Rhodium (Chief Bee)
06-24-03 05:01
No 442155
      Selective ortho-formylation of phenols     

Tetrahedron Letters 4, 243-245 (1965) (http://chemistry.mdma.ch/hiveboard/rhodium/pdf /ortho-formylation.mgbr-phenols.pdf)

(Someone please type and post the procedure below...)
(Hive Addict)
06-24-03 06:32
No 442163
      Where are the hetaerae to encourage me?
(Rated as: excellent)


G Casnati, M Crisafulli, A Ricca

Tetrahedron Letters 4 (1965) 243-245

In connection with our previous work on the synthesis of some phenolic mould metabolites [1] and the research in progress on the reactivity of phenoxymagnesium halides [2,3] ArOMgX (I) [4], we have investigated their behaviour towards orthoformic esters. We found that on heating the halides (I) with an excess of ethylorthoformate the corresponding ortho-hydroxyaldehydes are formed without any detectable amount of the para-isomer. This reaction offers therefore a valuable practical method for the selective orthoformylation of phenols.
A typical procedure is as follows: 0.1 mole of o-cresol was added at room temperature to the equivalent amount of EtMgBr in ether; when the evolution of ethane had ceased, 20-30 mL of ethylorthoformate was added, and the ether distilled at ordinary pressure allowing the temperature to rise to 100°C. At this point the reaction mixture was decomposed with aqueous 10% HCl and then extracted with ether. Steam distillation of the oil left after removal of the solvent gave 2-hydroxy-3-methylbenzaldehyde in 42% yield (calculated on the weight of the pure 2,4-dinitrophenylhydrazone, mp 251-252°C); no 4-hydroxy-3-methylbenzaldehyde could be detected in the residue of the steam distillation.

The results obtained with different phenols and phenolethers are presented in Table I.

phenol 2-hydroxy-benzaldehyde 7
o-cresol 2-hydroxy-3-methyl 42
m-cresol 2-hydroxy-4-methyl 22
p-cresol 2-hydroxy-5-methyl 30
2,5-xylenol 2-hydroxy-3,6-dimethyl 55
3,4-xylenol 2-hydroxy-4,5-dimethyl 25
3,5-xylenol 2-hydroxy-4,6-dimethyl 35
p-tert-butylphenol 2-hydroxy-3-methyl-5-tert-butyl 37
thymol 2-hydroxy-3-isopropyl-6-methyl 45
carvacrol 2-hydroxy-3-methyl-6-isopropyl 4.5
o-methoxyphenol 2-hydroxy-3-methoxy -
m-methoxyphenol 2-hydroxy-4-methoxy 18
p-methoxyphenol 2-hydroxy-5-methoxy 12
o-chlorophenol 2-hydroxy-3-chloro 1.5
p-chlorophenol 2-hydroxy-5-chloro 4.5

The reaction proved to be highly specific for the orthoformylation of phenols and in this regard differs from the methods already known [6]; no p-hydroxy isomer could be found in the reaction mixture in all the cases investigated, and ortho-disubstituted phenols suc as 2,6-xylenol were recovered unaffected.
Phenols containing electron-attracting substituents do not react indipendently (sic) from the position of the substituent in respect to the hydroxyl; thus, negative results have been obtained with the magnesium derivatives of o, m and p-carbomethoxy- and nitro-phenols, and very poor yields are given by chlorophenols. Alkyl substituents facilitate the process, but steric factors clearly affect its general course. Ortho alkylphenols are more reactive than their meta and para isomers; moreover, for 2,5-dialkylphenols, the yield decreases dramatically when a bulky substituent is present in 5-position as in the case of carvacrol.
The formation of inter- or intromolecular complexes concerning the phenoxymagnesium compounds play also an important role, as shown by the behaviour of the three isomeric methoxyphenole. The reaction is inhibited in aprotic solvents only when they possess a high complexing and/or solvating power on the cation [7]; accordingly, phenoxy- and p-methylphenoxymagnesium bromide do not react in pyridine or dioxane at 100°C with ethylformate, but they behave normally in benzene and xilene (sic) solution. In an experiment performed in a protic solvent (phenoxymagnesium bromide in a large excess of phenol) in the usual conditions, no reaction occured.


1. C Cardani et al. Gazz Chim It 87, 43 (1957); C Cardani et al. Gazz Chim It 88, 487 (1958).
2. About the reactivity of the phenoxymagnesium halides see H Gilman and F Schulz, Rec Trav Chim 47, 752 (1928).
3. Some examples of Kolbe's reaction for phenoxymagnesium halides were reported by B Oddo, Gazz Chim It 41, 255 (1911).
4. It is possible that equilibria of type:

2 ArOMgBr <------> (Ar)2Mg.MgBr2

or similar may occur in the conditions in which the reaction is carried out; the phenoxydierivative actually involved in the process might therefore possess a structure different from (I).
5. Some unchanged phenol is always present in the reaction mixture; actual yields on the reacted phenol are therefore somewhat higher. Gas chromatographic analysis of the crude reaction product showed that no other substance, besides the o-hydroxylaldehyde and the phenol, was present.
6. The Duff reaction is also highly selective, but frequently, besides the expected o-hydroxyaldehydes, o, p-dialdehydes are formed which may in some cases become the only reaction product. See Note 1.
7. N Kornblum et al. J Am Chem Soc 85, 1141 (1963).



