Supporting information
Oxidative cleavage of α-arylaldehydes using
iodosylbenzene
Nizam Havare and Dietmar A. Plattner
S1
General: All used substrate were prepared following published procedures [a m]. Starting materials: (diacetoxyiodo)benzene, Dess Martin reagent, 2 (4 nitrophenyl)ethanol, 2 (4 chlorophenyl)ethanol, phenylacetaldehyde, 2 (2 naphthyl)ethanol, 2 (4 methoxy)ethanol, 2 methoxy 2 phenylethanol, 2 phenylpropanal, 2 phenyl 1 butanol, cyclohexyl phenylacetonitrile, α tetralone, 2 acetylnaphthalene, anethol, 4 nitroacetophenone and solvents were obtained commercially from ABCR , Sigma Aldrich , Fluka , Alfa Aesar and Acros. Dichloromethane was dried over potassium carbonate, freshly distilled and stored under Ar prior to use. Cyclohexane was dried over sodium, freshly distilled and stored under Ar prior to use. Ethyl acetate was dried over phosphor pentaoxide, freshly distilled and stored under Ar prior to use. Column chromatography: Silica gel 60 : 0.06 0.2 mm, Carl Roth GmbH. 1 TLC: Silica gel 60 F 254 25 Aluminium sheets 20x20 cm from Merck KGaA co. Darmstadt. H spectra: Varian 300 and Bruker 500 spectrometer. GC MS: (GC Varian 3400 , achiral GC column Macherey Nagel optima 5 MS 30 m x0.25 mmØ, 0.25 µm film). MS: Thermo TSQ 700.
Preparation of CO detection reagent (PdCl 2/HCl): 100 ml of water is added to 130 mg of palladium(II)chloride (0.733 mmol, 99.7%) in a 250 ml volumetric flask. 1 ml of HCl solution is added, which was prepared from mixture of conc. HCl/water (V/V = 1:10). The suspension is stirred for one day at room temperature, until giving a clear solution. Then the flask is filled to the mark with water. The solution can be stored for up to eight months.
Preparation of CO 2 detection reagent (Ba(OH) 2): In a 500 ml two necked flask 200 ml of water is saturated with barium hydroxide, filtered, and stored under argon. (The saturated solution reacts rapidly with air carbon dioxide).
Synthesis of iodosylbenzene: To 32 g of (diacetoxyiodo)benzene (0.1 mol, 1 eq.) in a 1 l Erlenmeyer flask is added 532 ml of sodium hydroxide solution (1.88 M) dropwise at room temperature. The light yellow suspension is stirred for three hours at room temperature. The precipitate is filtered under high vacuum and washed with water until the washing water is neutral. The slightly yellow solid was dried in the air and then mortared into fine powder. The result of iodometric titration of one sample gave 99.5% (W/W) of iodosylbenzene. Yield: 86 90% S2
Entry 1
O PhIO/HBF4 (Et2O) no reaction CH2Cl2, r.t. Method A1
Entry 2
O O O PhIO / HBF4 (48 % in water) Ph Ph OH CH2Cl2, 1.5 h, r.t. Method B1 In a two necked flask equipped with two bubble counters, which are connected and filled with the CO 2 detection reagent (barium hydroxide) and with the CO detection reagent (PdCl 2/HCl in water), respectively, 608 mg of phenylglyoxal (4 mmol, 1 eq.) is dissolved in 20 ml
CH 2Cl 2. 1.32 g of iodosylbenzene (6 mmol, 1.5 eq) is added to the solution. Under stirring, 630 L of tetrafluoroboric acid (4.82 mmol, 1.2 eq., 48% in water) is added within a few minutes dropwise to the suspension. The reaction mixture is stirred for 1.5 hours at room temperature (TLC control after 1.5 hours). After 1.5 hours, BaCO 3 and Pd metal precipitated in bubble counter. The reaction mixture is concentrated under reduced pressure. The product is isolated by column chromatography (eluent: cyclohexane / ethyl acetate = 20:1 → 10:1).
