Enediolate-dilithium amide mixed aggregates in the enantioselective alkylation of arylacetic acids: Structural studies and a stereochemical model

Article abstract of DOI:10.1021/ja403076u

A combination of X-ray crystallography, ⁶Li, ¹⁵N, and ¹³C NMR spectroscopies, and density functional theory computations affords insight into the structures and reactivities of intervening aggregates underlying highly selective asymmetric alkylations of carboxylic acid dianions (enediolates) mediated by the dilithium salt of a C₂-symmetric chiral tetraamine. Crystallography shows a trilithiated n-butyllithium-dilithiated amide that has dimerized to a hexalithiated form. Spectroscopic studies implicate the non-dimerized trilithiated mixed aggregate. Reaction of the dilithiated amide with the dilithium enediolate derived from phenylacetic acid affords a tetralithio aggregate comprised of the two dianions in solution and the dimerized octalithio form in the solid state. Computational studies shed light on the details of the solution structures and afford a highly predictive stereochemical model.

Full text of DOI:10.1021/ja403076u

Article
pubs.acs.org/JACS
Enediolate−Dilithium Amide Mixed Aggregates in the
Enantioselective Alkylation of Arylacetic Acids: Structural
Studies and a Stereochemical Model
Yun Ma,‡ Craig E. Stivala,† Ashley M. Wright,† Trevor Hayton,† Jun Liang,‡ Ivan Keresztes,‡
Emil Lobkovsky,‡ David B. Collum,*,‡ and Armen Zakarian*,†
†Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
‡Baker Laboratory, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853-1301, United States
S
* Supporting Information
6
ABSTRACT: A combination of X-ray crystallography, Li,
15N, and 13C NMR spectroscopies, and density functional
theory computations affords insight into the structures and
reactivities of intervening aggregates underlying highly
selective asymmetric alkylations of carboxylic acid dianions
(enediolates) mediated by the dilithium salt of a C2-symmetric
chiral tetraamine. Crystallography shows a trilithiated n-
butyllithium−dilithiated amide that has dimerized to a hexalithiated form. Spectroscopic studies implicate the non-dimerized
trilithiated mixed aggregate. Reaction of the dilithiated amide with the dilithium enediolate derived from phenylacetic acid affords
a tetralithio aggregate comprised of the two dianions in solution and the dimerized octalithio form in the solid state.
Computational studies shed light on the details of the solution structures and afford a highly predictive stereochemical model.
demonstrated that high stereocontrol can correlate with high
structural control of the aggregates.13 Thus, we presumed that the
enantioselectivity in eq 1 derives from a well-defined chiral
aggregate, 2, composed of the dilithium enediolate and the chiral
dilithium amide.11,14 The optimized conditions suggested a 1:1
stoichiometry, although that assertion lacked direct support. Never-
theless, a detailed understanding of the enantioselectivity clearly
requires knowledge of the underlying coordination chemistry.
We describe herein a combination of X-ray crystallography,
6Li, 13C, and 15N NMR spectroscopies, and density functional
theory (DFT) computations that afford insight into the structures
and reactivities of intervening aggregates 5−8.15−17 These studies
suggest a mechanistic model affording remarkable agreement
between observed and computed enantioselectivities.
INTRODUCTION
■
Despite remarkable progress in the field of catalytic asymmetric
synthesis,1 asymmetric alkylations of lithium enolates are pre-
dominantly based on covalent chiral auxiliaries even in the simplest
functionalizations.2−5 Recently, we developed an alkylation of the
dianions of aryl and heteroaryl acetic acids6 (enediolates)7 in which
a dilithium amide derived from a C2-symmetric chiral diamine8,9
imparts high enantioselectivity (eq 1).10,11 The enediolate−
dilithiated amide complex is generated in situ, circumventing
discrete steps to add and remove when covalently bound chiral
auxiliaries are used. The reaction shows considerable generality for
activated, unactivated, and functionalized electrophiles.
To help guide the reader, we note that the detailed organolithium
chemistry delineated in the Results section is summarized for the
generalists at the start of the Discussion section. This summary is
followed by a discussion of the possible implications and predictive
capabilities of the seemingly robust stereochemical model.
RESULTS
■
The structures of mixed aggregates 5−8 were determined using a
combination of X-ray crystallography, multinuclear NMR spectros-
copies, and DFT computations as described below. In addition,
COSY, TOCSY, HSQC, HMBC, and ROESY spectroscopies
provided support to both the aggregate assignments and spatial
orientations. These are archived in the Supporting Information.
Evidence from a few enantioselective organolithium reactions
scrutinized through structural and mechanistic studies12 has
Received: March 30, 2013
© XXXX American Chemical Society
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amidolithium reagent was reported previously.19 The most
interesting feature of the solid-state structure of 5 is the binding
mode of the amine ligand. Each piperidine-derived nitrogen atom is
coordinated to a single lithium cation, whereas each amide nitrogen
atom is coordinated to two lithium cations. More specifically, Li2 is
chelated by three nitrogen atoms, N2, N3, and N4, thereby
generating a five-membered ring and a six-membered ring.
