WO2006100479A1

WO2006100479A1 - Methods for the synthesis of heteroaromatic compounds

Info

Publication number: WO2006100479A1
Application number: PCT/GB2006/001048
Authority: WO
Inventors: David W. Knight
Original assignee: University College Cardiff Consultants Ltd; Cardiff University
Current assignee: University College Cardiff Consultants Ltd; Cardiff University
Priority date: 2005-03-22
Filing date: 2006-03-22
Publication date: 2006-09-28
Anticipated expiration: 2007-09-22
Also published as: GB0505861D0

Abstract

Methods of making heteroaromatic compounds comprising a 5- membered ring, and dihydro forms thereof, by a metal catalysed 5-endo-cyclisation of alkynes (acetylenes) are disclosed. The methods involve the use of a catalyst comprising a silver salt, more preferably a silver (I) salt, which is employed as a heterogeneous catalyst for the cyclisation reaction. The methods can produce different types of heteroaromatic compounds and are capable of producing highly substituted products, i.e. products in which the 5-membered ring is disubstituted, trisubstituted or, with further simple reactions, tetrasubstituted. The methods described herein generally the advantages that they use conditions and reagents that are benign, cheap and flexible and amenable to scale up, and in which the only by-product is water.

Description

Methods for the Synthesis of Heteroaromatic Compounds

Field of the Invention

The present invention relates to methods for the synthesis of heteroaromatic compounds and compounds produced by the method. More particularly, the present invention provides methods which use a new catalyst for producing heteroaromatic compounds, and dihydro forms thereof, including those which are highly substituted.

Background of the Invention

Despite enormous advances in drug design and synthesis, heteroaromatics still form the basis of >70% of commercial pharmaceuticals. Heteroaromatics are also key structural features of a wide range of other "effect" chemicals, including polymer components, photochromies, organic semi-conductors, agrochemicals, insecticides, and herbicides. Naturally, in view of this, there is a plethora of methods available for the synthesis of such compounds. These range from venerable classical approaches which are still often used despite being discovered over one hundred years ago, to much more modern methods which exploit many of the new concepts in organic synthesis developed during the past twenty years or so. It is therefore perhaps surprising, but nevertheless true, that there remains a need in the art for fast, simple and practical methodology which is capable of producing, in a flexible manner, highly substituted heteroaromatics.

Cyclisation reactions for producing heteroaromatic compounds are known in the art using a range of different metal salts, but suffer from a variety of disadvantages. By way of example, cyclisation reactions employing Cu(I) catalysts usually require heating and provide products in yields of -60-75%. Pd(O) /(H) and Pt(O) catalysed reactions also require heating and have typical yields of -75%, but products are often contaminated by ligand residues. (Ph₃P)₄Ni mediated reactions usually require heating and the products are produced slowly and are contaminated with triphenylphosphine . Finally, although reactions using HgCl₂ work well to give isolable pyrrolomercuries, these reagents are tricky to handle, are toxic and require stoichiometric reagent.

Marshall & Robinson (J. Org. Chem. , 55:3450-3451, 1990, Chem. Abstr., 113, 242280) discloses the use of silver (I) salts including silver nitrate in cyclisations leading to furans from keto-allene precursors in a reaction taking place at 90²C in acetonitrile.

Hu et al (J. Org. Chem., 67: 2365-2368, 2002, Chem. Abstr., 136, 340547) discloses a method for the synthesis of benzofurans in three steps involving the palladium catalysed cyclisation of a 2-alkynylphenol, followed by carbonylation and finally arylation of the resulting acylpalladium species using an aryl iodide. Although the method disclosed in the papers uses a silver salt, AgBF₄, it is employed stoichiometrically in the production of the acylpalladium species and is not used as a catalyst for the cyclisation reaction.

Hiyama et al (JP 58013571 A, WPI Abstract Ace. No: 1983- 23253K[IO]) discloses the use of 2-alkyne-l , 4-diols to produce 3-acetoxy-2 , 5-dihydrofurans .

Kimura et al (JP 8176135 A, WPI Abstract Ace. No 1996- 368197 [37]) discloses the cyclisation of 2-alkynylcarboxylic acids to form ylidenephthalides in a 5-exo-trig reaction.

Summary of the Invention

Broadly, the present invention provides methods of making heteroaromatic compounds comprising a 5-membered ring by a metal catalysed 5-endo-cyclisation of alkynes (acetylenes) . More particularly, the methods involve the use of a catalyst comprising a silver salt, more preferably a silver (I) salt, which is employed as a heterogeneous catalyst. The methods are flexible in terms of the different types of heteroaromatic compounds that may be produced and have the advantage that they are capable of producing highly substituted products, i.e. products in which the 5-membered ring is disubstituted, trisubstituted or, with further simple reactions, tetrasubstituted. In preferred embodiments, the present invention provides an efficient route to trisubstituted compounds. In general, the methods described herein preferably have the advantage that they use conditions and reagents that are benign, cheap and flexible and amenable to scale up. Preferred embodiments of the present invention provide methods which are capable of producing heteroaromatic compounds by metal-catalysed 5-endo-cyclisation of alkyne-diols and hydroxy- alkyne amine derivatives to give furans and pyrroles and where the only by-product is water. The present invention also provides access to dihydro forms of 5-membered heteroaromatic compounds defined herein in which two hydrogen atoms are added across one of the double bonds of the 5-membered aromatic rings. Examples of such compounds include dihydrofurans , dihydropyrrazoles , dihydroisoxazoles and dihydropyrazoles .

While a number of prior art methods for synthesising heteroaromatic compounds are known, these methods tend to suffer from drawbacks such as poor yields, high temperatures, expensive and difficult to remove solvents and catalysts which cannot easily be re-used. In contrast, in preferred embodiments of the present invention, the methods work in benign solvents at ambient temperature, the catalyst can easily be recovered and reused and yields are essentially quantitative .

Accordingly, in a first aspect, the present invention provides a method of producing a compound comprising a 5-membered heteroaromatic ring, or a dihydro form thereof, the method comprising employing a silver salt to cause a substituted alkyne to undergo a 5-endo-cyclisation of the alkyne to form the compound comprising the 5-membered heteroaromatic ring. In this method, the silver salt acts as a catalyst for the reaction to produce the compound comprising the heteroaromatic ring.

In the present invention, the 5-membered heteroaromatic ring may comprise a single heteroatom, e.g. forming substituted pyrroles or substituted furans . Alternatively, the compounds may comprise further heteroatoms which may be the same or different from the first, i.e. forming isoxazoles and pyrazoles from hydroxylamine or hydrazine derivatives. Also, the substituents of the heteroaromatic ring may together form further rings, for example one or more aliphatic or heterocyclic rings, either saturated or unsaturated, and especially one or more further aromatic carbon or heteroaromatic rings, thereby producing substituted or unsubstituted bicyclic or polycyclic compounds, such as indoles, azaindoles, benzofurans, and azabenzofurans, and higher homologues in which the 5-membered ring is fused to more extended aromatics, such as naphthalene, anthracene, phenanthrene , together with aza-derivatives of these such as quinolines, isoquinolines, pyrazines, pyrimidines, pyridazines, and benzo-, naphtho-, phenanthro and higher homologues thereof. In particular, the methods disclosed herein are particularly suitable for producing compounds having heteroatom (s) which are nitrogen and/or oxygen. Dihydro forms of the above compounds with dihydro may also be produced.

Preferably, the silver salt is provided as a heterogeneous catalyst, for example by immobilisation on a solid phase. Examples of suitable silver (I) salts include silver nitrate, silver perchlorate, silver acetate, silver trifluoroacetate, silver tetrafluoroborate, silver hexafluorophosphate, silver halides such as silver chloride, silver bromide or silver fluoride, silver oxide, silver phosphate or silver sulfate. A particularly preferred silver (I) salt is silver nitrate. Preferred reactions employ 5-40 mol% of the silver salt, more preferably 10-20 mol%, the mol% being relative to the starting materials. A preferred example of a solid phase is silica gel, e.g. using 10% AgNO₃ on silica gel, although alternatives such as alumina, zeolites or plastic substrates, such as polyurea, polystyrene or polyurethane, might be employed.

