Benzoylchloride to something usefull

[Bandil]

I seem to stumble upon a lot of neat stuff these days. Yesterday i came into possession of quite an amount of 3,4,5-trimethoxybenzoylchloride. Happily not nociting that damned "o" i sang a little song and did a little dance. After some time i did notice that someone actually had been blasphemic enough to attach an oxygen to this otherwise wonderfull molecule.

Not, this stuff seems so close to the obvious end material that i could cry. Anr bright ideas on how to turn this into something usefull? The only this i could come up with is to reduce the acidchloride to the benzylalcohol, and turn this into the benzylchloride using thionylchloride or something similar, and then proceed with making the benzylnitrile. 

Any brilliant ideas folks?

Regards
Bandil

[roger2003]

To convert the Bezoylchloride into Benzaldehyde see:

Patent DE333154

[Bandil]

Thanks Roger!

The platinium / palladium catalysts does not pose a problem. I do not have access to hydrogenation apparatus unfortunately, so any ideas that does not involve hydrogenation?

Regards
Bandil

[Organikum]

The procedure in the patent doesnt involve pressure, so no Parrshaker would be needed, only Pt-catalyst and hydrogen with (boiling) toluene as solvent. But the chloride might have to get converted to the bromide as yields with the chloride suck (10-25%). With the bromide 90%+ are possible. I believe this is related to catalyst poisoning here.

ADDON:
perhaps this way:
Condensation of the benzoyl chloride with diethyl ethoxymagnesiummalonate, followed by hydrolysis of the ester.

Organic Syntheses, CV 4, 573
Preparation of o-methoxyphenylacetone

[Nicodem]

1.) Maybe the most practical reduction to the benzaldehide would be with the

Rosenmund catalyst

(http://themerckindex.cambridgesoft.com/TheMerckIndex/NameReactions/ONR344.htm) if you can prepare or have access to it:

3,4,5-Trimethoxybenzaldehyde.

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/mescaline.html)
To a solution of 200 g. of 3,4,5-trimethoxy benzoyl chloride in 1000 cc of xylene freshly distilled over sodium, there is added 60 g. of a 5 % palladium-barium sulfate catalyst. The mixture is heated in an oil bath maintained at 150 deg C and a vigorous stream of hydrogen is introduced into the boiling solution. The hydrogen should be washed with aqueous permanganate and the dried with sulfuric acid. After 60-80 hours the reaction is complete. The solution is filtered and the aldehyde conveniently isolated as its bisulfite compound. Yield 120 g. (70.6 % of theory), m.p. 74 deg C.

2.) The use of selective hydride reagents like DIBAL-H, RED-AL, LiAlH(OBu^t)3 usually requires low temperatures (<-70°C) and is more often done on the esters or amides (but getting an ester of your acylchloride is no sweat). But even if you make this reagents in situ from LiAlH4 it is still not cheap, safe and easy besides being unpractical (or unavailable) working at such low temperatures.

3.) Another somewhat more accessible reduction might be the

McFadyen-Stevens reaction

(http://themerckindex.cambridgesoft.com/TheMerckIndex/NameReactions/ONR239.htm). You can react you acid chloride with Ph-SO₂-NH-NH₂ (or Ts-NH-NH₂) and with the decomposition of the so formed hydrazide in Na₂CO₃/ethyleneglycol at about 150°C you should get the 3,4,5-trimethoxybenzaldehyde. However, it is said that yields are often poor (but in some cases they are >60%).

P.S. Does anybody knows if NaBH4 can reduce benzoylchlorides to benzylalcohols in aprotic solvents? I saw this slightly mentioned in a book, but there were no references.

[Bandil]

Thank you all for your nice ideas!

I just really really resent the idea of playing with hydrogen without the correct equipment. I think i'll just go for the reduction to the benzylalcohol and follow the standard route from there. Nothing like a good old challenge eh'?  

Regards
Bandil

[gsus]

this was the precursor for the original mescaline synthesis, using the Rosenmund reduction mentioned. you can turn it into many useful things that have been used to make PEA's, but its a long road from anything besides CHO and CH2OH. captain obvious strikes again. im sure you know and am sure you will have anhydrous conditions anyways, but just know i ought to post this:
 -if this 3,4,5 cpd is anything like the unsubbed cpd it hydrolyzes easy to the benzoic acid, especially when you dont want it to. its a lot of steps from benzoic acid to PEA if you dont have a hydride.
 on that note, anyone know if Na alkoxide reduces benzoic esters to alcohol like it does other esters? and what are the yields with NaBH4/benzoic ester? who wants to read for me?
  yeah, i saw the acyl halide to aldehyde via NaBH4 in DMF/THF too, and dont know if it applies either. but i do know that LAH or NaBH4 would be very handy for you to arrive at the benzyl OH, as you know. and benzyl alcohols can be turned in to benzyl Cl at RT w/HCl alone. tho its usually done cold. i assume this has something to do with ether cleavage. 
  hopefully this will get everyone to get some Pd, LAH, or at least NaBH4. even basic chemistry like this sucks without them.

