(Hive Bee)
02-08-03 17:44
No 405635
      Cheap aromatic iodination & bromination
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Aromatic Iodination of Activated Arenes and Heterocycles with Lead Tetraacetate as the Oxidant, Synthesis, 1995, pp 926

Abstract: An easy, quick, and fairly cheap laboratory method is presented for aromatic iodination of some highly activated arenes and heterocycles with molecular iodine in the presence of either pure lead tetraacetate dissolved in glacial acetic acid, or with the same oxidant but prepared in situ from Pb3O4 dissolved in hot AcOH/Ac2O prior to the iodination. 4-bromo- and 2,4-dibromoanisoles are obtained from anisole by the respective oxidative bromination.


Applicable for the steam-volatile iodo and bromo derivatives; higher boiling compounds may be distilled off with superheated steam to shorten the distillation times.

(a) Iodination in glacial AcOH in the presence of pure Pb(OAc)4; 4-iodoanisole from anisole:

Finely powdered iodine (5.1g, 20 mmol) was suspended in glacial AcOH (100mL) mixed with anisole (4.3g, 40 mmol). Pb(OAc)4 (9.25g, 22 mmol; 10% excess) was added with stirring, and the whole was stirred at room temperature for ~1 h, until the iodine colouration faded. Steam distillation gave the crystalline colourless product, recrystallized from hexane.

Yield: 85%.

The same procedure was applied to iodinate mesitylene, and 1,2-dimethoxy and 1,3-dimethoxybenzenes.

(b) Iodination in hot AcOH/Ac2O in the presence of pure Pb(OAc)4 prepared in situ from minium; 4-iodoanisole from anisole:

Finely powdered Pb3O4 (15g, 22 mmol; 120% excess with respect to iodine consumed) was suspended, with stirring, in glacial AcOH (25mL) and Ac2O (10mL, 106 mmol). The temperature was raised to 55-60° C (it must not exceed 65° C) and stirring was continued until complete (or nearly so) dissolution of Pb3O4 (15-30 min). The nearly colourless (sometimes greyish) solution was cooled to room temperature, then finely powdered iodine (2.5g, 9.8 mmol) was added followed by anisole (2.1g, 19.6 mmol). The whole was stirred at 45° C for 15-30 min until the iodine colouration faded, leaving the solution yellowish or greyish. It was cooled to room temperature and saturated aq. Na2S2 3 (10-15mL) was slowly added dropwise with vigorous stirring (the reaction is exothermic, thus the temperature may rise to 45° C) until a white (or slightly coloured) slurry resembling cream was obtained. Steam distillation gave a fairly pure product, which was collected, washed with cold water, dried, and recrystallized from hexane.

Yield: 93%

The same procedure was applied, with slight modifications, to iodinate phenetole, 1,2- and 1,3-dimethoxybenzenes, mesitylene, and thiophene. The last compound gave a liquid product, hence the cooled steam distillate was extracted three times with CHCl3, the extract was dried over MgSO4, the solvent was distilled off, and the oily residue was fractionated under reduced pressure, bp 85-87° C/36mmHg, to yield the pure product. In the case of iodomesitylene, the oily crude product was fractionated under vacuum, bp 148-150° C/50mmHg, to yield the pure solid product.

(c) Bromination in glacial AcOH in the presence of pure Pb(OAc)4; 4-bromoanisole and 2,4-dibromoanisole from anisole:

Pb(OAc)4 (9.75g, 22 mmol; 10% excess) was suspended in glacial AcOH(100mL) mixed with anisole (4.3g, 40 mmol). Then, at r.t., bromine (3.2g, 20 mmol) was added dropwise with stirring; the temperature rose to 40° C, and after ~10 min the bromine colouration faded. The contents of the flask were steam distilled and the cooled distillate was extracted with ether. The solvent was distilled off from the dried (MgSO4) extract, and the fraction boiling at 214-215° C was collected.

Yield: 82%

P.S.: Rhodium, I can upload the above article if you want it for your page.

