Synthetic applications and inversion dynamics of configurationally stable 2-lithio-2-arylpyrrolidines and -piperidines

Article abstract of DOI:10.1021/ja306276w

In diethyl ether, N-Boc-2-lithio-2-arylpiperidines have been found to be configurationally stable at -80 °C, whereas N-Boc-2-lithio-2- arylpyrrolidines are configurationally stable at -60 °C. Several tertiary benzylic carbanions derived from enantioenriched 2-aryl heterocycles have been successfully alkylated or acylated with little to no loss of enantiopurity. The scope of the reactions has been explored. The enantiomerization dynamics of N-Boc-2-lithio-2-phenylpyrrolidine and N-Boc-2-lithio-2-phenylpiperidine have been studied in the presence of different solvents and achiral ligands.

Full text of DOI:10.1021/ja306276w

Article
pubs.acs.org/JACS
Synthetic Applications and Inversion Dynamics of Configurationally
Stable 2‑Lithio-2-arylpyrrolidines and -piperidines
Timothy K. Beng, Jin Sun Woo, and Robert E. Gawley*
Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701, United States
S
* Supporting Information
ABSTRACT: In diethyl ether, N-Boc-2-lithio-2-arylpiperidines have been found
to be configurationally stable at −80 °C, whereas N-Boc-2-lithio-2-arylpyrroli-
dines are configurationally stable at −60 °C. Several tertiary benzylic carbanions
derived from enantioenriched 2-aryl heterocycles have been successfully alkylated
or acylated with little to no loss of enantiopurity. The scope of the reactions has
been explored. The enantiomerization dynamics of N-Boc-2-lithio-2-phenyl-
pyrrolidine and N-Boc-2-lithio-2-phenylpiperidine have been studied in the presence of different solvents and achiral ligands.
If lithiation/alkylation occurred at the benzylic position
without racemization of the intermediate carbanion, quaternary
stereocenters could be obtained by electrophilic substitution.
Benzylic organolithium compounds that exhibit significant
configurational stability are relatively rare.5 A recent review cites
several examples of quantitative studies on the inversion
dynamics of tertiary benzylic organolithiums where free energy
barriers ranging from 9 to 14 kcal/mol at −80 °C were
measured.6 Such low barriers indicate a high degree of
configurational instability of benzylic organolithiums (half-life
for inversion ≤10 min), which provides a challenge to
stereoselective synthesis.7 Approaches to lithiation/alkylation
sequences at benzylic sites often employ chiral auxiliaries8 or
chiral ligands such as (−)-sparteine9 or a bisoxazoline7e,10 to
impose configurational stability in the ground state or
diastereomeric bias in the transition state, thus leading to
diastereomerically or enantiomerically enriched products. Many
years ago, the necessity of diastereomeric bias in the alkylation
of a benzylic dipole-stabilized α-aminoorganolithium com-
pound was demonstrated by Meyers, who showed that an
enantioenriched tertiary tetrahydroisoquinoline formamidine
(97:3 er), in which the lithium was also intramolecularly
chelated, produced racemic product after a lithiation/
substitution sequence in THF at −100 °C.11
INTRODUCTION
■
Enantioenriched 2-arylpyrrolidines and -piperidines have
recently become available by a lithiation/transmetalation/
arylation sequence. Specifically, Campos demonstrated that
enantioenriched N-Boc-2-arylpyrrolidines are available by
enantioselective deprotonation using sec-butyllithium/(−)-spar-
teine followed by transmetalation with ZnCl2 and Pd-mediated
arylation.1 Coldham and co-workers reported the dynamic
thermodynamic resolution (DTR) of N-Boc-2-lithiopiperidine
(1), achieving enantiomer ratios as high as 85:15 using
stoichiometric amounts of monolithiated diaminoalkoxide
ligands.2 Inspired by Coldham’s work, we showed that 1 is
amenable to a catalytic dynamic resolution (CDR) using 10
mol % of diastereomeric ligands (S,S)-2 and (S,R)-2 (Figure
1A) at −45 °C in Et2O with 4 equiv of TMEDA.3 Combination
of the CDR with Campos’ arylation procedure effected
enantioselective arylation of N-Boc-piperidine, affording
compounds such as 3−7 in the er’s shown in Figure 1.4
In their synthesis of a 2,2-disubstituted piperidine NK1
antagonist, Xiao and co-workers reported that lithiation of
rac-N-Boc-2-phenylpiperidine (3) at −78 °C using n-BuLi
occurs exclusively at the benzylic position.12 We therefore
decided to explore stereoselective lithiation/substitutions of N-
Boc-2-arylpiperidines and -pyrrolidines, in the absence of any
chiral ligand or auxiliary. We find that enantioenriched 2,2-
disubstituted pyrrolidines and piperidines are produced with
little to no loss of enantiomeric purity. We then conducted a
detailed study of the effects of ligands and solvents on the
dynamics of enantiomerization of N-Boc-2-lithio-2-phenyl-
Figure 1. (A) N-Boc-2-lithiopiperidine and chiral ligands used to
resolve it under CDR conditions and (B) enantioenriched 2-
arylpiperidines.
