RESIN-BOUND PHOSPHONIUM SALTS AND THEIR USE IN ORGANIC SYNTHESIS

Abstract: The invention relates to carrying out organic chemistry on a solid support, and in particular to the use of a phosphonium salt as a linker for solid phase synthesis.

Description: /18592 RESIN-BOUND PHOSPHONIUM SALTS AND THEIR USE IN ORGANIC SYNTHESIS The present invention relates to carrying out organic chemistry on a solid support, and in particular to the use of a phosphonium salt as a linker for solid phase synthesis. Solid phase chemistry is well known in the art, particularly in the fields of peptide and oligonucleotide synthesis. Advantages of solid phase synthesis include the ability to drive reactions to completion by use of excess reagents, ease of work up and potential automation of synthetic procedures. Organic compounds have traditionally been attached to the solid support by certain cleavable linker groups which yield, on cleavage, compounds in which polar functionality remains at the point of attachment, for example a CO2H, OH, NH2, CONH2 or a CONHR group. In recent years there has been an increasing need to extend this methodology to the synthesis of non-oligomeric products both for the automated synthesis of single compounds as well as automated synthesis a single compounds (including variomer arrays) as well as combinatorial libraries. However to extend solid phase methodology to the synthesis of non-oligomeric molecules, which often lack polar functional groups at convenient sites for linkage to a solid support, additional linkages which furnish alkyl, alkenyl or aryl moieties on cleavage are required. It has now been found that phosphonium salts can act as a linkage for solid phase synthesis. In particular, it has been found that compounds can be attached to a solid support as phosphonium salts, chemically transformed on the support, and subsequently cleaved from the support in a number of ways, giving, for example, products of hydrolysis, inter-molecular Wittig reaction and intra¬ molecular Wittig reaction. Therefore in a first aspect the present invention provides a method or process for preparing organic compounds which comprises: A. Preparation of a resin-bound phosphonium salt, B. Elaboration of the phosphonium salt on the resin, and C. Optionally cleaving the organic product from the resin. As mentioned above, the method is particularly suitable for rapid synthesis of combinatorial libraries of compounds, that is to say, collections of compounds each having a common core structure. Therefore use of the method for synthesis of single compounds as well as for the simultaneous synthesis of compound libraries is within the scope of the invention. Those skilled in the art will appreciate that the phosphonium salt is acting as a linker group for solid phase synthesis. In a further aspect, the present invention therefore provides die use of a phosphonium salt as a linker for solid phase synthesis. By 'solid phase syndiesis' is meant synthesis of organic molecules which is carried out on a resin support. Preferably the phosphonium salt is a compound of formula (I): (I) in which R is the resin; X is a counter-ion; R-- is Cι_6alkyl, optionally substituted phenyl or heteroaryl; and R*** is an organic moiety. Suitable resins include materials well known in the art such as beads, pellets, disks, capillaries, hollow fibres, needles, solid fibres, cellulose beads, pore-glass beads, silica gels, polystyrene beads optionally cross-linked with divinylbenzene, grafted co-poly beads, poly-acrylamide beads, latex beads, dimethylacrylamide beads optionally cross-linked with N, N'-bis-acryloyl ethylene diamine, glass particles coated with a hydrophobic polymer, etc., i.e., a material having a rigid or semi-rigid surface. Suitably X