WO1998005671A1

WO1998005671A1 - Organosilicon compounds and their use in combinatorial chemistry

Info

Publication number: WO1998005671A1
Application number: PCT/GB1997/002128
Authority: WO
Inventors: Neal David Hone; Anthony David Baxter
Original assignee: Oxford Asymmetry International Plc.
Priority date: 1996-08-07
Filing date: 1997-08-07
Publication date: 1998-02-12
Also published as: GB9616563D0

Abstract

Compounds of general formula (I) and support-bound compounds of general formula (II), wherein R, R?1, R2, R3, R4¿, X, A, Y, P and n are as herein defined, and their use in combinatorial chemistry and in the synthesis of compounds comprising at least one carbon atom in an aromatic ring.

Description

ORGANOSILICON COMPOUNDS AND THEIR USE IN COMBINATORIAL CHEMISTRY

The invention relates to a method for preparing compounds comprising at least one carbon atom in an aromatic ring. This invention also relates to improved silane linkers, to methods for their preparation and to their use in the synthesis of such compounds and of compound libraries. Such libraries may be screened as pharmaceutical agents .

The recent explosion of combinatorial chemistry has been driven by the pharmaceutical industry's requirements for novel lead compounds and rapid lead optimisation. Combinatorial methods facilitate lead discovery through the simultaneous synthesis of large numbers of novel compounds within a short timescale. Similarly, the ability to rapidly produce analogue libraries allows the efficient optimisation and structure activity relationship (S.A.R.) investigation of known leads compared to the traditional "hand crafted" approach of the medicinal chemist.

Combinatorial chemistry may involve the reaction of each member of one pool of X number of preferably commercially available reagents (e.g. amines) with each of Y members of another pool (e.g. acid chlorides) to produce a library of X x Y number of compounds (e.g. amides) . Each member of the X x Y products could then be reacted with a further pool of Z number of compounds to give a total of X x Y x Z compounds and so on.

Alternatively, a library may comprise a collection of compounds based on a particular core structure. For example, if a core structure such as an aromatic ring can have three independently variable substituents A, B and C then all the possible combinations of A, B and C on the core structure would be present within a library. If substituent A could be any one of a chemical moieties, substituent B any one of b chemical moieties and substituent C any one of c chemical moieties, the total number of compounds in the library would be a x Jb x c.

Ideally, the use of very efficient or optimised reaction conditions allows the desired products to be formed in high yield and purity. Biological screening is therefore possible using crude reaction products without involving labourious purification procedures.

Combinatorial libraries have been prepared using both 'in solution' methods and by solid phase synthesis. Multiple simultaneous solution reactions have successfully yielded useful numbers of a variety of novel compounds for biological screening. However, the need to avoid purification of products in order to make this process viable limits this approach to the use of efficient one or, at the most, two step reactions. Solid phase synthesis on the other hand allows the use of excess reagents to drive reactions to completion, and the facile removal of excess reagents and by-products through simple washing procedures. This provides the possibility of synthesising more complex and diverse structures and lends itself well to automation. Solid phase chemistry therefore offers a more attractive approach to the generation of combinatorial libraries .

Numerous solid phase syntheses of small organic molecule libraries have recently been reported, demonstrating the power of this technique (Plunkett, M. J. and Ellman, J. A., J. Am. Chem. Soc, 1995, 112, 3306-3307; Virgilio, A. A. and Ellman, J. A., J. Am. Chem. Soc, 1994, 116. 11580-11581). However, resins currently employed to provide solid phase supports were originally developed for the synthesis of peptides. Thus existing resins are functionalised with linkers that cleave to release products with polar functionality, such as carboxylic acids and amides. More recent advances in linker technology have allowed for example the covalent attachment of amino and hydroxyl groups to solid resin supports and their subsequent release during final cleavage from the resin. Library members containing such functionality may, however, possess unfavourable pharmacological properties due to their inherent polarity. The development of technology which allows the release from a solid support of the type of non-polar or unfunctionalised aromatics so commonly found in medicinal agents would represent a significant advance.

WO 95/16712 discloses the use of silane linkers in the resin-bound synthesis of substituted aromatic carbocycles and heterocycles . The aromatic compounds are bound to the resin support through a silane linker comprising the moiety

D-CH₂-SiR' 'R' ' '

wherein D is a Ci-Cjo alkyl chain optionally having one or more intervening heteroatoms or aryl groups ; and

R' ' and R' ' ' are independently C_α to C₆ alkyl.

