megalodon
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Reductive Alkylation with Thiourea Dioxide?
I floated the idea of reductive amination using thiourea dioxide (thiox) a while ago in the thiox thread... I want to report an experiment and ask
again if anyone thinks this is feasible.
Reductive Alkylation
aka reductive amination, is the condensation of an amine with a carbonyl group to form an imine, hemiaminal or an imminium ion, followed by treatment
with a reducing agent to form a substituted amine. (Wikipedia, Solomon's Organic Chemistry 6th Ed p. 728-729, 916-917)
According to this, reductive alkylation procedes by an electron transfer mechanism.
The reducing agent employed can be hydrogen and a metal catalyst, lithium aluminum hydride, borohydrides, cyanoborohydrides, or more exotic compounds.
However, these present barriers in terms of access for the amateur chemist, as well as issues with the generation of toxic, flammable, or otherwise
hazardous and unpleasant substances, such as cyanide or THF. A truly green approach to reductive alkylation is wanting.
Thiourea Dioxide
or Thiox, is a white powder and a reducing agent used in the dye and textile industry, and is available over the counter. Its use as a reagent in
organic chemistry is underexplored, but the literature suggests that it can be used synthetically as a reducer, eg, to reduce ketones to alcohols (Nakagawa and Minami 1972).
Thiox's reducing power is activated in basic conditions, where it reacts with OH- to release electrons. (Zhou et al 2012) Given the mechanism above, it seems plausible that thiox could be used as a reductant in an amination.
Planned Procedure
A potential problem is that imine formation is catalyzed by acidic conditions. However, H3O+ is only necessary to catalyze the formation of an
iminium/imine from the hemiaminal. It does not appear to be necessary for the condensation of the carbonyl with the amine to form the hemiaminal. And,
the hemiaminal appears to be reducible in the same way that the imine is. (Solomon's)
Another potential problem is that the thiox could reduce the carbonyl directly. For this reason, the mixture of carbonyl and amine will be stirred for
a while to at least form the first imine.
The amine available and most interesting to me is tryptamine; deal with it. If successful, this reaction would have the extra appeal of avoiding the
Pictet-Spengler reaction which acidic conditions are prone to.
The procedure is a hybrid of the thiox reduction in (Nakagawa & Minami) and the turd/devchem borohydride reaction, ie 5 eq formaldehyde and 4 eq reducing agen to 1 eq amine.
Experimental
1.0 g B-grade tryptamine is available, ie, 6.25 mmol. This equates to 2.35 mL 40% formalin and 2.7 g thiox.
1.008 g Tryptamine were added to a 250 mL beaker and dissolved in 25 mL 200 proof ethanol. 3 mL formalin were added with stirring. The mixture stirred
for ~15 minutes.
2.108 g NaOH were added to a beaker with 20 mL water. 2.897g thiox were added to the beaker, and the mixture swirled to dissolve.
The basic thiox solution was dripped into the alcoholic tryptamine, turning it slightly cloudy. The mixture was stirred ~24 hours.
After stirring, the mixture, now clear, was poured into a separatory funnel. 2.997g more NaOH were massed and dissolved in a bit of water and added,
but no cloudiness was observed, though the pH was measured at 14. The aqueous mixture was extracted 2x with 10 mL toluene; the organic portions were
pooled and the solvent removed under vacuum.
A surprisingly small amount of waxy solid was left in the petri dish. When heated, it had a clear tryptamine odor, but also was clearly not the target
molecule. A TLC plate was run comparing the product to a sample of target molecule synthesized with STAB, and confirmed that they were different
compounds. No MP thusfar.
Results/Discussion
The reaction conditions do not appear to hit the target molecule of dimethylated tryptamine.
A few possibilities are:
*Thiox is too weak a reducer
*Thiox is too strong a reducer and is reacting with the substrate in unintended ways
*Thiox can methylate, but not dimethylate.
*Thiox attacks the carbonyl before it can condense with the amine
*pH is inappropriate for intermediate steps
*Reaction proportions are incorrect
If basic reduction proves infeasible, another possibility is reduction in acidic conditions. Thiox's reducing power can be 'unlocked' in acidic
conditions by heating the mixture (Zhou et al.), even down to pH 4-5, where imine formation is optimized (Solomons).
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stoichiometric_steve
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Not even NaBH4 works well with this. The most rigid method still seems to be amidation with formic acid esters, reduction with LAH, and repetition of
the process.
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megalodon
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I know a couple posts have been about alternative pathways and thus arguably off topic, but they appear to have been deleted without notice. Can
someone explain please?
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