In embodiments of the invention in which the reaction products include small amounts of the catalytic silver salts, an additional purification step may be used to remove them. By way of example, filtering a solution of the reaction products and silver salts through a material capable of absorbing the silver ions has been found to efficiently remove the contaminating salts . A convenient example of such a material is fresh silica gel.

Alternatively, the heterogeneous nature of the catalyst lends itself to use in a flow system or a batch reactor. These approaches may be employed to help to avoid the contamination of the reaction products with small amounts of the catalytic silver salts. In the flow system, the need for the purification step is obviated by using silver supported on an ion exchange resin. Examples of suitable ion exchange resins include Amberjet™ resin (Rohm & Haas Co) or another sulfonated or carboxylated resin. Thus, in one embodiment, the present invention provides a method which comprises:

(a) packing a column in the flow system with an ion exchange resin;

(b) passing a solution of a silver salt through the column to exchange silver ions with the cations initially present in the ion exchange resin; and

(c) washing the resin with solvent to prepare it for the reaction.

The method may also comprises the further steps of:

(d) passing a precursor solution comprising the substituted or unsubstituted alkyne through the column so that it reacts to form the compound comprising the 5-membered heteroaromatic ring, or dihydro form thereof; (e) eluting a solution of the compound comprising the 5- membered heteroaromatic ring, or dihydro form thereof, from the column; and optionally

(f) washing the column so that it can be re-used.

In a typical example, a column is packed with a sulfonated ion exchange resin in its commercial sodium salt form using water. An aqueous solution of a silver salt is then repeatedly passed through the column until no more silver exchanges onto the column, typically 3-4 times. This results in exchange of the bulk of the sodium ions for silver ions. The resulting resin is washed sequentially, e.g. with water, ethanol, ether and dichloromethane , and is then ready for use. The precursor solution is then pumped through the column at an appropriate rate to give only product and water in the effluent solution, given a suitable flow rate and precursor concentration. After washing with a suitable solvent, the column can be re-used. We have found that the silver (I) levels in the final products are not increased above the original background levels.

In an alternative embodiment, the heterogeneous nature of the reaction can be exploited using a batch reactor in which batches of the precursors in a suitable solvent are stirred with the solid catalyst before removal of the solution when cyclisation is complete and addition of another batch of precursor.

The reaction typically requires no additional reagents and has the advantage that the only by-product is water. Moreover, in preferred embodiments of the invention, the catalyst can be recycled and reused, as can the solvents . Suitable solvents for carrying out the reaction include dichloromethane, hexane, low-boiling petrol, ethers or chloroform, to name a few. The reactions generally run at ambient temperature and typically take from about one to about five hours to reach completion. In a preferred embodiment, the method may be employed for producing heteroaromatic compounds represented by Formula I:

wherein:

the X and Y substituents are defined such that:

when Y is C and X is 0 and R¹ is present; or

when Y is C and X is NR⁴ and R¹ is present;

when Y is N and X is 0 and R¹ is absent; or

when Y is N and X is NR⁴ and R¹ is absent; or

and further wherein:

R¹ and R² and/or R³ and R⁴ may optionally together form an aliphatic, a heterocyclic, an aromatic carbon or a heterocyclic ring structure fused to the 5-membered heteroaromatic ring, optionally substituted with one or more of the aromatic substituents as defined herein; and/or

R¹ (when present) , R² and R³ are independently selected from:

hydrogen, halogen, e.g. F, Br, Cl or I, hydroxy, carboxy;

substituted or unsubstituted alkyl, preferably

substituted or unsubstituted alkoxy, preferably Ci_₂oalkoxy;

substituted or unsubstituted alkenyl, preferably Ci_₂oalkenyl ;

substituted or unsubstituted alkynyl , preferably Ci_₂oalkynyl ; substituted or unsubstituted aryl, preferably C₅_₂oaryl;

substituted or unsubstituted heterocyclyl , preferably C₅_₂o heterocyclyl ;

substituted or unsubstituted carboxylic acid or substituted or unsubstituted carboxylic acid ester, preferably Ci-₂₀;

substituted or unsubstituted acyl or acyloxy, wherein the acyl group is preferably Ci-₂oacyl; and/or

amido, acylamido, thioamido, tetrazolyl, amino, nitro, nitroso, azido, cyano, isocyanato, sulfonic acid, sulfonate, sulfone, sulfonyloxy, sulfamino, sulfonamino, sulfamyl, or sulfonamido; and

R⁴ (when present) is selected from:

hydrogen

substituted or unsubstituted alkyl, preferably C₁_₂₀alkyl;

-CO₂R⁶ wherein R⁶ is substituted or unsubstituted alkyl, benzyl, alkenyl, aryl, heteroaryl, trimethylsilylethyl and relatives thereof ;

substituted or unsubstituted acyl or acyloxy, wherein the acyl group is preferably Ci_₂₀acyl; or

amido, acylamido, thioamido, tetrazolyl, amino, nitro, nitroso, azido, cyano, isocyanato, sulfonic acid, sulfonate, sulfone, sulfonyloxy, sulfamino, sulfonamino, sulfamyl, sulfonamido, or sulfonyl, such as tosyl- (Ts) , phenylsulfonyl (PhSO₂-) , mesyl (MeSO₂-) and relatives thereof, or an aryl or alkyl carbamate; or a dihydro form of a heteroaromatic compounds represented by Formula I as defined above.

Preferred examples of -CO₂R⁶ groups include groups which. comprise a t-butoxycarbonyl (BOC) group, commonly used as in the art as protecting groups . Examples of these groups include Boc, Boc-amino acids such as Boc-L-alanine and Boc-glycine, Boc-L-hydroxyproline methyl ester, Boc-L-proline methyl ester, Boc-L-phenylalanine methyl ester and Boc derivatives such as BAMA, BATT, BAHA, BAAA, CAMA, MTCA, HTCA, BSC, BSN, FMT, MTCM, HTCM, chlorosulfonic acid and chloranil.

The method can be used to produce different heteroaromatic compounds, or dihydro forms thereof, having one or more heteroatoms, which may be the same or different. Such compounds may be monocyclic, bicyclic or polycyclic. Examples of heterocyclic compounds comprising a 5-membered ring are provided in the definition section below and include:

When Y is C, X is NR⁴ and R¹ is present, the compounds produced are substituted pyrroles.

When Y is C, X is 0 and R¹ is present, the compounds produced are substituted furans .

When X is NR⁴, Y is N and R¹ is absent, the compounds produced are substituted pyrazoles.

When Y is N and X is 0 and R¹ is absent, the compounds produced are substituted isoxazoles.

When Y is C, X is NR⁴ and R¹ and R² together form a substituted or unsubstituted benzene ring, the compounds produced are substituted indoles . When Y is C, X is O and R¹ and R² together form a substituted or unsubstituted benzene ring, the compounds produced are substituted benzofurans.

When X = N and R¹ and R² together form a substituted or unsubstituted pyridine ring, the compounds produced are substituted or unsubstituted azaindoles.

In this aspect of the present invention, it is preferred that the compounds are disubstituted, in which case only one of the R¹, R² or R³ substituents is hydrogen, or are trisubstituted, in which case none of R¹, R² and R³ are hydrogen.

