SYNTHESIS OF AMIDES AND AMINES FROM ALDEHYDES OR KETONES BY HETEROGENEOUS METAL CATALYSIS

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

1. 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, Converting the amine to an amide, wherein the conversion to amine and/or amide is catalyzed by a heterogeneous metal catalyst.

2. Method according to the previous claim wherein the aldehyde is of formula ##STR00082## wherein R is selected from substituted or unsubstituted alkyl, cycloalkyl, aryl, cinnamyl and heterocyclic groups.

3. Method according to the previous claim wherein the ketone is of formula ##STR00083## wherein R and R.sup.1 are selected from substituted or unsubstituted alkyl, cycloalkyl, aryl and heterocyclic groups.

4. Method according to any one of the previous claims, wherein the heterogeneous metal catalyst is a heterogeneous palladium (Pd) catalyst, preferably a Pd(0) catalyst, more preferably a Pd(0)-nanoparticle catalyst

5. Method according to any one of the previous claims, wherein the heterogeneous palladium catalyst is selected from Pd.sup.0-AmP-MCF (palladium(0)-aminopropyl-mesocellular foam) and Pd.sup.0-AmP-CPG (palladium(0)-aminopropyl-controlled pore glass).

6. Method according to any one of the previous claim, wherein the step of converting the aldehyde or ketone to an amine is catalyzed by a heterogeneous metal catalyst in the presence of an amine donor and reducing agent.

7. Method according to the previous claim, wherein the amine donor is selected from: ammonium formate (HCO.sub.2NH.sub.4) or a derivative thereof, and amine.

8. Method according to the previous claim 6 or 7, wherein the reducing agent is selected from: ammonium formate (HCO.sub.2NH.sub.4) or a derivative thereof, formic acid, and H.sub.2.

9. Method according to the previous claims 6-8, wherein ammonium formate (HCO.sub.2NH.sub.4) is the amine donor and reducing agent.

10. Method according to any one of the previous claims, wherein the step of converting the aldehyde or ketone to an amine is carried out at a temperature of at least 22° C., preferably at 60-100° C., wherein the an organic solution is used as a solvent.

11. Method according to any one of the previous claims, wherein the step of converting the amine to an amide is carried out in the presence of an acyl donor, wherein said acyl donor is an acylating agent selected from acids, esters, alkyl ketene dimers, acid chlorides and anhydrides.

12. Method according to any one of the previous claims, wherein the step of converting the amine to an amide is catalyzed by a heterogeneous metal catalyst and/or an enzyme.

13. Method according to any one of the previous claims, wherein the step of converting the aldehyde or ketone to an amine is catalyzed by Pd.sup.0-AmP-MCF or Pd.sup.0-AmP-CPG, the step of converting the amine to an amide is catalyzed by Pd.sup.0-AmP-MCF and enzyme in the presence of acyl donor.

14. Method according to any one of the previous claims, wherein the enzyme is selected from lipase and amine transaminase (ATA), wherein the lipase is preferably lipase B, more preferably the lipase is CALB (Candida antarctica lipase B), wherein lipase B is optionally immobilized on a macroporous anionic resin, and wherein the amine transaminase is preferably selected from ATA-117, ATA-113 and CV-ATA (Chromobacterium violacum ATA), more preferably (R)-selective ATA or (S)-selective ATA.

15. Method according to any one of the previous claims, wherein the step of converting the aldehyde or ketone to an amine is catalyzed by Pd.sup.0-AmP-MCF or Pd.sup.0-AmP-CPG, and wherein methanol or toluene is used as solvent, the step of converting the amine to an amide is catalyzed by Pd.sup.0-AmP-MCF and enzyme in the presence of acyl donor, wherein the enzyme is preferably selected from lipase and ATA, and wherein toluene is used as solvent.

16. Method according to any one of the previous claims, wherein the step of converting the aldehyde or ketone to an amine is catalyzed by Pd.sup.0-AmP-MCF or Pd.sup.0-AmP-CPG, and wherein toluene is used as solvent, the step of converting the amine to an amide is catalyzed by Pd.sup.0-AmP-MCF and lipase B in the presence of acyl donor, and wherein toluene is used as solvent.

17. Method according to any one of the previous claims, 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 Pd.sup.0-AmP-MCF or Pd.sup.0-AmP-CPG in toluene, and subsequently stirring at a temperature of at least 22° C. for at least 1 hour, preferably at 60-100 C°, and wherein the reaction is carried for at least 1 hour, preferably for 1.5-7 hours, more preferably for 2.5-3.5 hours, the step of converting the amine to an amide comprises the steps of: adding lipase B and optionally an additive, wherein the additive is preferably molecular sieve, wherein the molecular sieve preferably has a diameter of 4 Å, adding an acyl donor, wherein the acyl donor is preferably an acid, and mixing at a temperature of at least 22° C., preferably at 60-100 C°, for at least 1 hour, preferably for 36 hours.