is a counter-ion such as halogen. Preferably X is bromo. Suitably R* is Ci.galkyl, optionally substituted phenyl or heteroaryl. Preferably R* is optionally substituted phenyl Suitably R**- is an organic moiety, for example a group CHR3R4 where R^ and R ** -" are the same or different and are hydrogen, optionally substituted Cι_galkyl, optionally substituted phenyl or optionally substituted heteroaryl. Preferably R-*- is a benzyl group, more preferably a substituted benzyl group. Suitable subsrituents include Cj.galkyl, Cι_6alkoxy, halogen, aryloxy, hydroxy, aldehyde, acid, nitro or amino groups. If necessary reactive groups such as amino can be protected using standard protecting groups. Suitable protecting groups and methods for their attachment and removal are conventional in the art of organic chemistry, such as those described in Greene T.W. 'Protective groups in organic synthesis' New York, Wiley (1981). Resin-bound phosphonium salts of formula (I) can be prepared using known methods, for example, by treatment of commercially available resin- bound triphenylphosphine or its hydrobromide with benzyl bromides or alcohols respectively, see Ford et al. J. Org. Chem. 1983, 48, 326. Resin-bound phosphonium salts of formula (I) are believed to be novel and form a further aspect of the invention. An important advantage in the use of phosphonium salts of formula (I) as a linker is that they tolerate a wide range of reaction conditions useful for elaboration of the supported molecule. Chemical reactions which can be carried out using phosphonium salts of formula (I) include supported reactions and cleavage reactions. By "supported reactions" is meant reactions where chemistry is caπied out on the resin-bound phosphonium salt and the resulting product remains bound to the support. The product is then optionally cleaved from the resin support in a separate cleavage step. Examples of such supported reactions include reductions, acylation and reductive amination reactions. By "cleavage reactions" is meant reactions where chemistry is carried out on the resin-bound phosphonium salt and the reaction mechanism leads to automatic cleavage of the product from the resin. It will be appreciated that steps B and C of the process may therefore be combined. Examples of such reactions include solvolysis under basic conditions (e.g. hydrolysis and methanolysis), inter-molecular Wittig reactions and intra-molecular Wittig reactions. A side product from the solvolysis and Wittig cleavage methods is triphenylphosphine oxide. Use of a polymer bound phosphonium salt as a linkage for supported chemistry is particularly advantageous since on cleavage of the desired products from the support, triphenylphosphine oxide remains bound to the support. Triphenylphosphine oxide is usually very difficult to remove from conventional reactions in solution, and therefore the fact that this compound does not contaminate the reaction products greatly facilitates the work up procedure. The invention will now be illustrated by the following examples. Description 1 Illustrating preparation of a polymer-bound phosphonium salt Polymer-bound (2-nitrobenzyl)triphenylphosphonium bromide (Dl) Polymer-bound triphenylphosphine (loading 3 mequ/g, 15 g, 45 mequ) was suspended in DMF (150 ml). After 10 min, 2-nitrobenzyl bromide (18.8 g, 87 mmol) and citric acid (0.5 g) were added and the mixture was stirred at room temperature for 48 h. The mixture was filtered and the polymer was washed with toluene and dichloromethane (3 cycles), then with dichloromethane and ether (3 cycles), then was dried in vacuo at 60 °C to give the title compound (24.7 g). Analysis: Br 12.3% (loading = 1.53 mequ/g) Description 2 Illustrating elaboration of a polymer-bound phosphonium salt