Lithium Enolates Derived from Weinreb Amides: Insights into Five-Membered Chelate Rings

Article abstract of DOI:10.1021/acs.joc.6b02067

Enolization of O-methyl hydroxamic acids (Weinreb amides) in tetrahydrofuran solution with lithium diisopropylamide affords predominantly tetrameric enolates. Aryl substituents on the enolates promote deaggregation. The aggregation states are assigned by

Full text of DOI:10.1021/acs.joc.6b02067

Article
pubs.acs.org/joc
Lithium Enolates Derived from Weinreb Amides: Insights into Five-
Membered Chelate Rings
Michael J. Houghton 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: Enolization of O-methyl hydroxamic acids (Weinreb amides) in
tetrahydrofuran solution with lithium diisopropylamide affords predominantly
tetrameric enolates. Aryl substituents on the enolates promote deaggregation. The
aggregation states are assigned by using the method of continuous variation in
6
conjunction with Li NMR spectroscopy. Decoalescence of the tetramer resonance
below −100 °C shows considerable spectral complexity attributed to isomerism of the
methoxy-based chelates. Density functional theory calculations were used to examine
the consequences of the bite angle of five-membered chelates in cubic tetramers and resulting solvation numbers that were higher
than anticipated.
INTRODUCTION
In 1981, Nahm and Weinreb
hydroxamic acids of general structure 1 undergo highly
selective nucleophilic addition to give ketones (eq 1). The
suggest an unusual role of cooperative solvation by external
THF ligands and the chelating methoxy moieties. The
coordination chemistry within lithium-based cubic tetramers
appears to be more complex than we anticipated and is
reshaping our thinking about both cubic tetramers and the
■
1
,2
reported that O-methyl
12,13
influence of chelate ring size on structure and reactivity.
observed monoadditions, which contrasted with the double
additions observed for the corresponding esters, were attributed
to chelate-stabilized tetrahedral intermediate 2, although the
3
mechanism proved far more complex than many surmised.
Weinreb amides are also precursors to propionate ester
4
−7
enolate equivalents, so-called Weinreb enolates.
The
potentially advantageous features of reactions with these
compounds include the anticipated high Z-selective enolization
8
characteristic of carboxamides and the synthetic utility of the
Weinreb amides (eq 2). Several strange observations are
RESULTS
■
Enolates were generated in situ with recrystallized LDA
[ Li]LDA or [ Li, N]LDA) prepared as described. Aging
6
6
15
14
(
for several hours at −78 °C was required to fully equilibrate the
15
enolate aggregates. Structures were determined using a
6
combination of Li NMR spectroscopy, the method of
1
5−17
continuous variation (MCV),
theory (DFT) calculations.
and density functional
Using MCV to characterize
1
1,18
included in the reports. Demethoxylation occasionally affords
7
,9
6
highly symmetric enolate aggregates entails mixing two
N-methyl carboxamides.
Davis and co-workers, incred-
structurally similar enolates, A and B , to generate an ensemble
n
n
ulously, metalated and functionalized a Weinreb amide by
using lithium diisopropylamide (LDA) in the presence of 5
equiv of water. In general, applications of Weinreb enolates are
19
of homo- and heteroaggregates (eq 3). The numbers and
symmetries of the heteroaggregates reveal the aggregation state,
n, which is confirmed by plotting the relative concentrations
5
−7
rare,
studies.
0,1a1nd we can find no structural or mechanistic
20
1
versus measured mole fraction (X or X ) to afford a Job plot
A B
17
(
exemplified by Figures 2 and 4).
We have explored the structure of Weinreb enolates 3a−g in
tetrahydrofuran (THF)/toluene mixtures. These enolates
routinely form tetramers and dimers depicted generically as 4
and 5, respectively. Spectroscopic and computational studies
Received: August 22, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b02067
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Article
A + B → A + An−1B1 + An−2B2 + ... + Bn
(3)
n
n
n
Enolate−LDA Mixed Dimers. The general approach to
characterizing Weinreb enolates is illustrated emblematically
with 3b as follows. Enolization of propionamide 1b with 1.1
6
equiv of [ Li]LDA in neat THF resulted in a single resonance
6
in Li NMR spectra obtained at −80 °C. NOESY revealed
exclusively Z enolate. Analogous samples in 1.0−12 M THF/
toluene solutions all contained the same aggregate. Enolization
6
15
14
6
15
with [ Li, N]LDA showed no Li− N coupling, confirming
that the species was a homoaggregated lithium enolate.