Additionally, Li2, N2, N3, and N4 are all roughly coplanar. This
orientation places both phenyl groups in the amine backbones
pseudoequatorially. Li1 is coordinated by two nitrogen atoms (N1
and N2), thereby generating a five-membered ring. Finally, Li3 is
only coordinated by one nitrogen atom (N3) in addition to the
carbon atom (C1 and C1A) of the n-Bu fragment. The Li−
N(amide) bond lengths are 1.979(5) Å (Li2−N2), 1.923(4) Å
(Li2−N3), 1.936(4) Å (Li1−N2), and 1.953(4) Å (Li3−N3),
whereas the Li−N(amine) bond lengths are 2.089(4) Å (Li1−N1)
and 2.167(4) Å (Li2−N4). Similar bond lengths
are seen in the lithium salt of a related bidentate Koga base,
N-neopentyl-1-phenyl-2-(1-piperidino)ethylamine.20
Solution Structure. The structural assignments used a
tetra-15N-labeled analogue, [15N4]3, prepared using a modifi-
cation of the original synthesis, as illustrated in Scheme 1.
n-BuLi−Dilithiated Amide Mixed Aggregate. X-ray
Crystal Structure.14,18 Addition of 4.0 equiv of n-BuLi (2.5 M)
to a hexane solution of amine 3 at −25 °C affords a pale yellow
solution. Subsequent crystallization from a hexane/pentane
mixture yields [Li3(1)(nBu)]2 (5) as a colorless microcrystalline
solid in 46% yield. The composition of 5 was confirmed with an
X-ray diffraction study, and its solid-state structure is shown in
Figure 1. Complex 5 crystallizes in the orthorhombic space group
Scheme 1
Figure 1. ORTEP of hexalithio n-BuLi−dilithiated amide mixed
aggregate 5.
P212121 as the pentane solvate 5. Complex 5 displays overall C2
symmetry and is assembled from two trilithio components each
constituted from an n-BuLi and a doubly deprotonated diamine
subunit.
The metrical parameters of each trilithiated fragment are
similar to those found in other alkyllithium aggregates.7
Incorporation of n-BuLi into the structure of an organo- or
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Figure 2. 6Li NMR spectra of 0.10 M [6Li,15N]6 prepared from [15N4]3 with 4.0 equiv of n-BuLi in 6.10 M THF/pentane recorded at −90 °C after
aging at −78 °C for 2.0 h: (A) fully coupled and (B) broadband 15N decoupled. * indicates unknown impurities that appear sporadically.
Figure 3. 15N NMR spectra of 0.10 M [6Li,15N]6 prepared from [15N4]3 with 4.0 equiv of n-BuLi in 6.10 M THF/pentane recorded at −90 °C after
aging at −78 °C overnight: (A) fully coupled and (B) broadband 15N decoupled. * indicates unknown impurities that appear sporadically.
Metalation of [15N4]3 with 2 equiv of recrystallized [6Li]n-BuLi21 in
THF at −78 °C was incomplete, affording lithium amide−n-BuLi
mixed aggregate 6 along with unreacted n-BuLi and diamine 3.22−24
Subsequent warming to −20 °C for 10 min caused complete
consumption of 3, affording dilithiated amide homoaggregate 4
as a complex mixture that was not investigated further.25,26
Lithiation of [15N4]3 with ≥3.0 equiv of [6Li]BuLi21 in 6.1 M
THF/hexane affords a dilithium amide−n-BuLi mixed
moieties showed characteristically large (3.6−5.8 Hz) coupling
constants,30 whereas the dative Li−N linkages deriving from
chelation by the piperidino moieties displayed much smaller
(1.9−2.2 Hz) coupling constants.31 The assignment as
trilithiated 6 rather than hexalithio 5 stems from a 13C NMR
spectrum showing a multiplet that was tentatively assigned as a
quintet corresponding to the Li−C−Li′ and the heptet of the n-
BuLi tetramer (Figure 4).26,32
DFT Computed Structure. DFT calculations were performed
with the Gaussian 09 package using Gaussview 5.0 and
WebMO as a graphical user interface.33 Geometry optimiza-
tions and frequency calculations were performed at the B3LYP
level of theory using the 6-31G(d) and 6-31+G(d) Pople basis
sets. Free energies were calculated from an MP2-derived single-
point energy [6-31G(d) basis set] and a B3LYP-derived
thermal correction [6-31G(d)] at 195 K (−78 °C) and 1 atm.
(MP2 corrections seem to provide superior correlations
of theory and experiment, especially for highly congested
structures.)
6
aggregate displaying three Li resonances (1:1:1) along with
resonances of residual n-BuLi dimer and tetramer26 at elevated
n-BuLi concentrations (Figures 2 and 3). The resonance count
and intensities, most easily observed in the 15N broadband
decoupled spectrum (Figure 2B), are consistent with those of
trilithiated mixed aggregate 6 or the corresponding dimerized
hexalithiated 5 observed crystallographically. (The trace
impurities noted by asterisks were initially believed to be
n-BuOLi-derived mixed aggregates, but addition of n-BuOH
incrementally reveals a distinctly different mixed aggregate.)