18. Method according to the previous claims 15-17, wherein the aldehyde or ketone is an aldehyde of structural formula ##STR00084## wherein R is selected from one of the following substituents: ##STR00085##

19. Method according to the previous claims 15-18, wherein the acyl donor is an acid of structural formula ##STR00086## wherein R.sup.1 is selected from one of the following substituents: ##STR00087##

20. Method according to the previous claims 15-19, wherein the resulting product is an amide of structural formula ##STR00088##

21. Method according to the previous claims 15-20, wherein the resulting product is novinamide, capsaicin or phenylcapsaicin having the following respective structural formula: ##STR00089##

22. Method according to any one of the previous claims 1-15, wherein the step of converting the aldehyde or ketone to an amine is catalyzed by Pd.sup.0-AmP-MCF and wherein methanol is used as solvent, the step of converting the amine to an amide is catalyzed by Pd.sup.0-AmP-MCF and enzyme in the presence of acyl donor, wherein the enzyme is preferably lipase B, more preferably the enzyme is CALB, and wherein toluene is used as solvent in the amidation step.

23. Method according to any one of the previous claims 1-15 and 22, wherein the step of converting the aldehyde or ketone to an amine is catalyzed by Pd.sup.0-AmP-MCF, ammonium formate is the amine donor, methanol is the solvent, wherein the reaction is carried out at least 22° C., preferably at 60-100 C°, and wherein the reaction is carried for at least 1 hour, preferably for 1.5-7 hours, more preferably for 1.5-4.5 hours. the step of converting the amine to an amide is catalyzed by Pd.sup.0-AmP-MCF and enzyme in the presence of acyl donor, wherein the enzyme is preferably lipase B, more preferably the enzyme is CALB, and wherein toluene is used as solvent in the amidation step.

24. Method according to any one of the previous claims 1-15, 22 and 23, wherein the step of converting the aldehyde or ketone to an amine is catalyzed by Pd.sup.0-AmP-MCF, ammonium formate is the amine donor, methanol is the solvent, wherein the reaction is carried out at least 22° C., preferably at 60-100 C°, and wherein the reaction is carded for at least 1 hour, preferably for 1.5-7 hours, more preferably for 1.5-4.5 hours. the step of converting the amine to an amide is catalyzed by Pd.sup.0-AmP-MCF and lipase B, wherein lipase B is preferably CALB, and wherein toluene is used as solvent in the amidation step.

25. Method according to any one the previous claims 1-15 and 22-24, 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 Pd.sup.0-AmP-MCF in methanol, and subsequently stirring at a temperature of at least 22° C. for at least 1 hour, preferably at 60-100 C°, and wherein the reaction is carried for at least 1 hour, preferably for 1.5-7 hours, more preferably for 1.5-4.5 hours, wherein the step of converting the aldehyde or ketone to an amine is preferably carried out under N.sub.2 atmosphere, the step of converting the amine to an amide comprises the steps of: evaporating the solvent, adding Pd.sup.0-AmP-MCF, adding CALB and optionally an additive, wherein the additive is preferably molecular sieve or Na.sub.2CO.sub.3, wherein the molecular sieve preferably has a diameter of 4 Å, and wherein Na.sub.2CO is preferably dry Na.sub.2CO, adding toluene under H.sub.2 atmosphere, adding an acyl donor under H.sub.2 atmosphere, and mixing under H.sub.2 atmosphere, preferably for at least 1 hour, more preferably for 6, 12 or 16 hours.

26. Method according to any one the previous claims 1-15 and 22-25, 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 Pd.sup.0-AmP-MCF in methanol, and subsequently stirring at a temperature of at least 22° C. for at least 1 hour, preferably at 60-100 C°, and wherein the reaction is carried for at least 1 hour, preferably for 1.5-7 hours, more preferably for 1.5-4.5 hours, wherein the step of converting the aldehyde or ketone to an amine is preferably carried out under N.sub.2 atmosphere, the step of converting the amine to an amide comprises the steps of: evaporating the solvent, adding Pd.sup.0-AmP-MCF, adding CALB and additive, wherein the additive is preferably molecular sieve or Na.sub.2CO.sub.3, wherein the molecular sieve preferably has a diameter of 4 Å, and wherein Na.sub.2CO is preferably dry Na.sub.2CO, adding toluene under H.sub.2 atmosphere, adding an acyl donor under H.sub.2 atmosphere, and mixing under H.sub.2 atmosphere, preferably for at least 1 hour, more preferably for 6, 12 or 16 hours.

27. Method according to any one the previous claims 1-15 and 22-26, 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 1 mol % Pd.sup.0-AmP-MCF in methanol, and subsequently stirring at a temperature of at least 22° C. for at least 1 hour, preferably at 60-100 C°, and wherein the reaction is carried for at least 1 hour, preferably for 1.5-7 hours, more preferably for 1.5-4.5 hours, wherein the step of converting the aldehyde or ketone to an amine is preferably carried out under N.sub.2 atmosphere, the step of converting the amine to an amide comprises the steps of: evaporating the solvent, adding 4 mol % Pd.sup.0-AmP-MCF, adding CALB and molecular sieve, wherein the molecular sieve preferably has a diameter of 4 Å, adding toluene under H.sub.2 atmosphere, adding an acyl donor under H.sub.2 atmosphere, and mixing under H.sub.2 atmosphere, preferably for at least 1 hour, more preferably for 6, 12 or 16 hours.

28. Method according to any one of the previous 1-15 and 22-27, wherein the acyl donor is ethyl methoxyacetate.

29. Method according to any one of the previous claims 1-15 and 22-28, wherein the aldehyde or ketone is a ketone of structural formula ##STR00090## wherein R is selected from H, alkoxy or alkyl, and wherein the resulting amide is of structural formula ##STR00091##

30. Method according to the previous claim, wherein the substituents R are identical and wherein R is either H or methoxy.

