Patent Application: US-201515536295-A

Abstract:
a mild and efficient synthesis of primary amines and amides from aldehydes or ketones using a heterogeneous metal catalyst and amine donor is disclosed . the initial heterogeneous metal - catalyzed reaction between the carbonyl and the amine donor components is followed by the addition of a suitable acylating agent component in one - pot , thus providing a catalytic one - pot three - component synthesis of amides . integration of enzyme catalysis allows for eco - friendly one - pot co - catalytic synthesis of amides from aldehyde and ketone substrates , respectively . the process can be applied to asymmetric synthesis or to the co - catalytic one - pot three - component synthesis of capsaicin and its analogues from vanillin or vanillyl alcohol . a co - catalytic reductive amination / dynamic kinetic resolution relay sequence for the asymmetric synthesis of optically active amides from ketones is disclosed . implementation of a catalytic reductive amination / kinetic resolution relay sequence produces the corresponding optically active amide product and optical active primary amine product with the opposite stereochemistry from the starting ketones .

Description:
the present invention relates to a method for conversion of an aldehyde or ketone to an amine or an amide . the method comprises the steps of ( i ) providing an aldehyde or a ketone , ( ii ) converting the aldehyde or ketone to an amine , and ( iii ) converting the amine to an amide . the conversion to an amine compound , as well as the conversion to an amide compound , is catalyzed by a heterogeneous metal catalyst . one of the advantages of the method is that it is a one - pot synthesis . the aldehyde which is used in the conversion method may be of formula wherein r is selected from substituted or unsubstituted alkyl , cycloalkyl , aryl , cinnamyl and heterocyclic groups . wherein r and r1 are selected from substituted or unsubstituted alkyl , cycloalkyl , aryl and heterocyclic groups . the heterogeneous metal catalyst may be a heterogeneous palladium ( pd ) catalyst such as a pd ( 0 ) catalyst or pd ( 0 )- nanoparticle catalyst . preferred heterogeneous palladium catalysts are pd 0 - amp - mcf ( palladium ( 0 )- aminopropyl - mesocellular foam ) and pd 0 - amp - cpg ( palladium ( 0 )- aminopropyl - controlled pore glass ). the conversion of an aldehyde or ketone to an amine is catalyzed by a heterogeneous metal catalyst in the presence of an amine donor and reducing agent . the amine donor can be ( i ) ammonium formate ( hco 2 nh 4 ) or a derivative thereof , or ( i ) an amine . the reducing agent can be selected ( i ) ammonium formate ( hco 2 nh 4 ) or a derivative thereof , ( ii ) formic acid , or ( iii ) h 2 . in a preferred embodiment , ammonium formate is the amine donor as well as the reducing agent . the reaction step of converting the aldehyde or ketone to an amine is carried out at a temperature of at least 22 ° c . the best yields are achieved when the temperature is at 60 - 100 ° c . an organic solvent such as methanol or toluene may be used in the amination step . the reaction step of converting the amine to an amide is carried out in the presence of an acyl donor . the acyl donor may be an acylating agent selected from acids , esters , alkyl ketene dimers , acid chlorides and anhydrides . the amidation step maybe catalyzed by a heterogeneous metal catalyst and / or an enzyme . preferably , the step of converting the aldehyde or ketone to an amine is catalyzed by pd 0 - amp - mcf or pd 0 - amp - cpg , whereas the step of converting the amine to an amide is catalyzed by pd 0 - amp - mcf and enzyme in the presence of acyl donor . the enzyme may be lipase or an amine transaminase ( ata ). lipase b such as calb ( candida