The connectivities in the trilithio subunit (indicated in red in
Table 1) were assigned from the splitting patterns in the
coupled spectra (Figures 2A and 3A) with the aid of single-
frequency decoupling27 and [6Li,15N]-HMQC spectroscopy28,29
(Supporting Information). Spectroscopic data are compiled in
Table 1. The primary Li−N linkages of the lithium amide
We followed a pedagogically interesting protocol by
providing only the atomic connectivitiesno detailed NMR
or crystallographic datato the co-worker (J.L.) doing computa-
tions. Comparing the computed structures to the crystal structure
revealed remarkable similarities, but we had computationally
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6
Table 1. Li and 15N NMR Spectroscopic Data for Mixed
Aggregates 6 and 8
Figure 5. DFT computed structure of 6 as disolvate (6a) showing
critical structural variables.
4. Solvation. Serial solvation of solvent-free trilithiated
fragment 6 shows a strong (8.3 kcal/mol) preference for the di-
THF solvate over the monosolvate. Additional solvation was
undetectable.37
5. Chelate Orientation. Reversing the role of the two
chelating piperidines (eq 3)inverting the absolute config-
uration of the backbone of the structurerevealed a
pronounced preference for diastereomer 6a relative to 6b.
missed the orientation of the three-carbon propanediamine
bridge and one of the five-membered chelates. With this addi-
tional information in hand, the computations were repeated
(Supporting Information).
Three important variables are summarized in Figure 5 and
described below.
1. Piperidine Chair−Chair Flip. Each piperidine ring can
exist in two chair conformers, which differ by 2.0−6.0 kcal/mol
(for all solvates; eq 2).34 The preferred conformers have
lithiums positioned axially as drawn in Figure 5. This proves to
be the overwhelming preference found crystallographically for
N-alkylpiperidine−lithium complexes.35,36
6. Dimerization. The association of 6 to give 5 proved to
be very high energy owing largely to a loss of solvation
energy. The crystal for X-ray determination of 5 was
obtained from hydrocarbon solutions wherein solvation
would not be an issue.
Enediolate−Dilithiated Amide Mixed Aggregate.
X-ray Crystal Structure. Addition of 4.0 equiv of n-BuLi to a
THF solution containing 3 and phenylacetic acid at −25 °C
yields a light yellow solution. Crystallization from hexanes, with
a small amount of added THF, affords [Li4(4)(PhCH
CO2)(THF)2]2 (7) as a light yellow powder in 48% yield. The
composition of 7 was confirmed by X-ray diffraction (Figure 6).
Although the data quality is poorer than that observed for 5, the
2. Chelate Conformation. The five-membered chelate rings
show two conformers orienting the phenyl in roughly the
equatorial plane and substantially displaced from this plane.
They are essentially of equal energy ( 0.2 kcal/mol).
3. n-Butyl Orientation. The n-butyl moiety always positions
on the opposite face of the six-membered ring from the two
THF ligands as drawn, regardless of starting geometry.
Figure 4. 13C NMR spectra of 0.10 M [6Li,15N]6 prepared from [15N4]3 with 4.0 equiv of n-BuLi in 6.10 M THF/pentane recorded at −90 °C after
aging at −78 °C overnight. The 13C resonance of the n-BuLi dimer is not shown but appears as a 1:2:3:2:1 quintet at 12.6 ppm.
D
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Figure 6. ORTEP of hexalithio enediolate−dilithiated amide mixed aggregate 7.
6
Figure 7. Li NMR spectra of 0.10 M [6Li,15N]8 and residual [6Li,15N]6 prepared from [15N4]3 with 4.0 equiv of n-BuLi in 6.1 M THF/pentane
recorded at −90 °C after aging at −78 °C for 2.0 h: (A) fully 15N coupled and (B) 15N broadband decoupled. * indicates unassigned resonances.
connectivity of the atoms in 7 is clearly defined. Complex 7
crystallizes in the orthorhombic space group P212121 as the
THF solvate 7·THF. Complex 7 comprises two tetralithio
subunits in the solid stateoctalithio overallwith C2
symmetry. It consists of two chiral dilithiated amides and two
enediolates. Four of the eight lithium cations are ligated by
THF molecules. The presence of the same dilithium amide core
in both 5 and 7 suggests its central importance. Because the
molecule is composed of two identical tetralithio subunits, the
metrical parameters of only one half are discussed. As was
observed for 5, one lithium atom (Li2) is chelated by three
nitrogen atoms from one tetra(amine) ligand: N2, N3, and N4,
thereby generating a five-membered ring and a six-membered
ring. One lithium atom (Li1) is coordinated by two nitrogen
atoms (N1 and N2), generating a five-membered ring. Additionally,
two lithium atoms (Li3 and Li4) bridge the chiral amine moiety
and the oxygen atoms of the enediolate ligands, [PhCHCO2]2−.
