Lithium diisopropylamide-mediated ortholithiations: Lithium chloride catalysis

Article abstract of DOI:10.1021/jo802713y

Ortholithiations of a range of arenes mediated by lithium diisopropylamide (LDA) in THF at -78 °C reveal substantial accelerations by as little as 0.5 mol % of LiCl (relative to LDA). Substrate dependencies suggest a specific range of reactivity within wh

Full text of DOI:10.1021/jo802713y

added LiCl was generated in situ from recrystallized
Et3N·HCl.10 The Et3N byproduct is a poor ligand11 that has no
effect on the ortholithiations.
Lithium Diisopropylamide-Mediated
Ortholithiations: Lithium Chloride Catalysis
Ortholithiations were monitored using in situ IR spectros-
copy12 following both the disappearance of the arene and the
formation of the resulting aryllithium.13 19F NMR spectroscopic
analysis provided comparable results in a number of instances.
Trapping experiments were consistent with lithiation but are
unreliable measures of the rates because they generate catalyti-
cally active lithium salts. Trimethylchlorosilane, for example,
generates LiCl,3c making LiCl-sensitive arene lithiations nearly
instantaneous.
Although some metalations display normal (exponential)
decays, autocatalysis14 arising from the aryllithiums was evident
in the form of linear and sigmoidal decays for many substrates
(Supporting Information). Consequently, the rates of uncatalyzed
ortholithiations are simply reported as half-lives (t1/2), and the
LiCl-mediated accelerations as the ratios of 1/t1/2 values with
and without added 0.5% LiCl (kLiCl).15 The approximation is
crude but adequate for our needs.
Lekha Gupta, Alexander C. Hoepker, Kanwal J. Singh, and
David B. Collum*
Department of Chemistry and Chemical Biology,
Baker Laboratory, Cornell UniVersity,
Ithaca, New York 14853-1301
dbc6@cornell.edu
ReceiVed December 10, 2008
Ortholithiations of a range of arenes mediated by lithium
diisopropylamide (LDA) in THF at -78 °C reveal substantial
accelerations by as little as 0.5 mol % of LiCl (relative to
LDA). Substrate dependencies suggest a specific range of
reactivity within which the LiCl catalysis is optimal. Standard
protocols with unpurified commercial samples of n-butyl-
lithium to prepare LDA or commercially available LDA
show marked batch-dependent ratessup to 100-foldsthat
could prove significant to the unwary practitioner. Other
lithium salts elicit more modest accelerations. The mecha-
nism is not discussed.
The results from LiCl-free and LiCl-catalyzed LDA-mediated
metalations are illustrated in Table 1. The accelerations reflected
by kLiCl values derive from adding only 0.5 mol % of LiCl.
Higher concentrations of LiCl produce greater accelerations
(resulting in immeasurably high rates in many instances.) The
substrates in Table 1 are ordered from the most reactive (small
t1/2) to the least reactive (large t1/2), revealing an interesting
(2) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624. (b) Seebach,
D. In Proceedings of the Robert A. Welch Foundation Conferences on Chemistry
and Biochemistry; Wiley: New York, 1984. (c) Tchoubar, B.; Loupy, A. Salt
Effects in Organic and Organometallic Chemistry; VCH Publishers: New York,
1992; Chapters 4, 5, and 7. (d) Caube`re, P. Chem. ReV. 1993, 93, 2317. (e)
Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.; Mukhopadhyay, T.; Simson, M.;