antarctica lipase b ) is particularly preferred . moreover , lipase b immobilized on a macroporous anionic resin may also be used . the amine transaminase is preferably selected from ata - 117 , ata - 113 and cv - ata ( chromobacterium violacum ata ). additionally , ( r )- selective ata or ( s )- selective ata can be used for preparing optically active chiral amines . the following examples provide various methods for preparing amines and amides from aldehydes and ketones , as well as from alcohols . chemicals and solvents were either purchased puriss p . a . from commercial suppliers or were purified by standard techniques . commercial reagents were used as purchased without any further purification . aluminum sheet silica gel plates ( fluka 60 f254 ) were used for thin - layer chromatography ( tlc ), and the compounds were visualized by irradiation with uv light ( 254 nm ) or by treatment with a solution of phosphomolybdic acid ( 25 g ), ce ( so 4 ) 2 . h 2 o ( 10 g ), conc . h 2 so 4 ( 60 ml ), and h 2 o ( 940 ml ), followed by heating . purification of the product was carried out by flash column chromatography using silica gel ( fluka 60 , particle size 0 . 040 - 0 . 063 mm ). the pd 0 - amp - mfc ( 8 . 25 wt % pd ) and pd 0 - amp - cpg ( 2 . 05 wt % pd ) catalysts were prepared according to previously reported procedures . infrared ( ir ) spectra were recorded on thermo fisher nicolet 6700 ft - ir spectrometer , □ max in cm − 1 . bands are characterized as broad ( br ), strong ( s ), medium ( m ), or weak ( w ). 1 h nmr spectra were recorded on a bruker avance ( 500 mhz ) spectrometer . chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance resulting from incomplete deuterium incorporation as the internal standard ( cdcl 3 : δ 7 . 26 ppm ). data are reported as follows : chemical shift , multiplicity ( s = singlet , d = doublet , q = quartet , br = broad , m = multiplet ), and coupling constants ( hz ), integration . 13 c nmr spectra were recorded on a bruker avance ( 125 . 8 mhz or 100 mhz ) spectrometer with complete proton decoupling , chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as the internal standard ( cdcl 3 : δ 77 . 16 ppm ). high - resolution mass spectrometry was performed on agilent 6520 accurate - mass q - tof lc / ms ( positive mode ). initial screening studies was conducted by using vanillin 1a as the model substrate . vanillin can be produced from the renewable resource lignin . ammonium formate ( hco 2 nh 4 ) was used as the amine donor and reducing agent in the presence of different palladium catalysts as indicated in table 1 . for example , aldehyde 1a was converted to the desired amine 2a in poor chemoselectivity together with significant amounts of 6a in the presence of palladium ( 0 )- aminopropyl - mesocellular foam ( pd 0 - amp - mcf , 5 mol %) in toluene at room temperature ( entry 1 ). increasing the temperature significantly accelerated the reaction as well as switched the chemoselectivity towards amine 2a formation ( entries 3 - 5 ). this was also the case when employing palladium ( 0 )- aminopropyl - controlled pore glass ( pd 0 - amp - cpg ) as the catalyst ( entry 7 ). the use of other commercially available heterogeneous and homogeneous pd catalysts resulted in low chemoselectivity ( entries 9 - 11 ). moreover , the same relay sequence using homogeneous pd ( pph 3 ) 4 as catalyst or performing the reaction in the absence of a palladium source did not deliver amine 2a ( only starting material was detected , entries 2 and 6 ). to a microwave - vial containing the pd 0 - catalyst ( 5 mol %) and ammonium formate ( 37 . 8 mg , 0 . 6 mmol , 3 . 0 equiv .) was added the solid vanillin 1a ( 0 . 2 mmol , 1 . 