# US 10,308,588 B2 · Synthesis of amides and amines from aldehydes or ketones by heterogeneous metal catalysis > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,308,588 B2 - Document ID: US10308588B2 - Status: Granted - Kind: B2 - Application number: 15/536,295 - Filed: 2015-12-15 - Published: 2017-12-21 - Granted: 2019-06-04 - Earliest claimed: 2014-12-15 - Assignees: Organofuel Sweden AB - Applicants: Organofuel Sweden AB - Inventors: Armando Córdova; Carlos Palo-Nieto; Samson Afewerki - Web page: https://patentgrep.com/patent/US10308588B2 ## CPC - C07C 209/28: by reduction with other reducing agents - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - B01J 23/44: Palladium - B01J 31/0238: {with a primary amino group} - B01J 35/19: {Catalysts containing parts with different compositions} - C07C 41/18: by reactions not forming ether-oxygen bonds - C07C 41/26: by introduction of hydroxy or O-metal groups - C07C 45/38: being a primary hydroxyl group - C07C 213/02: by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups - C07C 227/08: by reaction of ammonia or amines with acids containing functional groups - C07C 231/02: from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines - C07D 307/52: Radicals substituted by nitrogen atoms not forming part of a nitro radical - C07D 317/58: Radicals substituted by nitrogen atoms (nitro radicals C07D317/52) - B01J 2231/44: Allylic alkylation, amination, alkoxylation or analogues - B01J 2531/005: Catalytic metals - C07B 2200/07: Optical isomers - C07C 2601/14: The ring being saturated - C07C 2602/10: the other ring being six-membered, e.g. tetraline - C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - B01J: CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F) ## 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 (dkr) relay sequence for the asymmetric synthesis of optically active amides from ketones is disclosed. Implementation of a catalytic reductive amination/kinetic resolution (kr) relay sequence produces the corresponding optically active amide product and optical active primary amine product with the opposite stereochemistry from the starting ketones. ## Claims ### Claim 1 A method for conversion of an aldehyde or ketone comprising the steps of: Providing an aldehyde or a ketone, Converting the aldehyde or ketone to an amine, wherein the conversion to amine is catalyzed by a heterogeneous metal catalyst and the heterogeneous palladium catalyst is selected from Pd0-AmP-MCF (palladium(0)-aminopropyl-mesocellular foam) and Pd0-AmP-CPG (palladium(0)-aminopropyl-controlled pore glass), Converting the amine to an amide, wherein the conversion to amide is catalyzed by a heterogeneous metal catalyst. ### Claim 2 (depends on 1) The method according to claim 1, wherein the step of converting the aldehyde or ketone to an amine is catalyzed by the heterogeneous metal catalyst in the presence of ammonium formate (HCO2NH4) acting as an amine donor and reducing agent. ### Claim 3 (depends on 1) The method according to claim 1, wherein the step of converting the aldehyde or ketone to an amine is carried out at a temperature 22-100° C., wherein an organic solution is used as a solvent. ### Claim 4 (depends on 1) The method according to claim 1, wherein the step of converting the aldehyde or ketone to an amine is catalyzed by Pd0-AmP-MCF (palladium(0)-aminopropyl-mesocellular foam) or Pd0-AmP-CPG (palladium(0)-aminopropyl-controlled pore glass), the step of converting the amine to an amide is catalyzed by Pd0-AmP-MCF and enzyme in the presence of acyl donor. ### Claim 5 (depends on 1) The method according to claim 1, wherein an enzyme is selected from the group consisting of lipase and amine transaminase (ATA). ### Claim 6 (depends on 1) The method according to claim 1, wherein the step of converting the aldehyde or ketone to an amine comprises the steps of mixing a ketone or aldehyde with ammonium formate and Pd0-AmP-MCF or Pd0-AmP-CPG in toluene, and subsequently stirring at a temperature of 22-100° C. for at least 1 hour, and wherein the reaction is carried for at least 1 hour, the step of converting the amine to an amide comprises the steps of: adding lipase B, adding an acyl donor, and mixing at a temperature of at least 22-100 C.