Scheme 36 PS = polystyrene support of 100-200 mesh
3. Tetronic acids and oligocyclic systems
3.2 Original work: Synthesis of highly substituted bicyclic and tricyclic systems
3.2.3 Highly substituted cyclopentanols and their reactions
This part of the project deals with the use of metallacycles in the synthesis of highly substituted bicyclic systems. Many nine membered titanacycles have been successfully synthesised and characterised but most lack carbon in their metallacycle e.g.TiS8[114]. Therefore, carbon-rich titana-2,9-dioxacyclonona-3,7-dienes were prepared by past group members by reaction of two equivalents of an α,β-unsaturated ketone 105 with Cp2Ti(CO)2 using mild, non-basic conditions[115]:
Hydrogenolytic cleavage of titanocycle 106 drove an intramolecular aldol addition reaction and exclusive formation of the highly substituted cyclopentanol 107[115]. These reductive conditions promoted ring contraction of 106 to 107.
cis-1-Phenyl-2-phenylcarbonyl-3,4-diphenylcyclopentan-1-ol 107 with keteneylidenetriphenylphosphorane 1a[116] was tested in different solvents (THF, toluene and xylene), with and without a catalytic quantity of benzoic acid and a range of temperatures was applied (60 - 120oC), but no reaction took place. NMR experiments suggested that a molecule of water was lost from 107 leaving the cyclopenta-1,5-ene system which could not react with ylide 1a. Eventually the reaction was successfully carried out in a bomb-tube at 160oC generating the fused bicyclic system 108:
Ph O
Ph OH
Ph' Ph'
107
O O
Ph H Ph
Ph' Ph'
1.3 1a, benzoic acid, toluene, 160oC, 12 h.
108
81% 6
8 5 2 3 3
5 2
Scheme 64
The reaction took place via a domino style reaction, where 107 adds to 1a followed by an intramolecular Wittig alkenation to close the second ring. 108 was easily identified by a signal at 115 ppm in its 13C-NMR spectrum for C-3 and with the disappearance of the carbonyl peak of 107 at 205 ppm. The disappearance of the hydroxy signal in the IR-spectrum of 107 was also a clear indication of a successful reaction. Fig.20 shows the
1H-NMR spectrum of a CDCl3 solution of 108, which clearly shows a new signal at approx. 6.2 ppm for 3-H and the disappearance of peaks at 4.5 and 5.3 ppm for 2-H and O-H of 107 respectively.
Fig.20 13C-NMR of a CDCl3 solution of 108
Further work
• Water has been reported as having a special effect on Diels-Alder reactions[117]
by significantly enhancing their reaction rates. This enhancement can thus be
further magnified by addition of ionic solutes[118] e.g. LiCl, LiClO4. This could be tested on systems 98a and 98b (Scheme 60).
• Test the IMDA reactions of derivatives of 98 with a larger tether length and replacing the phenyl moiety with a less bulky group.
• Test IMDA reactions in an autoclave under pressure, as this has been shown to promote similar reactions[119].
4. Experimental
Methods and materials
Melting points were recorded on a Gallenkamp or a Wagner & Munz apparatus and are uncorrected. IR spectra were recorded on a Bruker FT-IR Vector 22; Perkin Elmer 983G coupled to a Perkin Elmer 3700 Data Station and a Perkin Elmer 1605 FT-IR as potassium bromide discs or as films on sodium chloride plates. Nuclear Magnetic Resonance (NMR) spectra were recorded using Bruker DPX-300, DPX-500 and Jeol JNM-EX-270-FT spectrometers with Xwin-NMR data system, version 3. Chemical shifts are reported in parts per million (ppm) with tetramethylsilane (internal, 1H- and
13C-NMR) or H3PO4 (85%, external, 31P-NMR) as standards and coupling constants (J) are reported in Hertz (Hz). Mass spectra were recorded on a Double Focusing Triple Sector VG Auto Spectrometer and a Double Focusing Finnigan MAT 95 Spectrometer with MAT SS 300 data system (EI). Microanalyses were recorded using a Perkin Elmer 2400 CHN and Heraues CHN Mikromonar elemental analyser. Analytical GC was recorded using a United Technologies Packard Model 438S with DB-5 silica column (J&W Scientific) and Shimadzu C-R3A integrator. Microwave reactions were carried out in a CEM Discoverer Microwave. The silica gel used in column chromatography was Merck silica gel 60, particle size 0.063 – 0.2mm (70 – 230 mesh). TLC analyses were carried out using Polygram® SIL G / UV254 0.2mm silica plates and a UV lamp or developing solution (conc. H2SO4, 6mL; Ce(SO4)2, 1.0g; 12MoO3.H3PO4, 2.5g and H2O, 94mL).
All solvents were obtained from Merck and were pre-distilled before use, some were rigorously dried: CH2Cl2 and CHCl3, PO5 (20g in 1L); MeOH, Mg turnings (2.5g in 500mL); toluene, THF, benzene, EtOH and Et2O, sodium (7g in 1L).
Compounds in italics were available within our working group and have been included for spectroscopic comparisons. See references for protocols.
4.1 Synthesis of Keteneylidenetriphenylphosphorane 1a
[87,120]Carbomethoxymethyl-triphenylphosphoniumbromide 14[121]
O
Ph3P 1 O Br
2
1'
Triphenylphosphine (262g, 1.0mol) was dissolved in toluene (1200mL) and methyl bromoacetate (152g, 1.0mmol) was added dropwise over a 30 min period. The reaction mixture was stirred for 24 h at r.t. forming a white precipitate (the progress of which was monitored by TLC). The solid was filtered using a Büchner apparatus, washed thoroughly with toluene (~500mL) and rinsed with Et2O (~1000mL). The solvent was removed under reduced pressure and dried on an oil pump yielding carbomethoxymethyl-triphenylphosphoniumbromide 14 as a white solid (348.8g, 0.84mol, 84%).