31. Method according to claim 29, wherein each R is selected from H, methoxy or methyl and the resulting amide is selected from the following amides: ##STR00092##

32. Method according to any one of the previous claims 1-15, the step of converting the ketone to an amine comprises the steps of mixing a ketone with ammonium formate and Pd.sup.0-AmP-MCF in methanol, and subsequently stirring at a temperature of at least 22° C. for at least 1 hour, preferably at 60-100 C°, and wherein the reaction is carried for at least 1 hour, preferably for 1.5-7 hours, more preferably for 1.5-4.5 hours, wherein the step of converting the ketone to an amine is preferably carried out under N.sub.2 atmosphere, the step of converting the amine to an amide comprises the steps of: evaporating the solvent, adding DIPEA, adding an organic solvent, preferably the organic solvent is dichloromethane, adding an acyl donor, preferably the acyl donor is methoxy acetylchloride, and mixing, preferably for at least 1 hour, more preferably overnight.

33. Method according to the previous claim, wherein the ketone is of structural formula ##STR00093## selected from: ##STR00094## wherein the corresponding resulting amine in the amination step is of structural formula ##STR00095## selected from: ##STR00096## 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 ##STR00097##

34. Method according to the previous claims 1-15, 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 Pd.sup.0-AmP-MCF in methanol, and subsequently stirring at a temperature of at least 22° C. for at least 1 hour, preferably at 60-100 C°, and wherein the reaction is carried for at least 1 hour, preferably for 1.5-7 hours, more preferably for 1.5-4.5 hours, preferably under N.sub.2 atmosphere, the step of converting the amine to an amide comprises the steps of: optionally putting the mixture on ice, adding methanol to the mixture, adding ATA and acyl donor, mixing for at least 1 hour, more preferably for 24 hours, wherein the mixing is preferably conducted in darkness.

35. Method according to the previous claims 1-15 and 34, 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 Pd.sup.0-AmP-MCF in methanol, and subsequently stirring at a temperature of at least 22° C. for at least 1 hour, preferably at 60-100 C°, and wherein the reaction is carried for at least 1 hour, preferably for 1.5-7 hours, more preferably for 1.5-4.5 hours, preferably under N.sub.2 atmosphere, the step of converting the amine to an amide comprises the steps of: putting the mixture on ice, adding methanol to the mixture, adding (R)-selective ATA or (S)-selective ATA, adding acyl donor, mixing for at least 1 hour, more preferably for 24 hours, wherein the mixing is preferably conducted in darkness.

36. Method according to the previous claims 34 or 35, wherein the acyl donor is sodium pyruvate.

37. Method according to any one of the previous claims, wherein said conversion is a one-pot synthesis, preferably, said conversion is performed in one pot without any purification of intermediates.

38. Method according to any one of the previous claims, wherein the aldehyde or ketone is provided by reacting an alcohol with Pd.sup.0-AmP-CPG in the presence of O.sub.2, wherein said alcohol is selected from a primary alcohol, secondary alcohol and aldol, preferably said alcohol is vanillyl alcohol, more preferably said alcohol is vanillyl alcohol derived from lignin.

39. 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.

40. Method according to the previous claim wherein the aldehyde is of formula ##STR00098## wherein R is selected from substituted or unsubstituted alkyl, cycloalkyl, aryl, cinnamyl and heterocyclic groups.

41. Method according to the previous claim 39, wherein the ketone is of formula ##STR00099## wherein R and R1 are selected from substituted or unsubstituted alkyl, cycloalkyl, aryl and heterocyclic groups.

42. Method according to any one of the previous claims 39-41, wherein the heterogeneous metal catalyst is a heterogeneous palladium (Pd) catalyst, preferably a Pd(0) catalyst, more preferably a Pd(0)-nanoparticle catalyst.

43. Method according to any one of the previous claims 39-42, wherein the heterogeneous palladium catalyst is selected from Pd.sup.0-AmP-MCF (palladium(0)-aminopropyl-mesocellular foam) and Pd.sup.0-AmP-CPG (palladium(0)-aminopropyl-controlled pore glass).

44. Method according to any one of the previous claim 39-43, wherein the step of converting the aldehyde or ketone to an amine is catalyzed by a heterogeneous metal catalyst in the presence of an amine donor and reducing agent.

45. Method according to any one of the previous claim 39-44, wherein the amine donor is selected from: ammonium formate (HCO.sub.2NH.sub.4) or a derivative thereof, and amine.

46. Method according to any one of the previous claim 39-45, wherein the reducing agent is selected from: ammonium formate (HCO.sub.2NH.sub.4) or a derivative thereof, formic acid, and H.sub.2.

47. Method according to any one of the previous claim 39-46, wherein ammonium formate (HCO.sub.2NH.sub.4) is the amine donor and reducing agent.

48. Method according to any one of the previous claims 39-47, wherein the step of converting the aldehyde or ketone to an amine is carried out at a temperature of at least 22° C., preferably at 60-100° C., wherein the an organic solution is used as a solvent.

49. Method according to any one of the previous claims 39-48, wherein the step of converting the aldehyde or ketone to an amine is catalyzed by Pd.sup.0-AmP-MCF or Pd.sup.0-AmP-CPG.

50. Method according to any one of the previous claims 39-49, wherein the step of converting the aldehyde or ketone to an amine is catalyzed by Pd.sup.0-AmP-MCF or Pd.sup.0-AmP-CPG, and wherein methanol or toluene is used as solvent.