Received: January 5, 2012
Published: August 11, 2012
© 2012 American Chemical Society
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pyrrolidine and N-Boc-2-lithio-2-phenylpiperidine and deter-
mined the enthalpies and entropies of activation for carbanion
inversion under several different conditions. While an earlier
version of this paper was in preparation, we became aware of a
related mechanistic study that included important details of
deprotonation relative to rotamer interconversion of these same
compounds.13
Table 1. Evaluating the Configurational Stability of N-Boc-2-
lithio-2-phenylpiperidine (8)
entry
solvent
ligand (amt, equiv)
er of 3·d1 (R:S)
RESULTS AND DISCUSSION
■
1
2
Et2O
Et2O
Et2O
Et2O
THF
THF
THF
TMEDA (1)
TMEDA (4)
TMEDA (4)
96:4
96:4
85:15
91:9
94:6
95:5
92:8
Previously, we and Coldham measured the dynamics of
enantiomerization of N-Boc-2-lithiopiperidine (1) in Et2O
and found that its configurational stability depended on the
amount of TMEDA present.14 Given these results, we
investigated the configurational stability of the benzylic
lithiopiperidine 8 in the presence and absence of TMEDA.
After treatment of R-3 of 96:4 er (0.06 M in Et2O or THF)
with 1 equiv of s-BuLi at −80 °C in the presence or absence of
TMEDA, 8 was generated and immediately trapped with
MeOD. The extent of lithiation was monitored using GC-MS
by comparing the integral ratio of the base beak for the singly
deuterated product, 3·d1, to that of the starting material 3. After
complete deuteration (as noted by the disappearance of m/z
206 and appearance of m/z 207; see Figure 2 and the
a
3
b
4
5
6
7
none
TMEDA (1)
TMEDA (4)
b
none
a
b
Transferred to a bath at −55 °C and stirred for 1 h. Lithiated for 1 h.
(i) The tertiary α-amino benzylic organolithium 8 racemizes
slowly in both Et2O and THF at −80 °C in the absence
of TMEDA. TMEDA enhances the configurational
stability of 8 in both solvents.
(ii) As expected, 8 is configurationally less stable at higher
temperatures (Table 1, entry 2 vs 3).
(iii) Deuteration of 8 with MeOD is stereoretentive.
Several other electrophiles and arylpiperidines were inves-
tigated, and the results are summarized in Table 2. In all cases,
good yields were obtained and retention of configuration was
observed. Methylation of 8 with Me2SO4 gave R-9 in 79% yield
and 95:5 er (Table 2, entry 2). Removal of the Boc group using
gaseous HCl gave unprotected 9, with the same sign of specific
rotation as that recently reported by Aggarwal for enantiopure
deprotected R-9.5f On the basis of retentive deuteration and
methylation, and the recently reported work of O’Brien and
Coldham in which the steric course of several such
substitutions were characterized,13 we have assigned all the
substitutions reported herein as retentive. Quenching with
Me3SiCl afforded S-10 in 88% yield and 96:4 er (entry 3).
Quenching with ethyl chloroformate afforded the ester R-11 in
85% yield, with no loss of er (entry 4). A carbonyl electrophile
was also evaluated. Quenching with (CD3)2CO15 and warming
to room temperature before adding methanol gave rise to the
oxazolidinone 12 in 90% yield and 95:5 er.
After transmetalation of the benzylic organolithium R-8 to its
organozinc counterpart, copper-mediated allylation and benzy-
lation3 afforded S-13 (entry 6) and S-14 (entry 7), respectively,
in good yields and er’s.
Figure 2. GC-MS and CSP-SFC traces for R-3 and R-3·d1.
Lithiation/substitution of highly electron-rich R-4 of 97:3 er
also proceeded easily, and the products R-4·d1 and R-15 were
formed after quenching with MeOD and (CD3)2CO,
respectively (entries 8 and 9). The presence of a bulky
electron-rich substituent on the aryl moiety did not affect the
configurational stability of the benzylic organolithium, as R-5 of
90:10 er also gave R-5·d1 with no loss of er after deuteration
with MeOD (entry 10). When electron-deficient R-6 of 91:9 er
was employed, lithiation and deuteration or reaction with
Me2SO4 provided R-6·d1 and R-16, respectively, with no loss of
enantiopurity (entries 11 and 12). Sterically crowded R-7 of
97:3 er gave R-7·d1 and R-17 after deuteration and methylation,
respectively (entries 13 and 14).
