Reversible enolizafion of β-amino carboxamides by lithium hexamethyldisilazide

Article abstract of DOI:10.1021/ja043470s

The enolization of β-amino carboxamides by lithium hexamethyldisilazide (LiHMDS) in THF/ toluene and subsequent diastereoselective alkylation with CH₃I are reported. In situ IR spectroscopic studies reveal that β-amino carboxamides coordinate to LiHMDS at -78°C before enolization. Comparison with structurally similar carboxamides suggests that the β-amino group promotes the enolization. IR spectroscopic studies also show that the enolization is reversible. Efficient trapping of the enolate by CH₃I affords full conversion to products. ⁶Li and ¹⁵N NMR spectroscopic studies reveal that lithium enolate-LiHMDS mixed dimers and trimers as well as a homoaggregated enolate are formed during the reaction. At ambient temperature, racemization of the β-position through a putative reversible Michael addition was observed.

Full text of DOI:10.1021/ja043470s

Published on Web 03/22/2005
Reversible Enolization of â-Amino Carboxamides by Lithium
Hexamethyldisilazide
Anne J. McNeil and David B. Collum*
Contribution from the Department of Chemistry and Chemical Biology, Baker Laboratory,
Cornell UniVersity, Ithaca, New York 14853-1301
Received October 28, 2004; E-mail: dbc6@cornell.edu
Abstract: The enolization of â-amino carboxamides by lithium hexamethyldisilazide (LiHMDS) in THF/
toluene and subsequent diastereoselective alkylation with CH I are reported. In situ IR spectroscopic studies
3
reveal that â-amino carboxamides coordinate to LiHMDS at -78 °C before enolization. Comparison with
structurally similar carboxamides suggests that the â-amino group promotes the enolization. IR spectroscopic
studies also show that the enolization is reversible. Efficient trapping of the enolate by CH
3
I affords full
conversion to products. Li and 15N NMR spectroscopic studies reveal that lithium enolate-LiHMDS mixed
dimers and trimers as well as a homoaggregated enolate are formed during the reaction. At ambient
temperature, racemization of the â-position through a putative reversible Michael addition was observed.
6
Introduction
We show herein that the LiHMDS-mediated enolization of
affords an equilibrium mixture of 1 and enolate 4. The high
yields of alkylated product derive from a relatively slow
19
As an adjunct to investigations of the enolization and alkyla-
tion of â-amino esters, we had occasion to study the enolization
1
2
enolization followed by an efficient trapping of enolate 4 with
and alkylation of â-amino carboxamides (eq 1). The protocol,
using an unprotected amino group,3-5 is synthetically interesting
CH I. We also show, however, that this seemingly simple
3
transformation belies a complex ensemble of lithium enolate
given the biochemical and pharmaceutical importance of
6
7
â-amino amides and â-amino acids. Furthermore, the revers-
ible enolization suggests an underlying complexity that piqued
our interest. The â-amino group may also be important because
enolizations of carboxamides generally require bases stronger
than lithium hexamethyldisilazide (LiHMDS).8
mixed aggregates. Moreover, an NMR spectroscopic technique
in conjunction with a Job plot suggests that the homoaggregate
of the enolate is hexameric.
(
1) (a) McNeil, A. J.; Toombes, G. E. S.; Chandramouli, S. V.; Vanasse, B.
J.; Ayers, T. A.; O’Brien, M. K.; Lobkovsky, E.; Gruner, S. M.; Marohn,
J. A.; Collum, D. B. J. Am. Chem. Soc. 2004, 126, 5938-5939. (b) McNeil,
A. J.; Toombes, G. E. S.; Gruner, S. M.; Lobkovsky, E.; Collum, D. B.;
Chandramouli, S. V.; Vanasse, B. J.; Ayers, T. A. J. Am. Chem. Soc. 2004,
1
26, 16559-16568.
(
2) An X-ray crystal structure of the N-Boc derivative of 2 was used to assign
1
the stereochemistry for the major product of the alkylation. H NMR spectra
8
(d -THF) recorded on the N-Boc derivatives of 2 and 3 gave coupling
constants for the R-H of 3.5 and 8.8 Hz, respectively (Supporting
Information).
(3) Chandramouli, S. V.; O’Brien, M. K.; Powner, T. H. WO Patent, 0040547,
2
000.
(
4) A similar enolization and alkylation of an unprotected â-alanine pseu-
doephedrine carboxamide with LiHMDS/MeI/LiCl at 0 °C in THF has been
reported: Nagula, G.; Huber, V. J.; Lum, C.; Goodman, B. A. Org. Lett.
2
000, 2, 3527-3529.
