Stereocontrol with Rotationally Restricted Amides - Jonathan ...

August 1998 Stereocontrol with Rotationally Restricted Amides 813
Ar–CO bond) stereochemical information could not survive from the
lithiation step through to the final product 14.
interconverting conformers. How could we observe an initial ratio of
products obtained at low temperature A rough calculation suggested
that the barrier to rotation 27 about the Ar–CO bond of 17 was such
(about 60 kJ mol –1 ) that if we carried out the reaction at –78 °C the two
stereoisomers might interconvert sufficiently slowly to be trappable as
atropisomers by carrying out a second ortholithiation in situ. And indeed
this worked: Jennifer laterally lithiated 17 (no ortholithiation was
observed here) and added ethyl iodide, to give 18. Then – still keeping
the reaction cold – she lithiated again, added methyl iodide, and got 19
as a 90:10 ratio of products. At –78 °C, 17 behaves as a chiral
compound!
As it happened, these laterally lithiated naphthamides were about to
inflict a series of blows to our confidence in making deductions from
precedents – the first being that 20 is in fact configurationally stable
even at –40 °C. 29 In the end, though, the experiments we designed to
investigate the structure of 20 told us much more than we had originally
expected, and we managed to get some important insights into the
mechanisms of electrophilic substitution reactions of organolithiums
and organostannanes.
Our understanding of all of these reactions was complicated by the fact
that there are two possible sources of stereoselectivity (Scheme 9): the
first step (the lithiation) or the second (the electrophilic quench). The
literature led us to expect the second, because Beak had shown that
lithiated 17 is configurationally unstable at the lithium-bearing centre, 28
and with a configurationally unstable organolithium 20 (that is,
configurational stability at the lithium-bearing centre: we know that a
2,6-disubstituted aromatic amide will be configurationally stable at the
The experiments started with the atropisomeric stannane 21a, which,
like its silyl analogues, was formed largely as a single atropisomeric
diastereoisomer (though we could not at this stage be sure which one, so
we must leave the stereochemistry of 21a undefined for the moment) on
quenching laterally lithiated 12 with Bu 3 SnCl. 29 Stannane 21a could be
transmetallated back to an organolithium and then quenched with an
electrophile (ethyl iodide) and gave a 60:40 mixture of diastereoisomers
of 14 (Scheme 10). Thanks to the thermal instability of atropisomeric
diastereoisomers, Jennifer was able to epimerise 21a to its
diastereoisomer 21b just heating it at 65 °C for a couple of days –
indeed, it required considerable care to prevent the thermodynamically
unstable 21a epimerising to 21b simply on work up. Unlike 21a, 21b
gave a single diastereoisomer of 14 on transmetallation–electrophilic
quench. The intermediate organolithium 20 clearly has some degree of
configurational stability (or the two stannanes would have given
identical results), but the results themselves raised yet more questions –
for example, was the 60:40 ratio we got from 21a a consequence of slow
equilibration between diastereoisomers of the intermediate
organolithium 20, or did the transmetallation itself produce a mixture of
organolithiums We spent some time designing and carrying out
experiments to eliminate possibilities one by one, but in the end, we
decided simply to run proton NMR spectra of the organolithiums we
had obtained (a) just by lithiating the amide 12, (b) by transmetallating
stannane 21a, and (c) by transmetallating stannane 21b. The aromatic
regions of the spectra we got (shifted upfield as these are anions) are
shown in Figures 6a, 6b and 6c, and remained the same after 1 hr at –40
°C.