Complex-induced proximity effects: The effect of varying directing-group orientation on carbamate-directed lithiation reactions

Article abstract of DOI:10.1021/ja002662u

A series of selected bicyclic carbamates in which the range of accessible angles and distances between the carbonyl group and the proton removed in an α-lithiation reaction are structurally defined have been investigated. Oxazolidinones 7-10 undergo stereoselective lithiation-substitution reactions to provide cis-18-27 and cis-31-35 as the major diastereomers. Two series of competition experiments show that the conformationally restricted carbamates 7, 10, 11, and 15 undergo lithiation via complexes more efficiently than Boc amines 4-6. These results along with semiempirical calculations suggest that a small dihedral angle and a calculated distance of 2.78 A between the carbamate carbonyl oxygen and the proton to be removed are favorable for a carbamate-directed lithiation. A series of tin-lithium exchange experiments on cis- and trans-18 and (S)-39 indicate that the configurational stability of a carbamate-stabilized organolithium species may be enhanced by restrictive geometry.

Full text of DOI:10.1021/ja002662u

J. Am. Chem. Soc. 2001, 123, 315-321
315
Complex-Induced Proximity Effects: The Effect of Varying
Directing-Group Orientation on Carbamate-Directed Lithiation
Reactions
Kathleen M. Bertini Gross and Peter Beak*
Contribution from the Department of Chemistry, Roger Adams Laboratory, UniVersity of Illinois at
Urbana-Champaign, Urbana, Illinois 61801
ReceiVed July 19, 2000
Abstract: A series of selected bicyclic carbamates in which the range of accessible angles and distances between
the carbonyl group and the proton removed in an R-lithiation reaction are structurally defined have been
investigated. Oxazolidinones 7-10 undergo stereoselective lithiation-substitution reactions to provide cis-
18-27 and cis-31-35 as the major diastereomers. Two series of competition experiments show that the
conformationally restricted carbamates 7, 10, 11, and 15 undergo lithiation via complexes more efficiently
than Boc amines 4-6. These results along with semiempirical calculations suggest that a small dihedral angle
and a calculated distance of 2.78 Å between the carbamate carbonyl oxygen and the proton to be removed are
favorable for a carbamate-directed lithiation. A series of tin-lithium exchange experiments on cis- and trans-
18 and (S)-39 indicate that the configurational stability of a carbamate-stabilized organolithium species may
be enhanced by restrictive geometry.
Introduction
To experimentally evaluate the effect of geometry in the
formation and on the stability of R-lithioamine derivatives of
carbamates we have carried out a systematic investigation of
lithiation-substitution of selected bicyclic structures 1 to give
3 via 2. The systems we prepared constrain the position of the
The course of many novel reactions in organolithium
chemistry can be rationalized by considering the pathways
available to a complex formed by association between an
organolithium reagent and a Lewis basic functionality of a
substrate.1 For deprotonative lithiation reactions the geometrical
constraints within a complex in the transition state for transfer
of the proton to the lithiating reagent have been shown to be
important for efficient reaction. For example, a systematic study
of secondary and tertiary benzamides and of benzylic alcohols
demonstrated that the orientation of the directing group with
respect to the proton removed in ortho lithiations significantly
affects the reaction efficiency.2 For reactions that provide
R-lithioamine derivatives of amides an orthogonal relationship
between the lithio carbanion and the pi system of the amide
has been established to be favorable.3-9 Qualitatively this
arrangement allows complexation of the lithium with the
carbonyl oxygen and relieves the possible repulsive interaction
between the electron pairs of the carbanion and the pi system
in which would be present a fully planar system. Theoretical
calculations and empirical observations support an orthogonal
arrangement in R-lithio N-Boc amines as well.6,8-12
carbonyl oxygen with respect to the proton removed in an
R-lithiation reaction and consequently with respect to the
organolithium base in the presumptive complex. We have found
by competition experiments that changes in the ring sizes
significantly affect the reactivities of 1 in the lithiations which
provide 2. The location of the carbonyl oxygen with respect to
lithium is also found to affect the configurational stability of 2.