MF : C21H20O2PBr MW : 415.27
MP = 162oC (Lit. mp.: 163oC [121]).
1H-NMR (300MHz, CDCl3); δ(ppm) = 3.57 (s, 3H, 1'-H), 5.55 (d, 2JPH = 13.40Hz, 2H, 2-H), 7.5-7.9 (m, 15H, Ph-H).
13C-NMR (75.5MHz, CDCl3); δ(ppm) = 33.1 (d, 1JPC = 58.0Hz, CH2; C-2), 55.1 (CH3; C-1'), 117.9 (d, 1JPC = 85.3Hz, Cq; C-ipso), 131.3 (d, 3JPC = 12.62Hz, m-CH; C-arom), 133.8 (d, 2JPC = 10.91Hz, o-CH; C-arom), 134.9 (CH; p-CH; C-arom), 166.6 (Cq; C-1).
31P-NMR (121.5MHz, CDCl3); δ(ppm) = 21.69
IR (KBr); ν(cm-1) = 3004(w), 2798(m), 2731(w), 1721(s), 1585(w), 1486(w), 1434(m), 1320(m), 1197(m), 1107(s), 994(w), 875(m), 800(w), 752(m), 724(m), 688(m).
Carbomethoxymethylene-triphenylphosphorane 15a[121]
O Ph3P 1 O
2
1'
Carbomethoxymethyl-triphenylphosphoniumbromide 14 (349g, 0.84mol) was dissolved in distilled water (4500mL), cooled to 4oC and 2M NaOH was added dropwise until the reaction mixture reached a pH of 7. A white precipitate was produced which was filtered using a Büchner filter and washed with a large quantity of water. The remaining solid was dissolved in DCM, the organic layer was separated from the aqueous phase, dried over MgSO4, filtered and the solvent was removed on a rotary evaporator. The product was recrystallised from toluene yielding carbomethoxymethylene-triphenylphosphorane 15a as a white, fluffy solid (221.9g, 0.66mol, 79%).
MF : C21H19O2P MW : 334.36
MP = 163.6 – 164.2oC (Lit. mp.: 163oC [121])
1H-NMR (300MHz, CDCl3); δ(ppm) = 2.90 (d, 2JPH = 11.1, 1H, 2-H), 3.45 (s, 3H, 1'-H), 7.4–7.7 (m, 15H, Ph-H).
13C-NMR (75.5MHz, CDCl3); δ(ppm) = 28.2 (d, 1JPC = 126.15Hz, CH; C-2), 46.0 (CH3; C-1'), 127.5 (d, 1JPC = 94.0Hz, Cq; C-ipso), 128.3 (d, 3JPC = 12.64Hz, m-CH; C-arom), 130.7 (p-CH; C-C-arom), 133.0 (d, 2JPC = 10.10Hz, o-CH; C-arom), 171.2 (d, 2JPC
= 15.78Hz, Cq; C-1).
31P-NMR (121.5MHz, CDCl3); δ(ppm) = 16.97, 18.81.
MS (EI, 70eV); m/z (%) = 334 (46) [M+], 333 (100) [M+-1], 303 (44) [M+-CH3O-], 275 (20) [M+-CH3CO2-], 77 (6) [C6H5+].
Keteneylidenetriphenylphosphorane 1a[120]
C C O Ph3P 2 1
To a solution of sodium amide (25.8g, 0.66mol) in dry benzene (1500mL), hexamethyldisilazane (HMDS; 106.6g, 0.66mol) was added and refluxed for 2 h. The resulting orange/brown solution was cooled, carbomethoxymethylene-triphenylphosphorane 15a (220.7g, 0.66mol) was added and the reaction mixture was heated to 60oC for 24 – 48 h. Completion of the reaction was indicated by the cessation of ammonia production. The warm solution was filtered under argon, using a heated Schlenk filter apparatus embedded with basic alumina (approx. 2 cm depth) to remove sodium methoxide. It was vital that the solution was kept warm (~50oC) during filtration to avoid premature crystallisation of the product. The filtrate was reduced to one tenth its original volume under reduced pressure (oil pump with additional collecting chambers), dry Et2O (~500mL) was added and the solution was cooled to -10oC for 24 h.
The yellow solid formed was collected on a Schlenk filter apparatus, under argon, and washed thoroughly with dry Et2O (750 – 1000mL) until the filtrate became neutral. The product was recrystallised from benzene yielding 1a as a pale yellow solid (143.7g, 0.48mol, 72%).
MF : C20H15OP MW : 302.31
MP = 173.5 – 174.9oC (Lit. mp.: 173oC [120c])
13C-NMR (125MHz, CDCl3); δ(ppm) = 10.5 (d, 1JPC = 189.1Hz, Cq; C-2), 128.2 (d,
3JPC = 11.68Hz, m-CH; C-arom), 129.0 (d, 1JPC = 95.13Hz, Cq; C-ipso), 133.0 (p-CH;
C-arom), 134.7 (d, 2JPC = 11.27Hz, o-CH; C-arom), 144.6 (d, 2JPC = 44.3Hz, Cq; C-1).
IR (KBr); ν(cm-1) = 2099(s), 1625(m), 1435(m), 1108(m).
31P-NMR (121.5MHz, CDCl3); δ(ppm) = 5.95