Lithium hexamethyldisilazide-mediated enolizations: Influence of triethylamine on E/Z selectivities and enolate reactivities

Article abstract of DOI:10.1021/ja800250q

Lithium hexamethyldisilazide (LiHMDS) in triethylamine (Et ₃N)/toluene is shown to enolize acyclic ketones and esters rapidly and with high E/Z selectivity. Mechanistic studies reveal a dimer-based mechanism consistent with previous studies of

Full text of DOI:10.1021/ja800250q

Published on Web 06/17/2008
Lithium Hexamethyldisilazide-Mediated Enolizations:
Influence of Triethylamine on E/Z Selectivities and Enolate
Reactivities
Peter F. Godenschwager and David B. Collum*
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell UniVersity,
Ithaca, New York 14853-1301
Received January 11, 2008; E-mail: dbc6@cornell.edu
Abstract: Lithium hexamethyldisilazide (LiHMDS) in triethylamine (Et
ketones and esters rapidly and with high E/Z selectivity. Mechanistic studies reveal a dimer-based
mechanism consistent with previous studies of LiHMDS/Et N. E/Z equilibration occurs when <2.0 equiv of
LiHMDS are used. Studies of the aldol condensation and Ireland-Claisen rearrangement of the resulting
Et N-solvated enolates show higher and often complementary diastereoselectivities when compared with
analogous reactions in THF. The Et N-solvated enolates also display a marked (20-fold) acceleration of
3
N)/toluene is shown to enolize acyclic
3
3
3
the Ireland-Claisen rearrangement with evidence of autocatalysis. A possible importance of amine-solvated
enolates is discussed.
Introduction
On the heels of investigations of the solvent-dependent
1
,2
structures of lithium hexamethyldisilazide (LiHMDS), we
began examining structure-reactivity relationships in LiHMDS-
3
mediated ketone enolizations (eq 1). We found that enolization
3
a
of ketone 1 in Et3N/toluene is >100 times faster than the
3b,c
analogous enolization in neat THF. This was surprising given
2
,3a,b,4
that simple trialkylamines are particularly feeble ligands
5
,6
that have rarely been used in organolithium chemistry. The
high rates imparted by trialkylamines were traced to a dimer-
based pathway exemplified by transition structure 3. The
exceptional steric demands of the trialkylamines were shown
to destabilize dimeric LiHMDS reactants more than they
destabilize transition structure 3. By contrast, the LiHMDS/THF-
mediated enolizations proceed via a more conventional disol-
3
b
vated monomer-based transition structure 4.
We describe herein LiHMDS/Et3N-mediated enolizations of
acyclic ketones. The enolizations are fast, dimer-based, and,
most important, highly E selective (eq 2). We also examine the
reactivity of the Et3N-solvated lithium enolates toward aldol
condensations and Ireland-Claisen rearrangements and find
some distinct advantages when compared with THF-solvated
7
(
(
(
1) Lucht, B. L.; Collum, D. B. Acc. Chem. Res. 1999, 32, 1035.
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Zhao, P.; Condo, A.; Keresztes, I.; Collum, D. B. J. Am. Chem. Soc.
enolates.
2
004, 126, 3113. (d) Zhao, P.; Lucht, B. L.; Kenkre, S. L.; Collum,
D. B. J. Org. Chem. 2003, 68, 242.
(
4) (a) Bernstein, M. P.; Collum, D. B. J. Am. Chem. Soc. 1993, 115,
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Results
Stereochemistry of Enolization. The E/Z selectivities for
LiHMDS-mediated enolizations were monitored by quenching
the resulting enolate solutions with Me3SiCl/Et3N and analyzing
(
i) Kaufmann, E.; Gose, J.; Schleyer, P. v. R. Organometallics 1989,
8
, 2577.
8
(
5) (a) Fukuzaki, T.; Kobayashi, S.; Hibi, T.; Ikuma, Y.; Ishihara, J.;
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the products with gas chromatography (GC) using well-
8
726 9 J. AM. CHEM. SOC. 2008, 130, 8726–8732
10.1021/ja800250q CCC: $40.75  2008 American Chemical Society

Lithium Hexamethyldisilazide-Mediated Enolizations
A R T I C L E S
The E selectivity rises markedly with increasing quantities of
LiHMDS, approaching 110:1 at g2.0 equiv of LiHMDS per
ketone.
