On the Mechanism of the Ortho-Directed Metalation of Anisole by n-Butyllithium

Full text of DOI:10.1021/jo962418e

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J . Org. Chem. 1997, 62, 3024-3025
Sch em e 1
On th e Mech a n ism of th e Or th o-Dir ected
Meta la tion of An isole by n -Bu tyllith iu m †
Manolis Stratakis1
Department of Chemistry, University of Crete,
Iraklion 71409, Greece
Received December 30, 1996 (Revised Manuscript Received
March 17, 1997)
The ortho-directed metalation of arenes2 bearing an
appropriate directing group (DMG), by alkyllithiums or
lithium amides, is a powerful method for achieving a
variety of functionalizations on the phenyl ring. Addition
of stoichiometric amounts of N,N,N′,N′-tetramethyleth-
ylenediamine (TMEDA) in hexane or ether increases both
reaction rates and yields. Although TMEDA is fre-
quently used as a cosolvent in metalations, its tendency
to chelate lithium in the presence of THFsespecially in
the case of lithium amidesshas been questioned by
Collum.3 Beak has proposed that complexation of the
alkyllithiums with the DMG (“complex induced proximity
effects”)2c,4 is the key feature of the metalation reactions.
On the other hand, Schleyer considered the term “kineti-
cally enhanced metalation”, proposing that directing and
activating effects are transition-state phenomena.5
The ortho-metalation of anisole was discovered by
Wittig6 and Gilman7 independently almost 60 years ago.
The yield of the reaction is remarkably high, especially
with the aid of several additive cosolvents.8 Roberts and
Curtin were the first to suggest9 that complexation of the
alkyllithium to the methoxy group facilitates ortho-proton
removal. Bauer and Schleyer,10 using 1D and 2D het-
eronuclear NMR, provided direct spectroscopic evidence
for the formation of an intermediate cubic aggregate
between anisole and n-BuLi upon mixing in toluene-d8
at -64 °C. The mixed aggregate does not give any
further reaction even on prolonged standing. However,
addition of 1 equiv of TMEDA causes the immediate
liberation of “free” anisole, while dimeric n-BuLi solvated
by TMEDA is formed. Under these conditions, o-anisyl-
lithium can be gradually formed. It was suggested that
dimeric n-BuLi partly solvated by anisole leads to the
product (Scheme 1). The proposed mechanism was also
supported by MNDO calculations.
Similar theoretical calculations and experimental ob-
servations by Saa11 and co-workers in the ortho-directed
metalations of phenol, naphthols, and 1,3-disubstituted
heteroaromatics indicated the significance of agostic
hydrogen-metal interactions in the intermediate com-
plexes.
Slocum and co-workers12 found that even incremental
amounts of TMEDA in diethyl ether (0.2 equiv per
alkyllithium) can cause a significant rate acceleration
and suggested a predictive model for the ortho-metala-
tion. According to that model, formation of a complex
between anisole and n-BuLi in ether occurs in the rate-
determining step, followed by a faster metal-hydrogen
exchange. Complex formation is necessary to reduce the
tendency of methoxy group to delocalize, thus increasing
the acidity of the ortho-protons. In the presence of
TMEDA, coordination probably is not involved, and a
simple “overriding base” reacts rapidly with the relatively
acidic ortho protons.
In order to shed some light on the mechanistic dis-
crepancy of the ortho-directed metalation, we report in
this paper an isotope effect study in the lithiation of
anisole by n-BuLi in diethyl ether with or without added
TMEDA (Scheme 2). The combination13 of intra- and
intermolecular isotope effects is a powerful tool for
distinguishing between stepwise and concerted reaction
mechanisms. Recently, by applying this combination, it
was found that the metalation of a benzylic urea14 by
s-BuLi/TMEDA proceeds through the prior formation of
an alkyllithium-urea complex in the rate-determining
step.
† Dedicated to Professor Andrew Streitwieser on the occasion of his
70th birthday.
(1) Permanent address after summer 1997: Department of Natural
Sciences, University of Cyprus, Nicosia 1678, Cyprus.
(2) (a) Beak, P.; Snieckus, V. Acc. Chem. Res. 1982, 15, 306-15. (b)
Narasimhan, N. S.; Mali, R. S. Synthesis 1983, 957-86. (c) Beak, P.;
Meyers, A. I. Acc. Chem. Res. 1986, 19, 356-64. (d) Klumpp, G W. Recl.