0 equiv .) under n 2 atmosphere . next , toluene ( 1 ml ) was added at room temperature . the temperature was then set to the one shown in table 1 and the reaction mixture was stirred under n 2 atmosphere . after the time shown in table 1 , the crude reaction mixture was filtrated through celite using chcl 3 ( 10 ml ) as eluent and evaporated . the crude material was purified by silica gel flash column chromatography . nmr samples for nmr - yield were prepared by removing 0 . 05 ml aliquots from the reaction mixtures , filtration through celite using cdcl 3 ( 1 . 5 ml ) as eluent and mesitylene as the internal standard . with these results in example 1 at hand , the scope of the catalytic amination of a range of aldehydes using pd 0 - amp - mcf or pd 0 - amp - cpg ( 6 . 6 mol %) as the heterogeneous catalysts was investigated . ammonium formate ( 3 equiv ) was used as amine donor and reducing agent . the reaction was carried out at 80 ° c . in toluene and the results are shown in table 2 . the reactions were highly chemoselective and a variety of aldehydes were converted to the corresponding amines and glycine derivative 2a - 2l . ( 55 - 93 % yield , table 2 ). notably , the transformation was chemospecific towards amine 2 - formation when aliphatic aldehydes were used as substrates . the total synthesis of natural products is a highly desirable aim . here , nonivamide 3a and capsaicin 3b are pungent amides that have been a part of the human diet of the americas since minimum 7500 bc ( chili pepper ). they activate the trpv1 receptor and a wide variety of physiological and biological activities induced by them have recently been reported . according to scheme 6 they should be possible to assemble via a heterogeneous metal / enzyme reductive amination / amidation or aerobic oxidation / reductive amination / amidation sequence . to a microwave - vial containing the pd 0 - catalyst ( pd 0 - amp - mfc , 13 . 4 mg , 0 . 01 mmol , 8 . 25 wt %, 5 mol %) or ( pd 0 - cpg , 569 å , 74 . 0 mg , 0 . 013 mmol , 2 . 05 wt %, 6 . 6 mol %) and ammonium formate ( 37 . 8 mg , 0 . 6 mmol , 3 . 0 equiv .) was added the solid 1 ( 0 . 2 mmol , 1 . 0 equiv .) under n 2 atmosphere . next , toluene ( 1 ml ) was added at room temperature . if the aldehyde substrate was a liquid it was added after the addition of toluene . the temperature was then increased and the reaction mixture was stirred 80 ° c . for the time shown in table 2 under n 2 atmosphere . before the purification of the products , the crude reaction mixture was filtrated through celite using chcl 3 ( 10 ml ) as eluent and evaporated . the crude material was purified by silica gel flash column chromatography to give the corresponding amines 2 . nmr samples for nmr - yield were prepared by removing 0 . 05 ml aliquots from the reaction mixtures , filtration through celite using cdcl 3 ( 1 . 5 ml ) as eluent and mesitylene as the internal standard . the hexan - 1 - amine 2d , furan - 2 - ylmethan amine 2h and propan - 1 - amine 2j were directly acylated by novozyme 435 to the corresponding amides and then isolated by silica gel column chromatography ( see table 2 ). with these results in example 1 at hand , a one - pot co - catalytic reaction between aldehyde 1a , hco 2 nh 4 and nonanoic acid 4a using commercially available candida antarctica lipase b ( novozyme - 435 , calb ) immobilized on a macroporous resin as the co - catalyst was developed . calb was chosen as the catalyst for its ability to amidate 2a . the one - pot co - catalytic relay sequence gave nonivamide 3a in high yield ( 74 %) using a pd ( 0 )- nanoparticle and enzyme catalyst system . however , no amide 3a was formed if either the enzyme or the pd catalyst was absent . thus , the enzyme and the pd - catalyst operated synergistically during the in situ amidation step . the scope of the co - catalytic one - pot cascade transformation