I'm dreaming of the white crystals.
(Hive Bee)
02-08-03 19:00
No 405652
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That's weird... I have always been under the impression that lead tetraacetate (LTA) would cause oxidation of the Ph nucleus. I remember of heaving read (in the Houben-Weyl I think) that LTA would oxidize methylenedioxybenzene to a quinone. At that time, I was wondering if methylenedioxybenzene + LTA could have been a useful precursor for 1,2-methylenedioxy-4,5-dimethoxybenzene, or for 1,2,4,5-dimethylenedioxybenzene (or whatever you would call this...). Or am I drunk again? crazy

Abusus non tollit usum
02-08-03 20:49
No 405677

From Organic Proceedings and Preparations International 23(4) 419-424 (1991)smile
In the course of preparation of a key intermediate for the synthesis of certain anthracycline analogs, we were in need of 6-bromo-2,5-dimethoxybenzaldehyde (3). Rubenstein reported 3 as the exclusive product of the bromination of 2,5-dimethoxybenzaldehyde (1) with bromine in acetic acid.' This assumption was apparently based on the finding' that nitration of 1 gave the 6-nitro and 4-nitro isomers in 80% and 20% yields, respectively. Later, an isomer of 3, namely 4-bromo-2,5-dimethoxy­benzaldehyde (2), was obtained from 1 utilizing anhydrous stannous chloride and bromine in methy­lene chloride, 2 since it was believed that 2 was unknown in the literature. Notably, Bortnik et al.' showed that the structure of the product of the bromination of 2,5-dimethoxybenzaldehyde (1) obtained by Rubenstein was actually 2. These authors further established the identity of this substance by comparing it with the aldehyde 2 obtained in the formylation of the dimethyl ether of bromohydroquinone with hydrogen cyanide and aluminum chloride. Furthermore, the aldehyde 2 was oxidized to the corresponding known acid and the structures confirmed by H NMR spectral analysis. Although the original incorrect assignment of the structure reported by Rubenstein' has since been corrected by several investigators,2-5 the regioisomer 3 was never identified from the reac­tion of 1 with bromine in acetic acid. We have repeated the bromination of 1 as described by Rubenstein and now report our findings.
The action of bromine on 2,5-dimethoxybenzaldehyde (1) in glacial acetic acid at room temperature afforded a mixture of two crystalline products, differing slightly in polarity, as indicated by thin layer chromatographic analysis. The separation of this mixture was achieved by fractional recrystallization (95% ethanol) and column chromatography to obtain 2 and 3. The 'H NMR spec­trum of 3 displayed an AB pattern for two protons in the aromatic region (S = 7.00 ppm, dd, J = 9 Hz). The desired product 3, was obtained in only 5% yield in contrast to 2 which comprised the major portion (87%) of the reaction product. The structure 2 was assigned based on 'H NMR spectral analysis and comparison with literature data.2.3 Final proof of the position of the bromine atom in the regioisomers 2 and 3 came from the subsequent synthesis of 3,6-dimethoxybenzocyclobutene (9) via Parham cyclialkylation6 of 8 (Scheme 1). Thus, the treatment of 3 with triphenyl­methoxymethylphosphonium chloride in the presence of sodium ethoxide in ethanol' at 65° resulted in a mixture of products. Among the products isolated were traps-6-bromo-2,5-dimethoxy-(3­methoxystyrene (4)(64%)8, mp. 66-67°, and its cis isomer 5(4%),8 mp. 92-95°, and 2-bromo-3,6­dirnethoxyphenylacetaldehyde (6) along with a trace of unreacted 3. The structural assignment for traps and cis compounds was made on the bases of coupling constant values exhibited by the olefinic protons (J trans = 13 Hz vs J cis = 6 Hz ). Hydrolysis of the E-Z mixture (4,5) with 70% perchloric acid in tetrahydrofuran9"10 at room temperature furnished 6 in 98% yield. Reduction of the aldehyde 6 with sodium borohydride in 95% ethanol at 50° afforded the alcohol 7(86%). Conversion of the bromo alcohol 7 to the corresponding bromide 8(62%) was effected utilizing tri-n-octylphosphine and carbon tetrabromide1' or triphenylphosphine dibromide.12 Finally, lithium halogen exchange of 8 with n-butyllithium in dry tetrahydrofuran (-105° to -95), followed by intramolecular cyclization upon warming, provided the benzocyclobutene 9 (Scheme 1).13 A similar synthetic sequence starting from the bromo isomer 2 resulted only in the isolation of the dehalogenated end products, as would be expected, upon attempted cyclization of 10, mp. 75-76°(EtOH).14 Only the regioisomer 8 with bromine atom ortho to the bromoalkyl side chain would readily undergo intramolecular cyclization, following the reaction conditions used, to form the cyclic product 9.
Thus, it is further confirmed that the structure of the minor product of the bromination of 1, following the method reported by Rubenstein', is 3, while the major product2-5 is indeed 2. To our knowledge, the minor isomer 3, isolated from the reaction mixture, is reported here for the first time.

