The Formylation of Indane

Written by Kinetic

HTML by Rhodium

There are numerous procedures for the formylation of aromatic systems in the literature. The Duff reaction is a well known procedure for the formylation of highly activated aromatics such as phenols and anilines. The yields are often terrible, and the procedure does not work at all on many substrates. Using trifluoroacetic acid1 as solvent overcomes this problem, with the reaction working on less activated nuclei.

Aldehyde formation has also been accomplished by the Bouveault aldehyde synthesis,2 in which a Grignard reagent is treated with an N,N-disubstituted formamide such as DMF, followed by acidic workup. Although the procedure was first reported 100 years ago, it was only relatively recently3 that a high-yielding general procedure appeared in the literature.

Graphical Abstract

Formylation of Indane

Indane4 seemed a valid substrate to test both of the above reactions out: it does not react well under standard Vilsmeier conditions,5 and the alternative, Friedel-Crafts formylation, uses the carcinogenic reagent dichloromethyl methyl ether.

The first method tried was the modified Duff formylation with hexamine in trifluoroacetic acid, giving the aldehyde directly. The same product was then made by a two step method. Indane was first brominated to give 5-bromoindane,6 and treated with Mg to give the Grignard reagent 5-indanylmagnesiumbromide. Addition of DMF followed by acidic workup furnished the corresponding carbonyl compound.

Experimental


Indane-5-carboxaldehyde via Duff reaction

A stirred solution of indane and hexamine in 75mla TFA was heated to 95°C for 12 hours. The deep red-brown solution was then removed from the heat and diluted with 250ml water. The resulting mixture was vigorously stirred for 30 minutes, then was made basic by the cautious addition of sodium carbonate decahydrate.b The dark oil which precipitated was extracted with 2x50ml ether and the combined extracts were dried over MgSO4. The solvent was removed and the product distilled at 127-129°C to give the title product as a clear, colourless, pleasant (marzipan!) smelling oil.

Yield: 8.8g (60mmol, 60%)

  1. This is half the amount of acid used in the original article and still gives comparable results. However, 100ml TFA is suggested for a reaction at this scale, using a slightly lower temperature.
  2. The anhydrous carbonate should work equally as well, as should potassium carbonate.

5-Bromoindane

A flask containing a solution of indane and ZnCl2 in 120ml acetic acid, wrapped in foil to exclude the contents from light, was cooled to 5°C. A solution of bromine in 20ml acetic acid was added over 1¾h, keeping the temperature around 5°C. The solution was stirred for a further 4 hours at 5°C, and was then poured into 400ml water. The product was extracted with 2x50ml DCM and the combined extracts were washed with 100ml water, 100ml sodium bicarbonate solution, 100ml 0.5M sodium metabisulfite solution,a 100ml sodium bicarbonate solution and 100ml brine. After drying over MgSO4, the solvent was removed and the product distilled at 112-116°C to give the title product as a clear, colourless, pleasant smelling oil.

Yield: 28.4g (144mmol, 72%)

a This removes all of the colour. Thanks to Barium for this tip.


Indane-5-carboxaldehyde via Grignard addition to DMF

To a stirred solution of 5mmol ethylmagnesiumbromidea in 100ml anhydrous THF containing magnesium turnings was added 5-bromoindane dropwise. The exothermic reaction initiated spontaneously and the remaining 5-bromoindane was added, taking care to keep the reaction from boiling over. When the reaction had returned to room temperature, the flask was cooled to 0°C. A solution of DMF in 75ml anhydrous THF was added over 15 minutes, causing a mild temperature rise. The flask was removed from the ice bath and allowed to stir for a further 2 hours. The colour changed from purple-brown to a light pea-green over this period. The reaction was then quenched by the addition of approximately 80ml 3M HCl. The biphasic mixture was added to 500ml water, and the product extracted with 2x50ml ether. The extracts were combined and washed with 100ml water, 100ml sodium bicarbonate solution and 50ml brine. Removal of the solvent and distillation under vacuum gave the title product as a clear, colourless oil boiling at 132-137°C,b with an identical smell to the product obtained by the first method.

Yield: 10.1g (69mmol, 69%)

  1. This trick7 enabled the otherwise difficult initiation of the Grignard reaction to occur extremely easily. The ethylmagnesiumbromide was formed in-situ but it should be equally possible to add the pre-made reagent. It could be a good way to initiate other tricky Grignard reactions, such as the formation of 2,5-dimethoxyphenylmagnesiumbromide.
  2. There was a slight forerun which had the smell of indane. This can be formed by quenching too early (Grignard degradation). The reaction may be slower in THF than in the ether used by G. Olah3; stirring for a further hour may increase the yield.

References

  1. Formylation of Aromatic Compounds with Hexamethylenetetramine and Trifluoroacetic Acid
  2. The Bouveault Aldehyde Synthesis
  3. G. Olah, et al., Synthesis, 228-230 (1984)
  4. J. Org. Chem. 37, 3972 (1972)
  5. Rhodium, Synthesis of Indanylamphetamine (IAP)
  6. The bromination gives a mixture of 4- and 5-bromoindane, with 5-bromoindane being the predominant isomer. Using low temperatures and a Lewis acid catalyst increases the selectivity for the desired 5-bromoindane. See Journal of the Americal Chemical Society, 63, 301-303 (giving a 2:1 ratio of 5- to 4-bromoindane with no Lewis acid catalyst), Journal of Organic Chemistry, 53, 4531-4534 (giving a 9:1 ratio of 5- to 4-bromoindane with 10mol% Fe turnings), and Organic Syntheses, CV 3, 138
  7. This was used by Nichols in the cyclisation of 1,4-bis(2-chloroethoxy)2,5-dibromobenzene: J. Med. Chem 44, 1003-1010 (2001)