Results
Syntheses of Bicyclic Carbamates. The bicyclic carbamates
7-11 containing a five-membered oxazolidinone ring were
synthesized by directed lithiation of N-Boc pyrrolidine (4),
N-Boc piperidine (5), and N-Boc perhydroazepine (6) and
reaction with diisopropyl ketone or di-tert-butyl ketone.9 Cy-
clization of the intermediate alkoxide occurred when the reaction
was warmed to room temperature. The installation of the
sterically bulky isopropyl and tert-butyl groups was necessary
to prevent addition by the butyllithium lithiating reagent to the
carbamate carbonyl group.
(1) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356-363;
Anderson, D. R., Faibish, N.-C., Beak, P. J. Am. Chem. Soc. 1999, 121,
7553.
(2) Beak, P.; Kerrick, S. T.; Gallagher, D. J. J. Am. Chem. Soc. 1993,
115, 10628-10636.
(3) Beak, P.; Zajdel, W. J. J. Am. Chem. Soc. 1984, 106, 1010-1018.
(4) Gawley, R. E.; Hart, G. C.; Bartolotti, L. J. J. Org. Chem. 1989, 54,
175-181.
(5) Meyers, A. I.; Edwards, P. D.; Reiker, W. F.; Bailey, T. R. J. Am.
Chem. Soc. 1984, 106, 3270.
(6) Meyers, A. I.; Milot, G. J. Org. Chem. 1993, 58, 6538-6540.
(7) Meyers, A. I.; Milot, G. J. Am. Chem. Soc. 1993, 115, 6652-6660.
(8) Kopach, M. E.; Meyers, A. I. J. Org. Chem. 1996, 61, 6764-6765.
(9) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109-1117.
(10) Rondan, N. G.; Houk, K. N.; Beak, P.; Zajdel, W. J.; Chandrasekhar,
J.; Schleyer, P. v. R. J. Org. Chem. 1981, 46, 4108-4110.
(11) Bach, R. D.; Braden, M. L.; Wolber, G. J. J. Org. Chem. 1983, 48,
1509-1514.
(12) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan,
S. Acc. Chem. Res. 1996, 29, 552-560.
10.1021/ja002662u CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/21/2000

316 J. Am. Chem. Soc., Vol. 123, No. 2, 2001
Gross and Beak
Table 1. Lithiation and Substitution of 7 and 8 to Provide 18-27
product
R
electrophile
E
time (h) yielda (%)
18
19
20
21
22
23
24
25
26
27
i-Pr
i-Pr
i-Pr
i-Pr
Me3SnCl
Bu3SnCl
TMSCl
SnMe3
SnBu3
SiMe3
5
3.5
4
4.5
2
2.5
3
5
3
5
78
67
64
PhMe2SiCl SiMe2Ph
43
t-Bu PhMe2SiCl SiMe2Ph
i-Pr
t-Bu Ph2CO
t-Bu PhCHO
i-Pr
77, 8a
68
i-Pr2CO
C(OH)i-Pr2
C(OH)Ph2
CH(OH)Ph
Me
48b
66c
68
The differences in yields observed for these reactions result
from differences in reactivities of the corresponding Boc amines
toward metalation (vide infra). The equatorial disposition of the
carbamate ring in the piperidine derivatives 9 and 10 is
established by the values of 1H NMR coupling constants and is
consistent with previous work.3,5,9
The oxazinan-2-one 15 was prepared to provide a compound
which, due to the carbamate in the six-membered ring changes
the position of the carbamyl oxygen with respect to the proton
of interest. The synthesis of carbamate 15 began with the
reaction of commercially available 2-piperidine ethanol with
ditert-butyl dicarbonate. The resulting alcohol 12 was oxidized
with pyridinium dichromate to afford the carboxylic acid 13
which was treated with diazomethane13 to form the methyl ester.
Treatment of the ester with 2.2 equiv of CeCl314 and isopro-
pylmagnesium chloride provided 14,15 which on treatment of
14 with sodium hydride in refluxing THF afforded the bicyclic
carbamate 15.
Me2SO4
t-Bu Me2SO4
Me
77
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 A compound tentatively identified as
the trans diastereomer was isolated in 8% yield. c Additional product
was present but was not separated from benzophenone. d Two diaster-
eomers were formed in a 1.5:1 ratio.
