Abstract:
The invention discloses an improved process for the preparation of 2,2,5,5-tetrasubstituted hexane-1,6-dicarbonyl compounds, and in particular diethyl 2,2,5,5-tetramethylhexanedioate and dimethyl 2,2,5,5-tetramethylhexanedioate, by the alkylation of 1,2-difunctional ethane compounds with enolates of carbonyl compounds. The process provides higher yields and greater synthetic brevity than existing processes.

Description:
[0001]    The present invention relates to processes for the preparation of 2,2,5,5-tetrasubstitutedhexane-1,6-dicarbonyl compounds. In particular, the invention relates to the synthesis of diethyl 2,2,5,5-tetramethylhexanedioate and dimethyl 2,2,5,5-tetramethylhexanedioate, key intermediates in the synthesis of 3,3,6,6-tetramethylcyclohexane-1,2-dione (CyMe 4 -diketone). 
       BACKGROUND TO THE INVENTION 
       [0002]    Certain N-heterocyclic ligands are highly selective actinide-extraction agents. Examples of these ligands are abbreviated as CyMe 4 -BTBP (1), CyMe 4 -BTP (3) and MF 2 -BTBP (2). 
         [0000]    
       
                 
         
             
             
         
       
     
         [0003]    The separation of actinides from lanthanides in high-level liquid waste produced in the nuclear fuel cycle (known as the SANEX process) is envisaged as a key step in the future reprocessing of spent nuclear fuels. Once the actinides are separated and removed from the lanthanides, they may be converted to short-lived radionuclides by neutron fission (transmutation). The remaining waste then loses most of its long-term radiotoxicity, thus reducing the burden on geological disposal. From the numerous European research programmes over the last 30 years (NEWPART, PARTNEW, EUROPART and currently ACSEPT), the ligands shown above have emerged as some of the most promising candidates for use in an industrial SANEX process. In particular, CyMe 4 -BTBP (1) shows most of the desirable qualities (such as hydrolytic and radiolytic stability, high levels of affinity and selectivity, reversible metal binding which allows stripping, comprises only carbon, hydrogen, oxygen, and nitrogen, is completely incinerable, and has sufficient solubility) for use in an industrial process and, since (1) is the most studied and the most well-understood ligand, will almost certainly be used in a future SANEX process. Its suitability for a SANEX process has been demonstrated in a recent ‘hot-test’ on genuine nuclear waste ( Solvent Extr. Ion Exch.,  2009, 27, 97). Until now, synthesizing useful and especially large quantities of (1) has been problematic owing to the limitations associated with the synthesis of the key intermediate, diketone (4). 
         [0000]    
       
                 
         
             
             
         
       
     
         [0004]    Most known routes to (4) involve the cyclisation of dialkyl 2,2,5,5-tetramethylhexanedioate esters (5) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R is methyl or ethyl. 
       BRIEF DESCRIPTION OF THE PRIOR ART 
       [0005]    Three principal methods have been published in the literature for the synthesis of (5): 
         [0000]    (a) Dimerization of pivalic acid (6) using Fenton&#39;s reagent (hydrogen peroxide and iron (II) sulfate) to afford the diacid (7), followed by esterification to (5; R=Et) with concentrated sulfuric acid in ethanol is disclosed in  J. Am. Chem. Soc.,  1958, 80, 2864 , Green Chemistry,  2001, 3, 126 , Ultrasonics Sonochemistry,  1996, 3, 47, and WO8703278A1. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (b) Kolbe electrolysis of the half ester of 2,2-dimethylbutane-1,4-dioic acid (8) is disclosed in  J. Am. Chem. Soc.,  1950, 72, 5388, 1 &amp;  EC Product Research and Development,  1964, 3, 105 and  Bull. Soc. Chim. Fr.,  1988, 3, 571. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (c) Alkoxycarbonylation of dichloride (9) under acidic conditions is disclosed in U.S. Pat. No. 3,354,198. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0006]    Although the prior art methods do provide processes for the preparation of dimethyl and diethyl 2,2,5,5-tetramethylhexanedioate (5), there remains a need for a process which provides these compounds in higher yield. Moreover, there remains a need for a process amenable to the preparation of these compounds on a large scale. 
         [0007]    The present invention addresses these and other problems known from the prior art. 
       SUMMARY OF THE INVENTION 
       [0008]    According to a first embodiment, there is provided a process for the preparation of a compound of the formula (10) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 1  and R 2  are independently selected from C 1 -C 10  alkyl, and
 