Yield: 73 %
O
Ph OH 1 H NMR (300 MHz, CDCl 3): δ = 8.13 (d, J = 8.0 Hz, 2H, Ar H), 7.62 (t, J = 7.4 Hz, 1H, Ar H), 7.52 7.45 (t, J = 7.4 Hz, 2H, Ar H).
S3
GC/MS EI m/z(%): 123.1(6), 122.0(100), 106.1(6), 105.0(88), 77.1(38).
Entry 3
OMe O O O PhIO/HBF4 Et2O Ph + 1,4-dioxane Ph H Ph OMe Method A2 In a 100 ml flask, 150 mg of 2 methoxy 2 phenylacetaldehyde (1 mmol, 1 eq.) and 50 mg of 1,4 dichlorobenzene (0.347 mmol) (internal standard) are dissolved in 10 ml of 1,4 dioxane (abs.) under argon atmosphere. 330 mg of iodosylbenzene (1.5 mmol, 1.5 equiv.) is added. The suspension is stirred for 5 minutes at room temperature. Then, 220 l of tetrafluoroboric acid etherat complex (395 mg, 2.2 mmol, 2.2 eq., 50 55% in ether), diluted with CH 2Cl 2 (abs.) to the total volume of 10 ml with 1,4 dioxane, is injected within 10 minutes to the suspension. After 10, 20, 40 and 60 minutes, and finally after 15 hours are taken each 700 l sample of the reaction environment. (The preparation of GC sample: the sample is first diluted to 2 ml with S4 diethyether, and then washed with saturated sodium thiosulfate. The aqueous solution is removed. The sample is washed then with saturated sodium bicarbonate. The aqueous phase is removed. The organic phase is dried with little sodium sulfate and filtered. After 15 hours, the reaction is processed with the same work up of the samples. The solvent is removed. The product is isolated by column chromatography (eluent: cyclohexane / ethyl acetate = 10:1).
Yield: 65% (GC yield), 3% (GC yield) methyl benzoate (oxidative cleavage product). O
Ph H Benzaldehyde: 1 H NMR (300 MHz, CDCl 3): δ = 10.02 (s, 1H, C HO), 7.85 (d, 2H, Ar H), 7.61 (t, 1H, Ar H), 7.51 (t, 2H, Ar H).
S5
O
Ph OMe Methylbenzoate 1 H NMR (300 MHz, CDCl 3):
δ = 8.028 (d, 2H, Ar H), 7.56 7.26 (m, 3H, Ar H), 3.89 (s, COOC H3).
Synthesis of 2-methoxy-2-phenylacetaldehyde
OMe OMe OH Oxalyl chloride / DMSO / Et3N Ph O Ph CH2Cl2, -78°C, 25 min.
1.26 ml (14.5 mmol, 1.1 eq.) oxalyl chloride is disolved in 60 ml of dichloromethane. The solution is cooled to 78 °C. 2.05 ml of DMSO (28.9 mmol, 2.2 eq.), dissolved in 10 ml of dichloromethane is added dropwise. The solution is stirred 20 min. at 78 ° C. 2 g of 2 methoxy 2 phenylethanol (13.1 mmol, 1 eq.) were added dropwise in 7 ml of dichloromethane. The solution is stirred for a further five minutes at 78 °C. Then 9.16 ml of S6 triethylamine is added at the same temperature. The mixture fades a yellow suspension. The reaction mixture is allowed to warm to 0°C and hydrolyzed with 20 ml of water. The aqueous phase is extracted three times with dichloromethane. The combined organic phase is washed once with saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The residue is diluted with ether and washed three times with 20 ml of 1% cold HCl solution and once with brine. The organic phase is dried over magnesium sulphate and the solvent is removed. The product is isolated by column chromatography (eluent: cyclohexane / ethyl acetate = 20:1).