In embodiments of the present invention in which R¹ and R² and/or R³ and R⁴ together form a ring structure, it may be an aliphatic ring, preferably having from 5 to 8 atoms in the ring, and being optionally substituted with one or more substituents (e.g. one, two, three or four substituents) as defined herein. In other embodiments, the ring structure formed from R¹ and R² and/or R³ and R⁴ may be an aromatic carbon or heterocyclic ring, preferably having from 5 to 8 atoms in the rings, and which may comprise zero, one, two or three heteroatoms in the ring and one or more aromatic substituents (e.g. one, two, three or four aromatic substituents) as defined herein. In either embodiment, preferably the further ring formed from the R¹ and R² and/or R³ and R⁴ substituents is six membered. Preferred examples of compounds of the present invention having further rings are defined by Formula II:

wherein :

X is 0 or NR⁴, wherein R⁴ is defined above; when I, J, K and L are C, the compound is a benzofuran when X is 0 or an indole when X is NR⁴; or

any one of I, J, K or L is N, forming azabenzofurans when X is 0 and azaindoles when X is NR⁴;

any two of I, J, K or L are N, in which case the compounds is a pyrimidinoindole (when I and K or J and L are N) , a pyridazinoindole (when I and L are N) or a pyrazinoindole (when I and J, or J and K, or K and L are N) ; or

any three of I, J, K or L are N, in which case the compound is a triazinoindole;

wherein R⁵ represents one or more aromatic substituents as defined herein (e.g. one, two, three or four aromatic substituents) .

An advantage of the present invention is that it allows the production of highly substituted heteroaromatics, including, but not limited to, disubstituted and trisubstituted compounds. The methods also allow convenient access to tetrasubstituted compounds. By way of example, this can be done by halogenation (e.g. iodination) of a trisubstituted compound produced by the method described herein, followed by a Pd(O) -catalysed coupling, for which there are many possibilities known in the art, or by halogen-metal exchange followed by reaction with an electrophile .

In some embodiments of the invention, the method may employ a starting material which is cyclised to produce the heteroaromatic compound, or dihydro form thereof, is an alkyne represented by Formula Ilia or IHb:

wherein :

in Formula Ilia;

when Y is C and X is 0, R¹ may be present and Q is a leaving group; or

when Y is C and X is NR⁴, R¹ may be present and Q is a leaving group;

when Y is N and X is 0, R¹ is hydrogen and Q is hydrogen; or

in Formula IHb;

when Y is 0, X is NR⁴, wherein when R⁴ is hydrogen, oxidation provides the heteroaromatic compound;

when Y is N, X is NR⁴, wherein when R⁴ is hydrogen, oxidation provides the heteroaromatic compound; and

wherein the X and Y substituents and R¹, R², R³ and R⁴ substituents are defined above.

In Formula Ilia and HIb, the skilled person will be able to readily select suitable leaving groups Q or protecting groups R⁴, when they are present in place of hydrogen. By way of example, preferred Q leaving groups include hydroxyl , -O-alkyl groups or -0-phenyl groups . The R⁴ groups which are eliminated from the starting material may be selected from groups which are substituted or unsubstituted Ts and protected derivatives, heteroaryl, carboxylic acid groups or carboxylic acid derivatives such as ester groups . In a further aspect, the present invention provides compounds represented by Formula I or II, or dihydro forms thereof, that are obtainable by the methods disclosed herein.

Embodiments of the invention will now be described in more detail, by way of example and not limitation, with reference to the accompanying figures .

Brief Description of the Figures

Figure 1 shows the cyclisation reactions of the present invention used to produce substituted furans and benzofurans . For furan compounds, substituents R, R¹, R², R³ may be alkyl, alkenyl, hydroxyalkyl and protected derivatives, aryl, heteroaryl, alkynyl carboxylic acid or carboxylic acid esters. For benzofuran compounds, R³ may be n- or branched alkyl or alkenyl, hydroxyalkyl or protected derivatives thereof, aromatic and heteroaromatics with a full range of substituents and R⁵ may be alkyl, alkenyl and aryl substituents in all possible combinations, halogens, phenols, protected amines, nitro and ester groups and sulfonic acid esters.

Figure 2 shows the cyclisation reactions of the present invention used to produce substituted pyrroles. For pyrrole compounds, substituents R, R¹, R², R³ may be alkyl, alkenyl, hydroxyalkyl and protected derivatives , aryl , heteroaryl , alkynyl carboxylic acid and carboxylic acid esters. Nitrogen substituents may be sulfonamide, both aryl and alkyl, carbamates, both alkyl and aryl, acetyl and higher homologues, trifluoroacetyl or forrαyl .

Figure 3 shows the cyclisation reactions of the present invention used to produce substituted indoles and azaindoles and analogues having additional N atoms present in the heterocyclic rings. For N-tosylindole compounds, R⁴ may be sulfonyl (Ts, PhSO₂, MeSO₂ and relatives thereof) , carbamates, CO₂R⁶, where R⁶ may be both straight chain and branched chain alkyl , benzyl , alkenyl , aryl , heteroaryl and trimethylsilylethyl and relatives thereof and acyl groups including acetyl (MeCO) and -lighter homologues, benzoyl, trifluoroacetyl and formyl . R⁵ may be alkyl alkenyl and aryl substituents in all possible combinations, halogens, phenols, protected amines, nitro and ester groups and sulfonic acid esters. R³ may be n- or branched alkyl or alkenyl, hydroxyalkyl or protected derivatives thereof, aromatic and heteroaromatics with a full range of substituents. In addition, aza-analogues having the same definitions of R^1"3 can be obtained using the method where any one of W-Z can be nitrogen, combinations of any two can be nitrogen, (i.e. the various isomers of pyrimidinoindoles , pyrazinoindoles, pyridazinoindoles) or three of W-Z can be nitrogen (isomers of triazinoindoles) .

Figure 4 shows the cyclisation reactions of the present invention used to produce substituted isoxazoles, where substituents R, R¹, R², R³ may be alkyl, alkenyl, hydroxyalkyl and protected derivatives, aryl, heteroaryl, alkynyl carboxylic acid and carboxylic acid esters. Nitrogen substituents may be alkyl, aryl, sulfonamide, both aryl and alkyl, carbamates, both alkyl and aryl, acetyl and higher homologues, trifluoroacetyl or formyl .

Figure 5 shows the cyclisation reactions of the present invention used to produce substituted pyrazoles, where substituents R, R¹, R², R³ may be alkyl, alkenyl, hydroxyalkyl and protected derivatives, aryl, heteroaryl, alkynyl carboxylic acid, carboxylic acid esters. Nitrogen substituents may be alkyl, aryl, sulfonamide, both aryl and alkyl, carbamates, both alkyl and aryl, acetyl and higher homologues, trifluoroacetyl or formyl .

Figure 6 shows the intermediate dihydroisoxazoles

(isoxazolines) and dihydropyrazoles (pyrazolines) which are the initial products of the cyclisations in Figures 4 and 5. By omitting the oxidation steps shown in Figures 4 and 5, these are isolated in >90% yields. Substituents R, R¹, R², R³ may be alkyl, alkenyl, hydroxyalkyl and protected derivatives, aryl, heteroaryl, alkynyl carboxylic acid, carboxylic acid esters. Nitrogen substituents may be alkyl, aryl, sulfonamide, both aryl and alkyl , carbamates , both alkyl and aryl , acetyl and higher homologues, trifluoroacetyl or formyl .

Detailed Description Abbreviations

For convenience, many chemical moieties are represented using well known abbreviations, including but not limited to, methyl (Me) , ethyl (Et) , n-propyl (nPr) , iso-propyl (iPr) , n-butyl (nBu) , sec-butyl (sBu) , iso-butyl (iBu) , tert-butyl (tBu) , n- hexyl (nHex) , cyclohexyl (cHex) , phenyl (Ph) , biphenyl (biPh) , benzyl (Bn) , naphthyl (naph) , methoxy (MeO) , ethoxy (EtO) , benzoyl (Bz) , and acetyl (Ac) .