R 3  is selected from hydroxy, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 6 -C 10  aryl, and C 6 -C 10  aryloxy, or a salt form thereof, comprising
 
reacting a compound of formula (11)
 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein X and Y represent independently selected leaving groups, with, in the case where R 3  is selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 6 -C 10  aryl, and C 6 -C 10  aryloxy, a compound of the formula (12) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 1  and R 2  are as defined above, R 3  is selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 6 -C 10  aryl, and C 6 -C 10  aryloxy, Z is a cation, and n is 1, 2, 3 or 4, or in the case wherein R 3  is hydroxy, a compound of the formula (12a) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 1  and R 2  are as defined above, m, n and q are positive integers such that n×q=2m. 
         [0009]    According to a second aspect, the invention provides a process for the preparation of a compound of the formula (10) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 1  and R 2  represent independently selected substituents other than hydrogen, and R 3  is selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 6 -C 10  aryl, and C 6 -C 10  aryloxy comprising
 
reacting a compound of formula (11)
 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein X and Y represent independently selected leaving groups, with a compound of the formula (12) 
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         [0000]    wherein R 1 , R 2  and R 3  are as defined above, Z n+ is a cation, and n is 1, 2, 3 or 4. 
         [0010]    In a third aspect, the invention relates to a compound prepared by a process of the invention. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
       [0011]    Preferably, R 1  and R 2  are independently selected from C 1 -C 10  alkyl. More preferably, at least one of R 1  and R 2  is methyl. More preferably, R 1  and R 2  are both methyl. 
         [0012]    Preferably, R 3  is C 1 -C 6  alkoxy. More preferably, R 3  is t-butoxy, methoxy or ethoxy. Most preferably, R 3  is ethoxy. 
         [0013]    Preferably, X and Y are independently selected from: 
         [0000]    —OSO 2 R 4  wherein R 4  is selected from C 1 -C 10  alkyl, C 1 -C 10  perfluoroalkyl, C 6 -C 10  aryl, and a 5- or 6-membered unsaturated heterocyclic ring containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
 
—OPOR 5 R 6 , wherein R 5  and R 6  are independently selected from C 1 -C 10  alkyl, C 1 -C 10  perfluoroalkyl, C 1 -C 10  alkoxy, C 6 -C 10  aryl, a 5- or 6-membered unsaturated heterocyclic ring containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, C 6 -C 10  aryloxy, and heteroaryloxy wherein the heteroaryl group is a 5- or 6-membered unsaturated heterocyclic ring containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
 
wherein each aryl or heteroaryl group may be substituted with up to three substituents independently selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy, nitro and halogen.
 