Seebach, D. Synthesis 1993, 1271.
(3) (a) Kummer, D. A.; Chain, W. J.; Morales, M. R.; Quiroga, O.; Myers,
A. G. J. Am. Chem. Soc. 2008, 130, 13231. (b) Galiano-Roth, A. S.; Kim, Y.-J.;
Gilchrist, J. H.; Harrison, A. T.; Fuller, D. J.; Collum, D. B. J. Am. Chem. Soc.
1991, 113, 5053. (c) Lipshutz, B. H.; Wood, M. R.; Lindsley, C. W. Tetrahedron
Lett. 1995, 36, 4385. (d) Dyke, A. M.; Gill, D. M.; Harvey, J. N.; Hester, A. J.;
Lloyd-Jones, G. C.; Munoz, M. P.; Shepperson, I. R. Angew. Chem., Int. Ed.
2008, 47, 5067. (e) Cottet, F.; Schlosser, M. Eur. J. Org. Chem. 2004, 3793.
(4) For beneficial effects of other lithium salts on ortholithiation, see: Cottet,
F.; Schlosser, M. Eur. J. Org. Chem. 2004, 3793.
(5) (a) Bakker, W. I. I.; Wong, P. L.; Snieckus, V. Lithium Diisopropylamide.
In e-EROS; Paquette, L. A., Ed.; John Wiley & Sons: New York, 2001. (b)
Clayden, J. Organolithiums: SelectiVity for Synthesis; Baldwin, J. E., Williams,
R. M., Eds.; Pergamon: New York, 2002.
We report herein lithium diisopropylamide (LDA)-mediated
ortholithiations1 that are markedly accelerated by LiCl (eq 1).
Beneficial effects of LiCl on the chemistry of LDA and other
organolithium reactions have been documented.2-4 Nevertheless,
the magnitudes of these accelerations of ortholithiation are
striking and the implications in synthesis are potentially
significant.
(6) Rennels, R. A.; Maliakal, A. J.; Collum, D. B. J. Am. Chem. Soc. 1998,
120, 421.
(7) Kim, Y.-J.; Bernstein, M. P.; Galiano-Roth, A. S.; Romesberg, F. E.;
Fuller, D. J.; Harrison, A. T.; Collum, D. B.; Williard, P. G. J. Org. Chem.
1991, 56, 4435.
(8) Evans, A. Potentiometry and Ion-SelectiVe Electrodes; Wiley: New York,
We preface the results with several comments about protocol.
Most investigators either purchase LDA as a THF solvate or
prepare it in situ from commercially available n-BuLi.5 The
implications of these procedures are discussed below. The LDA
used in this study was prepared from recrystallized n-BuLi,6
further recrystallized from hexane,7 and shown to contain
<0.02% LiCl by potentiometry8 and ion chromatography.9 The
1987.
(9) Dasgupta, D. K. Anal. Chem. 1992, 64, 775A.
(10) (a) Snaith and co-workers clearly articulated the merits of NH4X salts
as precursors to anhydrous LiX salts: Barr, D.; Snaith, R.; Wright, D. S.; Mulvey,
R. E.; Wade, K. J. Am. Chem. Soc. 1987, 109, 7891. Also, see: (b) Hall, P. L.;
Gilchrist, J. H.; Collum, D. B. J. Am. Chem. Soc. 1991, 113, 9571.
(11) Zhao, P.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 14411.
(12) Rein, A. J.; Donahue, S. M.; Pavlosky, M. A. Curr. Opin. Drug
DiscoVery DeV. 2000, 3, 734.
(13) Weymeels, E.; Awad, H.; Bischoff, L.; Mongin, F.; Tre´court, F.;
Que´guiner, G.; Marsais, F. Tetrahedron 2005, 61, 3245.
(14) Singh, K. J.; Hoepker, A. C.; Collum, D. B. J. Am. Chem. Soc. 2008,
130, 18008.
(1) (a) Hartung, C. G.; Snieckus, V. In Modern Arene Chemistry; Astruc,
D., Ed.; Wiley-VCH: Weinheim, Germany, 2002; Chapter 10. (b) Snieckus, V.
Chem. ReV. 1990, 90, 879. (c) Schlosser, M.; Mongin, F. Chem. Soc. ReV. 2007,
36, 1161. (d) Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4059.
(15) We define kLiCl ) t1/2(no LiCl)/t1/2(0.5% LiCl).
10.1021/jo802713y CCC: $40.75
Published on Web 02/04/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2231–2233 2231