Enolization with excess LDA, however, afforded mixed
1
9
6
aggregates displaying a single Li resonance at −80 °C. By
example, the mixed aggregate derived from 3e prepared using
6
15
6
15
[
Li, N]LDA displayed a Li 1:1 doublet and a 1:2:3:2:1 N
21
quintet (JLi−N = 5.3 Hz) consistent with mixed dimer 6. The
6
two anticipated distinct Li resonances emblematic of the
Figure 2. Job plot showing the relative integrations versus the
2
0
6
measured mole fraction of 3 for 0.10 M mixtures of [ Li]3f (A) and
[
chelate were not observable in 1.0 M THF/hexane at −120 °C.
However, broadening consistent with decoalescence was
significant.
6
Li]3e (B) in 1.0 M pyridine and THF at −80 °C (see Figure 1).
Dimers. Enolates 3e−g with aromatic rings conjugated to
the enolates exist as mixtures of two homoaggregates at low
THF concentrations and exclusively as the lower aggregate at
the elevated THF concentrations. Using MCV, we found that
the sole species in THF were dimers. Thus, spectra recorded on
3
e−3g mixtures in neat THF showed the two homoaggregates
along with a single heteroaggregate (Figure 1) consistent with
an ensemble of dimers and afforded the Job plot in Figure 2.
Dimer−Tetramer Mixtures. Enolates 3c and 3d in THF at
−
80 °C each existed as major and minor homoaggregates
shown to be tetramers and dimers, respectively (Figure 3a,e).
The minor species disappeared at low THF and high enolate
concentrations, consistent with aggregates that are at a higher
solvation state and lower aggregation state compared with the
6
6
Figure 3. Li NMR spectra of 0.10 M solutions of [ Li]3d (A) and
6
6
[ Li]3c (B) in 0.13 M THF at −80 °C with 0.13 M [ Li]LDA. The
measured mole fractions of B within the tetramer ensembles in (a)−
(
e) are 0.00, 0.28, 0.46, 0.67, and 1.00, respectively. For the dimers, the
20
measured mole fractions of B in (a)−(e) are 0.00, 0.27, 0.44, 0.61,
and 1.00, respectively.
major forms. The two aggregation states were assigned with
MCV in a single series of experiments as follows.
Mixtures of enolate 3c and 3d in THF at −80 °C showed the
resonances of the two dominant homoaggregates along with
3
:1, 2:2, and 1:3 heteroaggregate resonances characteristic of an
ensemble of tetramers in rapid intraaggregate lithium
exchange
trations of the five aggregates versus measured mole fraction
15c
(Figure 3). Monitoring of the relative concen-
20
afforded a Job plot (Figure 4) displaying a nearly statistical
distribution of homo- and heterotetramers. The tetrameric
forms of 3a−3e were characterized with MCV analogously
(
Supporting Information).
The displayed ensembles of minor (lower) aggregates were
consistent with dimers, affording the Job plot shown in Figure
5. We hasten to add that characterizing ensembles of aggregates
from such complex mixtures (even mixtures with unknown
impurities) is made possible by using the measured rather
than intended mole fraction.
6
6
Figure 1. Li NMR spectra of 0.10 M solutions of [ Li]3f (A) and
6
[
[
Li]3e (B) in 1.0 M pyridine and THF at −80 °C with 0.13 M
20
20
6
Li]LDA. The measured mole fractions B in (a)−(e) are 0.00, 0.31,
0
.54, 0.81, and 1.00, respectively.
B
DOI: 10.1021/acs.joc.6b02067
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Figure 6. Plot of [dimer]/[tetramer]1/2 of 3d versus [THF] in
toluene. The curve depicts an unweighted least-squares fit to y =
n
−3
K [THF] [K = (1.4 ± 0.3) × 10 ; n = 1.94 ± 0.09].
