Hi and wellcome to Part 3 of my video playlist
about the best methods to convert aliphatic
alcohols into alkyl iodides.
This presentation is about some additional
reagents that can be used to prepare iodides
from alcohols. These include mixtures of chlorosilanes
and alkali iodides, iminium iodides, and mixtures
of chloroformates and alkali iodides. These
reagents are not as versatile as those discussed
in the other two presentations, but may turn
out to be superior with some specific alcohols.
Iodosilanes can also be used, but most deoxyiodinations
by means of silanes are conducted with mixtures
of chlorosilanes and some ionic iodide. One
proposed mechanism is sketched here. It is
assumed that in this reaction the chlorosilane
is activated by reaction with the solvent.
Depending on the type of alcohol chosen, the
initially formed silylether can react directly
with iodide to yield the alkyl iodide, or
may require a second silylation to provide
a sufficiently reactive intermediate. Thus,
alcohols which readily form stable carbocations
will not require twofold silylation, and may
give high yields of alkyl iodide with only
one equivalent of chlorotrimethylsilane, while
a less reactive alcohol may require two equivalents.
This example is the conversion of cyclohexanol
to cyclohexyl iodide, as reported in the article
describing this strategy for the first time.
Because cyclohexene is often formed from cyclohexanol
in such reactions, the yield looks a bit too
high, and no purity of the final product was
given.
In this more recent example an allylic alcohol
was converted to the corresponding iodide.
Because allylic alcohols form carbocations
readily, only a slight excess of chlorosilane
was required. Nevertheless, both allylic rearrangement
and isomerization of the double bond took
place to a significant extent. Such side reactions
are problematic, because the resulting product
mixture will be difficult to separate into
its components, which will have very similar
boiling points and solubilities.
Treatment of prenol with only one equivalent
of chlorosilane in the presence of water again
caused some byproduct formation, namely addition
of hydrogen iodide to the double bond. Because
water will compete with the silylation of
the hydroxyl group of prenol, this reaction
appears to be more an acid-catalyzed deoxyiodination
than a reaction proceeding exclusively via
silyl ethers.
As with most other deoxyiodination procedures,
reduction is an important potential side reaction.
In particular when using a large excess of
iodide, as in this example, or when allowing
the reaction to proceed for too long, sensitive
groups can be reduced extensively. Despite
the use of a large excess of reagents, the
secondary, non-benzylic hydroxyl group was
only partially transformed into an iodide.
Iodide is a uniquely non-basic nucleophile
and will remain unprotonated even under strongly
acidic conditions. No other common nucleophile
shows so little basicity. Therefore, iodide
is well suited for nucleophilic substitutions
in the presence of acids, and will often displace
groups which require protonation or activation
by a Lewis acid to be displaced. As shown
in the example on this slide, ethers can also
be converted to alkyl iodides with the silane-iodide
mixture. The fact that the secondary alcohol
was not converted into an iodide suggests,
that this reaction is responsive to steric
effects, and will proceed much faster at primary
than at secondary C-O bonds.
Only few examples have been reported of the
use of iminium iodides as deoxyiodinating
reagents. The main reason for this is that
iminium iodides are not easy to prepare. Thionyl
iodide or carbonyl iodide are not readily
available, and sodium iodide is only well
soluble in acetone, but not in the less reactive
solvents required for the preparation of iminium
halides.
In the example on this slide a thioformamide-derived
iminium iodide was used to convert a primary
alcohol into the corresponding iodide. As
byproduct 4% of the formic acid ester was
obtained.
The required iminium iodide was prepared by
electrophilic methylation of thioformamide
with methyl iodide.
This reaction is likely to proceed by initial
formation of an alkoxyiminium iodide, which
undergoes nucleophilic substitution with iodide.
The formate must be formed by hydrolysis of
the intermediate iminium salt by traces of
water.
Here are some more examples. In the newest
reference DMF was activated by photolytic
alkylation with iodoform. Photochemistry has
become very fashionable in recent years.
Another way to generate the synthetic equivalent
of iminium iodides is to prepare iminium salts
with anions of low nucleophilicity, such as
chloride or triflate, in the presence of some
soluble ionic iodide. The older two references
on this slide are based on this strategy.
It has also been reported that alpha-chloroethylcarbonates
react with iodide to yield an intermediate
which upon heating yields alkyl iodides. This
intermediate may be an iodoformate, but I
couldn't find any proof of this.
There are almost no examples of the conversion
of alcohols into chloroformates, followed
by treatment with iodide. The only example
I found was an article from 1967 where cholesterol
was first converted into the chloroformate
and then into the iodide by treatment with
NaI in acetone. This could be a useful strategy,
but the few reported examples makes me suspect
that this reaction does not work well. One
reason could be the reduction of chloroformates
by iodide. Anyway, maybe this should be retested
with some effective phase-transfer catalyst.
That's it, hope you found this useful, and
stay tuned for the next presentations.