The Li−N(amide) and Li−N(amine) bond lengths in 7 are
similar to those in 5. Finally, the Li−Li distances in 7 range
from 2.418 to 2.661 Å, in line with structurally related lithium
aggregates.38
The most interesting structural feature of 7 is the incorpo-
ration of the enediolate moiety, [PhCHCO2]2−. The atoms
within the enediolate ligand are all coplanar, suggesting strong
π conjugation. Additionally, each oxygen atom of the endiolate
is coordinated to three lithium cations. For instance, one
oxygen atom (O4) is coordinated to a triangular face formed by
three lithium cations (Li1, Li2, Li4), whereas the other oxygen
atom (O2) is ligated by Li3, Li4, and Li4A. The Li−O bond
lengths range from 1.857 to 2.245 Å; however, the average
Li−O bond length of 1.96 Å is standard.39 Additionally, there
are two independent CC bonds that exhibit somewhat
different C−C bond lengths [C48−C49 = 1.408(8) Å and
C40−C41 = 1.356(15) Å]. The C−O bond lengths of the
two moieties are comparable [C48−O4 = 1.322(6) Å and
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Figure 8. 15N NMR spectra of 0.10 M [6Li,15N]8 and residual [6Li,15N]6 prepared from [15N4]3, 4.0 equiv of n-BuLi, and phenylacetic acid in 0.10
6
M THF/pentane recorded at −90 °C after aging at −78 °C for 2.0 h: (A) fully 15N coupled and (B) Li broadband decoupled.
C48−O3 = 1.283(7) Å versus C40−O1 = 1.312(7) Å and
C40−O2 = 1.326(7) Å].
Solution Structure. The structure of the centrally important
mixed aggregate of dilithiated amide 3 with the dianionic
enediolate of phenylacetic acid was studied using the protocols
and spectroscopic methods described above. Figure 7 shows 6Li
NMR spectra recorded on a solution prepared from a 1:4:1
mixture of [15N4]3, n-BuLi, and phenylacetic acid (1) in THF/
pentane. Residual n-BuLi-derived mixed aggregate 6 is observed
along with a new mixed aggregate corresponding to tetralithio
mixed aggregate 8. (The connectivities are highlighted in red in
Table 1.) Despite differential broadening, the four resonances
integrate to 1:1:1:1, consistent with a 1:1 mixed aggregate
constituted from the two dianions. The corresponding fully
coupled and broadband decoupled 15N NMR spectra are illus-
trated in Figure 8. Single-frequency decoupling and [6Li,15N]-
HMQC spectroscopy provided the connectivities and com-
pleted the assignments (Table 1). COSY, TOCSY, HSQC,
HMBC, and ROESY spectroscopies (Supporting Information)
supported the spatial orientations observed computationally
(below). Although tetralithio mixed aggregate 8 could have, in
theory, dimerized into an octalithio form, neither the physical
nor the computational models provided any support for such a
severely congested aggregate.
Calculated Transition Structures and Enantioselectiv-
ities. Aggregates 8a and 8c expose the si and re faces,
respectively, of the enediolate to the sterically accessible
exterior of the globular aggregate. All that remained was to
examine the transition structures for the alkylation and predict
the affiliated enantioselectivities. The calculations used methyl
chloride. Transition structures 17a and 17b correspond to the
alkylation of 8a and 8c, respectively (Figure 9). We explored
cyclic transition structures bearing Li−Cl contacts and found
they were only marginally viable.43−47 The ≥20 kcal/mol
barriers (referenced to common ground state 8a) do not
trouble us; barriers of alkylations are routinely overestimated.48
More importantly, the 6.4 kcal/mol preference for 17a suggests
a ≫99.9% ee. Although this value exceeds the experimental
value of 98% ee for allyl bromide,6 the model is impressively
robust, especially given possible sources of erosion exper-
imentally. Equilibration of the aggregates on the time scales of
alkylation is by no means certain.
DFT Computed Structure. The structure of 8 was examined
computationally.40−42 Many of the structural details such as
piperidino chair preferences and chelating side chain orientations
were analogous to those outlined above (and provided in detail in
the Supporting Information), warranting no additional comment.
We also observed no tendency of tetralithio 8 to form an octalithio
(dimerized) form. The three significant variables are described in
the following.
1. Solvation. The serial solvation of the core is exergonic to
the tetrasolvation state (7.1 kcal/mol favored over the
trisolvate). Additional solvation was undetected without
significant structural disruptions.
2. Enolate Orientation. The enolate orients favoring 8a as
shown in eq 4, presumably owing to the steric demands of the
disolvated lithium nucleus.
3. Phenyl Orientation. The orientation of the phenyl moiety
on the enediolate fragment is the variable that we believe is
at the heart of the enantioselectivity in eq 1. We observe a
7.7 kcal/mol preference for 8a versus 8c (eq 5).