Yield: 43% (842 mg)
OMe O Ph 1 H NMR (300 MHz, CDCl 3): δ = 9.60 (d, J = 1.5 Hz, 1H, CHO), 7.46 7.32 (m, 5H, Ar H), 4.64 (d, J = 1.5 Hz, 1H,
PhC H(OCH 3)CHO), 3.45 (s, 3H, PhCH(OC H3)CHO).
S7
Entry 4
O2N O O PhIO / HBF4 H Ph N NO2 Ph Ph N
1.2 g of phenylacetaldehyde (10 mmol, 1 eq.) is dissolved in 30 ml of dioxane water (15:15). 3.3 g of iodosylbenzene (15 mmol, 1.5 eq.) is added. Under stirring, 1:58 ml of tetrafluoroboric acid (12 mmol, d = 1.4 g/ml, 48% in water) is added dropwise to the suspension. The reaction mixture is stirred for six days at room temperature. After six days, the freshly prepared 2,4 dinitrophenylhydrazine solution is added to give the corresponding hydrazone compound. The precipitate is filtered and washed several times with water. The hydrazone is then dried. Preparation of 2,4 dinitrophenylhydrazine solution: To 3.1 g of 2,4 dinitrophenylhydrazine (11 mmol, 1.1 eq, 70%) are added 11.74 ml of sulfuric acid and 17.6 ml of water. 60 ml tech.
S8
Ethanol is then added to hot solution. The solution is stirred for 10 minutes at room temperature.
Yield: 98 % (2.82 g)
O2N H Ph N NO2 N
1 Benzylidene 2 (2,4 dinitrophenyl)hydrazine 1 H NMR (300 MHz, DMSO d6): δ = 11.7 (bs,1H, CHNN H ), 8.88 (d, J = 2.7 Hz, 1H, Ar H), 8.73 (s, 1H, CHNNH ), 8.43 8.36 (dd, J = 2.70 Hz, J = 9.70 Hz, 1H, Ar H), 8.15 8.10 (d, J = 9.70, 1H, Ar H), 7.85 7.75 (dd, J = 4.2 Hz, J = 2.06 Hz, 2H, Ar H), 7.54 7.46 (m, 3H; Ar H).
S9
Entry 5
O PhIO / HBF4 (48% in H2O) O
1,4-dioxane / water: 1 / 1 Method B2 170 mg of 2 (naphthalene 6 yl)acetaldehyde (1 mmol, 1 eq.) is dissolved in mixture of 20 ml 1,4 dioxane water (1:1). And then, 330 mg of iodosylbenzene (1.5 mmol, 1.5 equiv.) is added to the solution. 220 l of HBF 4 (1.7 mmol, 1.7 eq. 48% in water) is added dropwise to the suspension. The suspension is stirred for 6 days at room temperature. The reaction mixture will be clearer with time. After 6 days, the reaction mixture is washed with saturated sodium thiosulfate, and extracted twice with 30 ml diethyl ether. The organic layer dried over sodium sulfate and filtered. The solvent is removed. The product is isolated by column chromatography (eluent: cyclohexane / ethyl acetate = 10:1).
Yield: 51%
O
1 H NMR (300 MHz, CDCl 3): 10.17 (s, 1H, CHO), 8.35 (s, 1H, Ar H), 8.04 7.89 (m, 4H, Ar H), 7.72 7.56 (m, 2H, Ar H).
S10
Synthesis of 2-(naphthalene-6-yl)acetaldehyde
OAc AcO OAc I O
OH O O
CH2Cl2
2.58 g of Dess Martin reagent (6.1 mmol, 1.18 eq.) is dissolved in 50 ml of dichloromethane under nitrogen atmosphere. 888 mg of 2 (naphthalene 6 yl)ethanol (5.15 mmol, 1 eq.) is added in 40 ml of dichloromethane to the solution. The yellowish reaction mixture is stirred at room temperature for 1.5 hours. A precipitate is observed. After 1.5 hours, the reaction mixture hydrolyzed with saturated sodium bicarbonate solution. The organic phase is separated, and then is extracted with sodium thiosulfate solution (6 g in 100 ml water). The
S11 organic phase is dried over sodium sulfate and filtered. The solvent is removed. The product is isolated by column chromatography (eluent: cyclohexane / ethyl acetate = 1:1). The product is a yellow solid.
