Novel ruthenium complexes and their uses in processes for formation and/or hydrogenation of esters, amides and derivatives thereof

Abstract

The present invention relates to novel Ruthenium complexes and related borohydride complexes, and their use for (1) hydrogenation of amides (including polyamides) to alcohols and amines; (2) preparing amides from alcohols with amines (including preparing polyamides (e.g., polypeptides) by reacting dialcohols and diamines or by polymerization of amino alcohols); (3) hydrogenation of esters to alcohols (including hydrogenation of cyclic esters (lactones), cyclic di-esters (di-lactones) or polyesters); (4) hydrogenation of organic carbonates (including polycarbonates) to alcohols and of carbamates (including polycarbamates) or urea derivatives to alcohols and amines; (5) dehydrogenative coupling of alcohols to esters; (6) hydrogenation of secondary alcohols to ketones; (7) amidation of esters (synthesis of amides from esters and amines); (8) acylation of alcohols using esters; (9) coupling of alcohols with water to form carboxylic acids; and (10) dehydrogenation of beta-amino alcohols to form pyrazines. The present invention further relates to novel uses of certain pyridine Ruthenium complexes.

What is claimed is: 
     
         1 . A process for hydrogenating an ester, organic carbonate, carbamate or urea derivative to at least one alcohol, amine or combination thereof; or
 hydrogenating an amide to an alcohol and an amine,
 comprising the step of reacting the ester, organic carbonate, carbamate, urea derivative or amide with molecular hydrogen (H 2 ) in the presence of a borane derivative of a Ruthenium complex, wherein said borane derivative is represented by the structure of formula F: 
   
       
         
           
           
               
               
           
         
         wherein
 each L 1  is independently selected from the group consisting of phosphine (PR a R b ), phosphite P(OR a )(OR b ), phosphinite P(OR a )(R b ), amine (NR a R b ), imine, oxazoline, sulfide (SR a ), sulfoxide (S(═O)R a ), heteroaryl containing at least one heteroatom selected from nitrogen and sulfur; arsine (AsR a R b ), stibine (SbR a R b ) and a N-heterocyclic carbene represented by the structures: 
 
       
       
         
           
           
               
               
           
         
         L 3  is absent or is a mono-dentate two-electron donor selected from the group consisting of CO, PR a R b R c , P(OR a )(OR b )(OR c ), NO + , AsR a R b R c , SbR a R b R c , SR a R b , nitrile (RCN), isonitrile (RNC), N 2 , PF 3 , CS, heteroaryl and tetrahydrothiophene; 
         L 4  is —CH 2 -L 1 - or a group of the formula: 
       
       
         
           
           
               
               
           
         
         R a , R b  and R c  are each independently alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylcycloalkyl, alkylaryl, alkylheterocyclyl or alkylheteroaryl; 
         R, R 1 , R 2  and R 3  are each independently H, alkyl, cycloalkyl, aryl, heterocycyl, heteroaryl, alkylcycloalkyl, alkylaryl, alkylheterocyclyl or alkylheteroaryl;
 X 1  represents zero, one, two or three substituents and X 2  represents zero, one, two, three or four substituents, wherein each such substituent is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylcycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, halogen, nitro, amide, ester, cyano, alkoxy, alkylamino, arylamino, an inorganic support and a polymeric moiety. 
 
       
     
     
         2 . The process according to  claim 1 , wherein the borane derivative is represented by the structure of any of formulae G, H, D and E: 
       
         
           
           
               
               
           
         
         wherein each of L 1 , L 3 , X 1 , X 2 , R a  and R b  is as defined in  claim 1 . 
       
     
     
         3 . The process according to  claim 1 , wherein the borane derivative is represented by the structure of any of formulae 2′, 4′, 6′ and 8′: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The process according to  claim 1 , wherein X 1  and/or X 2  are absent, and the pyridyl or bipyridy moiety is unsubstituted. 
     
     
         5 . The process according to  claim 1 , wherein L 1  is phosphine (PR a R b ). 
     
     
         6 . The process of  claim 1 , comprising the step of hydrogenating an ester represented by the formula R 6 C(═O)—OR 7  to the corresponding alcohol or alcohols: 
       
         
           
           
               
               
           
         
         wherein
 R 6  is selected from the group consisting of H, an unsubstituted or substituted alkyl, alkoxyalkyl, cycloalkyl, aryl, alkylaryl, heterocyclyl and heteroaryl; and 
 
         R 7  is selected from the group consisting of an unsubstituted or substituted alkyl, alkoxyalkyl, cycloalkyl, aryl, alkylaryl, heterocyclyl and heteroaryl. 
       
     
     
         7 . The process of  claim 1 , comprising the step of hydrogenating a carbonate represented by the formula R 8 O—C(═O)—OR 8 , to the corresponding alcohols(s) and methanol: 
       
         
           
           
               
               
           
         
         wherein R 8  and R 8′  are the same or different and are selected from the group consisting of an unsubstituted or substituted alkyl, alkoxyalkyl, cycloalkyl, aryl, alkylaryl, heterocyclyl and heteroaryl. 
       
