

Info

Publication number: WO2017044043A1
Application number: PCT/SG2016/050432
Authority: WO
Inventors: Yugen Zhang; Shu Wen Diane LIM
Original assignee: Agency For Science, Technology And Research
Priority date: 2015-09-09
Filing date: 2016-09-02
Publication date: 2017-03-16

Abstract

This invention relates to a process for making an amide by directly reacting a ferf-butyloxycarbonyl or carboxybenzyl N substituted amine with a boroxine derivative in the presence of a rhodium(l) catalyst, in the presence of a solvent an optionally in the presence of a base. The process provides means to react protected amines to amides using th boroganic reagent without the deprotection of an amine such that it can be directly converted from protected form in on step, and results in good yields in amide formation even for sterically hindered amines. Potassium fluoride is the preferre base in the reaction run in dioxane. Typical rhodium catalysts that can be used include rhodium(l) complex monomer and dimers such as chloro(1,5-cyclooctadiene) rhodium(l) dimer ("[CI(cod)Rh]₂") or bis(1,5-cyclooctadiene)rhodium(l trifluoromethanesulfonate ("(cod)₂Rh(OTf)").

Description

Process for direct Amidation of Amines via Rh(I)-Catalyzed Addition of Boroxines

Technical Field

The present invention generally relates to a process for making amides by direct reaction of a protected amine in the presence of a rhodium catalyst with an organoboron reagent.

Background Art

Amide bonds feature prominently in biologically active small molecules, with amide bond formation estimated to constitute 1 in 6 of all reactions performed in drug molecule synthesis. Traditional amide synthesis by dehydrative condensation between an amine and carboxylic acid is dependent on coupling reagents that activate the carboxylic acid to nucleophilic amine attack. Despite the success of this approach, the stoichiometric application of coupling reagents inherently limits the overall atom economy of the reaction and the use of excess reagent alongside formation of organic by-products complicates isolation and purification of the final product. Furthermore, carbodiimides, the most frequently employed class of coupling reagent, can behave as sensitizers if present even as trace impurities in the final drug candidate. In light of this, there is a need for new catalytic methods for amide bond synthesis eschewing high molecular weight reagents for more efficient and environmentally benign drug molecule synthesis and production.

A catalytic amide synthesis can proceed via C-C bond formation between organometallic nucleophiles and isocyanates or carbamoyl chlorides. Such a method has been widely reported using complexes of palladium, rhodium or ruthenium. An assortment of organometallic partners has been generated by transition-metal insertion into halides, ethers, organoborons, organostannanes and organozincs, as well as by directed C-H activation. Recent work has suggested earth- abundant first-row transition metals cobalt and copper as viable catalysts for this transformation. In addition, access to sterically -hindered and electron-deficient amides by this disconnection has been also demonstrated. Despite these advances, application of such methodologies is limited by the high reactivity of isocyanates and carbamoyl chlorides, necessitating their installation immediately prior to amidation, thereby introducing an additional functional group interconversion to the synthetic route. In contrast, carbamates are widely utilized in multistep syntheses as common protecting groups for amines, and in many instances already bound to amines destined for condensation with a carboxylic acid to construct an amide linkage.

Therefore a process is desirable that can utilize these protected amines directly in a amidation reaction without a need of prior deprotection and further coupling reaction which is routinely done in traditional amide synthesis (see Figure 1). Summary of Invention

According to the invention a metal-catalyzed amidation is provided that allows making secondary benzamides directly from N-feri-butoxycarbonyl (N-Boc) or N- benzyloxycarbonyl (N-Cbz) amines via C-0 bond cleavage and new C-C bond formation.

According to a first aspect, there is provided a process for making an amide by directly reacting a feri-butyloxycarbonyl or carboxybenzyl N-substituted amine (N-Boc or N-Cbz protected amine) with a boroxine derivative in the presence of a rhodium(I) catalyst, in the presence of a solvent and optionally in the presence of a base. Advantageously, the invention utilizes the protected amine for a direct reaction with the organoboron reagent without a need of cleavage of the protecting group. Using boroxines in the presence of Rh(I) complexes as catalysts at lower temperatures in an inert organic solvent the formation of amidine side products can be avoided or reduced significantly. Advantageously a direct amidation can be achieved in this catalytic system with yields of about 90 %.

In one embodiment, potassium fluoride is used as a base in the amidation reaction. It has been found that higher yields of about 90 % or more can be obtained using this base.

In another embodiment the boroxine is a trisaryl- or trisheteroarylboroxine. Advantageously, arylboroxines featuring extended aromatic systems, alkyl-substitution in the ortho-position, and electron-donating functional groups can be smoothly converted in the amidation. Electron-poor boroxines with electron-withdrawing ester, trifluoromethyl and nitro groups in the para and meta-positions are tolerated in the inventive process. Halide-substituted arylboroxines may offer the possibility of further diversification of the benzamide, and these were found to be excellent substrates in the process according to the invention where the halide was chloride or bromide.

