GC_MS
(Hive Addict)
03-31-03 13:53
No 422838
      1-(4-iodo-2,5-dimethoxyphenyl)-2-propanone
(Rated as: excellent)
    

T Sargent III, AT Shulgin, CA Mathis
Radiohalogen-labeled imaging agents. 3. Compounds for measurement of brain blood flow by emission tomography
J Med Chem 27 (1984) 1071-1077

2,5-diiodo-1,4-dimethoxybenzene (2a) - To a solution of 6.9 g p-dimethoxybenzene (50 mmol) in 50 mL acetic acid there was added over the course of 3 min a solution of 20 g of ICl in 20 mL of acetic acid. The mixture was heated on a steam bath for 2 h and then cooled with external ice-water, resulting in the formation of a heavy steel-gray crystalline mass. This was removed by filtration, washed sparingly with cold acetic acid, and suspended in 200 mL of water. With good stirring, there was added small portions of Na2S2O4 until the color of the suspended solids had changed from gray to white. This product was removed by filtration, washed with water, and when reasonably dry, recrystallized from 50 mL of boiling acetonitrile. There was thus obtained 7.1 g (36% yield) of a white product, mp 161-165C. An analytical sample that was recrystallized again from acetonitrile had mp 167-168C (lit mp 171C).

4-iodo-2,5-dimethoxybenzaldehyde (3a) - To a stirred suspension of 19.6 g (50 mmol) of 2a in 500 mL of anhydrous ether (cooled externally with ice-water) there was added 34 mL of 1.6 N BuLi in hexane (54 mmol). After 10 min of stirring there was added 8.2 mL of N-methylformanilide, converting the loose white precipitate to a thick suspension. This was stirred for 10 min, then held at reflux for about 10 min, and then added to 800 mL of water acidified with HCl. Yellow solids were removed by filtration and washed with ether and acetonitrile (see below). The resulting clear mother liquors were separated, and the organic fraction was stripped in vacuo to yield, after air-drying, 17 g of a pale-yellow solid. This product was triturated under 20 mL of MeOH, filtered free of solvent, air-dried (7.5 g), and finally recrystallized from 60 mL of boiling 95% EtOH to yield 5.2 g of pale-yellow crystals of 3a: mp 136-137C.
The yellow insolubles obtained above (4.8 g) were ground under CH3CN, filtered free of solvent, and recrystallized from 35 mL of boiling CH3CN to yield 0.6 g of the yellow bisaldehyde 3c, mp 196-200C (lit mp 207C).
Attempts to iodinate 2,5-dimethoxybenzaldehyde in the 4-position with ICl employing the procedure in ref 13 were unsuccessfull.

1-(4-iodo-2,5-dimethoxyphenyl)-2-nitropropene (4) - To a solution of 4.8 g of 3a (16.4 mmol) in 100 mL of nitroethane was added 0.3 g of ammonium acetate, and the mixture was heated on a steam bath for 6 h. The orange-red solution was decanted from a small amount of insolubles and stripped of nitroethane in vacuo, and the residue was treated with 20 mL of boiling MeOH. Crystals of 4 formed spontaneously, removed by filtration, and recrystallized from 65 mL of boiling MeOH to yield 2.3 g of product: gold crystals with mp 117-118C; yield 40%. An analytical sample obtained by recrystallization from methanol melted at 119-120C.

1-(4-iodo-2,5-dimethoxyphenyl)-2-propanone (5a) - A solution of 2.1 g of 4 (6.6 mmol) in 10 mL of hot acetic acid was added to a suspension of 4 g of electrolytic iron in 20 mL of acetic acid. Upon heating on a steam bath, the reaction mixture became very dark, and finally there was the deposition of white solids beneath a heavy black oil. Heating was continued for 0.5 h, the reaction mixture was poured into 500 mL of water, a small amount of unreacted iron and an insoluble brown residue was removed by filtration and washed with DCM, and the mother liquors were separated with the aqueous phase being extracted with an additional 2 x 75 mL DCM. The organic phases were pooled, the solvent was removed in vacuo, and the residue (3.9 g of a pale amber oil) was distilled at 0.4 mmHg to yield a fraction, bp 120-130C, of a colorless oil (1.1 g, yield 52%) that spontaneously crystallized. Recrystallization of an analytical sample from methylcyclopentane gave white crystals: mp 62-63C.

The article explains N,N-dimethylation with NaCNBH3, but I guess we aren't interested in that compound since inactive. You can do other things with the ketone, no need to dimethylate it wink.

Ref 13 - CF Barfknecht, DE Nichols. J Med Chem 14 (1971) 370-372 = Post 453897 (weedar: "J. Med. Chem. 14(4), 370-372 (1971)", Methods Discourse)

The faster you run, the quicker you die.
 