51. Method according to any one of the previous claims 39-50, 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 Pd.sup.0-AmP-MCF or Pd.sup.0-AmP-CPG in toluene, and subsequently stirring at a temperature of at least 22° C. for at least 1 hour, preferably at 60-100 C°, and wherein the reaction is carried for at least 1 hour, preferably for 1.5-7 hours, more preferably for 2.5-3.5 hours.

52. Method according to any one of the previous claims 39-51, wherein the aldehyde or ketone is an aldehyde of structural formula ##STR00100## wherein R is selected from one of the following substituents: ##STR00101##

53. Method according to any one of the previous claims 39-52, wherein the step of converting the aldehyde or ketone to an amine is catalyzed by Pd.sup.0-AmP-MCF and wherein methanol is used as solvent.

54. Method according to any one of the previous claims 39-53, wherein the step of converting the aldehyde or ketone to an amine is catalyzed by Pd.sup.0-AmP-MCF, ammonium formate is the amine donor, methanol is the solvent, wherein the reaction is carried out at least 22° C., preferably at 60-100 C°, and wherein the reaction is carried for at least 1 hour, preferably for 1.5-7 hours, more preferably for 1.5-4.5 hours.

55. Method according to any one the previous claims 39-54, 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 Pd.sup.0-AmP-MCF in methanol, and subsequently stirring at a temperature of at least 22° C. for at least 1 hour, preferably at 60-100 C°, and wherein the reaction is carried for at least 1 hour, preferably for 1.5-7 hours, more preferably for 1.5-4.5 hours, wherein the step of converting the aldehyde or ketone to an amine is preferably carried out under N.sub.2 atmosphere.

56. Method according to any one of the previous claims 39-55, wherein the ketone is of structural formula ##STR00102## selected from: ##STR00103##

57. Method according to any one of the previous claims, wherein the aldehyde or ketone is provided by reacting an alcohol with Pd.sup.0-AmP-CPG in the presence of O.sub.2, wherein said alcohol is selected from a primary alcohol, secondary alcohol and aldol, wherein said alcohol is selected from a primary alcohol, secondary alcohol and aldol, preferably said alcohol is vanillyl alcohol, more preferably said alcohol is vanillyl alcohol derived from lignin.

Description

DETAILED DESCRIPTION

[0136] 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.

[0137] The aldehyde which is used in the conversion method may be of formula

##STR00022##

wherein R is selected from substituted or unsubstituted alkyl, cycloalkyl, aryl, cinnamyl and heterocyclic groups.

[0138] The ketone which may be used is of formula

##STR00023##

wherein R and R1 are selected from substituted or unsubstituted alkyl, cycloalkyl, aryl and heterocyclic groups.

[0139] 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.sup.0-AmP-MCF (palladium(0)-aminopropyl-mesocellular foam) and Pd.sup.0-AmP-CPG (palladium(0)-aminopropyl-controlled pore glass).

[0140] 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.sub.2NH.sub.4) or a derivative thereof, or (i) an amine. The reducing agent can be selected (i) ammonium formate (HCO.sub.2NH.sub.4) or a derivative thereof, (ii) formic acid, or (iii) H.sub.2. In a preferred embodiment, ammonium formate is the amine donor as well as the reducing agent.

[0141] 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.

[0142] 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.

[0143] Preferably, the step of converting the aldehyde or ketone to an amine is catalyzed by Pd.sup.0-AmP-MCF or Pd.sup.0-AmP-CPG, whereas the step of converting the amine to an amide is catalyzed by Pd.sup.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.

[0144] The following examples provide various methods for preparing amines and amides from aldehydes and ketones, as well as from alcohols.

[0145] General Experimental Condition

[0146] 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.

[0147] 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.sub.4).sub.2.H.sub.2O (10 g), conc. H.sub.2SO.sub.4 (60 mL), and H.sub.2O (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).

[0148] The Pd.sup.0-AmP-MFC (8.25 wt % Pd) and Pd.sup.0-AMP-CPG (2.05 wt % Pd) catalysts were prepared according to previously reported procedures.

[0149] Infrared (IR) spectra were recorded on Thermo Fisher Nicolet 6700 FT-IR spectrometer, □.sub.max in cm.sup.−1. Bands are characterized as broad (br), strong (s), medium (m), or weak (w). .sup.1H 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.sub.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. .sup.13C 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.sub.3: δ 77.16 ppm). High-resolution mass spectrometry was performed on Agilent 6520 Accurate-Mass Q-TOF LC/MS (positive mode).

Example 1—Screening for Heterogeneous Metal Catalyst

[0150] 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.sub.2NH.sub.4) was used as the amine donor and reducing agent in the presence of different palladium catalysts as indicated in Table 1.