For convenience, many chemical compounds are represented using well known abbreviations, including but not limited to, methanol (MeOH) , ethanol (EtOH) , iso-propanol (i-PrOH) , methyl ethyl ketone (MEK) , ether or diethyl ether (Et₂O) , acetic acid (AcOH) , dichloromethane (DCM) , methylene dichloride, acetonitrile (ACN) , trifluoroacetic acid (TFA) , dimethylformamide (DMF) , tetrahydrofuran (THF) , and dimethylsulfoxide (DMSO) .

Definitions

The term "saturated" as used herein is defined as compounds and/or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds .

The term "unsaturated" as used herein is defined as compounds and/or groups which have at least one carbon-carbon double bond or carbon-carbon triple bond. Compounds and/or groups may be partially unsaturated or fully unsaturated. The term "aliphatic" as used herein is defined as compounds and/or groups which are linear of branched or cyclic (also known as "acyclic" or "open-chain" groups) .

5 The term "alkyl" means a branched or unbranched saturated hydrocarbon radical, that may optionally be substituted with one or more of the substituents as defined herein. Preferred alkyl groups are substituted or unsubstituted Ci_₂₀alkyl groups and include, for example, unsubstituted Ci_₂o9-lkyl,

10 Ci_₂ohaloalkyl, Ci-₂ohydroxyalkyl , Ci-₂ocarboxyalkyl , C₁_₂oaminoalkyl and C₅_₂oa-3ryl-Ci-.₂oalkyl . Particular examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl , 2,2- dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2 dimethylbutyl , n-

15 heptyl, 2-methylhexyl and so on.

The term "alkoxy" means a branched or unbranched saturated hydrocarbon radical which is attached via an oxygen atom. Alkoxy groups may be optionally substituted with one or more of 20 the substituents as defined herein. Preferred alkoxy groups are substituted or unsubstituted Ci_₂oalkoxy groups and include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and similar groups .

25 The term "alkenyl" means a branched or unbranched hydrocarbon radical which contains one or more carbon-carbon double bonds. Each of the double bonds present in the alkenyl group may be cis, trans or non-geometric. The alkenyl group may be optionally substituted with one or more of the substituents as

30 defined herein. Preferred alkenyl groups are substituted or unsubstituted Ci_₂oalkenyl groups.

The term "alkynyl" means a branched or unbranched hydrocarbon radical which contains one or more carbon-carbon triple bonds . 35. The alkynyl group may be optionally substituted with one or more of the substituents as defined herein. Preferred alkynyl groups are substituted or unsubstituted Ci-₂oa-lkenyl groups. The term "acyl" means a radical derived from an organic acid by the removal of a hydroxyl group, generally represented by the formula R-CO-. Acyl groups may be optionally substituted with one or more of the substituents as defined herein. Preferred acyl groups are substituted or unsubstituted C^oacyl groups and include, for example, e.g. acetyl, benzoyl, trifluoracetyl and formyl groups . The term acyloxy" group means a radical derived from an organic acid by the removal of a hydrogen atom, generally represented by the formula R-CO₂-. Acyloxy groups may be optionally substituted with one or more of the substituents as defined herein. Preferred acyloxy groups are substituted or unsubstituted C^oacyloxy groups.

The term "ring" as used herein is defined as a closed ring of from 3 to 10 covalently linked atoms, more preferably 3 to 8 covalently linked atoms, yet more preferably 5 to 6 covalently linked atoms. A ring may be an alicyclic ring or an aromatic ring. The term "aliphatic ring" as used herein, pertains to a ring which is not an aromatic ring.

The term "hetero" as used herein is defined as compounds and/or groups which have at least one heteroatom, for example, multivalent heteroatoms (which are also suitable as ring heteroatoms) such as boron, silicon, nitrogen, phosphorus, oxygen, sulphur, and selenium (more commonly nitrogen, oxygen, and sulphur) and monovalent heteroatoms, such as fluorine, chlorine, bromine, and iodine.

The term "heterocyclic ring" as used herein is defined as a ring wherein at least one of the ring atoms is a multivalent ring heteroatom, for example, commonly nitrogen, oxygen or sulphur. Preferably, the heterocyclic ring has from 1 to 4 heteroatoms , and more typically one or two heteroatoms .

The term "heterocyclic compound" as used herein is defined as a cyclic compound which has at least one heterocyclic ring. The term "aromatic compound" as used herein is defined as a cyclic compound which has at least one aromatic ring.

The term "heteroaromatic compound" as used herein, is defined as a cyclic compound which has at least one heteroaromatic ring. The compounds produced by the methods of the present invention comprise a 5-membered heteroaromatic ring., that is either the compound is a 5-membered heteroaromatic compound or comprises a 5-membered heteroaromatic ring as part of a polycyclic ring system.

The term "dihydro form" when applied to dihydro forms of the 5- membered heteroaromatic compounds defined herein means a compound which differs from the 5-membered heteroaromatic compound in that two hydrogen atoms are added across one of the double bonds of the 5-membered heteroaromatic ring. This does not necessarily mean that such compounds are produced from the 5-membered heteroaromatic compounds only that there structures may be defined by comparison with them. Examples of such compounds include dihydrofurans , dihydropyrrazoles, dihydroisoxazoles and dihydropyrazoles .

The term, "aryl" as used herein is defined as a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified) . Preferably, each ring has from 5 to 7 ring atoms .

In this context, the prefixes (e.g., C₃_₂₀, C₅^₇, C₅_₆, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms . For example, the term "C₅_₆aryl" means an aryl group having 5 or 6 ring atoms.

The ring atoms may have carbon atoms, as in "carboaryl groups" (e.g., C₅_₂ocarboaryl ) . Examples of carboaryl groups include, but are not limited to, those derived from benzene (i.e., ^' phenyl) (C₆) , naphthalene (C₁₀) , azulene (C₁₀) , anthracene (C₁₄) , phenanthrene (C₁₄) , naphthacene (C₁₈) , and pyrene (C₁₆) .

Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from:

N₁: pyrrole (azole) (C₅) , pyridine (azine) (C₅) ;

O₁: furan (oxole) (C₅) ;

S₁: thiophene (thiole) (C₅);

N₁O₁: oxazole (C₅), isoxazole (C₅), isoxazine (C₆); N₂O₁: oxadiazole (furazan) (C₅) ;

N₃O₁: oxatriazole (C₅);

N₁S₁: thiazole (C₅) , isothiazole (C₅) ;

N₂: imidazole (1, 3-diazole) (C₅), pyrazole (1, 2-diazole) (C₅), pyridazine (1 , 2-diazine) (Cg), pyrimidine (1, 3-diazine) (C₆) (e.g., cytosine, thymine, uracil), pyrazine (1, 4-diazine) (Cg);

N₃: triazole (C₅), triazine (C₆); and,

N₄: tetrazole (C₅) . -

Examples of heterocyclic groups (some of which are also heteroaryl groups) which comprise fused rings, include, but are not limited to:

C₉heterocyclic groups (with 2 fused rings) derived from benzofuran (O₁) , isobenzofuran (O₁) , indole (N₁) , isoindole (N₁) , indolizine (N₁) , indoline (N₁) , isoindoline (N₁) , purine (N₄) (e.g., adenine, guanine), benzimidazole (N₂), indazole (N₂), benzoxazole (N₁O₁) , benzisoxazole (N₁O₁) , benzodioxole (O₂) , benzofurazan (N₂Oi) _• benzotriazole (N₃) , benzothiofuran (S₁) , benzothiazole (N₁S₁) , benzothiadiazole (N₂S) .