In another embodiment the amine which is used in protected form is an optionally substituted aromatic amine. Advantageously these amines with electron-donating and halide substituents can be converted to amides with satisfactory to excellent conversion rates. Amines with silyl ether functional groups on the aryl moiety are tolerated by this amidation and can be converted well without loss of the functionality. Advantageously the organoboron addition is selective for the amidation even in the presence of Michael acceptors. Further advantageously amines with sterical hindrance due to ortho-substituents of the aryl moiety linked to the protected N-atom can be converted in the process.

Further embodiments relate to processes wherein the amine which is used in protected form is an optionally substituted alkyl amine. Using monomeric rhodium(I) catalyst these amines advantageously can be amidated with the arylboroxines in high yields.

7¾ri-butyloxycarbonyl and carboxybenzyl N-substituted amines can be used as substrates. Advantegeously, carboxybenzyl N-substituted amines (N-Cbz amines) were readily transformed to the corresponding amides under fluoride -promoted rhodium(I) catalysis. The reaction profiles of these amines were generally cleaner than that of their tert- butyloxycarbonyl protected counterparts and corresponded to comparable or improved yields of amides. Definitions

The following words and terms used herein shall have the meaning indicated:

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features.

The term "teri-butyloxycarbonyl N-substituted amine" or "N-Boc amine" refers to an amine of which the amino function is protected with a feri-butyloxycarbonyl protecting group as carbamate.

The term "carboxybenzyl N-substituted amine" or "N-Cbz amine" refers to an amine of which the amino function is protected with a carboxybenzyl (or benzyloxycarbonyl) protecting group as carbamate.

In parts of the specification the term "amine" is used for the amine which is protected by the carboxybenzyl or feri-butyloxycarbonyl group and becomes the amine part of the amide made by the process according to the invention.

The term "boroxine" as use herein, may refer in a narrow meaning to B₃H₃0₃, a 6-membered, heterocyclic compound composed of alternating oxygen and singly -hydrogenated boron atoms, but in a broad meaning may also refer to boroxine derivatives.

The term "boroxine derivative" refers to a B₃H₃O₃ wherein the hydrogen atoms are replaced with other groups. Examples include Triphenyl boroxine or Trimethyl boroxine.

The term "TBSO" refers to a feri-butyldimethylsilyloxy group.

As used herein, the term "alkyl group", if not defined otherwise for a specific group, includes within its meaning monovalent ("alkyl") and divalent ("alkylene") straight chain or branched chain saturated aliphatic groups having from 1 to 10 carbon atoms, eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. For example, the term alkyl includes, but is not limited to, methyl, ethyl, 1 -propyl, isopropyl, 1 -butyl, 2-butyl, isobutyl, tert- butyl, amyl, 1,2- dimethylpropyl, 1,1-dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2- dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, 2- ethylpentyl, 3-ethylpentyl, heptyl, 1 -methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3- trimethylbutyl, 1, 1,2-trimethylbutyl, 1,1,3-trimethylbutyl, 5-methylheptyl, 1-methylheptyl, octyl, nonyl, decyl, and the like.

The term "alkenyl group" includes within its meaning monovalent ("alkenyl") and divalent ("alkenylene") straight or branched chain unsaturated aliphatic hydrocarbon groups having from 2 to 10 carbon atoms, eg, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms and having at least one double bond, of either E, Z, cis or trans stereochemistry where applicable, anywhere in the alkyl chain. Examples of alkenyl groups include but are not limited to ethenyl, vinyl, allyl, 1-methylvinyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 2-methyl- l-propenyl, 1- butenyl, 2-butenyl, 3-butentyl, 1,3-butadienyl, 1-pentenyl, 2-pententyl, 3-pentenyl, 4- pentenyl, 1,3-pentadienyl, 2,4-pentadienyl, 1,4-pentadienyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 2-methylpentenyl, 1-heptenyl, 2- heptentyl, 3-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, and the like.

The term "alkynyl group" as used herein includes within its meaning monovalent ("alkynyl") and divalent ("alkynylene") straight or branched chain unsaturated aliphatic hydrocarbon groups having from 2 to 10 carbon atoms and having at least one triple bond anywhere in the carbon chain. Examples of alkynyl groups include but are not limited to ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, l-methyl-2-butynyl, 3-methyl- l-butynyl, 1- pentynyl, 1-hexynyl, methylpentynyl, 1-heptynyl, 2-heptynyl, 1-octynyl, 2-octynyl, 1- nonyl, 1-decynyl, and the like.