A plurality of resin-bound aromatic compounds are derivatised to give a library of compounds . Such compounds may then be cleaved from the silane linker by protodesilylation with a strong protic acid, such as HF or 100% trifluoroacetic acid. Various other electrophiles are also disclosed which bring about cleavage from the linker. However, the cleavage reactions are lengthy and employ harsh reaction conditions, which may be incompatible with some functional groups present in a diverse library set.

A silane linker for use in the solid state synthesis of biphenyl derivatives is disclosed in Han et al, Tetrahedron Letters, ,12, 2703-2706, 1996. Cleavage of the biphenyl derivatives from the silane linker is brought about by treatment with trifluoroacetic acid or an electrophile . However, the yields of the cleavage reactions are variable and are dependent on the nature of the substituents on the phenyl rings.

The release of combinatorial compound libraries from a resin support ideally provides quantitative cleavage, or at least equimolar cleavage, of each component to allow viable comparisons to be made of biological data from arrays of compounds synthesised in insufficient quantity for accurate weight determination. The cleavage reactions must therefore be efficient and predictable in order for the silane linkers to be useful as combinatorial tools. In addition the linkers must themselves be stable to the cleavage conditions to avoid the possibility of product contamination through linker degradation.

Liquid hydrofluoric acid (HF) is known to effect aryl-silicon cleavage. However, the hazardous nature of this reagent and the specialised equipment required for its handling, especially in the simultaneous cleavage of a library of resin samples, makes its use in routine processes impractical.

There is thus still a need for compounds which can act as linkers and which can be used to tether a wide range of different aromatic compounds to a solid support and which can then be cleaved to release the derivatised compounds in a fast, efficient, predictable and clean manner, which is largely independent of the nature and substituents of the aromatic compounds. According to one feature of the present invention, there are thus provided compounds of general formula (I)

R¹ R^J J

Si C - ⁽X⁾„ i „ R⁴

(I)

wherein

R¹ and R², independently of one another, denote C_!-C₁₀ alkyl, cycloalkyl or aralkyl;

R³ and R⁴, independently of one another, denote hydrogen, alkyl, cycloalkyl or aralkyl;

n denotes 1 or 2 ;

where n denotes 1, X denotes 0, S, NR³,

OC(R³R⁴),

SC (R³R⁴ ) , NR³C (R³R⁴) , CR³ (C0₂H) , CR³ ( CONR³R⁴ ) , CR³ ( C0N )

where n denotes 2, X denotes CR³R⁴;

R denotes a group comprising at least one aromatic ring which is attached to the silicon atom via a covalent bond from an aromatic carbon atom;

A denotes C0₂R⁵, CONR⁵R⁶, COSR⁵ or CSNR⁵R⁶; and

R⁵ and R⁶, independently of one another, denote H, Ci-Cio alkyl, cycloalkyl or aralkyl.

The present invention thus provides compounds which are suitable as improved silane linkers for use in producing compounds comprising at least one carbon atom in an aromatic ring. The aromatic ring is attached via a bond from an aromatic carbon atom to a silicon atom to give the compounds of general formula (I) . The compounds of general formula (I) may be present in solution or may be tethered to a support via the group A. Synthetic chemistry is carried out to functionaliεe and/or derivatise the R group. Once the chemistry has been completed, the desired products are released from the linker by cleavage of the aromatic carbon-silicon bond.

In a further feature of the invention, there are provided support-bound compounds for use as silane linkers in chemical synthesis, said support-bound compounds being of general formula (II)

⁽X)„ Y - P (ID

Y denotes ; and?

where n denotes 1, Y may also denote CR³(CH₂OH) or together with X may denote NR³C=0 or NR³C(=0)NR³.

P denotes a support, optionally including a tether, attached to the group Y; and

R, R¹, R², R³, R⁴, X and n are as hereinbefore defined.

Surprisingly, it has now been found that compounds of general formula (I) or support-bound compounds of general formula (II) may be cleaved more quickly, cleanly and efficiently than conventional silane linkers. It is believed that the presence of the group Y in the compounds of formula (I) or the support-bound compounds of general formula (II) leads to the improved cleavage properties of the compounds of the present invention.

Preferred compounds of general formula (I) and support-bound compounds of general formula (II) according to the present invention are those wherein

R¹ and R² independently denote methyl, ethyl, propyl or benzyl ;

R³ and R⁴ independently denote hydrogen, methyl, ethyl, propyl or benzyl;

n denotes l; and

X denotes CR³R⁴.

Especially preferred compounds of general formula (I) and support-bound compounds of general formula (II) are those wherein

R¹ and R² both denote methyl;

R³ and R⁴ both denote hydrogen or both denote methyl;

n denotes 1; and

X denotes CH₂.