DISCUSSION
■
Summary. The studies of the mixed aggregates derived
from dilithiated amide 4 and the coordination chemistry
underlying the enantioselective alkylation of carboxylic acid
enediolates in eq 16 reveal a remarkably coherent picture
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Figure 9. Calculated transition structures 17a and 17b showing selectivity for alkylation from the si and re enolate faces, respectively.
Scheme 2
(Scheme 2). In the absence of coordinating ligand, dilithiated
amide 4 and n-BuLi affords a crystalline mixed aggregate
shown by X-ray crystallography to be an exceedingly complex
hexalithiated form, 5, comprising two n-BuLi−dilithiated amide
trilithio subunits. Analogous metalation in THF solution affords
trilithio form 6 as a single diastereomer, suggested by
computations to be disolvate 6a (vide supra).49
Mixing diamine 3, 4.0 equiv of n-BuLi, and phenylacetic acid
(1) affords octalithio mixed aggregate 7 comprising two di-
lithiated amides and two enediolate dianions in a C2-symmetric
dimerized form. Analogous mixtures in THF solution afford the
corresponding tetralithio mixed aggregate 8 composed of a
dilithiated amide and enediolate dianions and suggested by
computations to be tetrasolvated (8a). Once again, the structural
G
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and stereocontrol are predicted to be very high. Computations of
8a also indicate a strong (7.7 kcal/mol) preference for a single
orientation of the enediolate relative to the dilithium amide
fragment.
directly with the mixed aggregate without intervening
deaggregations and other structural changesare amenable
to computational prediction. For sluggish electrophiles,
intervening deaggregations could cause stereochemical leakage.
Of course, alkylations are a small subset of the reactions of
lithium enolates, so this story may be only in its infancy.
Stereochemical Model: Predictions. In essence, the
dilithium amide fragment concurrently controls the orientation
of the enediolate and blocks one of two enantiotopic enediolate
faces, ensuring a highly enantioselective alkylation. Com-
puted product-determining transition structures 17a and 17b
(Figure 9) do not contain Cl−Li interactions. Importantly, the
computations predict the correct facial selectivity and an
enantioselectivity of >99% ee compared with the experimental
values of up to 98% ee. This satisfying theory-experiment
correlation attests to a potentially robust stereochemical model.
One should note, however, that the predicted selectivity based
on reactant preference or transition structure preference will
depend critically on whether the aggregates equilibrate on
the time scale of the alkylation. Instantaneous alkylation could
be construed as evidence of non-equilibrium kinetics. Given the
enormous energetic bias, this would not measurably affect the
observed selectivities.
Of course, many variables had to be controlled to obtain the
highly enantioselective alkylations. Ultimately, however, the
orientation of the enediolate phenyl moiety appears to be the
central variable (eq 5). The robustness of this model is easily
tested. The data showed a priori that the propionate enediolate
is poorly selective (eq 6). Computations confirmed the inferior
(1.3 kcal/mol) selectivity of the enediolate geometry (eq 7).
The corresponding computed transition structures for iso-
propyl and cyclohexyl-substituted enolates are akin to the 4.2
and 5.2 kcal/mol facial preference of the phenyl-substituted
enediolate. The cyclohexyl- and isopropyl-substituted enolates
force a conformational flip of the piperidine (dotted line in 19b
and 20b).
EXPERIMENTAL SECTION
■
Reagents and Solvents. THF and hexanes were distilled from
blue or purple solutions containing sodium benzophenone ketyl. The
hexane contained 1% tetraglyme to dissolve the ketyl. n-BuLi was
prepared and recrystallized as described previously.21 Solutions of
n-BuLi were titrated using a literature method.51 Amine 3 was
prepared as described previously.8 [15N4]1 was prepared as described
below.
NMR Spectroscopic Analyses. All NMR tubes were prepared
6
using stock solutions and sealed under partial vacuum. Standard Li,
13C, and 15N NMR spectra were recorded on a 500 MHz spectrometer
6
at 73.57, 125.79, and 50.66 MHz, respectively. The Li, 13C, and 15N
resonances are referenced to 0.30 M [6Li]LiCl/methanol at −90 °C
(0.0 ppm), the CH2O resonance of THF at −90 °C (67.57 ppm), and
neat Me2NEt at −90 °C (25.76 ppm), respectively.
Computations. DFT computations were optimized at B3LYP/6-
31G(d) level33 with single-point calculations at the MP2 level of
theory.
Synthesis of [15N4]3: General. Unless the reaction procedure
states otherwise, all reactions requiring inert atmosphere were carried
out with dry argon in oven or flame-dried glassware. THF and diethyl
ether were distilled from sodium/benzophenone in a continuous still
under an atmosphere of argon. Dichloromethane, diisopropylamine,
pyridine, triethylamine, and chlorotrimethylsilane were distilled from
calcium hydride in a continuous still under and atmosphere of argon.