sequence and the total synthesis of capsaicin 3b and “ phenylcapsaicin ” 3c were next investigated as indicated in table 3 . the co - catalytic one - pot total syntheses were highly chemoselective and gave the corresponding valuable 3b and 3c after one - step purification in 73 and 78 % overall yield , respectively . moreover , the synergistically heterogeneous pd and lipase - catalyzed in situ amidation step tolerated aromatic , heterocyclic and aliphatic substituents with respect to the aldehyde component as well as functional acids to give 3a - 3d mostly in good to high overall yields ( two in situ steps ). here , a clear substrate specificity of calb with respect towards both the in situ generated amine substrate and the amide donor was observed . for example , acid 4a was a better donor for the intermediate vanillyl amine 2a as compared to n - hexyl amine 2d ( entries 1 and 7 ). the long - chain alkyne functionalized fatty acid 4b turned out to be a very good donor for the enzyme . performing the co - catalytic one - pot reductive amination / amidation cascade reaction at a 0 . 5 g scale of 1a provided 3a in good yield ( 51 %, 0 . 5 g ). a microwave - vial containing a solution of 1 ( 0 . 2 mmol , 1 . 0 equiv . ), ammonium formiate ( 37 . 8 mg , 0 . 6 mmol , 3 . 0 equiv .) and pd 0 - catalyst ( pd 0 - amp - mfc , 13 . 4 mg , 0 . 01 mmol , 8 wt %, 5 mol %) or ( pd 0 - cpg , 569 å , 74 . 0 mg , 0 . 013 mmol , 6 . 6 mol %) in toluene ( 1 ml ) under n 2 conditions was stirred at 80 ° c . for the time shown in table 3 . afterwards , molecular sieves 4 å , acid 4 ( 0 . 2 mmol , 1 . 0 equiv .) and lipase ( 120 mg / mmol ) were added to reaction mixture and stirred at 80 ° c . for 36 h . the crude reaction mixture was filtrated through celite using chcl 3 ( 10 ml ) as eluent and evaporated . the crude material was purified by silica gel flash column chromatography to afford the corresponding amide 3 as indicated in table 3 . the lipase is preferably novozyme - 435 immobilized on a macroporous anionic resin . a flask containing a solution of 1a ( 500 mg , 3 . 28 mmol , 1 . 0 equiv . ), ammonium formate ( 620 mg , 9 . 84 mmol , 3 . 0 equiv .) and pd 0 - amp - mcf catalyst ( 219 . 7 mg , 0 . 16 mmol , 8 wt %, 5 mol %) in toluene ( 16 . 4 ml ) under n 2 conditions was stirred at 80 ° c . for 3 h . afterwards , molecular sieves 4 å , acid 4 ( 3 . 28 mmol , 1 . 0 equiv .) and lipase ( 120 mg / mmol ) were added to reaction mixture and stirred at 80 ° c . for 40 h . the crude reaction mixture was filtrated through celite using chcl 3 ( 10 ml ) as eluent and evaporated . the crude material was purified by silica gel flash column chromatography . the final product 3a was isolated in 51 % yield ( 491 mg , 1 . 7 mmol ). a co - catalytic aerobic oxidation / reductive amination / amidation sequence starting from an alcohol substrate 5a was also developed as indicated in scheme 7 . notably , alcohol 5a was converted to nonivamide 3a in one - pot ( 49 % yield ) using a multi - catalyst system . to a microwave - vial containing a solution of alcohol 5a ( 0 . 2 mmol , 1 . 0 equiv .) and pd — amp - cpg ( 10 . 1 mg , 0 . 002 mmol , 1 mol %) in dry toluene ( 0 . 25 ml ) was connected a o 2 balloon . after stirring the reaction mixture for 16 h at 80 ° c ., hco 2 nh 4 ( 37 . 8 mg , 0 . 6 mmol , 3 . 0 equiv . ), pd 0 - amp - mfc ( 10 . 8 mg , 0 . 008 mmol , 8 wt / o , 4 mol %) and toluene ( 0 . 75 ml ) were added under n 2 conditions and the reaction mixture was stirred at 80 ° c . for 2 . 5 h . next , molecular sieves 4 å , acid 4a ( 0 . 2 mmol , 1 . 0 equiv .) and lipase ( 120 mg / mmol ) were added to the reaction mixture , which was stirred at 80 ° c . for 40 h . the crude reaction mixture was filtrated through celite using chcl 3 ( 10 ml ) as eluent and next concentrated under reduced pressure . the crude material was purified by silica gel flash column chromatography . a solution of ketone ( 0 . 