The dependencies of the E/Z selectivities on the equivalents
of LiHMDS could be construed as evidence of intervening
lithium enolate/LiHMDS mixed aggregates in a kinetically
Figure 1. E/Z selectivity (E-6:Z-6, eq 3) versus molarity (M) of LiHMDS
in samples containing 0.10 M ketone 5 and 1.2 M excess Et3N in toluene
at -78 °C.
9
,13–15
1
6
controlled enolization.
It is mathematically impossible,
however, for a 100:1 selectivity at 50% conversion (2.0 equiv
of base) to be reversed to a 1:2 selectivity at full conversion
9
established protocols (eq 3). The proportion of LiHMDS to
ketone proves to be the key determinant of stereochemistry
(1.0 equiv of base) without an intervening equilibration. Indeed,
when a reaction mixture resulting from a highly E-selective
enolization of ketone 5 is subsequently treated with cyclohexyl
ethyl ketone as a surrogate to consume the remaining LiHMDS
(
Figure 1). At low base loadings the enolization shows a modest
10–12
ZselectivityakintothatobservedforLiHMDS/THFmixtures.
(
eq 4), the E selectivity in the enolization of 5 is lost. Under no
(
6) (a) Chalk, A. J.; Hay, A. S. J. Polym. Sci., A 1969, 7, 691. (b) Carreira,
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(
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4
in toluene as the cosolvent afforded the E/Z selectivities listed
in Table 1. LiHMDS/Et3N affords the highest selectivities.
1
1
56, 1. (g) Hallden-Aberton, M.; Engelman, C.; Fraenkel, G. J. Org.
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The selectivity reversal caused by decreasing the THF concen-
trations was noted by Xie and Wielgosh.
The generality of the E-selective enolization by LiHMDS/
Et3N was established by surveying the enolizations summarized
in Table 2. Results derived from LiHMDS/THF are included
for comparison. Although the selectivities were not optimized
12
5
957. Zgonnik, V. N.; Sergutin, V. M.; Kalninsh, K. K.; Lyubimova,
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(
(
8) Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90, 4462.
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(16) The concentration of LiHMDS, although expressed in units of molarity,
refers to the concentration of the monomer unit (normality). Concen-
trations of the Et3N refer to the concentrations of the free (uncom-
plexed) amine rather than to the total unless stated otherwise.
1
13, 9571.
10) Masamune, S.; Imperiali, B.; Garvey, D. S. J. Am. Chem. Soc. 1982,
04, 5526.
(
1
J. AM. CHEM. SOC. 9 VOL. 130, NO. 27, 2008 8727

A R T I C L E S
Godenschwager and Collum
a
Table 1. Solvent-Dependent E/Z Selectivities Resulting from the
Table 3. NMR Spectroscopic Data
a
Enolization of Ketone 5 (eq 3)
6
15
compd
δ
Li (mult, JLiN
)
δ
N (mult, JLiN)
solvent, S
Et3N
Me2NEt
i-Pr)2NEt
E-6:Z-6
7
1.00 (t, 4.0)
1.48 (t, 3.1)
1.85 (t, 3.3)
0.48 (d, 3.4)
0.51 (d, 3.5)
41.4 (q, 3.8)
110:1
90:1
40:1
60:1
13:1
1:13
40:1
30:1
8
10
11
38.7 (q, 3.4)
40.34 (q, 3.4)
40.31 (m, -)
(
i-Bu3N
THF (0.5 M)
THF (10 M)
a
6
15
Spectra were recorded in 0.10 M [ Li, N]LiHMDS in toluene
b
Me4THF
containing Et3N. Coupling constants were measured after resolution
enhancement and reported in hertz. Multiplicities are denoted as follows:
d ) doublet, t ) triplet, and q ) quintet. The chemical shifts are
reported relative to 0.30 M LiCl/MeOH at -90 °C (0.0 ppm) and neat
Me2NEt at -90 °C (25.7 ppm).