C₁₀heterocyclic groups (with 2 fused rings) derived from chromene (O₁) , isochromene (O₁) , chroman (O₁) , isochroman (O₁) , benzodioxan (O₂) , guinoline (N₁) , isoquinoline (N₁) , quinolizine (N₁) , benzoxazine (N₁O₁) , benzodiazine (N₂) , pyridopyridine (N₂) , quinoxaline (N₂) , quinazoline (N₂) , cinnoline (N₂) , phthalazine (N₂) , naphthyridine (N₂) , pteridine (N₄) . Ci₃h.eterocyclic groups (with 3 fused rings) derived from carbazole (Ni) , dibenzofuran (0χ) , dibenzothiophene (Si) , carboline (KT₂) , perimidine (N₂), pyridoindole (N₂); and, '

^heterocyclic groups (with 3 fused rings) derived from acridine (Ni) , xanthene (Oi) , thioxanthene (Si) , oxanthrene (O₂) , phenoxathiin (OiSi) , phenazine (N₂) , phenoxazine (NiOi) , phenothiazine (NiSi) , thianthrene (S₂) , phenanthridine (Ni) , phenanthroline (N₂) , phenazine (N₂) .

Heterocyclic groups (including heteroaryl groups) which have a nitrogen ring atom in the form of an -NH- group may be N-substituted, that is, as -NR-. For example, pyrrole may be N-methyl substituted, to give N-methypyrrole. Examples of N- substitutents include, but are not limited to Ci_₇alkyl, C₃_₂olieterocyclyl, C₅_₂₀aryl, and acyl groups.

Heterocyclic groups (including heteroaryl groups) which have a nitrogen ring atom in the form of an -N= group may be substituted in the form of an N-oxide, that is, as -N(-»0) = (also denoted -N⁺.(→0^~)=) . For example, quinoline may be substituted to give quinoline N-oxide; pyridine to give pyridine N-oxide; benzofurazan to give benzofurazan N-oxide (also known as benzofuroxan) .

Cyclic groups may additionally bear one or more _oxo (=0) groups on ring carbon atoms. Monocyclic examples of such groups include, but are not limited to, those derived from: C₅: eye1opentanone, cyclopentenone, cyclopentadienone; Cg: cyclohexanone, cyclohexenone, cyclohexadienone; Oi : furanone (C₅), pyrone (C₆);

Ni: pyrrolidone (pyrrolidinone) (C₅) , piperidinone (piperidone) (C₆) , piperidinedione (C₅) ; N₂: imidazolidone (imidazolidinone) (C₅), pyrazolone (pyrazolinone) (C₅) , piperazinone (C₆) , piperazinedione (C₆) , pyridazinone (C₆), pyrimidinone (C₆) (e.g., cytosine) , pyrimidinedione (C₆) (e.g., thymine, uracil), barbituric acid (Cs) ;

NiSi-. thiazolone (C₅), isothiazolone (C₅); NiOi: oxazolinone (C₅).

General Substituents

As indicated herein, the compounds of the present invention may be unsubstituted or substituted by one or more functional groups. Unless otherwise specified, the term "substituted" means a parent group which bears one or more substituents. The term "substituent" is used herein in the conventional sense and refers to a chemical moiety which is covalently attached to, appended to, or if appropriate, fused to, a parent group. A wide variety of substituents are well known in the art, and methods for their formation and introduction into a variety of parent groups are also well known.

In the present invention, the substituent (s) , e.g. the R5 substituent, is or are "aromatic substituents", for example substituents which are independently selected from hydrogen,

-F, -Cl, -Br, -I, -OH, -OMe, -OEt, -SH, -SMe, -SEt, -C(=O)Me, - Ci=O)OE, -C(=0)0Me, -CONH₂, -CONHMe, -NH₂, -NMe₂, -NEt₂, -N(IiPr)₂, -NdPr)₂, -CN, -NO₂, -Me, -Et, -CF₃, -OCF₃, -CH₂OH, -CH₂CH₂OH, -CH₂NH₂, -CH₂CH₂NH₂, substituted or unsubstituted phenyl groups, substituted or unsubstituted alkoxy groups (e.g. Ci_₇alkoxy) ; substituted or unsubstituted ester,- amido; amino; and substituted or unsubstituted alkyl (e.g. Ci_₇alkyl, Ci-₇haloalkyl , Ci_₇hydroxyalkyl , Ci_₇carboxyalkyl , Ci_₇aminoalkyl or C₅_₂oaryl-Ci_₇alkyl) .

In the present invention, "substituted" when used in connection with a functional groups that may be present in one of the compounds of the invention means that the functional group in question may have one or more additional substituents present, e.g. in place of a hydrogen atom. The substituents may be independently selected from hydrogen, halo; hydroxy; oxo,- ether; formyl; acyl; C₅_₂₀arylacyl; acylhalide,- carboxy; ester; acyloxy; amido; acylamido; thioamido; tetrazolyl; amino; nitro,- nitroso; azido; cyano; isocyano; cyanato; isocyanato; thiocyano; isothiocyano ; sulfhydryl; thioether (e.g., C₁_₇alkylthio) ; sulfonic acid; sulfonate; sulfone; sulfonyloxy; sulfinyloxy; sulfamino; sulfonamino; sulfinamino; sulfamyl; sulfonamido; alkyl; C_3-.₂₀heterocyclyl ; or Cs_₂oa.ryl (including, e.g., C₅_₂₀carboaryl , C₅-₂₀heteroaryl , Ci-₇alkyl-C₅_₂oaryl and C₅_₂₀haloaryl) ) .

In addition, substituents R¹ and R² and/or R³ and R⁴ may form an aliphatic carbon or heterocyclic ring structure or an aromatic carbon or heterocyclic ring structure, optionally substituted with one or more of the aromatic substituents as defined herein. Examples of the types of ring that may be produced in accordance with the present invention are provided above.

In one preferred embodiment, the substituent (s) are independently selected from: -F, -Cl, -Br and -I; =0

-OH;

-OMe, -OEt, -O(tBu) and -OCH₂Ph;

-SH;

-SMe, -SEt, -S(tBu) and -SCH₂Ph; -C(=O)H;

~C(=0)Me, -C(=O)Et, -C(=O)(tBu) and -C (=0) Ph,^•

-C(=O)OH;

-C(=0)0Me, -C(=O)OEt and -C (=0) 0 (tBu) ;

-C(=0)NH₂, -C(=0)NHMe, -C(=0)NMe₂ and -C (=0) NHEt; -NHC (=0) Me, -NHC (=0) Et, -NHC (=0) Ph, succinimidyl and maleimidyl; ^'

-NH₂, -NHMe, -NHEt, -NH(iPr), -NH(nPr), -NMe₂, -NEt₂, -N(IPr)₂/

-N(nPr)₂, -N(nBu)₂ and -N(tBu)₂;

-CN; -NO₂;

-Me, -Et, -nPr, -iPr, -nBu and -tBu;

-CF₃, -CHF₂, -CH₂F, -CCl₃, -CBr₃, -CH₂CH₂F, -CH₂CHF₂ and -CH₂CF₃; -OCF₃, -OCHF₂, -OCH₂F, -OCCl₃, -OCBr₃, -OCH₂CH₂F, -OCH₂CHF₂ and -OCH₂CF₃;

-CH₂OH, -CH₂CH₂OH and -CH(OH)CH₂OH; -CH₂NH₂, -CH₂CH₂NH₂ and -CH₂CH₂NMe₂; and, substituted or unsubstituted phenyl .

If the phenyl group has less than the full complement of substituents, they may be arranged in any combination. For example, if the phenyl group has a single substituent other than hydrogen, it may be in the 2-, 3-, or 4-position.

Similarly, if the phenyl group has two substituents other than hydrogen, they may be in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3 ,'5-positions . If the phenyl group has three substituents other than hydrogen, they may be in, for example, the 2,3,4-, 2,3,5-, 2,3,6-, 2 , 4, 5-, .2 , 5 , 6- , or 3 , 4, 5-positions . If the phenyl group has four substituents other than hydrogen, they may be in, for example, the 3,4,5,6-, 2,4,5,6-, 2,3,5,6-, 2,3,4,6-, or 2 , 3 , 4, 5-positions .