Supporting Information), the enantiomer ratios of 3 and 3·d1
were evaluated by CSP-SFC. In the presence of TMEDA (1 or
4 equiv) and with Et2O as the solvent, quenching with MeOD
showed complete deuteration after 30 min at −80 °C and 3·d1
of 96:4 er (Table 1, entries 1 and 2) was obtained. When the
reaction mixture was quickly transferred to a bath at −55 °C
and stirred for 1 h, quenching at −80 °C with MeOD gave 3·d1
of 85:15 er (entry 3). In the absence of a ligand, after 60 min of
lithiation, 3·d1 was obtained in 91:9 er (entry 4). In THF, slight
loss of enantiopurity was observed (entries 5 and 6), which was
most pronounced in the absence of TMEDA (entry 7).
The following findings emerged from these experiments.
The configurational stability of the homologous N-Boc-2-
arylpyrrolidines was also evaluated. Initially, R-18 of 96:4 er was
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a
Table 2. Lithiation/Substitution of Enantioenriched N-Boc-2-arylpiperidines
entry
Ar
er (R:S)
E+
product
yield, %
er of product
b
1
Ph
96:4
96:4
96:4
96:4
96:4
96:4
96:4
97:3
97:3
90:10
90:10
90:10
97:3
MeOD
R-3·d1
R-9
100
96:4
95:5
96:4
96:4
95:5
92:8
94:6
97:3
97:3
90:10
90:10
90:10
97:3
93:7
2
Ph
Me2SO4
Me3SiCl
EtOCOCl
(CD3)2CO
79
88
85
90
66
71
3
Ph
S-10
4
Ph
Ph
R-11
R-12
S-13
5
c
6
Ph
allyl-Br
c
7
Ph
BnBr
S-14
b
8
3,4-(MeO)2-C5H3
3,4-(MeO)2-C6H3
4-(tBu)-C6H4
4-(NC)-C6H4
4-(NC)-C6H4
1-Np
MeOD
R-4·d1
R-15
R-5·d1
R-6·d1
R-16
R-7·d1
R-17
100
9
(CD3)2CO
MeOD
93
b
10
11
12
13
14
100
b
MeOD
100
Me2SO4
MeOD
71
b
100
1-Np
97:3
Me2SO4
74
a
b
c
See also Figure 1B. Percent conversion by GC. Via zinc and copper-mediated coupling.
synthesized using the Campos procedure, which employs a
stoichiometric amount of (−)-sparteine.1a However, following a
recent report by O’Brien and Campos on the use of catalytic
amounts of the chiral ligand to effect a catalytic enantioselective
arylation of N-Boc-pyrrolidine, subsequent (R)-N-Boc-2-
arylpyrrolidines (R-18−R-21, Figure 3) were synthesized
using this method.1b,16 The enantiomeric (S)-N-Boc-2-
arylpyrrolidines (S-18 and S-22) were synthesized using
Beak’s lithiation/cyclization method.17
Xiao et al. reported that lithiation/alkylation of rac-18
occurred at C2 at −78 °C using n-BuLi/TMEDA in THF.12
We found that lithiation of R-18, using s-BuLi/TMEDA in
Et2O, was somewhat slower than that of 3 under the conditions
used for the piperidines. Although we were able to obtain 100%
lithiation of 18 at −80 °C using s-BuLi/TMEDA, Coldham and
O’Brien have shown that interconversion of rotamers at −80
°C is slow, and lithiation at C-5 is competitive at this
temperature.13
Figure 3. Enantioenriched 2-arylpyrrolidines and diisopropylbispidine
(23).