TMEDA
a
6
[
5] ) 0.050 M; [LiHMDS] ) 0.15 M; [S] ) 1.5 M in toluene; -78
C. Me4THF ) 2,2,5,5-tetramethyltetrahydrofuran (1.5 M in toluene).
b
°
to monitor structures and rates in some instances.) Dimers
bearing one or two complexed ketones (7 and 8) are readily
6
15
1,20,21
characterized with Li and N NMR spectroscopy
[
using
6
15
22
Li, N]LiHMDS (Table 3). Putative LiHMDS-ketone com-
plex 9 was too reactive to characterize but is almost certainly
isostructural to the closely related complex characterized
3
b
previously. Enolization of 5 with 3.0 equiv of LiHMDS/Et3N
at -78 °C affords mixed dimer 10 (Table 3). If the enolization
is carried out under poorly selective conditions at 0 °C using
6
15
3
.0 equiv of [ Li, N]LiHMDS, both mixed dimer 10 and the
corresponding Z-enolate-derived mixed dimer 11 are ob-
11
Table 2. Solvent-Dependent E/Z Selectivities for Enolization by
a
LiHMDS (eq 5)
1
5b
served.
Mechanism of Enolization. The structural similarities of
ketones 1 and 5 certainly suggest a common mechanism. Indeed,
3
,21
rate studies using well-documented protocols
confirm the
mechanistic parallels as follows. Pseudo-first-order conditions
were established by maintaining low concentrations of ketone
5
(0.004-0.010 M) and high, yet adjustable, concentrations of
a
b
22
[
ketone] ) 0.05 M; [LiHMDS] ) 0.15 M. [Et3N] ) 1.5 M in
recrystallized LiHMDS (0.05-0.40 M) and Et3N (0.15-2.40
M), with toluene as the cosolvent. Monitoring the loss of
LiHMDS-ketone complex 9 with in situ IR spectroscopy (1698
c
toluene; -78 °C. Neat THF.
for each case, we suspect there is only limited room for
improvement.
-1
cm ) shows clean first-order decays to g5 half-lives. The
resulting pseudo-first-order rate constants (kobsd) are independent
of ketone concentration (0.004-0.040 M). Re-establishing the
IR baseline and monitoring a second aliquot of ketone reveals
no significant change in the rate constant, showing that
Aggregate Structures. Adding ketone 5 to LiHMDS in either
toluene or Et3N/toluene mixtures at -78 °C and monitoring with
-
1
in situ IR spectroscopy reveals that 5 (1714 cm ) is quanti-
1 17,18
-
tativelyconvertedtoLiHMDS-ketonecomplexes(1698cm ).
1
9
(
The less reactive 2,4,4-trideuterated ketone, 5-d3, was used
(18) For a general discussion of ketone-lithium complexation and related
ketone-Lewis acid complexation, see: Shambayati, S.; Schreiber, S. L.
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I. Eds.;
Pergamon: New York, 1991; Vol. 1, p 298.
(
17) For leading references and recent examples of detectable organo-
lithium-substrate pre-complexation, see:(a) Klumpp, G. W. Recl. TraV.
Chim. Pays-Bas 1986, 105, 1. (b) Andersen, D. R.; Faibish, N. C.;
Beak, P. J. Am. Chem. Soc. 1999, 121, 7553. (c) Pippel, D. J.;
Weisenberger, G. A.; Faibish, N. C.; Beak, P. J. Am. Chem. Soc. 2001,
(19) Peet, N. P. J. Label. Compound. 1973, 9, 721.
(20) Collum, D. B. Acc. Chem. Res. 1993, 26, 227.
(21) Collum, D. B.; McNeil, A. J.; Ramirez, A. Angew. Chem., Int. Ed.
2007, 49, 3002.
1
1
23, 4919. (d) Bertini-Gross, K. M.; Beak, P. J. Am. Chem. Soc. 2001,
23, 315.
(22) Romesberg, F. E.; Bernstein, M. P.; Gilchrist, J. H.; Harrison, A. T.;
Fuller, D. J.; Collum, D. B. J. Am. Chem. Soc. 1993, 115, 3475.
8
728 J. AM. CHEM. SOC. 9 VOL. 130, NO. 27, 2008

Lithium Hexamethyldisilazide-Mediated Enolizations
A R T I C L E S
Figure 2. Plot of kobsd versus [Et3N] in toluene cosolvent for the enolization
of 5-d3 (0.005 M) by LiHMDS (0.10 M) at -78 °C. The curve depicts an
unweighted least-squares fit to kobsd ) a[Et3N]/(1 + b[Et3N]), where a )
Figure 3. Plot of kobsd versus [LiHMDS] in 4.0 M Et3N/toluene solution
for the enolization of 5-d3 (0.005 M) by LiHMDS at -78 °C. The curve
depicts an unweighted least-squares fit to kobsd ) a[LiHMDS] + b, where
a ) 5 ( 1, b ) 3.0 ( 0.1.