Preferred compounds of general formula (I) are those wherein A denotes C0R⁵ or CONR⁵R⁶, especially CONHBn.

Preferred support-bound compounds of general formula (II) are those wherein Y denotes CONR³, especially CONH or CONMe. The aromatic carbon atom attached to the silicon atom of the linker may be part of an optionally substituted aryl or heteroaryl ring or ring system which may include bi- or tri-cyclic ring systems. The rings may contain one or more heteroatoms selected from sulphur, oxygen and nitrogen.

Examples include, but are not limited to, optionally substituted phenyl, naphthyl, pyridyl, thiophenyl, bi-phenyl, quinolinyl, thiazinyl, isoquinolinyl, imidazolyl, furanyl, pyrrolidinyl, fluorenyl, indolyl or indanyl .

Examples of possible substituents of the aromatic ring or ring system include, but are not limited to, alkyl, cycloalkyl, aryl, carboxyl, carboxylic ester, amide, CHO, F, Cl, Br, I, SH, CN, N0₂, R₃Sn (wherein R⁷ denotes Cj-Cg alkyl, cycloalkyl or benzyl), NR⁸R⁹ (wherein R⁸ and R⁹, independently of one another, denote H, C^Ce alkyl, cycloalkyl or benzyl) or OR¹⁰ (wherein R¹⁰ denotes H, C_α-C₆ alkyl, cycloalkyl, phenyl or benzyl) .

In compounds of general formula (II) , the Y group is linked covalently, optionally via a tether, to^~ a support, which may be an insoluble support. Compounds of general formula (I) wherein A is C0₂H may, for example, be attached to a support or tether via formation of an amide bond with an amino group on said support or tether, to give compounds of general formula (II) .

Examples of supports include polystyrene-divinyl benzene co-polymer (Merrifield Resin) , polyamide, aminomethylated polystyrene resin, aminomethylated Tentagel resin, polyamide-kieselguhr composites, polyhipe, cotton, paper and the like.

In the above definitions, alkyl denotes a straight or branched chain alkyl group and cycloalkyl denotes a cyclic 4, 5 or 6 membered alkane ring.

The compounds may be synthesised in solution and then in a final step attached to a support, for example by formation of an amide bond to give compounds of general formula (II) . The following scheme exemplifies this general approach.

.qrhpme 1

Mg or BuLi then

ClSi(CH3)2CH2Cl

R—Br R-Si-

Cl

Et02CCH2C02Et, NaOEt

Heat

TBTU, HOBt, DIEA,

Any functional groups present in R may be protected if necessary using conventional protecting groups.

As a further feature of the invention, there is therefore provided a process for the preparation of support-bound compounds of general formula (II) which comprises attaching a compound of formula (la)

R¹

I

R_a- Si- C (X)_n- (la) I-

R⁴

wherein

R_a denotes R as hereinbefore defined, or

R_a denotes SnR^uR¹²R¹³ wherein R¹¹, R¹² and R¹³, independently of one another, denote -Ce alkyl, cycloalkyl or benzyl,

and R¹, R², R³, R⁴, X, A and n are as hereinbefore defined,

to a support and, when R_a denotes SnR^ιαR¹²R¹³, subsequently reacting the compound thereby formed with a compound of formula (IV)

R-Hal (IV)

wherein R is as hereinbefore defined and Hal denotes bromine or iodine.

Alternatively, the introduction of the group R may be final step in the synthesis of compounds of general formula (I) or (II) , for example by displacement of a tin atom attached to the silicon. The following scheme illustrates this general approach. rhffltip 2

>12 R¹ R³ I

R¹¹— Sn- SiC (X) ή- (or P)

I l o

R 13 R⁴

R - I or R - Br, 1 Pd (Ph₃P)₄, toluene, reflux.

R¹ R³

R- Si— C (X)_n A (or -Y P)

R² R⁴

wherein R¹¹, R¹ and R¹³ are as hereinbefore defined.

As a further feature of the invention there is therefore provided a process for the preparation of compounds of general formula (I) which comprises reacting a compound of general formula (III)

R¹² R¹ R³

I I I

R¹¹— Sn — Si — C — (X) „ — A ( III)

R ¹³ R² R⁴

wherein R¹, R², R³, R⁴, X, A, n, R¹¹, R¹² and R¹³ are as hereinbefore defined,

with a compound of formula (IV)

R-Hal (IV)

wherein R is as hereinbefore defined and Hal denotes bromine or iodine.