TABLE-US-00001 TABLE 1 Optimization of reductive amination reaction. [00024] [00025] Entry Catalyst HCO.sub.2NH.sub.4 (equiv.) temp. (° C.) time (h) Conv. (%).sup.[a] Ratio (2a:6a:5a).sup.[a]  1 Pd(0)-AmP-MCF 3 22 12 90 38:62:0  2 — 3 80 24 <1 —  3 Pd(0)-AmP-MCF 2 80 2.5 >99 88:12:0  4 Pd(0)-AmP-MCF 3 80 2.5 >99 94:6:0  5 Pd(0)-AmP-MCF 3 60 7 >99 86:14:0  6 Pd(PPh.sub.3).sub.4 3 80 24 <1 —  7 Pd(0)-AmP-CPG.sup.[c] 3 80 2.5 >95 81:15:4  8 Pd(0)-AmP-CPG 3 80 2.5 >95 79:14:7  9 Pd(OH).sub.2/C 3 80 20 >99 55:45:0 10 Pd/C 3 80 20 >99 34:60:6 11 Pd(OAc).sub.2 3 80 20 >99 39:38:23 12.sup.[b] Pd(0)-AmP-MCF 3 80 12 >99 42:5:53 .sup.[a]Determined by .sup.1H-NMR analysis of the crude reaction mixture. .sup.[b]The reaction was run with molecular sieve 4Å. .sup.[c]6.6 mol % cat.

[0151] 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.sup.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.sup.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.sub.3).sub.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).

[0152] General Procedure for the Screening:

[0153] To a microwave-vial containing the Pd.sup.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.sub.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.sub.2 atmosphere. After the time shown in Table 1, the crude reaction mixture was filtrated through Celite using CHCl.sub.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.sub.3 (1.5 mL) as eluent and mesitylene as the internal standard.

Example 2—Synthesis of Amines

[0154] With these results in Example 1 at hand, the scope of the catalytic amination of a range of aldehydes using Pd.sup.0-Amp-MCF or Pd.sup.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.

TABLE-US-00002 TABLE 2 Examples of prepared amines [00026] Entry Pd(0) cat. R Time (h) Product Yield (%).sup.[a]  1  2 Pd(0)-AmP-MCF Pd(0)-AmP-CPG.sup.[c] [00027] 2.5 2.5 2a 2a 87  78   3 Pd(0)-AmP-MCF [00028] 3   2b 85   4 Pd(0)-AmP-MCF [00029] 3   2c 92.sup.[b]  5 Pd(0)-AmP-MCF n-Pent 4   2d 91.sup.[b]  6 Pd(0)-AmP-CPG.sup.[c] n-Pent 3.5 2d 87.sup.[b]  7 Pd(0)-AmP-MCF n-Octyl 4   2e 78   8  9 Pd(0)-AmP-MCF Pd(0)-AmP-CPG.sup.[c] [00030] 4   4   2f 2f 85  76  10 Pd(0)-AmP-MCF [00031] 3   2g 90  11 Pd(0)-AmP-MCF [00032] 3   2h 71.sup.[b] 12 Pd(0)-AmP-MCF [00033] 3   2i 72  13 Pd(0)-AmP-MCF Et 3   2j 93.sup.[b] 14 Pd(0)-AmP-MCF CO.sub.2Et 3   2k 55.sup.[d] 15 Pd(0)-AmP-MCF [00034] 3.5 2l 63  .sup.[a]Isolated yield of pure 2. .sup.[b]1H-NMR yield using mesitylene as internal standard. .sup.[c]6.6 mol % cat. .sup.[d]1 (0.4 mmol).

[0155] 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.

##STR00035##

[0156] General Procedure for the Synthesis of Amines:

[0157] To a microwave-vial containing the Pd.sup.0-catalyst (Pd.sup.0-AmP-MFC, 13.4 mg, 0.01 mmol, 8.25 wt %, 5 mol %) or (Pd.sup.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.sub.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.sub.2 atmosphere. Before the purification of the products, the crude reaction mixture was filtrated through Celite using CHCl.sub.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.sub.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).

Example 3—Reductive Amination/Amidation Catalytic Relay

[0158] With these results in Example 1 at hand, a one-pot co-catalytic reaction between aldehyde 1a, HCO.sub.2NH.sub.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.

TABLE-US-00003 TABLE 3 Reductive amination/amidation catalytic relay. [00036] [00037] Entry R R.sup.1 Prod. Yield.sup.[a] 1 [00038] [00039] 3a 74 2.sup.[b] [00040] [00041] 3a 53 3.sup.[c] [00042] [00043] 3b 73 4 [00044] [00045] 3c 78 5 [00046] [00047] 3d 62 6 [00048] [00049] 3e 76 7 n-pent [00050] 3f  40.sup.[d] 8 n-pent [00051] 3g 70 9 [00052] [00053] 3h 71 .sup.[a]Isolated yield of pure product 6. .sup.[b]Pd.sup.0-AmP-CPG (6.6 mol %) as catalyst. .sup.[c]Starting acid 4b (Z:E = 85:15). .sup.[d]100% conv. to 2d and 3f (50:50 ratio).

[0159] 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).

[0160] General Procedure for Reductive Amination/Amidation Catalytic Relay.

[0161] 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.sup.0-catalyst (Pd.sup.0-AmP-MFC, 13.4 mg, 0.01 mmol, 8 wt %, 5 mol %) or (Pd.sup.0-CPG, 569 Å, 74.0 mg, 0.013 mmol, 6.6 mol %) in toluene (1 mL) under N.sub.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.sub.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.

[0162] Large Scale General Procedure:

[0163] 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.sup.0-AmP-MCF catalyst (219.7 mg, 0.16 mmol, 8 wt %, 5 mol %) in toluene (16.4 mL) under N.sub.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.sub.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).

Example 4—Aerobic Oxidation/Reductive Amination/Amidation Catalytic Relay

[0164] 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.

