Azaaldol condensation of a lithium enolate solvated by N,N,N′, N′ -tetramethylethylenediamine: Dimer-based 1,2-addition to imines

Article abstract of DOI:10.1021/ja400345c

The lithium enolate of tert-amylacetate solvated by N,N,N′,N′- tetramethylethylenediamine (TMEDA) is shown to be a doubly chelated dimer. Adding the dimeric enolate to 4-fluorobenzaldehyde-N-phenylimine affords an N-lithiated β-amino ester shown to be monomeric using ⁶Li and ¹⁵N NMR spectroscopies. Rate studies using ¹⁹F NMR spectroscopy reveal reaction orders consistent with a transition structure of stoichiometry [(ROLi)₂(TMEDA)₂(imine)]^?. Density functional theory computations explore several possible dimer-based transition structures with monodentate and bidentate coordination of TMEDA. Supporting rate studies using trans-N,N,N′,N′-1,2- tetramethylcyclohexanediamine showing analogous rates and rate law suggest that TMEDA is fully chelated.

Full text of DOI:10.1021/ja400345c

Article
pubs.acs.org/JACS
Azaaldol Condensation of a Lithium Enolate Solvated by N,N,N′,N′-
Tetramethylethylenediamine: Dimer-Based 1,2-Addition to Imines
Timothy S. De Vries, Angela M. Bruneau, Lara R. Liou, Hariharaputhiran Subramanian,
and David B. Collum*
Department of Chemistry and Chemical Biology Baker Laboratory, Cornell University, Ithaca, New York 14853-1301, United States
S
* Supporting Information
ABSTRACT: The lithium enolate of tert-amylacetate solvated
by N,N,N′,N′-tetramethylethylenediamine (TMEDA) is shown
to be a doubly chelated dimer. Adding the dimeric enolate to
4-fluorobenzaldehyde-N-phenylimine affords an N-lithiated β-
6
amino ester shown to be monomeric using Li and 15N NMR
spectroscopies. Rate studies using 19F NMR spectroscopy
reveal reaction orders consistent with a transition structure of
stoichiometry [(ROLi)2(TMEDA)2(imine)]⧧. Density func-
tional theory computations explore several possible dimer-based transition structures with monodentate and bidentate
coordination of TMEDA. Supporting rate studies using trans-N,N,N′,N′-1,2-tetramethylcyclohexanediamine showing analogous
rates and rate law suggest that TMEDA is fully chelated.
INTRODUCTION
■
Lithium enolates are of undeniable importance to synthetic
chemists1 yet pose particularly onerous mechanistic challenges
owing to complex aggregation phenomena. Solid-state
structural studies initiated by Seebach with significant
structural, rate, and computational studies revealed an enolate
contributions by Williard have grown into a considerable
dimer-based mechanism.
body of work.2 Much less is known about the structures of
enolates in solution3 and how solvation and aggregation
RESULTS
■
influence reactivity.4−8 The seminal spectroscopic and mech-
Solution Structures. Previous studies of TMEDA-solvated
anistic studies were those of Jackman and co-workers.4 The
enolates using the method of continuous variation (the method
of Job) have shown enolate 2 to be doubly chelated dimer 2a.19
preponderance of progress in untangling the contributions of
Adduct [6Li,15N]3 prepared from [15N]1 and [6Li]LDA.20 was
equilibrating aggregates and monomers to enolate reactivity
comes from Streitwieser and co-workers.6 Most recently, Reich
and co-workers have focused on measuring relative reactivities
of aggregates and monomers under nonequilibrium conditions.7
The present study of 1,2-additions of metal enolates to
imines (so-called azaaldol condensations) dovetails a long-
standing program aimed at understanding 1,2-additions9 and
lithiations10 of imines with an emergent interest in structures
and reactivities of lithium enolates.1,2,11−13 Azaaldol condensa-
tions are of particular importance in the synthesis of biologically
and medicinally significant β-amino esters, β-lactams, and 1,3-
amino alcohols.14−16 The flexibility of imines that synthetic
chemists find appealing16the capacity to vary the substituents
on the imine moietyhas proven to be equally important in
untangling organolithium structure−reactivity relationships.