Similar methodology may also be used to prepare support-bound compounds of general formula (II) . The invention therefore also provides a process for the preparation of support-bound compounds of general formula (II) which comprises reacting a compound of general formula (V)

R¹² R¹ R³

I I I

R _ sn— Si C — (X) _n — Y P (V)

R¹³ R² R⁴

wherein R¹, R², R³, R⁴, X, Y, P, n, Rⁿ, R¹² and R¹³ are as hereinbefore defined,

with a compound of formula (IV)

R-Hal (IV)

wherein R is as hereinbefore defined and Hal denotes bromine or iodine.

Once the compounds of formula (I) or the support bound compounds of formula (II) are prepared, further synthetic chemistry may be carried out on the R groups to derivatise and/or functionalise them using standard techniques .

Chemistry may be carried out on the compounds of general formula (I) in solution, for example in dichloromethane . The rapid cleavage of the R-Si bond in the compounds of the invention allows the introduction of groups which it would otherwise be difficult to introduce. For example, the compounds of formula (I) may be cleaved to leave compounds which are labelled at the cleavage site, for example with deuterium, tritium or radio-labels such as ¹²⁵I.

The invention also provides a method for producing a library of compounds. To prepare a compound library, a plurality of compounds comprising at least one carbon atom in an aromatic ring are attached to individual supports via a silane linker to form bound intermediates of general formula (II) . The silicon atom of the linker is covalently bonded to an aromatic carbon atom in the bound compounds . Additional synthetic chemistry is then carried out on the bound compounds to derivatise and/or functionalise them. The support-bound compounds may optionally be divided into a plurality of portions and each portion subjected to different synthetic chemistry. Different portions may optionally be recombined and further synthetic chemistry performed.

The steps of dividing the portions, performing additional synthetic chemistry and recombining the portions may be carried out more than once, using standard techniques .

As a further feature of the invention there is therefore provided a method of producing a compound library comprising a plurality of compounds comprising at least one carbon atom in an aromatic ring, said method comprising carrying out synthetic chemistry on the R groups of support-bound compounds of general formula (II) to derivatise and/or functionalise them. The method may also include the further step of releasing the R groups as derivatised or functionalised compounds from the support by cleavage of the R-silicon bond.

For example, a combinatorial library of 100 compounds may be synthesised from support-bound compounds as shown in Scheme 3. Resin bound biaryl aldehydes may be prepared via four Suzuki and one Stille reaction (R¹) . Reductive a ination of each aldehyde with four amines (R²) may provide 20 resin bound secondary amines which may each be capped with 5 electrophiles (R³) . Aryl-silicon bond cleavage with 50% TFA in DCM may then yield each library member as a single compound. Sπh^Pm^P 1

[Si] Denotes position of aryl-silicon bond prior to cleavage.

Cleavage of the silicon-aromatic carbon bond may be effected by treatment with a strong, preferably protic, acid. Preferred acids include trifluoroacetic acid (TFA) , HCl, H₂S0₄, HF, triflie acid, methanesulfonic acid and pyridinium hydrofluoride. It is preferable to use acids which are volatile, and therefore easy to remove once cleavage has occurred. The preferred cleavage conditions are TFA in an organic solvent, for example about 50% TFA in a solvent such as chloroform or dichloromethane . The use of deuterated or tritiated TFA or other protic acids yield the corresponding ²H or ³H labelled products respectively.

Average cleavage times have been found to be significantly shorter than those of the prior art linkers. Cleavage is in general clean, efficient and high-yielding with no significant formation of undesired by-products .

The use of protic acids leaves hydrogen substitution at the carbon atom originally bonded to the silicon atom (protodesilylation) . In addition, aromatic carbon-silicon bond cleavage may be effected in the presence of electrophiles to yield substituted aromatic products. Examples of possible electrophiles include Br₂, Cl₂, I₂, acid chlorides, HN0₂, chloromethyl ethers, acetals and acyl peroxides. The compounds may also be labelled at the cleavage site, for example by using ¹²⁵I₂ as the electrophile.

Thus, treatment of a bound compound with a solution of molecular halogen may yield the corresponding halide directly, via a halodesilylation reaction.

A ketone functionality may be introduced by effecting desilylation with an acyl chloride in the presence of a Lewis acid such as A1C1₃. Nitrodesilylation may be effected by treatment with a solution of nitrous acid. Ether formation may be effected by treatment of the bound compound with a chloromethyl ether or an acetal in the presence of a Lewis acid such as A1C1₃ or TiCl₄.

If the bound compound has an electron withdrawing substituent (e.g. Cl or N0₂) ortho to the silicon, treatment with aldehydes or alkyl halides in the presence of a fluoride ion source (e.g. KF, CsF or TBAF) may yield products with secondary alcohol or alkyl substituents on the aromatic carbon atom which was bound to the silicon. If no such electron withdrawing substituents are present, analogous reactions may be performed through prior activation of the aromatic ring as a chromium tricarbonyl complex.