Alternative Forms of Compounds

The compounds of the invention may be derivatised in various ways. As used herein "derivatives" of the compounds includes well known ionic, salt, solvate and protected forms of the compounds or their substituents mentioned herein. For example, a reference to carboxylic acid (-C00H) also includes the anionic (carboxylate) form (-COO^") , a salt or solvate thereof, as well as conventional protected forms. Similarly, a reference to an amino group includes the protonated form (-N⁺HR¹R²) , a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group. Similarly, a reference to a hydroxyl group also includes the anionic form (-0^") , a salt or solvate thereof, as well as conventional protected forms.

Isomers, Salts, Solvates, Protected Forms, and Prodrugs Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and transforms; E- and Z-forms; c-, t~, and r- forms; endo- and exo- forms; R-, S-, and meso-forms; D- and L-forms; d- and 1-forms; (+) and {-) forms; keto-, enol-, and enolate-forms ; syn- and anti-forms; synclinal- and anticlinal-forms; α and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

Note that, except as discussed below for tautomeric forms, specifically excluded from the term "isomers", as used herein, are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space) . For example, a reference to a methoxy group, -OCH₃, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH₂OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta- chlorophenyl . However, a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., Ci_₇alkyl includes n-propyl and iso-propyl; butyl includes n- , iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl) .

The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms , as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro .

keto enol enolate

Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions . For example, H may be in any isotopic form, including ¹H, ²H (D) , and ³H (T) ; C may be in any isotopic form, including ¹²C, ¹³C, and ¹⁴C; 0 may be in any isotopic form, including ¹⁶O and ¹⁸O; and the like.

Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof . Methods for the preparation (e.g. asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods , in a known manner .

It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al . , "Pharmaceutically Acceptable Salts", J. Pharm. Sci . , Vol. 66: 1-19, ^' 1977.

For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO^") , then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na⁺ and K⁺, alkaline earth cations such as Ca²⁺ and Mg²⁺, and other cations such as Al³⁺. Examples of suitable organic cations include, but are not limited to,, ammonium ion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺, NH₂R₂ ⁺, NHR₃ ⁺, NR₄ ⁺) . Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dieyelohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine , as well as amino acids, such as lysine and arginine . An example of a common quaternary ammonium ion is N(CH₃)₄ ⁺. If the compound is cationic, or has a functional group which may be cationic (e.g. , -NH₂ may be -NH₃ ⁺) , then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulphuric, sulphurous, nitric, nitrous, phosphoric, and phosphorous .

Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the active compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.

It may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form. The term ^' "chemically protected form" is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions T/GB2006/001048

(e.g., pH, temperature, radiation, solvent, and the like) . In practice, well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group) . By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999) .

A wide variety of such "protecting", "blocking" or "masking" methods are widely used and well known in organic synthesis. For example, a compound which has two nonequivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups "protected" and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only- one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be "deprotected" to return it to its original functionality.

For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl) , or trityl

(triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC (=0) CH₃, -OAc) .

For example, an aldehyde or ketone group may be protected as an acetal (R-CH(OR)₂) or ketal (R₂C(OR)₂)/ respectively, in which the carbonyl group (>C=0) is converted to a diether (>C (OR)₂), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.

For example, an amine group may be protected as an amide

(-NRCO-R) or a urethane (-NRCO-OR) , for example, as: a methyl amide (-NHCO-CH₃); a benzyloxy amide (-NHCO-OCH₂C₆H₅, -NH-Cbz) ; as a t-butoxy amide ( -NHCO-OC (CH₃) ₃, -NH-Boc) ; a 2-biphenyl-2- propoxy amide (-NHCO-OC (CH₃) ₂C₆H₄C₆H₅, -NH-Bpoc) , as a 9- fluorenylmethoxy amide (-NH-Fmoc) , as a 6-nitroveratryloxy amide (-NH-Nvoc) , as a 2-trimethylsilylethyloxy amide (-NH- Teoc) , as a 2 , 2 , 2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-Alloc) , as a 2 (-phenylsulphonyl) ethyloxy amide (-NH-Psec) ; or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>N-0) ; or as an aryl or alkyl sulfonamide derivative thereof.

For example, a carboxylic acid group may be protected as an ester for example, as: an Ci_₇alkyl ester (e.g., a methyl ester; a t-butyl ester); a Ci_₇haloalkyl ester (e.g., a Ci_₇trihaloalkyl ester) ; a triCi-₇alkylsilyl-Ci_₇alkyl ester; or a C₅_₂oaryl- Ci_₇alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.

For example, a thiol group may be protected as a thioether

(-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH₂NHC (=0) CH₃) .

Solvents Solvents may conveniently be classified according to one or more of their physical or chemical properties. For example, solvents may be classified according to their polarity, that is, their permanent dipole moment. Examples of highly polar solvents include dimethylformamide (DMF) , dimethylacetamide, and acetonitrile (ACN) . Examples of moderately polar solvents include acetone, methanol, tetrahydrofuran (THF) , ethyl acetate (AcOEt) , and water. Examples of relatively non-polar solvents include diethyl ether, chloroform, and dichlororαethane (DCM) . Examples of non-polar and virtually non-polar solvents include alkanes, benzene, toluene, and carbon tetrachloride.

Solvents may also be classified as "protic" or "aprotic" according to their proton-exchange properties. Protic solvents accept and/or donate protons. Examples of protic solvents include water, alcohols, carboxylic acids (e.g., acetic acid), and amines (e.g., ammonia, pyridine). Aprotic solvents neither accept nor donate protons. Examples of aprotic solvents include carbon tetrachloride, chloroform, dichloromethane (DCM) , acetonitrile (ACN) , ethyl acetate (AcOEt) , dimethylacetamide, tetrahydrofuran (THF) , dimethylformamide (DMF), toluene, benzene, acetone, ethers (e.g., diethyl ether), alkanes (e.g., hexane) , dimethylsulfoxide (DMSO), sulphur dioxide, hexamethylphosphoramide (HMPA), and, tetramethylurea . Amphoteric solvents, such as water, are capable of both accepting and donating protons .

Solvents may also be classified as "organic" or "inorganic" according to their chemical composition. Conventionally, organic solvents comprise, at least, carbon atoms, while inorganic solvents do not. Examples of inorganic solvents include water, ammonia, and sulphur dioxide. Examples of organic solvent include carbon tetrachloride (CCl₄) ; chloroform (CHCl₃); dichloromethane (DMC, CH₂Cl₂); acetonitrile (ACN); ethyl acetate (AcOEt) ; ethanol (EtOH) ; methanol (MeOH) ; dimethylacetamide; tetrahydrofuran (THF) ; dimethylformamide (DMF); toluene; benzene; acetone; ethers (e.g., diethyl ether); alkanes (e.g., hexane); water; liquid ammonia; dimethylsulfoxide (DMSO) ; sulphur dioxide, hexamethylphosphoramide (HMPA) ; tetramethylurea; tetramethylene sulfone (sulfolane) .

Applications of the Compounds

Compounds that can be made according to the present invention have a wide range of industrially useful applications for example in the areas of pharmaceuticals, agrochemicals , perfumes, photochromic compounds, polymers, insecticides, organic semi-conductors and fine chemicals.

Experimental

The methodology of the present invention, described herein by way of example, employs cyclisation using a silver (I) salt as a heterogeneous catalyst, that can be carried out using a flow system. The method is particularly well adapted for the elaboration of trisubstituted heteroaromatics . Although the emphasis in the following outlines will be directed towards the synthesis of highly-substituted derivatives, the methods of the present invention are equally adaptable to the synthesis of less substituted compounds. The application of the method for the synthesis of furans , benzofurans, pyrroles, indoles, isoxazoles, pyrazoles, and dihydroisoxazoles and dihydropyrazoles is shown schematically in Figures 1 to 6. These figures shows examples of the substituted alkynes that can be treated according to the silver (I) catalysed method of the present invention to produce compounds which comprise a 5- membered heteroaromatic ring .