-
1
4
.0 ( 0.1, b ) 8.2 ( 0.6 × 10
.
cally demanding Et3N ligands and compared them with those
observed in neat THF. For example, eq 9 illustrates a sequential
enolization with LiHMDS (3.0 equiv) in Et3N/toluene followed
by an aldol condensation with isobutyraldehyde affording
primarily anti-13 (anti/syn ) 25:1). By contrast, the analogous
reaction in neat THF shows decidedly inferior stereocontrol with
opposite selectivity. Several additional aldol condensations are
included as Supporting Information.
By carrying out the enolizations in different solvents, we are
comparing the chemistry of enolates that differ in both stere-
ochemistry and coordinating ligand. To isolate the influence of
solvent on only the aldol condensation, we enolized 5 with
LiHMDS/Et3N and subsequently added THF prior to the
addition of i-PrCHO; the anti/syn selectivity drops to 18:1. Thus,
there is no apparent advantage offered by the THF-solvated
enolate. Nonetheless, we believe that such strategies can be
important (vide infra).
conversion-dependent autocatalysis or autoinhibition are unim-
2
3,24
portant under these conditions.
Comparison of 5 and 5-d3
25
provided a large kinetic isotope effect (kH/kD > 10), confirming
2
6,27
rate-limiting proton transfer.
A plot of kobsd versus [Et3N] shows saturation kinetics (Figure
30
3
b,24,28
2
).
At low Et3N concentrations, unsolvated complex 7 is
the dominant form (see above), affording a first-order [Et3N]
dependence. At high concentrations of Et3N, fully solvated
complex 9 becomes the dominant form, and a zeroth-order Et3N
dependence results. A plot of kobsd versus [LiHMDS] at elevated
Et3N concentration reveals a zeroth-order dependence (Figure
3
). (The slight upward drift results from residual saturation
3
a
kinetics affording complex 9). The idealized rate law (eq 6)
is consistent with the generic mechanism described by eqs 7
2
9
and 8 and monosolvated dimer-based transition structure 12.
-
d[complex]total ⁄ dt +
(
k ′ K [Et N][complex] ) ⁄ (1 + K [Et N])
Ireland-Claisen Rearrangement. We examined a lithium
eq
3
total
eq
3
7
,11b,31
such that [complex]total ) [7] + [9] (6)
enolate variant of the Ireland-Claisen rearrangement
to
Keq
w x
[
{
(Me
3
3
Si)
2
NLi
}
2
(ketone)
]
+ Et
3
N
(
23) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624. (b) Sun,
X.; Collum, D. B. J. Am. Chem. Soc. 2000, 122, 2459. (c) McGarrity,
J. F.; Ogle, C. A. J. Am. Chem. Soc. 1984, 107, 1810. (d) Thompson,
A.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J.; Remenar,
J. F.; Collum, D. B. J. Am. Chem. Soc. 1998, 120, 2028.
(7)
[{Me Si) Nli} (Et N)(ketone)
3
2
2
3
(
7)
8)
(9)
(
24) Depue, J. S.; Collum, D. B. J. Am. Chem. Soc. 1988, 110, 5524.
{
(Me
Si)
NLi
}
(Et N)(ketone)
]
3
9)
k′
8
(25) The undeuterated ketone reacted so quickly at-78 °C that only a lower
[
2
2
9
limit on the measured isotope effect is warranted.
(
(
26) Isotope effects for LiHMDS-mediated ketone enolizations have been
measured previously. (a) Held, G.; Xie, L. F. Microchem. J. 1997,
55, 261. (b) Xie, L. F.; Saunders, W. H. J. Am. Chem. Soc. 1991,
‡
[
{Me Si) NLi} (Et N)(ketone)]
3
2
2
3
(
1
13, 3123.
(12)
(
(
(
27) The regioselectivity indicated in eq 1 was shown to be >20:1 by
trapping with Me3SiCl/Et3N mixtures and comparing the crude product
2
6
with authentic material by GC.