         [0014]    More preferably X and Y are independently selected from −OSO 2 R 4  wherein R 4  is selected from C 1 -C 10  alkyl, C 1 -C 10  perfluoroalkyl, and C 6 -C 10  aryl optionally substituted with up to three substituents independently selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy, nitro and halogen. 
         [0015]    More preferably, X and Y are independently selected from p-toluenesulfonate (tosylate or OTs), p-bromobenzenesulfonate (brosylate), p-nitrobenzenesulfonate (nosylate), methanesulfonate (mesylate) and trifluoromethanesulfonate (triflate or OTf). 
         [0016]    More preferably, X and Y are independently selected from trifluoromethanesulfonate or tosylate. Preferably, X and Y are the same. 
         [0017]    In a very preferred embodiment X and Y are both trifluoromethanesulfonate. In an alternative very preferred embodiment X and Y are both p-toluenesulfonate. 
         [0018]    Preferably, Z n+ is a cation selected from the group consisting of at least one of alkali metal cations with n=1, alkali earth metal cations with n=2, boron and aluminium cations with n=3, molybdenum, tungsten, manganese, iron, cobalt, nickel, copper, zinc, and unsubstituted or substituted ammonium cations, e.g. the ammonium ion or substituted ammonium cations, especially mono-, di-, tri- or preferably tetrasubstituted ammonium cations where the substitutents are preferably organic moieties bound via a carbon atom and may, for example, be selected from the group consisting of alkyl, such as C 1 -C 10 -alkyl, aryl of 6 to 10 ring atoms. More preferably, Z n+ is a cation selected from the group consisting of at least one of alkali metal cations with n=1. Still more preferably, Z n+ is a cation selected from Li + , Na + , K + and Cs + . Most preferably, Z n+ is Li + . 
         [0019]    Preferably, compound (12) is prepared by reaction of a carbonyl compound of formula (13) with a suitable base (14) 
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         [0000]    wherein R 1 , R 2  and R 3 , Z and n are as defined above, and A −  is a basic anion. Suitable anions A −  include alkoxides, preferably C 1 -C 6  alkoxides; alkylamines, preferably C 1 -C 6  alkylamines; dialkylamines, preferably di(C 1 -C 6 )alkylamines, carbanions, preferably C 1 -C 6  carbanions; hydride; hydroxide; oxide; carbonate; and silicon-based amides, such as bis(trimethylsilyl)amide. Preferred are di(C 1 -C 6 )alkylamines, especially diisopropyl amides. 
         [0020]    In those embodiments wherein R 3  is hydroxy, compound (12a) is a dianion, formed by reaction of corresponding carboxylic acid (13a) with a suitable base (14) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 1  and R 2 , Z and A −  are as defined above, and m, n and q are positive integers such that n×q=2m. 
         [0021]    A very preferred base Z n+ (A − ) n  is lithium diisopropylamide (LDA). 
         [0022]    Preferably, at least one molar equivalent (relative to the amount of carbonyl compound (13)) of base (14) is employed. This helps complete conversion of carbonyl compound to anion (12). Preferably, a slight excess of base is used, such as at least 1.05 equivalents, more preferably at least 1.1 equivalents. Preferably, from 1.05 to 1.5, equivalents, more preferably from 1.1 to 1.2 equivalents of base are used. 
         [0023]    Reaction of carbonyl compound of formula (13) with the base suitably takes place in a solvent. Suitable solvents will be selected by one skilled in the art. Preferred solvents are those which do not react with either base or carbonyl compound. Suitable solvents are selected from alkanes (such as pentane, hexane and octane), aromatic solvents (such as benzene, xylene and toluene), ethers (such as diethyl ether, methyl t-butyl ether and diisopropyl ether), cyclic ethers (such as tetrahydrofuran and dioxane), and mixtures of two or more of such solvents. Preferred solvents are ethers, and in particular diethyl ether. 
         [0024]    The reaction of the carbonyl compound (13) with base (14) is suitably conducted at a reduced temperature, such as between 20 and −70° C., more preferably between 0 and −40° C., more preferably between −10 and −30° C., still more preferably between −15 and −25° C., most preferably about −20° C. 
         [0025]    Preferably, the reaction of the carbonyl compound (13) with base (14) is conducted under an inert atmosphere. Suitable inert atmospheres are selected from nitrogen and argon. 
         [0026]    The base (14) may be added to the carbonyl compound (13), or vice versa. The addition of either reagent to the other may be over a suitable period of time, to prevent temperature increases and unwanted side reactions. 
         [0027]    Reaction of the base and the carbonyl compound is suitably continued until substantially all the carbonyl compound has been converted to the anion (12). 
         [0028]    An alternative process for the preparation of (12) involves the exchange of cations. In this process, the enolate anion is formed with one specific cation, which is subsequently exchanged for an alternative cation. 
         [0029]    Several compounds (11) are known per se in the art, or are commercially available. Alternatively, these compounds may be prepared using techniques known in the art of organic chemistry. For example, compounds (11) wherein X and Y are both selected from −OSO 2 R 4  are suitably prepared from ethylene glycol (15) and two equivalents of sulfonyl halide (16) or sulfonic anhydride in pyridine or dichloromethane. Dimethylaminopyridine (DMAP) may be used to catalyze the reaction. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 4  is as defined above. 