The cis configuration of the methyl substituted oxazolidinone
26 was determined by comparison of this product to authentic
trans-26, which was synthesized by sequential enantioselective
metalations of pyrrolidine 4 with s-BuLi/(-)-sparteine.16 Treat-
ment of N-Boc pyrrolidine with s-BuLi/(-)-sparteine followed
by dimethyl sulfate provided methyl pyrrolidine 28, which was
treated with s-BuLi/(-)-sparteine followed by diisopropyl ketone
to yield trans-26. Physical and spectroscopic evidence confirmed
that trans-26 is different from cis-26, the product generated from
lithiation of 7 and substitution with Me2SO4. By analogy to 18
and 26 the remaining products in Table 1 are assigned the cis
configuration.
Stereoselective Lithiation-Substitutions of Bicyclic Car-
bamates. As shown in Table 1, the pyrrolidine-derived oxazo-
lidinones 7 and 8 upon treatment with sec-butyllithium (s-BuLi)/
TMEDA at -78 °C followed by electrophiles provide the
substituted products 18-27 in good yields. Stannyl and silyl
chlorides, dimethyl sulfate, ketones, and benzaldehyde were
successfully used as electrophiles. A significant feature of this
lithiation-substitution reaction is the generally high cis dia-
stereoselectivity; only single diastereomers of products 18-21
and 23-27 were isolated.
The relative configuration of stannane 18 was determined to
be cis by X-ray crystallography. An interesting feature of this
structure is the near coplanarity of the carbonyl group and the
carbon-tin bond. Assuming the reaction with trimethyl tin
chloride proceeds with retention of configuration, this coplanar
disposition in 18 may be taken to suggest that the proton in 7
that is more nearly coplanar with the carbonyl group is favored
for removal.
With benzaldehyde as the electrophile, alcohol 25 was isolated
as a 1.5:1 mixture of two diastereomers with different configu-
rations at the hydroxy bearing carbon. Evidence for highly
diastereoselective lithiation-substitution at the ring carbon in
this reaction was provided by deoxygenation17 of 25 to provide
a single diastereomer of the benzyl substituted oxazolidi-
none.18,19
The lithiation-substitutions of 9 and 10 were investigated
as shown in Table 2. Treatment of 9 with s-BuLi/TMEDA
(16) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994,
116, 3231-3239.
(17) Dolan, S. C.; MacMillan, J. J. Chem. Soc., Chem. Commun. 1985,
1588-1589.
(18) In addition, two diastereomers were observed when benzyl bromide
was used as the electrophile, but the products were not isolated. It is likely
that lithiation occurred selectively in these reactions, but substitution of 16
with these halides occurs with lower selectivity. Low facial selectivity in
the substitution of R-lithioamines with alkyl halides has been reported.19
An 8% yield of a compound tentatively identified as trans-22 was isolated
when chlorodimethylphenylsilane was used as an electrophile.
(19) Gross, K. M. B.; Jun, Y. M.; Beak, P. J. Org. Chem. 1997, 62,
7679.
(13) Black, T. H. Aldrichimica Acta 1983, 16, 3-10.
(14) Dimitrov, V.; Bratovanov, S.; Simova, S.; Kostova, K Tetrahedron
Lett. 1994, 35, 6713-6716.
(15) The presence of CeCl3 was necessary for the success of the addition.

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.

318 J. Am. Chem. Soc., Vol. 123, No. 2, 2001
Gross and Beak
Table 3. Competitive Efficiencies for Selected Carbamates from
the Two Series of Competition Experiments
The order of competitive efficiency in each set of experiments
in Table 3 is the same, but there are clearly quantitative
differences. In the second-order series, bicyclic carbamate 11
is lithiated greater than 1 order of magnitude faster than
pyrrolidine 4, the most efficiently lithiated Boc amine. In
contrast the results of the pseudo-first-order experiments indicate
that 4, 11, and 10 are lithiated with rather similar efficiencies.
If it is presumed that under pseudo-first-order conditions the
competitions involve fully complexed and equilibrated species,
the competitive efficiencies in this series may be attributed only
to differences in the rates of deprotonation of the substrates.