Herein we describe rate and mechanistic studies of the
azaaldol addition of tert-amyl acetate 2 (t-Am = C(CH3)2Et) to
imine 1 (eq 1) mediated by N,N,N′,N′-tetramethylethylenedi-
amine (TMEDA).8 The reaction is clean, proceeds at tractable
rates without complicating lactamization,17 and is readily
monitored with 19F NMR spectroscopy.18 A combination of
shown using 6Li and 15N NMR spectroscopies21−23 to be
6
6
monomer 3a. The Li spectrum shows a 1:1 Li doublet (J =
6.6 Hz) and 1:1:1 15N triplet J = 6.9 Hz).24 No mixed
aggregates are formed. Treatment of β-amino ester 4 with 1.0
equiv of [6Li]LDA in the presence of TMEDA regenerates 3a.
Kinetics. Adding 1.0 equiv of imine 1 to enolate 2 in 0.65 M
TMEDA/toluene at −60 °C and monitoring with in situ IR
spectroscopy revealed an overall second-order decay (Figure 1),
Received: January 11, 2013
Published: February 17, 2013
© 2013 American Chemical Society
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Figure 2. Plot of kobsd versus concentration of enolate 2 for the
condensation of imine 1 (0.005 M) with lithium enolate 2 in 0.55 M
TMEDA/toluene at −60 °C. The curve depicts the unweighted least-
squares fit to kobsd = k[2]b (k = 0.049 0.007, b = 1.01 0.08).
Figure 1. Curve fitting for the condensation of the lithium enolate of
tert-amyl acetate enolate 2 (0.10 M)26 with equimolar imine 1 (0.10
M) in 0.65 M TMEDA/toluene at −60 °C. The curve depicts an
unweighted least-squares fit to the second-order function: y = [A]0/(1
+ [A]0kt) ([A]0 = 0.101 0.001 M, k = 0.24 0.01 M−1 s−1). The
inset shows the loss of 1 and formation of 3 using lithium enolate 2
(0.10 M), imine 1 (0.005 M), and 0.55 M TMEDA/toluene at −60 °C
(pseudo-first-order conditions). Imine 1 is represented by the symbol
●
○
and the product 3 by . The curves depict unweighted least-squares
fits to yS2 = y0e−bt (y0 = 108.6 0.1, b = 3.32 0.03 × 10−3 s−1) and
yS3 = y0(1 − e−bt) (y0 = 104.9 0.1, b = 3.28 0.03 × 10−3 s−1).
offering no evidence of autocatalysis or other mixed aggregation
effects.25 To conduct detailed rate studies under pseudo-first-
order conditions we turned to 19F NMR spectroscopy. Injecting
imine 1 (resulting in 0.005 M 1) into a solution of enolate 2
and TMEDA afforded clean first-order decays and affiliated
values of kobsd (Figure 1 inset). A standard control experiment
confirmed the absence of autocatalysis: sequential injections of
imine 1 (0.005 M) into a solution of enolate and TMEDA
afforded indistinguishable values of kobsd (within 10%).
Monitoring kobsd versus enolate concentration26 revealed a
first-order dependence consistent with a dimer-based addition
(Figure 2). An analogous plot of kobsd versus TMEDA
concentration revealed a zeroth-order dependence (Figure 3).
The idealized rate law27 described by eq 2 implicates the
transition structure of stoichiometry shown in eq 3.28
Figure 3. Plot of kobsd versus free TMEDA concentration26 in toluene
cosolvent for the condensation of lithium enolate 2 (0.10 M) with
imine 1 (0.005 M) at −60 °C. The curve depicts the unweighted least-
squares fit to kobsd = k + k′[TMEDA]free (k = 0.0044 0.0003, k′ =
0.0003 0.0005).
such fully ionized forms.37,38 We do, however, believe that 5h is
worthy of further consideration.