Yield: 72% (630 mg)
O
1 H NMR (300 MHz, CDCl 3): δ = 9.83 (t, 1H, C HO)), 7.84 (m, 3H, Ar H), 7.69 (s, 1H, Ar H), 7.49 (m, 2H, Ar H), 7.32 (dd,
1H, Ar H), 3.85 (d, 2H, CH2CHO).
S12
Entry 6
Me O O PhIO / BF3 OEt2 Me 1,4-dioxane, r.t., 26 h O2N O2N
In a 50 ml flask, 50 mg of 2 (4 nitrophenyl)propanal (0.280 mmol, 1 eq.) and 50 L of n heptane (internal standard) (0.360 mmol, d = 0.865 g/ml) are dissolved in 5 ml of 1,4 dioxane (abs.) under argon atmosphere. 61 mg of iodosylbenzene (0.280 mmol, 1 eq.) is added to the solution. The suspension is stirred for 5 minutes at room temperature. Then, 110 l of
BF 3 OEt 2 complex (0.42 mmol, 1.5 eq. 48% in ether), diluted to the total volume of 5 ml with 1,4 dioxane, is added dropwise within 10 minutes to the suspension. After 10, 20, 40 and 60 minutes, and finally 26 hours, sample is taken each 300 l from the reaction mixture. The samples work up: the sample is first diluted to 2 ml with ethyl acetate, and then washed with saturated sodium thiosulfate solution. The aqueous solution is removed. The sample is washed this time with saturated sodium bicarbonate solution. The aqueous phase is removed. The organic phase is dried over little sodium sulfate and filtered. After 26 hours, the reaction is processed with the same treatment of the samples. The solvent is removed. The product is isolated by column chromatography (eluent: cyclohexane / ethyl acetate = 10:1).
Yield: 63% (GC Yield).
O
Me
O2N 1 H NMR (300 MHz, CDCl 3): δ = 8.29 (dt, J = 8.97, J = 1.94, 2H, Ar H), 8.09 (dt, J = 8.97, J = 2.16, 2H, Ar H), 2.66 (s, 3H).
S13
Synthesis of rac -ethyl 3-methyl-3-(4-nitrophenyl)oxirane-2-carboxylate
O Me O O Me 1) Na, Benzol-Xylol, t-Butanol OEt O2N 2) Ethyl chloroactetate O2N
5.52 g of sodium (0.24 mol) in 72 ml benzene (abs.), 7.2 ml of xylene (abs.) and 2.4 ml t butanol are suspended under argon. Under stirring and ice cooling, a mixture of 20 g (0.12 mmol) 4 nitro acetophenone and 22 g of ethyl chloroacetate are added to the suspension. The reaction mixture is stirred 24 hours at r. t., and then poured into ice water. The aqueous phase is separated and extracted several times with toluene. The combined organic phases are washed several times with water and NaHCO 3 solution, separated, dried over sodium sulfate and filtered. The solvent is removed. The residue is distilled (bp. (0.23 mbar) = 120 °C).
S14
Yield: 61% (18.24 g, after distillation) Me O O OEt
O2N 1 H NMR (400 MHz, CDCl 3): δ = 8.21 (tt, J = 8.99, J = 2.01, 2H, Ar H), 7.60 (tt, J = 8.99, J = 2.01, 2H, Ar H), 3.93 (qd, J =
7.16, J = 1.95, 2H, COOC H2CH 3), 3.72 (s, 1H, C (O) CHCOOCH 2CH 3), 1.78 (s, 3H,
CH3C(Ar) (O) CH ), 0.97 (t, J = 7.04, 3H, COOCH 2CH3).
