New syntheses of arylphosphinic acids from the reaction of ethyl diethoxymethylphosphinate with aryl bromides and phenols

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1995 New syntheses of arylphosphinic acids from the reaction of ethyl diethoxymethylphosphinate with aryl bromides and phenols Stuart N. L. Bennett and Roger G. Hall*.? Central Research Laboratories, Ciba Geigy PLC, Hulley Road, MacclesJield, Cheshire SKlO 2NX, UK The chemistry of the hypophosphorous acid synthon, ethyl diethoxymethylphosphinate 1 has been further developed to afford efficient new routes to arylphosphinic acids 6and 2-hydroxyphenylphosphinicacids 10. In one approach, a palladium(0) catalysed P-H insertion has been used; the second approach utilises a lithium-based ortho rearrangement of aryl phosphonates, readily prepared from the Atherton-Todd reaction of 1with phenols. In both cases, the phosphinic acids were obtained in a final step by acid deprotection.Our interest in the synthesis of functional phosphinic acids RP(O)(OH)H has been established for several reasons. These compounds have demonstrated interesting biological activity as close analogues of biologically important carboxylic acids, e.g. a-and y-amino acids. 1,2 In addition, such functional phosphinic acids are readily transformed, via oxidation to the correspond- ing phosphonic acids 'or through Arbuzov or Michael addition chemistry, into unsymmetrical phosphinic acids 3,4 underlining their utility as important synthetic intermediates. Synthons of hypophosphorous acid,5*6 such as ethyl diethoxymethyl- phosphinate 1 have previously been shown to be valuable building blocks for the synthesis of functional aliphatic phos- phinic acids.The phosphinate 1undergoes reactions typical of P-H species-protection of the P-H function as the diethoxy- methyl group allows functional group transformations to be performed on the intermediates 2, and a final deprotection step then regenerates the phosphinic acid functionality, leading to products 3 (Scheme 1). protectionH-P--H * (EtOkCH-P-HI (EtO)$H, TFA I OH OEt 1 chemistryI deprotection H-P-R (EtOhCH-P-RI I OH OEt 3 2 Scheme 1 As a continuation of our studies into the utility of such reagents, we now report the use of 1 in the synthesis of functional arylphosphinic acids. Two methods are described; a palladium(0)-catalysed coupling with aryl bromides and base- induced rearrangement of phenolic phosphonates.Existing routes to arylphosphinic acids generally involve the synthesis of the corresponding dichlorophosphine and subse- quent aqueous hydrolysis (Scheme 2). The reaction conditions employed together with the difficulty in handling of the inter- mediates, makes an alternative approach attractive. (I) PdO-catalysed P-H insertion We have found that a tetrakis(tripheny1phosphine)palladium 7 Present address: Ciba Crop Protection, CH 4002 Basel, Switzerland. P02H2 y2 I PC13 Q -QAlC13 or FeC13 a H20 R R R Scheme 2 (0)-catalysed reaction of aryl bromides 4a-g with ethyl diethoxymethylphosphinate 1 affords arylphosphinate esters 5a-g in good to excellent yield (Scheme 3). Hydrolysis of the esters with 4 mol dmP3 hydrochloric acid afforded the arylphosphinic acids 6a-e directly.Similar methodology had been previously employed in the synthesis of arylphosphonic esters,' disubstituted phosphinic esters ' and tertiary phosphine oxides. ' The diethoxymethyl PH protecting group is sufficiently stable to permit further elaboration of substituents on the aryl ring, prior to acid deprotection, and hence afford a wider range of substituted aryl phosphinic acids. Thus, the nitro 5a, b and cyano 5f, g substituted arylphosphinates can be easily reduced (H, over Pd/C) to yield the corresponding amino 5h, i or aminomethyl 5j, k substituted phosphinates (Scheme 4). Deprotection as described above gives the corresponding phosphinic acids 6f, g and 6h, i, respectively.Such hydrogenolysis in the presence of an unprotected PH function would be thwarted by poisoning of the metal catalyst. (2) Phosphonate-phosphinate rearrangement The base-induced rearrangement of phenolic phosphates to give 2-hydroxyphenyl phosphonates has been reported in the literature. 