solution of R-18 of 96:4 er in Et2O using n-BuLi at −60 °C in
the absence of a ligand, quenching of 24 with MeOD revealed
complete lithiation after 3 h. CSP-SFC analysis also revealed
stereoretentive deuteration, and R-18·d1 was obtained in 96:4
er. Similar configurational stability was observed in the presence
of stoichiometric or excess amounts of TMEDA. For example,
when S-18 of 96:4 er, in Et2O containing 1 equiv of TMEDA at
−60 °C, was treated with n-BuLi for 3 h and then quenched
with MeOD, S-18·d1 having 96:4 er was obtained. In the
We sought reaction conditions that would maximize the
efficient generation of the C2-lithiated pyrrolidine 24 without
compromising its configurational stability. After lithiation of a
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Table 3. Lithiation/Substitution of Enantioenriched N-Boc-2-aryl pyrrolidines Using Indicated Conditions, Except As Noted
entry
Ar
er (R:S)
E+
Me2SO4
product
yield, %
er
a
1
Ph
Ph
96:4
96:4
96:4
96:4
96:4
50:50
90:10
90:10
95:5
95:5
95:5
7:93
R-25
86
94:6
>99:1
94:6
94:6
92:8
50:50
90:10
90:10
95:5
95:5
95:5
93:7
b
c
2
DMF
R-26
83 (88 )
b
c
3
Ph
EtOCOCl
(CD3)2CO
2-bromotoluene
2-bromotoluene
MeOD
R-27
70 (79 )
b
c
4
Ph
R-28
85 (92 )
b,d
5
Ph
R-29
8
a,d,e
6
Ph
rac-29
R-19·d1
R-20·d1
R-21·d1
R-31
12
c
c
c
7
2-tolyl
2-pyridyl
1-Np
1-Np
1-Np
4-(NC)-C6H4
100
100
100
8
MeOD
9
MeOD
a
10
11
12
Me2SO4
91
cde
, ,
PhBr
S-32
<5
c
MeOD
S-22·d1
100
a
b
c
Isolated yield. Isolated yield of C2 and C5 substitution products after deprotonation by s-BuLi/TMEDA. Percent conversion by GC after
d
e
deprotonation using n-BuLi/TMEDA. Via Pd-catalyzed coupling for 48 h at 40 °C. Lithiated in the absence of TMEDA.
presence of hindered diisopropylbispidine 23,18 R-18·d1 of 95:5
er was obtained. O’Brien and Coldham have shown that, at this
temperature, rotation of the Boc group is fast enough for
interconversion, and C-5 deprotonation is not competitive
when n-BuLi is used as the base.13
gives only C2 lithiation, but only analyzed for percent
conversion by GC.
We reasoned that the low yield in entry 5 could be due to
steric crowding or the presence of TMEDA, known to be
problematic in the Pd-catalyzed arylation of racemic N-Boc-2-
lithiopyrrolidine, obtained from deprotonation of N-Boc-
pyrrolidine using sec-BuLi/TMEDA.1b To test this possibility,
we generated rac-24 by deprotonation using n-BuLi and
subjected it to the same arylation conditions, affording rac-29
in just 12% yield (entry 6). GC-MS analysis of the crude
product mixture showed complete consumption of rac-18, but a
significant byproduct was found, dehydropyrrolidine 30,
probably produced by β-hydride elimination of the organo-
palladium intermediate.
Other arylpyrrolidines with varying stereoelectronic proper-
ties were also evaluated after deprotonation using n-BuLi/
TMEDA in Et2O. Lithiation/deuteration of electron-rich R-19
and heteroaromatic R-20 proceeded with high levels of
configurational stability (entries 7 and 8, respectively). The
naphthyl substituent was found to be compatible, as R-21 of
95:5 er gave R-21·d1 and R-31 after deuteration and
methylation, respectively (entries 9 and 10). When R-21 was
lithiated in the absence of TMEDA, transmetalation to the
organozinc and palladium-catalyzed coupling to bromobenzene
afforded only trace amounts of S-32 (entry 11). Enamide 33
was also detected, consistent with undesirable β-hydride
elimination during the arylation. We therefore concluded that
the low yield in the arylation at C-2 of the 2-arylpyrrolidines
Knowing that configurationally stable R-24 can be efficiently
generated after 3 h at −60 °C in the presence or absence of
TMEDA in Et2O, other electrophiles and arylpyrrolidines were
evaluated, and the results are summarized in Table 3. Lithiation
of R-18 of 96:4 er with n-BuLi/TMEDA followed by alkylation
with Me2SO4 gave R-25 of 94:6 er in 86% yield (Table 3, entry
1). Lithiation with sec-BuLi/TMEDA and quenching with
dimethyl formamide afforded crude aldehyde R-26 in 96:4 er.
After column chromatography on silica, a slight improvement
in the er was observed and enantiopure R-26 was obtained in
83% yield (entry 2), possibly due to self-disproportionation of
enantiomers on the achiral stationary phase.19 Ethyl chlor-
oformate gave ester R-27 in 70% yield and 95:5 er (entry 3).
With (CD3)2CO, oxazolidinone R-28 was obtained in 85%
yield and 96:4 er (entry 4). When R-24 was transmetalated to
its organozinc counterpart followed by Pd-catalyzed coupling to
2-bromotoluene, R-29 was obtained in very low yield (entry 5).