The second-order experiments may then reflect differences in
the extent of complex formation or other steps prior to
deprotonation. The quotient of the second-order competitive
efficiency and the pseudo-first-order competitive efficiency may
provide an estimate of the differences in equilibrium constants
for complexation for two substrates in a given competition
experiment. For example, in a competition between piperidine
5 and oxazolidinone 10, 10 may be considered to undergo
lithiation 230 times faster and complexation 5 times faster than
5. However, the data is not sufficient to allow firm interpretation.
A more detailed kinetic analysis of these reactions is needed.
Nonetheless, the consistent order in differences in lithiation
efficiencies for carbamates of diverse structure are consistent
with a geometrical requirement for carbamate-directed lithia-
tions. Under both pseudo-first-order and second-order condi-
tions, the oxazolidinones 7, 10, and 11 are lithiated more
efficiently than each of the N-Boc amines. The differences
between lithiation efficiencies of N-Boc amines 4, 5, 6, and 28
were observed previously and are semiquantitatively defined
here.9,16
A comparison of the piperidine-based carbamates illustrates
the effects of varying directing group geometry on the efficiency
of lithiation. In the second-order series, the oxazinan-2-one 15,
which contains a six-membered carbamate ring, was lithiated
>200 times less efficiently than the corresponding oxazolidinone
10, which contains a five-membered carbamate ring. However,
15 was lithiated approximately 5 times more efficiently than
the less restricted piperidine 5. These results indicate that
constraining the carbamate in a six-membered ring increases
the efficiency of the lithiation reaction with respect to the less
restricted N-Boc amine, but the geometry achieved by the
carbamate of the oxazolidinone 10 is more favorable.23
Calculations of Ground-State Structures of the Carbam-
ates. In an effort to obtain insight into the effect of the carbamate
directing group orientation on competitive efficiency, semiem-
pirical PM3 calculations were carried out to identify the lowest-
energy ground state conformations of the carbamates. If the
ground-state structures are reflective of constraints in the
transition states for deprotonation, a correlation may be found
between dihedral angles and distances between the directing
group and the proton removed. The results are shown in Table
3.24
a The values for angles and distances of the lowest energy conforma-
tions were averaged. b The dihedral angle is defined as the angle
between the planes containing H, C, N, and N, CO. c Since two distinct
sets of conformers were generated, the sets were not averaged. d Only
conformations with the carbonyl pointing away from the methyl group
were considered. e Under pseudo-first-order conditions, the lithiation
of 7 was complete in less than one minute.
comparison of these two carbamates under pseudo-first-order
conditions. However, data comparisons from the other competi-
tion experiments in the series would predict a competitive
efficiency of >200 for this experiment as shown in Table 3.
This higher value for the competitive efficiency is more
consistent with the series of experiments. Also a direct
comparison of pyrrolidine 4 and oxazolidinone 11 under pseudo-
first-order conditions was not highly reproducible, and the
competitive efficiency for 11 is considered the least reliable
data point.
A control experiment was carried out to determine if
equilibration of lithiated products was occurring. Pyrrolidine 4
was treated with s-BuLi/TMEDA for 2 h, and a solution of
oxazolidinone 7 was added. The mixture was allowed to stir
for 30 min, followed by quenching with an excess of AcOD.
In this experiment, carbamate 7 was recovered with 1.81%
deuterium incorporation, and 4 was formed with 72.59%
deuterium incorporation. This experiment shows that the deu-
terated products were formed from kinetic deprotonations and
the competitive efficiencies calculated for the competition
experiments do not reflect thermodynamic products.
The Effect of the Position of the Carbonyl Group on the
Configurational Stabilities of Lithiated Carbamates: A
Comparison of Rigid Carbamates and N-Boc Amines. To
evaluate the effect of restricting the position of the carbamate
carbonyl group on the configurational stability of a dipole-
(23) Oxazinan-2-one 15, the third entry of Table 3, was subjected to
lithiation in the presence of pyrrolidine 4 under second-order conditions,
and the deuterated product from 15 was obtained in 66% yield and 6% d1,
and side products were observed by GC and GC/MS. The GC/MS data for
the side products were consistent with addition of s-BuLi to the carbamate
carbonyl group. If the remaining 34% of the material generated from 15
can be attributed to addition products, it may be concluded that this
carbamate undergoes addition approximately 5 times faster than metalation.