2 mmol , 1 . 0 equiv .) in ch 3 oh ( 0 . 3 ml ) was added to a microwave vial containing ammonium formate ( 126 mg , 2 mmol , 10 . 0 equiv .) and pd 0 - nanocatalyst ( pd 0 - amp - mfc , 2 . 69 mg , 0 . 002 mmol , 8 wt %, 1 mol %) under n 2 conditions and stirred at 70 ° c . for 1 - 3 h . next , the reaction mixture was cooled to room temperature and a saturated aqueous nahco 3 solution ( 0 . 3 ml ) was added . the aqueous layer was extracted five times with ch 2 cl 2 ( 0 . 3 × 5 ml ). the combined organic layers were dried over anhydrous na 2 so 4 and concentrated under reduced pressure . the crude material was purified by silica gel flash column chromatography obtaining the corresponding amines . a heterogeneously pd ( 0 )- nanoparticle catalyzed reductive amination of ketones 1 with hco 2 nh 4 to give chiral primary amines was develop . the extensive condition screening revealed that the pd 0 - amp - mcf - catalyzed reductive amination of acetophenone 1m gave the corresponding alcohol 5m as the major product in toluene . the chemoselectivity switched to 2m when the transformation was performed in meoh with a decreased and optimized catalyst loading ( table 4 ). thus , the scope of the catalytic reductive amination of ketones 1 was investigated using this condition ( table 4 ). a vial containing a solution of 1 ( 0 . 2 mmol , 1 . 0 equiv . ), hco 2 nh 4 ( 37 . 8 mg , 2 mmol , 10 . 0 equiv .) and pd 0 - nanocatalyst ( pd 0 - amp - mfc , 2 . 68 mg , 0 . 002 mmol , 8 wt %, 1 mol %) in meoh ( 0 . 3 ml ) under n 2 atmosphere was stirred at 70 ° c . for the time shown in table 4 . next , the solvent was evaporated and a solution of dipea ( n , n - diisopropylethylamine , 0 . 052 ml , 0 . 3 mmol , 1 . 5 equiv .) in dry dichloromethane ( 2 . 0 ml ) followed by the addition of methoxy acetylchloride ( 0 . 4 ml , 0 . 51 mmol / ml , 1 equiv .) were added to the vial , which was flushed with ar . after stirring overnight at room temperature , reaction mixture was filtered through celite with ch 2 cl 2 ( 2 . 5 ml ) and the solvent was removed under reduced pressure . the racemic α - methoxy - acetamides 3 were next isolated by silica gel flash column chromatography . with these results in example 6 at hand , the heterogeneous metal / enzyme asymmetric relay catalysis strategy was tested . the heterogeneous metal / enzyme co - catalyzed reductive amination / kr relay sequence was first investigated ( scheme 8 ). here ester 7 was employed as the acyl donor since it has been previously been shown to improve the acylation rate of amines by hydrogen bond - activation in the active site of calb . the use of pd - nanoparticles in combination with calb as co - catalysts for the dkr of secondary amines has recently been reported . thus , we could also expect this type of process instead of kr in the presence of the pd - catalyst . the catalytic relay sequence was performed in one - pot converting ketones 1m and 1n to the corresponding amides ( r )- 3m and ( r )- 3n in 36 % and 25 % overall isolated yield with 97 and 92 % enantiomeric excess , respectively . while & gt ; 76 % of the ketone 1m was converted to 2m , it was next converted in around 50 % to amide ( r )- 3m by the co - catalytic amidation . thus , the final transformation of the catalytic relay sequence had performed according to a kinetic resolution step . the presence of pd 0 - amp - mcf catalyst was essential for the amidation to occur since also this time the pd 0 - amp - mcf had operated as a co - catalyst converting the excess formic acid to h 2 , co 2 and h 2 o as described vide supra . a vial containing a solution of 1 ( 0 . 2 mmol , 1 . 