Polymer-bound (2-aminobenzyl)triphenylphosphonium bromide (D2) Polymer-bound (2-nitrobenzyl)triphenylphosphonium bromide (Dl, 24.5 g, 37.5 mequ) was suspended in ethanol (500 ml) and heated to 80 °C. A solution of 85% sodium dithionite (36.8 g, 180 mmol) in water (120 ml) was added dropwise over 25 min. The mixture was stirred at 80 °C for 45 min. A sample of polymer gave a positive test (dark colouration of beads) for nitro-ylide on treatment with dilute NaOH/methanol. Further sodium dithionite (9 g, 45 mmol) in water (30 ml) was added over 15 min and heating was continued for 30 min. A sample of polymer gave a negative nitro-ylide test. The mixture was filtered and the polymer was washed well with water, aqueous ethanol, ethanol and ether. The polymer was then suspended in dioxane (150 ml) and methanol (150 ml) and treated dropwise with 48% aqueous HBr (50 ml). After stirring for 5 h, the mixture was filtered, and the polymer was treated again with dioxane, methanol and HBr as above. The polymer was filtered off and washed well with dioxane, methanol and ether, then dried in vacuo at 60 °C to give the title compound (22.3 g). Description 3 Illustrating elaboration of a polymer-bound phosphonium salt Polymer-bound (2-(4-methoxybenzoylamino)benzyl)triphenylphosphonium bromide (D3) A suspension of polymer-bound (2-aminobenzyl)triphenylphosphonium bromide (D2, 2 g) in dichloromethane (30 ml) was treated with pyridine (1.0 ml, 12.4 mmol) and 4-methoxybenzoyl chloride (1.82 g, 10.6 mmol) for 3 h at room temperature. The polymer was washed well with dichloromethane and a small sample was treated with a methanolic solution of 4-nitrobenzaldehyde. The beads became yellow coloured indicating residual unreacted amine. The polymer was treated with fresh reagents as above for a further 3 h, when a sample gave no colour change on treatment with 4-nitrobenzaldehyde. The polymer was filtered and washed well with dichloromethane and dried in vacuo at 70 °C to give the title compound (2.14 g). Description 4 Illustrating preparation of a polymer-bound phosphonium salt Polymer-bound (3-formylbenzyl)triphenylphosphonium bromide (D4) Polymer-bound triphenylphosphine (loading 3 mequ/g, 2.7 g, 8.1 mequ) was suspended in DMF (70 ml), then was treated widi 3-bromomethylbenzaldehyde (3.16 g, 16 mmol) and stiιτed at 70 "C for 24 h. The mixture was filtered and d e polymer was washed alternately with toluene and dichloromethane (3 cycles), then with dichloromethane and ether (3 cycles), then was dried in vacuo at 60 °C to give the title compound (4.2 g). Analysis: Br ' 12.6% (loading = 1.58 mequ/g) Description 5 Illustrating elaboration of a polymer-bound phosphonium salt Polymer-bound {3-[N-(4- methoxyphenyl)aminomethyl]benzyl]triphenylphosphonium bromide (D5) Polymer-bound (3-formylbenzyl)triphenylphosphonium bromide (D4, 500 mg, 0.79 mequ) was suspended in dichloromethane (30 ml) and treated with molecular sieves, p-anisidine (246 mg, 2 mmol), and acetic acid (0.17 ml, 3 mmol), followed by sodium triacetoxyborohydride (636 mg, 3 mmol). After 5 h at room temperature, methanol (10 ml) was added and the mixture was filtered. The polymer was washed with methanol and dichloromediane, then was dried to give the title compound (620 mg). Description 6 Illustrating elaboration of a polymer-bound phosphonium salt Polymer-bound {3-[N-acetyl-N-(4- methoxyphenyl)aminomethyl] benzyl Jtriphenylphosphonium bromide (D6) Polymer-bound {3-[N-(4- methoxyphenyl)aminomethyl] benzyl } triphenylphosphonium bromide (D5, 207 mg, approx. 