2
0
eq
eq
Figure 4. Job plot showing relative integration versus measured mole
6
6
fraction of tetramer for 0.10 M mixtures of [ Li]3d (A) and [ Li]3c
Chart 1
(B) in 0.13 M THF at −80 °C (see Figure 3).
2
0
Figure 5. Job plot showing relative integration versus the measured
6
6
mole fraction of dimer for 0.10 M mixtures of [ Li]3d (A) and [ Li]3c
(B) in 12.2 M THF at −80 °C (see Figure 3).
Dimer and Tetramer Solvation. We began with a
simplistic view of the role of THF. We imagined that the
tetramers existed as either D2d or S core structures (7 and 8,
4
respectively) and were unsolvated by THF owing to the
saturation of the cube by the chelating methoxy groups.
Monitoring the tetramer−dimer ratio versus THF concen-
tration for enolate 3d (eq 4) and fit according to eq 5 afforded
a relative solvation number, n, of 1.94 ± 0.09 (Figure 6). If we
presume that the tetramer is unsolvated (m = 0)an
assumption brought into serious question belowthen the
dimer favored at high THF concentration is consistent with
disolvate 9 (Chart 1). Dimer 10 could also exist undetected if
the chelates are in the rapid-exchange limit. Thus, 7−10 are
potentially consistent with the spectroscopic data presented so
far; however, the results of two experiments undermined our
fundamental underlying presumptions and, thus, the assigned
solvation states.
Incrementally adding pyridine as a chemical shift reagent to
THF/hexane solutions of organolithiums qualitatively probes
the absence or presence of coordinating solvent. Resonances
corresponding to lithiums bearing substitutionally labile THF
ligands shift markedly downfield, whereas unsolvated lithiums
15a,23
do not move appreciably.
More highly solvated forms
22
(often the lower aggregates) also increase in intensity relative
that of the lesser-solvated forms owing to mass action. In the
6
event, incremental addition of pyridine markedly shifted the Li
resonances of dimers and tetramers. Thus, the tetramers were
solvated by external ligands. It is tempting to assume that the
chelates must be cleaved by THF, but we present a more
nuanced model in the discussion.
Another critical observation was that cooling solutions of
tetrameric enolates from −80 °C to below −100 °C caused
broadening in all cases. In several instances (3c and 3d),
decoalescence clearly yielded a pair of resonances that further
decoalesced to complex envelopes of resonances (Figure 7).
1
/2(ROLi) (THF) + nTHF ⇌ (ROLi) (THF)
1/2m+n
4
m
2
(4)
n
K [THF] = [(ROLi) (THF)
]
eq
2
1/2m+n
/2
1
/
[(ROLi) (THF) ]
(5)
4
m
C
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Article
significant only at elevated temperatures (above −30 °C).
Possible advantages of Weinreb enolates relative to propionate
8
ester enolates include total selectivity for Z enolate geometry
and formation of Weinreb amide products poised for further
transformation (eq 1). With this untapped potential in mind,
we studied the aggregation and solvation of Weinreb enolates.
Experimental data prompted DFT calculations of chelation and
solvation that led us in unexpected directions. Despite
uncontested evidence that five-membered rings are the
12,13
preferred chelate ring size for lithium,
the impact of chain
length on reactivity and selectivity may be less straightforward
than we realized.
Aggregation. Weinreb enolates bearing small, saturated
substituents such as 3a and 3b are predominantly tetrameric
even in neat THF (Chart 1), whereas enolates 3e−g, which are
conjugated to aromatic rings, are susceptible to deaggregation
10b
owing to anion stabilization. Spectral data do not distinguish
D tetramer 8 from S tetramer 7: both should display a single
2d
4
6
6
Figure 7. Li NMR spectra of 0.10 M solutions of [ Li]3d in 0.50 M
6
Li resonance and have ample precedent in the structural
THF/toluene recorded at various temperatures.
15c,26,27
organolithium literature.
We cannot exclude a fluctional
stereochemical mixture; the facility of chelate exchange was
suggested by the observed high symmetry of LDA mixed
aggregate 6.
Solvation and Chelation: An Orthodox Model. We
were predisposed to endorse the tetramer−dimer relationship
in eq 7. The relative solvation numbers (eq 4) were ascertained
by quantitating the THF concentration dependence (Figure 6).