The term "cycloalkyl" as used herein refers to cyclic saturated aliphatic groups and includes within its meaning monovalent ("cycloalkyl"), and divalent ("cycloalkylene"), saturated, monocyclic, bicyclic, polycyclic or fused polycyclic hydrocarbon radicals having from 3 to 10 carbon atoms, eg, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, 2-methylcyclopropyl, cyclobutyl, cyclopentyl, 2-methylcyclopentyl, 3-methylcyclopentyl, cyclohexyl, and the like,

The term "cycloalkenyl" as used herein, refers to cyclic unsaturated aliphatic groups and includes within its meaning monovalent ("cycloalkenyl") and divalent ("cycloalkenylene"), monocyclic, bicyclic, polycyclic or fused polycyclic hydrocarbon radicals having from 3 to 10 carbon atoms and having at least one double bond, of either E, Z, cis or trans stereochemistry where applicable, anywhere in the alkyl chain. Examples of cycloalkenyl groups include but are not limited to cyclopropenyl, cyclopentenyl, cyclohexenyl, and the like.

The term "heterocycloalkyl" as used herein, includes within its meaning monovalent ("heterocycloalkyl") and divalent ("heterocycloalkylene"), saturated, monocyclic, bicyclic, polycyclic or fused hydrocarbon radicals having from 3 to 10 ring atoms wherein 1 to 5 ring atoms are heteroatoms selected from O, N, NH, or S. Examples include pyrrolidinyl, piperidinyl, quinuclidinyl, azetidinyl, morpholinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.

The term "halogen" or variants such as "halide" or "halo" as used herein refers to fluorine, chlorine, bromine and iodine.

The term "heteroatom" or variants such as "hetero-" as used herein refers to O, N, NH and S.

The term "alkoxy" as used herein refers to straight chain or branched alkyloxy groups. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, and the like.

The term "amino" as used herein refers to groups of the form -NR R^b wherein R and R^b are individually selected from the group including but not limited to hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted aryl groups. The term "aryl" or "arylene" as used herein refers to monovalent ("aryl") and divalent ("arylene") single, polynuclear, conjugated and fused residues of aromatic hydrocarbons having from 6 to 10 carbon atoms. Examples of such groups include phenyl, biphenyl, naphthyl, phenanthrenyl, and the like.

The term "aralkyl" as used herein, includes within its meaning monovalent ("aryl") and divalent ("arylene"), single, polynuclear, conjugated and fused aromatic hydrocarbon radicals attached to divalent, saturated, straight and branched chain alkylene radicals.

The term "heteroaralkyl" as used herein, includes within its meaning monovalent ("heteroaryl") and divalent ("heteroarylene"), single, polynuclear, conjugated and fused aromatic hydrocarbon radicals attached to divalent saturated, straight and branched chain alkylene radicals. Unless specified otherwise, the terms "comprising" and "comprise", and grammatical variants thereof, are intended to represent "open" or "inclusive" language such that they include recited elements but also permit inclusion of additional, unrecited elements.

As used herein, the term "about", in the context of concentrations of components of the formulations, typically means +/- 5% of the stated value, more typically +/- 4% of the stated value, more typically +/- 3% of the stated value, more typically, +/- 2% of the stated value, even more typically +/- 1% of the stated value, and even more typically +/- 0.5% of the stated value.

Throughout this disclosure, certain embodiments may be disclosed in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosed ranges. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

Certain embodiments may also be described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the disclosure. This includes the generic description of the embodiments with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

Detailed Disclosure of Embodiments

Non-limiting embodiments of the invention will be further described in greater detail by reference to specific examples, which should not be construed as in any way limiting the scope of the invention.

According to a first aspect, there is provided a one-step process for making an amide by directly reacting a teri-butyloxycarbonyl or carboxybenzyl N-substituted amine with a boroxine derivative in the presence of a rhodium(I) catalyst, in the presence of a solvent and optionally in the presence of a base. The process is a one-step process. The amide is synthesized without isolation of a deprotected amine ("direct reaction").

The feri-butyloxycarbonyl N-substituted amine (or N-Boc amine) may preferably be a mono N-substituted amine. This means that the Boc group is the only N-substituent. It can be prepared according to well-known methods, such as the reaction of a respective isocyanate with tert-butanol at elevated temperatures or the reaction of the amine with di- tert-butyl dicarbonate in the presence of ethanol as solvent to form the N-Boc carbamate.

The carboxybenzyl N-substituted amine (or N-Cbz amine) may preferably be a mono N- substituted amine. This means that the Cbz group is the only N-substituent. It can be prepared according to well-known methods, such as the reaction of a respective isocyanate with benzyl alcohol at elevated temperatures to form the N-Cbz carbamate.

The amines which are used in N-substituted (or protected) form may be an in each case an optionally substituted alkyl amine or an optionally substituted aromatic amine.

The term "optionally substituted" may mean that aromatic, alkyl or cycloalkyl group or the substituents of these groups in the amine may be unsubstituted, or may be substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, thioalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, halogen, carboxyl, haloalkyl, haloalkynyl, hydroxyl, alkoxy, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, nitro, amino, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroheterocycloalkyl, alkylamino, dialkylamino, alkenylamino, alkynylamino, acyl, alkenoyl, alkynoyl, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, heterocycloxy, heterocycloamino, haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, alkylsilyloxy, phosphorus-containing groups such as phosphono and phosphinyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, cyano, cyanate, isocyanate, -C(0)NH(alkyl), and -C(0)N(alkyl)_2. The alkyl, alkenyl or alkynyl groups in the substituents are those defined above.