5) Enolates derived from unprotected R-amino amides have been alkylated:
a) Myers, A. G.; Schnider, P.; Kwon, S.; Kung, D. W. J. Org. Chem.
999, 64, 3322-3327. (b) Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung,
(
(
1
D. W. J. Am. Chem. Soc. 1997, 119, 656-673. (c) Roy, R. S.; Imperiali,
B. Tetrahedron Lett. 1996, 37, 2129-2132. (d) Myers, A. G.; Yoon, T.;
Gleason, J. L. Tetrahedron Lett. 1995, 36, 4555-4558. (e) Myers, A. G.;
Gleason, J. L.; Yoon, T. J. Am. Chem. Soc. 1995, 117, 8488-8489.
6) For related alkylations of N-protected â-amino carboxamide enolates, see:
(7) (a) EnantioselectiVe Synthesis of â-Amino Acids; Juaristi, E., Ed.; Wiley-
VCH: New York, 1997. (b) Sewald, N. Angew. Chem., Int. Ed. 2003, 42,
5794-5795. (c) Ma, J.-A. Angew. Chem., Int. Ed. 2003, 42, 4290-4299.
(d) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991-8035. (e) Abele, S.;
Seebach, D. Eur. J. Org. Chem. 2000, 1-15. (f) Cardillo, G.; Tomasini,
C. Chem. Soc. ReV. 1996, 117-128. (g) Cole, D. C. Tetrahedron 1994,
32, 9517-9582. (h) Juaristi, E.; Quintana, D.; Escalante, J. Aldrichimica
Acta 1994, 27, 3-11.
(
(
a) Guti e´ rrez-Garc ´ı a, V. M.; Reyes-Rangel, G.; Mu n˜ oz-Mu n˜ iz, O.; Juaristi,
E. HelV. Chim. Acta 2002, 85, 4189-4199. (b) Guti e´ rrez-Garc ´ı a, V. M.;
L o´ pez-Ruiz, H.; Reyes-Rangel, G.; Juaristi, E. Tetrahedron 2001, 57, 6487-
6
496. (c) Ponsinet, R.; Chassaing, G.; Vaissermann, J.; Lavielle, S. Eur. J.
Org. Chem. 2000, 83-90. (d) Davies, S. G.; Edwards, A. J.; Walters, I. A.
S. Recl. TraV. Chim. Pays-Bas 1995, 114, 175-183. (e) Kurihara, T.;
Terada, T.; Satoda, S.; Yoneda, R. Chem. Pharm. Bull. 1986, 34, 2786-
(8) For example, see: Coumbarides, G. S.; Eames, J.; Ghilagaber, S. J. Labelled
Compd. Radiopharm. 2003, 46, 1033-1053.
2
798. (f) McGarvey, G. J.; Williams, J. M.; Hiner, R. N.; Matsubara, Y.;
(9) The N,N-di-n-butyl moiety offers superior solubility in THF/toluene
solutions at -78 °C when compared to structurally related â-amino
carboxamide enolates.
Oh, T. J. Am. Chem. Soc. 1986, 108, 4943-4952. (g) Yoneda, R.; Terada,
T.; Satoda, S.; Kurihara, T. Heterocycles 1985, 23, 2243-2246.
10.1021/ja043470s CCC: $30.25 © 2005 American Chemical Society
J. AM. CHEM. SOC. 2005, 127, 5655-5661
9
5655

A R T I C L E S
McNeil and Collum
[
THF]-dependent structures of both LiHMDS12 and lithium
enolate-LiHMDS mixed aggregates (vide infra), the percent
conversion is invariant over a 10-fold range of THF concentra-
1
3
tions (1.0-10 M).
LiHMDS-1 + (Me Si) NLi(THF) h 4 + HN(SiMe3)2
3
2
3-4
(2)
6
Structural Studies: General. We used a combination of Li
and 15N NMR spectroscopic studies to investigate the LiH-
MDS-1 complexes and the lithium enolate aggregates formed
during the enolization. Previous work revealed that LiHMDS
14
exists as dimer 5 in neat toluene; disolvated dimer 6 in toluene
containing low concentrations of THF; and tri- and tetrasolvated
monomers 7 and 8 at high concentrations of THF.12
Figure 1. In situ IR spectra showing the enolization of 1 (0.01 M) with
LiHMDS (0.02 M) in 10.2 M THF/toluene at -78 °C.