12-' 2-Hydroxyphenylphosphinic acids 10, are, how- ever virtually unknown in the literature. An X-ray structure of the parent compound, 2-hydroxyphenylphosphinicacid 10a was presented in poster form.17 This compound, a close analogue of salicyclic acid, was prepared '*via coupling of a Grignard reagent derived from a suitably protected 2-bromophenol with a chlorobis(dialky1amino)phosphine and subsequent hydrolysis of the aryl phosphine so formed.We found that the phenols 7a-d are readily phosphorylated by 1 under Atherton-Todd conditions, to afford aryl phosphonates 8a-d in good yield. Treatment of these phosphonates with LDA in tetrahydrofuran at -70 "C gave the rearranged products, 2-hydroxyphenylphosphinates 9a4. Hydrolysis of the phosphinates with mineral acid, as above gave the crystalline arylphosphinic acids 10a-d in high yield (Scheme 5). The yield obtained for the parent rearranged phosphinate 9a was disappointing. Attempts to improve this by varying reaction conditions such as choice of base, temperature, 1146 J. CHEM. SOC. PERKIN TRANS. 1 1995 4 5 6 R' R2 Yield () Yield () a NO, H 5a 89 6a 88 b H NO2 5b 67 6b 83 c NMe, H 5c 65 6c 74 d Me H !I72 6d 53 e Ac H 5e 89 6e 65 f CN H 5f 73 gH CN 5g 75 Scheme 3 Reagents and conditions: i, (EtO),CHP(O)OEtH 1, Pd(PPh,), 1-10 h, 90-100 "C; ii, 4 mol dm-, HCl sequence of addition did not improve the process.The corresponding phosphate-phosphonate rearrangement pro-ceeds in much higher yield." One reason for the low yield obtained for 9a could be competing deprotonation of the acetal C-H proton by the ortho lithium species, leading to decomposition products (see below). uecornpowuon* products Direct deprotonation of the acetal C-H by LDA can comfortably be ruled out, on the basis of earlier results with alkyl phosphinate~.~ To try and prove this hypothesis, a deuterium quench experiment was performed.Generation of the anion of 8a with LDA at -70 "C followed by an immediate quench with deuterioacetic acid, gave a product identical with 8a, except with a greatly reduced signal in the 'H NMR spectrum corresponding to the acetal C-H. With a second ovtho-directing group, as in 8b4, where the lithium would be expected to be more strongly coordinated, this process is suppressed in favour of the rearrangement, resulting in higher yields for phosphinates 9b-d. The regiochemistry shown for the rearranged products 9b-d was established by NMR experiments on the corresponding acids (see Tables 1 and 2). With the P-H functionality protected as the di- ethoxymethyl group, it was possible to reduce the chloro n1 II,CH(OEt)2OH I ?-pNOEt 7 10 9 7 R Yield ()8 Yield () 9 Yield () 10 a H 90 15 90 b c Fc1 74 77 78 63 90 50 d Br 78 52 77 Scheme 5 Reagents and conditions: i, compound 1 Et,N, CCl,; ii, LDA, THF, -70 "C; iii, 4 mol dm-3 HCl, 90-100 "C substituent in phosphinate 9c (HJPd-C) to give 9a in high yield, thus circumventing the poor yield previously obtained.(3) 2-Naphthol derivatives We were interested to study the regioselectivity of the re-arrangement of 2-naphthol-derived phosphonates which, at the time of this work, was unknown in the literature. Phos- phorylation of 2-naphthol with 1 gave the phosphonate 11 which, on treatment with LDA, gave a 2:l mixture of phosphinates 12 and 13, again in a rather poor yield of 27 (Scheme 6).Subsequently, a similar study has been published, reporting the analogous phosphate-phosphonate rearrange-ment." The authors obtained a similar 2: 1 ratio of isomers, although only the major isomer was characterised. Conclusions We have demonstrated that ethyl diethoxymethylphosphinate 1 may be successfully employed to prepare substituted arylphospinic acids. This broadening of the utility of such hypophosphorous acid synthons, which are stable and easily prepared, underlines their key role in synthetic organophos- phorus chemistry. 5 h-k 6 R' R2 R' R2 Yield () R' RZ Yield () a NO, H h NH, H 70 f NH, H 75 b f g H CN H NO2 H CN i jk H CH,NH, H NH, H CH,NH, 92 75 90 g h i H CH,NH, H NH, H CH,NH, 76 90 79 Scheme 4 Reagents and conditions: i, Pd-C, H, EtOH; ii, 4 mol dm-j HCI, 9S100 "C J.CHEM. SOC. PERKIN TRANS. 