0.26 mequ) was suspended in dichloromethane (20 ml), then treated with pyridine (0.27 ml, 3.3 mmol) and acetyl chloride (0.12 ml, 1.7 mmol). After 5 h at room temperature the mixture was filtered and the polymer was washed with dichloromethane and dried to give the tide compound which was used directly in Example 5. Example 1 Illustrating cleavage from the polymer by methanolysis 4-Methoxy-N-o-tolylbenzamide (El) A suspension of polymer-bound (2-(4-methoxybenzoylamino)benzyl)- triphenylphosphonium bromide (D3) (500 mg) in methanol (15 ml) was treated widi 2.0 M sodium methoxide (0.9 ml, 1.8 mmol), then was heated under reflux for 4.5 h. The mixture was cooled, filtered through Kieselguhr and the polymer was washed well with dichloromethane. The filtrate was washed with water (2 x 50 ml) and brine (50 ml), then dried (Na2SO_*.) and evaporated in vacuo to leave the title compound as a white solid (151 mg) NMR: δ (CDCl 3 ) 2.33 (3 H, s), 3.88 (3 H, s), 6.98 (2 H, d, J = 8 Hz), 7.10 (1 H, t, J = 8 Hz), 7.25 (2 H, m), 7.60 (1 H, br m), 7.86 (2 H, J = 8 Hz) and 7.96 (1 H, d, J = 8 Hz) Exam p le 2 Illustrating cleavage from the polymer by intramolecular Wittig react i 2-(4-Methoxyphenyl)indole (E2) A suspension of polymer-bound (2-(4-methoxybenzoylamino)benzyl)- triphenylphosphonium bromide (D3) (500 mg) in toluene (25 ml) and DMF (5 ml) was distilled until approx. 5 ml distillate was collected. Potassium t- butoxide (134 mg, 1.2 mmol) was added and the mixture was heated under reflux for 45 min. The mixture was cooled, acidified with 2 N HCl and filtered through Kieselguhr, and the polymer was washed well with dichloromethane. The filtrate was washed with water (2 x 50 ml) and brine (50 ml), then was dried (Na2SO_ and evaporated in vacuo, to give the title compound (135 mg). NMR: δ (CDCl 3 ) 3.86 (3 H, s), 6.71 (1 H, d, J = 3 Hz), 6.98 (2 H, d, J = 8 Hz), 7.12 (2 H, m), 7.39 (1 H, d, J = 8 Hz), 7.60 (3 H, d, 8 Hz) and 8.25 (1 H, br s) Example 3 Illustrating cleavage from the polymer by intermolecular Wittig reaction E- and Z- 4-Methoxy-N-{2-[2-(4-methoxycarbonylphenyl)vinyl]phenyl}- benzamides (E3) A suspension of polymer- bound (2-(4-methoxybenzoylamino)benzyl)- triphenylphosphonium bromide (D3) (500 mg) in dry methanol (15 ml) was treated with 2.0 M sodium methoxide (0.9 ml, 1.8 mmol) immediately followed by methyl 4-formylbenzoate (295 mg, 1.8 mmol). The mixture was heated under reflux for 2 h, then was cooled and treated with glacial acetic acid (0.5 ml) and (carboxymethyl)trimethylammonium chloride hydrazide (452 mg, 2.7 mmol) then was stirred at room temperature overnight. The mixture was filtered through Kieselguhr and washed well with dichloromethane. The filtrate was washed wid water (3 x 50 ml) and brine (50 ml) then was dried (Na2SO4) and evaporated in vacuo to leave a mixture of geometrical isomers of the title compound as a pale yellow solid (247 mg). NMR: 5 (CDCI3) 3.85 (3 H, s, Z-isomer), 3.87 (3 H, s, Z-isomer), 3.88 (3 H, s, E-isomer), 3.92 (3 H, s, E-isomer), 6.7-8.3 (Complex multiplets, incuding: 6.74 (1 H d, J = 12.8 Hz, Z-isomer), 6.82 (1 H, d, J = 12.8 Hz, Z-isomer), 6.87 (2 H, d, J = 8.5 Hz, Z-isomer), 6.98 (2 H, d, J = 8.5 Hz, E-isomer), 7.07 (1 H, d, J = 15.8 Hz, E-isomer), 7.22 (1 H, d, J = 15.8 Hz, E-isomer), 7.52 (2 H, d, J = 8.3 Hz, E+Z-isomers), 7.87 (d, J * = 8.9 Hz), and 8.01 (d, J = 7.9 Hz). Example 4 Illustrating cleavage from the polymer by intermolecular Wittig reaction E- and Z- N-(4-Methoxyphenyl)-3-[(4- methoxycarbony lphenyl)vinyl] benzylamines (E4) A suspension of polymer-bound {3-[N-(4- methoxyphenyl)aminomethyl]benzyl]triphenylphosphonium bromide (D5, approx. 