         [0030]    Reaction of enolate (12) with (11) is preferably conducted in a suitable solvent. Suitable solvents are selected from alkanes (such as pentane, hexane and octane), aromatic solvents (such as benzene, xylene and toluene), ethers (such as diethyl ether, methyl t-butyl ether and diisopropyl ether), cyclic ethers (such as tetrahydrofuran and dioxane), and mixtures of two or more of such solvents. Preferred solvents are ethers, and in particular diethyl ether. 
         [0031]    Preferably, compound (11) is added to a solution of enolate (12). Compound (11) may be in solution, in the reaction solvent or another solvent, or may be added in solid form (for example, as aliquots). Preferably, the addition is conducted at a reduced temperature, such as between 20 and −70° C., more preferably between 0 and −40° C., more preferably between −10 and −30° C., still more preferably between −15 and −25° C., most preferably at about −20° C. 
         [0032]    Preferably, the reaction is conducted under an inert atmosphere, such as a nitrogen or argon atmosphere. Preferably, the reaction is conducted with stirring or agitation. The reaction is preferably heated to achieve an acceptable rate of reaction. Preferably, the reaction is heated at the reflux temperature of the solvent. 
         [0033]    The progress of the reaction may be monitored, for example, by using thin layer chromatography, nuclear magnetic resonance spectroscopy, gas chromatography or any other suitable analytical technique. 
         [0034]    On completion of the reaction, the desired product is suitably isolated from the reaction mixture by techniques known in the art. Preferably, the mixture is filtered to remove any undissolved solids, the filtrate quenched with weak aqueous acid (such as ammonium chloride), the aqueous and organic phases separated and the organic phase dried over a desiccating agent (such as magnesium sulfate). The solvent is evaporated to leave crude product. Suitable techniques are disclosed in L. M. Harwood and C. J. Moody,  Experimental Organic Chemistry: Principles and Practice , Blackwell Science, 1996 and L. M. Harwood, C. J. Moody, J. M. Percy,  Experimental Organic Chemistry: Standard and Microscale , Blackwell Science, 1998 (second edition). 
         [0035]    The product is purified, if desired, by techniques known to the skilled person, such as recrystallization, distillation, and/or chromatography. Distillation is preferred. Suitable techniques are disclosed in L. M. Harwood and C. J. Moody,  Experimental Organic Chemistry: Principles and Practice, Blackwell Science,  1996 and L. M. Harwood, C. J. Moody, J. M. Percy,  Experimental Organic Chemistry: Standard and Microscale , Blackwell Science, 1998 (second edition). However, the product need not be purified, and may be suitable for further transformations in crude form. 
         [0036]    An advantage of the present route is that the diester compound (5) can be produced in larger quantities more rapidly than the above literature routes. This is due to the higher overall yield of (5) obtained. In literature route (a) above, the yield quoted for the diacid (7) is 37% and, from the inventor&#39;s experience of using this route, the yields are often lower. In the present route, the yield of (5; R=Et) is 69% when X=OTs and 70% when X=OTf. The present route also avoids the need to use large electrochemical cells which would place a limit on the reaction scale (route (b) above) or the need to employ high pressures of carbon monoxide and the extremely corrosive hydrofluoric acid which requires the exclusion of glassware (route (c) above). 
         [0037]    Another significant advantage of the present route is the minimization of waste and thus costs involved. In particular, the need to use large quantities of pivalic acid and iron (II) sulfate in route (a) above is avoided in the present route. This is particularly significant in the context of large-scale industrial production of (5) and thus the diketone (4). In addition, the present route also allows for the recycling of the lithium salts produced by filtration of the reaction mixture prior to quenching. Thus, for example, if X=OTs, the lithium tosylate may be recovered and converted back to tosyl chloride, which may then be used to prepare more of the C-2 electrophile ethylene glycol di(p-tosylate) from ethylene glycol, thus closing the production cycle. This represents a further aspect of the invention. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0038]    Another significant advantage of the present route is that the diester (5), and hence the diketone (4) are obtained in higher purity compared to route (a) above. Thus, in the present route, we have found that the diketone (4) is obtained pure without the need for recrystallisation whereas in route (a) above, the crude diketone needs to be recrystallised, thus lowering the yield of (2) further (eg: in one typical run, 3.88 g of crude diketone (2) obtained from 200 g of pivalic acid in route (a) above was recrystallised to yield 1.05 g of pure diketone (4); overall yield of diketone (4)=&lt;1%. This compares with an overall yield of the diketone (4)=33% (X=OTs) or 41% (X=OTf) when using the present method. 
         [0039]    In a further embodiment, the invention comprises the further steps of converting a compound of formula (10) wherein R 3  is C 1 -C 6  alkoxy to 3,3,6,6-tetrasubstitutedcyclohexane-1,2-dione (17). This conversion is achieved using methods known in the art. 
         [0040]    A first method involves conducting an intramolecular acyloin reaction of a compound of formula (10) wherein R 3  is C 1 -C 6  alkoxy in the presence of chlorotrimethylsilane to give 1,2-bis-(siloxene) (18). This compound is subsequently oxidized, e.g. with bromine in carbon tetrachloride to give diketone (17). The inventors have also discovered that carbon tetrachloride may be replaced with dichloromethane with no adverse consequences in terms of yield. This change of solvent has significant advantages in terms of safety, availability of solvent and environmental profile, and represents a further aspect of the invention. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    R 3 =C 1 -C 6  alkoxy; R 1 , R 2  as defined above. 