Substrate-LiHMDS Complexation. IR spectroscopic stud-
ies show that the carboxamide moiety of 1 readily coordinates
to LiHMDS under conditions in which LiHMDS is predomi-
1
2 6
nantly monomeric. Li NMR spectra recorded on mixtures of
6
15
carboxamide 1 and [ Li, N]LiHMDS in >2.0 M THF/toluene
6
afford the Li resonances corresponding to enolate 4, LiHMDS
dimer 6, and LiHMDS monomer. The spectra show a larger
LiHMDS monomer/dimer ratio, and the monomer signal is
downfield compared to carboxamide-free THF solutions, im-
plicating complex 9, consistent with previous studies of LiH-
Figure 2. Plot of the percent conversion for the enolization of 1 (0.01 M)
with LiHMDS in 8.0 M THF/toluene at -78 °C vs the equivalents of added
LiHMDS (b) and HMDS (9).
15
MDS solvated by bidentate ligands.
Results and Discussion
Reversible Enolization. Treatment of 1 with >1.0 equiv of
LiHMDS in 0.6-12.3 M THF/toluene at -78 °C causes a 10
-1
-1
cm shift in the carbonyl stretch of 1 (from 1640 to 1630 cm ),
indicating that 1 quantitatively coordinates to LiHMDS (Figure
-1
1
). Subsequent enolization affords 4 (1550 cm ) and significant
At lower THF concentrationssconditions that promote the
LiHMDS dimersIR spectroscopy shows clear evidence of the
concentrations of unreacted 1 still coordinated to lithium (1630
cm ). In short, the reaction stalls.
It is quite common for intervening mixed aggregates to
decelerate organolithium reactions because of their markedly
lower reactivity,10,11 and, indeed, mixed aggregates derived from
LiHMDS and 4 are observed (vide infra). In this case, however,
the incomplete conversion is due to an equilibration described
generically by eq 2 and shown in Figure 2. For example, addition
of 1.2 equiv of LiHMDS (0.012 M) in 8.0 M THF/toluene
affords enolate 4 at 37% conversion, whereas addition of 20
equiv of LiHMDS (0.20 M) increases the conversion to 80%.
The reversibility of the enolization was confirmed when added
hexamethyldisilazane (HMDS) caused an enolization at 80%
conversion to revert to 25% conversion. Despite the highly
-
1
-
1
â-amino carboxamide binding to lithium (1630 cm ), yet the
6
Li NMR spectra show no changes that could be construed as
evidence of coordination or even formation of a new species.
To ascertain whether the NMR spectral result was inherent to
the coordination chemistry of the carboxamide moiety, we
briefly investigated the ligating properties of a structurally
analogous carboxamide and found that carboxamide binding to
the LiHMDS dimer in neat toluene and low THF concentrations
(
12) For leading references, see: (a) Lucht, B. L.; Collum, D. B. Acc. Chem.
Res. 1999, 32, 1035-1042. (b) Lucht, B. L.; Collum, D. B. J. Am. Chem.
Soc. 1995, 117, 9863-9874. (c) Lucht, B. L.; Collum, D. B. J. Am. Chem.
Soc. 1994, 116, 6009-6010.
(
13) At less than 1.0 equiv of THF per lithium, however, we observed a
significant decrease in the extent of enolization with 20 equiv of LiHMDS.
Conversely, we observed an inverse [THF]-dependence on the extent of
enolization when excess HMDS was present.
(
10) For leading references to mixed aggregation effects on organolithium
reactions, see: (a) Pratt, L. M.; Streitwieser, A. J. Org. Chem. 2003, 68,
2
830-2838. (b) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624-
(14) LiHMDS dimer 5 is stabilized in toluene relative to a higher oligomer owing
to a hydrocarbon-lithium interaction: Lucht, B. L.; Collum, D. B. J. Am.
Chem. Soc. 1996, 118, 2217-2225.
(15) Lucht, B. L.; Bernstein, M. P.; Remenar, J. F.; Collum, D. B. J. Am. Chem.
Soc. 1996, 118, 10707-10718.
1
654.
(11) For leading references to decelerations owing to formation of lithium amide
mixed aggregates, see: Sun, X.; Collum, D. B. J. Am. Chem. Soc. 2000,
1
22, 2459-2463.
5656 J. AM. CHEM. SOC.
9
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Enolization of
â
-Amino Carboxamides by LiHMDS
A R T I C L E S
6
6
15
6
15
Figure 3. Li NMR spectra recorded in neat toluene at -75 °C. (A) [ Li, N]LiHMDS (0.08 M), 1 (0.023 M). (B) [ Li]LiHMDS (0.08 M), [ N]1 (0.023
2
3
M).