0.79 mequ) in methanol (15 ml) was treated with 2.0 M sodium methoxide (1 ml, 2 mmol) followed immediately by methyl 4-formylbenzoate (328 mg, 2 mmol). The mixture was heated under reflux for 2 h, then was cooled and treated with glacial acetic acid (0.5 ml) and (carboxymethyl)trimethylammonium chloride hydrazide (502 mg, 3 mmol) and was stirred at room temperature overnight. The mixture was filtered through Kieselguhr and washed well with dichloromethane. The filtrate was washed with water (4 x 50 ml) and brine (50 ml), then was dried (Na.SO 4 ) and evaporated in vacuo to leave an approximately equimolar mixture of geometrical isomers of the title compound as a pale yellow solid (262 mg, 0.70 mmol). NMR: δ(CDCl 3 ) 3.75 (6 H, s), 3.91 (3 H, s), 3.93 (3 H, s), 4.18 (2 H, s), 4.32 (2 H, s), 6.5-6.8 (10 H, m), 7.1-7.5 (12 H, m), 7.57 (2 H, d, J = 8 Hz), 7.87 (2 H, d, J = 8 Hz), and 8.02 (2 H, d, J = 8 Hz). Example 5 Illustrating cleavage from the polymer by intermolecular Wittig reaction E- and Z- N-Acetyl-N-(4-methoxyphenyl)-3-[(4- methoxycarbonylphenyl)vinyl]benzylamines (E5) A suspension of polymer-bound {3-[N-acetyl-N-(4- methoxyphenyl)aminomethyl] benzyl Jtriphenylphosphonium bromide (D6, approx 0.26 mequ) in methanol (15 ml) was treated with 2.0 M sodium methoxide (0.33 ml, 0.66 mmol) followed immediately by methyl 4- formylbenzoate (108 mg, 0.66 mmol). The mixture was heated under reflux for 2 h, then was cooled and treated with glacial acetic acid (0.25 ml) and aminomethyl polystyrene (0.79 mequ/g, 830 mg, 0.66 mmol) and was stirred at room temperature for 90 min. The mixture was filtered through Kieselguhr and 18592 P washed well with dichloromethane. The filtrate was evaporated to dryness and partitioned between dichloromethane (30 ml) and water (20 ml). The organic phase was washed with brine (30 ml), then was dried (Na_SO 4 ) and evaporated in vacuo to leave an approximately equimolar mixture of geometrical isomers of the title compound as a clear oil (106 mg, 0.25 mmol). NMR: δ(CDCl-) 1.82 (3 H, s), 1.89 (3 H, s), 3.80 (3 H, s), 3.81 (3 H, s), 3.89 (3 H, s), 3.93 (3 H, s), 4.75 (2 H, s), 4.87 (2 H, s), 6.58 (1 H, d, J = 12 Hz), 6.66 (1 H, d, J = 12 Hz), 6.80-6.95 (8 H, m, including: 6.82 (s)), 7.05-7.30 (10 H, m), 7.40 (2 H, m), 7.55 (2 H, d, J = 8 Hz), 7.85 (2 H, d, J = 8 Hz), and 8.02 (2 H, d, J = 8 Hz).

Claims: Claims 1. A method for preparing organic compounds which comprises: A. Preparation of a resin-bound phosphonium salt, B. Elaboration of the phosphonium salt on the resin, and C. Optionally cleaving the organic product from the resin. 2. The method according to Claim 1 wherein the phosphonium salt is a compound of formula (I): ( RVPP (I) in which R is the resin; X is a counter-ion; R-- is Cι_6alkyl, optionally substituted phenyl or heteroaryl; and R*** is an organic moiety. 3. The method according to claim 1 or 2 in which R* is a substituted benzyl group. 4. The method according to any one of claims 1 to 3 in which the phosphonium salt is chemically transformed on the resin by reduction or acylation. 5. The method according to any one of claims 1 to 3 in which the phosphonium salt is chemically transformed by intra- or inter-molecular Wittig chemistry or solvolysis. Use of a phosphonium salt as a linker for solid phase synthesis. 7. Use according to claim 6 in which the phosphonium salt is a compound of formula (I) as defined in claim 2. 8. A compound of formula (I): (I) in which R is the resin; X is a counter-ion; R 1 is Cj.galkyl, optionally substituted phenyl or heteroaryl; and R2 is an organic moiety. 9. A compound according to claim 8 in which R2 is a group CHR3R4 where R-- 5 and R^ are the same or different and are hydrogen, optionally substituted C j .galkyl, optionally substituted phenyl or optionally substituted heteroaryl. 10. A compund according to claim 8 in which R-*- is a substituted benzyl group

Inventors: HUGHES IAN, HUGHES, IAN
Applicants: HUGHES IAN, SMITHKLINE BEECHAM PLC, HUGHES, IAN
Application year: 1995
Main classification: C07B61
IPC codes: B01J31, C07B61, C07C227, C07C231, C07C235, C07D209, C08F8