Trav. Chim. Pays-Bas 1986, 105, 1-21. (e) Brandsma, L.; Verkuisjsse,
H. Preparative Polar Organometallic Chemistry; Springer: Berlin,
1987; Vol. I. (f) Snieckus, V. Chem. Rev. 1990, 90, 879-933. (g)
Qeuguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J . Adv. Heterocycl.
Chem. 1991, 52, 187-304.
Metalation of anisole-2-d15 was achieved by addition
of 0.5-2 equiv of n-BuLi.16 The anions were quenched
by TMSCl; the resulting 2-(trimethylsilyl)anisoles were
purified by preparative GC (SE-30, Tcol ) 120 °C) and
then analyzed by 1H NMR. The isotope effects found
(3) Collum, D. B. Acc. Chem. Res. 1992, 25, 448-54.
(4) (a) Hay, D.; Song, Z.; Smith, S. G.; Beak, P. J . Am. Chem. Soc.
1988, 110, 8145-53. (b) Warmus, J . S.; Rodkin, M. A.; Barkley, R.;
Meyers, A. I. J . Chem. Soc., Chem. Commun. 1993, 1357-59. (c) Beak,
P.; Kerrick, S. T.; Gallagher, D. J . J . Am. Chem. Soc. 1993, 115, 10628-
36.
(11) (a) Saa`, J . M.; Deya`, P. M.; Suner, G. A.; Frontera, A. J . Am.
Chem. Soc. 1992, 114, 9093-100. (b) Saa`, J . M.; Morey, J .; Frontera,
A.; Deya`, P. M. J . Am. Chem. Soc. 1995, 117, 1105-16. (c) Saa`, J . M.;
Martorell, G.; Frontera, A. J . Org. Chem. 1996, 61, 5194-95.
(12) (a) Slocum, D. W.; Moon, R.; Thompson, J .; Coffey, D. S.; Li, J .
D.; Slocum, M. G.; Siegel, A.; Gayton-Garcia, R. Tetrahedron Lett. 1994,
35, 385-88. (b) Slocum, D. W.; Thompson, J .; Friesen, C. Tetrahedron
Lett. 1995, 36, 8171-74.
(13) (a) Song, Z.; Beak, P. J . Am. Chem. Soc. 1990, 112, 8126-34.
(b) Orfanopoulos, M.; Smonou, I.; Foote, C. S. J . Am. Chem. Soc. 1990,
112, 3607-14.
(14) Resek, J . E.; Beak, P. J . Am. Chem. Soc. 1994, 116, 405-06.
(15) Anisole-2-d was prepared by quenching the Grignard reagent
of 2-bromoanisole with D2O. It was purified by distillation. M+ ) 109.
(16) The values of the intermolecular isotope effect are the same
when using 0.5, 1, 1.5, or 2 equiv of n-BuLi/TMEDA per 1 equiv of
anisole-2-d.
(5) (a) van Eikema-Hommes, N. J . R.; Schleyer, P. v. R. Angew.
Chem., Int. Ed. Engl. 1992, 31, 755-58. (b) van Eikema-Hommes, N.
J . R.; Schleyer, P. v. R. Tetrahedron 1994, 50, 5903-16. (c) Kremer,
T.; J unge, M.; Schleyer, P. v. R. Organometallics 1996, 15, 3345-59.
(6) Wittig, G.; Fuhrmann, G. Chem. Ber. 1940, 73, 1197-218.
(7) Gilman, H.; Bebb, R. L. J . Am. Chem. Soc. 1939, 61, 109-12.
(8) For the highest yield ever observed (80%), using a 1/1 mixture
of n-BuLi/anisole in a solution containing 14% (v/v) THF in hexane,
see: Slocum, D. W.; Reed, D.; J ackson, F., III; Friesen, C. J . Organomet.
Chem. 1996, 512, 265-67. Higher yields (>95%) have been achieved
by using 2 equiv of n-BuLi/TMEDA in ether (ref 12a).
(9) Roberts, J . D.; Curtin, D. Y. J . Am. Chem. Soc. 1946, 68, 1658-
60.
(10) Bauer, W.; Schleyer, P. v. R. J . Am. Chem. Soc. 1989, 111,
7191-98.
S0022-3263(96)02418-8 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 10, 1997 3025
Sch em e 2
isotope effects are also in accordance with a single-step
mechanism where a highly reactive low n-BuLi aggregate
that is formed by the action of TMEDA deprotonates
anisole without any precoordination as postulated
earlier.12a It is difficult to distinguish between the two
mechanisms on the basis of the kinetic isotope effects.