28) Espenson, J. H. Chemical Kinetics and Reaction Mechanisms, 2nd
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1
990, 46, 2401. For a bibliography of lithium amide open dimers,
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1
(
4
Soc. 1981, 103, 3099. (c) Van Horn, D. E.; Masamune, S. Tetrahedron
Lett. 1979, 2229.
Aldol Condensation. We examined the reactivities and
selectivities of enolates bearing poorly coordinating and steri-
(31) Corey, E. J.; Lee, D.-H. J. Am. Chem. Soc. 1991, 113, 4026.
J. AM. CHEM. SOC. 9 VOL. 130, NO. 27, 2008 8729

A R T I C L E S
Godenschwager and Collum
compare selectivities and reactivities of THF- and Et3N-solvated
enolates. Enolization of 14 using LiHMDS (3.0 equiv) and Et3N
(
2
10 equiv per lithium) in toluene at -78 °C affords an estimated
0:1 preference for enolate 15 (see Table 2, R ) OMe). Claisen
3
1
Figure 4. IR absorbance of enolate 15 versus time in (A) 1.5 M Et3N/
toluene and (B) 1.5 M Et3N/1.5 M THF/toluene.
rearrangement of 15 at -20 °C affords a 35:1 ratio of 16 and
1
3
1
7
in 79% isolated yield. Addition of 10 equiv of THF (per
lithium) subsequent to enolization in Et3N/toluene affords a
comparable 33:1 selectivity in 70% yield (albeit much more
slowly; vide infra). Curiously, the standard protocol-enolization
and rearrangement in neat THF-proceeds in 11% yield. The
low yields using LiHMDS/THF could stem from either a poor
enolization or a poor rearrangement from the Z isomer as noted
3
b,29
the accelerations to a dimer-based mechanism.
We hasten
to add that the high rates are only observed using g2.0 equiv
of LiHMDS. (Equimolar LiHMDS and ketone afford an inert
bis-ketone solvated LiHMDS dimer.) Of course, such accelera-
tions are notable, but the procedure may also be cost-effective.
LiHMDS is now used routinely on large scales for complex
1
1i
by Ireland in a similar silyl Claisen.
3
5,36
drug synthesis.
Using Et3N/hydrocarbon mixtures instead
1
0,37
of THF could offer considerable savings.
E-Selective Enolizations. Acting on a hunch, we found
LiHMDS/Et3N-mediated enolizations of acyclic ketones are very
fast and afford high E/Z selectivities (Tables 1 and 2). Excess
(
g2.0 equiv) LiHMDS is required to maintain high rates and
selectivities. Enolizations of ketone 5 with only 1.0 equiv of
LiHMDS/Et3N suffer from E/Z equilibration. Overall, the
procedure is more selective and more convenient than that using
LiTMP/LiBr mixtures, which has afforded lithium enolates with
9
the highest E-selectivity (up to 50:1) reported to date.
Mechanism of Enolization. NMR spectroscopic studies of the
enolization of ketone 5 using 3.0 equiv of LiHMDS revealed
lithium enolate-LiHMDS mixed dimer 10. The loss in stereo-
3
Qualitative rate studies of the rearrangement are quite interesting.
In situ IR spectroscopy revealed the loss of the Et3N-solvated ester
selectivity when <2.0 equiv LiHMDS/Et N was used derived
-1
enolate 15 (1675 and 1659 cm ) and formation of carboxylate
-1 32
absorbances (1610, 1600, 1582, and 1424 cm ). A sigmoidal
(
34) (a) Besson, C.; Finney, E. E.; Finke, R. G. J. Am. Chem. Soc. 2005,
27, 8179. (b) Besson, C.; Finney, E. E.; Finke, R. G. Chem. Mater.