Complex-Induced Proximity Effects
J. Am. Chem. Soc., Vol. 123, No. 2, 2001 319
Table 4. Tin-Lithium Exchange of 18 to Provide 26a
stabilized organolithium, the organolithiums 38, cis-16, and
trans-16 were prepared from the corresponding organostannanes
and their stabilities investigated.
stannane diamine temp (°C) time (h) yield 26 (%) cis:trans 26
cis-18
cis-18
cis-18
cis-18
trans-18 none
trans-18 none
TMEDA
TMEDA
none
-78
-40
-78
-40
-78
-40
-78
-78
4
1
6
5
5
1
1
6.5
57
44
69
21
56
24
44
21
>99:1
>99:1
>99:1
>99:1
<1:99
2:1
none
trans-18 TMEDA
trans-18 TMEDA
1:1
>99:1
a When aging at -40 °C was desired, the solution was maintained
at -78 °C for 20 min and then placed in a -40 °C bath for the indicated
time before cooling to -78 °C and adding Me2SO4 to provide 26.
Syntheses of Organostannanes. The stannane (S)-39 was
generated in 86% yield and with 96:4 er by treatment of
pyrrolidine 4 with s-BuLi/(-)-sparteine followed by substitution
with Me3SnCl. The stannane cis-18 was synthesized as shown
in Table 1. The synthesis of trans-18 was accomplished in five
steps using sequential asymmetric deprotonations of pyrrolidine
4 as described for the synthesis of trans-26. Pyrrolidine 4 was
treated with s-BuLi/(-)-sparteine followed by diisopropyl
ketone.25 After recrystallization, alcohol 40 was isolated in 55%
yield with >99:1 er and was protected as the 2-(trimethylsilyl)-
ethoxymethyl (SEM) ether 41 in 76% yield. Ether 41 was treated
with s-BuLi/(-)-sparteine for 24 h followed by reaction with
Me3SnCl to provide a mixture of products which contained
disubstituted pyrrolidine 42. Desilyation and cyclization pro-
vided the trans-disubstituted pyrrolidine 18 in 24% yield.
The results in Table 4 indicate that in the presence or absence
of TMEDA and at either -78 °C or at -40 °C, a highly
stereoselective transmetalation-substitution takes place and the
organolithium cis-16 maintains its configuration. The remainder
of the material isolated from these reactions was destannylated
7. Both transmetalation-substitution of cis-18 and lithiation-
substitution of 7 provide cis products, and the configurations
of cis-18 and cis-26 are both known unambiguously. Trans-
metalation-substitution is reasonably assigned as doubly reten-
tive.
When trans-16 was maintained at -78 °C in the absence of
TMEDA for 6 h, no epimerization of the organolithium was
observed by GC, and only trans-26 was isolated along with
destannylated 7. The organolithium trans-16 is significantly
more configurationally stable than the rotationally unrestricted,
diastereomerically biased, carbamate-stabilized organolithiums
reported by Pearson and Lindbeck, which epimerize at -78 °C
within 5 min.26,27 However, when our reaction was warmed to
-40 °C in the absence of diamine, some epimerization occurs
after 1 h, and a 2:1 ratio of cis:trans 26 was observed after
reaction with dimethyl sulfate. In the presence of TMEDA the
epimerization occurs at -78 °C. After 1 h, a 1:1 ratio of cis:
trans 26 was observed, and after 5 h at -78 °C only the cis-26
diastereomer was isolated from the reaction. As in the trans-
metalations of cis-18, the remainder of the material isolated from
these reactions was destannylated 7.
The comparison of the transmetalations of cis- and trans-18
indicate that cis-16 is more thermodynamically stable than trans-
16 and the position of the carbamate functionality with respect
to the lithium ion affects the stability of a dipole-stabilized
carbanion. Complexation of the lithium by the carbonyl oxygen
of trans-16 would be expected to be more difficult than in cis-
16 due to the longer distance between the lithium and oxygen
atoms in the former.