1 1995 11li omo P -CH(OEt)2 'OEt 12 13 Scheme 6 Reugenrs and conditions: i, LDA, THF, -70 "C Experimental All compounds for which analytical and spectroscopic data are quoted were homogeneous by TLC and 31PNMR. TLC was carried out on Merck high performance silica gel 6OF,,, pre-coated glass plates (10 x 5 cm). Products were visualised by UV light or by spraying with aqueous alkaline potassium permanganate. Preparative chromatography was performed on silica gel 60 (70-230 mesh ASTM) (Merck). Solvents were routinely dried before use using procedures described in The Purification of Laboratory Chemicals, D.D. Perrin and W. L. F. Armarego, Pergamon Press. Melting points were carried out on a Biichi type S apparatus and are uncorrected. 'H NMR spectra were recorded on a Bruker AC400 spectrometer operating at 400.13 MHz or a JEOL FX-90Q spectrometer operating at 89.55 MHz. Referenced internally to Me, (for CDC1, solutions) and externally to sodium (trimethylsily1)propionate (for D,O solutions). I3C NMR spectra were recorded on the above instruments operating at 100.614 and 22.49 MHz, respectively (and referenced internally to I3CDCl3) as were 31P NMR spectra operating at 161.91 and 36.21 MHz, respectively (and Table 1 400 MHz spectroscopic data (6,) for phosphinic acids 10 a-d GH(ZH,-DMSO) Compound 3-H 4-H 5-H 6-H P-H Table 2 100 MHz spectroscopic data (S,)for phosphinic acids 1Oa-d Chemical shift Gc(ZH,-DMSO) Compound C-1 c-2 c-3 c-4 c-5 C-6 1Oa 118.32 159.92 116.02 134.07 119.03 131.59 (4 (4 (s) (s) (4 (410b 104.83 162.21 112.92 135.54 105.81 163.54 (W (dd) (dd) (4 (W (d) 1OC 113.27 163.30 116.34 135.21 120.57 135.68 (4 (d) (4 (4 (4 (41Od 114.67 163.53 116.93 135.44 124.01 124.52 (4 (s) (4 (s) (4 (4 1147 referenced externally to H,PO, for both CDCl, and D,O solutions).19FNMR spectra were obtained on the JEOL FX- 90Q instrument operating at 84.25 MHz (and referenced externally to CFC1,). JValues are given in Hz. TR spectra were measured on a Perkin-Elmer 88 1 grating spectrophotometer as thin films or Nujol mulls. Only significant absorptions are quoted. Microanalyses were obtained by Instrumentation, Research and Consultancy Services, University of Manchester.Physical analytical data for the arylphosphinic acids 6 and 10 are summarised in Table 3. Ethyldiethoxymethyl(4nitrophenyl)phosphinate5a A mixture of ethyl diethoxymethylphosphinate 1 (3.9 g, 20 mmol), 4-bromonitrobenzene 4a (4.0 g, 20 mmol), dry triethylamine (4.0 g, 40 mmol), toluene (15 cm3) and tetrakis(triphenylphosphine)palladium(o) (2.3 g, 2 mmol) was sealed in a thick-walled tube under argon. The mixture was heated at 90 "C for 1 h during which time the reaction mixture became clear and then deposited a precipitate (of triethylamine hydrobromide). The reaction mixture was poured onto ethyl acetate (50 cm3), filtered, and evaporated to afford an oil.Purification by column chromatography over silica gel with diethyl ether as eluent afforded compound 5a (5.7 g, 89) as an oil; v,,,(thin film)/cm-' 1600 (Ar), 1520, 1350 (NO,), 1440 (ArP), 1240 (PO) and 1060 (POAlk); G,(CDCl,, 90 MHz), 8.4-7.95 (4 H, m, ArH), 4.85 (1 H, d, J 7.2, PCH), 4.4-4.0 (2 H, m, POCH,), 4.0-3.5 (4 H, m, CH, x 2) and 1.3 (9 H, m, CH3 x 3); Sp(CDCI3, 36 MHz) 28.8. Ethyl diethoxymethyl(3-nitropheny1)phosphinate 5b This compound was similarly prepared from 1 (2.0 g, 10 mmol) and 3-nitrobromobenzene 4b (2.0 g, 10 mmol) with heating at 90deg;C for 6 h. Purification by column chromatography over silica gel eluting with diethyl ether afforded compound 5b (2.1 g, 67) as an oil; vmax(thin film)/cm-' 1600 (Ar), 1530, 1350 (NO,), 1230 (PO) and 1060 (POAlk); GH(CDCIj,90 MHz) 8.8- 8.25 (3 H, m, ArH), 7.95-7.6 (1 H, m, ArH), 4.9 (1 H, d, J 7.2, PCH), 4.5-3.5 (6 H, m, CH, x 3) and 1.3 (9 H, m, CH, x 3); G,(CDCl,, 36 MHz) 28.3.Ethyl diethoxymethyl(4-N-Ndimethylaminophenyl) phosphinate5c This compound was similarly prepared from 1(3.9 g, 20 mmol) and 4-bromo-N,N-dimethylaniline 4c (4.1 g, 20 mmol) with heating at 100 "C for 10 h. Purification by column chromato- graphy over silica gel eluting with ethyl acetate-diethyl ether (1 :1) afforded compound 5c (4.1 g, 65) as an oil; v,,,(thin film)/cm-' 1600 (Ar), 1440,1230 and 1040; GH(CDCl,, 90 MHz), 7.7(2H,m,ArH),6.7(2H,dd,ArH),4.75(1H,d, J7.2,PCH), 4.4-3.4(6H,m,CH2 x 3),3.0(6H,s,NCH3 x 2)and1.3(9H, m, CH, x 3); Gp(CDCl,, 36 MHz) 32.8.Carbon-phosphorus coupling constant (J/Hz) Carbon-fluorine (J/Hz) C-1P C-2P C-3P C-4P C-5P C-6P 128.8 4.82 7.75 -12.98 7.85 _-121.24 7.74 6.94 -5.23 C21.33) C1.611 C3.121 C11.261 C22.031 C246.801 125.9 3.01 7.44 -6.13 3.32 127.2 -7.34 -7.24 4.95 1148 J. CHEM. SOC. PERKIN TRANS. 