Entries 2−5 of Table 3 were initially conducted by
deprotonationation using sec-BuLi/TMEDA at −80 °C and
probably produced a mixture of C2 and C5 lithiation/
substitution products.13 The products of C2 substitution were
characterized after chromatographic purification. Later, entries
2−5 of Table 3 were repeated using n-BuLi/TMEDA, which
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was largely due to steric hindrance. Complete and efficient
lithiation of S-22 of 93:7 er followed by quenching with MeOD
gave S-22·d1 (entry 12).
In order to determine the rate constants for enantiomeriza-
tion at specified temperatures, the organolithium R-24 was
generated using n-BuLi at −60 °C for 3 h followed by
transferring to a bath set at the desired temperature to monitor
inversion. At various time intervals, duplicate tubes were
transferred to a bath at −80 °C and quenched with MeOD.
GC-MS analysis of the crude mixture of each tube was carried
out to ensure 100% deuterium incorporation, prior to
evaluation of the enantiomer ratio by CSP-SFC. The GC
traces showed evidence of some decomposition at higher
temperatures, but we were still able to obtain good kinetic data.
Due to the slow racemization in Et2O at −43 °C, the dynamics
were subsequently studied at temperatures ranging from −20 to
18 °C. After generating 24 using n-BuLi at −60 °C for 1 h, we
followed the evolution of er as a function of time in the absence
of any ligand in THF at −57, −43, and −31 °C. With 2-
MeTHF, the kinetics were studied at −31 °C. The zero-order
plots for the enantiomerization are in the Supporting
Information. Eyring analysis of the rate constants at their
respective temperatures provided the activation parameters
given in Table 4 (see the Supporting Information for details on
Enantiomerization Dynamics of α-Amino Tertiary
Benzylic Organolithiums 24 and 8. The dynamics of
enantiomerization of benzylic organolithiums through a
solvent-separated ion pair has been reported by Peoples and
Grutzner using a benzylic lithiohydrocarbon20 and by Ahlbrecht
et al. using α-thio and α-seleno compounds.21 Cram and co-
workers reported the enantiomerization of a chelated α-
silylbenzylic organolithium22 via the conducted tour mecha-
nism.23 In all of these examples, negative entropies of activation
were observed, consistent with additional solvation in the
transition state. In collaboration with the Coldham group, we
have studied the dynamics of carbanion inversion of α-amino
organolithium compounds. The activation parameters for
enantiomerization of N-substituted 2-lithiopyrrolidines24 and
for dynamic thermodynamic resolution (DTR) and racemiza-
tion of N-Boc-2-lithiopiperidine3,14 have been measured. It
became clear to us that the role of an additive such as TMEDA
in the racemization of α-amino organolithium compounds can
change dramatically, depending on conditions. For example,
whereas TMEDA catalyzes the racemization of N-Boc-2-
lithiopyrrolidine,24c the effect of TMEDA on the racemization
of N-Boc-2-lithiopiperidine is dependent on the stoichiometry.
TMEDA catalyzes the racemization of N-Boc-2-lithiopiperidine
up to 1 equiv,14 but 2 equiv of TMEDA retards racemization.3
In another striking difference, when generated by tin−lithium
exchange, enantioenriched N-Boc-2-lithiopiperidine racemizes
in a matter of minutes at −80 °C in the presence of 1 equiv of
diisopropylbispidine (DIB) in Et2O, whereas N-Boc-2-lithio-
pyrrolidine exhibits configurational stability under identical
conditions.24c We therefore undertook an investigation of the
activation parameters for enantiomerization of pyrrolidine 24
and piperidine 8 in the presence of varying solvents and ligands.
Dynamics of Inversion of 24. Detailed kinetic measure-
ments on the effects of solvents and ligands on the rate of
enantiomerization of R-24 were performed using previously
reported methods.14,24c,d Thus stock solutions of R-18 of 96:4
er (0.06 M in Et2O, THF, or 2-methyltetrahydrofuran (2-
MeTHF)) were prepared and placed in six oven-dried, septum-
capped test tubes, each equipped with a stir bar. Prior to
embarking on the time-dependent studies, we performed
exploratory runs using different solvents and ligands at −43
°C. The results are summarized in Scheme 1. These data clearly
indicate configurational stability in Et2O, even at −43 °C, and
significantly faster racemization at the same temperature in
either THF or 2-MeTHF. As a result of these experiments, we
realized that the dynamics of inversion in Et2O would have to
be studied at temperatures higher than −43 °C.