02-08-03 20:50
No 405680

'H NMR spectral data were obtained in deuteriochloroform (CDC13) on an EM-360 (Varian Associates) and QE-300 (General Electric) NMR spectrometers at 60 and 300 MHz respectively. Chemical shifts (S) are expressed in ppm downfield from internal TMS. Combustion analysis were performed by Midwest Microlab Ltd., Indianapolis, Indiana. Column chromatography was performed with E. Merck silica gel 60 (particle size 0.063-0.200 mm, 70-230 mesh ASTM).
Bromination of 2,5-Dimethoxybenzaldehyde.- A cold solution of 20.0 g (0.12 mol) of 2,5­dimethoxybenzaldehyde in glacial acetic acid (115 mL) was treated with 20.0 g of bromine in glacial acetic acid ( 60 mL). The solution was stirred at room temperature for two to three days and diluted with ice water. The yellow precipitate was collected by filtration and dried (28 g, 95%), mp. 118-126°(lit.' mp. 125-126°). Recrystallization from ethanol gave 15.20 g of 2, mp.132-133° (lit.2-3 mp. 132-133°). Ethanol was removed from the mother liquor in vacuo and the residue was subjected to column chromatography (silica gel, benzene). The solid (10.4 g) collected in initial fractions was 4-bromo-2,5-dimethoxybenz aldehyde (2), total yield 25.6 g (87%), mp. 132-133°; IR (KBr): 3025, 2860, 1710 and 1610 cm -' ; 'H NMR : 6 3.85 (s, 6H, -OCH3), 7.20-7.30 (2s, 2H, Ar-H), and 10.33 (s, 1H; CHO). Subsequent fractions gave 1.5 g (5%) of 6-bromo-2,5-dimethoxybenzaldehyde(3), mp. 102 -103°(EtOH); IR (KBr): 3030, 2880, 1705, 1610 and 1575 cm-1; 'H NMR: S 3.83 (s, 6H, - OCH3), 7.00 (dd, J = 9 Hz, 2H, Ar-H), and 11.02 (s,1H; CHO).
Anal. Calcd. for C9H9BrO3: C, 44.11; H, 3,70; Br, 32.60
Found: C, 44.03; H, 3.66; Br, 32.70
6-Bromo-2.5-dimethoxv-B-methoxvstvrenes (4,5).- To a solution of sodium ethoxide (prepared
from 0.15 g, 6.61 mmol of sodium in 10 mL of absolute ethanol) was added 1.78 g (5.19 mmol) of triphenylmethoxymethylphosphonium chloride. The mixture was stirred at room temperature for fifteen minutes. To this mixture was added 1.27 g (5.18 mmol) of 6-bromo-2,5-dimethoxybenzalde­hyde (3) in portions. The reaction mixture was stirred at room temperature for ten minutes followed by 24 hrs at 65° in an argon atmosphere. After cooling, the reaction mixture was poured over ice water and repeatedly extracted with ether. The ether extract was washed with water and dried (Na2SO4). Removal of the solvent gave a yellow viscous oil which was chromatographed (silica, benzene). Initial fractions contained some triphenylphosphine. Subsequent fractions gave tra sn -6­bromo-2,5-dimethoxy-(3-methoxystyrene (4), (0.92g; 64%), mp. 66-67°; IR(CHC13): 3000, 2820, 1630, 1570,1470,1430, and 910 cm-';'H NMR: S 3.77 (s, 3H, olefinic OCH3), 3.84 and 3.87 (2s, 6H, Ar-OCH3), 6.07 (d, J=13 Hz, 1H, olefinic, geminal to -OCH3), 6.77 (dd, J=9 Hz, 2H, Ar-H), 7.53 (d, J=13 Hz, 1H, olefinic, geminal to -Ar); .i,g,-6-bromo-2,5-dimethoxy-G3-methoxystyrene (5), (0.060 g, 4%), mp. 92-95'; IR (KBr): 3010, 2840, 1675, 1605, 1580, 1475, 1440, 795, 770, and 715 cm-'; 'H NMR: 8 3.70 (s, 3H, olefmic OCH), 3.82 and 3.86 (2s, 6H, Ar- OCH), 5.26 (d, J = 6 Hz, 1H, olefinic, geminal to -OCH), 6.24 (d, J = 6 Hz,1H, olefinic, geminal to -Ar), and 6.82 (s, 2H, Ar-H); (3-(6-bromo-2,5-dimethoxyphenyl)acetaldehyde (6), (0.12 g, 9%) (analytical data similar to the structure described below). In addition, a trace amount of unreacted aldehyde 3(10 mg) , triph­enylphosphine and triphenylphosphineoxide were isolated. Due to apparent instability during recrystallization, the stereoisomers 4 and 5 were hydrolyzed to 6 which was characterized as its 2,4­dinitrophenylhydrazone.
046-Bromo-2,5-dimethoxyphenyl)acetaldehyde (6).- The E-Z mixture (4,5) (0. 7 g, 2.56 mmol) in tetrahydrofuran (40 mL) was treated with 6 mL of 70% perchloric acid. After stirring at room temperature for twenty minutes, the solution was poured over crushed ice and extracted with ether. The ether layer was washed with water and dried (MgSO4). Removal of the solvent gave a pale yellow solid (0.65 g, 98%), mp. 67-69°; IR(KBr): 3010, 2860,1730,1600,1580,1480, and 1390 cm '; 'H NMR: 5 3.76 and 3.83 (2s, 6H, -OCH3)3.97 (d, J = 2 Hz, 2H, -CH2-), 6.83 (s, 2H, Ar-H), and 9.70 (t, J = 2 Hz, 1H, -CHO). It was analyzed as its 2,4-dinitrophenylhydrazone, mp.195-196° (EtOH-EtOAc).
Anal. Calcd. for C16H,5BrN406: C, 43.75; H, 3.44; N, 12.76; Br, 18.19
Found: C, 43.81; H, 3.34; N, 12.72; Br, 18.29 j3-(6-Bromo-2.5-dimethoxyphenvl)ethanol (7).- A solution of 6 (600 mg, 2.32 mmol) in 40 mL of 95% ethanol at 50°was treated with sodium borohydride (40 mg). The reaction mixture was stirred at room temperature for forty-five minutes. The solvent was removed in vacuo and the residue was treated with hydrochloric acid (10%) and extracted with ether. The ether layer was washed succes­sively with water, sodium bisulfite(10%), sodium carbonate(10%), and dried (MgSO4). Removal of the solvent gave a white solid (0.52 g, 86%), mp. 112-113° (benzene-hexane); IR(KBr): 3380-3280 (br), 3020, 2840,1590,1490 and 1435cm-' ;'H NMR: S 1.67 (bs,1H, -OH), 3.19 (t, J = 6.60 Hz, 2H,
-CH2-), 3.80 and 3.85 (2s, 6H, -OCH3), also present among methoxy peaks are 2H's for benzylic hydrogens, 6.76 (d, J = 9 Hz, 1H, Ar-H), and 6.80 (d, J = 9 Hz, 1H, Ar-H). j_l. Calcd. for C10H13Br03: C, 46.00; H, 5.02; Br, 30.60
Found: C, 46.05, H, 5.04; Br, 30.64
