Sciencemadness Discussion Board

Synthesis of 2-(benzhydrylthio)acetamide

Stramonium - 14-5-2007 at 20:12

Can anyone find any issues with this synthesis-

The reaction of diphenylmethanethiol with 2-chloroacetamide to give 2-(benzhydrylthio)acetamide?

The proposed synthesis would follow a similar procedure to below [1].

"Benzhydryl-thioacetic acid
10 g (0.05 mol) of diphenylmethane-thiol and 2g (0.05 mol) of NaOH dissolved in 60 ml of demineralised water are introduced successively into a 250 ml flask equipped with a magnetic stirrer and a reflux condenser. The reactants are left in contact for 10 minutes whilst stirring, and a solution consisting of 7g (0.075 mol) of chloroacetic acid, 3g (0.075 mol) of NaOH pellets and 60 ml of demineralized water is then added all at once. The aqueous solution is gently warmed to about 50°C for 15 minutes, washed with 50 ml of ether, decanted and acidified with concentrated hydrochloric acid. after filtration, 10.2g of benzhydryl-thioacetic acid are thus obtained. Melting point 129-130°C. Yield 79%."

with the exception that an equimolar quantity of 2-chloroacetamide would substitute the chloroacetic acid to (hopefully) give 2-(benzhydrylthio)acetamide.

The 2-(benzhydrylthio)acetamide could then be oxidised with a H2O2/AcOH system to give 2-(benzhydrylsulphinyl)acetamide as detailed in [1].

Any input would be greatly appreciated!

REFERENCES
[1] US Pat 4,066,686 & 4,177,290

EDIT: changed the names of some of the compounds to remove confusion and added a reaction scheme.

[Edited on 15-5-2007 by Stramonium]

[Edited on 15-5-2007 by Stramonium]

synthesis.gif - 10kB

stoichiometric_steve - 14-5-2007 at 22:22

you can use potassium peroxymonosulfate (oxone) to selectively oxidize the sulfide and prevent oxidation to the sulfone.

solo - 15-5-2007 at 00:43

Quote:
Originally posted by Stramonium
Can anyone find any issues with this synthesis-

The reaction of diphenylmethanethiol with 2-chloroacetamide to give 2-(benzhydrylthio)acetamide?

The proposed synthesis would follow a similar procedure to below [1].

"Benzhydryl-thioacetic acid
10 g (0.05 mol) of diphenylmethane-thiol and 2g (0.05 mol) of NaOH dissolved in 60 ml of demineralised water are introduced successively into a 250 ml flask equipped with a magnetic stirrer and a reflux condenser. The reactants are left in contact for 10 minutes whilst stirring, and a solution consisting of 7g (0.075 mol) of chloroacetic acid, 3g (0.075 mol) of NaOH pellets and 60 ml of demineralized water is then added all at once. The aqueous solution is gently warmed to about 50°C for 15 minutes, washed with 50 ml of ether, decanted and acidified with concentrated hydrochloric acid. after filtration, 10.2g of benzhydryl-thioacetic acid are thus obtained. Melting point 129-130°C. Yield 79%."

with the exception that an equimolar quantity of 2-chloroacetamide would substitute the chloroacetic acid to (hopefully) give 2-(benzhydrylthio)acetamide.

The 2-(benzhydrylthio)acetamide could then be oxidised with a H2O2/AcOH system to give 2-(benzhydrylsulphinyl)acetamide as detailed in [1].

Any input would be greatly appreciated!

REFERENCES
[1] US Pat 4,066,686 & 4,177,290

EDIT: changed the names of some of the compounds to remove confusion and added a reaction scheme.

[Edited on 15-5-2007 by Stramonium]

[Edited on 15-5-2007 by Stramonium]


This looks like the discussion posted by Rhodium, where plenty of leads were given and references ......solo

...........source,

http://www.erowid.org/archive/rhodium/chemistry/adrafinil.mo...

Stramonium - 15-5-2007 at 01:33

Thanks for both of the replies. I had seen the Rhodium synthesis but thanks for the link. A further search of a closely related forum found this (below) which answers the questions I had. I've posted it incase anyone else has any use for it.

[Source: Posted by Antoncho Post No 429898, originally by Fomalhaut and Dionket]

benzhydryl-sulfanylacetamide.

Diphenylbromomethane (4,95g = 0.02 moles) and thiourea (1,52g=0.02moles) were refluxed in 20mls water for 30mins. As the synth from Rh's says, a clear solution must have been formed in 5 mins, but in the end we still had a lot of oil at the bottom (the reasion to blame was old, semidecomposed diphenylbromomethane - when we opened the can, it emitted HBr). We were too lazy to separate the oil , so 2.5g (0.04moles) KOH in 15mls water was added straight and the reflux continued for 30 more mins. A disgusting stench filled the lab.

Thus obtained solution of potassium salt of diphenylmercaptane was cooled to 50-60 C and 1.9g (0.02moles) of chloroacetamide was added thereto. The mixtr was left to its own devices for 2hours - the precipitated oil crystallized. The xtals were filtered, washed thrice w/water, thrice w/ether (removing all benzhydrol). After drying there was obtained 1.9g (37%) of finely divided crystals with mp of 111 C.

With fresh diphenylbromomethane this will give not less than 80% - otherwise I'll bee a reddish (this is an idiom which I am again unable to translatesmile).