Treatment of the bound compounds with acyl peroxides may yield the acylated products at the original site of attachment to the silicon atom. Hydrolysis of the ester functionality may then yield the resulting hydroxyl derivatives .

Alternatively, direct hydroxy-desilylation may be effected by treatment with sulphonyloxaziridines .

Aminodesilylation may be effected with an electrophilic nitrogen source (e.g. NH₂C1) in the presence of fluoride ions. If the aromatic ring has no electron withdrawing substituents, prior activation via chromium tricarbonyl complexation may be required.

The wide range of possible cleavage agents further increases the usefulness of the compounds of the present invention in combinatorial chemistry, as it offers a further dimension in product diversity. 17

Examples

The following Examples are non-limiting illustrations of the invention.

Example 1

(1) (2)

(5) (6)

Dry ether (15ml) was added to 1, 4-dibromobenzene (1) (12g) , magnesium turnings (1.24g) and an iodine crystal and the mixture stirred with gentle warming, On completion of Grignard formation, the volume was increased to 50ml with dry ether and

(chloromethyl) dimethylchlorosilane (6.7ml) was adde . The mixture was then refluxed for 24 h. The mixture was poured carefully into ice water and extracted with ether. Ethereal extracts were dried (MgS0₄) and evaporated, the residue chromatographed on silica using hexane for elution to yield (2) as a colourless oil (6.46g, 48%) .

Sodium metal (323mg) was dissolved in dry ethanol (10ml) with cooling followed by the addition of diethyl malonate (1.56ml), then (2)(2.47g), and the mixture heated under reflux for 12 h. After cooling, the mixture was poured into ice water, acidified with acetic acid and extracted with ether. Ethereal extracts were dried (MgS0₄) and evaporated, the residue chromatographed on silica using 5% ethyl acetate in hexane to yield the product (3) as a colourless oil (2.38g, 66%).

KOH (300mg) in water (2ml) was added to the malonate derivative (3) (500mg) and the mixture heated at reflux with vigorous stirring for 2 h. The resultant solution was diluted with water, cooled to 0° C, carefully acidified with 1M HCl and extracted with ethyl acetate . The organic extracts were dried (MgS0₄) and evaporated to give (4) as a thin colourless oil which slowly crystallised (402mg, 94%) .

Neat (4) (2.1g) was heated at 150° C for 5 h to yield (5) as a colourless oil which crystallised on trituration (1.6g, 88%) .

Aminomethylated polystyrene resin (l mmol N/g) was swelled and washed with N,N-dimethylformamide (DMF) for 15 min. DMF was removed and a solution of 2-(lH- benzotriazole-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate (TBTU, 1.284g), hydroxybenzotriazole (HOBt, 306mg) and (5) (1.14g) in DMF added. Diisopropylethylamine (DIEA, 1.38ml) was added to the above suspension with stirring, which was continued at room temperature for 2 h. The resin was washed with DMF, MeOH, dichloromethane (DCM) , MeOH and dried under vacuum to provide functionalised resin (6) . F.vamplp 2

Alternative synthesis of compound (2) from 1,4-dibromobenzene (1).

1, 4-Dibromobenzene (1) (59g) was dissolved in dry tetrahydrofuran (THF) (ca. 500ml) in a round bottom flask and cooled to -78°C. n-Butyllithium (2.5M in hexanes, 100ml) was added to the reaction mixture slowly over 15 minutes with stirring. The reaction was then stirred for a further 30 minutes.

(Chloromethyl) dimethylchlorosilane (33ml) was added dropwise over 20 minutes and the reaction allowed to stir for a further 2 hours at -78°C. The reaction mixture was then poured into ice water (ca. 11) and extracted with ether (3 x 400ml) . The ethereal extracts were combined, dried (MgS0₄) and evaporated to yield (2) (65g) .

Example 3

(15) A solution of 4-bromoaniline (7) (lOg) , allyl bromide (40ml) and DIEA (25ml) in toluene was heated under reflux for 2 h. The suspension was cooled, filtered, washed with water, dried (MgS0₄) and evaporated, the residue chromatographed on silica using 5% ethyl acetate in hexane for elution to yield (8) as a tan oil (12.75g, 87%) .