Table 1. 6Li and 15N NMR Spectral Data of LiHMDS/4 Aggregatesa
compd
6Li
δ
(mult, JLiN)b
6Li (mult, JLiN)c
15N
δ
(mult, JLiN)b
15N (mult, JLiN)c
δ
5
6
7
9
6
0.35 (t, 3.5)
1.0 (t, 3.4)
0.01 (d, 5.1)
0.14 (d, 4.8)
0.19 (d, 4.0)
-
-
43.0 (q, 3.7)
38.5 (q, 3.4)
41.9 (t, 4.9)
42.0 (t, 5.0)
40.7 (q, 3.9)
-
-
-
-
-
/8
-
d
1
1
-
49.9 (t, 4.3)
1.72 (d, 3.8)
(d, 4.3)
-
-
7
1.01 (t, 4.5)
42.9 (q, 4.1)
45.4 (q, 4.3)
-
46.7 (t, 4.0)
1
1
.22 (d, 4.4)
.50 (d, 3.9)
-
-
-
(d, 4.5)
e,f
1
2
9
0
0.96
0.61 (d, 3.1)
(d, 3.9)
-
43.9
d
43.5e
51.7e
a
Spectra were recorded on 0.08 M Li solutions at various THF concentrations with toluene at -75 °C. Multiplicities are denoted as follows: d ) doublet,
6
t ) triplet, q ) quintet. The chemical shifts are reported relative to 0.3 M LiCl/MeOH at -90 °C (0.0 ppm) and neat Me2NEt (25.7 ppm). All J values are
reported in hertz. Spectra were recorded with [ Li, N]LiHMDS and [ N]1. Spectra were recorded with [ Li]LiHMDS and [ N]1. Coupling was poorly
resolved in the Li NMR spectra. Coupling was poorly resolved in the N NMR spectra. There were two unassigned resonances (42.8, 44.9).
b
6
15
14
c
6
15
d
6
e
15
f
is readily observed by Li NMR spectroscopy.16,17 We also
examined the binding of sec-BuNH2 to LiHMDS in neat toluene
and low THF concentrations and found that it too binds readily
to the LiHMDS dimer with the consequent formation of new
resonances.18 We are unsure as to why carboxamide 1 does not
elicit similar spectral changes but suspect it may be forming
6
Structures of Lithium Enolate-LiHMDS Mixed Ag-
gregates. We initiated studies of mixed aggregation based on
enolizations using neat toluene. Figure 3 shows that the
enolization of 1 in toluene mediated by excess LiHMDS affords
mixed dimer 16 and mixed trimer 17 (or isomeric ladder 18).
6
15
6
15
15
Li- N couplings from both [ Li, N]LiHMDS and [ N]1
1
5
19
extended structures as noted previously for bidentate ligands.
(Table 1) are consistent with the proposed structures. Related
lithium enolate-lithium amide mixed aggregates have been
2
0
21,22
(
16) Serial additions of carboxamide 10 to LiHMDS in toluene afford
sequentially (1) mono- and disolvated dimers 11 and 12 (respectively) at
observed both spectroscopically and crystallographically.
<
1.0 equiv of 10, and (2) monomer 13 with excess 10. Analogous serial
additions in 2.0 M THF/toluene afford (sequentially) 14, 12, and 15. It is
notable that 10 does not enolize even with warming to ambient temperature.
Furthermore, IR spectroscopy shows that the CdO moiety of â-amino
carboxamide 1 binds quantitatively in THF, whereas isostructural carbox-
amide 10 does not, indicating that chelation of lithium by the â-NH is
2
important (Supporting Information).
In general, cyclic trimers and higher oligomers of lithium
amides are converted to lower aggregates by adding coordinating
19) For calculations of 6Li- N coupling constants, see: (a) Parisel, O.;
15
(
Fressign e´ , C.; Maddaluno, J.; Giessner-Prettre, C. J. Org. Chem. 2003, 68,
290-1294. (b) Koizumi, T.; Morihashi, K.; Kikuchi, O. Bull. Chem. Soc.
1
Jpn. 1996, 69, 305-309.
(
20) For spectroscopic characterization of lithium enolate-lithium amide mixed
aggregates in solution, see: (a) Kim, Y.-J.; Streitwieser, A. Org. Lett. 2002,
4, 573-575. (b) Romesberg, F. E.; Collum, D. B. J. Am. Chem. Soc. 1994,
116, 9198-9202. (c) Hall, P. L.; Gilchrist, J. H.; Harrison, A. T.; Fuller,
D. J.; Collum, D. B. J. Am. Chem. Soc. 1991, 113, 9575-9585. Also, see
refs 1 and 11.
(
17) Carboxamide 10 was prepared using methyl isovalerate and Et
NH. Patterson, J. W. J. Org. Chem. 1995, 60, 4542-4548.