Stereoisomeric tetramer 7 or 8 and dimer 9 or 10 (Chart 1) are
fully consistent with the data. Dimer 10 would require a facile
chelate exchange, which is plausible.
Presumably owing to the slowed exchange of the chelates, the
structure of the tetramers appeared to be much more complex
than that suggested by 7 or 8. We cannot rigorously exclude
ladders such as 11, 12, and a few others as the source of this
complexity, but asymmetry is often readily observed owing to
slow site-site exchange in ladders. Moreover, they are all
substantially (>6 kcal/mol) less stable than isomeric cubic
tetramers in which chelation and external solvation are
cooperative (vide infra).
24
1
/2(ROLi) + 2THF ⇌ (ROLi) (THF)
4
2
2
7
or 8
9 or 10
(7)
Two observations disavowed us of such an orthodox
structural model during studies of solvation: (1) using pyridine
as a chemical shift reagent shows that both dimers and tetramers
are solvated, and (2) tetramers show unusual spectral
complexity at temperatures below −100 °C. In the discussion
that follows, we rely heavily on DFT calculations to develop a
markedly different view of chelation and solvation that might
reach beyond the specific examples presented by Weinreb
enolates.
Demethoxylation. Warming solutions of Weinreb enolates
(
typically to temperatures above −30 °C) provided evidence of
demethoxylation and a formaldehyde aldol adduct (eq 6), both
7
,9,25
of which have been mentioned previously.
about the mechanism.
We know little
Solvation and Chelation: Dimers. The computed serial
solvation of dimers and their affiliated free energies (−80 °C)
afforded the three lowest-energy forms of each stoichiometry
shown in Scheme 1. We were moderately surprised that
displacing the chelate by THF to afford tetrasolvated dimer 17
is favorable. Inspection of 15 and 16 (with a graphical
interface) reveals potentially destabilizing chelate distortions as
annotated. Such distortions might have been missed (or
dismissed) if not for the investigations of tetramers discussed
below.
DISCUSSION
■
Weinreb enolates (3) have found limited use in organic
5
−7
synthesis. Evidence of an odd demethoxylation (eq 6) might
7
,9
preclude some applications,
but this outcome becomes
Scheme 1
D
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The Journal of Organic Chemistry
Article
Solvation and Chelation: Tetramers. DFT calculations
suggest disruption of the tetramer chelates by THF is not
favorable for interesting and unexpected reasons. Starting with
uncomplexed methoxy moieties, minimizations converge on
structures in which the methoxy moieties reassociate to lithium
without loss of THF (eq 8). We can find only a few particularly
idiosyncratic examples of five-coordinated lithium nuclei within
allow for cooperative solvation by THF (19) and geminal chelation
29,30
(20).
The computed cubic structural forms in Chart 2 include the
simplest S from D2d tetramers (7 and 8) and other forms
4
containing various combinations of four- and five-coordinate
lithium nuclei deriving from geminal chelation and cooperative
chelation−THF solvation. The indicated resonance counts (in
parentheses) correspond to the number of magnetically
inequivalent lithiums assuming slow solvent and chelate
exchange. Slow solvent exchanges on lithium are rare (except
28
organolithium cubes.
10b
15
hexamethylphosphoramide ); only recently we observed
slow exchange on cubic tetramers. However, the structures in
Chart 2 underscore the possible origins of spectral complexity
in Figure 7, and the calculated stabilities, even if viewed as
crude approximations, also illustrate the stabilization stemming
from five-coordinate lithium. In fact, the solvation energies are
remarkably similar to those routinely observed when the corner
of a simple cubic tetramer is solvated to afford four-coordinate
lithium. Given the greatest stabilization for tri-THF solvate 26,
our failure to detect tetra-THF solvated analogues of 7 or 8 is
notable. Although five-coordinate lithiums could, in theory,
closely approximate a trigonal bipyramid, the distortions from
There is a subtle structural feature to five-membered-ring
chelates on tetrameric cubes that we had never noticed: the
internal ligand cannot reach the true corner of a cubic tetramer
(
Figure 8). A partial structure of a computed tetramer (18)
shows that the small bite angle forces the geometry around the
chelated lithium to approximate a trigonal monopyramid.
Crystal structures of analogous tetrameric chelates show this
32,33
1
5,26,27
that geometry are considerable.
same motif.