−d[imine]/dt = k[imine][TMEDA]0[enolate]
(ROLi)2(TMEDA)2 + imine → [(ROLi)2(TMEDA)2(imine)]⧧
(2)
Kinetics Revisited: Enolate-TMCDA. To resolve the
ambiguity about whether TMEDA is functioning as a mono-
or bidentate ligand we investigated N,N,N′,N′-tetramethylcy-
clohexane-diamine (TMCDA).39 The notion was simple:
TMCDA is a surrogate of TMEDA but is more strongly
chelating40 and displays no tendency to bind as a monodentate
ligand.41 Cursory examination of azaaldol condensation of
enolate 2 revealed rates that were nearly indistinguishable
(kTMCDA/kTMEDA = 0.9)42 and provided an analogous rate law
(Supporting Information). Computations offered transition
(3)
Computations. Density functional theory (DFT) compu-
tations at the B3LYP/6-31G(d) level29 evaluated dimer-based
pathways including cyclic dimers, open dimers,30 and triple
ions.31−34 We modeled the tert-amyl group with a methyl. The
reported energies correspond to the calculated free energies of
activation at −60 °C and to fully balanced equilibria. Intrinsic
reaction coordinate (IRC) calculations were performed to
confirm the validity of the transition structures.35 Figure 4
shows the computed structures in order of increasing free
energy. A number of configurations were calculated including
open and closed dimers with combinations of mono- and
bidentate TMEDA ligands (5a−5f).36 Structure 5g manifests
an imine nitrogen bridging two lithiums. The structure of the
lowest energy form, 5a, is an open dimer with both mono- and
bidentate TMEDA. Triple ion 5h with an (η2-TMEDA)2Li+
counterion is energetically ridiculous; DFT routinely fails with
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Figure 4. Computed transition structures of stoichiometry [(ROLi)2(TMEDA)2(imine)]⧧.
Scheme 1
structures 7a and 7b. The (η2-TMCDA)2Li+ counterion in 7b
has crystallographic support.43 Despite considerable effort, we
found no closed dimer analogous to 5d.
rate law (eq 2) is consistent with reaction via a bis-TMEDA-
solvated enolate dimer as depicted generically in eq 3.
The experimentally elusive details of the dimer-based
transition structure were examined using DFT computations,
revealing a number of candidates (Figure 4). The two most
viable pathways are summarized in Scheme 1. Dimer-based
DISCUSSION
■
6
Using a combination of Li and 15N NMR spectroscopies we
2
transition structure 5a, containing both η1- and η -bound
have shown that tert-amyl acetate enolate 2 is disolvated dimer
2a in the presence of TMEDA.12 Rate studies using 19F NMR
spectroscopy revealed that there is no autocatalysis and that the
addition of 2a to fluorinated imine 1 is first order in imine, first
order in enolate dimer 2a, and zeroth order in TMEDA. The
TMEDA ligands, was predicted to be the lowest energy form.
We would be reckless, however, to distinguish them using
calculated ΔG⧧’s alone. For example, we found doubly
chelating structure 5b is very plausible. Consequently, we
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capped with a syringe containing 100 μL of a stock solution of imine 1
in toluene. The NMR tube was then cooled in a dry ice/acetone bath,
charged sequentially with the LDA/TMEDA (400 μL) and tert-amyl
acetate/fluorobenzene standard (100 μL) stock solutions, and
vortexed for 10s. The tubing was adjusted to reach the curved portion
of the tube. The stock solutions were prepared to give final
concentrations of 0.005 M each of 1 and fluorobenzene standard,
0.11 M LDA, and 0.10 M tert-amyl acetate upon completion of the
final injection of imine 1. The NMR tube was then inserted into the
pre-cooled NMR probe and equilibrated at −60 °C. Stock solutions of
LDA (400 mL) and ester (100 mL) were injected by standard syringe
(not via the tubing). A collection array at 30 s intervals was initiated,
and a 100 μL stock solution of imine was injected into the tube giving
10 s to thermally equilibrate before spectral acquisition. The loss of 1
(δ −107.4 ppm) and formation of 3 (δ −117.2 ppm) were monitored
relative to a fluorobenzene internal standard (0.007 M, δ −112.96
ppm). The decay of 1 was followed to beyond five half-lives. In
processing, the integral area was normalized relative to the
fluorobenzene standard. The rate constant was obtained by fitting
the decay for each run to the first-order function, f(x) = aebx.
investigated TMCDA as a strongly chelating surrogate for
TMEDA. We know of no evidence, experimental or computa-
tional, that TMCDA can coordinate as a monodentate ligand.