3
2
Al/Bu -
6
15
6
15
(18) Analogous Li and N NMR spectroscopic studies on mixtures of [ Li, N]-
2
LiHMDS and sec-BuNH are archived in Supporting Information. Also,
see ref 14.
J. AM. CHEM. SOC.
9
VOL. 127, NO. 15, 2005 5657

A R T I C L E S
McNeil and Collum
6
6
15
Figure 4. Li NMR spectra recorded on [ Li, N]LiHMDS (0.08 M) and 1 (0.023 M) in various THF concentrations with toluene at -75 °C. (A) 0.01 M.
(
B) 0.06 M. (C) 0.5 M. (D) 8.0 M.
ligands.24 Serial solvation of the LiHMDS-4 dimer/trimer
mixture, however, displays more complicated behavior. For
example, addition of fractional equivalents of THF (<0.2 equiv/
lithium) to mixed dimer 16 and mixed trimer 17 causes trimer
by using 1.0 equiv of [ Li]LiHMDS and 0.8 equiv of THF,
6
allowing us to characterize 19 as described in the next section.
Further addition of THF (>1.0 equiv/lithium) caused the
mixed dimer to reappear in a solvated form (20; Figure 4C).
An analogous mixed dimer derived from â-amino ester enolates
was previously observed. Mixed dimer 20 displays coupling
constants consistent with a cyclic dimer motif and appears as
17 to be replaced by enolate oligomer 19 and solvated LiHMDS
1
dimer 6. Further addition of THF (0.5-1.0 equiv/lithium)
affords LiHMDS dimer 6 and enolate 19 to the exclusion of
mixed dimer 16 (Figure 4B). Although the lithium enolate could
be readily detected by IR spectroscopy, a perfect superposition
1
9
6
a single Li resonance at -75 °C that resolves into two broad
resonances on cooling to -115 °C (Supporting Information).
At high THF concentrations, the lithium enolate exists exclu-
sively as mixed dimer 20, and the excess LiHMDS is converted
to monomers 7/8 (Figure 4D).
The disappearance of mixed dimer 16 at low concentrations
of THF and the reappearance of THF-solvated mixed dimer 20
at higher THF concentrations, although odd on first inspection,
may be understood through the balanced expressions described
by eqs 3 and 4. Related phenomena were observed for mixtures
6
of the Li resonances of 6 and 19 made it particularly
6
challenging to detect 19 using Li NMR spectroscopy. The
superposition was noted by (1) the anomalously high integration
6
15
of the center triplet of 6 in [ Li, N]LiHMDS/4 mixtures, and
2) the doublet flanking the signal of 6 in analogous solutions
(
6
15
prepared from [ Li]LiHMDS and [ N]1 that was confirmed by
1
5
N decoupling. We found that the homoaggregated enolate
could be generated as the sole observable form of the enolate
2
5
of LiHMDS solvated by a protic diamine.
(
21) For crystal structures of lithium enolate-lithium amide mixed aggregates,
see: (a) Williard, P. G.; Hintze, M. J. J. Am. Chem. Soc. 1990, 112, 8602-
2
[(Me Si) NLi](4) [(Me Si) NLi] (4)
3
2
+
3
2
2
+ 4THF h
8
604. (b) Williard, P. G.; Hintze, M. J. J. Am. Chem. Soc. 1987, 109, 5539-
(16)
(17)
5
541. Also, see ref 10b.
(
22) Lithium enolate-lithium amide mixed aggregates have been examined
computationally: (a) Pratt, L. M.; Newman, A.; Cyr, J. S.; Johnson, H.;
Miles, B.; Lattier, A.; Austin, E.; Henderson, S.; Hershey, B.; Lin, M.;
Balamraju, Y.; Sammonds, L.; Cheramie, J.; Karnes, J.; Hymel, E.;
Woodford, B.; Carter, C. J. Org. Chem. 2003, 68, 6387-6391. (b)
Henderson, K. W.; Dorigo, A. E.; Liu, Q.-Y.; Williard, P. G.; Schleyer, P.
v. R.; Bernstein, P. R. J. Am. Chem. Soc. 1996, 118, 1339-1347. (c)
Romesberg, F. E.; Collum, D. B. J. Am. Chem. Soc. 1994, 116, 9187-
3/n(4)n 2[(Me Si) NLi] (THF)
+
3 2 2
2
3
(3)
(4)
(19)
(6)
1
/n(4)n
[(Me Si) NLi] (THF)
+
3
2
2
2
+ 3THF h
(19)
(6)
(Me Si) NLi](4)(THF)
[
[(Me Si) NLi](THF)
3 2
9
197. Also, see ref 10a.
3
2
2
+
(
23) The relative intensity changes of 16 and 17 in Figure 3, parts A and B,
result from unintentional stoichiometry differences from using different
samples of â-amino carboxamide and LiHMDS.
