The most difficult step in the synthesis of ketamine seems to be the grignard. Avoiding it might be possible by doing a pinacol
coupling between cyclopropanone and o-chlorobenzaldehyde; the analogue lacking the chlorine atom would be even more simple to make.
The coupling would be followed by a pinacol rearrangement to give the usual intermediate that can then be further processed.
Tgoughts/suggestions/improvements? A synthesis of o-chlorobenzaldehyde would also come in handy...
Helgoland

Electrophilic Chlorination of Toluene could be done with Cl₂ in Acetic acid but you will have to fraction your product as selectivity is low. From that there is a few ways to the aldahyde but all I have tried so far have been finiky. If Toluene is cheep to you its a viable route to o-chlorobenzaldehyde

I believe if one managed to get this synthesized where the amine is in place chlorination using a chlorinated solvent and Cl₂ should proceed fine giving a higher selectivity of the Ortho product via the chloramine intermediate.

Reporting what doesn't work is equally as important as what will.  I hate when I read a paper and all I see are great yields: it means you're not telling me where the weakness are in the methodology.

Not to mention putting threads with legitimate discuss in the 'den of iniquity' certainly doesn't promote conversation.

Sedit provided information on electrophilic chlorination and I provided information on an allylboration procedure, I guess I don't understand what comprehends worthless

""Reporting what doesn't work is equally as important as what will.  I hate when I read a paper and all I see are great yields: it means you're not telling me where the weakness are in the methodology."" -- Agreed, and hence I put this in a place where the conversation could have continued.


""Not to mention putting threads with legitimate discuss in the 'den of iniquity' certainly doesn't promote conversation."
--- More so than the "frozen" vacuous post section. It allows the conversation to continue..



I do not think this is cluttering the search engine results either, though that is subjective; I think others who have this thought, or related idea should find the information realising by this conversation that it does not work, and why it does not work.

I wonder, if there is any possibility to alkylate an oxime anion(resonance structure same as nitrosocompound a-anion) at C-center with carbonyl compound. Google is silent about that. Oximates are known to be alkylated mostly at oxygen, BUT the examples are given for RX as alkylating agents, at the same time it is known that alkylating of any oxygen nucleophile with carbonyl alkylator is impossible. So what i suggest is, 1) to find out if there are any examples in literature of that kind aldol condensation of oximes with carbonyl compounds. 2) if not, then what reason (kinetics or thermodynamics) prevents it. I suppose that is kinetics, because a-hydroxy oximes are known to be stable, and are used as chelators for some metals. Even if that is still thermodinamics, the same metals can be used to make reaction both thermodinamically(due to chelate formation) and kinetically(coordination of nucleophile and electrophile reducing the enthropy loss in transition state, activation of carbonyl group) possible. If metal does not want to coordinate with cyclopentanone, then making imine out of that(with ammonia) in undydrous conditions may help, provided there is a possibility of same kind rearrangement with cyclopentylamine derivative like with cyclopentanol (the last step in K synthesis).

Another potential "fromcrap" route to ketamine could be base-catalysed o-nitrotoluene aldol condensation with cyclopentanone (like in US4497966, non-enolizable carbonyl compounds are preferred, but enolizable can also be used as they wrote "acetaldehyde" there http://www.patsnap.com/patents/view/US4497966.html) , then reduction of the resulting nitroalcohol into aniline, then diazotation in HCl to get o-chloro alcohol, in which acid eilmination of H2O should easily proceed(due to tertiary carbocation stability and conjugation). Then epoxidation, basic hydrolisys of epoxide, oxidation of benzylic OH into carbonyl, methylamination and heating.