To a solution of (8) (8g) in dry tetrahydrofuran (THF) was added n-butyllithium (2.5M in hexane, 12.7ml) at -78° C with stirring under argon. Stirring was continued at -78° C for 1 h, (chloromethyl) dimethylchlorosilane (4.18ml) added dropwise over 10 min and stirring continued at -78° C for a further hour. The reaction mixture was poured into ice water and extracted with ether. Ethereal extracts were dried (MgS0₄) and evaporated to yield (9) as a tan oil (6.77g, 76%).

Sodium metal (1.15g) was dissolved in absolute ethanol (15ml) with stirring and cooling. Diethyl malonate (7.34ml) was added followed by (9) and the mixture refluxed for 12 h. The mixture was poured into ice water, acidified with acetic acid and extracted with ether. Ethereal extracts were dried (MgS0) and evaporated, the residue chromatographed on silica using 6% ethyl acetate in hexane to yield the product (10) as a colourless oil (10.49g, 54%).

A solution of (10) (lg) and N,N' -dimethylbarbituric acid (1.55g) in DCM (20ml) was degassed with argon, tetrakis (triphenylphosphine) palladium (0) (140mg) added and the solution stirred at 30° C overnight under argon. Volatiles were evaporated and the residue chromatographed on silica using 30% ethyl acetate in hexane for elution to yield the aniline (11) as a pale yellow oil (700mg, 87%) .

A solution of KOH (1.99g) in water (5ml) was added to neat (11) (2.88g) and the mixture heated to 100° C with vigorous stirring for 2 h. The solution was diluted with water, carefully acidified with 1M citric acid and extracted into ether. The organic extracts were washed with water, dried (MgS0₄) and evaporated to give (12) as a tan solid (1.3g, 70%) .

A solution of (12) (lOOmg) and 5, 5-dimethyl-2- (dimethylaminomethylene)cyclohexane-l,3-dione (146mg) in ethanol (4ml) was stirred at room temperature overnight. Volatiles were removed in vacuo, the residue partitioned between DCM and saturated sodium bicarbonate solution. The aqueous layer was further washed with DCM, carefully acidified with 1M citric acid and extracted with ethyl acetate. The organic extracts were dried (MgS0₄) and evaporated to give (13) as an off-white crystalline solid (153mg, 98%) .

A solution of (13) (50mg) in dimethyl sulphoxide (DMSO) (1ml) was heated at 150° C for 15 min, the solution partitioned between ethyl acetate and water, the organic layer again washed with water, dried (MgS0₄) and evaporated to give (14) as an off-white crystalline solid (44mg, 86%) .

Amino-functionalised Tentagel resin (0.25 mmol N/g) (lg) was swelled and washed with DMF for 20 min. DMF was removed and a solution of (13) (187mg) , TBTU (161mg) and HOBt (38mg) in DMF added, followed by DIEA (174μl) , the suspension then stirred at room temperature for one hour. The resin was washed with DMF, MeOH, DCM, MeOH and dried under vacuum to yield the functionalised resin (15) . 23

Byam le 4

(17)

(19)

A solution of (5) (300mg) , methyl iodide (195μl) , and DIEA (181μl) in ethyl acetate was heated under reflux for 5 h. The solution was washed with water, dried (MgS0₄) and evaporated, the residue chromatographed on silica using 10% ethyl acetate in hexane for elution to yield (16) as a colourless oil (229mg, 73%) .

A solution of (16) (200mg) and hexamethylditin (179μl) in toluene was degassed with argon, tetrakis (triphenylphosphine)palladium (0) (20mg) added and the mixture heated under reflux for 4 h. Volatiles were removed in vacuo and the residue chromatographed on silica using 3% ethyl acetate in hexane for elution to yield (17) as a colourless oil (135mg, 53%) . To a solution of (17) (lOOmg) in THF (2ml) was added NaOH (41mg) in water (2ml) and the mixture stirred vigorously for 12 h at room temperature. The resultant homogenous solution was diluted with water, carefully acidified with 1M citric acid and extracted with ethyl acetate. The organic extracts were washed with water, dried (MgS0) and evaporated to yield (18) as a thin oil which quickly crystallised (70mg, 73%) .

Aminomethylated polystyrene resin (1 mmol N/g) was swelled and washed with DMF for 15 min. DMF was removed and a solution of (18) (60mg) , TBTU (52mg) , HOBt (13mg) and DIEA (84μl) in DMF added, the suspension then stirred at room temperature for one hour. The resin was washed with DMF, MeOH, DCM, MeOH and dried under vacuum to yield the functionalised resin (19) .