24,33
behavior (Figure 4, curve A) is indicative of autocatalysis
1
occurring as the enolate is replaced with carboxylates, presumably
within aggregates. By contrast, addition of 10 equiv of THF (per
lithium) subsequent to enolization affords a THF-solvated enolate,
as evidenced by the replacement of absorbances at 1675 and 1659
2005, 17, 4925. (c) Espenson, J. H. Chemical Kinetics and Reaction
Mechanisms, 2nd ed.; McGraw-Hill: New York, 1995. (d) Huang,
K. T.; Keszler, A.; Patel, N.; Patel, R. P.; Gladwin, M. T.; Kim-
Shapiro, D. B.; Hogg, N. J. Biol. Chem. 2005, 280, 31126. (e) Huang,
Z.; Shiva, S.; Kim-Shapiro, D. B.; Patel, R. P.; Ringwood, L. A.; Irby,
C. E.; Huang, K. T.; Ho, C.; Hogg, N.; Schechter, A. N.; Gladwin,
M. T. J. Clin. InVest. 2005, 115, 2099. (f) Tanj, S.; Ohno, A.; Sato,
I.; Soai, K. Org. Lett. 2001, 3, 28.
-1
-1 34
cm with an absorbance at 1657 cm
. Of special importance,
rearrangement in Et3N/toluene (Figure 4, curve B) proceeds
approximately 20 times faster than with added THF. The Et3N
solVated enolate is substantially more reactiVe.
(35) (a) Dugger, R. W.; Ragan, J. A.; Ripin, D. H. B. Org. Process Res.
DeV. 2005, 9, 2943. (b) Wu, G.; Huang, M. Chem. ReV. 2006, 106,
2
596. (c) Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. J.
Discussion
Chem. ReV. 2006, 106, 2734.
(
36) For selected examples in which LiHMDS is used on large scale, see:
(a) Kauffman, G. S.; Harris, G. D.; Dorow, R. L.; Stone, B. R. P.;
Parsons, R. L., Jr.; Pesti, J. A.; Magnus, N. A.; Fortunak, J. M.;
Confalone, P. N.; Nugent, W. A. Org. Lett. 2000, 2, 3119. (b) Boys,
M. L.; Cain-Janicki, K. J.; Doubleday, W. W.; Farid, P. N.; Kar, M.;
Nugent, S. T.; Behling, J. R.; Pilipauskas, D. R. Org. Process Res.
DeV. 1997, 1, 233. (c) Ragan, J. A.; Murry, J. A.; Castaldi, M. J.;
Conrad, A. K.; Jones, B. P.; Li, B.; Makowski, T. W.; McDermott,
R.; Sitter, B. J.; White, T. D.; Young, G. R. Org. Process Res. DeV.
2001, 5, 498. (d) Rico, J. G. Tetrahedron Lett. 1994, 35, 6599. (e)
DeMattei, J. A.; Leanna, M. R.; Li, W.; Nichols, P. J.; Rasmussen,
M. W.; Morton, H. E. J. Org. Chem. 2001, 66, 3330.
We previously showed that LiHMDS/Et3N-mediated eno-
lizations are very fast compared to LiHMDS/THF and traced
(
32) Spectrometric Identification of Organic Compounds; Silverstein, R. M.,
Webster, F. X. Eds.; John Wiley & Sons, Inc.: New York, 1998; p
9
7.
(
33) (a) Nudelman, N. S.; Velurtas, S.; Grela, M. A. J. Phys. Org. Chem.
2
003, 16, 669. (b) Alberts, A. H.; Wynberg, H. J. Am. Chem. Soc.
989, 111, 7265. (c) Alberts, A. H.; Wynberg, H. J. Chem. Soc., Chem.
1
Commun. 1990, 453. (d) Xie, L.; Saunders, W. H. J. Am. Chem. Soc.
991, 113, 3123.
1
(37) Rutherford, J. L.; Collum, D. B. J. Am. Chem. Soc. 2001, 123, 199.
8
730 J. AM. CHEM. SOC. 9 VOL. 130, NO. 27, 2008

Lithium Hexamethyldisilazide-Mediated Enolizations
A R T I C L E S
from a facile equilibration and consequent formation of mixed
dimers 10 and 11. There is no affiliated regiochemical
equilibration.
provocative species. As expected, the high E selectivities can
be translated into relatively highly stereoselective aldol con-
densations and Ireland-Claisen rearrangements. Moreover, the
potential importance of amine-solvated lithium enolates is
underscored by a marked (20-fold) acceleration of the Ireland-
Claisen rearrangement when compared with the rates observed
using THF-solvated variant. One might ask why, if Et3N elicits
such favorable reactivities, have simple (monodentate) trialkyl-
Rate studies of the enolization under pseudo-first-order
conditions (a large excess of LiHMDS) confirmed that a dimer-
based enolizationstransition structure 12sis the source of the
high selectivities. Previous semiempirical computational studies
of enolizations by amine-solvated lithium amides failed to
3
8
5,6
predict the observed high selectivities.
amines played such a minor role in organolithium chemistry?