In case of the aromatic amine, the amino group is bound to an aromatic group. The "aromatic" group" may be a monovalent ("aryl") and divalent ("arylene") single, polynuclear, conjugated and fused residue of aromatic hydrocarbons having from 6 to 10 carbon atoms. Examples of such groups include phenyl, biphenyl, naphthyl, phenanthrenyl, and the like. The aromatic group, in a broader sense which is included, may further be a heteroaromatic group. The term "heteroaromatic group" includes within its meaning monovalent ("heteroaryl") and divalent ("heteroarylene"), single, polynuclear, conjugated and fused aromatic radicals having 6 to 20 atoms wherein 1 to 6 atoms are heteroatoms selected from O, N, NH and S. Examples of such groups include pyridyl, 2,2'-bipyridyl, phenanthrolinyl, quinolinyl, thiophenyl, and the like.

Preferably the aromatic group is an optionally substituted phenyl or coumarin group. Optional substituents of the substituents of the aromatic group that can be especially mentioned include methyl, isopropyl, methoxy, chlorine, bromine, nitro, tert-butyldimefhylsilyloxy. The aromatic group may be substituted by one or more substituents selected from this group. The inventive process is well suited for reacting sterically hindered aniline where the phenyl group has substituents in both ortho-positions to the amine.

Carboxybenzyl N-substituted amine can be amidated at very high yields according to another embodiment. High yields can then be obtained also with electron-withdrawing groups substituted arylboroxines, such as tri(3-nitrophenyl)boroxine. In case of the alkyl amine, the amino group is bound to an alkyl or cylcoalkyl group. The alkyl group itself may be further substituted by a cyloalkyl group or aryl group. The alkyl amine may be for instance selected from optionally substituted benzylamine, naphthylethylamine, cyclohexylamine or alkylamine. Optional substituents of the substituents of the alkyl amine that can be especially mentioned include methyl, -C0₂-phenyl or -0-C(phenyl)₃. The alkyl amine may be optionally substituted by one or more substituents selected from this group.

In case of alkyl amines in the inventive process a monomeric rhodium(I) catalyst may be preferred. Bis(l,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate ("(cod)₂Rh(OTf)" ) may be preferred as such monomeric catalyst.

The aromatic or alkyl amine introduces the amine part to the final amide.

According to the invention the protected amine is reacted with a boroxine derivative. The boroxine derivatives can be made by dehydration from commercially available boronic acids under reduced pressure and elevated temperatures according to known methods.

The boroxine derivative may be an in each case optionally substituted arylboroxine or heteroarylboroxine. The aryl group of the arylboroxine may be be a single, polynuclear, conjugated and fused residue of a hydrocarbon having from 6 to 10 carbon atoms. Examples of such groups include phenyl, biphenyl, naphthyl, phenanthrenyl, and the like. The heteroaryl group may be a single, polynuclear, conjugated and fused aromatic radicals having 6 to 20 atoms wherein 1 to 6 atoms are heteroatoms selected from O, N, NH and S. Examples of such groups include pyridyl, 2,2 '-bipyridyl, phenanthrolinyl, quinolinyl, thiophenyl, thiophenyland the like.

The boroxine derivate may be a trisarylboroxine or trisheteroarylboroxine of the formula (I),

(ArBO)₃ (I)

wherein Ar represents optionally methyl, methoxy, methoxycarbonyl, nitro, trifluoromethyl, chlorine or bromine substituted phenyl, naphthyl or thiophenyl.

The aryl group of the arylboroxine or the heteroaryl group of the heteroarylboroxine may be optionally substituted.

The term "optionally substituted" may mean that the aryl or heteroaryl group of the boroxine derivative may be unsubstituted, or may be substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, thioalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, halogen, carboxyl, haloalkyl, haloalkynyl, hydroxyl, alkoxy, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, nitro, amino, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroheterocycloalkyl, alkylamino, dialkylamino, alkenylamino, alkynylamino, acyl, alkenoyl, alkynoyl, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, heterocycloxy, heterocycloamino, haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, alkylsilyloxy, phosphorus-containing groups such as phosphono and phosphinyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, cyano, cyanate, isocyanate, -C(0)NH(alkyl), and -C(0)N(alkyl)_2. The alkyl, alkenyl or alkynyl groups in the substituents are those defined above.

According to the stoichiometry the boroxine derivatives can introduce up to three aryl or heteroaryl groups in to the amides made in the process. Usually the boroxines are used in equal stoichiometry or in stoichiometric excess to the amine in the amidation reaction. That means that molar ratio of amine to boroxine is about 1:0.33 to about 1 : 1. Preferably it is about 1 :0.4 to 1 :0.6, but it can be also be between 1 :0.25 to 1 :1,5.