The basal assumption, therefore, is that the rates and
mechanisms using TMCDA and TMEDA diverge only if
TMEDA is functioning as a nonchelating ligand somewhere
along the reaction coordinate. Experimentally indistinguishable
rates and rate laws for the two diamines cast the deciding vote
for 5b as the most logical transition structure. We hasten to
add, however, that despite the enormous computed barrier
(DFT is notoriously incapable of modeling ionization
energies38) triple ion 5h has considerable appeal. Triple ions,
including those derived from lithium enolates,32 are well
precedented.31,32 The (η2-TMEDA)2Li+ counterion has been
observed,37 and the (η2-TMCDA)2Li+ cation has been
documented as well.43 The bidentate interaction of the ester
enolate in 5h also has structural precedent.44
CONCLUSION
Aminoester 4. Lithium diisopropylamide (218 mg, 2.04 mmol)
was dissolved in toluene (16.0 mL) and TMEDA (2.0 mL, 13.3 mmol)
in a 50 mL round-bottom flask and cooled to −60 °C. To this mixture
was added tert-amyl acetate (330 μL, 2.22 mmol) with stirring for 5
min to ensure full enolization. Then imine 1 (307 mg, 1.53 mmol)
dissolved in toluene (2.5 mL) was added. After 2 h, the reaction was
quenched with methanol (4 mL), allowed to warm to room
temperature, and acidified with saturated aq NH4Cl (4 mL). The
organic layer was washed with water (8 mL), dried over Na2SO4, and
rotary evaporated. The resulting yellowish oil was recrystallized from
hot methanol (3.5 mL), yielding 399 mg of white needles (78% yield)
with mp = 89−90.5 °C. 2-Methyl-2-butyl 3-(4-fluorophenyl)-3-
phenylamino-propanoate (4): analytical thin layer chromatography
(TLC) on K6F silica gel 60 Å, 4:1 hexanes/EtOAc, Rf = 0.39. IR (neat,
■
The azaaldol addition of a disolvated dimeric lithium enolate to
an aryl imine occurs through a transition structure consisting of
a disolvated dimeric enolate. Although some of the details of
the transition structure remain unresolved, calculations slightly
favor an open dimer (1.6 kcal/mol) with only one of the two
TMEDA molecules chelating.
The dimer-based reaction is interesting in light of dominant
beliefs in the earlier days of organolithium chemistry that
monomers are the central fleeting intermediate. Streitwieser has
wrestled with this question for a number of years and concludes
that monomers are often key intermediates. Similarly, Reich has
found that in nonequilibrating mixtures of monomers and
dimers the monomers are almost always more reactive. That is
not to say, however, that when dimers or tetramers are the
observable form in solution the most favorable pathway
necessarily proceeds via energetically costly deaggregations.45
A number of groups have endorsed the notion of aggregate-
based enolate reactivity. Enolates are a very broad class of
intermediate. Throw into the debate the huge roles of solvent,
temperature, concentration, and choice of electrophile, and
considerable mechanistic variation is to be expected.
1
cm−1) 3380, 2975, 2922, 1703, 1603, 1507. H NMR: δ 7.34 (1H,
AA′BB′Y, JA‑A′ = 2.2 Hz, JA‑B = 8.7 Hz, JA‑X = 5.0 Hz), 7.34 (1H,
AA′BB′Y, JA‑A′ = 2.2 Hz, JA′‑B′ = 8.7 Hz, JA′‑X = 5.0 Hz), 7.09 (2H, dd, J
= 8.2, 7.3 Hz), 6.99 (1H, AA′BB′Y, JB−B′ = 2.5 Hz, JA‑B = 8.7 Hz, JB‑X
=
8.7 Hz), 6.99 (1H, AA′BB′Y, JA′‑B′ = 8.7 Hz, JB′−B = 2.5 Hz, JB′‑X = 8.7
Hz), 6.67 (1H, t, 7.3 Hz), 6.52 (2H, d, 8.2 Hz), 4.75 (1H, ABMX, JA‑M
= 5.8 Hz, JB‑M = 7.2 Hz, JM‑X = 6.1 Hz), 4.61 (1H, ABMX, JM‑X = 6.1
Hz), 2.71 (1H, ABMX, JA‑B = 14.6 Hz, JA‑M = 5.8 Hz), 2.69 (1H,
ABMX, JA‑B = 14.6 Hz, JB‑M = 7.2 Hz), 1.70 (2H, q, J = 7.5 Hz), 1.34
(6H, s), 0.78 (3H, t, J = 7.5 Hz). 13C NMR: δ 170.4, 162.2 (d, JC−F
=
245 Hz), 146.9, 138.1 (d, JC−F = 3 Hz), 129.3, 128.1 (d, JC−F = 8 Hz),
117.9, 116.7 (d, JC−F = 21 Hz), 113.7, 84.1, 54.7, 44.2, 33.6, 25.6, 25.6,
8.3. 19F NMR: δ −115.6. Molecular ion calculated for C20H24FNO2:
329.1791; EIMS found m/z = 329.1793. 1H NMR ABMX and
AA′BB′Y couplings were identified using spin simulation in
MestReNova 7.1.1.