Modafinil

Into the solution of 3.6g benzhydrylsulfanylacetamide (0.014moles) in 15mls of GAA there was added 3mls (~0.03moles) 30% hydrogene peroxide. The mixture was left at RT (15 Ñ in our case, better not to heat above) for 20 hrs. Then into the solution there was added 30mls aqua, scratching the walls with a glass rod. After 1 hr the precipitate was filtered, washed w/water twice, then w/ether and dried. Yield - 2,3g (61%), mp - 158-159 C. After some time the mother liquor yielded some more product but we were too lazy to work it up.

heksogen pl - 17-1-2010 at 11:11

Sorry for digging out a dinosaur,
I'm currently searching for a synthesis of diphenylmethyl bromide from diphenylmethanol which is easily obtainable from aldrich.
This seems a relatively easy SN1 reaction, but the workup would be different than in synthesis of other aliphatic bromides - the product is a solid MP= 45°, BP= 184° @ 20 mm Hg, while the corresponding alcohol has MP = 65-67*C, BP= 298*C @ 780mm Hg making it rather hard to isolate via vacuum distillation.
I wonder if I could extract the product with toluene - but again cannot find any info about solubility of diphenylmethanol (alas, seems hydrophobic). Maybe adding toluene to the reaction mixture (48% HBr, H2SO4, diphenylmethanol) and using very rapid stirring would simplify the procedure and move the equilibrium towards product.

I'll try digging beilstein, but maybe someone has some valuable info ?

Nicodem - 17-1-2010 at 11:41

You can use acetic acid as solvent and about 3-fold excess of 48% or 62% HBr (whichever you have). Then just heat for a dozen of minutes on a steam bath, check with TLC, if finished dilute with water and crystallize the dropped out oil by using whatever solvent is recommended (for benzhydryl bromide I would guess methanol is used). Never really used this on a benzhydryl alcohol, but it works satisfactorily on benzyl alcohols which are much less prone for SN1 substitutions.

PS: I don't know what you need benzhydryl bromide for, but you should consider that many nucleophiles can be easily alkylated with benzhydyl alcohol just as easily (under acidic conditions in SN1 substitutions).

heksogen pl - 17-1-2010 at 12:15

I will use it for synthesis of modafinil or its analogs (too much work to do to waste time for sleeping ;) ). I haven't seen any synthesis of diphenylmethanethiol using benzhydryl alcohol, though there is a mention about direct synthesis of thiols from corresponding alcohols, thiourea and HBr (5.17.1, page 754, Vogel 5th edition)
Thanks for help nicodem.

smuv - 17-1-2010 at 12:18

You can make the starting halide as well through the friedel crafts alkylation of benzene with CHX3. Do the reaction in an excess of chloroform (or bromoform if you must). The amount of AlCl3 doesn't matter, I have had luck with between .1 and 1 eq. You know the reaction is done when the evolution of HCl ceases. I did this reaction many times on p-xylene with chloroform. Once initiated the reaction is pretty quick even at ice bath temperatures (appreciably done in an hour). I expect the reaciton will proceed pretty quickly with benzene. Just a note, it fails with p-methoxyanisole, at least at room temp, with even a >>2x excess of AlCL3.

With para-xylene, upon hydrolysis, the mix becomes blue fluorescent, I never isolated this impurity (trace by tlc), it might be the 9,10-dichloroanthracene, or the 9-chloroanthracene. Based on this, I would not try to heat the reaction to try to squeeze out better yields from this reaction (the yields are already pretty good anyways).

[Edited on 1-17-2010 by smuv]

heksogen pl - 17-1-2010 at 12:39

@ smuv :
Unfortunately, despite toxicity of benzene, the friedel-crafts reaction can go further forming disubstituded benzene (Steric hindrance won't preserve it from going into para position). To worsen the case, the first substituent will activate the ring.
Benzene and dibromophenylmethane (benzal bromide) should be used to form the mentioned bromide.

smuv - 17-1-2010 at 12:43

You have no idea what you are talking about, I am speaking from real world experience.

The alkylation with chloroform is a special case, because the benzal chloride formed is very deactivated and will not undergo further alkylation. Even the possible presence of the anthracene derivatives is surprising, in light of how ring deactivated the phenylhalomethanes are.

heksogen pl - 17-1-2010 at 12:56

Yes I do know the reaction, it is the intermediate of Reimer-Tiemann reaction. It was my mistake, sorry. But again - I'm supprised that the diphenylmethyl halide does not undergo another electrophilic attack.

Nicodem - 18-1-2010 at 04:49

Quote: Originally posted by heksogen pl  
I haven't seen any synthesis of diphenylmethanethiol using benzhydryl alcohol, though there is a mention about direct synthesis of thiols from corresponding alcohols, thiourea and HBr (5.17.1, page 754, Vogel 5th edition)

Thiourea is a powerful nucleophile also in acidic media and can be thus used in SN1 substitutions. See WO2008031227 or Bulletin of the Chemical Society of Japan, 77, 2011-2020 for the synthesis of benzhydrylthiol from benzhydryl alcohol.

Bitburger - 21-10-2011 at 05:56

Quote: Originally posted by stoichiometric_steve  
you can use potassium peroxymonosulfate (oxone) to selectively oxidize the sulfide and prevent oxidation to the sulfone.


It think it doesn't make any sense to use oxone instead of hydrogen peroxide to prevent over-oxidation to the sulfone. (James R. McCarthy, Donald P. Matthews, and John P. Paolini (1998), "Reaction of Sulfoxides with Diethylaminosulfur Trifluoride", Org. Synth.; Coll. Vol. 9: 446)

It might be useful to add hydrogen peroxide in the presence of a alcohol & mineral acid and at low temperature. (US patent 7057068)

I think you can reduce the sulfone to the corresponding sulfoxide (modafinil) by using a reducing agent like NaBH4 Not sure or side reactions would take place like a too strong reduction, which might give rise to the previously obtained sulfanyl (sulfide) structure?