         [0041]    A second method involves conducting an intramolecular acyloin reaction to give hydroxyketone (19). This compound is subsequently oxidized e.g. with chromium (VI) oxide or thionyl chloride to give diketone (17). 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 1  and R 2  are as defined above. 
         [0042]    In a further embodiment, the invention comprises the further steps of converting a 3,3,6,6-tetrasubstitutedcyclohexane-1,2-dione (17) into 6,6′-Bis(5,5,8,8-tetrasubstituted-5,6,7,8-tetrahydro-1,2,4-benzotriazin-3-yl)-2,2′-bipyridine (20), and the 4-t-butyl analogue (21), comprising reacting 2,2′-bipyridine-6,6′-dicarbohydrazonamides (22) or (23) with 3,3,6,6-tetrasubstitutedcyclohexane-1,2-dione (17) in the presence of a base such as triethylamine. In the hands of the inventors, the use of THF gave a yield of (20) of only 10%, whereas the reported yield of (20) using this solvent is 60% (see M. R. S. Foreman, M. J. Hudson, M. G. B. Drew, C. Hill, C. Madic,  Dalton Trans.,  2006, 1645). Surprisingly, the use of dioxane as a solvent has been found to give a yield of (20) of 56%. The use of dioxane in this context represents a further aspect of the invention. 
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         [0043]    In a further embodiment, the invention comprises the further steps of converting a 3,3,6,6-tetrasubstituted cyclohexane-1,2-dione (17) into 2,6-bis(5,5,8,8-tetrasubstituted-5,6,7,8-tetrahydro-1,2,4-benzotriazin-3-yl)-pyridine (24), comprising reacting pyridine-2,6-dicarbohydrazonamide (25) with 3,3,6,6-tetrasubstitutedcyclohexane-1,2-dione (17) in the presence of a base, such as triethylamine. Conditions for performing this transformation are disclosed in New J. Chem., 2006, 30, 1171. 
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         [0044]    In a further embodiment, the invention comprises the further steps of converting a 3,3,6,6-tetrasubstitutedcyclohexane-1,2-dione (17) to a compound of formula (25) 
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         [0045]    Suitable techniques for effecting this transformation are disclosed for example in WO8703278, which is incorporated by reference in its entirety. 
         [0046]    Diketone (4) may be used to synthesize quinoxaline heterocyclic compounds of general structure (27). These compounds exhibit retinoid activity and act as agonists/antagonists of Retinoic acid, which is the oxidised form of Vitamin A and is used as a drug in the treatment of various dermatological and inflammatory conditions (eg: rheumatoid arthritis, colitis, psoriasis and acne vulgaris) as well as leukaemia. Methods for achieving the conversion are set out in WO9613478 and WO9702244, which are incorporated by reference in their entirety. 
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       DEFINITIONS 
     Alkyl 
       [0047]    Alkyl, as used herein refers to an aliphatic hydrocarbon chain and includes straight and branched chains e.g. of 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isohexyl. 
       Alkoxy 
       [0048]    Alkoxy as used herein refers to the group —O-alkyl, wherein alkyl is as defined above. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, isopentoxy, neo-pentoxy, n-hexyloxy, and isohexyloxy. 
       Perfluoroalkyl 
       [0049]    As used herein, the term “perfluoroalkyl” refers to an alkyl group as hereinbefore defined, wherein all the hydrogen atoms have been replaced with fluorine atoms. Examples of perfluoroalkyl groups are trifluoromethyl, pentafluoroethyl, and nonafluorobutyl. 
       Perfluoroalkoxy 
       [0050]    As used herein, the term “perfluoroalkoxy” refers to an alkoxy group as hereinbefore defined, wherein all the hydrogen atoms have been replaced with fluorine atoms. Examples of perfluoroalkyl groups are trifluoromethoxy, pentafluoroethoxy, and nonafluorobutoxy. 
       Aryl 
       [0051]    As used herein, “aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to 10 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl). Preferred aryl groups include phenyl, naphthyl and the like. 
       Heteroaryl 
       [0052]    As used herein, the term “heteroaryl” refers to a 5- or 6-membered unsaturated heterocyclic ring containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Examples of heteroaryl groups include thiophene, furan, pyridine, pyrimidine, pyridazine, imidazole, isoxazole, oxadiazoles, quinolines, benzotriazines and the like. 
       Aryloxy 
       [0053]    As used herein, “aryloxy” refers to the group —O-aryl, wherein aryl is as defined above. Preferred aryloxy groups include phenoxy, naphthyloxy and the like. 
       Heteroaryloxy 
       [0054]    As used herein, “heteroaryloxy” refers to the group —O-heteroaryl, wherein heteroaryl is as defined above. 
       Leaving Group 
       [0055]    The term “leaving group” as used herein, refers to a group capable of being displaced from a molecule when said molecule undergoes reaction with a nucleophile. 
       Salt Form 
       [0056]    As used herein, the term “salt form” includes salts of alkali metals, including lithium, potassium and caesium, alkaline earth metals, including magnesium, calcium and strontium, ammonium salts, such as ammonium and alkylammonium salts. 
       EXAMPLES 
     General 
       [0057]    Anhydrous diethyl ether was dried and distilled from sodium benzophenone ketyl immediately prior to use. Diisopropylamine was dried and distilled over calcium hydride immediately prior to use. Toluene was dried over calcium chloride prior to use. All other reagents were obtained from Aldrich Chemical Company Inc. 
       Diethyl 2,2,5,5-tetramethylhexanedioate (5; R=Et) 
     Method A: 
       [0058]    
       
