US 20090069569Al (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0069569 A1 Nolan et al. (43) Pub. Date: Mar. 12, 2009 (54) CYCLOADDITION OF AZIDES AND Related US. Application Data ALKYNES (60) Provisional application No. 60/971,779, ?led on Sep. 12, 2007. (75) Inventors: Steven P. Nolan, Tarragona (ES); Silvia Diez-Gonzalez, Publication Classi?cation Barakaldo-Vizcaya (ES) (51) Int. C1. 0070 249/04 (2006.01) Correspondence Address: (52) us. c1. ...................................................... .. 548/255 McGLINCHEY STAFFORD, PLLC (57) ABSTRACT Attn: IP Group 301 Main Street, 14th Floor This invention provides a process Which comprises contact BATON ROUGE, LA 70802 (US) ing, in a reaction Zone, at least one organic aZide, at least one alkyne, and at least one N-heterocyclic carbene copper com pound in Which the ligands are either (i) a halide and an (73) Assignees: Institut Catala d’Investigacio N-heterocyclic carbene or (ii) tWo N-heterocyclic carbenes Quimica, Tarragona (ES); and a BF; or PF; anion, to form a l,2,3-triaZole in Which at Institucio Catalana de Recerca i least the l and 4 positions each has a substituent. The N-het Estudis Avancats, Barcelona (ES) erocyclic carbene either an imidaZol-2-ylidene in Which the l and the 3 positions each has a substituent Which has at least (21) Appl. No.: 12/209,323 one carbon atom, or a 4,5-dihydro-imidaZol-2-ylidene in Which the l and the 3 positions each has a substituent Which (22) Filed: Sep. 12, 2008 has at least one carbon atom. US 2009/0069569 A1 Mar. 12, 2009 CYCLOADDITION OF AZIDES AND triaZole in Which at least the 1 and 4 positions each has a ALKYNES substituent. The N-heterocyclic carbene is either an imidaZol 2-ylidene in Which the 1 and the 3 positions each has a REFERENCE TO RELATED APPLICATION substituent Which has at least one carbon atom, or a 4,5 [0001] This application claims priority from US. Applica dihydro-imidaZol-2-ylidene in Which the 1 and the 3 positions tion No. 60/971,779, ?led Sep. 12, 2007, the disclosure of each has a substituent Which has at least one carbon atom. Which is incorporated herein by reference. [0006] These and other features of this invention Will be still further apparent from the ensuing description and TECHNICAL FIELD appended claims. [0002] This invention relates to copper-catalyzed cycload FURTHER DETAILED DESCRIPTION OF THE dition of aZides and alkynes. INVENTION BACKGROUND [0007] Throughout this document, the term ‘reaction Zone’ [0003] Cycloaddition of aZides and alkynes to yield 1,2,3 means any place Where the organic aZide, alkyne, and catalyst triaZoles is a type of Huisgen cycloaddition. Most often, come together. As used throughout this document, the term catalytic systems enabling this transformation consist of a ‘catalyst’ refers to the N-heterocyclic carbene copper com copper(II) salt and a reducing agent. Metallic copper or cop pound, and the term ‘N-heterocyclic carbene copper com per clusters have also been employed. Copper(I) has also been pound’ means the copper(I) complexes in Which the ligands reported in the catalysis of this process. One report of copper are either (i) a halide and an N-heterocyclic carbene or (ii) tWo (I) catalyZed cycloaddition of aZides and terminal alkynes N-heterocyclic carbenes and a BF4_ or PE; anion. Through utilized cuprous halides in reactions in Which the alkyne Was out this document, the term “mol %” is used as an abbrevia on a support, but the reaction did not Work When both the tion for mole percent. aZide and the alkyne Were in solution; see Tomoe et al., .1. Org. [0008] The reaction in the processes of this invention can be Chem, 2002, 67, 3057-3064. Tomoe et al. reported that the represented by the folloWing equation: solution-phase reaction, using simple copper(I) salts in the presence of a nitrogen base, resulted in cross-coupling of the R N terminal alkynes, along With other by-products (J. Org. / \ Chem, 2002, 67, 3057-3064). Another report of copper(I) \N \N catalysis of cycloadditions of aZides and terminal alkynes employed copper(I) generated in situ from copper(II) salts, see Rostovtsev et al., Angew. Chemie Int. Ed. EngL, 2002,41, 2596-2599. In the above equation, When R":H, the alkyne is a terminal SUMMARY OF THE INVENTION alkyne. The reaction shoWn in the equation takes place in the [0004] Pursuant to this invention, cycloaddition of organic presence of a N-heterocyclic carbene copper compound in aZides and alkynes to form 1,2,3-triaZoles is provided. Sur Which the ligands are either (i) a halide and an N-heterocyclic prisingly, internal alkynes as Well as terminal alkynes can be carbene or (ii) tWo N-heterocyclic carbenes and a BF4_ or used to form such cycloaddition products. When a terminal PE; anion. A solvent is optional for the above reaction. The alkyne is used, a 1,4-substituted 1,2,3-triaZole is obtained, R, R', and R" groups, as