(20)
(7)
(24) (a) Gregory, K.; Schleyer, P. v. R.; Snaith, R. AdV. Inorg. Chem. 1991, 37,
Structure of Enolate Homoaggregates. We previously
4
7-142. (b) Barr, D.; Snaith, R.; Clegg, W.; Mulvey, R. E.; Wade, K. J.
reported a strategy to assign the structure of homoaggregated
Chem. Soc., Dalton Trans. 1987, 2141-2147. (c) Armstrong, D. R.; Barr,
D.; Snaith, R.; Clegg, W.; Mulvey, R. E.; Wade, K.; Reed, D. J. Chem.
Soc., Dalton Trans. 1987, 1071-1081. (d) Armstrong, D. R.; Barr, D.;
Clegg, W.; Mulvey, R. E.; Reed, D.; Snaith, R.; Wade, K. J. Chem. Soc.,
Chem. Commun. 1986, 869-870. (e) Barr, D.; Clegg, W.; Mulvey, R. E.;
Snaith, R.; Wade, K. J. Chem. Soc., Chem. Commun. 1986, 295-297.
â-amino ester enolates in solution using variable-temperature
6
1
Li NMR spectroscopy. In short, warming the sample to
(25) Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc. 1996, 118, 3529-3530.
5658 J. AM. CHEM. SOC.
9
VOL. 127, NO. 15, 2005

Enolization of
â
-Amino Carboxamides by LiHMDS
A R T I C L E S
6
6
Figure 5. Li NMR spectra recorded on [ Li]LiHMDS (0.10 M) and 1 (0.10 M, XR ) 0.8) in 0.075 M THF/toluene at (A) -75 °C and (B) 35 °C. R3S3/
R4S2/R2S4 (b); R5S1/R1S5 ([); R6/S6 (9).
the point at which intra-aggregate exchanges are fast but inter-
aggregate exchanges remain slow produces a single resonance
for aggregates that differ only in stereoisomerism or positional
26
isomerism. Aggregates that differ by subunit composition (cf.,
:2 versus 3:3 mixed hexamers) or by virtue of their aggregation
4
numbers (cf., dimers versus tetramers) appear as separate species
6
in the Li NMR spectra.
The inherent symmetry of the lithium enolate aggregates can
be disrupted by using combinations of R and S antipodes to
generate an ensemble of homo- and heterochiral aggregates. In
the limit of rapid intra-aggregate exchange, dimers (R1S1 and
R2/S2), tetramers (R4/S4, R1S3/R3S1, and R2S2), and hexamers
(
R6/S6, R1S5/R5S1, R2S4/R4S2, and R3S3) are expected to afford
6
two, three, and four Li resonances, respectively. (RnSN-n/
RN-nSn and RN/SN refer to pairs of spectroscopically indistin-
guishable enantiomers.)
Figure 6. Job plot of the mole fraction of RnS4-n/R4-nSn (Xn + X4-n) as
a function of the mole fraction of the R enantiomer (XR) at 30 °C. The best
6Li NMR spectra recorded on R/S mixtures of enolate 4
32a
fit to the data is also shown: R S (blue); R S /R S (green); R /S (red).
2
2
1
3
3
1
4
4
contain multiple resonances at -75 °C, consistent with inordi-
nate structural complexity stemming from both stereoisomerism
and positional isomerism as well as from aggregates with
varying R/S proportions (Figure 5A). On warming to 30 °C,
we obtained three distinct lithium resonances, suggesting that
Although some of the qualitative features of the data are
reflected in the curves, there are a number of egregious
quantitative discrepancies, including a failure to account for the
positions of the maxima of the R3S1/R1S3 curve and a poor fit
to the curvature for each aggregate.
27
1
9 may be an ensemble of tetramers (Figure 5B). A Job plot
of the relative integration of the three resonances versus the
N
mole fraction of the R enantiomer (XR) is illustrated in Figure
2
8
n × [RnSN-n]
6
.
The curves in Figure 6 correspond to implicit fits of the
∑
[
RnSN-n]
n)0
XR ) N
aggregate populations to the Boltzmann distribution (eqs 5 and
Xn ) N
(5)
1
,29-31
6
) for a model based on an ensemble of tetramers.
N × [RnSN-n]
[RjSN-j]
∑
∑
j)0
(
26) (a) Arvidsson, P. I.; Ahlberg, P.; Hilmersson, G. Chem.-Eur. J. 1999, 5,
348-1354. (b) Bauer, W. J. Am. Chem. Soc. 1996, 118, 5450-5455. (c)
Bauer, W.; Griesinger, C. J. Am. Chem. Soc. 1993, 115, 10871-10882.
d) DeLong, G. T.; Pannell, D. K.; Clarke, M. T.; Thomas, R. D. J. Am.
n)0
1
nµ + (N - n)µS
(
N!