                 
         
             
             
         
       
     
         [0059]    Anhydrous diethyl ether (500 mL) was placed in an oven-dried 1 L 3-neck flask and sealed under an atmosphere of nitrogen. Diisopropylamine (40.36 mL, 1.1 equiv) was added via syringe and the solution was cooled to −20° C. using a dry ice-acetone bath. n-Butyllithium (104.73 mL, 2.5 M, 1 equiv) was added dropwise via syringe and the solution was stirred at −20° C. for 1 h. Ethyl isobutyrate (35 mL, 30.42 g, 261.837 mmol) was slowly added dropwise via syringe over 45 mins and the solution was then allowed to warm to room temperature and stirred for an additional 1 h. Solid ethylene di(p-toluenesulfonate) (48.49 g, 0.5 equiv) was added in small aliquots over 10 mins and the suspension was heated under reflux for 24 h. The flask was allowed to cool to room temperature and the insoluble solid was filtered and washed with ether (100 mL) and DCM (200 mL). The resulting white solid (43.8 g, 94%) was shown by  1 H NMR to be pure lithium p-toluenesulfonate. The filtrate was quenched with satd. aq. ammonium chloride (200 mL) and the phases were mixed and separated. The aqueous phase was extracted with ether (100 mL). The combined organic extracts were washed with water (150 mL), dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford the crude product (38.29 g) as a yellow liquid. The crude product was purified by vacuum distillation using a 10 inch tall Vigreux column to afford the title compound (23.35 g, 69%) as a clear liquid (Bp 72-76° C. at 0.1 mm Hg). Two additional fractions were obtained (3.02 g, Bp 52-60° C. and 2.86 g, Bp 98-104° C.) which were shown by  1 H NMR to be unidentified impurities and unreacted ethylene di(p-toluenesulfonate), respectively. 
       Method B: 
       [0060]    
       