L6-Bromo-2.5-dimethoxyphenydiethyl bromide (8).- A solution of bromoalcohol 7 (86 mg, 0.33 mmol) in dry carbon tetrachloride (3 mL) was added dropwise to a suspension of triphenylphosphine dibromide (prepared from 250 mg of triphenylphosphine and 160 mg of bromine in 10 mL of carbon tetrachloride). The mixture was stirred for one hour at room temperature and then refluxed for seven hours in an inert atmosphere. After cooling, the reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was chromatographed(silica, 50% heptane in chloroform) to obtain the dibromide 8 (66 mg, 62%), mp. 68-69° (hexane); IR(KBr): 3020, 2850, 1610, 1590, 1490, 1445,800, and 720 cm-1; 'H NMR: S 3.38-3.50 (m, 4H; CH2-CH2-), 3.80 and 3.85 (2s, 6H, -OCH), and 6.79 ( s, 2H, Ar-H).
Anal. Calcd. for C10H12Br202: C, 37.07; H, 3.73
Found: C, 36.98; H, 3.78
3.6-Dimethoxyhenzocyclobutene (9).- In a 10 mL three-neck flask compound 8 (0.194 g , 0.60 mmol) was dissolved in tezrahydrofuran (5mL, dry, freshly distilled) and hexane (1 mL, dry) in an argon atmosphere. The solution was cooled (- 95° to -105). To this solution was added n_-butyl­lithium (0.45 mL,1.55M in hexane) at such a rate that the internal temperature did not exceed -95' After stirring for one-half hour (-100° to -105), the reaction mixture was warmed to room tempera­ture and poured into ice water and extracted with ether. The ether layer was washed with water and dried (MgSO4). The residue, obtained after evaporation of the solvent, was subjected to preparative layer chromatography (silica gel, 50% heptane in chloroform). The band at Rf 0.4 gave 9 (0.064 g, 65%); mp. 59-60° (EtOH-H20); IR(KBr): 3000, 2840, 1600, 1490, 1430, 1250, 1000, 930, 800, 780, and 725 cm -';'H NMR: S 3.28 (s, 4H, -CH2-CH2-), 3.83 (s, 611, -OCH), and 6.61 (s, 2H, Ar-H).
Anal. Calcd. for C1OH1202: C, 73.15; H, 7.37
Found: C, 72.84; H, 7.49
1. L. Rubenstein, J. Chem. Soc., 127, 1998 (1927).
2. C. F. Barfknecht and D. E. Nichols, J. Med. Chem., 14,370 (1971).
3. S. P Bortnik, M. A. Landau, B. V Siryachenko, S. S. Dubov and N. N. Yarovenko, Zhur Org. Khim., 8, 340 (1972).
4. A. Luttringhaus and H. Gralheer, Ann., 550, 67 (1942). 5. F. B. H. Ahmad and J. M. Bruce, Pertanika, 7,1 (1984).
6. W. E.Parham, L. D.Jones and Y A. Sayed, J. Org. Chem., 41,1184 (1976). 7. G. Wittig and M. Schlosser, Chem. Ber., 94,1373 (1961).
8. Purified sample obtained from column chromatography (silica gel, benzene). 9. G. Wittig, W. Boell and K. Krueck, Chem. Ber., 95,2514 (1962).
10. S. G. Levine, J. Am. Chem. Soc., 80, 6150 (1958).
11. J. Hooz and S. S. Gilani, Can. J. Chem., 46, 86 (1968).
12. L. Homer, P V Subramaniam and K. Eiben, Ann., 714, 91(1968).
13. J. Laduranty, L. Lepage and Y Lepage, Can. J. Chem., 58,1161 (1980).
(Chief Bee)
02-08-03 22:05
No 405688
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Thank you lugh, I have cleaned it up somewhat and placed it at ../rhodium/chemistry /bromodimethoxybenzaldehyde.html but I think I might need some assistance to spot smaller omissions, like some of the reference superscripts which didn't make it through the OCR (marked with a * in the document).