[Lilienthal]

Think Grignard...

[Bandil]

Hmm... yes?

As far as i can see a grignard reactant will add twice to give an alcohol with two new alkyl groups attached. How is this usefull?

Lithium dialkylcuprate could be used, which would add once to form a ketone with one alkyl chain attached. Maybe something far out could be made with that compound, but it's not as "attractive" as a single LAH reduction followed by the usual route...

Regards
Bandil

[Kinetic]

If you were to make the acetophenone or propiophenone via an organometallic compound, you could then brominate to give the alpha-bromoketone, followed by the addition of sodium azide. Reduce the formed azidoketone to the azidoalcohol, acetylate and CTH to the amine.

Based on experience, the transformation of the acetophenone/propiophenone to the azidoalcohol should be very high yielding. I have yet to test the next two steps, but they are based on a combination of

Preparation of amphetamines from phenylpropanolamine

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/amph.cth.ppa.html) and

CTH - Catalytic Transfer Hydrogenation

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/cth.txt).

There are also many ways of reducing the benzoylchloride to the benzyl alcohol, using various borohydrides, often in very high yield. I use the example below because the yield is so impressive, but there are 25 other refs for the same transformation, most of which use less exotic reagents:

Reaction Classification: Preparation
Yield: 100 percent (BRN=878307)
Reagent:   (i-PrO)2TiBH4
Solvent: CH₂Cl₂
Time: 8 minutes
Temperature: -20^oC
Ref. 1: Ravikumar, K. S.; Chandrasekaran, Srinivasan; J.Org.Chem.; 61; 3; 1996; 826-830.

I'll post some refs for the same reduction using NaBH₄ (though in slightly lower yield) if anyone's interested.

[Nicodem]

I'll post some refs for the same reduction using NaBH4 (though in slightly lower yield) if anyone's interested.

I'm interested. It sounds much better than using LAH (not to mention more accesible).

[Kinetic]

All the following refs are for the unsubstituted benzoyl chloride -> benzyl alcohol transformation, but aryl alkyl ethers are stable to borohydrides so the procedures should be just as applicable to 3,4-5-trimethoxybenzoyl chloride:


Reductions with plain sodium borohydride:

Reaction Classification: Preparation
Yield: 78 percent
Reagent:   NaBH₄
Solvent:   various solvent(s)
Time: 3 hour(s)
Temperature: 80^oC
Ref. 1: Santaniello, Enzo; Fiecchi, Alberto; Manzocchi, Ada; Ferraboschi, Patrizia; J.Org.Chem.; 48; 18; 1983; 3074-3077.

Reaction Classification:   Preparation
Reagent:   NaBH₄
   dioxane
Ref. 1: Chaikin; Brown; J.Amer.Chem.Soc.; 71; 1949; 122, 124.

Reaction Classification: Preparation
Reagent NaBH₄
   dioxane
Ref. 1: Schlessinger; Brown;

Patent US2683721

; 1952.


Reductions using modified sodium borohydride:

Reaction Classification: Preparation
Reagent:   NaBH₄
   AlCl₃
   O,O'-dimethyl-diethylene glycol
Ref. 1: Brown; Subba Rao; J.Amer.Chem.Soc.; 78; 1956; 2582, 2587.


With sodium trimethoxyborohydride:

Reaction Classification Preparation
Reagent:   sodium trimethoxy borate
   diethyl ether
Ref. 1: Brown; Mead; J.Amer.Chem.Soc.; 75; 1953; 6263.

Sodium trimethoxyborohydride can be made from sodium hydride and methyl borate as in the equation:

NaH + B(OCH₃)₃ -> NaBH(OCH₃)₃


And finally with LAH/SiO₂ in quantitative yield:
 
Reaction Classification: Preparation
Yield: 100 percent
Reagent:   LiAlH₄/SiO₂
Solvent:   hexane
Time: 3 hour(s)
Temperature: 25^oC
Ref. 1: Kamitori, Yasuhiro; Hojo, Masaru; Masuda, Ryoichi; Izumi, Tatsuo.; Inoue, Tatsuro; Synthesis; 5; 1983; 387-388.