1 1995 Table 3 Physical analytical data for aryl phosphinic acids 6a-i, 1Oa-d Found () (Required) MP ( T/OC) 31PNMR Compd. (Lit.) C H N P G(so1vent) JPHIHZ 6a 175-177 38.55 3.40 7.30 16.40 13.7 562.0 6b (134)21 163-168 (38.50) 38.45 3.25 3.00 7.50 7.30 (16.55) 16.20 13.0 ('H,-DMSO) 572.5 6c 152-154 (38.50) 51.40 3.25 6.35 7.50 7.45 (16.55) 17.0 16.1 (*H,-DMSO) 563.0 6d (162)22 102-103 (51.90) 53.70 6.55 5.60 7.55 (16.75) 19.8 18.5(D2O) 523.9 6e (1 04)2 115-118 (53.85) 52.00 5.8 1 4.80 (19.85) 16.55 (D20-NaOD) 20.3 570.0 6f 171-174 (52.2) 45.70 4.95 5.10 8.80 (16.80) 19.50 17.4(D2O) 540.0 6g 6h (169)24 240-244 250 (45.85) 45.65 (45.85) 48.90 5.15 5.0 5.15 5.80 8.90 8.80 8.90 (19.70) 19.70 (19.70) 18.1 19.9 17.8 (D2O) (D2O-DCl) 577.0 529.2 6i 250 (49.15) 48.90 5.90 5.70 8.20 8.00 (18.1) 18.3 17.7 P2O) 530.0 (49.15) 5.90 8.20 (18.1) (D@) 1Oa 128-1 32 45.5 4.3 (45.6) 4.45 10b 105 41.15 3.3 (40.49) 3.45 1oc 112 37.05 2.9 (37.4) 3.15 1Od 122- 125 30.25 2.6 (30.4) 2.55 Ethyl diethoxymethyl(4-methylpheny1)phosphinate 5d This compound was similarly prepared from 1 (3.9 g, 20 mmol) and 4-bromotoluene 4d (3.4 g, 20 mmol), with heating at 100 "C for 1 h.Purification by column chromatography over silica gel eluting with diethyl ether afforded compound 5d (4.1 g, 72) as an oil; v,,,(thin film)/cm-' 1605 (Ar), 1405, 1240 (PO), and 1060 (POAlk); G,(CDCl,, 90 MHz), 7.8 (2 H, m, ArH), 7.4 (2 H, m, ArH), 4.8 (1 H, d, J7.2, PCH), 4.5-3.5 (6 H, m, CH, x 3), 2.45 (3 H, s, ArCH,) and 1.3 (9 H, m, CH, x 3); G,(CDCl,, 36 MHz) 31.6. Ethyl 4-acetylphenyl(diethoxymethyl)phosphinate 5e This compound was similarly prepared from 1 (3.9 g, 20 mmol) and 4-bromoacetophenone 4e (4.0 g, 20 mmol), with heating at 100deg;C for 1 h. Purification by column chromatography over silica gel eluting with ethyl acetate-diethyl ether (1 : 1) afforded compound 5e (5.6 g, 89) as an oil; v,,,(thin film)/cm-' 1700 (CO), 1440 (ArP), 1260, (PO) and 1060 (POAlk); G,(CDCl,, 90 MHz), 8.2-7.8 (4H, m, ArH), 4.8 (1 H, d, J7.2, PCH), 4.45-3.75 (6 H, m, CH, x 3), 2.6 (3 H, s, COCH,) and 1.5-1.1 (9 H, m, CH, x 3); Gp(CDC1,, 36 MHz) 30.3.Ethyl 4-~yanophenyl(diethoxymethyl)phosphinate5f This compound was similarly prepared from 1 (3.9 g, 20 mmol) and 4-bromobenzonitrile 4f (3.7 g, 20 mmol) with heating at 90deg;C for 1 h. Purification by column chromatography over silica gel eluting with diethyl ether afforded compound 5f(4.4 g, 75) as an oil; v,,,(thin film)/cm-' 2240, (CN), 1400, 1230, (PO) and 1060 (POAlk); G,(CDCI,, 90 MHz) 8.2-7.7 (4 H, m, ArH), 4.9 (1 H, d, J7.2, PCH), 4.5-3.5 (6 H, m, CH, x 3) and 1.35 (9 H, m, CH, x 3); G,(CDCl,, 36 MHz) 26.3.Ethyl 3-~yanophenyl(diethoxymethyl)phosphinate 5g This compound was similarly prepared from 1 (3.9 g, 20 mmol) and 3-bromobenzonitrile 4f (3.7 g, 20 mmol) with heating at 100 "C for 1 h. Purification by column chromatography over 19.6 22.3 590.0 (1 9.6) 17.6 14.5-14.4(D2O) 591.0 (17.6) 16.2 18.5(J-320) 591.0 (16.1) 13.15 13.4(D2O) 556.5 (13.1) (D20-NaOD) silica gel eluting with diethyl ether afforded compound 5g (4.3 g, 73) as an oil; v,,,(thin film)/cm-l 2240, (CN), 1240, (PO) and 1060 (POAlk); G,(CDCl,, 90 MHz), 8.0-7.6 (4 H, m, ArH), 4.9 (1 H, d, J 7.2, PCH), 4.5-3.6 (6 H, m, CH, x 3) and 1.3 (9 H, m, CH, x 3); G,(CDCl,, 36 MHz) 28.5.Ethyl 4-aminomethylphenyl(diethoxymethyl)phosphinate 5j A solution of the nitrile 5f(0.6 g, 2 mmol) in ethanol (25 cm3) and chloroform (1 cm3) was reduced over 5 Pd/C (0.2 g) with hydrogen at 40 psi at 45 "C. After 24 h, filtration and evaporation of the solvents afforded the crude product as the hydrochloride. The salt was dissolved in THF, treated with triethylamine, filtered and evaporated to an oil. Purification by column chromatography over silica gel eluting with 5 methanol in chloroform afforded compound 5j (450 mg, 75) as a colourless oil; v,,,(thin film)/cm-' 3400br (NH,), 1600, 1220 and 1060 (POAlk); S,(CDCI,, 90 MHz) 7.9-7.6 (4 H, m, ArH), 6.7 (2 H, br s, NH,), 4.75 (1 H, d, J 7.6, PCH), 4.2 (2 H, s, ArCH,), 4.34.0 (2 H, m, CH,OP), 4.0-3.5 (4 H, m, CH, x 2) and 1.2 (9 H, m, CH, x 3); G,(CDCI,, 36 MHz) 30.9.Ethyl 3-aminomethylphenyl(diethoxymethyl)phosphinate 5k This compound was similarly prepared as described above, with reduction of the nitrile 5g for 30 h. The crude product was