                 
         
             
             
         
       
     
         [0061]    Anhydrous diethyl ether (100 mL) was placed in an oven-dried 250 mL 3-neck flask and sealed under an atmosphere of nitrogen. Diisopropylamine (4.86 mL, 1.1 equiv) was added via syringe and the solution was cooled to −20° C. using a dry ice-acetone bath. n-Butyllithium (19.7 mL, 1.6 M, 1 equiv) was added dropwise via syringe and the solution was stirred at −20° C. for 1 h. Ethyl isobutyrate (4.21 mL, 3.66 g, 31.533 mmol) was slowly added dropwise via syringe over 30 mins and the solution was then allowed to warm to 0° C. and stirred for an additional 1 h. A solution of ethylene bis(trifluoromethanesulfonate) (5.14 g, 0.5 equiv) in anhydrous diethyl ether (15 mL) was added dropwise via syringe over 30 mins and the solution was allowed to warm to room temperature and stirred for 1 h. The solution was then heated under reflux for 24 h. 
         [0062]    The flask was allowed to cool to room temperature, the solution was quenched with satd. 
         [0063]    aq. ammonium chloride (50 mL) and the phases were mixed and separated. The aqueous phase was extracted with ether (50 mL). The combined organic extracts were washed with water (50 mL), dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford the crude product (4.39 g) as a yellow liquid. The crude product was purified by vacuum distillation using a 6 inch tall Vigreux column to afford the title compound (2.85 g, 70%) as a clear liquid (Bp 72-76° C. at 0.1 mm Hg). One additional fraction was obtained (0.08 g, Bp 58-62° C.) which was shown by  1 H NMR to be unidentified impurities. 
         [0064]      1 H NMR (400 MHz, CDCl 3 ): δ 1.15 (12H, s, 2×2-CH 3  and 2×5-CH 3 ), 1.25 (6H, t, J=7.8 Hz, CH 2 CH 3 ), 1.45 (4H, s, 3-CH 2  and 4-CH 2 ), 4.12 (4H, q, J=7.8 Hz, CH 2 CH 3 ) ppm. 
       1,2-Bis(trimethylsilyloxy)-3,3,6,6-tetramethylcyclohex-1-ene 
       [0065]    
       
                 
         
             
             
         
       
     
         [0066]    Anhydrous toluene (300 mL) was placed in an oven-dried 500 mL 1-neck flask and sealed under an atmosphere of nitrogen. Sodium (10.41 g, 5 equiv) was added and the flask was heated under reflux until the sodium melted. The starting material (23.35 g, 90.503 mmol) was added and then chlorotrimethylsilane (57.20 mL, 5 equiv) was added. The mixture was heated under reflux for 24 h. The mixture was allowed to cool to room temperature and was suction-filtered through a sintered disk under nitrogen using a wide Schlenk tube. The solid residue was washed with toluene (100 mL) and THF (50 mL) and the filtrate was evaporated under reduced pressure to afford the crude product (26.57 g) which was purified by vacuum distillation to afford the title compound (17.79 g, 63%) as a clear liquid (Bp 68-72° C. at 0.1 mm Hg). Two additional fractions were obtained (1.23 g, Bp 48-60° C. and 1.43 g, Bp 82-86° C.) which were shown by  1 H NMR to be impure product and unidentified impurities. The excess sodium was quenched under nitrogen by washing the solid residue with EtOH (150 mL). 
         [0067]      1 H NMR (400 MHz, CDCl 3 ): δ 0.00 (18H, s, 2×OSi(CH 3 ) 3 ), 0.83 (12H, s, 2×3-CH 3  and 2×6-CH 3 ), 1.25 (4H, s, 4-CH 2  and 5-CH 2 ) ppm. 
       3,3,6,6-Tetramethylcyclohexane-1,2-dione (4) 
     Method A: 
       [0068]    
       