Aldol Condensation. The facile enolizations in Et3N/toluene
allowed us to examine the reactivity of Et3N-solvated enolates
and to compare them with their THF-solvated counterparts. We
first examined the aldol condensation-the most prevalent
application of E-selective enolizations-to ascertain whether the
high enolization selectivities could be translated into high syn/
anti selectivities. The aldol condensations are generally anti
selective using the LiHMDS/Et3N-based protocol (eq 9 and
Supporting Information). We examined whether the selectivity
might improve if THF was added before the addition of the
aldehyde. This sequence is tantamount to doing the enolization
in Et3N and the aldol condensation in THF. The selectivities
did not improve.
The answer may be simple. Et3N is a poorly coordinating ligand
that cannot compete with ethereal solvents for coordination to
lithium: Et3N requires hydrocarbons as cosolvents to be
effective. We suggest that trialkylamine/hydrocarbon mixtures
are worthy of more careful consideration in other applications
within organolithium chemistry.
Experimental Section
Reagents and Solvents. Coordinating ligands and toluene were
distilled by vacuum transfer from blue or purple solutions containing
sodium benzophenone ketyl. The toluene still contained 1%
6
tetraglyme to dissolve the ketyl. Li metal (95.5% enriched) was
obtained from Oak Ridge National Laboratory (Oak Ridge, TN).
4
0
6
6
15
LiHMDS, [ Li]LiHMDS, and [ Li, N]LiHMDS were prepared
Claisen Rearrangement. We investigated a lithium enolate
2
2
7
and purified as described previously. Ketone 5-d was prepared
3
variant of the Ireland-Claisen rearrangement shown in eq 10.
19
as described previously. Air- and moisture-sensitive materials
were manipulated under argon or nitrogen using standard glovebox,
vacuum line, and syringe techniques.
The low yields using LiHMDS/THF were previously observed
by Ireland on a closely related case and were attributed to the
formation of an unreactive stereoisomer. We concur with this
notion. The improved selectivity toward enolate 15 expected
for LDA/THF could, in principle, solve the problem, but we
obtained complex mixtures that probably derived from allylic
NMR Spectroscopic Analyses. Samples were prepared, and the
Li and N NMR spectra were recorded as described elsewhere.
IR Spectroscopic Analyses. Spectra were recorded with an in
6
15
2
situ IR spectrometer fitted with a 30-bounce, silicon-tipped probe
optimized for sensitivity. The spectra were acquired in 16 scans
(30-s intervals) at a gain of 1 and a resolution of 4 or 8. The probe
was inserted through a nylon adapter and O-ring seal into an oven-
dried, cylindrical flask fitted with a magnetic stir bar and T-joint.
The T-joint was capped with a septum for injections and an argon
line. After evacuation under full vacuum and flushing with argon,
the flask was charged with the reagents via syringe.
3
9
metalation of, or 1,2-addition to, the cinnamyl ether moiety.
By contrast, LiHMDS/Et3N-mediated enolization affords 15
rapidly and selectively. Subsequent rearrangement proceeded
in good yield and exceptional selectivity.
A distinct benefit of the Ireland-Claisen rearrangement is
that it is slow enough to allow us to readily monitor reaction
rates. We found that Et3N-solvated enolates rearrange ap-
proximately 20 times faster than the analogous THF solvates,
Representative Enolization. A 5 mL serum vial was charged
with a solution of LiHMDS (50 mg, 0.30 mmol) in Et N (420 µL,
3
3
3
and there is evidence of autocatalysis. We are likely to
examine Ireland-Claisen rearrangements in more detail later.
On the Role of Solvent Mixtures. There are Very few
ligandssprobably far fewer than most organic chemists
3
.0 mmol) and toluene (1.53 mL) and cooled to -78 °C. Ketone 5
(12 µL, 0.10 mmol) in toluene (38 µL) was added with stirring.
