Complex-Induced Proximity Effects
J. Am. Chem. Soc., Vol. 123, No. 2, 2001 317
Table 2. Lithiation-Substitution of Bicyclic Carbamates 9 and 10
to Give 31-35
Scheme 1
product
R
electrophile
E
yielda (%)
31
32
33
34
35
t-Bu
i-Pr
t-Bu
i-Pr
Me2SO4
Ph2CO
Ph2CO
PhMe2SiCl
PhMe2SiCl
Me
85
C(OH)Ph2
C(OH)Ph2
SiMe2Ph
SiMe2Ph
59b
62c
N-Boc amines 4, 5, 6, and rac-23 were subjected to a series of
competition experiments to determine whether they undergo
directed lithiation with significantly different efficiencies.
A previous kinetic analysis of a carbamate-directed lithiation
provided evidence for fast complex formation between N-Boc
pyrrolidine and isopropyllithium/(-)-sparteine prior to the
deprotonation step.22 The equilibrium favored complexation and
was followed by a rate-determining deprotonation. Under this
mode, Scheme 1 can be used to describe the kinetic competition
experiments carried out on two carbamates. Reactants A and B
are the two carbamates used in the competition experiment, and
KA and KB are the equilibrium constants for complexation of A
and B with RLi to form CA and CB, the resulting complexes.
The constants kA and kB are the rate constants for deprotonation
to form lithiated products, PA and PB, respectively. The
magnitudes of both the equilibrium constants and the rate
constants can affect the competitive efficiencies of the reactions
compared.
47, 14d
50, 10d
t-Bu
a A careful search for diastereomers in each case did not reveal their
presence. We estimated at least 2% of any diastereomers would have
been detected by GC analyses. b Olefin 36 was isolated in 8% yield.
c Olefin 37 was isolated in 10% yield, and a compound tentatively
identified as trans-33 was isolated in 2% yield. d The yields of the cis
and trans isomers are reported.
followed by dimethyl sulfate provided diastereomerically pure
31 in 85% yield. The reactions of 9 and 10 with benzophenone
were also highly stereoselective, and cis-32 and cis-33 were
obtained in 59 and 62% yields, respectively, along with small
amounts of olefins 36 and 37. The substitutions of organolithi-
ums 29 and 30 with chlordimethylphenylsilane were not
completely selective; 34 and 35 were formed as 3:1 and 5:1
cis:trans mixtures, respectively.
The competition experiments were carried out in two ways:
under pseudo-first-order conditions with 15 equiv of s-BuLi or
under second-order conditions with a deficient amount of
s-BuLi. Under pseudo-first-order conditions, the equilibria
shown in Scheme 1 are assumed to lie far on the side of the
complexes CA and CB. If two carbamates have different
equilibrium constants for complexation with s-BuLi, the pres-
ence of a large excess of s-BuLi may compensate for the
difference by forcing the equilibria to the side of the complex.
In that case, the pseudo-first-order competition experiments
would reflect differences in competitive efficiencies for the
deprotonation step. Comparisons of the relative extents of
lithiation of two carbamates under pseudo-first-order and second
order would test this assumption. The observed extents of
reaction should be the same if complexation is not a determining
factor and different if complexation is important. We recognize
that this simplification and the discounting of possible differ-
ences in side reactions and effects of organolithium products
PA and PB on the reaction restrict us to a semiquantitative
interpretation of the results.2
The major diastereomers isolated from the reactions of 9 and
10 with electrophiles were assigned the cis configuration on
the basis of H NMR coupling constants of the protons at C-2
1
and C-6. For each of the compounds 31-33 and the major
diastereomers of 34 and 35, both H-2 and H-6 have characteristic
axial-axial coupling constants (8-13 Hz) and characteristic
axial-equatorial coupling constants (3-6 Hz).20 These data
indicate that both H-2 and H-6 in the disubstituted piperidines
31-35 are axial protons and that the cis diequatorially substi-
tuted diastereomers are the major products obtained from
diastereoselective lithiations-substitutions of 9 and 10.20
In the oxazolidinones 7-10 the cis protons are more nearly
planar with and in closer proximity to the carbonyl group than
are the trans protons (vide infra). On the basis of analogy to
the lithiation-substitution of Boc amines, retentive substitutions
are assumed, and the organolithiums 16, 17, 29, and 30 are
assigned cis geometry. Lithiation-substitution occurs highly
selectively on the more sterically encumbered concave face of
the bicyclic systems. This stereochemistry suggests that there
is a geometrical requirement for a carbamate-directed lithiation
in which the carbamate carbonyl group complexes to s-BuLi to
direct lithiation to the same face of the bicyclic system.1
Competitive Efficiency in Carbamate-Directed Lithia-
tions: Comparison of Constrained Carbamates and Boc
Amines. Oxazolidinones 7, 10, and 11, oxazinan-2-one 15, and
For both sets of competition experiments shown in Table 3,
two carbamates were treated with s-BuLi/TMEDA followed by
a deuterium source. Not all the substrates were directly
compared, but selected substrates were used in direct competi-
tion experiments as described in Supporting Information to
determine an order of competitive efficiencies for each series.
The yields for each of the products were generally above 80%.
A typical competition is shown for 4 and 10.
Some inconsistencies were observed in the competition
experiments. A competitive efficiency of 28 for oxazolidinone
10 with respect to piperidine 5 was calculated from a direct
(21) The cis-2,6-disubstituted piperidines 31-35 arise from sequential
equatorial lithiation-substitutions. It was reported previously that in
sequential metalations of 2, 2,6-disubstituted piperidines with trans geometry
are obtained.9 The equatorial lithiation and substitution of pipieridine 2
followed by trapping with Me2SO4 provides 2-methyl N-Boc piperidine.
In this case, the methyl group R to the nitrogen interacts unfavorably with
the Boc group through A1,3 strain, and a ring flip occurs placing the
substituent in the axial position. A second equatorial lithiation of the
substituted N-Boc piperidine results in a product with trans geometry. For
equatorially substituted cyclic carbamates 9 and 10, A1,3 strain is not a factor,
and the expected second equatorial lithiation results in the cis diastereomers
31-35.
(20) Pretsch, E.; Siebel, J.; Clerc, T.; Bieman, K. Tables of Spectral Data
for Structure Determination of Organic Compounds; 2nd ed.; Springer-
Verlag: Berlin, 1989.
(22) Gallagher, D. J.; Beak, P. J. Org. Chem. 1995, 60, 7092-9093.