0 equiv . ), hco 2 nh 4 ( 37 . 8 mg , 2 mmol , 10 . 0 equiv .) and pd 0 - nanocatalyst ( pd 0 - amp - mfc , 2 . 68 mg , 0 . 002 mmol , 8 wt %, 1 mol %) in meoh ( 0 . 3 ml ) under n 2 atmosphere was stirred at 70 ° c . for the time shown in table 4 . next , the solvent was evaporated and pd 0 - pd 0 - amp - mfc ( 5 . 4 mg , 0 . 008 mmol , 8 wt %, 2 mol %), novozyme - 435 ( 50 mg / mmol ) and mol . sieves ( 4 å , 100 mg ) were added to the vial with amine product . the vial was evacuated three times and refilled with h 2 . dry toluene ( 0 . 6 ml ) was added to the vial and the mixture was heated 70 ° c . followed by addition of ethyl methoxyacetate ( 47 μl , 0 . 4 mmol ) and stirred for 6 h . next , the crude reaction mixture was filtrated through celite using chcl 3 ( 10 ml ) as eluent and evaporated . the crude material was purified by silica gel flash column chromatography . with these results in example 7 at hand , a heterogeneous metal / enzyme co - catalyzed reductive amination / dkr relay sequence was developed ( scheme 9 ). it is known from the literature that the addition of h 2 gas can promote the racemization of amines 2 during a dynamic kinetic resolution step . we therefore increased the pd catalyst loading as well as added h 2 after the catalytic reductive amination to 2 had been completed ( scheme 9 ). the co - catalytic reaction sequences assembled the corresponding amides ( r )- 3 in good overall yields with high enantiomeric excess from ketones 1 . a vial containing a solution of 1 ( 0 . 2 mmol , 1 . 0 equiv . ), hco 2 nh 4 ( 37 . 8 mg , 2 mmol , 10 . 0 equiv .) and pd 0 - nanocatalyst ( pd 0 - amp - mfc , 2 . 68 mg , 0 . 002 mmol , 8 wt %, 1 mol %) in meoh ( 0 . 3 ml ) under n 2 atmosphere was stirred at 70 ° c . for the time shown in table 4 . next , the solvent was evaporated and pd 0 - nanocatalyst ( pd 0 - amp - mfc , 10 . 72 mg , 0 . 008 mmol , 8 wt %, 4 mol %), novozyme - 435 ( 50 mg / mmol ) and additive ( mol . siev . 4 å ( 100 mg ) or dry na 2 co 3 ( 20 mg )] were added to the vial with amine product . the vial was evacuated three times and refilled with h 2 . dry toluene ( 0 . 6 ml ) was added to the vial , and a balloon containing h 2 was connected to the vial . the mixture was heated 70 ° c . followed by addition of ethyl methoxyacetate ( 47 μl , 0 . 4 mmol ) and stirred for the time shown in the scheme . next , the crude reaction mixture was filtrated through celite using chcl 3 ( 10 ml ) as eluent and evaporated . the crude material was purified by silica gel flash column chromatography . a heterogeneous metal / enzyme co - catalyzed reductive amination / kinetic resolution relay sequence using a combination of pd 0 - amp - mcf and transaminase ( ata , ec 2 . 6 . 1 . 18 ) as catalysts was also developed ( scheme 10 ). the one - pot catalytic relay sequence was successful and the corresponding amines ( s )- 2 or ( r )- 2 were assembled from ketones 1 and ammonium formate with high enantiomeric excess , respectively . a vial containing a solution of 1 ( 0 . 2 mmol , 1 . 0 equiv . ), hco 2 nh 4 ( 37 . 8 mg , 2 mmol , 10 . 0 equiv .) and pd 0 - nanocatalyst ( pd 0 - amp - mfc , 2 . 68 mg , 0 . 002 mmol , 8 wt %, 1 mol %) in meoh ( 0 . 3 ml ) under n 2 atmosphere was stirred at 70 ° c . for the time shown in table 4 . next , the vial was put on ice and methanol ( 0 . 367 ml ) was added , followed by 6 ml of an aqueous buffer solution ( 50 mm hepes , ph 8 . 2 ) containing amine transaminase ( ata ) and 2 - 5 equivalents sodium pyruvate ( 1 equiv .= 0 . 2 mmol , 22 mg ). the tubes were put in darkness and room temperature for 24 hours with gentle mixing on an orbital shaker . enantiomeric excess ( ee ) was determined by hplc analysis ( triplicate samples ). a microwave - 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