S15
Synthesis of rac -sodium 3-methyl-3-(4-nitrophenyl)oxirane-2-carboxylate
Me O Me O O O OEt NaOEt, Wasser O O N 2 O2N Na
To 1.84 g of sodium (0.08 mol) is added enough ethanol (abs.) in a 100 ml two necked flask under reflux condenser and argon atmosphere, until formation of clear solution. In an ice bath, 18.2 g (0.725 mol) glycid ester is added dropwise. The reaction mixture is stirred 10 min. at r.t. 1.8 ml of water (0.1 mol) added dropwise to solution. This is stirred 10 min. The flask is allowed one day to the crystallization of the product in a refrigerator at 4 °C. The product is filtered after 24 hours, and dried over phosphorus pentoxide.
Yield: 82% (13.65 g)
Me O O O
O2N Na 1 H NMR (400 MHz, DMSO d6): δ = 8.12 (dt, J = 8.90, J = 1.91, 2H, Ar H), 7.22 (dt, J = 8.90, J = 1.91, 2H, Ar H), 3.38 (s,
1H, CH 3(Ar )C (O) CHCOO), 1.66 (s, 3H, CH3(Ar )C (O) CHCOO).
S16
Synthesis of 2-(4-nitrophenyl)propanal
Me Me O O O HCl, H2O O Na ∆, -CO2 O N O2N 2
13.65 g of rac sodium 3 methyl 3 (4 nitrophenyl)oxirane 2 carboxylate (0.557 mol, 1 eq.) is dissolved in 250 ml water under heating, until formation of a clear solution. The solution is heated to 70 °C under reflux condenser, equipped with a bubbler. 3.37 ml of conc. HCl (0.067, 1.2 eq.) is added dropwise to the solution. The reaction is complete, when no more are bubbles formed at the bubble counter (4 5 hours). The solution is then extracted three times with diethyl ether. The organic phase is dried over sodium sulfate. The solvent is removed. The product is isolated by column chromatography (eluent: mixture of cyclohexane / ethyl acetate). The reaction should not be heated too long. The product decomposes during distillation or heating. S17
Yield: 8% (1 g isolated, the product decomposed during distillation or heating)
Me O
O2N 1 H NMR (400 MHz, CDCl 3): δ = 9.72 (d, J = 1.19, 1H, CHO), 8.24 (dt, J = 8.84, J = 1.78, 2H, Ar H), 7.39 (dt, J = 8.48, J
= 1.65, 2H, Ar H), 3.78 (q, J = 6.95, 1H, ArC H(CH 3)CHO), 1.52 (d, J = 7.17, 3H,
ArCH(C H3)CHO).
S18
Entry 7
Me Me O PhIO/HBF4 OEt2 O mol. sieve 4Å, r.t. MeO MeO
Method A2 In 50 ml flask, 164 mg of 2 (4 methoxyphenyl)propanal (1 mmol, 1 eq.) and 50 l of n heptane (0.360 mmol, d = 0.865 g/ml) (internal standard) are dissolved in 5 ml 1,4 dioxane (abs.) under argon atmosphere. 220 mg of iodosobenzene (1 mmol, 1 eq.) is added to the solution. Ca. 5 g of molecular sieve 4 Å is added to the suspension. 193 l of tetrafluoroboric acid etherat complex (1.1 mmol, 1.1 eq. 50 55% diethyl ether), diluted to the total volume of 5 ml in 1,4 dioxane, is added dropwise within 10 minutes to the suspension. The reaction is stirred for another 10 days at room temperature. A few of samples are taken during the reaction. The samples are analyzed by GC. Preparation of the samples: 700 l of the sample is first diluted to 2 ml in diethyether, and then washed with saturated sodium thiosulfate solution. The aqueous solution is removed. The organic phase is washed then with saturated sodium bicarbonate solution. The aqueous phase is removed. The organic phase is dried with little sodium sulfate and filtered. At the end of the reaction is worked up analogously to the procedure of the samples. The product is isolated by column chromatography (eluent = cyclohexane / ethyl acetate = 10:1).