 
 
 
    Chimimanie
(Hive Bee)
11-07-03 15:44
No 469528
      halogenation of 2,5-DMB & benzonitrile + DOI ?
(Rated as: excellent)
    

Here follow text to make 4-(bromo or iodo)-2,5-dimethoxybenzaldehyde as well as their respective benzonitriles.

As 2,5-DMA is illegal, but DOI is still legal, it would be cool to have a route to DOI from dimethoxybenzaldehyde without passing trough poor 2,5-DMA.

Well, when we have the 4-iodo-2,5-DMB, to transform it into DOI, i see two main practicable routes:

-condensation with nitroethane and reduction (NaBH4 then CTH ala Barium or formic/Zn ala Bandil).
-Darzen reaction ala Post 333551 (Barium: "benzaldehydes to phenylacetones", Novel Discourse) to make the 4-iodo-2,5-DMP2P, then reduction with Al amalgams for instance.

Now what i would like to know is:

which is the best route to make the DOI without dehalogenating the iodine and forming illegal DMA?

or: which reductions are believed to rip of iodine out of the aromatic ring and which are believed to leave it untouched?

I thank all knowledgable bees replying to my question, here is the text:

Enjoy!smile

Selective preparation of 4-(bromo or iodo)-2,5-dimethoxybenzonitrile and 2-(bromo or iodo)-3,6-dimethoxybenzonitrile from 2,5-dimethoxybenzaldehyde. Bruce A. Hathaway, Brian E. Taylor, and Jeremy S. Wittenborn Synthetic Communications, 28(24), 4629-4637 (1998)

Abstract:

By use of appropriate reactions and sequence of steps, 2,5-dimethoxybenzaldehyde can be converted either to 4-(bromo or iodo)-2,5-dimethoxybenzonitrile or 2-(bromo or iodo)-3,6-dimethoxybenzonitrile.

In the course of other work, we needed to prepare either 4-bromo-2,5-dimethoxybenzonitrile or 4-iodo-2,5-dimethoxybenzonitrile. Neither of these compounds had been previously reported in the literature. Two possible pathways to these compounds were pursued, both of which began with 2,5-dimethoxybenzaldehyde, 1.

In the first pathway, I was brominated to form 4-bromo-2,5-dimethoxybenzaldehyde, 2, using either the procedure of Barfknecht and Nichols [1], or by treatment with bromine in acetic acid. Neither of these procedures worked in high yield. Treatment of 2 with hydroxylamine hydrochloride and sodium hydroxide in ethanol yielded the oxime, which was converted to the 4-bromo-2,5-dimethoxybenzonitrile, 3, with acetic anhydride [2].

Iodination of 1 using a similar procedure as for bromination was unsuccessful. Use of iodine monochloride had also been reported not to work [3]. Using stoichiometric amounts of iodine and silver nitrate in methanol (a) gave an 85% yield of 4-iodo-2,5-dimethoxybenzaldehyde, 4. This was converted to 4-iodo-2,5-dimethoxybenzonitrile, 5, in the same manner as the bromo compound.

Since bromination or 1 did not occur in good yield, 1 vas converted to 2,5-dimethoxybenzonitrile, 6, and bromination or 6 was investigated. Bromination in acetic acid did not occur in the 4-position to form 3, but rather in the 6-position to form (using correct numbering) 2-bromo-3,6-dimethoxybenzonitrile, 7, in low yield. Exhaustive extraction of the reaction mixture did not yield more product. The proton NMR spectrum of 7 showed a pair of doublets with a 9 Hz coupling in the aromatic region, in contrast to the spectrum of 3, which showed a pair of singlets. Bromination as in reference [1] yielded a mixture of 3 and 7, by proton NMR.

Iodination of 6 yielded only 2-iodo-3,6-dimethoxybenzonitrile, 8, in low yield, by either of two methods [4,5]. No 5 could be detected in the crude products by proton NMR.

In conclusion, 4-(bromo or iodo)-2,5-dimethoxybenzonitrile and 2-(bromo or iodo)-3,6-dimethoxybenzonitrile have been prepared by simple three-step procedures from 2,5-dimethoxybenzaldehyde. Although the overall yields are not
high in some cases, pure products are readily obtained by recrystallization of the crude reaction products.

Experimental Procedures:

4-Bromo-2,5-dimethoxybenzaldehyde, 2.

To a solution of 5.0 g of 2,5-dimethoxybenzaldehyde, 1, in 20 mL of acetic acid was added 1.8 mL of bromine dropwise. The solution was allowed to stir for 4 hours. TLC (silica gel, ethyl acetate:hexane (1:1)) indicated starting material was still present, so 1.0 mL of bromine was added, and the solution stirred overnight. The reaction mixture was poured into water, and treated with 5% sodium bisulfite solution to remove the excess bromine. The solid was filtered and washed with water. The solid was recrystallized from methanol to yield 3.45 g (46.9%) of 2, mp 122-4 , literature mp 132-3 [1].