R
Chem. Soc. 1993, 115, 7013-7014. (e) Thomas, R. D.; Clarke, M. T.;
Jensen, R. M.; Young, T. C. Organometallics 1986, 5, 1851-1857. (f)
Bates, T. F.; Clarke, M. T.; Thomas, R. D. J. Am. Chem. Soc. 1988, 110,
[RnSN-n] ) C ×
× φ × exp
(
)
n
n!(N - n)!
kT
(6)
5
109-5112. (g) Fraenkel, G.; Hsu, H.; Su, B. M. In Lithium: Current
Applications in Science, Medicine, and Technology; Bach, R. O., Ed.;
Wiley: New York, 1985; pp 273-289. (h) Heinzer, J.; Oth, J. F. M.;
Seebach, D. HelV. Chim. Acta 1985, 68, 1848-1862. (i) Fraenkel, G.;
Henrichs, M.; Hewitt, J. M.; Su, B. M.; Geckle, M. J. J. Am. Chem. Soc.
-
gP
where φ ) φ
) exp
n
N-n
〈
(
)〉
kT
1
980, 102, 3345-3350.
(27) The temperature required to obtain intra-aggregate exchange for â-amino
Accordingly, we considered the alternative possibility that a
fourth resonance, characteristic of an ensemble of hexamers,
was failing to resolve. From distortions in the fit to the tetramer
model, we suspected that the fourth resonance, corresponding
to R2S4/R4S2, might be concealed by the resonance of R3S3.
Figure 7 shows the least-squares fit to the data, assuming that
the three resonances are R6/S6, R1S5/R5S1, and R2S4/R4S2/R3S3.
The fit to the hexamer model is approximately three times better
than the fit to the tetramer model. The free energies for the
equilibria described in eqs 7-9 are listed in Table 2. Curiously,
carboxamide enolate 4 is markedly higher than that previously needed for
1
â-amino ester enolate hexamers (-50 °C).
(
(
(
(
28) (a) Job, P. Ann. Chim. 1928, 9, 113-203. (b) Gil, V. M. S.; Oliveira, N.
C. J. Chem. Educ. 1990, 67, 473-478.
R S P
29) Where µ and µ are the chemical potentials of R and S, g corresponds to
the free energy of assembly for each permutation, and C is a constant.
30) Widom, B. Statistical Mechanics: A Concise Introduction for Chemists;
Cambridge University Press: New York, 2002.
31) For an example of a Job plot for an ensemble of tetramers, see: Desjardins,
S.; Flinois, K.; Oulyadi, H.; Davoust, D.; Giessner-Prettre, C.; Parisel, O.;
Maddaluno, J. Organometallics 2003, 22, 4090-4097. For an early
application of a Job plot to assign the stoichiometry of equilibrating species,
see: Weingarten, H.; Van Wazer, J. R. J. Am. Chem. Soc. 1965, 87, 724-
7
30.
J. AM. CHEM. SOC.
9
VOL. 127, NO. 15, 2005 5659

A R T I C L E S
McNeil and Collum
Racemization. We noted a curious time-dependent change
6
in the Li NMR spectra recorded on the enolate homoaggregate.
On standing at 30 °C for 2 h, samples of optically pure enolate
6
4
1
show Li resonances indicating racemization. The re-isolated
1
was subjected to H NMR spectroscopic analysis with the
3
4
chiral shift reagent (+)-TADDOL, revealing the sample to
be 44% ee. While this racemization may add some error in the
Job plot data analysis, we obtained reproducible data by
6
acquiring the Li NMR spectra immediately after removal from
a -78 °C bath with a 10 min equilibration at 30 °C. Although
the mechanism of the racemization remains unclear, a reversible
Michael addition seems possible (eq 10).
Figure 7. Job plot of the mole fraction of RnS6-n/R6-nSn (Xn + X6-n) as
a function of the mole fraction of the R enantiomer (XR) at 30 °C. The best
fit to the data is also shown: R3S3/R2S4/R4S2 (blue); R1S5/R5S1 (green);
3
2b
R6/S6 (red).