##STR00054##

[0165] General Procedure for Aerobic Oxidation/Reductive Amination/Amidation Catalytic Relay

[0166] 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.sub.2 balloon. After stirring the reaction mixture for 16 h at 80° C., HCO.sub.2NH.sub.4 (37.8 mg, 0.6 mmol, 3.0 equiv.), Pd.sup.0-AmP-MFC (10.8 mg, 0.008 mmol, 8 wt/o, 4 mol %) and toluene (0.75 mL) were added under N.sub.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.sub.3 (10 mL) as eluent and next concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography.

Example 5—Synthesis of Amines from Ketones

[0167] A solution of Ketone (0.2 mmol, 1.0 equiv.) in CH.sub.3OH (0.3 mL) was added to a microwave vial containing ammonium formate (126 mg, 2 mmol, 10.0 equiv.) and Pd.sup.0-Nanocatalyst (Pd.sup.0-AmP-MFC, 2.69 mg, 0.002 mmol, 8 wt %, 1 mol %) under N.sub.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.sub.3 solution (0.3 mL) was added. The aqueous layer was extracted five times with CH.sub.2Cl.sub.2 (0.3×5 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography obtaining the corresponding amines.

Example 6—Catalytic Reductive Amination of Ketones

[0168] A heterogeneously Pd(0)-nanoparticle catalyzed reductive amination of ketones 1 with HCO.sub.2NH.sub.4 to give chiral primary amines was develop. The extensive condition screening revealed that the Pd.sup.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).

TABLE-US-00004 TABLE 4 Ketone 1 substrate scope. [00055] Entry Ketone Amine Ratio 2:5.sup.[a] Time (h) Conv. (%).sup.[a] Yield of 3 (%).sup.[b] 1 [00056] [00057] 88:12 1.5 >99 74 2 [00058] [00059] 94:6  3    94 77 3 [00060] [00061] 93:7  4.5  95 78 4 [00062] [00063] 95:5  3.5  96 82 5 [00064] [00065] 89:11 1.5 >99 79 6 [00066] [00067] 97:3  1.5 >99 84 7 [00068] [00069] 99:1  2.5  85 68 8 [00070] [00071] 99:1  3    93 75 .sup.[a]Determined by .sup.1HNMR analysis of the crude reaction mixture. .sup.[b]Isolated yield of pure racemic 3.

[0169] The catalytic transformation exhibited high chemoselectivity and the corresponding racemic amides 3 were isolated in high yields after in situ amidation of amines 2.

[0170] General Procedure for Catalytic Reductive Amination of Ketones.

[0171] A vial containing a solution of 1 (0.2 mmol, 1.0 equiv.), HCO.sub.2NH.sub.4 (37.8 mg, 2 mmol, 10.0 equiv.) and Pd.sup.0-nanocatalyst (Pd.sup.0-AmP-MFC, 2.68 mg, 0.002 mmol, 8 wt %, 1 mol %) in MeOH (0.3 mL) under N.sub.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.sub.2Cl.sub.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.

Example 7—Reductive Amination/Kr Catalytic Relay

[0172] 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).

##STR00072##

[0173] 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 >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.sup.0-Amp-MCF catalyst was essential for the amidation to occur since also this time the Pd.sup.0-Amp-MCF had operated as a co-catalyst converting the excess formic acid to H.sub.2, CO.sub.2 and H.sub.2O as described vide supra.

[0174] General Procedure for Reductive Amination/Kr Catalytic Relay.

[0175] A vial containing a solution of 1 (0.2 mmol, 1.0 equiv.), HCO.sub.2NH.sub.4 (37.8 mg, 2 mmol, 10.0 equiv.) and Pd.sup.0-nanocatalyst (Pd.sup.0-AmP-MFC, 2.68 mg, 0.002 mmol, 8 wt %, 1 mol %) in MeOH (0.3 mL) under N.sub.2 atmosphere was stirred at 70° C. for the time shown in table 4. Next, the solvent was evaporated and Pd.sup.0-Pd.sup.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.sub.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.sub.3 (10 mL) as eluent and evaporated. The crude material was purified by silica gel flash column chromatography.

Example 8—Reductive Amination/Dkr Catalytic Relay

[0176] 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.sub.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.sub.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.

##STR00073##

[0177] Reductive Amination/Dkr Catalytic Relay.

[0178] A vial containing a solution of 1 (0.2 mmol, 1.0 equiv.), HCO.sub.2NH.sub.4 (37.8 mg, 2 mmol, 10.0 equiv.) and Pd.sup.0-nanocatalyst (Pd.sup.0-AmP-MFC, 2.68 mg, 0.002 mmol, 8 wt %, 1 mol %) in MeOH (0.3 mL) under N.sub.2 atmosphere was stirred at 70° C. for the time shown in table 4. Next, the solvent was evaporated and Pd.sup.0-Nanocatalyst (Pd.sup.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.sub.2CO.sub.3 (20 mg)] were added to the vial with amine product. The vial was evacuated three times and refilled with H.sub.2. Dry toluene (0.6 mL) was added to the vial, and a balloon containing H.sub.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.sub.3 (10 mL) as eluent and evaporated. The crude material was purified by silica gel flash column chromatography.

Example 9—Reductive Amination/Kr Catalytic Relay

[0179] A heterogeneous metal/enzyme co-catalyzed reductive amination/kinetic resolution relay sequence using a combination of Pd.sup.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.