The process of the invention is run in the presence of a rhodium(I) catalyst. Such rhodium(I) catalysts may a be rhodium(I) metal complex with organic molecules. They are known catalysts and commercially available. The process wherein the rhodium(I) catalyst is selected from a chloro(l,5-cyclooctadiene) rhodium(I) dimer ("[Cl(cod)Rh]₂") or bis(l,5- cyclooctadiene)rhodium(I) trifluoromethanesulfonate ("(cod)₂Rh(OTf)") may be specifically mentioned. rhodium(I) dimer complexes may be especially preferred for the reaction with aromatic amines.

The rhodium(I) catalyst can be used in all catalytic effective amounts. Typical amounts used for such rhodium(I) catalysts in the reaction are in the range of about 0.5 to 20 mol % compared to the amount of amine employed. More preferred ranges may be 2.5 to 5 mol % compared to the amount of amine employed.

The process is run in the presence of a solvent. In further embodiments, solvents from the class known as polar aprotic solvents may be mentioned as preferred. Examples of such polar aprotic solvents include diglyme, sulfolane, dimethylformamide (DMF), dioxane, acetonitrile, hexamethylphosphoramide (HMPA), dimethyl sulphoxide (DMSO) and N-methyl pyrrolidone (NMP). Anhydrous dioxane is most preferred.

The process according to the invention may be run in the presence of a base. Alkali metal alcoholates and alkali metal fluorides may be mentioned as suitable bases. Preferably the base in the process comprises a fluoride base. Potassium fluoride is a most preferred base. It may be used in anhydrous dioxane as solvent.

The amount of base used can be varied in broad ranges. Preferably the base is used in about equimolar amounts to the amine. It may however be also used in at a molar amount 20 % below or 50 % above the amount of amine to obtain high yields.

The reaction according to the invention can be run at elevated temperature. Temperatures of above about 80 °C may be used. Temperatures of about 100 °C to about 140 °C can be mentioned. The process can be used to obtain amides in high yields at lower temperatures of about 100 °C to about 110 °C. At such lower temperature range the presence of a potassium fluoride base may be especially preferred.

Examples

Non-limiting examples of the invention and a comparative example will be further described in greater detail by reference to specific Examples, which should not be construed as in any way limiting the scope of the invention.

Materials and Methods

All solvents were purchased from Sigma-Aldrich in anhydrous form and used without further purification. All other reagents were used as received, except where otherwise noted. rhodium(I) complexes were purchased from Strem or Sigma-Aldrich and used as received. All reactions were carried out under an argon atmosphere unless otherwise stated. Yields were usually determined after separation and purification by flash chromatography. Flash column chromatography was carried out on Kieselgel 60 (0.040-0.063 mm) supplied by Merck under positive pressure.

Amide products and side products (if applicable) were identified by meting points or spectroscopic methods. Melting points (mp) were measured on a Buchi Melting Point B - 540 apparatus. and ¹³C nuclear magnetic resonance (NMR) spectra were recorded on Bruker AV-400 (400 MHz) spectrometer. Chemical shifts (δ) were noted in parts per million (ppm) with the residual solvent peak of tetramethylsilane used as the internal standard at 0.00 ppm. 'H NMR data are reported in the following order: chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet and m = multiplet), coupling constants (J, Hz), integration and assignment. High resolution mass spectra (HRMS) were recorded on a Bruker micrOTOF-QII spectrometer.

Description of Drawings

The accompanying drawings illustrate a disclosed embodiment or reaction scheme and serve to explain the principles of the disclosed embodiments. It is to be understood, however, that the drawings are designed for purposes of illustration of examples only, and not as a limitation of the invention.

Fig.l

[Fig. 1] is a schematic drawing of the new reaction pathway.

Fig.2

[Fig. 2] is a schematic drawing of the initial results with comparative processes.

Fig.3

[Fig. 3] shows examples of various (hetero)arylboroxine substitutions. Reaction conditions: la (0.5 mmol), arylboroxine (0.2 mmol), [Cl(cod)Rh]2 (0.0125 mmol), KF (0.5 mmol), dioxane (1 mL), 100 °C, 16 h. 24 h Reaction time; ^b 0.6 mmol of heteroarylboroxine employed.

Fig.4

[Fig. 4] shows examples of various N-Boc aniline substitutions. Reaction conditions: N-Boc amine (0.5 mmol), 6a (0.2 mmol), [Cl(cod)Rh]₂ (0.0125 mmol), KF (0.5 mmol), dioxane (1 mL), 100 °C, 16 h. ^a 24 h Reaction time; ^b reaction performed at 120 °C.