The critical observation is that five-
Dimer/Tetramer Relative Solvation Revisited. Let us
revisit investigations of the tetramer/dimer proportions in
various THF concentrations (Figure 6) that implicated the
orthodox tetramer/dimer equilibrium in eq 7. Additional
possibilities that are mathematically consistent with the
measured relative solvation numbers are illustrated in eqs 9
and 10. (We exclude those requiring noninteger solvation
numbers.) Equation 9 is what might be expected if all chelates
are disrupted. Computational evidence for such a tetra-THF
solvated tetramer, whether chelated or not, is lacking. By
contrast, the model in eq 10 is consistent with computationally
viable (although not most viable) disolvated tetramers 22−24 in
exchange with the computationally viable trisolvated dimer 16
membered-ring chelates with relatively small methoxy ligands
(
Scheme 1). The model in eq 10 is unorthodox, arguably a
paradigm shift.
1
1
/2(ROLi) (THF) + 2THF ⇌ (ROLi) (THF)
4
4
2
17)
4
(
(9)
/2(ROLi) (THF) + 2THF ⇌ (ROLi) (THF)
4
2
2
(16)
3
(
22−24)
(10)
Possible Mechanistic Consequences. Provided that
tetramers can, under some circumstances, react directly without
34,35
deaggregating,
the possibility of high-coordinate lithium
nuclei in tetrameric cubes offers a vehicle with which a substrate
could enter the coordination sphere without disrupting the
structurally organizing chelates. Could an aldol condensation
proceed via some fleeting complex such as 27? It is curious that
the aldehyde in 27 is not precomplexed to the lithium chelated
by the enolate undergoing the 1,2-addition: 27 exemplifies a
uniquely aggregate-based mechanism.
These implications contrast markedly with recent studies of
tetrameric oxazolidinone-derived enolates (Evans enolates) in
which a six-membered chelate capable of saturating the lithium
nuclei closer to the idealized tetrahedral angle was shown to
have no penchant for accepting additional coordinating
1
5a
solvent.
Unusual solvation numbers in the tetrameric
Figure 8. DFT computed partial structures of cubic tetramers showing
an open coordination site (18), THF saturated lithium (19), and
doubly chelated saturated lithium (20).
enolates, if undetected, would wreak havoc on kinetics-derived
mechanistic models owing to the incorrectly assigned reactant.
E
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Article
Chart 2
ice/acetone bath. The appropriate amounts of Weinreb amide and
LDA (1.1 equiv) were added sequentially via syringe. The tube was
sealed under partial vacuum and vortexed three times on a vortex
mixer for 5 s with cooling between each treatment. Equilibrated
samples were stored in a freezer at −86 °C. Each sample routinely
contained 0.10 M total enolate with a 0.030 M excess of LDA. Mixed
6
15
dimers (8) generated from excess [ Li, N]LDA were characterized by
6
15
21
6
13
15
using Li and N NMR spectroscopy. Standard Li, C, and
N
NMR spectra were recorded on a 500 MHz spectrometer at 73.57,
6
13
15
1
25.79, and 50.66 MHz, respectively. Li, C, and N resonances
6
were referenced to 0.30 M [ Li]LiCl/MeOH at −80 °C (0.0 ppm), the
CH O resonance of THF at −90 °C (67.57 ppm), and neat Me NEt at
2
2
CONCLUSIONS
−90 °C (25.7 ppm).
■
2
-Benzyl-3-hydroxy-N-methoxy-N-methylpropanamide (14). N-
Weinreb enolates are sufficiently robust for additional
applications in synthesis. The most important results described
herein were obtained when experimental and computational
data suggested that seemingly simple cubic tetramers may attain
Methoxy-N-methyl-3-phenylpropanamide (0.050 g, 0.259 mmol) was
dissolved in THF and added dropwise to a solution of lithium
diisopropyl amide (0.0357 g, 0.337 mmol) at −78 °C. The solution
was allowed to warm to rt and was stirred for an additional 30 min.
The reaction was quenched with pH 7 phosphate buffer and extracted
with EtOAc (3×). The combined organic layer was washed with brine
15,32
unusually high coordination numbers.
