| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | May 3, 2005 |
| PATENT TITLE |
Transition-metal-catalyzed carbon-nitrogen bond-forming methods using carbene ligands |
| PATENT ABSTRACT |
The present invention relates to a process for the preparation of N-aryl amine and N-aryl amide compounds. Generally, the process of the present invention involves reacting a compound having a primary or secondary amino or amido group with an arylating compound, in the presence of a weak base and a transition metal catalyst, under reaction conditions effective to form an N-aryl amine or N-aryl amide compound, the transition metal catalyst comprising a Group 8 metal, e.g., Ni, Pd, or Pt, and at least one carbene-containing ligand. Typically, the transition metal catalyst is formed in a preceding step from the conjugate acid form of the carbene ligand, a stoichiometric amount of a strong base, and a Group 8 metal atom or ion. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | January 22, 2003 |
| PATENT REFERENCES CITED |
Böhm et al.; "N-Heterocyclic Carbenes Part 26. N-Heterocyclic Carbene Complexes of Palladium (0): Synthesis and Application in the Suzuki Cross-Coupling Reaction", Journal of Organometallic Chemistry, 595: 186-190, (2000). Cheng and Trudell; "Synthesis of N-Heteroaryl-7-azabicyclo[2.2.1]heptane Derivatives via Palladium- Bissimidazol-2-Ylidene Complex Catalyzed Amination Reactions", Organic Letters, 3(9):1371-1374, (2001). Gradel et al.; "Nickel-Catalyzed Amination of Aryl Chlorides Using a Dihydroimidazoline Carbene Ligand", Tetrahedron Letters 42:5689-5692, (2001). Huang and Nolan; "Efficient Cross-Coupling of Aryl Chlorides with Aryl Grignard Reagents (Kumada Reaction)Mediated by a Palladium/Imidazolium Chloride System", J. Am. Chem. Soc. 121:9889-9890. (1999). Huang et al.; "General and Efficient Catalytic Amination of Aryl Chlorides Using a Palladium/Bulky Nucleophilic Carbene System", Organic Letters, 1(8): 1307-1309, (1999). Lee and Nolan; "Efficient Cross-Coupling Reactions of Aryl Chlorides and Bromides with Phenyl- or Vinyltrimethoxysilane Mediated by a Palladium/Imidazolium Chlode System", Organic Letters, 2(14):2053-2055, (2000). Lee and Hartwig; "Improved Catalysts for the Palladium-Catalyzed Synthesis of Oxindoles by Amide α-Arylation. Rate Acceleration, Use of Aryl Chloride Substrates, and a New Carbene Ligand for Asymmetric Transformation", J. Org. Chem, 66: 3402-3415, (2001). Lee et al.; "Palladium -Catalyzed Synthesis of Arylamines from Aryl Halides and Lithium Bis(trimethylsilyl)amide as an Ammonia Equivalent", Organic Letters, 3(17): 2729-2732, (2001). Stauffer et al.; "High Turnover Number and Rapid, Room-Temperature Amination of Chloroarenes Using Saturated Carbene Ligands", Organic Letters, 2(10): 1423-1426, (2000). Viciu et al.; "An Air-Stable Palladium/N-Heterocyclic Carbene complex and Its Reactivity in Aryl Amination", Organic Letters, 4(13): 2229-2231; (2002). Viciu et al; "Catalytic Dehalogenation of Aryl Halides Mediated by a Palladium/Imidazolium Salt System", Organometallics 20: 3607-3612, (2001). Ziegler and Heck, "Palladium Catalyzed Vinylic Substitution with Highly Activated Aryl Halides", The Journal of Organic Chemistry, 43(15): 2941-2946, (Jul. 21, 1978). Grasa et al.; "Amination Reactions of Aryl Halides with Nitrogen-Containing Reagents Mediated by Palladium/Imidazolium Salt Systems", J. Org. Chem. 66: 7729-7737, (2001). International Search Report Completed on May 9, 2003 and Mailed on Jun. 20, 2003. |
| PATENT GOVERNMENT INTERESTS |
GOVERNMENT SUPPORT The invention was made with support provided by the National Institutes of Health; therefore, the government has certain rights in the invention |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
1. A method represented by Scheme 1: ##STR20## wherein X represents I, Br, Cl, alkylsulfonate, or arylsulfonate; Ar represents optionally substituted aryl or heteroaryl; catalyst consists essentially of a Group 8 atom or ion; and at least one carbene-containing ligand; base represents a phosphate, carbonate, bicarbonate, fluoride, tertiary amine, or hydride; R represents alkyl, alkenyl, cycloalkyl, aralkyl, aryl, heteroaryl, formyl, acyl, —CO2alkyl, —CO2aryl, —CO2aralkyl, —N(R′)acyl, —N(R′)C(O)Oalkyl, —N(R′)C(O)Oaryl, —N(R′)C(O)Oaralkyl, —N═C(alkyl)2, or —N═C(aryl)2; R′ represents H, alkyl, cycloalkyl, aralkyl, aryl, heteroaryl, formyl, acyl, or amino; R and R′ taken together may represent C(alkyl)2, or =C(aryl)2; and R and R′ are optionally connected by a covalent bond to form a cyclic structure which incorporates the amine nitrogen. 2. The method of claim 1, wherein X is Br or Cl. 3. The method of claim 1, wherein Ar represents optionally substituted phenyl. 4. The method of claim 1, wherein R′ represents H, alkyl, cycloalkyl, aralkyl, aryl, or heteroaryl. 5. The method of claim 1, wherein the catalyst consists essentially of a palladium atom or ion and at least one carbene-containing ligand. 6. The method of claim 1, wherein X is Br or Cl; and Ar represents optionally substituted phenyl. 7. The method of claim 1, wherein X is Br or Cl; Ar represents optionally substituted phenyl; and R′ represents H, alkyl, cycloalkyl, aralkyl, aryl, or heteroaryl. 