Example 5

A suspension of resin (6) (1 mmol/g) (500mg) in DME was degassed with argon, followed by the addition of naphthalene-1-boronic acid (172mg) , 2M sodium carbonate solution (0.63ml) and tetrakis (triphenylphosphine) palladium (0) (29mg) . The mixture was refluxed for 12 hours under argon, cooled, 25% ammonium acetate added, and stirring continued for 5 min at room temperature. The biphasic solutions were separated from the resin which was then washed with 1,2- dimethoxyethane (DME) , DME-water, 5% acetic acid, water, DME-water, DME, methanol, DMF, methanol, DCM, methanol, then dried in vacuo to provide the resin (20) .

Resin (20) (lOOmg) was treated with trifluoroacetic acid- DCM (1:1, 10ml) , the suspension stirred at room temperature for 2 h. Filtration of the cleavage solution from the resin followed by evaporation yielded the biarylnapthalene (21) (21mg, 100%) .

xample 6

(23)

Resin (15) (0.25mmol substitution/g) (800mg) was swelled in DMF for 15 min. DMF was removed, the resin then treated with 1% hydrazine monohydrate in DMF for 30 min at room temperature. The resin was then washed with DMF, MeOH, DCM, MeOH and dried to yield the aniline functionalised resin (22) .

Resin (22) (70mg) was swelled and washed in DMF for 15 min, DMF removed and fresh DMF added. 4-Anisoyl chloride

(21mg) and DIEA (181μl) were added and the suspension stirred at room temperature for 2 h. The resin was then washed with DMF, MeOH, DCM, MeOH and dried to give resin

(23) . The resin (23) (70mg) was treated with TFA:DCM (1:1, 2ml) with stirring at room temperature for 2 h. Filtration of the cleavage solution from the resin followed by evaporation yielded the aniline amide (24) (5mg, 100%) .

Example 7

(26)

The resin (25) (lmmol substitution/g) (50mg) , derived from the Suzuki coupling of 4-tolylboronic acid and resin (6) via the method for the preparation of resin (20) was treated with TFA-DCM (1:1) at room temperature with stirring for 2 h. Filtration of the cleavage solution from the resin followed by evaporation yielded the product (26) (6mg, 71%) .

Bva ple B

The resin (20) was suspended in a solution of 3% bromine in 85% aqueous acetic acid, the mixture then stirred at room temperature for 12 h. Filtration of the cleavage solution from the resin followed by evaporation yielded the brominated product (27) (17mg, 61%) .

Example g

The resin (25) (50mg) was washed and swelled in dry 1,2- DCE for 15 min, DCE removed and fresh dry DCE added. Cyclopropanecarbonyl chloride (23μl) and aluminium trichloride (7mg) were added, the suspension stirred at room temperature for 5 min. Anhydrous potassium carbonate was then added, stirring then continued overnight. The cleavage solution was filtered off the resin and volatiles removed in vacuo. The solid residue was triturated with dry ether which was filtered and evaporated to yield the ketone (28) (2mg, 18%) .

Example in

Compound (29) was synthesised from l-bromo-4- methylbenzene in a process analogous to the synthesis of compound (5) in Example 1. The acid (29) was dissolved in ice cold oxalyl chloride/tetrahydrofuran (1:1, 5ml) followed by addition of benzylamine (200mg) . After stirring for 10 minutes the reaction mixture was quenched with saturated ammonium chloride solution and the crude reaction mixture purified by chromatography

(diethyl ether/petroleum ether, 1:1) to afford the amide

(30) (71%).

Claims

n airns

1. Compounds of general formula (I)

R¹ R³

R - Si - C - (X)_n - A R² R⁴

(I)

wherein

R¹ and R², independently of one another, denote C^-C_K, alkyl, cycloalkyl or aralkyl;

R³ and R⁴, independently of one another, denote hydrogen, C_α-Ci_o alkyl, cycloalkyl or aralkyl;

n denotes 1 or 2 ;

where n denotes 1 , X denotes 0, S , NR³ , CR³R⁴ , OC (R³R⁴) ,

S C ( R³R⁴ ) , NR³C ( R³R⁴ ) , CR³ ( C0₂H ) , CR³ ( CONR³R⁴ ) , CR³ ( CON

where n denotes 2 , X denotes CR³R⁴ ;

A denotes C0₂R⁵, CONR⁵R⁶, COSR⁵ or CSNR⁵R⁶; and

R⁵ and R^fi, independently of one another, denote H, C_!-C₁₀ alkyl, cycloalkyl or aralkyl.

2. Compounds as claimed in claim 1 wherein

R¹ and R² independently denote methyl, ethyl, propyl or benzyl ;

R³ and R⁴ independently denote hydrogen, methyl, ethyl, propyl or benzyl;

n denotes 1; and

X denotes CR³R⁴.