In neat diethyl ether, n-butyllithium exists as a tet-
ramer.18 According to the isotope effects found in this
solvent, we propose the following mechanistic possibili-
ties: (i) Products are formed in a slow step via a
transition state achieved from an intermediate containing
n-BuLi and anisole. The intermediate may be either a
tetrameric or a dimeric aggregate. In both cases, the rate
of the reaction is expected to be significantly retarded
as occurs, indeed because in the transition state of
hydrogen abstraction achieved through the tetrameric
aggregate severe steric repulsions are existing or, on the
other hand, the concentration of a reactive dimeric
aggregate19 is expected to be very low. (ii) The possibility
that no precomplexation occurs and deprotonation occurs
in a single step cannot be ruled out. Although further
experimental work is neccesary to delineate the meta-
lation mechanism in neat ether, it is clear that a
previously proposed mechanism12a (formation of an in-
termediate complex in the rate-limiting step) is not
consonant with the observed isotope effects.
are kH/kD ) 2.3 ( 0.1 in ether (in a typical experiment
using 1.5 equiv of base per 1 equiv of anisole, conversion
to products was achieved in 50% yield after 16 h) and
kH/kD ) 3.1 ( 0.1 in the presence of TMEDA (95%
conversion in 20 min using again 1.5 equiv of n-BuLi).
In all experiments, the amount of added TMEDA was
equimolar with respect to the amount of base.
In conclusion, it is important to emphasize that the
current results neither require nor exclude the existence
of a preequilibrium complex. They establish the abstrac-
tion of hydrogen as the rate-determining step and are
consistent with transition-state phenomena, as predicted
by theoretical calculations.5
The intermolecular isotope effects17 in neat ether (kH/
kD ) 2.5 ( 0.2) and in ether with added TMEDA (kH/kD
) 3.2 ( 0.2) are identical within experimental error, to
the intramolecular isotope effects in the same solvent
systems. This indicates that the ortho-hydrogen abstrac-
tion of anisole by the base in both cases occurs in the
rate-determining step.
For the case of added TMEDA in ether, if we assume
that the dimeric intermediate complex between anisole
and n-BuLi exists,10 its formation undoubtedly occurs in
a faster step compared to the step leading to the forma-
tion of the o-anisyllithium. The activation energy for its
formation must be substantially lower compared to the
second deprotonation step; otherwise, a significant de-
crease in the overall calculated isotope effect would be
expected.13a The identical intra- and intermolecular
Ack n ow led gm en t. The author is grateful to Profes-
sors G. J . Karabatsos and M. Orfanopoulos for valuable
discussions and comments and to Professor M. Orfan-
opoulos for a generous hospitality in his laboratory.
Su p p or tin g In for m a tion Ava ila ble: Copies of proton
NMR spectra (9 pages).
J O962418E
(18) Bergander, K.; He, R.; Chandrakumar, N.; Eppers, O.; Gu¨nther,
H. Tetrahedron 1994, 50, 5861-68.
(19) The possibility that the reactive intermediate is a dimeric
aggregate, despite the fact that n-BuLi in ether is a tetramer, cannot
be excluded. Athough most of the organoalkali compounds exist as high
aggregates, usually many of their reactions proceed through spectro-
scopically undetectable lower aggregates or even monomers. For some
representative examples, see: (a) Waack, R.; Doran, M. A. J . Am.
Chem. Soc. 1969, 91, 2456-61. (b) McGarrity, J . F.; Ogle, C. A.; Brich,
Z.; Loosli, H.-R. J . Am. Chem. Soc. 1985, 107, 1810-15. (c) Galiano-
Roth, A. S.; Collum, D. B. J . Am. Chem. Soc. 1989, 111, 6772-80. (d)
Abu-Hasanayn, F.; Stratakis, M.; Streitwieser, A. J . Org. Chem. 1995,
60, 4688-89. (f) Abu-Hasanayn, F.; Streitwieser, A. J . Am. Chem. Soc.
1996, 118, 8136-37.
(17) Anisole-d5 was prepared by methylation of the Na salt of phenol-
d6 (Aldrich, 99% D) with dimethylsulfate. M+ ) 113. Kinetic competi-
tion between anisole-d0 versus anisole-d5 was accomplished by adding
a limited amount of n-BuLi to an equimolar mixture of anisoles-d0 and
-d5 (20-25% conversion to the trimethylsilyl adducts). The observed
values of the intramolecular isotope effects were also obtained, in
addition to 1H NMR integration, by GC analysis of the reaction mixture
on a 5% phenyl methyl silicone capillary column, where anisole-d0 and
anisole-d5 have different retention times.