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42090-B1
Investigation of Arene-Heteroatom and Arene-Carbon Bond Formation by Aryllithiums
Donald Slocum, Western Kentucky University
As part of
our program to introduce hydrocarbon solvents as exceptional media for the execution
of ortho-metalations, we have studied
several selected substrates with the intent of improving their respective
metalation procedures. How better to demonstrate the efficiency of metalation
in hydrocarbon solvents than to successfully tackle systems that present a
problem. Recent studies in our laboratory have resulted in significant
improvements in the metalation of several substrates. In each case a 1:1 ratio
of alkyllithium reagent was utilized at concentrations ranging between 0.67 M
and 2.0 M. These substrates and the conditions for their metalation are listed
in Table I. For those where >95% of the ortho-lithio
intermediate has been generated, atom-economy is deemed to have been
achieved.
Each of
these procedures requires additional description and explanation. For the
metalation of anisole, the catalytic system that produces 95-97% o-LiA is 0.1 equiv. of TMEDA. If the
product o-LiA, a flocculent precipitate,
is allowed to settle in the reaction flask, the supernate drawn off with a
syringe and replaced with an equal volume of pure cyclohexane, a system which
analyzes as 97-99% o-LiA is produced.
Likewise, metalation of DMA at 60oC utilizes just 0.15 equiv. of
TMEDA to achieve the highest percent o-LiDMA.
The initially generated 90-93% o-LiDMA
system can be enriched in a fashion similar to that for o-LiA. For both systems use of a full equivalent of TMEDA results
in lower yields of the desired ortho-lithio
intermediate.
Metalation
of DMBA and o-MA each exhibit a problem with contamination by a
secondary site of metalation. For DMBA, lateral α-metalation needed to be
excluded to cleanly afford the ortho-lithiated
amine while for o-MA, ortho-lithiation
was to be avoided to cleanly produce the α-product. In each case,
examination of our “designer media” systems, fractional equiv. of TMEDA in
hydrocarbon solvent and equiv. of THF in hydrocarbon solvent, failed to afford
the sought selectivity. 7Li NMR suggested that MTBE at relatively
low concentrations in cyclohexane deoligomerizes n–BuLi at least as
effectively as THF. From this observation a successful, regiospecific ortho-metalation of DMBA was developed.
A somewhat
similar approach led to the successful α-metalation of o-MA.
This realization was most promising for our program in that, in addition to
literature studies assessed in a recent review, a computational study also concluded
that regiospecific lithiation of o-MA could not be accomplished using
alkyllithium reagents. The formulation for this successful metalation procedure
for o-MA arose from the confluence of ideas and observations reflecting
our original proposition that metalation reactions, in this case an
α-metalation, can be significantly improved by being performed in
designer hydrocarbon media.
The above
described protocols for ortho-lithiations
of anisole (A), dimethylaniline (DMA), dimethylbenzylamine (DMBA) and o-methylanisole (o-MA) in hydrocarborbon solvents have been extended to the dimethoxybenzenes
(DMB's) the p-haloanisoles (p-XA's) and p-tetramethylphenylenediamine (p-TMPDA).
In these instances, previously designed protocols or slight modifications
thereof, were discovered which satisfied two of our stated criteria (1) that
ether media were to be avoided or their complement minimized and (2) that
higher, atom-economical procedures be developed that were at least equal to any
recorded in the literature. In certain instances, e.g., those for p-BrA and p-IA, procedures were found that avoided the literature described
use of phenyllithium. Metalations utilizing phenyllithium produce benzene,
TABLE 1.
Efficient Metalation of Arenes in Hydrocarbon Solvents
Substrate | Solvent/Catalyst | T(°C) | Alkyllithium | %Yield |
Anisole (A) | cyclohexane/0.1 equiv. TMEDA | 60 | n-BuLi | 97-99 |
Anisole (A) | cyclohexane/0.2 equiv. (-)-sparteine | 25 | n-BuLi | 85 |
Anisole (A) | n-hexane/3 equiv. THF | 25 | n-BuLi | 85 |
Dimethylaniline (DMA) | cyclohexane/0.15 TMEDA | 60 | n-BuLi | 90-93 |
Dimethylbenzylamine (DMBA) | cyclohexane/1.5 equiv. MTBE | 60 | n-BuLi | 95 |
o-Methylanisole (o-MA) | cyclohexane/1.0 equiv. MTBE | 0 | t-BuLi | 80 |
o-dimethoxybenzene (o-DMB) | cyclohexane/0.2 eqiv. TMEDA | 25 | n-BuLi | 88 |
m-DMB | cyclohexane/0.1 eq. TMEDA | 25 | n-BuLi | 96 |
p-DMB | cyclohexane/0.1 eq. TMEDA | 25 | n-BuLi | 92 |
p-CIA | cyclohexane/1.0 eq. THF | 25 | n-BuLi | 88 |
p-BrA | cyclohexane | 25 | o-LiDMA | >90 |
p-IA | cyclohexane | 25 | o-LiDMA | >80 |
p-tetramethylphenylenediamine (p-TMPDA) | cyclohexane | 60 | n-BuLi | >70 |
The generation
of which is to be avoided in the present day. By the minimumization or
avoidance all together of the use of ethers for these metalations, the plagues normally
associate with the use of ethers (hydroscopic nature, peroxides, reactivity with
alkyllithiums) are avoided, thus rendering our developed protocols more
environmentally acceptable and more sustainable.
Of the
students listed on the personnel form, one is teaching high school chemistry,
one is in medical school, one is in graduate school in a School
of Architecture, one is in chemistry graduate
school (U. of Ill.), and one is in pharmacy school.
The remaining two are still deciding what they plan to do. As for myself, this
funding allowed me to prepare a much more comprehensive proposal, which has
been funded by the NSF.
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