                 
         
             
             
         
       
     
         [0069]    The starting material (20.14 g, 64.166 mmol) was dissolved in carbon tetrachloride (130 mL) in a 250 mL 1-neck flask. Bromine (3.28 mL, 1 equiv) was added dropwise over 15 mins. The solution was stirred at room temperature for 30 mins. The solution was then washed with water (2×75 mL) and satd. aq. sodium sulfite (50 mL), dried over magnesium sulfate and evaporated under reduced pressure to afford the title compound as a yellow solid (10.68 g, 99%). 
       Method B: 
       [0070]    
       
                 
         
             
             
         
       
     
         [0071]    The starting material (1.78 g, 5.668 mmol) was dissolved in DCM (20 mL) in a 100 mL 1-neck flask. Bromine (0.29 mL, 1 equiv) was added dropwise over 5 mins. The solution was stirred at room temperature for 30 mins, The solution was diluted with DCM (50 mL) and then washed with water (2×20 mL) and satd. aq. sodium sulfite (30 mL), dried over magnesium sulfate and evaporated under reduced pressure to afford the title compound as a yellow solid (0.94 g, 99%). 
         [0072]      1 H NMR (400 MHz, CDCl 3 ): δ 1.15 (12H, s, 2×3-CH 3  and 2×6-CH 3 ), 1.87 (4H, s, 4-CH 2  and 5-CH 2 ) ppm. 
       6,6′-Bis(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1,2,4-benzotriazin-3-yl)-2,2′-bipyridine 
       [0073]    
       
                 
         
             
             
         
       
     
         [0074]    2,2′-Bipyridine-6,6′-dicarbohydrazonamide (2.51 g, 9.296 mmol) was suspended in dioxane (300 mL) and 3,3,6,6-tetramethylcyclohexane-1,2-dione (3.28 g, 2.1 equiv) was added. Triethylamine (25 mL) was added and the flask was heated under reflux for 24 h. The flask was allowed to cool to room temperature, the mixture was filtered and the insoluble solid was washed with THF (50 mL). The filtrate was evaporated under reduced pressure to afford the crude product as an orange solid (5.74 g). The crude product was triturated with EtOH (100 mL) and the insoluble solid was filtered and washed with EtOH (50 mL) and diethyl ether (40 mL) to afford the title compound as a yellow solid (1.31 g). The filtrate was evaporated under reduced pressure and the resulting solid was again triturated with EtOH (150 mL) and the insoluble solid was filtered and washed with EtOH (50 mL) and diethyl ether (20 mL) to afford an additional 1.46 g of product. Total yield: 2.77 g (56%). 
         [0075]      1 H NMR (400 MHz, CDCl 3 ): δ 1.48 (12H, s, 4×5-CH 3 ), 1.53 (12H, s, 4×8-CH 3 ), 1.90 (8H, s, 2×6-CH 2  and 2×7-CH 2 ), 8.04 (2H, t, J=7.8 Hz, 4-CH and 4′-CH), 8.54 (2H, dd, J 7.8 and 0.8 Hz, 5-CH and 5′-CH), 8.96 (2H, dd, J 7.8 and 0.8 Hz, 3-CH and 3′-CH) ppm.  13 C NMR (100 MHz, CDCl 3 ): δ 29.2 (4×5-CH 3 ), 29.7 (4×8-CH 3 ), 33.3 (2×6-CH 2 ), 33.8 (2×7-CH 2 ), 36.5 (2×quat), 37.2 (2×quat), 122.8 (C-3 and C-3′), 123.9 (C-5 and C-5′), 137.8 (C-4 and C-4′), 152.8 (2×quat), 156.1 (2×quat), 160.9 (2×quat), 163.0 (2×quat), 164.3 (2×quat) ppm.