Benzothiophene-3-carboxaldehyde

[phenyl]

Swim needed this for a starting material and explored the most inexpensive routes.  The routes found were
1. Buy it.
2. Start with 3-methylbenzothiophene, brominate, make salt with hexamethylenetetramine, oxidize with acetic acid.
3. Start with benzothiophene, chloromethylation with formaldehyde/hcl, make the hexamethylenetetramine salt, oxidize.
Of course, the 3-methyl and the aldehyde were expensive to buy so the chloromethylation route was chosen.  The problem is that the distillation done to purify is at an unacceptable pressure.  Continuing to the HMTA salt provided a dismal yield.
So the reason for this post is to ask for advice, or any alternate routes to the aldehyde.

[Rhodium]

As far as I know, electrophilic reactions of Benzothiophene occurs in the 2-position, not the 3-position like with indoles. A review of the chemistry of Benzothiophenes can be found in Adv. Het. Chem. 29, 172 (1981).

[phenyl]

benzothiophene can and does react at the three position.  One method is the above mentioned, the chloromethylation with formaldehyde and hcl.  a newer method is the reaction between bt and dichloromethyl butyl ether with titanium tetrachloride as the catalyst.  this is the next method to try. thanks.

[phenyl]

Dichloromethyl methyl ether
To a 250ml roundbottom flask submerged in an ice bath was added 85g. PCl_{5.  To this 30g. of methyl formate was slowley added dropwise from a pressure equalized addition funnel under N}2.  The temperature was allowed to return to room temperature and then heated to 60C and held there for 15 min.  The dichloromethyl methyl ether distilled at 86C. yield, 25.3 g.
Benzothiophene-3-carboxaldehyde
Dichloromethyl methyl ether was added dropwise to an icecold solution of 10.8g. benzothiophene and 30mL titanium tetrachloride in 200mL freshly distilled carbon disulfide under argon.  After two hours 10mL concentrated HCl was added, producing a solid blach mass.  Chloroform was added, along with water to break up the mass.  The organic solution was washed twice with water, twice with bicarbonate, and once with brine.  The crude product was stripped of solvent under vacuum, leaving a red oil.  extraction of this with boiling hexane gave 2.8g. of aldehyde.  The rest of the residue was purified by column chromatography using silica gel and hexane as the mobile.

^{1H nmr, 10.14 (aldehyle)}

[Lilienthal]

I read a paper about benzothiophen analogs of tryptamines in J. Med. Chem a few years ago from the D. E. Nichols lab. From what I remember they were less active than the tryptamines.

[dmitri]

Considering the yields, wouldn't the Vilsmeyer be preferable in this situation? After all, if you've gone through the trouble of obaining PCl₅, POCl₃ isn't much more difficult to obtain, and the yields for this are generally quite good. It scales up well, and all the reagents, with the exception of benzothiophene, are cheap.

This does beg the question: how willing are you to actually work with this kind of stuff? I once had a gram of benzothiophene, and the smell is more horrible than I can describe. It will get in your skin, and you will stink for weeks. It's a cute idea, but I'd strongly recommend a glove box.

[phenyl]

The vilsmeyer formylation gives at best 9% yield.  Benzothiophene doesn't give up its electrons to make the 3 position into anysort of nucleophile, hence the harsh conditions.  On a brighter note, the condensation with nitromethane (solvent) is smooth, with a.a. as catalyst in a 1:1 ratio, reflux 1.5 hours.  recrystalize from etOH.

[yellium]

dmitri: doesn't that mean that if you ingest something based on benzothiophene, you'll sweat out benzothiophene degradation products for weeks?
When all you've got is a nailgun, every problem looks like a messiah...

[dmitri]

phenyl,

How does the Vilsmeyer give yields of 9%?  According to whom? I've looked into this, and there's nothing in the public literature on any Vilsmeyer formylation of a benzothiophene at all -- so where do you get this 9% figure? The only heterocycle Vilsmeyer formylations I've had personal experience with have been indoles, where the yields tend to be good to quantitative (85%-100%.)

The thing is, indoles and benzothiophenes have a lot of similarities in terms of how they react. "Benzothiophene doesn't give up its electrons to make the 3 position into anysort of nucleophile"? In fact, nothing could fail less completely to be further from falsehood. The sulfur in benzothiophene has more lone pairs of electrons and holds onto them more loosely than the nitrogen in indole. The 3-position is nucleophilic, period. In fact, when it comes to electrophilic aromatic substitution reactions (halogenations, Friedel-Crafts acylations, nitrations, etc.), the 3-position on benzothiophenes  is just as activated as its indole counterpart, and there are plenty of published examples that demonstrate this.

[phenyl]

dmitri,
benzothiophene does not react like indole.  Sulfur does not act like nitrogen.  Their chemistry is completely different!  Does nitrogen act like oxygen?  Some research brings up a number of papers on this subject.  Regarding the vilsmeyer, I refer you to W.J. King and F.F. Nord, J. Org. Chem, 1948, 13, 635.  The 3-chloromethyl route has better yields, but has 3 steps and 3-chloromethylbenzothiophene is a severe allergin.  Do you think that titanium tetrachloride and carbon disulfide were used for fun?  Harsh conditions are necessary for this conversion.  The Rieche formylation is definitly the way to go.  Rieche, A., Chem. Ber., 1960, 93, 88
Z. Chem, 1964, 4, 401
If you are interested in this reaction the most recent papers are: Buu-Hoi, J. Chem. Soc. (C), 1969, 339.
     Clark, P.D., Irvine, N. M., Phosphorus, Sulfur and Silicon, 1996, 118, 61-77.

[dmitri]

phenyl,

There are a lot of instances where the reactivity and behavior of nitrogen and sulfur are very similar. In this case, benzothiophene does act like indole. Think of it this way: both nitrogen and sulfides are activating substituents on aromatic rings because they're both donate electron density via lone pairs, right? In fact, sulfur has considerably more lone electron pairs than its counterpart nitrogen, and holds onto them more loosely, which would make sulfur a stronger activator of aromatic systems... And when you perform an electrophilic addition the most activated position  on either heterocycle is the 3, just like with indole, right?... And the Vilsmeier is an electrophic addition?

I looked up the article that you mentioned, J. Org. Chem, 1948, 13, 635. They use the Vilsmeier as discussed, but they are preparing thiophene carboxaldehydes rather than benzothiophene carboxaldehydes. Still, the yields are 65-70%, which isn't too bad. The system is formylated at the 2-position rather than the 3, but this is the exact same pattern that you see with pyrrole.
In any event, I didn't see them using any titanium chloride or carbon disulfide, though.