Fig.5 [Fig. 5] shows examples of various N-Boc alkylamine substitutions. Reaction conditions: N-Boc amine (0.5 mmol), 6a (0.2 mmol), (cod)₂Rh(OTf) (0.025 mmol), KF (0.5 mmol), dioxane (1 mL), 100 °C, 16 h. ^a Reaction performed at 120 °C.

Fig.6

[Fig. 6] shows examples of an amidation of various N-Cbz anilines with arylboroxines. Reaction conditions: N-Cbz amine (0.5 mmol), 6a (0.2 mmol), [Cl(cod)Rh]₂ (0.0125 mmol), KF (0.5 mmol), dioxane (1 mL), 100 °C, 16 h. 24 h reaction time.

Example 1:

Amidation of N-Boc and N-Cbz protected anilines

N-Boc or N-Cbz protected aniline (0.50 mmol), KF (29 mg, 0.50 mmol) and [Cl(cod)Rh]₂ (6.2 mg, 13 μιηοΐ) were combined in a 20 mL headspace vial equipped with a magnetic stirrer bar. The vial was taken into a glovebox under Ar, where triarylboroxine (0.20 mmol) and 1 ,4- dioxane (1 mL) were added. The vial was sealed with a PTFE/silicon crimp-on septa and removed from the glovebox. The mixture was stirred at 100 to 120 °C over 12 to 24 h, then cooled to room temperature before it was diluted with CH₂C1₂ (5 mL) and quenched with H₂0 (5 mL). The aqueous layer was extracted with CH₂C1₂ (2 x 5 mL) and the combined organic layers were dried over anhydrous Na₂S0₄ and concentrated in vacuo. The residue was purified by flash column chromatography to afford the corresponding amide product.

Specific example of making N-(3,5-Dimethylphenyl)benzamide:

N-Boc protected 3,5-Dimethylaniline (111 mg, 0.50 mmol), KF (29 mg, 0.50 mmol) and [Cl(Cod)Rh]₂ (6.2 mg, 0.013 mmol) were weighed into a 20 mL -headspace flat-bottom vial on the benchtop. The vial was taken into the glovebox, where trisphenylboroxine (62 mg, 0.20 mmol) and anhydrous dioxane (0.5 mL) were added before it was sealed with a crimp-on aluminium cap. The vial was removed from the glovebox and the reaction mixture stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature, then diluted with dichloromethane (5 mL) and quenched with distilled water (5 mL). The aqueous layer was extracted with dichloromethane (2 x 5 mL) and the combined organic layers were dried over Na₂S0₄, filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (0 ^→ 30% diethyl ether in hexanes) to obtain N-(3,5- Dimethylphenyl)benzamide as a colourless solid (94 mg, 0.42 mmol, 83%).

Melting Point 141-143 °C; *H NMR (400 MHz, CDC1₃) δ 8.04 (br s, 1H, NH), 7.83 (d, J = 7.5 Hz, 2H, ArH), 7.49 (t, J = 7.5 Hz, 1H, ArH), 7.41 (t, J = 7.5 Hz, 2H, ArH), 7.27 (s, 2H, ArH), 6.76 (s, 1H, ArH), 2.27 (s, 6H, 2 x CH₃); ¹³C NMR (101 MHz, CDC1₃) δ 166.0, 138.8, 137.9, 135.1, 131.8, 128.7, 127.1, 126.4, 118.2, 21.5.

Example 2:

Amidation of N-Boc protected (alkyl)amines N-Boc protected amine (0.50 mmol), KF (29 mg, 0.50 mmol) and (cod)₂Rh(OTf) (12 mg, 25 μιηοΐ) were combined in a 20 mL headspace vial equipped with a magnetic stirrer bar. The vial was taken into a glovebox under Ar, where triphenylboroxine (62 mg, 0.20 mmol) and 1 ,4- dioxane (1 mL) were added. The vial was sealed with a PTFE/silicon crimp-on septa and removed from the glovebox. The mixture was stirred at 100 to 120 °C over 16 to 24 h, then cooled to room temperature before it was diluted with ethyl acetate (5 mL) and quenched with H₂0 (5 mL). The aqueous layer was extracted with ethyl acetate (2 x 5 mL) and the combined organic layers were dried over anhydrous Na₂S0₄ and concentrated in vacuo. The residue was purified by flash column chromatography to afford the corresponding amide product.

Further Examples and Comparative Examples, Results

First results were obtained in line with the schemes in Figure 2. Carbamate la was prepared. It was reacted with phenyl boronic acid glycol ester 2 and was isolated with low yield of amide 3a, along with significant amounts of amidine 4 and 3,5 -dimethylaniline (Table 1 , Entry 1 , comparative example). A survey of different combinations of boronic acid derivatives and transition metal complexes revealed that both carbamate deprotection and amidine formation could be suppressed by conducting the reaction at a lower temperature in dioxane when arylboroxine 6a was employed in conjunction with dimeric Rh(I) complexes (Entries 2-4). Surprisingly, none of the boronic esters included were compatible with these conditions, and were recovered in varying amounts as biphenyl homocoupling side products (Entry 5 , comparative example). Exchanging sodium tert- butoxide for a fluoride base allowed the reaction to be conducted at a slightly lower temperature, while exploring different fluoride sources revealed KF to be the most suitable base (Entries 6-7). Interestingly, with the more commonly employed, albeit costly and moisture sensitive, cesium fluoride no product formation was detected in this specific reaction and carbamate la was completely recovered (Entry 8). Reducing the amount of organometallic nucleophile to 1.2 equivalents resulted in minimal loss of isolated amide product (Entry 9).

