lemuralia
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Formlyating Dimethoxytoulene
When formylating Dimethoxytoulene could SWIM possibly substitute perchloric acid for POCl3 as the catalyst?
Thanks for any help.
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Kinetic
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Vilsmeier Formylation
In short, no. Furthermore, POCl3 is not a catalyst as it is used in stoichiometric amounts and isn't retrievable at the end of the reaction. If
you look at (and understand) the mechanism you will see that POCl3 (and similar reagents) play a very specific role in this reaction. You cannot
substitute this for something that cannot act in this way. There are other reagents that have been reported to work in this reaction, such as SOCl2.
I found myself wondering whether cyanuric chloride may work given the complex it forms with DMF, but I don't know. This idea was based on a
proposed mechanism given in Org. Lett., 4(4), 553-555 (2002). [NB. especially having just found this paper online: Direct Formylation of Enol Ethers Using Cyanuric Chloride and N,N-Dimethylformamide]
I think there are better ways to your target compound than the Vilsmeier reaction. I am too tired to do further searching right now so I will leave
details to someone else.
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Sergei_Eisenstein
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HCN
The Gattermann reaction works very well for this substrate.
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Vitus_Verdegast
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Vilsmeier alternative
Large scale preparation of 2,4-dihydroxybenzaldehyde using a variation of the Vilsmeierhaack reaction and isolated intermediates
patent US5599988
| Quote: |
The aldehyde, 5-Scheme 3, in another aspect of the present invention may also be produced using a Vilsmeier formylation of resorcinol with either
phosphorous oxychloride/DMF or oxalyl chloride/DMF in acetonitrile at below room temperature, using resorcinol as a starting material in good yield
and high purity.
These methods have advantages over Nenitzescu, et al. Chem. Abst. 1930, 24, 2442 formylated resorcinol in an ether solution with oxalyl
chloride-formamide and produced 1-Scheme 4 via a crystalline intermediate in an unspecified yield. The reaction however produced mixtures, and the
aldehyde in low yield, as well as using diethyl ether. Recently Downie, et al., Tetrahedron 1993, 49, 4015 used pyrophosphoryl chloride and DMF to
efficiently formylate resorcinol as well as many heterocyclic systems. The expense and unavailability of pyrophosphoryl chloride for large scale work,
as well as the ecological undesirability, renders this synthesis not commerically feasible. The novel use of activating agents phosphoryl chloride and
oxalyl chloride, both readily available in large quantires, is a key feature to the usefulnes of this reaction. Generally, older methods for carrying
out similar formylations use hazardous solvents, such as ether, as well as toxic reagents. The present method utilizes inexpensive, generally safe,
commerically available reagents.
In the first example, the Vilsmeier reagent is prepared by the addition of POCl3 in acetonitrile to DMF in the same solvent at room temperature. The
reaction is then cooled to about-15 DEG C., resorcinol in acetonitrile is added, and after about 2 hours the reaction is warmed to 28 DEG -30 DEG C.
The crystalline Vilsmeier-formamidinium phosphorodichloridate salt is isolated by filtration, in a high state of purity in about 75-80% yield. The
optimum temperature range is about -10 DEG to about 25 DEG C. during the addition of resorcinol to the Vilsmeier reagent; and the reaction may be
compeleted from about 25 DEG to about 50 DEG C. Customarily, for this reaction, for rescorinol about 7 to 12 parts of acetonitrile are used, and from
about 1 to 1.5 equivalents of DMF, and about 1 to 1.5 equivalents of POCl3 are used. Isolation of this novel intermediate salt 3-Scheme 4 provides a
simple, convenient means of purification useful in application to large scale work. The salt is stable for several weeks in the dark at -10 DEG C.,
but it acquires a pink color on standing in the laboratory at ambient temperature for 2-3 days.
The intermediate salt is readily convened to aldehyde 1-Scheme 4 by treatment with water at about 50 DEG C. The desired aldehyde is isolated by
precipitation directly from the aqueous solution as a single component in 70-75% overall yield. The conversion can be monitored by NMR by adding D2 O
to a sample of 3-Scheme 4 in DMSO-d6. The use of low temperatures of the reaction (-25 DEG to 10 DEG C.) prevents side reactions of resorcinol with
the Vilsmeier reagent. Further, isolation of the intermediate formamidinium salt provides a convenient means of purification.
Therefore, another aspect of the present invention is the novel process of using POCl3 in acetonitrile and DMF to yield the novel formamidinium
phosphorodichloridate salt as an isolable intermediate, which upon the addition of water forms 2,4-dihydroxybenzylaldehyde.
Similar results are obtained using the oxalyl chloride-DMF Viismeier reagent as also indicated in Scheme 4. In this case the Vilsmeier reagent,
[H(Cl)C=N(CH3)2 ]+ Cl-, precipitates from acetonitrile as a thick solid, and more dilute reactions are used to achieve efficient stirring. The reagent
subsequently dissolves as resorcinol is added at about -15 DEG C.; and the novel formamidinium chloride salt 4-Scheme 4 precipitates from the
reaction. This salt is converted to 2,4-dihydroxybenzaldehyde on crystallization from warm water in an overall yield of about 69-70% from resorcinol.
The employment of acetonitrile and low temperatures during the Vilsmeier coupling are important factors in these high throughput, cost-effective
preparations of 1-Scheme 4.
Therefore, another aspect of the present invention is the novel process of using oxalyl chloride in acetonitrile and DMF with resorcinol to yield the
novel formamidinium chloride salt as an isolatable intermediate, which upon the addition of water forms 2,4-dihydroxybenzylaldehyde.
The oxalyl chloride and POCl3 in combination with DMF or N-methyl formanilide are also useful to produce other aromatic aldehydes which are presently
synthesized by the Gatterman reaction, the use of HCN or cyanide salts can thus be avoided. "The Gatterman Synthesis of Aldehydes", Organic Reaction,
Vol. 9, pp 37-72 (1957). Further, the method will also be useful where the product aldehyde is a liquid; the isolation of the formamidinium salt
provides a convenient means of purification, avoiding fractional distillation. The use of oxalyl chloride also provides an alternative to the
phosphorous containing reagents and the disposal of phosphorous containing waste streams. |
How effective this would be on 2,5-dimethoxytoluene I don't know. Maybe it is better to use a formanilide instead of DMF for this particular
substrate?
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