3. Compounds as claimed in claim 1 or claim 2 wherein

R¹ and R² both denote methyl;

R³ and R⁴ both denote hydrogen or both denote methyl;

n denotes 1; and

X denotes CH₂.

4. Compounds as claimed in any of claims 1 to 3 wherein A denotes C0₂R⁵ or CONRR⁶.

5. Compounds as claimed in any of claims 1 to 4 wherein R denotes optionally substituted phenyl, naphthyl, pyridyl, thiophenyl, bi-phenyl, quinolinyl, thiazinyl, isoquinolinyl, imidazolyl, furanyl, pyrrolidinyl, fluorenyl, indolyl or indanyl.

6. Support-bound compounds for use as silane linkers in chemical synthesis, said support-bound compounds being of general formula (II)

R - (X)n (ID

R wherein

Y denotes CONR³, CSNR³, CR³OH or

where n denotes 1, Y may also denote CR³(CH₂OH) or together with X may denote NR³C=0 or NR³C(=0)NR³;

R, R¹, R², R³, R⁴, X and n are as defined in any of claims 1 to 3 and 5.

7. Support-bound compounds as claimed in claim 6 wherein Y denotes CONR³.

8. Support-bound compounds as claimed in claim 6 or claim 7 wherein the support is polystyrene-divinyl benzene co-polymer (Merrifield Resin) , polyamide, aminomethylated polystyrene resin, aminomethylated Tentagel resin, polyamide-kieselguhr composites, polyhipe, cotton or paper.

9. A process for the preparation of compounds as claimed in any of claims 1 to 5 which comprises reacting a compound of general formula (III)

R¹² R¹ R³

R¹¹- Sn — Si — C (X) _n A ( III )

R¹³ R² R⁴

wherein R¹¹, R¹² and R¹³, independently of one another, denote C-C_e alkyl, cycloalkyl or benzyl, and

R¹, R², R³, R⁴, X, A and n are as defined in any of claims 1 to 4 with a compound of formula (IV)

R-Hal (IV)

wherein R is as defined in claim 1 or claim 5 and Hal denotes bromine or iodine.

10. A process for the preparation of support-bound compounds as claimed in any of claims 6 to 8 which comprises reacting a compound of general formula (V)

R¹² R¹ R³ i i t

R^u — Sn — Si C (X) _n — Y — P (V)

R¹³ R² R⁴

wherein R¹¹, R¹² and R¹³, independently of one another, denote Ci-Cg alkyl, cycloalkyl or benzyl, and

R¹, R², R³, R⁴, X, Y, P and n are as defined in any of claims 6 to 8,

with a compound of formula (IV)

R-Hal (IV)

wherein R is as defined in claim l or claim 5 and Hal denotes bromine or iodine.

11. A process for the preparation of support-bound compounds as claimed in any of claims 6 to 8 which comprises attaching a compound of formula (la)

wherein R_a denotes R as defined in claim l or claim 5, or R_a denotes SnRⁿR¹²R¹³ wherein R¹¹, R¹² and R¹³, independently of one another, denote C_!-C₆ alkyl, cycloalkyl or benzyl, and R¹, R², R³, R⁴, X, A and n are as defined in any of claims 1 to 4, to a support and, when R_a denotes SnR^uR¹²R¹³, subsequently reacting the compound thereby formed with a compound of formula (IV)

R-Hal (IV)

12. A process as claimed in claim 11, wherein the attachment of the compound of general formula (la) to the support is made by formation of an amide bond.

13. A method of cleavage of the R-silicon bond in the compounds as claimed in any of claims 1 to 5 or the support-bound compounds as claimed in any of claims 6 to 8, which comprises treating a compound of general formula (I) or a support-bound compound of general formula (II) with a strong acid or an electrophile.

14. A method as claimed in claim 13 wherein the acid is trifluoroacetic acid (TFA) , HCl, H₂S0, HF, triflic acid, methanesulfonic acid or pyridinium hydrofluoride .

15. A method as claimed in claim 13 or claim 14 wherein the acid is a deuterated or tritiated protic acid.

16. A method as claimed in claim 13 wherein the electrophile is Br₂, Cl₂, I₂, an acid chloride, HN0_2; a chloromethyl ether, an acetal or an acyl peroxide.

17. A method of producing a compound library comprising a plurality of compounds comprising at least one carbon atom in an aromatic ring, said method comprising carrying out synthetic chemistry on the R groups of support-bound compounds as claimed in any of claims 6 to 8 to derivatise and/or functionalise them.

18. A method as claimed in claim 17 which includes the further step of releasing the R groups as derivatised or functionalised compounds from the support by cleavage of the R-silicon bond.