Well as the N-heterocyclic carbene and When an internal alkyne is used, a 1,4,5-substituted 1,2, copper compounds, are as detailedbeloW. In the 1,2,3-triaZole 3-tr‘iaZole is obtained. To date, other regiochemistries have formed in the reaction, When the alkyne is a terminal alkyne, not been seen using this process, and very feW side products the 1 and 4 positions each has a substituent; the substituent at have been observed. The catalysts in the processes of this the 1 position (R) is from the aZide, and the substituent at the invention are copper(I) compounds in Which the ligands are 4 position (R') is from the terminal alkyne. For internal either (i) a halide and an N-heterocyclic carbene or (ii) tWo alkynes, in the 1,2,3-triaZole formed in the reaction, the 1, 4 N-heterocyclic carbenes and a BF4_ or PE; anion. The pro and 5 positions each has a substituent; the substituent at the 1 cesses of this invention are robust to many types of solvents, position (R) is from the aZide, and the substituents at the 4 (R') including Water, and the processes can be conducted in the and 5 (R") positions are from the internal alkyne. absence of ancillary solvent. Another advantage is that the [0009] The types of organic aZides employed in this inven presence of oxygen is not detrimental to the processes of this tion include alkyl aZides, ether aZides, aryl aZides, and aralkyl invention. The processes of this invention are considered to aZides. One or more functional groups, including cyano fall under the umbrella of “click” chemistry, reactions in groups and nitro groups, may be present in an aryl aZide, in an Which carbon-heteroatom-carbon links are made, With such aralkyl aZide, or in an alkyl aZide. The alkyl portion of the reactions being stereospeci?c, insensitive to oxygen and alkyl aZides can be a branched, straight chain, or cyclic group. Water, and able to produce high yields of the product. For Typically, the alkyl aZides have one to about ?fteen carbon further details on “click” chemistry, see Kolb et al., Angew. atoms, and preferably about three to about ten carbon atoms. Chemie Int. Ed. EngL, 2001, 40, 2004-2021. In the etheric portion of an ether aZide, there can be more than [0005] An embodiment of this invention is a process Which one ether linkage. Ether aZides generally have about three to comprises contacting, in a reaction Zone, at least one organic about ?fteen carbon atoms, and preferably about ?ve to about aZide, at least one alkyne, and at least one N-heterocyclic ten carbon atoms. Preferred types of aZides include aryl carbene copper compound in Which the ligands are either (i) aZides and aralkyl aZides. Mixtures of any tWo or more a halide and an N-heterocyclic carbene or (ii) tWo N-hetero organic aZides can be used, if desired. The use of mixtures of cyclic carbenes and a BF4_ or PE; anion, to form a 1,2,3 organic aZides Will yield a mixture of triaZoles. US 2009/0069569 A1 Mar. 12, 2009 [0010] Suitable alkyl aZides include, but are not limited to, the alkali metal aZide (e.g., about 1.01 to about 1.10 moles of methyl aZide, ethyl aZide, n-propyl aZide, isopropyl aZide, alkali metal aZide per mole of organic halide) is preferred. cyclopropyl aZide, 3-cyanopropyl aZide, n-butyl aZide, sec [0017] Both terminal alkynes and internal alkynes can be butyl aZide, tert-butyl aZide, cyclobutyl aZide, 4-cyanobutyl used in the practice of this invention; both types of alkyne can aZide, pentyl aZide, 3-cyanopentyl aZide, cyclopentyl aZide, 2,2-dimethylpropyl aZide, hexyl aZide, cyclohexyl aZide, contain functional groups. Suitable functional groups in these 4-cyanocyclohexyl aZide, methylcycxlohexyl aZide, heptyl alkynes include carbon-carbon double bonds, ether groups, aZide, octyl aZide, cyclooctyl aZide, nonyl aZide, and decyl ester groups, ketyl groups, hydroxyl groups, chlorine atoms, aZide. Preferred alkyl aZides include methyl aZide, 3-cyano ?uorine atoms, trihydrocarbylsilyl groups, nitrogen atoms propyl aZide, and heptyl aZide. It is noted that methyl aZide, (e.g., as amino groups), and the like. In the practice of this ethyl aZide, and n-propyl aZide are quite explosive, and thus invention, terminal alkynes typically have three to about care should be exercised in their handling. tWenty carbon atoms, and preferably about ?ve to about [0011] Examples of ether aZides that can be used in the tWelve carbon atoms. When expressed as RCECH, groups R practice of this invention include 3,3-dimethoxypropyl aZide, that may be part of a terminal alkyne in this invention include 3,3-diethoxypropyl aZide, 4-butyloxybutyl aZide, 4-propoxy alkyl groups (straight chain, cyclic, or, preferably, branched), pentyl aZide, 5-methoxyhexyl aZide, 4-(2 -tetrahydrofuranyl) alkenyl groups (straight chain, branched, or, preferably, butyl aZide, 2-[2-(1,3-dioxolanyl)]-ethyl aZide, 2-[2-(1,3-di cyclic), aryl groups, and silyl groups.