Configurational Stability of Organolithiums, 38, cis-16 and
trans-16. The trimethyl tin compounds (S)-39, cis-18 and trans-
18 were used to prepare 38, cis-16 and trans-16 by tin-lithium
exchanges. The results of transmetalation experiments with cis-
18 and trans-18 are summarized in Table 4. Treatment of
stannane 18 with s-BuLi or n-BuLi at -78 °C in the presence
or absence of TMEDA provided the organolithiums 16, which
were treated with dimethyl sulfate to give cis- or trans-26. The
diastereomeric ratios for 26 were determined by GC analyses
and comparison to mixtures of authentic cis- and trans-26 (vide
supra).
(24) The Spartan software was used to carry out the calculations, and
conformational searches were carried out on PM3 minimized structures to
find global minima. Systematic searches, in which selected bonds are rotated
systematically at specified angles, were carried out on bicyclic carbamates
7, 10, 11, and 15 and Boc amines 4, 28, and 5. For the constrained
carbamates, the isopropyl and tert-butyl substituents were allowed to rotate
to generate possible conformations for minimization. For the Boc amines,
rotation about the N-CO bond was allowed. An Osawa search, which
carries out ring flips as well as systematic bond rotations, was carried out
on perhydroazepine 6.
Semiempirical PM3 calculations indicate that trans-16 to be
6.5 kcal/mol higher in energy than cis-16. In these calculations,
(26) Pearson, W. H.; Lindbeck, A. C. J. Am. Chem. Soc. 1991, 113,
8546-8548.
(27) Pearson, W. H.; Lindbeck, A. C.; Kampf, J. W. J. Am. Chem. Soc.
1993, 115, 2622-2636.
(25) Quenching the reaction at -78 °C was necessary to prevent
cyclization of the alkoxide.

320 J. Am. Chem. Soc., Vol. 123, No. 2, 2001
Gross and Beak
Table 5. Tin-Lithium Exchange of (S)-39 To Give (S)-28a
generated from asymmetric deprotonation of 4 and substitution
with dimethyl sulfate. The absolute configuration of (S)-28 was
established previously by conversion to (S, S)-N-Boc-2,5-
dimethylpyrrolidine, and the assignment of (S)-39 is based on
analogy to this previous work and doubly retentive reactions.16
solvent
temp (°C)
time (h)
yield 28 (%)
er 28
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O/TMEDA
Et2O/TMEDA
-78
-40
-40
-40
-40
-40
-40
-78
-40
2
1
2
3
5
6.5
8
10
1
65
65
53
76
33
54
20
66
50
95:5
89:11
82:18
80:20
65:35
61:39
55:45
90:10
46:54
Discussion
The results summarized in Tables 1-4 show that lithiations
of the carbamates 7-10 and 15 proceed with removal of the
proton nearest to the carbonyl oxygen in reactions which are
kinetically, as well as thermodynamically favored.
a For reactions at -40 °C, transmetalation was carried out at -78
°C for 20 min, and the solution was warmed to -40 °C over 50 min.
The data in Table 3 do not show a clear trend between the
dihedral angles available to the calculated ground state confor-
mations of carbamates 7, 10, 11, and 15 and the competitive
efficiencies. In each case, however, the dihedral angle between
the carbamate carbonyl group and the cis proton is much smaller
than the angle between the carbonyl and the trans proton. In
conjunction with the observation that 7-10 undergo lithiation-
substitution with high cis stereoselectivity, these data suggest
that the angle between the carbonyl group and the proton to be
removed can be a controlling factor in carbamate-directed
lithiations. For N-Boc amines 4, 5, and 6, the range of possible
angles between the carbamate carbonyl group and the proton
removed is expected to be greater since Boc group is less
restricted than in the constrained carbamates. The fact that the
bicyclic carbamates are lithiated with greater efficiency than
the Boc amines also suggests that constraining the position of
the proton to be removed at an appropriate angle to the
carbamate increases the efficiency of lithiation.
chelation between the lithium and the carbonyl oxygen was
specified, and the remaining valences of the lithium were
occupied by Et2O molecules. In the absence of chelation and
in the presence of an additional Et2O molecule, trans-16 was
calculated to be 1.6 kcal/mol lower in energy than cis-16. These
results support the possibility that trans-16 has a weaker
chelating interaction between the carbonyl oxygen and the
lithium than cis-16. Additionally, the orthogonal relationship
between pi system and the anion that is favorable in dipole-
stabilized carbanions appears to be less accessible trans-16 than
in cis-16.
