Alkali-metal-mediated zincation of anisole: Synthesis and structures of three instructive ortho-zincated complexes

Article abstract of DOI:10.1021/ja061898g

The new concept of alkali-metal-mediated zincation (AMMZ), formally a zinc-hydrogen exchange reaction but one that requires the participation of an alkali metal, is applied here to the alkyl aryl ether anisole, an important molecule for studying directed ortho-metalation (DoM) chemistry. Treating one molar equivalent of anisole with the lithium dialkyl-TMP zincate reagent [THF·Li(μ-TMP)(μ-^tBu)Zn(^tBu)] (1) in hexane solution affords the mono-ortho-zincated complex [THF·Li(μ-TMP)(μ-o-C₆H₄OMe)Zn(^tBu)] (2), which establishes that 1 functions as an alkyl base although previously it was regarded as an amido (TMP) base in other DoM applications. Treating two molar equivalents of anisole with 1, and increasing the reaction time, affords the bis-ortho-zincated complex [THF·Li(μ-TMP)(μ-o-C₆H₄OMe)Zn(o-C₆H₄OMe)] (3), which establishes that 1 can also function as a dual alkyl base. Omitting THF and rerunning the reaction with one or two molar equivalents of anisole affords [Ph(Me)O·Li(μ-TMP)(μ-o-C₆H₄OMe)Zn(^tBu)] (4), which remarkably contains a combination of neutral and ortho-deprotonated anisole ligands. On isolating crystalline 4 from solution and adding THF, it converts to 2 and then to 3 on further stirring of the solution, as determined by NMR studies. This fact, along with other observations, would suggest that a complex-induced proximity effect does not need to be invoked to explain the observed zincation of anisole. The crystal structures of 2-4 are presented, as are their ¹H, ¹³C, and ⁷Li NMR spectra recorded in C₆D₆ solution. Copyright

Full text of DOI:10.1021/ja061898g

Published on Web 05/20/2006
Alkali-Metal-Mediated Zincation of Anisole: Synthesis and Structures of
Three Instructive Ortho-Zincated Complexes
William Clegg,† Sophie H. Dale,† Allison M. Drummond,‡ Eva Hevia,‡ Gordon W. Honeyman,‡ and
Robert E. Mulvey*,‡
WestCHEM, Department of Pure and Applied Chemistry, UniVersity of Strathclyde, Glasgow G1 1XL, U.K., and
School of Natural Sciences (Chemistry), UniVersity of Newcastle, Newcastle upon Tyne NE1 7RU, U.K.
Received March 20, 2006; E-mail: r.e.mulvey@strath.ac.uk
Scheme 1. Lithium-Mediated Zincation Reactions of Anisole with
[(i), (ii)] and without [(iii)] the Presence of THF
Anisole has been a key molecule in both the practical and
theoretical development of directed ortho-metalation (DoM) chem-
istry.1 Historically, it was pioneering lithiations of anisole by
Gilman2 and by Wittig3 that sowed the seeds of this ever-blossoming
synthetic methodology, which arguably has now outgrown classic
aromatic electrophilic substitution as the most powerful method
for regioselective functionalization of aromatic rings.4 The lithiation
of anisole has been studied using NMR spectroscopy,5 semiem-
pirical calculations,5,6 kinetic isotope effects,7 and X-ray crystal-
lography.8 Especially noteworthy are the rate studies by Collum9
which show that methoxy-lithium dative interactions are negligible
in the rate-limiting transition structure, thus suggesting that the
acidifying inductive effect of the methoxy substituent is more
important than the complex-induced proximity effect (CIPE)10 in
directing the metalation. We describe here the first study in which
the new concept of alkali-metal-mediated zincation (AMMZ)11 is
applied to anisole. This study establishes that anisole can be ortho-
zincated by AMMZ. Furthermore, due to stabilization of the ortho-
deprotonated anisole anion by the mixed-metal cation, ortho-
zincated “intermediates” can be isolated from solution, permitting
their crystallographic and spectroscopic characterization. Three such
intermediates, demonstrating explicitly the ligand transfer selectiv-
ity, stoichiometric dependence, and solvent dependence of the
AMMZ process, are described, thus providing collectively a
structural study of the metalation of anisole of unprecedented clarity.