8. The method of claim 1, wherein X is Br or Cl; Ar represents optionally substituted phenyl; R′ represents H, alkyl, cycloalkyl, aralkyl, aryl, or heteroaryl; and the catalyst consists essentially of a palladium atom or ion and at least one carbene-containing ligand. 9. The method of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein the at least one carbene-containing ligand is represented by the following formula: ##STR21## wherein R1 and R2 are independently selected from the group consisting of optionally substituted aryl; and R3 and R4 are independently selected from the group consisting of H and alkyl. 10. The method of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein the at least one carbene-containing ligand is represented by the following formula: ##STR22## wherein R1 and R2 are independently selected from the group consisting of optionally substituted phenyl; and R3 and R4 are H. 11. The method of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein the at least one carbene-containing ligand is represented by the following formula: ##STR23## wherein R1 and R2 are independently selected from the group consisting of optionally substituted aryl; and R3 and R4 are independently selected from the group consisting of H and alkyl. 12. The method of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein the at least one carbene-containing ligand is represented by the following formula: ##STR24## wherein R1 and R2 are independently selected from the group consisting of optionally substituted phenyl; and R3 and R4 are H. 13. The method of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein base represents a phosphate. 14. The method of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein base represents potassium phosphate. 15. The method of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein R represents aryl or heteroaryl. 16. The method of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein R′ represents H. 17. The method of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein R represents aryl or heteroaryl; and R′ represents H. 18. The method of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein the method is practiced at a temperature less than about 150 C. 19. The method of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein the method is practiced at a temperature in the range from about 90 C to about 110 C. 20. The method of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein the method is practiced at about 100 C. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION N-Aryl amines and amides are important substructures in natural products and industrial chemicals, such as pharmaceuticals, dyes, and agricultural products. Palladium-catalyzed methods for the N-arylation of amines and amides are now widely-exploited for the synthesis of arylamine and N-arylamide moieties in pharmaceuticals, materials with important electronic properties, and ligands for early metal catalysts. In particular, the palladium-catalyzed reaction of aryl bromides and aryl iodides with primary and secondary amines and amides is a general method employed for the formation of N-aryl amines and N-aryl amides. However, the reaction conditions employed in these palladium-catalyzed reactions are sufficiently harsh, e.g., in terms of reaction time, reaction temperature, or the requirement for the use of strong base, that many functionalized aryl halide or amine or amide reagents are not suitable reactants because their functional groups will undergo undesired reactions, e.g., decomposition, under the reaction conditions. Moreover, aryl chlorides are typically less suitable reactants in these reactions, due to their low reactivity relative to aryl bromides and aryl iodides. Therefore, it would be advantageous to have additional methods for preparing N-aryl amines and N-aryl amides from arylating compounds, such as aryl halides, and amines and amides. Further, many currently-practiced methods of producing N-aryl compounds are somewhat inefficient or economically unattractive. For example, workers at Tosoh Company reported that catalysts containing the P(t-Bu)3 ligand provided high turnover numbers for the formation of aryl piperazines with excess ligand (4:1 ratio of P(t-Bu)3 to Pd) at 120 C. Nishiyama, N. et al. Tetrahedron Lett. 39:617-620 (1998); and Yamamoto, T. et al. Tetrahedron Lett. 39:2367-2370 (1998). However, the high temperatures required for this reaction scheme make it somewhat unattractive for commercial use. In another example, Hartwig et al. have shown that a sterically hindered alkylphosphine, prepared in one step, allows for room temperature amination of aryl halides, and that another commercially-available, sterically-hindered alkylphosphine allows for the reaction of aryl chlorides with primary alkylamines under mild conditions. Hamann, B. C. and Hartwig, J. F., J. Am. Chem. Soc. 120:7369-7370 (1998). It has also been reported recently that a P,N ligand containing a biphenyl backbone, which is prepared in three steps, generates a catalyst that leads to examples of room temperature amination chemistry with aryl bromides and room temperature Suzuki chemistry with aryl chlorides. Old, D. W. et al. J. Am. Chem. Soc. 120:9722-9723 (1998). Notably, nucleophilic N-heterocyclic carbenes, i.e., the imidazoline-2-ylidenes (sometimes called imidazol-2-ylidenes) or so-called "phosphine mimics", have attracted