The faster you run, the quicker you die.
(Chief Bee)
06-25-03 04:24
No 442416
      That has been taken care of     

All Hive martyrs who die on their post from exhaustion while doing either practical or theoretical work for the Hive will naturally recieve their own personal harem of choice.
(Active Asperger Archivist)
07-02-03 08:08
No 443997

Great! Now I've only got about 1,000,000 more to go before I die of blood loss from the bloody stumps that were once my fingers!

Act quickly or not at all.
(Hive Addict)
07-03-03 05:21
No 444206
      o-Formylation with dichloromethyl methyl ether
(Rated as: excellent)

o-Formylation of electron-rich phenols with dichloromethyl methyl ether and TiCl4
O Garcia, E Nicolįs, F Albericio
Tet. Lett. 44(27), 4961-4963 (2003) (http://chemistry.mdma.ch/hiveboard/rhodium/pdf /o-formylation.dcmme.ticl4.pdf)

Abstract - o-Formylation of electron-rich phenols is accomplished with dichloromethyl methyl ether and TiCl4. The reaction gives excellent yields, good regioselectivity and does not leading to diformylation.

General procedure for the formylation reaction - Reagent were used as received without further purification. Dichloromethane (DCM) was passed through an alumina column, stored over CaH2 under an Ar atmosphere, and protected from the light.
A solution of the appropriate phenol (20-150 mmol) in DCM (1.5 mL/g phenol) was purged with N2, cooled with an ice bath, and TiCl4 (2.2 eq to obtain 1 and 2 and 5 eq to obtain 3-5) was added dropwise over 15-30 min. The reaction mixture was left to react for 30-60 min. Dichloromethyl methyl ether (1 eq) was added over 15  min and the mixture left to react for a further 1-2 h. The reaction was quenched by the addition of saturated NH4Cl solution and the mixture was left to stand for 1 h. The organic phase was separated and washed with 0.1 N HCl, saturated with NaHCO3 solution, and brine. The solution was dried over MgSO4, filtered, and the solvent evaporated under reduced pressure. The purified products were homogeneous by HPLC (nucleosil C18, 250x40 mm, 10 µm; linear gradient of CH3CN (+0.036% TFA) into H2O (+0.045% TFA) at 1.0 mL/min flow rate; 220 nm), and there were characterised using different physical techniques.

1 - 2-formyl-3,5-dimethoxyphenol
2 - 2-formyl-3,5,6-trimethylphenol
3 - 2-formyl-3,4,5-trimethoxyphenol
4 - 2,3-dihydro-2,2-dimethyl-4,5,6-trimethoxybenzofuran-7-carbaldehyde
5 - (8-formyl-3,4-dihydro-2-methyl-5,6,7-trimethoxy-2H-1-benzopyran-2-yl)-acetic acid

Pitty that dichloromethyl methyl ether is rather expensive. There have been more posts in the past concerning this formylation method. I suggest using TFSE for those who show interest in the reaction.

The faster you run, the quicker you die.
(Chief Bee)
07-03-03 07:02
No 444218
      Dichloromethyl methyl ether synthesis     

Here is a synthesis of Dichloromethyl methyl ether: http://chemistry.mdma.ch/hiveboard/rhodium /dcmme.htm
(Hive Addict)
07-04-03 11:41
No 444530
      Dichloromethyl methyl ether     

Maybe I should give the dichloromethyl methyl ether synthesis a shot. I'm not a big fan of PCl5 though... The formylation looks elegant. Anyone practical experience to share?

All Hive martyrs who die on their post from exhaustion while doing either practical or theoretical work for the Hive will naturally recieve their own personal harem of choice.

I already feel quite dead... *making zombie-like movements* Is that sufficient to receive compensation? Or can elite members as myself get the compensation in advance? wink

The faster you suck, the quicker it squirts.
(Chief Bee)
07-04-03 17:09
No 444578
      dichloromethyl methyl ether formylation     

Yes, the dichloromethyl methyl ether formylation is great, and while it doesn't require an inert atmosphere, it is great to at least work with septa and syringes, as TiCl4, SnCl4 and other suitable catalysts reacts with atmospheric moisture.
(Chief Bee)
12-17-03 00:35
No 477358
      Related Article
(Rated as: excellent)

Über -Halogenäther, XIII
Neue Verfahren zur Darstellung von Phenolaldehyden

H Gross, A Rieche, G Matthey
Chem. Ber. 96, 308-313 (1962) (http://chemistry.mdma.ch/hiveboard/rhodium/djvu /alpha-halogenether.djvu)

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