First introduced by Kondo and Uchiyama in 1999,12 lithium di-
tert-butyltetramethylpiperidinozincate (1) was employed as the
AMMZ reagent. We chose 1 because of its track record in effecting
DoM (for example, of alkyl benzoates)12 and because its crystal
structure, formulated as [THF‚Li(µ-TMP)(µ-tBu)Zn(tBu)], has
recently been determined,13 thus providing a structural foundation
from which subsequent reactions can be monitored. Scheme 1
summarizes the reactions investigated. Adapting the original Kondo/
Uchiyama preparation of 1 by replacing the bulk solvent THF with
hexane to which was added sequentially a single stoichiometric
amount of THF and one molar equivalent of anisole [pathway (i)]
afforded crystals of [THF‚Li(µ-TMP)(µ-o-C6H4OMe)Zn(tBu)] (2),
with the coproduct being tert-butane gas. These crystals were
characterized by 1H/13C/7Li NMR spectroscopy14 and X-ray crystal-
lography (see below).14
surprising. This switch appears to be activated by changing the bulk
reaction solvent from THF to hexane. In 2 the tBu bridge is replaced
by an ortho-deprotonated anisole fragment, with two potentially
t
basic ligands, a TMP and a terminal Bu, remaining on zinc. This
led us to ponder the question, “Could 1 also function as a dibasic
reagent?” Accordingly, the reaction was repeated but with two molar
equivalents of anisole [pathway (ii)], and the reaction mixture
was stirred for a longer time. Also characterized spectroscopic-
ally and crystallographically, the product was the bis(ortho-
deprotonated anisole) complex [THF‚Li(µ-TMP)(µ-o-C6H4OMe)-
Zn(o-C6H4OMe)] (3).14 In 3, TMP is again retained in its rigid
bridge disposition (corresponding Me resonances at 1.61/1.35 and
36.56/33.45 ppm), with two indistinguishable (on the NMR time
scale at room temperature) ortho-deprotonated anisole fragments
bound to Zn. Here, therefore, 1 functions as a stoichiometrically
efficient dialkyl reagent, subjecting two molecules of anisole to
ortho-metalation (t-BuH is also produced), whereas with the afore-
mentioned other substrates it had functioned as a TMP base and
was usually employed in excess. The most surprising result came
when THF was omitted altogether [pathway (iii)]. As we have found
t
here that LiTMP and Bu2Zn require a donor solvent (either in a
stoichiometric amount or in bulk) to effect cocomplexation, we
introduced two molar equivalents of anisole to a LiTMP/tBu2Zn/
hexane mixture, reasoning that the ether might act as both a Lewis
base and a C-H acid. Remarkably, both features are exhibited
in the crystalline product [Ph(Me)O‚Li(µ-TMP)(µ-o-C6H4OMe)-
Zn(tBu)] (4), which has also been fully characterized.14 In this
reaction, reagent 1 again functions as a tBu base. As with 2 and 3,
the TMP Me groups in 4 are inequivalent (corresponding resonances
at 1.39/1.21 and 35.59/34.99 ppm). Note that 4 is also produced,
but in a smaller yield, when only one molar equivalent of anisole
is used. This implies that the rate of anisole metalation is faster
Noteworthy in the NMR data is the inequivalence of the R-Me
groups of the TMP ligand (at 1.61/1.56 ppm in the 1H spectrum; at
35.34/35.14 ppm in the 13C spectrum), indicative of a fixed,
stereochemically inflexible Li(µ-TMP)Zn bridge. In the previous
DoM reactions with a variety of aromatic and heteroaromatic
substrates, 1 functions as a TMP base,12,15 so the retention of TMP
within 2, concomitant with 1 switching to an alkyl basic mode, is
‡ University of Strathclyde.
† University of Newcastle.
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C O M M U N I C A T I O N S
deprotonated anisole ligands. In conventional organolithium chem-
istry, reactive intermediates of this type would normally be expected
to decompose long before ambient temperature was reached, but
the dual metal coordination, combined with the steric protection
of TMP and coligands, appears to enhance stabilization in these
heterometallic cases. Diluting this possibility of a CIPE, we note
that adding THF to 4 (isolated and then redissolved in hexane
solution) converts it to 2, which in turn leads to 3 on further stirring.