     
     
         8 . The process of  claim 1 , comprising the step of hydrogenating a carbamate represented by the formula R 9 O—C(═O)—NHR 10  to the corresponding amine, alcohol and methanol: 
       
         
           
           
               
               
           
         
         wherein R 9  is selected from the group consisting of an unsubstituted or substituted alkyl, alkoxyalkyl, cycloalkyl, aryl alkylaryl, heterocyclyl and heteroaryl; and R 10  is selected from the group consisting of H or an unsubstituted or substituted alkyl, alkoxyalkyl, cycloalkyl, aryl, alkylaryl, heterocyclyl and heteroaryl. 
       
     
     
         9 . The process of  claim 1 , comprising the step of hydrogenating a urea derivative to the corresponding amine and methanol: 
       
         
           
           
               
               
           
         
         wherein each of R 9a  and R 10a , which may be the same or different, is selected from the group consisting of an unsubstituted or substituted alkyl, alkoxyalkyl, cycloalkyl, aryl, alkylaryl, and heterocyclyl, and each of R 9b  and R 10b , which may be the same or different, is selected from the group consisting of H, an unsubstituted or substituted alkyl, alkoxyalkyl, cycloalkyl, aryl, alkylaryl, and heterocyclyl; or wherein at least one of R 9a  and R 10a , and/or R 9b  and R 10b  together with the nitrogen to which they are attached form a heterocyclic ring. 
       
     
     
         10 . A process for preparing an amide from amine and an alcohol, comprising the step of reacting a primary or secondary amine with a primary alcohol in the presence of a borane derivative of a Ruthenium complex; or
 a process for preparing an ester by dehydrogenative coupling of primary alcohols, comprising the step of reacting a primary alcohol or a combination of primary alcohols in the presence of a borane derivative of a Ruthenium complex; or   a process for preparing an ester by dehydrogenative coupling of a primary alcohol and a secondary alcohol comprising the step of reacting the primary and secondary alcohol in the presence of a borane derivative of a Ruthenium complex; or   a process for preparing a ketone by dehydrogenation of a secondary alcohol, comprising the step of reacting the secondary alcohol in the presence of a borane derivative of a Ruthenium complex; or   a process for preparing an amide from amine and an ester, comprising the step of reacting a primary or secondary amine with an ester in the presence of a borane derivative of a Ruthenium complex; or   a process for preparing an ester from an alcohol and an ester, by reacting a primary or secondary alcohol with an ester in the presence of a borane derivative of a Ruthenium complex; or   a process for preparing a carboxylic acid comprising the step of reacting a primary alcohol with water and a base in the presence of a borane derivative of a Ruthenium complex,   wherein said borane derivative is represented by the structure of formula F:   
       
         
           
           
               
               
           
         
         wherein 
         each L 1  is independently selected from the group consisting of phosphine (PR a R b ), phosphite P(OR a )(OR b ), phosphinite P(OR a )(R b ), amine (NR a R b ), imine, oxazoline, sulfide (SR a ), sulfoxide (S(═O)R a ), heteroaryl containing at least one heteroatom selected from nitrogen and sulfur; arsine (AsR a R b ), stibine (SbR a R b ) and a N-heterocyclic carbene represented by the structures: 
       
       
         
           
           
               
               
           
         
         L 3  is absent or is a mono-dentate two-electron donor selected from the group consisting of CO, PR a R b R c , P(OR a )(OR b )(OR c ), NO + , AsR a R b R c , SbR a R b R c , SR a R b , nitrile (RCN), isonitrile (RNC), N 2 , PF 3 , CS, heteroaryl and tetrahydrothiophene; 
         L 4  is —CH 2 -L 1 - or a group of the formula: 
       
       
         
           
           
               
               
           
         
         R a , R b  and R c  are each independently alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylcycloalkyl, alkylaryl, alkylheterocyclyl or alkylheteroaryl; 
         R, R 1 , R 2  and R 3  are each independently H, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylcycloalkyl, alkylaryl, alkylheterocyclyl or alkylheteroaryl; 
         X 1  represents zero, one, two or three substituents and X 2  represents zero, one, two, three or four substituents, wherein each such substituent is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylcycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, halogen, nitro, amide, ester, cyano, alkoxy, alkylamino, arylamino, an inorganic support and a polymeric moiety. 
       
     
     
         11 . The process according to  claim 10 , wherein the borane derivative is represented by the structure of any of formulae G, H, D and E: 
       
         
           
           
               
               
           
         
         wherein each of L 1 , L 3 , X 1 , X 2 , R a  and R b  is as defined in  claim 1 . 
       
     
     
         12 . The process according to  claim 10 , wherein the borane derivative is represented by the structure of any of formulae 2′, 4′, 6′ and 8′: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The process according to  claim 10 , wherein X 1  and/or X 2  are absent, and the pyridyl or bipyridy moiety is unsubstituted. 
     