Table 4. Thermodynamic Parameters for Inversion of 24
ΔH⧧
entry
description
(kcal/mol)
ΔS⧧ (cal/(mol K))
1
2
3
4
no ligand in Et2O
18.0 1.7
16.0 1.3
21.3 0.2
8.6 1.6
−8.6 0.3
−18.7 1.6
−1.0 0.4
−37.5 2.5
1 equiv of TMEDA in Et2O
1 equiv of 23 in Et2O
no ligand in THF
the analysis of the kinetic data). Examination of the enthalpic
and entropic contributions to the free energies for the
enantiomerization revealed significant differences. In the
absence of any ligand in Et2O, carbanion inversion is mostly
enthalpy controlled (Table 4, entry 1). Addition of TMEDA
leads to little or no change in the enthalpy of activation but the
entropic barrier changes by a factor of 2 (entry 2). With the
hindered and weakly coordinating 23, the racemization is
enthalpy controlled (entry 3). On comparison of Et2O and
THF, the enthalpy of activation in THF drops from 18.0 to 8.6
kcal/mol and the entropy of activation changes from −8.6 to
−37.5 cal/(mol K) (entries 1 vs 4). The activation parameters
for enantiomerization of 24 in the absence of any ligand in 2-
MeTHF were not determined, but we found that at −31 °C the
rate of enantiomerization of 24 is 9 times faster in THF (t1/2
11.7 min) than in 2-MeTHF (t1/2 = 1.8 h).
=
A plot of ΔG⧧ vs temperature for the different systems
studied is illustrated in Figure 4. Although the observed rate
constants increase with an increase in temperature, the negative
entropies of activation reveal that the free energy barriers
increase with temperature. Interestingly, O’Brien and Coldham
have recently reported deprotonation of N-Boc-2-phenyl-
pyrrolidine using n-BuLi in THF at −50 °C for 5 min,
followed by electrophilic quench.13 The half-life for enantiome-
rization at this temperature is 50 min.
Scheme 1. Enantiomer Ratios for the Racemization of 24
under Different Reaction Conditions at −43 °C
Dynamics of Inversion of 8. Using the method described
above for the dynamics of inversion of 24, the barriers to
enantiomerization of piperidine 8 in the absence of any ligands
in Et2O or THF, and in the presence of TMEDA in Et2O, were
measured. With Et2O as the solvent, the dynamics of inversion
of 8 were studied at temperatures ranging from −40 to −20 °C
with and without TMEDA. In THF, colder temperatures (−60
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differences in half-life due to the exponential relationship
between ΔG⧧ and t1/2
.
In Et2O at similar temperatures, we find that the rate of
inversion of piperidine 8 is significantly faster than that of
pyrrolidine 24. Interestingly, the observed trend is similar to
that reported for the racemization of the secondary, non-
benzylic organolithiums N-Boc-2-lithiopiperidine14 and N-Boc-
2-lithiopyrrolidine24c in Et2O.
Mechanistic Hypothesis. A possible mechanism for the
enantiomerization of 8 or 24 which is consistent with the
observed negative entropies is via the conducted tour, known to
be operative in the inversion of N-substituted 2-lithiopyrroli-
dines and -piperidines.24a,b Infrared studies have shown that the
carbonyl oxygen chelates the lithium in both 8 and 24.13,25 In
the conducted tour, the lithium−oxygen distance is shortened
and the lithium−carbon distance is lengthened as the transition
state is approached. This necessitates a reorganization of the
coordination sphere around the lithium, but the lithium
remains coordinated to the carbonyl oxygen as it moves from
one face of the carbanion to the other. This is consistent with
the observation that a strongly coordinating ligand (TMEDA)
and a more coordinating solvent (THF) result in more negative
entropies for the enantiomerization of 24 or 8 than in Et2O
alone. Since the coordinating ability of 2-MeTHF is
intermediate between Et2O and THF,26 it is perhaps not
surprising that the rate of enantiomerization of 24 is faster than
with Et2O but slower than with THF.
Summary and Conclusions. In summary, the configura-
tional stability of several α-amino tertiary benzylic organo-
lithiums has been demonstrated at low temperatures on two
different heterocycles, in the absence of any chiral ligand or
auxiliary. TMEDA enhances the configurational stability of both
8 and 24. A variety of 2,2-disubstituted piperidines and
pyrrolidines have been synthesized bearing α-amino quaternary
stereocenters. The thermodynamic parameters for racemization
of 8 and 24 in the absence of any ligand in Et2O and THF are
significantly different. In THF, the racemization is faster than in
Et2O and is mostly entropy-controlled.