The cyclisation method of the present invention can deliver trisubstituted furans and pyrroles, along with disubstituted isoxazoles and pyrazoles and, in preferred embodiments, has the advantage of using a catalytic heterogeneous trigger which should be amenable to operation as a flow system. This type of production method clearly has many advantages , especially for large-scale synthesis by continuous flow. This is exemplified by the conversion of the generalised furan and pyrrole precursors into the corresponding heteroaromatics (see Figures 1 and 2) . In detail, the method of the present invention can be carried out by stirring a solution of the precursor compound in a solvent such as hexane or dichloromethane at ambient temperature with the silver catalyst, for example 10-20 mol% silver nitrate on silica gel. Cyclisations are rapid and very clean (typically ~ 95% yields) . The methodology can equally well be applied to the elaboration of the isoxazole and pyrazole precursors (see Figures 4 and 5) from the hydroxylamine and hydrazine derivatives respectively. It has even proven possible to cyclise directly using free amino groups to give the dihydroisoxazoles and dihydropyrazoles in excellent yields (Figure 6) . These reactions will also be of use in heteroaromatic synthesis. An additional significant feature is that the precursors can be obtained as single enantiomers and thus this chemistry will be capable of applications in the synthesis of homochiral amino-alcohols , 1,3-diamines and hydroxy-ketones.

Finally, the catalytic silver-based cyclisation technology may be used to access indoles of all types.

The necessary precursors compounds are readily obtainable in general by known couplings between a very wide range of substituted anilines and a 1-alkyne. The silver-catalysed cyclisations which give indoles work exceptionally efficiently (>90% isolated yields). The latter^' method, unusually, also work with unsubstituted alkynes leading to valuable 2,3-di- unsubstituted indoles .

Returning to the potential for the development of a flow system, this is a most viable prospect as the single flask method works well with a relatively small catalytic amount of the bound silver salt. Hence, by passing a solution of a suitable precursor through a column of the bound salt, the former will inevitably be exposed to a very considerable excess of the catalyst. Therefore, given due care with substrate concentrations and flow routes, only the desired product should emerge from the column, with all that this implies in terms of efficiency and cost effectiveness.

The figures also disclose preferred examples of functional groups that are present in the heteroaromatic compounds of the present invention, or dihydro forms therof. These functional groups may be unsubstituted or substituted as described above, and the substituents provided in the figures are applicable for the synthesis of the respective classes of compounds.

Examples

Example 1: Conversion of l,2-diphenylocfc-3-yne-l,2-diol into 2, 3-diphenyl-5-butylfuran ^■ To a stirred solution of the precursor alkyne-diol (5.88 g, 20 mmol) in dry dichloromethane (60 ml) protected from light using aluminium foil, was added silver nitrate-silica gel complex (3.4-g of 10wt%, 2 mmol) . The resulting suspension was stirred at ambient temperature for 4 h, then filtered through a pad of celite. The solid was washed with fresh dichloromethane and the combined filtrates evaporated at ambient temperature using a rotary evaporator. The residue was pure furan according to proton NMR analysis. Analytically pure material was secured by short column chromatography using silica gel eluted with 20% ethyl acetate in hexanes, collecting a single fraction, to give the furan (5.24 g, 95%) as an oil which showed IR (film) 3028, 1682, 1557, 1501, 1448, 1129 and 1070 cm-1; ¹H NMR (CDC13, 400 MHz) 0.90 (3H, t, J = 7.4 Hz, Me), 1.32-1.42 (2H, m) , 1.56-1.70 (2H, m) , 2.63 (2H, t, J= 7.4 Hz, furan-CH₂), 6.10 (IH, s, 4-H) and 7.10-7.49 (1OH, m) ppm, ¹³C NMR (CDCl₃, 100.6 MHz) 13.9 (Me), 22.4, 27.8, 30.2 (all CH₂) , 109.3, 122.9, 125.9, 129.2, 131.6, 134.8, 146.5 and 155.8 ppm, MS: m/z (APcI) 277 (M+H+, 100%), 187 (28), 107 (29) and 105 (96) [Found: M+H+, 277.1591. C₂₀H_2IO requires M₁ 277.1592],

Example 2: An experimental procedure for the ion-exchange flow system for the synthesis of compounds of the invention

A steel column 15 cm long with a 1.0 cm diameter was packed with ion exchange resin which had been fully exchanged with silver (I) ions. The precursor, in solution in dichloromethane, was pumped through at a rate of 0.3 mmol per minute.

Evaporation of the effluent provided the cyclised product in essentially quantitative yield. Many representative examples from all Schemes 1-6 have been successfully carried out using the column flow method, with the same results as the silica gel method described in Example 1.

Example 3 : Further examples

The results of further examples of this methodology are set out in the reaction schemes on the following pages demonstrating that the reactions can be applied for the synthesis of a wide range of heteroaromatic compounds, or dihydro forms thereof.

The references mentioned herein are all expressly incorporated by reference in their entirety.

Furans:

The following cyclisations have all been carried out using the recipe detailed in the main text. In each case, the yields were similarly excellent, as indicated below.

2,5-disubstituted

[also obtained 96% yield after distillation on a 105 g scale]

2,4-disubstituted

[TMS (trimethylsilyl group lost during cyclisation]

Furans:

2.4,5-trisubstituted

[product very volatile, hence lower isolated yield]

Pyrroles

2,3-disubstituted

2,5-disubstituted

2,4-disubstituted

2,3,5-trisubstituted 97%

R¹-² = Ph, R³ = C(Me)=CH₂, 97%

4,5,6,7-tetrahydro indoles 96%

^'

Alternative Me (98%), /V-protection (99%), Ph

R¹ = Ph, R² = Me, R³ = Bu then R of NCOR = Me (97%), OBu', (95%), OMe (99%), Ph (99%).

Substituents [R, R¹, R², R³] = alkyl, alkenyl, hydroxyalkyl and protected derivatives, aryl, heteroaryl, alkynyl carboxyiic acid, carboxylic acid esters.

Nitrogen substituents: sulfonamide, both aryl and alkyl, carbamates, both alkyl and aryl, acetyl and higher homolσgues, trifluoroacety! and formyl. Indoles:

%

Isoxazoles [ex Fig 4]

The following cyclisations have all been carried out using the recipe detailed in the main text. In each case, the yields were similarly excellent, as indicated below, but the reaction times were much shorter: typically the cyclisations were complete within less than 30 minutes at ambient temperature.

Disconnection A

R² = ⁿPr

R³ = Ph, 90% R³ = Bu, 94%

Disconnection B

R² = Ph

R³ = Ph, 89% R³ = Bu, 92%

R^ = cyclohexyl

R³ = Ph, 91% R³ = Bu, 91%

Disconnection B, with alternative /V-protecting groups

Pyrazoles [ex Fig 5]

The following cyclisations have all been carried out using the recipe detailed in the main text. In each case, the yields were similarly excellent, as indicated below, but the reaction times, just as in the case of the isoxazoles, were much shorter: typically the cyclisations were complete within less than 30 minutes at ambient temperature.

R² = Ph

R³ = Ph, 90% R³ = Bu, 89%

R² = Bu

R = COMe, 97% R = COPh, 98%

Dihydroisoxazoles and dihydropyrazoles [Isoxazolines and pyrazolines] 97%

R² = Ph

R³ = Bu, R = COMe; 96% R³ = Ph, R = COMe; 96%

No W-protecting group.