Tab.l

[Tab. 1] shows reaction conditions for various Rh(I)-catalyzed carbamate amidation reactions and results.

Entry PhB(OR)₂ ^fl Catalyst (mol%) Base⁴ Solvent (T/°C) Yield^c / %

1 2 (IPr)CuCl (5.0) NaOi-Bu DMF (140) 16 + 9 (4)

2 5 (SlPr)CuCl (5.0) NaOi-Bu DMF (140) 30 + 20 (4)

3 6a [Cl(nbd)Rh]₂ (2.5) NaOi-Bu 1 ,4-dioxane (110) 25

4 6a [Cl(cod)Rh]₂ (2.5) NaOi-Bu 1 ,4-dioxane (110) 37

5 2 / 5 / 7 [Cl(cod)Rh]₂ (2.5) NaOi-Bu 1 ,4-dioxane (110) —

6 6a [Cl(cod)Rh]₂ (2.5) KF 1 ,4-dioxane (100) 89

7 6a [Cl(cod)Rh]₂ (2.5) NaF 1 ,4-dioxane (100) 14

8 6a [Cl(cod)Rh]₂ (2.5) CsF 1 ,4-dioxane (100) —

6a [Cl(cod)Rh]₂ (2.5) KF 1 ,4-dioxane (100) 86 Reaction conditions: 0.25 mmol of carbamate la in 0.5 mL of solvent over 16-24 h. 2.0 equivalents of 2, 5, or 7 and 0.67 equivalents of 6a unless otherwise stated; ^b 1.0 equivalent; ^c isolated yield after purification by column chromatography; ^d 0.4 equivalents of boroxine 6a.

Arylboroxines featuring extended aromatic systems, alkyl-substitution in the ortho position, and electron-donating functional groups were smoothly converted to amides 3b-d in excellent yields (see Figure 3). It was found that that electron-poor boroxines with electron- withdrawing ester, trifluoromethyl and nitro groups in the para and meta positions were tolerated in light of the tendency for these boronic acids to undergo homocoupling and protodeboronation (3e-g). However, when a tri(4-cyanophenyl)boroxine was employed as a substrate, complete recovery of carbamate la and benzonitrile was observed. Performing the amidation with the meta- substituted regioisomer afforded amide 3h in a low but isolable yield, along with significant amounts of benzonitrile. Halide-substituted arylboroxines would offer the possibility of further diversification of the benzamide, and these were found to be excellent substrates where the halide was chloride or bromide (3i-j). Heteroaromatic carboxamides, such as thiophene-containing 3k, can also be prepared using the process according to the invention by increasing the amount of heteroarylboroxine reagent employed in the reaction.

A similar pattern of reactivity was observed when substitution on the N-Boc aniline was varied (Figure 4): electron- donating and halide substituents underwent satisfactory to excellent conversion to amides 31-n, while the electron-withdrawing nitro group returned a modest yield of amide 3o after an extended reaction time. Despite the use of a fluoride activator, silyl ether functional groups are tolerated by this amidation, as evinced by the isolation of silyl-protected phenol 3p in good yields. Furthermore, the formation of coumarin-based amide 3q in moderate yields suggests that organoboron addition is selective for carbamates in the presence of Michael acceptors. Notably, Boc-protected amines derived from, 2,6-dimethylaniline and 2,6-diisopropylaniline proved to be competent substrates, allowing sterically-hindered amides 3r and 3s to be prepared using this methodology.

When the same reaction conditions were applied to N-Boc alkylamines, only trace amounts of product formation was observed alongside near-complete recovery of the carbamate partner (Figure 5). Employing a monomeric rhodium catalyst, (cod)₂Rh(OTf) led to excellent conversion of Boc-protected benzylamine to amide 3t under otherwise identical reaction conditions. This reaction manifold was found to be applicable to a wide range of N-alkyl carbamates, affording excellent yields of naphthyl and adamantyl amides 3u and 3v. Amides of primary and secondary amines can also be accessed in this manner, with the former requiring slightly elevated temperatures to achieve complete conversion of the carbamate precursors (3w-3z).