     
         14 . The process according to  claim 10 , wherein L 1  is phosphine (PR a R b ). 
     
     
         15 . The process of  claim 10 , for preparing an amide from amine and an alcohol, wherein said process comprises reacting an amine represented by formula R 11 R 11′ NH with an alcohol represented by the formula R 12 CH 2 OH to generate an amide represented by the structure R 12 —C(═O)—NR 11 R 11′ : 
       
         
           
           
               
               
           
         
         wherein R 10 , R 11  and R 12  are each independently selected from the group consisting of H an unsubstituted or substituted alkyl, alkoxyalkyl, cycloalkyl, aryl, alkylaryl, heterocyclyl and heteroaryl. 
       
     
     
         16 . The process of  claim 10 , for preparing an amide from amine and an alcohol, wherein the process is for preparing a polypeptide or a cyclic dipeptide, and wherein the primary or secondary amine and the primary alcohol are a beta-aminoalcohol. 
     
     
         17 . The process of  claim 10 , for preparing an ester by dehydrogenative coupling of primary alcohols, wherein the process comprises the step of converting a primary alcohol represented by formula R 13 CH 2 OH to an ester by the structure R 13 —C(═O)—OCH 2 R 13 : 
       
         
           
           
               
               
           
         
         wherein R 13  is selected from the group consisting of H, an unsubstituted or substituted alkyl, alkoxyalkyl, cycloalkyl, aryl, alkylaryl, heterocyclyl and heteroaryl; or 
         wherein the process comprises the steps of reacting a first primary alcohol represented by formula R 13 CH 2 OH with a second alcohol represented by formula R 13′ CH 2 OH so as to generate an ester by the structure R 13 —C(═O)—OCH 2 R 13′  or an ester of formula R 13′ —C(═O)—OCH 2 R 13   
       
       
         
           
           
               
               
           
         
         wherein R 13  and R 13′  are the same or different from each other and are each independently selected is from the group consisting of H, an unsubstituted or substituted alkyl, alkoxyalkyl, cycloalkyl, aryl, alkylaryl, heterocyclyl and heteroaryl. 
       
     
     
         18 . The process of  claim 10 , for preparing an ester by dehydrogenative coupling of a primary alcohol and a secondary alcohol, wherein the process comprises the step of reacting a primary alcohol represented by formula R 13 CH 2 OH with a secondary alcohol of formula R 13′ R 13″  CHOH so as to generate an ester by the structure R 13 —C(═O)—OCHR 13′ R 13″ : 
       
         
           
           
               
               
           
         
         wherein R 13 , R 13′  and R 13″  are each independently selected from the group consisting of H, an unsubstituted or substituted alkyl, alkoxyalkyl, cycloalkyl, aryl, alkylaryl, heterocyclyl and heteroaryl. 
       
     
     
         19 . the process of  claim 10 , for preparing a ketone by dehydrogenation of a secondary alcohol, wherein the process comprises the step of converting a secondary alcohol represented by formula R 14 CH(OH)R 14′  to a ketone represented by the structure R 14 —C(═O)—R 14′ : 
       
         
           
           
               
               
           
         
       
     
     
         20 . The process of  claim 10 , for preparing an amide from amine and an ester, wherein the process comprises the step of reacting an amine represented by formula R 15 R 15′  NH with an ester represented by the formula R 16 —C(═O)—OCH 2 R 16′  to generate an amide represented by the structure R 16 —C(═O)—NR 15 R 15′ : 
       
         
           
           
               
               
           
         
         wherein R 15 , R 15′ , R 16  and R 16′  are each independently selected from the group consisting of H, an unsubstituted or substituted alkyl, alkoxyalkyl, cycloalkyl, aryl, alkylaryl, heterocyclyl and heteroaryl. 
       
     
     
         21 . The process of  claim 10  for preparing an ester from an alcohol and an ester, wherein the process comprises the step of reacting a primary or secondary alcohol represented by formula R 17 R 17′ CHOH with an ester by the structure R 18 —C(═O)—OCH 2 R 18′ : 
       
         
           
           
               
               
           
         
         wherein R 17 , R 17′ , R 18  and R 18′  are each independently selected from the group consisting of H, an unsubstituted or substituted alkyl, alkoxyalkyl, cycloalkyl, aryl, alkylaryl, heterocyclyl and heteroaryl. 
       
     
     
         22 . The process of  claim 10 , for preparing a carboxylic acid, wherein the process comprises the step of reacting a primary alcohol represented by formula R 17 CH 2 OH with water in the presence of a base so as to generate a carboxylic acid salt represented by the structure R 17 —C(═O)O −  and, optionally, if desired, converting the carboxylic acid salt to the corresponding carboxylic acid of formula R 17 —C(═O)OH. 
       
         
           
           
               
               
           
         
         wherein R 17  is selected from the group consisting of H, an unsubstituted or substituted alkyl, alkoxyalkyl, cycloalkyl, aryl, alkylaryl, heterocyclyl and heteroaryl.