purified by column chromatography eluting with 5 methanol in chloroform to yield recovered starting material 5g (2.8 g, 68) and then the desired compound 5k (1.2 g, 29) as a colourless oil; v,,,(thin film)/cm-' 3350br (NH,), 1230 and 1060 (POAIB); G,(CDCl,, 90 MHz), 8.0-7.3 (4 H, m, ArH), 5.25 (2 H, br s, NH,), 4.8 (1 H, d, J7.5, PCH), 3.95 (2 H, s ArCH,), 4.4-3.5 (6 H, m, CH, x 3) and 1.2 (9 H, m, CH, x 3); G,(CDCl,, 36 MHz) 31 -2.Ethyl 4-aminophenyl(diethoxymethyl)phosphinate 5h A solution of compound 5a (1.6 g, 5 mmol) in absolute ethanol (25 cm3) was reduced over 5 Pd-C (0.2 g) with hydrogen at 40 psi. After 24 h, the reaction mixture was filtered and con- J. CHEM. SOC. PERKIN TRANS. 1 1995 centrated. Purification by column chromatography over silica gel eluting with 10 methanol in ethyl acetate afforded compound 5h as a viscous oil (1 .O g, 70); v,,,(thin film)/cm-' 3350br (NH,), 1640, 1600, 1440, 1220 and 1060 (POAlk); G,(CDCl,, 90 MHz), 7.7-7.2 (2 H, m, ArH), 6.6 (2 H, dd, ArH), 4.7 (1 H, d, J 7.6, (PCH), 4.2-3.5 (8 H, m, CH, x 3 and NH,) and 1.2 (9 H, m, CH, x 3); G,(CDCl,, 36 MHz) 32.4. Ethyl 3-aminophenyl(diethoxymethyl)phosphinate 5i This compound was similarly prepared as described above, compound 5b (1.5 g, 4.7 mmol) being reduced to a colourless solid (1.2 g, 92), mp 82 "C; v,,,(thin film)/cm-' 3370br (NH,), 1635,1600,1440,1230 and 1060 (POAlk); d,(CDCl,, 90 MHz), 7.3-7.0(3H,m,ArH),6.9-6.7(1H,m,ArH),4.75(1H,d,J7.2, PCH), 4.4-3.5 (8 H, m, CH, x 3 and NH,) and 1.25 (9 H, m, CH, x 3); G,(CDCl,, 36 MHz) 31.6.4Nitrophenylphosphinic acid 6a A solution of 5a (0.3 g, 0.95 mmol) in 4 mol dmP3 hydrochloric acid (20 cm3) was heated at 100 "C for 4 h and then evaporated to afford an oil which upon co-evaporation with water gave a solid. Recrystallisation from ethanol yielded compound 6a (0.15 g, 88) as yellow crystals; v,,,(Nujol)/cm-' 2420 (PH), 1540, 1350 (NO,), 1200 and 1080; GH(CD3),S0 90 MHz, 9.0 (1 H, br s, POH), 8.48.2 (2 H, m, ArH), 8.15-7.8 (2 H, m, ArH) and 7.6 (1 H, d, J 562, PH).3-Nitrophenylphosphinic acid 6b This compound was similarly prepared from 5b (1.0 g, 3.2 mmol) by treatment with 4 mol dm-, hydrochloric acid (25 cm3), to give a yellow solid (0.50 g, 83); v,,,(Nujol)/cm-' 2380 (PH), 1530 and 1350 (NO,); G,(CD,),SO, 90 MHz, 7.9 (1 H, br s, POH), 8.67.4 (4 H, m, ArH) and 7.6 (1 H, d, J 572, PH). 4N,N-Dimethylaminophenylphosphinicacid 6c A solution of 5c (3.2 g, 10.2 mmol) in 4 mol dmP3 hydrochloric acid (30 cm3) and ethanol (30 cm3) was heated for 3 h and then evaporated to yield an oil. This was partitioned between water and ether. The aqueous phase was separated, concentrated and purified by passage down an ion-exchange column (Dowex 50-W H+ form) eluting with water.Evaporation of appropriate fractions afforded compound 6c (1.4 g, 74) as a colourless solid; v,,,(Nujol)/cm-' 2380 (PH), 1600; SH(D20, 90 MHz), 8.3-7.8 (4 H, m, ArH), 7.8 (1 H, d, J563, PH) and 3.5 (6 H, s, NCH, x 2). 4Methylphenylphosphinic acid 6d A solution of 5d (3.6 g, 12.6 mmol) in 4 mol dm-, hydrochloric acid (30 cm3) and ethanol (20 cm3) was heated at reflux for 6 h. Evaporation of solvents and co-evaporation with water (4 x ) afforded a crude solid, which was recrystallised EtOAc-light petroleum (bp 60-80 "C), 1 :51 to afford compound 6d (1.O g, 53) as a colourless solid; vmax(Nujol)/cm-' 2420 (PH), 1600 and 1460; G,(D,O/NaOD, 90 MHz), 7.6-7.0 (4 H, m, ArH), 7.3 (1 H, d, J 524, PH) and 2.2 (3 H, s, CH,).4Acetylphenylphosphinic acid 6e This compound was similarly prepared from 5e (0.5 g, 1.6 mmol), 4 mol dm-3 hydrochloric acid (10 cm3) and ethanol (3 cm3). Recrystallisation (toluene) afforded compound 6e(0.2 g, 65) as white crystals; v,,,(Nujol)/cm-l 2400 (PH), 1660, 1600 and 1250; 6,(D,O, 90 MHz) 7.9-7.3 (4H, m, ArH), 7.5 (1 H, d, J 570, PH) and 2.4 (3 H, s, CH,). 4-Aminophenylphosphiic acid 6f A solution of 5h (I .8 g, 6.2 mmol) in 4 mol dmP3 hydrochloric 1149 acid (25 cm3) was heated at 100 "C for 6 h. Evaporation and co- evaporation with water (2 x ) afforded the crude product hydrochloride salt. The salt was dissolved in ethanol and propylene oxide added dropwise to the solution.The resultant precipitate was filtered off to afford the compound 6f (1.2 g, 75) as a colourless solid; v,,,(Nujol)/crr-l 3400br (NH,) and 2375 (PH); GH(D,O, 90 MHz) 8.7-7.8 (4 H, m, ArH) and 7.8 (1 H, d, J 540, PH). 