slowest (t1/2 > 105 s) metalations are relatively insensitive to
external LiCl.
TABLE 1. Rates of Lithium Diisopropylamide-Mediated
Ortholithiations (Eq 1) Listed in Order of Decreasing Reactivity
We draw the readers attention to entry 8, which does not
follow the pattern. Notably, increasing the LiCl concentration
to 10 mol % has no effect. In short, a kLiCl of 2 appears to be
within the experimental error of unity. But why is entry 8
aberrant? Curiously, the LiCl-sensitive ortholithiations involve
substrates containing halogen-based directing groups (F, Cl, or
CF3). Similarly, the ortholithiation in entry 3 shows only a
marginal increase in kLiCl with larger aliquots of LiCl. This result
may foreshadow conclusions from ongoing mechanistic studies.
It would be especially provocative if the accelerations elicited
significant changes in regioselectivity. Schlosser, for example,
noted advantageous regiochemical effects of a brew containing
both i-Pr2NCOOLi and catalytic LiBr.4 Metalations of 1 and 2,
however, reveal strong LiCl catalysis, but the regioselectivities
(indicated by the arrows) remain unchanged, as expected for
reversible metalations.4,16,17
Using standard protocols in which the LDA is unpurified,
we observed >102-fold swings in the reaction rate depending
on the commercial source of the n-BuLi or LDA. These
variations were not supplier dependent per se, but rather batch
dependent. A statistically marginal sampling suggests that
commercially available LDA may have a lower LiCl titer and
be less prone to inadvertent accelerations compared to LDA
generated from commercial n-BuLi. Lloyd-Jones noted batch
dependencies of aryl triflate metalations that appeared to stem
from lithium halides.3d Nonetheless, the variations were enor-
mous, inspiring us to repeat a timeless maxim: buyer beware.
Cursory investigation of the influence of other lithium salts
(10 mol %) revealed the accelerations illustrated in eq 2. Clearly,
LiCl is the most efficient catalyst.
We have explicitly deferred mechanistic speculation. The
dramatic LiCl-mediated accelerations do, however, appear to
correlate with arene metalations that are also prone to autoca-
talysis.14
In conclusion, LDA/THF/-78 °C-mediated ortholithiations
are anomalous in many respects, 14 including a marked penchant
for LiCl catalysis. The catalysis is observed in a narrow but
potentially consequential window. Unsuspecting academic
a Measured at -78 °C unless otherwise noted.
pattern: Substrates of intermediate reactivity are most prone to
catalysis. Both the fastest metalations (t1/2 < 200 s) and the
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bar and a T-joint. The T-joint was capped by a septum for injections
and a nitrogen line. After evacuation under full vacuum, heating,
and flushing with nitrogen, the flask was charged with LDA (129
mg, 1.20 mmol) in THF and cooled in a dry ice-acetone bath
prepared from fresh acetone. LiCl (0.5 mol % relative to LDA)
was added as a stock solution (0.50 mL) containing Et3N·HCl (8.3
mg, 0.06 mmol) and LDA (13.5 mg, 0.12 mmol) in 5 mL of THF.
After recording a background spectrum, we added an arene (1.0
mmol) with stirring. IR spectra were recorded over the course of
the reaction. Absorbances corresponding to the arene moieties
(1350-1650 cm-1) were monitored in most cases. Spectra were
recorded every 3 s.
chemists may have detected irregularitiessbatch dependenciess
that proved a source of annoyance. The results suggest op-
portunities to optimize protocols. We believe, however, that
industrial chemists should be especially wary of these results.
Rate variations that go undetected on small scales could give
way to unexpected and potentially costly variations on process
and plant scales. Our advice to both communities is the same:
try adding a few mole percent of Et3N·HCl to LDA at the outset.
Experimental Section
Reagents and Solvents. THF and hexane were distilled from
blue or purple solutions containing sodium benzophenone ketyl.
The hexane contained 1% tetraglyme to dissolve the ketyl. Both
n-BuLi and LDA were recrystallized.6,7 Solutions of n-BuLi and
LDA were titrated using a literature method.18 Arenes were either
commercially available or prepared via literature protocols.19
Et3N·HCl was recrystallized from THF/2-propanol.
IR Spectroscopic Analyses. Spectra were recorded using an in
situ IR spectrometer fitted with a 30-bounce, silicon-tipped probe.
The spectra were acquired in 16 scans at a gain of 1 and a resolution
of 4 cm-1. A representative reaction was carried out as follows:
The IR probe was inserted through a nylon adapter and O-ring seal
into an oven-dried, cylindrical flask fitted with a magnetic stir
Acknowledgment. We thank the National Institutes of Health
(GM39764) for direct support of this work and Pfizer, Boe-
hringer-Ingelheim, and Sanofi-Aventis for indirect support.
Supporting Information Available: Spectroscopic data, rate
data, and select experimental procedures including LiCl titration
protocols. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO802713Y
(18) Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41, 1879.
(19) Arene preparations: (a) Table 1, entries 2, 3, 14, 15, and compound 2:
Lustig, E.; Benson, W. R.; Duy, N. J. Org. Chem. 1967, 32, 851. Yamagami,
C.; Takao, N.; Nishioka, T.; Fujita, T.; Takeuchi, Y. Org. Magn. Reson. 1984,
22, 439. (b) Table 1, entry 7: Newman, M. S.; Kannan, R. J. Org. Chem. 1979,
44, 3388. (c) Table 1, entry 8: Tsukazaki, M.; Snieckus, V. Can. J. Chem. 1992,
70, 1486. (d) Table 1, entry 17: Harris, T. D.; Neuschwander, B.; Boekelheide,
V. J. Org. Chem. 1978, 43, 727.
(16) (a) The regioselectivity for 2 is assigned based on a marked upfield
shift of the 19F resonance in one isomer but not the other. The regioselectivity
in 1 is based on a literature report: (b) Dabrowski, M.; Kubicka, J.; Lulinski, S.;
Serwatowski, Tetrahedron Lett. 2005, 46, 4175.
(17) Trecourt, F.; Mallet, M.; Marsais, F.; Queguiner, G. J. Org. Chem. 1988,
53, 1367.
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