Chlorotriethylsilane (TESCl) and diisopropylethylamine (Hunig’s
base) were distilled from calcium hydride under an inert atmosphere
of dry argon and stored over calcium hydride. Room temperature
reactions were carried out between 22 and 24 °C. Analytical thin-layer
chromatography was visualized using combinations of ultraviolet,
anisaldehyde, ceric ammonium molybdate, potassium permanganate,
and iodine staining. Flash chromatography was preformed using
40−63 mm silica gel (Merck, Geduran, no. 11567-1) as the stationary
phase. Proton magnetic resonance spectra were recorded at 400, 500,
or 600 MHz. Carbon magnetic resonance spectra were recorded at
100, 125, or 150 MHz. All chemical shifts were reported in δ units
relative to tetramethylsilane. High-resolution mass spectroscopic data
were obtained at the Mass Spectrometry Laboratory at the University
of California, Santa Barbara.
Benzamide-15N (12).52 Sodium hydroxide (10 M in water, 16.7
mL, pre-cooled to 0 °C) was added to a solution of benzoyl chloride
(12.55 mL, 0.108 mol) and ammonium-15N chloride (2.50 g, 45.88
mmol) in water (8.3 mL) and diethyl ether (12.5 mL) at 0 °C. After
15 min, the solids were filtered, collected, and dried under high
vacuum to deliver benzamide-15N (4.62 g, 37.83 mmol, 82%) which
1
was used directly without further purification. H NMR (600 MHz;
CDCl3): δ 7.81−7.80 (m, 2H), 7.54−7.51 (m, 1H), 7.45 (m, 2H),
5.91 (m, 2H).
CONCLUSIONS
■
Only in a few instances has stereocontrol been correlated with
the underlying organolithium aggregation.12,13 We suspect,
however, that high stereocontrol is often affiliated with high
structural control.13 To borrow a familiar phrase, “what you see
is what you get” (WYSIWYG). The structural studies described
herein certainly are supportive. The emergent model appears to
be highly predictive. Ongoing studies may reveal why certain
electrophiles are poorly selective owing to specific steric
interactions. At this time we do not know the relative rates
of alkylations and aggregate exchanges.50 We suspect, however,
that highly reactive electrophilesthose most likely to react
1-Benzoylpiperidine-15N (13). 1,5-Dibromopentane was added
to a mixture of benzamide-15N (4.62 g, 37.83 mmol), tetrabutylam-
monium hydrogen sulfate (1.41 g, 4.16 mmol), potassium carbonate
(7.37 g, 53.34 mmol), and sodium hydroxide (7.41 mol, 0.185 mol) in
dry toluene (162 mL). The solution was heated at reflux for 18 h. After
cooling to room temperature (rt), the solids were filtered off and the
residue was purified via flash chromatography (silica, 30% → 70%
ethyl acetate/hexanes) to deliver 1-benzoylpiperidine-15N (6.41 g,
H
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33.69 mmol, 90%). 1H NMR (400 MHz; CDCl3): δ 7.52−7.21
(m, 5H), 3.75−3.68 (m, 2H), 3.38−3.31 (m, 2H), 1.72−1.48 (m, 6H).
N,N′-Trimethylenediphthalimide-15N (10).55 Phthalimide-15N
(6.80 g, 45.88 mmol) was added to a suspension of sodium hydride
(3.30 g, 82.58 mmol) in dimethylformamide (91.8 mL) at rt. After
15 min 1,3-diiodopropane (2.63 mL, 22.94 mmol) was added and the
reaction stirred at rt for 15 min and then heated in a sealed flask at
100 °C for 3 h. The reaction was cooled to rt and diluted with water
and ethyl acetate. The aqueous layer was extracted with ethyl acetate
(3 × 300 mL). The combined organic layers were washed with water
(2 × 300 mL) and brine, dried with sodium sulfate, and concentrated.
The residue was dissolved in ethyl acetate and dichloromethane, and
silica gel was added. The solution was evaporated to dryness. The
residue, absorbed onto the silica gel was purified via flash
chromatography (silica, 10% → 30% ethyl acetate/dichloromethane)
1-Benzylpiperidine-15N (14). A solution of 1-benzoylpiperidine-
15N (6.41 g, 33.69 mmol) in diethyl ether (50 mL total with rinses)
was added to a suspension of lithium aluminum hydride (5.11 g,
0.135 mol) in diethyl ether (122 mL) at 0 °C. After the addition of
1-benzoylpiperidine-15N was complete, the solution was refluxed for
18 h. The reaction was cooled to 0 °C, and water (5.10 mL) was added
carefully. After 5 min 3 M NaOH (5.10 mL) was added and the
reaction was stirred for an additional 5 min. Water (15.30 mL) was
added, and the reaction was stirred for 5 min at 0 °C before warming
to rt. After 3 h the solids were filtered and rinsed with diethyl
ether. The filtrate was concentrated under reduced pressure to deliver
1-benzylpiperidine-15N (5.94 g, 33.69 mmol, 100%), which was used
1
to give the desired product (4.35 g, 12.93 mmol, 56%). H NMR
(500 MHz; CDCl3): δ 7.87−7.82 (m, 4H), 7.74−7.69 (m, 4H), 3.79−
3.75 (m, 4H), 2.14−2.07 (m, 2H).