After years of studying structures and mechanisms of dimeric
lithium amides and dimeric carbanions, we are finding that
contending with four subunits in tetrameric enolates is quite
challenging. The relative reactivities of tetramers, dimers, and
monomers are becoming well-defined through studies under
(
1×), dried (Na SO ), and concentrated under reduced pressure. The
2 4
resulting mixture was purified by chromatography (SiO , 100% ether)
2
to give a 1:2 inseparable mixture of 2-benzyl-3-hydroxy-N-methoxy-N-
methylpropanamide (14) and N-methyl-3-phenylpropanamide (13) as
1
a clear oil after flash chromatography (0.0135 g, 23%). H NMR (599
10b
nonequilibrium conditions by Reich and co-workers
under equilibrium conditions by Streitwieser and co-workers.
There is only spartan evidence that enolate aggregates react
and
MHz, Chloroform-d) δ 7.25 (m, 2H), 7.17 (m, 3H), 3.73 (m, 2H),
11
3
.48 (s, 3H), 3.26 (m, 1H), 3.14 (s, 3H), 2.96 (dd, J = 13.4, 7.4 Hz,
13
1H), 2.90 (s, 1H), 2.83 (dd, J = 13.4, 7.6 Hz, 1H); C NMR (151
MHz, Chloroform-d) δ 175.6, 139.3, 129.2, 128.5, 126.5, 63.0, 61.5,
45.0, 34.4, 31.9.
35,36
without intervening deaggregation.
Evaluations of the
detailed coordination chemistry of the cubic tetramers comprise
a crucial niche in the elucidation of tetramer reactivity.
ASSOCIATED CONTENT
■
EXPERIMENTAL SECTION
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b02067.
Reagents and Solvents. THF and toluene were distilled from
solutions containing sodium benzophenone ketyl. Toluene stills
contained approximately 1% tetraglyme to dissolve the ketyl.
6
6
15
14
[
Li]LDA and [ Li, N]LDA were prepared as described previously.
Spectroscopic, kinetic, and computational data and
authors for ref 18 (PDF)
Solutions of LDA were titrated for an active base with a literature
37
method. Air- and moisture-sensitive materials were manipulated
under argon with standard glovebox, vacuum line, and syringe
techniques. Substrates are all known and prepared using standard
AUTHOR INFORMATION
■
*
38
literature procedures.
Corresponding Author
E-mail: dbc6@cornell.edu.
NMR Spectroscopy. Individual stock solutions of substrates and
LDA were prepared at room temperature. An NMR tube under
vacuum was flame-dried on a Schlenk line and allowed to return to
room temperature, backfilled with argon, and placed in a −78 °C dry
Notes
The authors declare no competing financial interest.
F
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Article
(
15) (a) Tallmadge, E. H.; Collum, D. B. J. Am. Chem. Soc. 2015, 137,
ACKNOWLEDGMENTS
■
1
2
3087. (b) Bruneau, A. M.; Collum, D. B. J. Am. Chem. Soc. 2014, 136,
885. (c) Jin, K. J.; Collum, D. B. J. Am. Chem. Soc. 2015, 137, 14446.
We thank the National Institutes of Health (GM077167) for
support.
(16) Renny, J. S.; Tomasevich, L. L.; Tallmadge, E. H.; Collum, D. B.
Angew. Chem., Int. Ed. 2013, 52, 11998.
(
(
17) Job, P. Ann. Chim. 1928, 9, 113.
18) Frisch, M. J. et al. GaussianVersion 3.09, revision A.1; Gaussian,
REFERENCES
■
(
(
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19) We surveyed a subset of the community and have chosen to
refer to (LiX)n and (LiX) (LiX′) as a “homoaggregate” and
(
3
m
n
“
heteroaggregate”, respectively, and reserve the term “mixed
aggregate” for (LiX) (LiY) .
m
n
(
20) The measured mole fractionthe mole fraction within only the
(
(
ensemble of interestrather intended mole fraction of the enolates
added to the samples eliminates the distorting effects of impurities.
(
(
(
21) Collum, D. B. Acc. Chem. Res. 1993, 26, 227.
22) For examples and leading references, see ref 10b.
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DOI: 10.1021/acs.joc.6b02067
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The Journal of Organic Chemistry
Article
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