##STR00074##

[0180] Reductive Amination/Kr Catalytic Relay.

[0181] A vial containing a solution of 1 (0.2 mmol, 1.0 equiv.), HCO.sub.2NH.sub.4 (37.8 mg, 2 mmol, 10.0 equiv.) and Pd.sup.0-nanocatalyst (Pd.sup.0-AmP-MFC, 2.68 mg, 0.002 mmol, 8 wt %, 1 mol %) in MeOH (0.3 mL) under N.sub.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).

Example 10—Procedure for the Recycling of the Pd Nanoparticles (Tables 5-7)

[0182] A microwave-vial containing a solution of 1d or 1a (0.2 mmol, 1.0 equiv.), ammonium formate (37.8 mg, 0.6 mmol, 3.0 equiv.) and Pd.sup.0-catalyst (Pd.sup.0-CPG, 569 Å, 74.0 mg, 0.013 mmol, 6.6 mol %) in toluene was stirred at 80° C. Next, the reaction mixture was transferred to a centrifuge-vial and CH.sub.2Cl.sub.2 (8 mL) was added and after centrifugation, the supernatant liquid was removed and the catalyst washed with CH.sub.2Cl.sub.2 (8 mL) 3 times. Afterwards the catalyst was dried under vacuum.

TABLE-US-00005 TABLE 5 Recycling studies of Pd.sup.0-AmP-CPG for the synthesis 2d. [00075] [00076] Cycle Time (h) Conv. to 2d (%).sup.[a] 1 3.5 93 (87% yield).sup.[b] 2 3.5 93 3 3.5 92 4 3.5 93 5 3.5 92 6 3.5 90 .sup.[a]Determined by .sup.1H NMR analysis of the crude reaction mixture. .sup.[b]Isolated yield of pure compound after silica gel column chromatography.

TABLE-US-00006 TABLE 6 Recycling studies of Pd.sup.0-AmP-MCF for the synthesis 2d. [00077] [00078] Cycle Time (h) Conv. to 2d (%).sup.[a] 1 3.5 94 (91% yield).sup.b 2 3.5 92 3 3.5 93 4 3.5 92 5 3.5 93 6 3.5 90 .sup.[a]Determined by 1H NMR analysis of the crude reaction mixture. .sup.[b]Isolated yield of pure compound after silica gel column chromatography.

TABLE-US-00007 TABLE 7 Recycling studies of Pd.sup.0-AmP-CPG for the synthesis of 2a. [00079] [00080] Cycle Time (h) Conv. to 2a(%).sup.[a] 1 2.5 81 (78% yield).sup.[b] 2 2.5 81 3 2.5 80 4 2.5 80 5 2.5 80 6 2.5 80 .sup.[a]Determined by .sup.1H NMR analysis of the crude reaction mixture. .sup.[b]Isolated yield of pure compound after silica gel column chromatography.

Example 11—HRMS Analysis the Reaction Mixture (Intermediate)

[0183] General Procedure:

[0184] The reaction was performed either between 1a and 2a. After stirring at 80° C. for 20 min., an aliquot (20 μL) was removed from the reaction mixture using a syringe and dissolved in 1.0 mL of a mixture of CH.sub.3CN/H.sub.2O (70/30, v/v) and directly analysed by HRMS. LC-HRMS condition: ZORBX Eclipse Plus C18, 2.1×100 mm, 1.8-Micro column, Mobile Phase: CH.sub.3CN/H.sub.2O (70/30, v/v), 0.3 mL/min, 230 nm. MS: Dual ESI ion source, positive mode, 65 eV. The intermediate I was confirmed by the HRMS analyses.