3-Aminophenylphosphinic acid 6g Similarly, the phosphinate 5i (2.2 g, 7.6 mmol) afforded compound 6g (0.9 g, 76); v,,,(Nujol)/cm- '3950br (NH,) and 2375 (PH); d,(D,O-DCl, 90 MHz), 7.9-7.4 (4 H, m, Ar-H) and 7.25 (1 H, d, J 577, PH). 4Aminomethylphenylphosphinicacid 6h A solution of 5j (0.4 g, 1.3 mmol) in 4 mol dm-, hydrochloric acid (20 cm3) was heated to 100 "C for 6 h. Evaporation of the solvent and co-evaporation of the residue with water (4 x ) afforded the crude product which was purified by ion-exchange chromatography (Dowex 50-W H+ form) with water as eluent.Compound 6h was isolated as a white powder (0.2 g, 90); v,,,(Nujol)/cm-' 3440, 3400br (NH,) and 2360 (PH); d,(D,O, 90 MHz), 7.8-7.3 (4 H, m, ArH), 7.28 (1 H, d, J 592.2, PH) and 4.2 (2 H, s, CH,). 3-Aminomethylphenylphosphinic acid 6i Similarly, compound 5k (1.4 g, 4.6 mmol) afforded compound 6i (0.5 g, 79); vmax(Nujo1)/cm-' 3350, 3280br (NH,) and 2360 (PH); amp;(D,O, 90 MHz), 7.8-7.2 (4 H, m, ArH), 7.28 (1 H, d, J 530, PH) and 4.15 (2 H, s, CH,). Ethyl diethoxymethyl(pheny1)phosphonate 8a A solution of the phenol 7a (1.9 g, 20 mmol) and 1 (3.9 g, 20 mmol) in carbon tetrachloride (50 cm3) was cooled to 0deg;C under argon after which dry triethylamine (2.0 g, 20 mmol) was added dropwise to it over 10 min.After being warmed to 23 "C and stirred for 0.5 h, the mixture was filtered. The filtrate was washed with cold 1 mol dmP3 hydrochloric acid, 1 mol dm-, aqueous sodium hydroxide and brine, dried (MgSO,) and evaporated to yield the crude product as an oil. Purification by distillation on a wiped-wall distillation unit at 80 "C/O.1 mmHg afforded compound 8a (5.1 g, 90) as a clear oil; v,,,(thin film)/cm-' 1590, 1500, 1260, 1200 and 1060; G,(CDCl,, 90 MHz) 7.3 (5 H, m, ArH), 4.95 (1 H, d, J7.2, CHP), 4.5-4.2 (2 H, m, CH,), 4.0-3.8 (4 H, m, CH, x 2) and 1.3 (9 H, m, CH, x 3); G,(CDCl,, 36 MHz) 10.5. Ethyl diethoxymethyl(3-fluoropheny1)phosphate 8b This compound was similarly prepared from 3-fluorophenol7b (5.6 g, 50 mmol) and 1(9.8 g, 50 mmol).Distillation on a wiped- wall distillation unit at 90 "C/O.l mmHg gave compound 8b (1 1.4 g, 74); v,,,(thin film)/cm-' 1260, 1240, 1 100 and 1040; G,(CDCl,, 90 MHz) 7.54.8 (4 H, m, ArH), 4.95 (1 H. d, J 7.2 CHP), 4.55-4.2 (2 H, m, CH,), 4.1-3.8 (4 H, m, CH, x 2) and 1.3 (9 H, m, CH, x 3); Gc(CDC13, 22.5 MHz) 165.0 (d, JC-,,F 245.8,C-3), 154.1 (dd,Jc-l,p8.2, Jc-i,Fll.O,C-l), 132.8(d,J22.0, C-4), 110.5 (dd, Jc-2.p 4.1, JC-2.F 24.7, C-2), 101 .O (d, Jc.p 210.1, PCH), 66.5(d,JC,, 5.5,POCH,)65.7(d,Jc,, 6.9, PCHOCH,), 18.3 (d, Jc,p5.5, POCH,CH,) and 17.0 (s, CH,); G,(CDCl,, 36 MHz) 10.6; amp;(CDCl,, 84 MHz) -I1 1.2. Ethyl 3chlorophenyl(diethoxymethyl)phosphate 8c Similarly, 3-chlorophenol7c (12.8 g, 0.1 mol) and 1 (1 9.6 g, 0.1 mol) gave compound 8c (24.8 g, 77) after distillation at 100 "C/O.l mm; 1 mm; v,,,(thin film)/cm-' 1590, 1260, 1210, 1050 and 780; G,(CDCl,, 90 MHz) 7.4-7.1 (4 H, m, ArH), 1150 J.CHEM. SOC. PERKIN TRANS. I 1995 4.95(1 H,d,J7.2,PCH),4.5-4.2(2H,m,CH2),4.l-3.8(4H,m,light petroleumdiethy1 ether (2: 1) to afford compound 9d (3.8 CH, x 2) and 1.3 (9 H, m, CH, x 3); Gp(CDCl,, 36 MHz) 10.6. Ethyl 3-bromophenyl(diethoxymethyl)phosphonate8d Similarly, 3-bromophenol7d (8.6 g, 50 mmol) and 1 (9.8 g, 50 mmol) gave compound 8d (21.7 g, 78) as a clear oil after distillation at 100 "C/O. I mmHg; v,,,(thin film)/cm -l, 1250, 1210,1050 and 710;GH(CDC1,, 90 MHz) 7.6-7.2 (4 H, m, ArH), 4.95 (1 H, d, J7.2, PCH), 4.6-4.2 (2 H, m, CH,), 4.1-3.8 (4 H, m, CH, x 2) and 1.3 (9 H, m, CH, x 3); Gp(CDCl,, 36 MHz) 10.6.Ethyl diethoxymethyl(2-hydroxypheny1)phosphinate 9a A solution of lithium diisopropylamide (10 mmol) in dry tetrahydrofuran (10 cm3) was added dropwise to a solution of compound 8a (2.9 g, 10 mmol) in THF (20 cm3) at -70 "C under argon. The reaction mixture was stirred at -70 "C for 1 h and then allowed to warm to room temperature. The reaction mixture was poured into saturated aqueous ammonium chloride (50 cm3). The organic phase was washed with water, dried (MgSO,) and evaporated to afford a crude product, purification of which by column chromatography over silica gel eluting with light petroleum-diethyl ether (1 :1) afforded compound 9a (0.43 g, 15) as a colourless solid, mp 110-111 "C; v,,,(Nujol)/cm-' 3000 (OH), 1440 (ArP), 1200 (PO) and 1040 (P-OAlk); G,(CDCl,, 90 MHz) 10.41 (1 H, br s, OH), 7.6-7.2(2H,m,ArH),7.l-6.8(2H7m,ArH),4.85(1H,d,J7.5, PCH),4.44.0(2H,m,CH2),4.O-3.8(4H,m,CH,x 2)and 1.3 (9 H, m, CH, x 3); Gc(CDCl,, 22.5 MHz) 163.3 (d, Jc-2,p5.5 C-2),135.3(d, Jc-,,p2.7,C-4), 132.5(d,Jc_,,p6.9,C-6), 119.2(d, Jc-5,P 12.4, C-5), 117.8 (d, JC-3.p 8.2, C-3), 108.6 (d, Jc-1,p 119.4, C-1), 101.2 (d, Jc,p 160.6, PCH), 66.0-65.4 (dd, PCHOCH, x 2), 62.2 (d, Jc,p6.1, POCH,), 16.45 (d, Jc,p5.5, CH,) and 15.1 (s, CH,) GP(CDC1,, 36 MHz) 37.9 (Found: C, 54.55; H, 7.5; P, 10.95. C13H210,P requires C, 54.15; H, 7.35; P, 10.75).Ethyl diethoxymethyl(2-fluoro-6-hydroxyphenyl)phosphinate 9b Similarly, 8b (6.1 g, 20 mmol) gave a crude product which was purified by column chromatography eluting with light pet- roleum-diethyl ether (1 :1) to afford compound 9b (4.8 g, 78) as an oil; v,,,(Nujol)/cm-' 3 100 (OH), 1580, 1450 (ArP), 1140 (PO), 1080 and 1040; amp;(CDCl,, 90 MHz) 11.2 (1 H, S, OH), 7.6-7.2 (1 H, m, ArH), 6.8-6.4 (2 H, m, ArH), 5.0 (1 H, dd, Jc,p 7.2 JC,F 2.0, PCH), 4.4-3.7 (6 H,m, CH, x 3) and 1.3 (9 H, m, CH3 x 3); Gc(CDCl3, 22.5 MHz) 164.9 (d, Jc-6,~10.5, C-6), 163.2(d, Jc-2,,248.5,C-2), 136.1 (d,Jc-4,~ ll.O,C-4), 113.9(dd, JC-5,P 8.2, JC-5.F 2.7, C-5), 105.5 (dd, JC-3.p 6.9, Jc-3,F 23.3, C-3), 100.0(dd, Jc,p 166.1, JC,F4.1,PCH),98.0(dd7 Jc-1.p 114.0,Jc-1,F 23.3, C-1), 64.8 (dd, CH,), 62.6 (d, J8.2, CH,), 16.2 (d, J6.8, CH,) and 15.0 (d, J 8.0, CH,); G,(CDCl,, 36 MHz) 37.4 (d, JP,F 3.9); GF(CDC1,, 84 MHz) -103.7 (Found: C, 50.9; H, 6.9; P, 10.1.C,,H,,FO,P requires C, 51.0; H, 6.6; P, 10.1). Ethyl Zchloro-6-hydroxyphenyl(diethoxymethyl)phosphinate 9c Similarly, 8c (6.4 g, 20 mmol) gave a crude product which was purified by column chromatography eluting with light pet- roleum-diethyl ether (1 : 1) to afford compound 9c (4.0 g, 63) as a clear oil; v,,,(thin film)/cm-' 3000 (OH), 1580, 1440, 1200, 1060 and 780; G,(CDCl,, 90 MHz) 11.95 (1 H, s, OH), 7.6-6.7 (3 H,m,ArH),5.25(1H,d,J7.O,PCH),4.2-3.7(6H,m,CH2x 3) and 1.3 (9 H, m, CH, x 3); G,(CDCl,, 36 MHz) 39.7. Ethyl 2-bromo-6-hydroxyphenyl(diethoxymethyl)phosphinate 9d Similarly, 8d (7.3 g, 20 mmol) gave a crude product which was purified by column chromatography over silica gel eluting with g, 52) as a low-melting waxy solid; v,,,(thin film)/cm-' 3100 (OH), 1580, 1440, 1200 and 1050; GH(CDC1,, 90 MHz) 11.95 (I H, s, OH), 7.5-6.8 (3 H, m, ArH), 5.5 (1 H, d, J 10.0, PCH), 4.4- 3.5(6H,m,CH2 x 3),1.3(6H,2 x t,CH, x 2)andl.O(3H,t, J 7.0, CH,); Gp(CDCl,, 36 MHz) 40.1 (Found: C, 42.75; H, 5.4; P, 8.45.C1 ,H,,BrO,P requires C, 42.50; H, 5.50; P, 8.45). Reduction of 9c by catalytic hydrogenation A mixture of 9c (200 mg, 0.62 mmol) and 10 palladium-on- carbon (50 mg) in absolute ethanol (10 cm3) was hydrogenated at 40 "C for 24 h. Filtration and evaporation afforded an oil that was purified by column chromatography over silica gel with light petroleum-diethyl ether (1 :1) to afford compound 9a (1 25 mg, 70), identical in all respects with that obtained previously. 2-Hydroxyphenylphosphinic acid 10a Compound 9a (1.0 g, 3.5 mmol) was dissolved in absolute ethanol (12.5 cm3) and 4 mol dm-, hydrochloric was added to the solution.The mixture was heated at 100 "C for 3 h and then evaporated to afford an oil that was co-evaporated with water (4 x 25 em) and absolute ethanol (4 x 25 an3).The resulting oil crystallised on storage and was recrystallised from ethyl acetate to give compound 10a (0.49 g, 90) as white needles; v,a,(Nujol)/cm-l 3100 (OH), 2410 (PH), 1600 and 1440; G,(CD,),SO, 400 MHz 7.53 (1 H, d, JpH 560.2, PH), 7.50 (1 H, ddd, J6p 9.2, J5.6 7.5, J4.6 1.7, 6-H), 7.40 (1 H, dt, J4,5 7.5, J4.6 1.7, 4-H), 6.92 (1 H, dt, J5,67.5, J2.0, 5-H) and 6.87 (1 H, m, 3-H).6-Fluoro-(2-hydroxyphenyl)phosphinic acid 10b Similarly, 9b (1.0 g, 3.3 mmol) gave a product which was recrystallised from toluene to afford compound 10b (520 mg, 90) as colourless needles; vmaX(Nujol)/cm-' 3 100 (OH), 2420 (PH), 1590, 1440 and 1100 (CF); SH(CD,),SO, 400 MHz 7.73 (1 H,d, JpH591.0,PH),7.44(1 H,dt, J8.25,7.16,4-H),6.72(1 H, m, H-3) and 6.69 (1 H, m, 5-H). 