The distance between the carbamate carbonyl group and the
proton removed appears to be important. The distance between
the carbonyl and the proton of interest generally decreases as
the amine ring size increases in the ground state. Carbamate 7
is lithiated with the greatest competitive efficiency and a distance
of 2.78 Å between the carbamate carbonyl group and the proton
removed as calculated by PM3 is taken to be optimal. Generally,
competitive efficiency decreases as the calculated distance
between the carbamate carbonyl group and the proton removed
decreases from 2.78 Å.
Wilberg and Bailey have recently calculated a transition state
for the enantioselective removal of the pro-S hydrogen of 4
with i-PrLi-(-)-sparteine.28 The hydrogen oxygen distance is
2.64 Å in the ground state of the complex and 2.80 Å in the
transition state. Wu¨rthwein, Behrens, and Hoppe have carried
out a calculation for lithiation adjacent to oxygen in an i-PrLi-
(-)-sparteine complex and obtain a transition state value of
2.799 Å.29
The configurational stability of 38 was studied by transmeta-
lation of stannane (S)-39 and subsequent reaction with dimethyl
sulfate. It was established previously that organolithium 38 is
configurationally stable in Et2O at -78 °C.16 In the present study
the configurational stability of 38 at -40 °C in Et2O in the
presence or absence of TMEDA and at -78 °C in THF was
investigated. The results of the transmetalation experiments
under various conditions are listed in Table 5.
The results in Table 5 indicate that the organolithium 38 is
configurationally stable at -78 °C in THF for at least 2 h. At
-40 °C epimerization of 38 was observed after 1 h, and 28
was isolated with 89:11 er. The amount of epimerization of
organolithium 38 increased over time, and nearly racemic methyl
pyrrolidine 28 was obtained after 8 h at -40 °C.
Our studies of the configurational stability of 38 show that
epimerization is slow at -40 °C in the absence of diamine but
rapid in the presence of TMEDA. The epimerization of trans-
16 is also greatly facilitated by the presence of TMEDA. The
ligand may coordinate to the lithium and form an ion pair in
which the lithium can be delivered to the opposite face of the
bicyclic system. In the absence of TMEDA, the configurational
stability of trans-16 is greater than that of more flexible dipole-
stabilized diastereomerically biased carbanions. Organolithium
cis-16 is more thermodynamically stable than trans-16, and
chelation between the carbamate carbonyl group and the lithium
is considered to provide a driving force for the epimerization
of trans-16. This study suggests that rotationally restricted
dipole-stabilized carbanions with a favorable geometry between
While a slow epimerization of organolithium 38 was observed
at -40 °C, the configurational lability of 38 was much higher
in the presence of TMEDA. Transmetaltion of 39 in the presence
of TMEDA at -78 °C for 10 hours followed by the addition of
dimethyl sulfate provided 28 with 90:10 er. This result indicates
that epimerzation occurs at -78 °C in the presence of TMEDA
and is consistent with a previous report.16 The organolithium
38 is rapidly configurationally labile at -40 °C in the presence
of TMEDA, and racemic 28 was provided after only 1 h.
The transmetalation-substitution of (S)-39 provides (S)-28,
which has the same absolute configuration as the product
(28) Wiberg, K. B.; Bailey, W. F. Angew. Chem., Int. Ed. 2000, 39, 2127.
(29) Wu¨rthwein, E. U.; Behrrens; and Hoppe, D. Eur. J. Org. Chem.
1999, 5, 3459.

Complex-Induced Proximity Effects
J. Am. Chem. Soc., Vol. 123, No. 2, 2001 321
the lithium and the carbonyl group may have enhanced
configurational stability relative to less restricted carbanions.