Table 2. Results of the Least-Squares Fits Illustrated in Figure 7
K
∆
G (kcal/mol)a
K1 ) 0.046 ( 0.008
K2 ) 0.52 ( 0.06
K3 ) 0.36 ( 0.08
0.0 ( 0.1
Alkylation. Under conditions affording <50% conversion to
the lithium enolate, treatment with CH3I (1.2 equiv, -78 °C)
affords 2 in high yield (80%) with minimal recovered carbox-
amide 1. The high anti selectivity observed is consistent with
alkylation at the more accessible face. Kinetic control of the
alkylation was evidenced when a 7:1 mixture of 2:3 remained
unchanged after treatment with excess LiHMDS at -78 °C. The
reluctance of 2 and 3 to enolize probably stems from severe
-0.33 ( 0.07
0.4 ( 0.1
a
The deviations in ∆G beyond those expected for a statistical distribution
were obtained from the relationship ∆G ) -RT ln(K/Kstatistical).
if we assume that the R2S4/R4S2 resonance is obscured by the
R1S5/R5S1 resonance, we obtain a fit of equal quality, yet the
resulting free energies indicate that the R2S4/R4S2 aggregate is
absent (Supporting Information).
3
5
allylic strain (22).
K1
1
1
φ0
20φ3
R S y
\
z / R + / S
K )
(7)
(8)
(9)
3
3
2
6
2
6
1
K2
1
1
3φ
1
R S y
\
z / R S + / R S
K )
3
3
2
5
1
2
1
5
2
10φ
3
Summary
K3
1
1
3φ2
The enolization and alkylation of the unprotected â-amino
carboxamide depicted in eq 1 is a deceptively simple reaction.
In principle, one could ascertain the overall mechanism for the
enolization-alkylation sequence. In practice, however, the
reaction is quite complicated owing to a reversible enolization
and to the formation of a highly solvent-dependent mixture of
mixed dimers, mixed trimers, and homoaggregated enolate
hexamers. We also continue to be intrigued by the strategy of
determining lithium enolate structures via Job plots.
R S y\
z / R S + / R S
K )
3
4φ3
3
3
2
4
2
2
2
4
On the basis of analogy to â-amino ester enolates for which
a crystal structure was obtained, we tentatively assigned the
ensemble of â-amino carboxamide enolates as prismatic hex-
amers (21). Although â-amino carboxamides present steric
demands considerably different from those of â-amino esters,
it is intriguing that their respective lithium enolates appear to
provide isostructural hexamers.
3
3
This study serves as a reminder that optimizing reaction rates,
yields, and diastereoselectivities using strategies that are more
than simple empiricism continues to pose enormous challenges.
In fact, it is fortunate that synthetic chemists convincingly
demonstrated the utility of lithium enolates before structural and
mechanistic organolithium chemists had the opportunity to
reveal the daunting complexity.
(
32) (a) For the case in which n ) 2, only X
For the case in which n ) 3, only X is plotted (rather than 2X
33) For crystal structures of lithium enolates derived from carboxamides, see:
a) Meyers, A. I.; Seefeld, M. A.; Lefker, B. A.; Blake, J. F.; Williard, P.
2
is plotted (rather than 2X
2
). (b)
3
3
).
(34) (a) Bussche-H u¨ nnefeld, C.; Beck, A. K.; Lengweiler, U.; Seebach, D. HelV.
Chim. Acta 1992, 75, 438-441. (b) Tanaka, K.; Ootani, M.; Toda, F.
Tetrahedron: Asymmetry 1992, 3, 709-712.
(35) (a) Evans, D. A.; Ennis, M. D.; Le, T.; Mandel, N.; Mandel, G. J. Am.
Chem. Soc. 1984, 106, 1154-1156. (b) Hoffmann, R. W. Chem. ReV. 1989,
89, 1841-1860.
(
(
G. J. Am. Chem. Soc. 1998, 120, 7429-7438. (b) Bauer, W.; Laube, T.;
Seebach, D. Chem. Ber. 1985, 118, 764-773. (c) Laube, T.; Dunitz, J. D.;
Seebach, D. HelV. Chim. Acta 1985, 68, 1373-1393.
5660 J. AM. CHEM. SOC.
9
VOL. 127, NO. 15, 2005

Enolization of
â
-Amino Carboxamides by LiHMDS
A R T I C L E S
Acknowledgment. We thank Gilman E. S. Toombes, Emil
Lobkovsky, Ivan Keresztes, and Anthony M. Condo for their
analytical support. We also thank the National Institutes of
Health and Sanofi-Aventis for direct support of this work. In
particular, we would like to thank Timothy A. Ayers, Sithamalli
V. Chandramouli, and Benoit J. Vanasse of Sanofi-Aventis for
enlightening discussions.
Supporting Information Available: Experimental prepara-
tions, NMR spectroscopic data, IR spectroscopic data (PDF),
and X-ray crystallographic data (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA043470S
J. AM. CHEM. SOC.
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VOL. 127, NO. 15, 2005 5661