considerable attention as possible alternatives to phosphine ligands in homogeneous catalysis. A primary advantage of these ligands is that an excess of the ligand is not required. It appears that these ligands do not dissociate from the metal center, thereby preventing aggregation of the catalyst to yield the bulk metal. Further, these imidazoline-2-ylidene carbenes appear to be more thermally stable than phosphine ligands. A small number of publications describe the limited use of carbene ligands of this type in palladium-catalyzed reactions of aryl halides with various nucleophiles, e.g., hydride, amines, and metal amides. See Viciu, M. S. et al. Organometallics 2001, 20, 3607-12; Cheng, J. et al. Org. Lett. 2001, 3, 1371-74; Lee, S. et al. Org. Lett. 2001, 3, 2729-32; Stauffer, S. R. et al. Org. Lett. 2000, 2, 1423-26; Huang, J. et al. Org. Lett. 1999, 1, 1307-09; and published PCT application WO 01/66248. Importantly, the various methods disclosed in these publications are of dubious practical synthetic utility because each of them has an absolute requirement for the use of a strong base at an elevated temperature. As outlined above, an absolute requirement for the use of a strong base at an elevated temperature in a palladium-catalyzed arylation reaction limits the set of reactants that may be used in the reaction due to the limited number of functional groups that are robust to withstand the reaction conditions for the necessary period of time. Accordingly, a need continues to exist for a general and efficient process of synthesizing N-aryl amines and N-aryl amides from readily available arylating compounds and amines and amides. The discovery and implementation of such a method would simplify the preparation of commercially significant organic N-aryl amines and amides, and would also likely enhance the development of novel polymers and pharmacologically active compounds. The methods of the present invention address that need. SUMMARY OF THE INVENTION The present invention is directed to a process for the preparation of N-aryl amine and N-aryl amide compounds. The products of the process of the present invention are valuable intermediates and end products in the pharmaceutical and polymer fields. Generally, the process of the present invention involves reacting a compound having a primary or secondary amino or amido group with an arylating compound, in the presence of a weak base and a transition metal catalyst, under reaction conditions effective to form an N-aryl amine or N-aryl amide compound, the transition metal catalyst comprising a Group 8 metal, e.g., Ni, Pd, or Pt, and at least one carbene-containing ligand. Typically, the transition metal catalyst is formed in a preceding step from the conjugate acid form of the carbene ligand, a stoichiometric amount of a strong base, and a Group 8 metal atom or ion. In other words, this invention provides a process for forming a bond between an sp2-hybridized carbon atom and an sp2-hybridized or sp3-hybridized nitrogen atom. The processes of the present invention make use of N-heterocyclic carbenes as ancillary ligands in couplings of aryl halides, e.g., aryl chlorides, and aryl sulfonates, e.g., aryl triflates, with primary or secondary amines or amides. Preferred N-heterocyclic carbenes are derived from cations A and B, wherein Ar represents independently for each occurrence aryl or heteroaryl; and R represents independently for each occurrence hydrogen, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. ##STR1## In certain embodiments, the arylating compound is selected from the group consisting of aryl halides, heteroaryl halides, aryl sulfonates, and heteroaryl sulfonates. In certain embodiments, the arylating compound is selected from the group consisting of aryl iodides, aryl bromides, and aryl chlorides. In certain embodiments, the arylating compound is selected from the group consisting of aryl chlorides and aryl bromides. In certain embodiments, the transition metal catalyst comprises palladium and at least one carbene-containing ligand. In certain embodiments, the transition metal catalyst is prepared by combining palladium, a 1,1,3,3-tetra-substituted-1,3-diazapropene ammonium ion, and a strong base, e.g., an alkoxide. In preferred embodiments, a 1,1,3,3-tetra-substituted-1,3-diazapropene ammonium ion and an alkoxide base are first combined, thereby producing the at least one carbene-containing ligand, followed by addition of palladium to give the transition metal catalyst. As outlined above, Group 8 transition metals other than palladium may form a component of the transition metal catalyst. Further, other cationic compounds, which upon treatment with a base yield a carbene-containing ligand, may be used to prepare a transition metal catalyst useful in the methods of the present invention. In certain embodiments, the base used in the carbon-nitrogen bond-forming reaction is a phosphate, carbonate, fluoride, tertiary amine, or hydride. In certain embodiments, the base used in the carbon-nitrogen bond-forming reaction is a phosphate. In certain embodiments, the base used in the carbon-nitrogen bond-forming reaction is potassium phosphate. |
| PATENT EXAMPLES | available on request |
| PATENT PHOTOCOPY | available on request |
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