6-Chloro(2-hydroxyphenyl)phosphinic acid 1Oc Similarly, 9c (1.0 g, 3.1 mmol) gave a product which was recrystallised from toluene-light petroleum (1 :3) to afford compound 1Oc (300 mg, 50) as a white solid; v,,,(Nujol)/cm-' 3000 (OH), 2400 (PH), 1600, 1400 and 780 (CCl); 6,-(CD,),SO, 400 MHz 10.4 (1 H, br s, OH), 7.78 (1 H, d, JpH 597.1, PH), 7.42(1 H, t, J8.2, 4-H), 6.96 (1 H, dd, J8.35,4.05, 5-H) and 6.84 (1 H, dd, J 7.85,4.55, 3-H).6-Bromo-(2-hydroxyphenyl)phosphinicacid 1Od Similarly, 9d (2.0 g, 5.5 mmol), gave a product which was recrystallised from toluene-light petroleum (3 :1) to afford compound 10d (l'.O g, 77) as a white solid; v,,,(Nujol)/cm-l 3200 (OH), 2420 (PH), 1590 and 1440; dH(CD,),SO, 400 MHz 8.0 (1 H, br s, OH), 7.69 (1 H, d, JpH 597.8, PH), 7.33 (1 H, t, J8.15, 4-H), 7.13 (1 H, ddd, J7.85, 4.5, 0.6, 5-H) and 6.86 (1 H, dd, J8.35,4.0, 3-H). Ethyl diethoxymethyl(2-naphthy1)phosphonate 11 2-Naphthol (14.4 g, 0.1 mol) and 1 (19.6 g, 0.1 mol) were dissolved in a mixture of dry THF-CCl, (1 :5) (100 cm3) at room temperature.Dry triethylamine (10.0 g, 0.1 mol) was added dropwise to the mixture the internal temperature of which was maintained at 30 "C by means of an ice-bath. The mixture was then stirred at room temperature for 4 h, filtered and the filtrate washed with cold 1 mol dm-3 hydrochloric acid, 1 mol dm-, aqueous sodium hydroxide and water and dried (MgSO,). Evaporation followed by distillation on a wiped-wall distillation unit at 140 "C/O. 1 mmHg afforded compound 11 (26.4 g, 78) as a clear oil; v,,,(thin film)/cm-' 1600/1510 (Ar), J. CHEM. SOC. PERKIN TRANS. 1 1995 1280 (PO), 1210and 1060;S,(CDCl3, 90 MHz) 7.9-7.7 (4 H, m, Ar), 7.6-7.3 (3 H, m, Ar), 4.95 (1 H, d, J7.2, PCH), 4.5-4.2 (2 H, m, CH,), 4.1-3.6 (4 H, m, CH, x 2) and 1.25 (9 H, m, CH, x 3); Gp(CDC1,, 36 MHz) 10.8.LDA-induced rearrangement of 11 A solution of lithium diisopropylamide (10 mmol) in dry tetrahydrofuran (THF) (10 cm3) was added dropwise to a solution of compound 11 (3.4 g, 10 mmol) in THF (40 cm3) at -70 "C under argon. The reaction mixture was stirred at -70 "C for 1 h and then at room temperature for 1 h. The reac- tion mixture was poured into saturated aqueous ammonium chloride (50 cm3) and extracted with ethyl acetate. The organic extracts were dried (MgS04) and evaporated to give the crude product as an oil. Purification by column chromatography over silica gel eluting with light petroleum-diethyl ether (3 :1) afforded ethyl diethoxymethyl(2-hydroxy-1-naphthyl)phosphi-nate 13 (0.3 g, 9) as an oil; GH(CDCl,, 90 MHz) 13.1 (1 H, s, OH), 8.4-7.5 (6 H, m, Ar), 5.5 (1 H, d, J 10.8,PCH), 4.8-3.6 (6 H, m, CH, x 3) and 1.3 (9 H, m, CH, x 3);Gc(CDC13,22.5 MHz) (quaternary carbons) 169.5 (d, Jc-2,p4.3, C-2), 137.3 (d, Jc-8,p 9.5, C-8), 132.0 (d, Jc-4,p11.0,C-4) and 102.5(d, Jc-l,p 117.0, C-1); Gp(CDCI,, 36 MHz) 42.6.Additionally obtained was ethyl diethoxymethyl(2-hydroxy-3-naphthyl)phosphinate12 (0.6 g, 18)as a white solid, mp 108-1 12 "C; G,(CDCl,, 90 MHz) 10.7 References 1 E. K. Baylis, C. D. Campbell and J. G. Dingwall, J. Chem. Soc., Perkin Trans., 1, 1984,2845. 2 E. P. 0181833 (Ciba-Geigy PLC) CA: 106 P18814k. 3 M. C. Allen, W.Fuhrer, B. Tuck, R. Wade and J. M. Wood, J. Med. Chem., 1989,32, 1652. 4 A. C. Baillie, C. L. Cornell, B. J. Wright and K. Wright, Tetrahedron Lett., 1992,33, 5133. 5 E. 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Wunderlich, Poster Abstract, Proceedings of the International Conference on Phos- phorus Chemistry, Bonn, Germany 1986, Phosphorus and Sulphur, 3.8 (6 H, m, CH, x 3) and 1.3 (9 H, m, CH, x 3); Gc(CDC13, 22.5 MHz) (quaternary c) 158.2 (d, Jc-z,p5.5, C-2), 138.4 (d, Jc-8.p2.0, C-8), 127.9 (d, Jc-4.p13.0, C-4) and 113.0 (d, Jc-3,p 1 16.7, C-3); Gp(CDCI3, 36 MHz) 36.3. Acknowledgements This work was, in part, presented for a Post-graduate Research Diploma of Manchester Polytechnic (Manchester Metro-politan University). s.N. L. Bennett is grateful to Dr G. V. Garner for encouragement and support. 1987,820.(lH,s,OH),8.4-7.8(6H,m,Ar),5.2(1H,d,J7.9,PCH),4.8-18 K. Diemert, personal communication. 19 B. Dwahan and D. Redmore, J. Org. Chem., 1991,56,833. 20 V. M. Plets, J. Gen. Chem. USSR (Engl. Transl.), 1937, 7, 84. 21 R. Michaelis and A. Schenk, Liebigs Ann. Chem., 1890,260. 22 T. Weil, B. Prifs and H. Erlenmeyer, Helv. c'him. Acta, 1953, 36, 1314. 23 I. M. Klotz and R. T. Morrison, J. Am. Chem. Soc., 1947,69,473. Paper 4/06777K Received 7th November 1994 Accepted 4th January 1995