° for at least 1 hour. ### Claim 7 (depends on 6) The method according to claim 6, wherein the aldehyde or ketone is an aldehyde of structural formula wherein R is selected from one of the following substituents: ### Claim 8 (depends on 6) The method according to claim 6, wherein the acyl donor is an acid of structural formula wherein R1 is selected from one of the following substituents: ### Claim 9 (depends on 6) The method according to claim 6, wherein the resulting product is novinamide, capsaicin or phenylcapsaicin having the following respective structural formula: ### Claim 10 (depends on 1) The method according to claim 1, wherein the step of converting the aldehyde or ketone to an amine comprises the steps of mixing a ketone or aldehyde with ammonium formate and Pd0-AmP-MCF in methanol, and subsequently stirring at a temperature of 22-100° C. for at least 1 hour, and wherein the reaction is carried for at least 1 hour, the step of converting the amine to an amide comprises the steps of: evaporating the solvent, adding Pd0-AmP-MCF (palladium(0)-aminopropyl-mesocellular foam), adding CALB (Candida Antarctica lipase B), adding toluene under H2 atmosphere, adding an acyl donor under H2 atmosphere, and mixing under H2 atmosphere for at least 1 hour. ### Claim 11 (depends on 1) The method according to claim 1, wherein the aldehyde or ketone is a ketone of structural formula wherein R is selected from the group consisting of H, alkoxy and alkyl, and wherein the resulting amide is of structural formula ### Claim 12 (depends on 11) The method according to claim 11, wherein each R is selected from the group consisting of H, methoxy and methyl, and wherein the resulting amide is selected from the following amides: ### Claim 13 (depends on 1) The method according to claim 1, the step of converting the ketone to an amine comprises the steps of mixing a ketone with ammonium formate and Pd0-AmP-MCF in methanol, and subsequently stirring at a temperature of 22-100° C. for at least 1 hour, and wherein the reaction is carried for at least 1 hour, the step of converting the amine to an amide comprises the steps of: evaporating the solvent, adding DIPEA (N,N-Diisopropylethyamine), adding dichloromethane, adding methoxy acetylchloride, and mixing for at least 1 hour. ### Claim 14 (depends on 13) The method according to claim 13, wherein the ketone is of structural formula selected from: wherein the corresponding resulting amine in the amination step is of structural formula selected from: wherein the amino group of the above amine is in the amidation step acylated with a methoxyacetyl group and thereby the resulting amide in the amidation step is of formula wherein R and R1 is each selected from the group consisting of H, alkoxy, and alkyl. ### Claim 15 (depends on 1) The method according to claim 1, wherein the step of converting the aldehyde or ketone to an amine comprises the steps of mixing a ketone or aldehyde with ammonium formate and Pd0-AmP-MCF in methanol, and subsequently stirring at a temperature of 22-100° C. for at least 1 hour, and wherein the reaction is carried for at least 1 hour, the step of converting the amine to an amide comprises the steps of: putting the mixture on ice, adding methanol to the mixture, adding amine transaminase (ATA) and acyl donor, mixing for at least 1 hour. ### Claim 16 (depends on 1) The method according to claim 1, wherein said conversion is performed in one pot without any purification of intermediates. ### Claim 17 (depends on 1) The method according to claim 1, wherein the aldehyde or ketone is provided by reacting an alcohol with Pd0-AmP-CPG in the presence of O2, wherein said alcohol is selected from the group consisting of primary alcohol, secondary alcohol and aldol. ### Claim 18 A method for conversion of an aldehyde or ketone comprising the steps of: Providing an aldehyde or a ketone, Converting the aldehyde or ketone to an amine, wherein the conversion to amine is catalyzed by a heterogeneous metal catalyst and the heterogeneous palladium catalyst is selected from Pd0-AmP-MCF (palladium(0)-aminopropyl-mesocellular foam) and Pd0-AmP-CPG (palladium(0)-aminopropyl-controlled pore glass). ### Claim 19 (depends on 18) The method according to claim 18, wherein the step of converting the aldehyde or ketone to an amine comprises the steps of mixing a ketone or aldehyde with ammonium formate and Pd0-AmP-MCF (palladium(0)-aminopropyl-mesocellular foam) or Pd0-AmP-CPG (palladium(0)-aminopropyl-controlled pore glass) in toluene or methanol, and subsequently stirring at a temperature of 22-100° C. for at least 1 hour, and wherein the reaction is carried for at least 1 hour.