1
directly without further purification. H NMR (400 MHz; CDCl3):
δ 7.32−7.21 (m, 5H), 3.49−3.47 (m, 2H), 2.41−2.32 (m, 4H), 1.60−
1.52 (m, 4H), 1.45−1.38 (m, 2H).
1,3-Diaminopropane-15N (11). Potassium hydroxide (5.81 g,
0.104 mol) was added to a suspension of N,N′-trimethylenediph-
thalimide-15N (4.35 g, 12.93 mmol) in water (18 mL) and heated at
70 °C for 18 h, at which point the reaction became clear and
homogeneous. The reaction was distilled into a flask containing
2.15 mL of 12.1 M hydrochloric acid. After distilling to dryness, water
(45 mL) was added to the reaction flask and again distilled to dryness.
This process was repeated twice with water (45 mL) and once with
methanol (45 mL). The combined distillates were concentrated under
reduced pressure to deliver 1,3-diaminopropane-15N as its hydro-
chloride salt (1.78 g, 11.94 mmol, 92%), which was used without
Piperidine-HCl-15N (15). Following a literature protocol53a
hydrogen gas was bubbled through a solution of 1-benzylpiperidine-15N
(2.97 g, 16.85 mmol) and palladium on carbon (0.297 g) in methanol
(112 mL) and dichloromethane (56 mL), which generates HCl in situ
under the reaction conditions.53b After 15 min the hydrogen needle
was removed from the solution, and the reaction was allowed to stir
under a hydrogen atmosphere for 24 h. The solution was filtered
through a Celite pad. The filtrate was concentrated under reduced
pressure to deliver piperidine-15N (1.45 g, 11.83 mmol, 70%) as its
hydrochloride salt, which was used directly without further
purification. 1H NMR (500 MHz; D2O): δ 3.27−3.09 (m, 4H),
1.90−1.74 (m, 4H), 1.74−1.62 (m, 2H).
1
further purification. H NMR (600 MHz; CD3OD): δ 3.05 (m, 4H),
2.05 (m, 2H). 13C NMR (150 MHz; CD3OD): δ 36.4, 25.1. 15N NMR
(60.5 MHz, CD3OD): δ 31.8. LRMS (ESI) calcd for C3H1315N2
[M+H] 77.09, found 76.98.
(1S)-1-(1-Phenyl)-2-(1-piperidinyl)ethanol-15N (16). Sodium
hydroxide (0.437 g, 11.83 mmol) was added to a solution of
piperidine-15N (1.45 g, 11.83 mmol) and (S)-styrene oxide (1.29 mL,
11.26 mmol) in ethanol (28.2 mL) and heated at 120 °C for 4 h. After
cooling to rt, the reaction was diluted with water and ethyl acetate.
The aqueous layer was extracted with ethyl acetate (3 × 75 mL). The
combined organic layers were washed with brine, dried with sodium
sulfate, and concentrated. The residue (2.29 g, 11.08 mmol, 94%) was
used directly without further purification. 1H NMR (400 MHz;
CDCl3): δ 7.41−7.15 (m, 5H), 4.73−4.69 (m, 1H), 3.70−3.57
(m, 1H), 2.76−2.64 (m, 2H), 2.60−2.52 (m, 1H), 2.53−2.45 (m, 1H),
2.43−2.32 (m, 2H), 1.74−1.41 (m, 6H).
Phthalimide-15N (9).54 Ammonium-15N chloride (2.50 g, 45.88 mmol)
and sodium hydroxide were combined in a flask and connected via
cannula to a separate flask containing phthalic anhydride (6.80 g,
45.88 mmol) in methanol (113 mL) cooled to −10 °C. The flask
containing ammonium-15N chloride and sodium hydroxide was heated
with a propane torch, and the resulting gas was bubbled through the
mentholic solution of phthalic anhydride. After gas evolution ceased
the solution was stirred for an additional hour. The methanol
was distilled at atmospheric pressure. The crude residue was heated
to 230 °C for 10−15 min. After cooling, phthalimide-15N (6.80 g,
45.88 mmol, 100%) was obtained and used directly without further
purification. 1H NMR (500 MHz; DMSO-d6): δ 11.33 (d, J = 93.9 Hz,
1H), 7.85−7.82 (m, 4H).
Tetraamine-15N (3). Methanesulfonyl chloride (2.10 mL, 26.58
mmol) was added to a solution of (1S)-1-(1-phenyl)-2-(1-piperidinyl)-
ethanol-15N (4.57 g, 22.15 mmol) and triethylamine (9.30 mL,
66.45 mmol) in diethyl ether (74 mL) at 0 °C. After 30 min the
solution was warmed to rt and stirred for an additional hour. Then,
I
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Journal of the American Chemical Society
Article
triethylamine (12.4 mL, 88.6 mmol), 1,3-diaminopropane-15N hydro-
chloride (1.65 g, 11.08 mmol), and water (12.8 mL) were added to the
reaction, and the solution was allowed to stir for 2 days at rt. The
reaction was diluted with water and diethyl ether. The aqueous layer
was extracted with diethyl ether (3 × 100 mL). The combined organic
layers were washed with brine, dried with sodium sulfate, and
concentrated, and the residue was purified via flash chromatography
(silica, 5% → 10% → 20% triethylamine/ethyl acetate). The product
was then recrystallized from isopropanol:water (1.1:1) to deliver the
purified tetraamine-15N (2.10 g, 4.64 mmol, 42%) as a white solid and
1.25 g (2.76 mmol, 25%) of tetraamine-15N 3 from the mother liquors
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: New York, 1989;
Vol. 1, p 1. (e) Martin, S. F. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: New York, 1989; Vol. 1, p 475.