R¹ = Ph

R² = Bu; 97% R² = Ph; 90%

93%

No Λ/-protecting group. 94%

R = COMe

R¹ = Bu¹, R² = Bu; 96% R¹ = Bu', R² = Ph; 95%

Substituents [R, R¹, R², R³] = alkyl, alkenyl, hydroxyalkyl and protected derivatives, aryl, heteroaryl, . alkynyl carboxylic acid, carboxyiic acid esters.

■ Nitrogen substituents: alkyl, aryl, sulfonamide, both ary! and alkyl, carbamates, both alkyl and aryl, acetyl and higher homologues, trifluoroacetyl and formyl.

Claims

Claims ;

1. A method of producing a compound comprising a 5-membered heteroaromatic ring, or a dihydro form thereof, the method comprising employing a silver salt to cause a substituted or unsubstituted alkyne to undergo a 5-endo-cyclisation of the alkyne to form the compound comprising the 5-membered heteroaromatic ring, or dihydro form thereof, wherein the silver salt is catalytic.

2. The method of claim 1, wherein the silver salt is provided as a heterogeneous catalyst.

3. The method of claim 2, wherein the silver salt is immobilised on a solid phase.

4. The method of claim 3, wherein immobilising the silver salt on a solid phase comprises supporting the silver salt on silica gel.

5. The method of claim 4, wherein the method comprises the further step of purifying a solution of the compound comprising the 5-membered heteroaromatic ring, or a dihydro form thereof, and the silver salt by filtering the solution through a material capable of absorbing the silver salt.

6. The method of claim 5, wherein the absorbing material is fresh silica gel.

7. The method of claim 3, wherein the silver salt is immobilised on a solid phase in a flow system.

8. The method of claim 7, wherein the method comprises supporting the silver salt on an ion exchange resin in the flow system.

9 . The method of claim 8 , which comprises : (a) packing a column in the flow system with, an ion exchange resin;

(c) washing the resin with solvent to prepare it for the reaction.

10. The method of claim 9, which comprises the further steps of:

(d) passing a precursor solution comprising the substituted or unsubstituted alkyne through the column so that it^' reacts to form the compound comprising the 5-membered heteroaromatic ring, or a dihydro form thereof; (e) eluting a solution of the compound comprising the 5- membered heteroaromatic ring, or the dihydro form thereof, from the column.

11. The method of claim 10, which comprises washing the column so that it can be re-used.

12. The method of claim 3 , wherein the solid phase on which the silver salt is immobilised is used in a batch reactor.

13. The method of any one of the preceding claims, wherein the silver salt is a silver (I) salt.

14. The method of claim 13, wherein the silver (I) salt is silver nitrate, silver perchlorate, silver acetate, silver trifluoroacetate, silver tetrafluoroborate, silver hexafluorophosphate, silver halides, silver oxide, silver phosphate or silver sulfate.

15. The method of claim 13 or claim 14, wherein the silver (I) salt is silver nitrate.

16. The method of claim 14, wherein the silver halide salt is silver chloride, silver bromide or silver fluoride.

17. The method of any one of the preceding claims, wherein the method employs 5-40 mol% of the silver salt, the mol% being relative to the starting materials.

18. The method of any one of claims 3 to 17, wherein the solid phase is silica gel, alumina, a zeolite or a plastic substrate such as polyurea, polystyrene or polyurethane .

19. The method of any one of the preceding claims, wherein the reaction is carried out in dichloromethane, hexane, low-boiling petrol, ether or chloroform.

20. The method of any one of the preceding claims, wherein the reaction takes place at ambient temperature.

21. The method of any one of the preceding claims, wherein the reaction takes from about one to about five hours to reach completion.

22. The method of any one of the preceding claims, wherein the 5-membered heteroaromatic ring, or dihydro form thereof, has a single heteroatom.

23. The method of claim 22, wherein the compound is a substituted pyrrole or a substituted furan.

24. The method of any one of claims 1 to 21, wherein the compound comprises two or three heteroatoms .

25. The method of claim 24, wherein the compound is a substituted isoxazole or a substituted pyrazole. ^■

26. The method of any one of the claims 1 to 21, wherein the heteroaromatic ring is linked to one or more further rings, thereby producing a substituted bicyclic or polycyclic compound.

27. The method of claim 26, wherein the bicyclic or polycyclic compound is an indole, an azaindole, a benzofuran or a azabenzofuran, a naphthalene, an anthracene, an phenanthrene, or an aza-derivative such as a quinoline or isoquinoline.

28. The method of any one of claims 1 to 23 wherein the dihydro form of the compound comprising a 5-membered heteroaromatic ring is a substituted or unsubstituted dihydrofuran, dihydropyrrazole, dihydroisoxazole or dihydropyrazole .

29. The method of any one of the preceding claims, wherein the heteroaromatic compound is represented by Formula I:

wherein the X and Y substituents are defined such that: when Y is C and X is 0 and R¹ is present; or when Y is C and X is NR⁴ and R¹ is present; when Y is N and X is 0 and R¹ is absent; or when Y is N and X is NR⁴ and R¹ is absent; or

and further wherein:

R¹ and R² and/or R³ and R⁴ may together form an aliphatic, a heterocyclic, an aromatic carbon or a heterocyclic ring structure fused to the 5-membered heteroaromatic ring, optionally substituted with one or more of the aromatic substituents as defined herein; and/or

R¹ (when present) , R² and R³ are independently selected from hydrogen, halogen, hydroxy, carboxy; substituted or unsubstituted alkyl; substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl , substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl , substituted or unsubstituted carboxylic acid or substituted or unsubstituted carboxylic acid ester,

substituted or unsubstituted acyl or acyloxy, wherein the acyl group, amido, acylamido, thioamido, tetrazolyl, amino, nitro, nitroso, azido, cyano, isocyanato, sulfonic acid, sulfonate, sulfone, sulfonyloxy, sulfamino, sulfonamino, sulfamyl, or sulfonamido;

R⁴ is selected from hydrogen, substituted or unsubstituted alkyl, -CO₂R⁶ wherein R⁶ is substituted or unsubstituted alkyl, benzyl, alkenyl, aryl, heteroaryl, trimethylsilylethyl and relatives thereof substituted or unsubstituted acyl or acyloxy, amido, acylamido, thioamido, tetrazolyl, amino, nitro, nitroso, azido, cyano, isocyanato, sulfonic acid, sulfonate, sulfone, sulfonyloxy, sulfamino, sulfonamino, sulfamyl, sulfonamido, or sulfonyl or an aryl or alkyl carbamate;

or a dihydro form thereof.

30. The method of any one of claims 1 to 28, wherein the compound is represented by Formula II:

wherein :

R³ is as defined in claim 29 ;

X is 0 or NR⁴ , wherein R⁴ is as defined in claim 29 ; R⁵ represents one or more aromatic substituents ;

and wherein one, two or three of I, J, K and/or L may be nitrogen such that:

when I, J, K and L are C, the compound is a benzofuran when X is 0 or an indole when X is NR⁴; or

any three of I, J, K or L are N, in which case the compound is a triazinoindole.

31. The method of any one of the preceding claims, wherein the compound is produced by cyclising a starting material represented by Formula Ilia or IHb:

Ilia IHb wherein:

in Formula Ilia; when Y is C and X is 0, R¹ is present and Q is a leaving group; or when Y is C and X is NR⁴, R¹ is present and Q is a leaving group; when Y is N and X is 0, R¹ is hydrogen and Q is hydrogen; or

in Formula IHb; when Y is O, X is NR⁴, wherein when R⁴ is hydrogen, oxidation provides the heteroaromatic compound;

and further wherein the R¹, R², R³ and R⁴ substituents as defined in claim 29.

32. The method of any one of the preceding claims, comprising further reacting the compound produced by the method to provide a compound comprising a 5-membered heteroaromatic ring, wherein the 5-membered ring is tetrasubstituted.

33. A compound as obtainable by a method of any one of the preceding claims .