Edit: On page 3 of the linked patent there is some nice information:

The hydrogenation of benzoyl chloride

In a 1-liter round-bottom flask fitted with a condenser, stirrer and dropping funnel is placed 200ml of anhydrous ethyl ether and 128g (1.00 mole) of sodium trimethoxyborohydride. To the stirred suspension is added a solution of 70g benzoyl chloride dissolved in anhydrous ethyl ether. A vigorous reaction ensues. The acid chloride should be added to the hydrogenation agent slowly, at such a rate that the ether refluxes gently. After the acid chloride has been added, the mixture is permitted to stand for 1 hour and 200ml water is added. The reaction mixture is then poured into a separatory funnel, the ether layer is separated and dried with calcium hydride. The ether is removed on a steam cone and the benzyl alcohol is obtained by distilation under vacuum. The product yield is 49g., B.P. 93-96^o at 11mm., n_D²⁵ 1.5375. The yield is 90% of the theoretical. By addition of sodium trimethoxyborohydride (1.00 mole) to benzoyl chloride (1.00 mole) in ether at 0^o, benzaldehyde is formed. The benzaldehyde is conveniently recovered as its bisulfite addition compound. It was converted into the phenylhydrazone, M.P. 154-156^o.

[gsus]

acyl Cl=>(benz)aldehydes:
Reduction of Acid Chlorides with NaBH4 in DMF...
Babler & Invergo,  Tetrahedron Letters 22(1), 11-14 (1981)

Post 306703

(PEYOTE: "Acid Chlorides to Aldehydes w/o Rosenmund", Chemistry Discourse)


All of these NaBH4 reductions seem to use THF/DMF to make the borate, but JCS Perkin Trans. 1, 27, 1980 uses CH3CN and Cd salt i guess.
  a way that looks better than these reacts the COCl at RT 24 hrs. with NaBH4 in THF/DMF(1:1) then the borate/solvents reacts with PCC in CH2Cl2 at RT 24 hrs. for high yield of the aldehyde:

Reductive Oxidation of Acid Chlorides to Aldehydes with Sodium Borohydride and Pyridinium Chlorochromate
Jin Soon Cha and Dae Yon Lee

Bull. Korean Chem. Soc. Vol. 21(12), 1260-1263 (2000)

(http://journal.kcsnet.or.kr/publi/bul/bu00n12/1260.pdf)

[Bandil]

Ahhh, sweet! Borohydride will do the job  

Guess that's settled then. Thanks folks!

Regards
Bandil

[Nicodem]

Bandil or anybee else that have at his disposition a nicely substituted benzoylhalide, benzoic anhydride or methyl benzoate might want to check the following idea of general bee-interest.

I was reading a nitroalkane reactions review^* when I saw the following general reaction:

R-CH=NO₂^- + R’-CO-X  ==>  R’-CO-CHR-NO₂ + X^-

and realized I actually already tried something similar only that I used it the “other way”. I acylated the sodium salt of nitrotoluene with acetanhydride to get 2- and 4-nitro-P2P. I don’t know why I didn’t realize its further use for the opposite reaction.
The R-CH=NO₂^- is off course the nitronate salt produced from a nitroalkane and a base, for example of nitromethane or preferably nitroethane with sodium ethoxyde or hydroxide. X is a halide or other groups that activate the carboxylic acid.
By having the R=H for the PEA’s (or R=Me for the amphetamines) and R’=aryl (in Bandil’s case it is 3,4,5-trimethoxyphenyl) you get an alpha-nitro-3,4,5-trimethoxy-acetophenone:

CH₂=NO₂^- + {3,4,5-triMeO-phenyl}-CO-X  ==>  {3,4,5-triMeO-phenyl}-CO-CH₂-NO₂

The alpha-nitro-acetophenones can presumably be reduced with NaBH4/EtOH to the 1-phenyl-2-nitro-etanoles which on acidification/dehydration turn into the appropriate beta-nitrostyrenes:

{3,4,5-triMeO-phenyl}-CO-CH₂-NO₂  ={NaBH4/EtOH}=> {3,4,5-triMeO-phenyl}-CH(OH)-CH₂-NO₂ 
{3,4,5-triMeO-phenyl}-CH(OH)-CH₂-NO₂  ={H⁺}=>  {3,4,5-triMeO-phenyl}-CH=CH-NO₂ + H₂O

Both of these two reactions can probably bee done in a one pot procedure.
I guess there is no need to explain the further use of the nitrostyrene. This might bee a better alternative to the reduction of benzoylhalides to alcohols, their oxidations to the aldehyde and the Henry condensation. After all many substituted benzoic acids are readily avaible and the method might work also with their methyl esters (from a simple Fisher esterification).

Sorry if I posted this before doing a literature search but I would need Beilstein for that and I won’t bee having access to it in the next days. So, maybe some interested bee could find some references to similar reactions with preparation details.

* Rosini and Ballini. Functionalized Nitroalkanes as Useful Reagents for Alkyl Anion Synthons. SYNTHESIS (1988) 833-847.