(f) Plaquevent, J.-C.; Cahard, D.; Guillen, F.; Green, J. R. Science of
Synthesis; Georg Thieme Verlag: New York, 2005; Vol. 26, pp 463−
511. (g) Comprehensive Organic Functional Group Transformations II;
Katritzky, A. R., Taylor, R. J. K., Eds.; Elsevier: Oxford, 1995; pp 834−
835. (h) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry
2007, 18, 569.
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C. R.; Bade, T. R. Synthesis 1982, 4, 284. (c) Miyashita, M.;
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1
as an oil. H NMR (600 MHz; CDCl3): δ 7.34 (d, J = 7.2 Hz, 4H),
7.30 (t, J = 7.6 Hz, 4H), 7.22 (t, J = 7.2 Hz, 2H), 3.72 (dd, J = 11.0,
3.1 Hz, 2H), 2.52−2.22 (m, 18H), 1.66 (t, J = 5.6 Hz, 2H), 1.57−1.49
(m, 8H), 1.41 (d, J = 5.1 Hz, 4H). 13C NMR (150 MHz; CDCl3): δ
143.3, 128.2, 127.3, 126.9, 66.6, 60.2, 54.6, 46.3, 30.5, 26.1, 24.5.
HRMS (ESI) calcd for C29H4515N4 [M+H] 453.3518, found 453.3526.
(8) (a) Yamashita, Y.; Odashima, K.; Koga, K. Tetrahedron Lett. 1999,
40, 2803. (b) Yamashita, Y.; Emura, Y.; Odashima, K.; Koga, K.
Tetrahedron Lett. 2000, 41, 209.
(9) For other applications of diamine 3 in asymmetric synthesis, see:
(a) Swingle, N. M.; Reddy, K. V.; Rossiter, B. E. Tetrahedron 1994, 50,
4455. (b) Frizzle, M. J.; Nani, R. R.; Martinelli, M. J.; Moniz, G. A.
Tetrahedron Lett. 2011, 52, 5613. (c) Fehr, C.; Galindo, J.; Farris, I.;
Cuenca, A. Helv. Chim. Acta 2004, 87, 1737.
ASSOCIATED CONTENT
* Supporting Information
Spectroscopic, crystallographic, and computational data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
(10) (a) Kizirian, J.-C. Chem. Rev. 2008, 108, 140. (b) Wu, G.;
Huang, M. Chem. Rev. 2006, 106, 2596. (c) Farina, V.; Reeves, J. T.;
Senanayake, C. H.; Song, J. J. Chem. Rev. 2006, 106, 2734.
(d) Rathman, T. L.; Bailey, W. F. Org. Process Res. Dev. 2009, 13,
144. (e) Clayden, J. Organolithiums: Selectivity for Synthesis; Pergamon:
New York, 2002.
AUTHOR INFORMATION
Corresponding Author
dbc6@cornell.edu; zakarian@chem.ucsb.edu
Notes
■
The authors declare no competing financial interest.
(11) For leading references and discussions of mixed aggregation
effects and their applications in synthesis, see: (a) Seebach, D. Angew.
Chem., Int. Ed. Engl. 1988, 27, 1624. (b) Tchoubar, B.; Loupy, A. Salt
Effects in Organic and Organometallic Chemistry; VCH: New York,
1992; Chapters 4, 5, and 7. (c) Briggs, T. F.; Winemiller, M. D.; Xiang,
ACKNOWLEDGMENTS
■
A.Z. thanks the National Institutes of Health (NIGMS
GM077379) and Amgen for direct support of this work.
D.B.C. thanks the National Institutes of Health (NIGMS
GM39764 and NIGMS GM 077167). We also thank Dr. Guang
Wu for assistance with X-ray crystallography.
̀
B.; Collum, D. B. J. Org. Chem. 2001, 66, 6291. (d) Caubere, P. Chem.
Rev. 1993, 93, 2317. (e) Gossage, R. A.; Jastrzebski, J. T. B. H.; van
Koten, G. Angew. Chem., Int. Ed. 2005, 44, 1448. (f) Seebach, D. In
Proceedings of the Robert A. Welch Foundation Conferences on Chemistry
and Biochemistry; Wiley: New York, 1984; p 93. (g) Luderer, M. R.;
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Tetrahedron: Asymmetry 2009, 20, 981. (h) Reich, H. J. J. Org. Chem.
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