EXPERIMENTAL SECTION
■
Reagents and Solvents. TMEDA, TMCDA, and toluene were
distilled from solutions containing sodium benzophenone ketyl. The
toluene stills contained approximately 1% tetraglyme to dissolve the
ketyl. LDA, [6Li]LDA, and [6Li,15N]LDA were prepared as described
previously.23 Solutions of LDA were titrated for active base using a
literature method.46 Air- and moisture-sensitive materials were
manipulated under argon using standard glovebox, vacuum line, and
syringe techniques. Imine 1 was prepared using a literature
procedure.47
Aminoester [15N]4. Prepared as above using [15N]S2, made from
1
commercially available 15N-aniline. H NMR: δ 7.34 (2H, app dd),
7.10 (2H, dd, J = 8.3, 7.3 Hz), 6.99 (2H, app t), 6.67 (1H, t, J = 7.3
Hz), 6.52 (2H, d, J = 7.8 Hz), 4.75 (1H, app q), 4.61 (1H, app d),
2.75−2.65 (2H, app m), 1.70 (2H, q, J = 7.5 Hz), 1.34 (6H, s), 0.78
(3H, t, J = 7.5 Hz). 13C NMR: δ 170.4, 162.2 (d, JC−F = 245 Hz),
146.9 (d, JC−N = 13 Hz), 138.1 (d, JC−F = 3 Hz), 129.4, 128.1 (dd, JC−F
= 8, 1 Hz), 118.0, 115.7 (d, JC−F = 21 Hz), 113.7 (d, JC−N = 2 Hz),
84.1, 54.7 (d, JC−N = 10 Hz), 44.2, 33.6, 25.6, 25.6, 8.3. 19F NMR: δ
−115.6. 15N NMR: δ 73.2. Molecular ion calculated for
C20H24F15NO2: 330.1761; EIMS found m/z = 330.1759.
NMR Techniques. All NMR samples were prepared using stock
solutions and sealed under partial vacuum. Standard 6Li, 13C, 15N, and
19F NMR spectra were recorded on a 500 MHz spectrometer at 73.57,
6
125.79, 50.66, and 470.35 MHz (respectively). The Li, 13C, and 15N
resonances are externally referenced to 0.30 M [6Li]LiCl/MeOH at
−90 °C (0.0 ppm), the CH2O resonance of THF at −90 °C (67.57
ppm), and neat Me2NEt at −90 °C (25.7 ppm), respectively.
Azaaldol Adduct [6Li,15N]3. Individual stock solutions of imine
[15N]1 (0.22 M in toluene) and [6Li]LiHMDS (0.20 M in TMEDA/
toluene) were prepared at room temperature. An NMR tube was
flame-dried under vacuum and allowed to come to room temperature.
It was then backfilled with argon and placed in a −78 °C dry ice/
acetone bath. Base (300 μL of stock solution) and imine [15N]1 (300
μL of stock solution) were added sequentially via syringe. The tube
was sealed under partial vacuum, vortexed for approximately 10 s at
Kinetics. Samples for NMR kinetics were prepared from stock
solutions at room temperature: (1) tert-amyl acetate in toluene, (2)
imine 1 and fluorobenzene internal standard in toluene, and (3) LDA/
TMEDA in toluene. The NMR tube was capped with a septum,
evacuated, flushed several times with argon, flame-dried, and put under
argon. A length of 25 μm i.d. flexible capillary tubing was inserted into
the tube and flushed with argon for several minutes before the end was
6
room temperature, and cooled to −78 °C. Li NMR spectra were
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recorded at −60 °C on a 500 MHz spectrometer with and without
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0.30 M 6LiCl/MeOH standard at the reported probe temperature. 15
N
NMR spectra were recorded using the INEPT pulse sequence at −60
°C on a 500 MHz spectrometer with and without broadband 6Li
6
decoupling. Li NMR: δ 1.54 (JLi−N = 6.6 Hz). 19F NMR: δ −117.1.
15N NMR: δ 123.9 (t, JLi−N = 6.6 Hz).
ASSOCIATED CONTENT
* Supporting Information
■
S
NMR and computational data, experimental protocols, and
complete ref 29. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
dbc6@cornell.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Institutes of Health (GM 077167).
■
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