In addition to N-Boc amines, it was found that N-Cbz amines and arylboroxines were readily transformed to the corresponding amides under fluoride -promoted rhodium(I) catalysis (Figure 6). The reaction profiles of N-Cbz amines were generally cleaner than that of their N-Boc protected counterparts and corresponded to comparable or improved yields of amides in almost every substrate combination evaluated. In particular, amide 3f prepared from tri(3-nitrophenyl)boroxine with N-Cbz 3,5-dimethylphenylaniline was obtained in an excellent yield of 90% compared to a modest 53% yield when it was prepared from the analogous N-Boc protected aniline (see Figure 3). Other common carbamate-based amine protecting groups such as N-allyloxycarbonyl (N- Alloc) and N-fluorenylmethyloxycarbonyl (N-Fmoc) failed to afford any amide products, instead undergoing deprotection to the aniline and decomposition to a complex mixture, respectively.

The results show that a rhodium(I) -catalyzed amidation of O-tertbutyl and O-benzyl carbamates with arylboroxines provide direct access to secondary benzamides from N-Boc amines. Both electron-rich and electron-poor substituents on either coupling partner are compatible with the reaction conditions, as are sterically hindered N-Boc amines.

Industrial Applicability

The process for making amides may find a multiple number of applications in the synthesis of amides as bioactive molecules or for other amide applications. Amides are pervasive in nature. Amide linkages constitute a defining molecular feature of proteins, the secondary structure of which is due in part to the hydrogen bonding abilities of amides. Amide can be found in peptide bonds when they occur in the main chain of a protein and isopeptide bonds when they occur to a side -chain of the protein. Therefore the making of amides is an important way to obtain bioactive molecules based on amides. The process of the invention enables the amidation of O- tertbutyl and O-benzyl carbamates with arylboroxines with a direct access to secondary benzamides from N-Boc or N-Cbz amines. Both electron-rich and electron-poor substituents on either coupling partner are compatible with the reaction conditions, as are sterically hindered N-Boc amines. Such new process will give access to bioactive molecules in a one step process in good yields. Many drugs or agrochemicals are amide compounds. The process may find intense use in making such compounds.

It will be apparent that various other modifications and adaptations of the invention are available to the person skilled in the art after reading the foregoing disclosure without departing from the spirit and scope of the invention and it is intended that all such modifications and adaptations come within the scope of the appended claims.

Claims

1. A process for making an amide by directly reacting a teri-butyloxycarbonyl or carboxybenzyl N-substituted amine with a boroxine derivative in the presence of a rhodium(I) catalyst, in the presence of a solvent and optionally in the presence of a base.

2. The process according to claim 1 wherein the base comprises a fluoride base.

3. The process according to claim 2 wherein the fluoride base comprises potassium fluoride.

4. The process according to claim 2, wherein the base is used in about equimolar amounts to the amine.

5. The process according to claim 1 wherein the rhodium(I) catalyst is selected from a chloro(l,5-cyclooctadiene)rhodium(I) dimer or bis(l,5- cyclooctadiene)rhodium(I) trifluoromethanesulfonate.

6. The process according to claim 1 wherein the solvent is a polar aprotic solvent

selected from diglyme, sulfolane, dimethylformamide (DMF), dioxane, acetonitrile, hexamethylphosphoramide (HMPA), dimethyl sulphoxide (DMSO) and N-methyl pyrrolidone (NMP) or mixtures thereof.

7. The process according to claim 1 or 6 wherein the solvent comprises anhydrous dioxane.

8. The process according to claim 1 wherein the amine which is used in protected form is an optionally substituted aromatic amine.

9. The process according to claim 8 wherein the amine is selected from in each case optionally methyl, isopropyl, methoxy, chlorine, bromine, nitro, tert- butyldimethylsilyloxy substituted aniline or coumarin amine.

10. The process according to claim 9 wherein the amine is a sterically hindered aniline with substituents in both ortho-positions of the phenyl group.

11. The process according to claim 1 wherein the amine which is used in protected form is an optionally substituted alkyl amine.

12. The process of claim 11 wherein the amine is selected from optionally substituted benzylamine, naphthylethylamine, cyclohexylamine or Cj-Qo -alkyl-amine.

13. The process of claim 11 wherein the catalyst is bis(l,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate.

14. The process according to claim 1, wherein the N-substituted amine is a mono N- substituted amine.

15. The process according to claim 1, wherein the boroxine derivative is a trisarylboroxine or trisheteroarylboroxine of the formula (I),

(ArBO)₃ (I) wherein Ar represents in each case optionally methyl, methoxy, methoxycarbonyl, nitro, trifluoromethyl, chlorine or bromine substituted phenyl, naphthyl or thiophenyl.

16. The process according to claim 1 , wherein the process is performed at elevated

temperatures of about 100 °C to about 140 °C.

17. The process of claim 1 , wherein the process is performed at elevated temperatures of about 100 °C to about 1 10 °C in the presence of a potassium fluoride base.

18. The process of claim 1 , wherein the protected amine is a carboxybenzyl N-substituted amine and the boroxine derivative is tri(3-nitrophenyl)boroxine.