##STR00081##

REFERENCES

[0185] [1] a) P. N. Rylander, Hydrogenation Methods, Academic Press, New York, 1985, 82. b) S. Gomez, J. A. Peters, T. Maschmeyer, Adv. Synth. Catal. 2002, 344, 1037. c) V. A. Tarasevich, N. G. Kozlov, Russ. Chem. Rev. 1999, 68, 55. d) W. S. Emerson, Org. React. 1948, 4, 174. [0186] [2] L. Sung-Chan, B. P. Seung, Chem. Commun. 2007, 3714. [0187] [3] Recent reviews: a) S. Gomez, J. A. Peters, T. Maschmeyer, Adv. Synth. Catal. 2002, 344, 1037. b) V. I. Tararov, A. Bömer, Synlett 2005, 203. c) A. F. Abdel-Magid, S. J. Mehrman, Org. Process Res. Dev. 2006, 10, 971. d) T. C. Nugent, M. El-Shazly, Adv. Synth. Catal. 2010, 352, 753. [0188] [4] a) R. P. Tripathi, S. S. Verma, J. Pandey, V. K. Tiwari, Curr. Org. Chem. 2008, 12, 1093; b) K. S. Hayes, Appl. Catal. 2001, 221, 187; c) T. S. Zatsepin, D. A. Stetsenko, M. J. Gait, T. S. Oretskaya, Bioconjugate Chem. 2005, 16, 471; d) J. M. Antos, M. B. Francis, Curr. Opin. Chem. Biol. 2006, 10, 253. [0189] [5] a) R. Leuckart, Ber. Dtsch. Chem. Ges. 1885, 18, 2341; b) O. Wallach, Ber. Dtsch. Chem. Ges. 1891, 24, 3992; (c) C. B. Pollard, D. C. Young, J. Org. Chem. 1951, 16, 661. d) V. J. Webers, W. F. Bruce, J. Am. Chem. Soc. 1948, 70, 1422. e) M. L. Moore, The Leuckart Reaction, In Organic Reactions, Vol. 5, Ed. R. Adams, John Wiley and Sons, New York, 301. (1949). [0190] [6] a) M. Kitamura, D. Lee, S. Hayashi, S. Tanaka, M. Yoshimura, J. Org. Chem, 2002, 67, 8687. b) C. Wang, A. Pettman, J. Bacsa, J. Xiao, Angew. Chem. Int. Ed. 2010, 49, 7548. c) R. Kadyrov, H. Riermeier, Angew. Chem. Int. Ed. 2003, 44, 5472. [0191] [7] a) S. Ram, L. D. Spicer, Tetrahedron Lett. 1998, 29, 3741. b) R. W. Hanson, J. Chem. Ed. 1997, 74, 430. [0192] [8] a) L. Yin, J. Liebscher, Chem. Rev. 2007, 107, 133; b) E. W. Ping, R. Wallace, J. Pierson, T. F. Fuller, C. W. Jones, Microporous Mesoporous Mater. 2010, 132, 174; c) M. Shakeri, C.-W. Tai, E. Gothelid, S. Oscarsson, J. E. Bäckvall, Chem. Eur. J. 2011, 17, 13269; d) E. V. Johnston, O. Verho, M. D. Kärkäs, M. Shakeri, C.-W. Tai, P. Palmgren, K. Eriksson, S. Oscarsson, J.-E. Bäckvall, Chem. Eur. J. 2012, 18, 12202; e) W. Long, N. A. Brunelli, S. A. Didas, E. W. Ping, C. W. Jones, ACS Catal. 2013, 3, 1700; f) K. Engström, E. V. Johnston, O. Verho, K. P. J. Gustafson, M. Shakeri, C.-W. Tai, J. E. Bäckvall, Angew. Chem. 2013, 125, 14256. g) O. Verho, A. Nagendiran, E. V. Johnston, C. W. Tai, J.-E. Bäckvall, ChemCatChem 2013, 5, 612. h) K. P. J. Gustafson, R. Lihammar, O. Verho, K. Engström, J-E. Bäckvall, J. Org. Chem. 2014, 79, 3747. i) O. Verho, K. P. Gustafson, A. Nagendiran, C.-W. Tai, ChemCatChem 2014, Early view. j) D. B. Bagal, R. A. Watile, M. V. Khedkar, K. P. Dhake, B. M. Bhanage, Catal. Sci. Technol. 2012, 2, 354. [0193] [9] a) L. Deiana, S. Afewerki, C. Palo-Nieto, O. Verho, E. V. Johnston, A. Cordova, Sci. Rep. 2012, 2, 851. b) L. Deiana, L. Ghisu, O. Córdova, S. Afewerki, R. Zhang, A. Córdova, Synthesis 2014, 1303. c) L. Deiana, L. Ghisu, S. Afewerki, O. Verho, E. V. Johnston, N. Hedin, Z. Bacsik, A. Córdova, Adv. Synth. Catal. 2014, 356, 2485. d) G. Ma, S. Afewerki, L. Deiana, C. Palo-Nieto, L. Liu, J. Sun, I. Ibrahem, A. Córdova, Angew. Chem. 2013, 52, 6050. [0194] [10] a) Multicomponent Reactions. Eds J. Zhu, H. Bienayme, WILEY-VCH, Weinheim, 2005. b) R. C. Cioc, E. Ruijer, R. V. A. Orru, Green. Chem. 2014, 16, 2958. [0195] [11] a) A. Leyva-Perez, P. Garcia-Garcia, A. Corma, Angew. Chem. 2014, 53, 8687. b) M. Anderson, S. Afewerki, P. Berglund, A. Córdova, Adv. Synth. Catal. 2014, 356, 2113. b) L. Deiana, Y. Jiang, C. Palo-Nieto, S. Afewerki, C. Incerti-Pradillos, O. Verho, C-W. Tai, E. V. Johnston, A. Córdova, Angew. Chem. 2014, 53, 3447; [0196] [12] a) M. J. Caterina, M. A. Schumacher, M. Tominaga, T. A. Rosen, J. D. Levine, D. Julius, Nature 1997, 389 816. b) M. J. Caterina, T. A. Rosen, M. Tominaga, S. J. Brake, D. Julius, Nature 1999, 398, 436. c) D. Julius, A. I. Basbaum, Nature 2001, 413, 203. d) V. S. Govindarajan, M. N. Sathyanarayana, Crit. Rev. Food Sci. Nutr. 1991, 29, 435. e) T. Suzuki, K. Iwai, In The Alkaloids; Brossi, A., Ed.; Academic: New York, N.Y., 1984, 23, Chapter 4. f) R. Sancho, C. Lucena, A. Macho, M. A. Calzado, M. Blanco-Molina, A. Minassi, G. Appendino, E. Munoz, Eur. J. Immunol. 2002, 32, 1753. g) A. Morita, Y. Iwasaki, K. Kobata, T. Iida, T. Higashi, K. Oda, A. Suzuki, M. Narukawa, S. Sasakuma, H. Yokogoshi, S. Yazawa, M. Tominaga, T. Watanabe, Life Sci. 2006, 79, 2303.