4-Bromo-2,5-dimethoxybenzonitrile, 3.

Following the procedure in reference [2], 2.0 g of 2 was converted to the 1.69 g (81.2%) of the oxime. Refluxing 1.07 g of the oxime in 5 mL of acetic anhydride for six hours, followed by dilution with ice water, suction filtration, and recrystallization from methanol, yielded 0.865 g (76.6%) of 3, mp 175-7.

4-Iodo-2,5-dimethoxybenzaldehyde, 4.

A mixture of 1 (5.10 g, 0.0307 moles), silver nitrate (5.60 g, 0.033 moles), and iodine (8.10 g, 0.032 moles) in 125 mL of methanol was stirred under nitrogen for seven hours. The yellow precipitate was filtered and washed with methanol. The filtrate was treated dropwise with just enough saturated sodium bisulfite solution to reduce the remaining iodine, and the solvent was removed on a rotary evaporator. The solid was suspended with 50 mL of water, filtered, and
recrystallized from 95% ethanol to yield 7.62 g (84.9%) of 4, mp 137-9, literature mp 136-7 [3].

4-Iodo-2,5-dimethoxybenzonitrile, 5.

A solution of 4 (7.30 g, 0.025 moles) in 125 mL warm 95% ethanol was prepared on a steam bath. Hydroxylamine hydrochloride (2.08 g, 0.030 moles) was dissolved in 15 mL of water, and added to aldehyde solution. Sodium hydroxide (1.60 g, 0.040 moles) was dissolved in 15 mL of water, and added to the aldehyde solution. The solution was heated on the steam bath for 3 hours. The volume of solution was reduced to about 75 ml- on the rotary evaporator, and the solution cooled to yield 3.97 g of off-white crystals of thc oxime. Further reduction of volume of the filtrate to about 40 mL yielded another 2.47 g, for a total yield of 6.44g (84.0%) of the oxime. The oxime (5.0 g) was dissolved in 25 mL of acetic anhydride, and hcated at reflux for 6 hours. The reaction mixture was cooled and diluted with water. The precipitated solid was filtered, washed with water, and recrystallized from methanol to yield 4.11 g (87.3%) of 5, mp 153-5.

2,5-dimethoxybenzonitrile 6.

Using the same procedure as that in reference [2], 6 was prepared from 1 in 60% overall yield, mp 77-9, literature mp 82 [6].

2-Bromo-3,6-dimethoxybenzonitrile, 7.

To a mixture of 6 (3.5Og, 0.021 moles) in 15 mL of warm acetic acid was added bromine (1.2 mL, 0.024 moles) dropwise with stirring. The reaction was stirred at room temperature overnight, poured into 80 mL of water, and the solid filtered by suction. The solid was recrystallized from methanol to yield 1.122g (22.1%) of 7, mp 150-2.

2-Iodo-3,6-dimethoxybenzonitrile, 8.

Following the procedure in reference [5], 6 (1.82g, 0.0122 moles), iodine (1.275g, 0.00479 moles), periodic acid (0.365g, 0.0016 moles), 0.5 mL of sulfuric acid, 15 mL of acetic acid, and 5 mL of water were stirred and heated at 60 overnight. The reaction was cooled and diluted with water. The excess iodine was removed by treatment with sodium bisulfite solution, and the solid filtered, then recrystallized from methanol to yield 0.575g (17.7%) of 8, mp 167-9.

To a solution of 6 (1.Og , 6.0 mmoles) in 50 mL of methylene chloride was added silver nitrate (2.04g, 12.0 mmoles) and iodine (3.10g, 12.0 mmoles). The solution was stirred under nitrogen overnight. The silver iodide was filtered, and the methylene chloride solution was washed with 2 x 50 mL of 5% sodium bisulfite solution and then with 50 mL of water. The methylene chloride was dried over magnesium sulfate, then removed under reduced pressure to yield a yellow solid, which was recrystallized from methanol to yield 0.58g (33.4%) of 8, mp 168-170. The proton NMR spectrum was identical to that of the material produced by the preceding procedure.

References:

[1]. Barfkneckt, C. F. and Nichols. D. L., J. Med. Chem. 1971, 14, 370.
[2]. Buck, J. S. and Ide, W. S., Organic Svntheses 1943, Coll. Vol. 2, 622.
[3]. Sargent, T., Shulgin, A. T.. and Mathis, C. A., J. Med. Chem. 1984, 27, 1071.
[4]. Sy, W.-W. and Lodge, B. A., Tetrahedron Letters 1989, 30, 3769.
[5]. Suzuki, H., Organic Svntheses 1988, Coll. Vol. 6, 700.
[6]. CRC Handbook of Chemistry and Physics, 51st edition, R. C. Weast, Editor, 1970, p. C-183.