Figure 4. Relationship between free energy of activation and
temperature for inversion of 24. The solid lines indicate free energy
barriers in the temperature region where the kinetics were measured;
dashed lines are extrapolations.
to −40 °C) were required due to faster racemization. The
activation parameters are given in Table 5 (details are in the
Table 5. Thermodynamic Parameters for Inversion of 8
ΔH⧧
entry
description
(kcal/mol)
ΔS⧧ (cal/(mol K))
1
2
3
no ligand in Et2O
17.5 0.8
16.0 1.3
10.1 0.9
−2.0 0.06
−9.6 0.5
−29.1 4.2
1 equiv of TMEDA in Et2O
no ligand in THF
Supporting Information), and a plot of ΔG⧧ vs temperature for
the three systems studied is shown in Figure 5. The significantly
EXPERIMENTAL SECTION
■
For general experimental conditions, see the Supporting Information.
Lithiation of (R)-N-Boc-2-arylpiperidine Followed by Direct
Trapping with the Electrophile: General Procedure. In an oven-
dried, septum-capped round-bottom flask equipped with a stir bar,
freshly distilled TMEDA (4.0 equiv) and Et2O under argon were
added. The solution was cooled to −80 °C, and a solution of s-BuLi in
cyclohexane (1.0 equiv) was added. A precooled solution of the N-
Boc-2-arylpiperidine (1.0 equiv) in Et2O was added to the flask
containing the TMEDA/s-BuLi solution. After 30 min at this
temperature, the reaction was quenched with the electrophile
(∼1.1−1.5 equiv). After 2−16 h, MeOH was added and the mixture
was stirred for 5 min. After the mixture was warmed to room
temperature, 2 M HCl was added. The layers were separated, and the
aqueous layer was extracted with Et2O. The combined organic layers
were dried over MgSO4 and evaporated to obtain the crude product.
The er was determined before and after purification by column
chromatography. See the Supporting Information for details.
Lithiation of (R)-N-Boc-2-arylpiperidine Followed by Zinc
and Copper-Mediated Allylation or Benzylation: General
Procedure. In an oven-dried, septum-capped round-bottom flask
equipped with a stir bar freshly distilled TMEDA (4.0 equiv) and Et2O
under argon were added. The solution was cooled to −80 °C, and a
solution of s-BuLi in cyclohexane (1.0 equiv) was added. A precooled
solution of the N-Boc-2-arylpiperidine (1.0 equiv) in Et2O was added
to the flask containing the TMEDA/s-BuLi mixture. After 30 min, a
solution of ZnCl2 (1.3 equiv, 1.0 M in Et2O) was added slowly. After
Figure 5. Relationship between the free energy of activation and
temperature for inversion of 8.
higher barriers in Et2O reveal significantly higher configura-
tional stability than in THF. Our results in THF, from Tables 1
and 5 and Figure 5, are somewhat at odds with the results of
O’Brien and Coldham.13 Their conditions for deprotonation
and alkylation of 3 in THF are −50 °C for 30 min, and they
report 94:6 to 99:1 er’s after alkylation. In our hands, we begin
to see racemization of 8 even at −80 °C (Table 1, entry 7).
One of our kinetic runs was conducted at −50 °C in THF; after
30 min, we observe 66:34 er. From the parameters of entry 3 of
Table 5, we calculate a half-life for enantiomerization of 22 min.
Slight differences in temperature produce small differences in
free energy barriers, but these can result in significant
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Journal of the American Chemical Society
Article
30 min, a solution of CuCN·2LiCl (prepared from CuCN (1.2 equiv)
and LiCl (2.5 equiv)) in THF was added. After 30 min, allyl bromide
or benzyl bromide (1.1 equiv) was added. The mixture was stirred for
10 h at this temperature prior to addition of MeOH and warming to
room temperature. A solution of NH4Cl was added, and the aqueous
layer was extracted with Et2O. The combined organic layers were dried
over Na2SO4 and evaporated to give the crude product. The er was
determined before and after purification by column chromatography.
See the Supporting Information for details.
100% deuterium incorporation (indicative of complete lithiation). The
enantiomer ratio (er) of 3·d1 was determined by CSP-SFC monitoring
at 210 nm under the following column conditions: column, Pirkle
Whelk-O-1; flow rate, 0.5 mL/min; polarity modifier, 10.0% IPA. S-
3·d1 elutes after ∼17.2 min, and R-3·d1 elutes after ∼21 min. In some
cases, the enantiomer ratio (er) of 3·d1 was determined by CSP-HPLC
monitoring at 254 nm. The rate constants were determined by
nonlinear fitting of the zero-order plots using reversible first-order
kinetics. See the Supporting Information for details.