The presence of TMEDA increased the rate of epimerization
of both 38 and trans-16. It has been proposed that highly
coordinating additives and solvents facilitate the epimerization
of organolithiums by providing stabilization to charge-separated
species.30-32 It is believed that in cases where this effect is
observed, the rate-determining step for epimerization is the
separation of the carbon and lithium into an ion pair. The
accelerating effect of highly coordinating additives was not
observed for the epimerization of R-thio- and R-selenoorgano-
lithiums.33,34 For these organolithiums rotation about the car-
banionic carbon-heteroatom bond is proposed to be the rate-
determining step. The results from the configurational stability
studies in Tables 4 and 5 are consistent with a mechanism in
which separation of the carbon and lithium into an ion pair is
the rate-determining step. The ligand TMEDA may facilitate
the epimerization of trans-16 by chelating to the lithium atom
and delivering it to the opposite side of the molecule. Epimer-
ization of trans-16 is also observed in the absence of TMEDA
at higher temperatures. It is possible that at -40 °C in the
absence of diamine, the solvent may facilitate separation of the
carbon and lithium to provide a pathway to the more thermo-
dynamically stable organolithium cis-16. Alternatively, a dimer-
ization dissociation process can be envisioned.
The results of these studies indicate that the orientation of
the carbamate carbonyl group with respect to the lithium affects
the configurational stability of a carbanion. The organolithium
cis-16, a rigid structure in which a dipole-stabilizing group is
in close proximity to the lithium atom, was found to undergo a
highly stereoselective substitution reaction with dimethyl sulfate
at -78 °C and -40 °C to provide cis-26. The structurally rigid
trans-16 is less thermodynamically stable than cis-16 but
maintains its configuration at -78 °C in the absence of TMEDA.
Therefore, it is more configurationally stable than rotationally
flexible diastereomerically biased organolithiums studied by
Pearson and co-workers.26,27 At -40 °C, trans-16 undergoes
epimerization within 1 h, and this epimerization, which is
facilitated by TMEDA or the solvent, may be driven by chelation
of the lithium to the carbamate carbonyl oxygen. On the other
hand, the organolithium 38 epimerizes at -40 °C and is
therefore less configurationally stable than 2-lithio-N-meth-
ylpyrrolidine, which was studied by Gawley and co-workers.35
It is possible that chelation of the carbonyl oxygen to the lithium
may facilitate epimerization in 38 since a rotation which carries
the lithium away from the carbanionic carbon is possible. These
rationales assume the epimerization is unimolecular; a prospect
which has not been established. An alternative pathway involv-
ing another lithium in a complex which assists backside
epimerization is also possible.
Summary
The selectivity of proton transfer in these reactions are
reasonably attributed to favorable arrangements for transfer of
the proton to the lithiating reagent within a complex of the
carbamates with the reagent. The competition experiments
between a series of bicyclic carbamates and N-Boc amines show
that the rigid carbamates were lithiated significantly faster than
less rotationally restricted N-Boc amines. Differences between
competition experiments carried out under second-order and
pseudo-first-order conditions suggest that an additional factor
favoring the rigid carbamates may be a more favorable pre-
lithiation complex formation. The sum of these results suggest
that appropriate restriction of the geometry of the substrate can
increase the efficiency of the lithiation reaction and a small angle
between the carbonyl group and the proton removed is favored.
This work is consistent with the importance of complexation
in the reactions and stabilities of lithio dipole-stabilized car-
banions.
Acknowledgment. We are grateful to the National Institutes
of Health (GM-18874) and the National Science Foundation
(NSF-19422) for support of this work.
(30) Curtin, D. Y.; Koehl, W. J., Jr. J. Am. Chem. Soc. 1962, 84, 1967-
1973.
(31) Letsinger, R. L. J. Am. Chem. Soc. 1950, 72, 4842.
(32) Reich, H. J.; Medina, M. A.; Bowe, M. D. J. Am. Chem. Soc. 1992,
114, 11003-11004.
Supporting Information Available: The experimental detail
is provided (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
(33) Reich, H. J.; Dykstra, R. R. Angew. Chem., Int. Ed. Engl. 1993, 32,
1469-1470.
JA002662U
(34) Reich, H. J.; Kulicke, K. J. Am. Chem. Soc. 1995, 117, 6621-
6622.
(35) Gawley, R. E.; Zhang, Q. Tetrahedron 1994, 50, 6077-6088.