After 20 min, the reaction was quenched with 180 µL of a 4:1
solution of Me
toluene (3.0 mL). After warming to RT, dilution with pentane, and
quenching with cold aqueous NaHCO , the solution was subjected
3 3 3
SiCl/Et N (centrifuged free of solid Et N-HCl) in
1,20
realizesthat can displace THF from lithium. When an enolate
is generated in THF, the subsequent reaction is necessarily THF
dependent in most instances. By contrast, highly hindered
trialkylamines are substitutionally labile, potentially allowing
many ligands to coordinate and influence subsequent reactions.
Although substituting THF for Et3N in a few instances described
herein did not offer obvious benefits, the principle is an
important one. Organolithium intermediates generated in poorly
coordinating solVents are especially well suited for subsequent
ligand substitutions. If Et3N and the electrophile are incompat-
ible (alkyl halides, for example), highly hindered dialkylethers
3
to a standard aqueous workup. The crude enol silyl ethers E-6 and
9
Z-6 were analyzed by GC as described previously.
Representative Aldol Condensation. The enolate solution
prepared as described above was quenched with isobutyraldehyde
(
27 µL, 0.30 mmol). After an additional 10 min at -78 °C and
quenching with aqueous NH Cl, a standard aqueous workup
4
afforded a crude mixture of adducts anti-13 and syn-13 in 25:1
ratio as shown by GC. Flash chromatography afforded pure anti-
13 in 72% yield as shown by comparison with previously reported
3
0
spectroscopic data.
Ireland-Claisen Rearrangement. A solution of enolate in Et N
3
d
3
may suffice.
41
(
1.5 M)/toluene was prepared at -78 °C as described above. The
Conclusion
sample was slowly warmed to RT to allow the rearrangement to
proceed. After 10 min at RT, the reaction mixture was poured into
LiHMDS/Et3N offers a particularly convenient, cost-effective
protocol for generating lithium enolates with the highest E
selectivity reported to date. The Et3N-solvated enolates are also
1
0 mL of 5% aqueous NaOH and washed with ether. The aqueous
layer was cooled to 0 °C and acidified with concentrated HCl, and
(
40) LiHMDS dimers solvated by hindered ethers were shown to enolize
3d
(
(
38) Romesberg, F. E.; Collum, D. B. J. Am. Chem. Soc. 1995, 117, 2166.
39) (a) Mukaiyama, T.; Hayashi, H.; Miwa, T.; Narasaka, K. Chem. Lett.
ketone 1 via a dimer-based mechanism analogous to 3.
(41) LiHMDS/Et3N mixtures were used inadvertently by Murai and co-
workers when they carried out LiHMDS/toluene-mediated enolizations
1
982, 1637. (b) Conor, S. B.; Simpkins, N. S. Tetrahedron Lett. 2007,
6
4
8, 8192.
with a Et3N/Me2SiCl2 in situ trap.
J. AM. CHEM. SOC. 9 VOL. 130, NO. 27, 2008 8731

A R T I C L E S
Godenschwager and Collum
the carboxylic acid was extracted with ether. The carboxylic acid
were discarded. The rate constant was determined using an
4
2
was converted to its methyl ester by adding distilled CH
2
N
2
at 0
unweighted, nonlinear least-squares fit to the function f (x) ) a
bx
°
C until a yellow color persisted. The resulting methyl esters were
e .
3
1
31
analyzed using GC to show a 35:1 mixture of 16 and 17. Flash
Acknowledgment. We thank the National Institutes of Health
for direct support of this work. We also thank Merck Research
Laboratories, Pfizer, Sanofi-Aventis, R. W. Johnson, Boehringer-
Ingelheim, Schering-Plough, and DuPont Pharmaceuticals for
indirect support.
chromatography afforded a 79% combined yield.
Kinetics. Rate constants were determined using a standard
protocol exemplified as follows: The IR cell described above was
charged with a solution of LiHMDS (167 mg, 1.00 mmol) in Et
3
N
(
2.09 mL, 1.5 M) and toluene (7.74 mL) and cooled to -78 °C.
After recording a background spectrum, ketone 5 (50 µL, 0.050
mmol, 0.005 M final concentration) was added neat with stirring.
IR spectra were recorded over 5 half-lives. To account for mixing
and temperature equilibration, spectra recorded in the first 1.0 min
Supporting Information Available: NMR spectra and rate
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
(
42) Black, T. H. Aldrichimica Acta 1983, 16 (1), 3.
JA800250Q
8
732 J. AM. CHEM. SOC. 9 VOL. 130, NO. 27, 2008