Lithiation of (R)-N-Boc-2-arylpyrrolidine Followed by Direct
Trapping with the Electrophile: General Procedure. In an oven-
dried, septum-capped round-bottom flask equipped with a stir bar,
freshly distilled TMEDA (1.0 equiv) and Et2O under argon were
added. The mixture was cooled to −60 °C, and a solution of n-BuLi in
hexanes (1.0 equiv) was added. A precooled solution of the N-Boc-2-
arylpyrrolidine (1.0 equiv) in Et2O was added to the flask containing
the TMEDA/n-BuLi mixture. After 3 h at this temperature, the
mixture was quenched with the electrophile (∼1.1−1.5 equiv). After
2−16 h, MeOH was added and the mixture was stirred for 5 min. After
the mixture was warmed to room temperature, 2 M HCl was added.
The layers were separated, and the aqueous layer was extracted with
Et2O. The combined organic layers were dried over MgSO4 and
evaporated to obtain the crude product. The er was determined before
and after column chromatography.
ASSOCIATED CONTENT
* Supporting Information
Text, figures, and tables giving full experimental details and
spectroscopic and kinetic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*bgawley@uark.edu.
Notes
■
The authors declare no competing financial interest.
Lithiation of (R)-N-Boc-2-arylpyrrolidine Followed by Zinc-
and Palladium-Catalyzed Arylation: Attempted Synthesis of
32. In an oven-dried, septum-capped round-bottom flask equipped
with a stir bar, R-21 of 95:5 er (75 mg, 0.25 mmol, 1.0 equiv) in Et2O
(2 mL) under argon was added. The mixture was cooled to −60 °C,
and a solution of n-BuLi in hexanes (0.1 mL, 0.25 mmol, 2.5 M, 1.0
equiv) was added slowly. After 3 h at this temperature, a solution of
ZnCl2 (0.15 mL, 1.0 M solution in Et2O, 0.6 equiv) was added slowly
over a 2 min period and the mixture was stirred for 30 min followed by
warming to room temperature. After 30 min, Pd(OAc)2 (2.5 mg, 4
mol %), t-Bu3P·HBF4 (6 mg, 8 mol %), and phenyl bromide (0.033
mL, 0.28 mmol, 1.1 equiv) were added sequentially. After it was stirred
for 48 h at 40 °C, the heterogeneous mixture was warmed to room
temperature. NH4OH (2 mL, 10% aqueous solution) was added
dropwise, and the mixture was stirred for 30 min. The resulting slurry
was filtered through Celite and rinsed with 5 mL of Et2O. The filtrate
was washed with 1 M HCl(aq) (10 mL) and then with water (2 × 5
mL), dried over Na2SO4, and evaporated under reduced pressure to
obtain the crude product. Analysis of the crude product by CG-MS
showed complete conversion of 21 but less than a 5% yield of 32 was
present.
Activation Parameters for Racemization of 24 with 1.0
equiv of TMEDA in Et2O: Typical Kinetic Run. In oven-dried,
septum-capped tubes equipped with a stir bar, R-18 (0.06 M in ether,
0.5 mL) and 0.06 M TMEDA (1.00 equiv) were treated with n-BuLi
(1.0 equiv) at −60 °C for 3 h under nitrogen. The total volume of
each tube was maintained at 1.0 mL. The tubes were quickly
transferred to a second bath thermostated at the desired temperature.
At various time intervals, a tube was transferred to the bath at −80 °C
and the mixture rapidly quenched with MeOD. Each tube was
analyzed by GC-MS to ensure 100% deuterium incorporation
(indicative of complete lithiation). The enantiomer ratio (er) of
18·d1 was determined by CSP-SFC monitoring at 210 nm under the
following column conditions: column, Pirkle Whelk-O-1; flow rate, 2.0
mL/min; polarity modifier, 2.0% EtOH. S-18·d1 elutes after ∼4.2 min,
and R-18·d1 elutes after ∼5.7 min. The rate constants were determined
by nonlinear fitting of the zero-order plots using reversible first-order
kinetics. See the Supporting Information for details.
ACKNOWLEDGMENTS
■
We thank the Arkansas Biosciences Institute and the National
Science Foundation (CHE 1011788) for direct support of this
work. Core facilities were funded by the Arkansas Biosciences
Institute and the National Institutes of Health (P30 RR031154
and GM103450). J.S.W. thanks the NSF-REU for a summer
fellowship (CHE 0851505). We are grateful to Professors Peter
O’Brien and Iain Coldham for sharing their related manu-
script13 prior to publication.
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