Yield: 42% (GC yield) Conversion: 47%
Me
O
MeO 1 H NMR (400 MHz, CDCl 3): δ = 7.93 (dt, J = 8.88, J = 2.07, 2H, Ar H), 6.93 (dt, J = 8.93, J = 2.10, 2H, Ar H), 3.86 (s,
3H, ArOC H3), 2.55 (s, 3H, ArCOC H3).
S19
Synthesis of 2-(4-methoxyphenyl)propanal
Me Me O Ag2O, I2
MeO 1,4-dioxane / water = 5:1 MeO
2.96 g of trans anethol (20 mmol, 1 eq.) is dissolved in 120 ml mixture of 1,4 dioxane water (5:1). 7.23 g of silver oxide (31 mmol, 1.55 eq.) is added in one portion. To the vigorously stirred suspension, 7.87 g (31 mmol, 1.55 eq.) iodine is added in portionwise within 5 min. The first purple and then red colored solution is stirred for an hour at room temperature. The suspension is then filtered. The clear red solution is washed with saturated sodium thiosulfate, and the red color disappears. The mixture is then extracted three times with diethyl ether. The organic phase is dried over sodium sulfate, and filtered. The solvent is removed. The residue is distilled under high vacuum (bp. 0.36 mbar = 65 °C).
S20
Yield: 83% (2.73 g)
Me O
MeO 1 H NMR (400 MHz, CDCl 3): δ = 9.64 (d, J = 1.47, 1H, CHO), 7,13 (dt, J = 8.72, J = 2.07, 2H, Ar H), 6.91 (dt, J = 8.72, J
= 2.18, 2H, Ar H), 3.80 (s, 3H, OC H3), 3.58 (qd, J = 6.94, J = 1.37, 1H, CHCHO), 1.41 (d, J
= 7.15, 3H, C H3CH(Ar)CHO).
S21
Entry 8
O O PhIO/BF3 OEt2 Ph Me r.t. Ph Me CH2Cl2, molsieve 4Å, 0°C Method C1 In a two necked flask equipped with two bubble counters, which are connected and filled with the CO 2 detection reagent (barium hydroxide) and with the CO detection reagent (PdCl 2/HCl in water), respectively, 804 mg of 2 phenylpropanal (6 mmol, 1 equiv.) is dissolved in 30 ml of abs. CH 2Cl 2. 1.32 g (6 mmol, 1 eq.) iodosylbenzene and ca. 5 g of mol. sieve 4Å are added to the solution. Under stirring, 1.740 ml of BF 3·OEt 2 (48% solution in ether) (6.6 mmol, 1.1 eq), diluted to 30 ml with CH 2Cl 2 (abs.), is added dropwise using a syringe pump with a drop rate of 5 ml/h over four hours to the suspension under ice bath. Gas is formed and in bubble counter; and later a precipitate of Pd metal is observed. The reaction mixture is then stirred for 44 hours at room temperature. The reaction mixture is washed with saturated sodium thiosulfate, and extracted twice with ether. The organic phase is washed with saturated sodium bicarbonate solution, separated, dried over sodium sulfate, and filtered. The solvent is evaporated to 4 5 ml, and the product was isolated by column chromatography (eluent: cyclohexane / ethyl acetate = 10:1).
Yield: 40% Conversion: 82%
O
Ph Me 1 H NMR (300 MHz, CDCl 3): δ = 7.96 (d, 2H, Ar H), 7.56 (tt, J = 7.43, J = 1.29, 1H, Ar H), 7.46 (t, 2H, Ar H), 2.61 (s, 3H,