Hence, in agreement with Collum’s findings on the lithiation
reaction, it appears not to be necessary to invoke a CIPE to explain
this zincation of anisole, though a donor ligand is required to
generate the mixed-metal base.
To conclude, this study adds a new dimension to the use of 1 as
a reagent for deprotonative zincation. In establishing that it can
effect directed ortho-zincation of anisole, the ability to tune the
reactivity of the reagent from a TMP base to a monoalkyl base or
a dialkyl base has been demonstrated. This exceptional versatility
for a single zincate reagent broadens significantly the potential scope
of utility of AMMZ in synthetic chemistry, especially considering
that both “R” alkyl groups, the R2N amide group and the alkali
metal cation, can also be interchanged and that auxiliary ligands
such as TMEDA (not used here, but proving effective in sodium
zincate reactions)16 can be introduced.
Figure 1. Molecular structure of 2 with 30% probability displacement
ellipsoids. H atoms have been omitted for clarity.
Acknowledgment. We thank the EPSRC (Grant Award Nos.
GR/T27228/01 and GR/R81183/01) and the Royal Society/Lever-
hulme Trust (Fellowship to R.E.M.) for generously sponsoring this
research.
Supporting Information Available: Full experimental details and
crystallographic data for 2-4 (PDF, CIF). This material is available
free of charge via the Internet at http://pubs.acs.org
Figure 2. Molecular structure of 3 with 30% probability displacement
ellipsoids. H atoms have been omitted for clarity.
References
(1) For key reviews of DoM, see: (a) Anctil, E.; Snieckus, V. The Directed
ortho Metalation-Cross Coupling Nexus. Synthetic Methodology for Aryl-
Aryl and Aryl-Heteroatom-Aryl Bonds. In Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed.; Diederich, F., de Meijere, A., Eds.; Wiley-
VCH: Weinheim, 2004; pp 761-813. (b) Hartung, C. G.; Snieckus, V.
The Directed ortho Metalation Reaction. A Point of Departure for New
Synthetic Aromatic Chemistry. In Modern Arene Chemistry; Astruc, D.,
Ed.; Wiley-VCH: New York, 2002; pp 330-367. (c) Gschwend, H. W.;
Rodriguez, H. R. Org. React. 1979, 26, 1-360.
(2) Gilman, H.; Bebb, R. L. J. Am. Chem. Soc. 1939, 61, 109.
(3) Wittig, G.; Fuhrman, G. Chem. Ber. 1940, 73, 1197.
(4) Clayden, J. Organolithiums: SelectiVity for Synthesis; Pergamon/Elsevier
Science Ltd.: Oxford, U.K., 2002.
(5) Bauer, W.; Schleyer, P. v. R. J. Am. Chem. Soc. 1989, 111, 7191.
(6) Saa`, J. M.; Deya`, P. M.; Suner, G. A.; Frontera, A. J. Am. Chem. Soc.
1992, 114, 9093.
Figure 3. Molecular structure of 4 with 30% probability displacement
ellipsoids. H atoms have been omitted for clarity.
(7) Stratakis, M. J. Org. Chem. 1997, 62, 3024.
(8) Harder, S.; Boersma, J.; Brandsma, L.; Kanters, J. A. J. Organomet. Chem.
1988, 339, 7.
(9) (a) Rennels, R. A.; Maliakal, A. J.; Collum, D. B. J. Am. Chem. Soc.
1998, 120, 421. (b) Chadwick, S. T.; Rennels, R. A.; Rutherford, J. L.;
Collum, D. B. J. Am. Chem. Soc. 2000, 122, 8640.
than the rate of formation of the mixed-metal reagent, presumably
[anisole‚Li(µ-TMP)(µ-tBu)Zn(tBu)], and that this intermediate, once
formed, reacts with non-coordinated anisole to generate 4.
Linking Li to Zn through a mixed TMP-ortho-deprotonated
anisole ligand set, a six-membered (LiNZnCCO) ring is common
to the molecular structures of 2-4 (Figures 1-3, respectively).14
The trigonal planar Zn coordination is completed in 2 and 4 by a
(10) For an authoritative review, see: Whisler, M. C.; MacNeil, S.; Snieckus,
V.; Beak, P. Angew. Chem., Int. Ed. 2004, 43, 2206.
(11) Mulvey, R. E. Organometallics 2006, 25, 1060.
(12) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am. Chem. Soc.
1999, 121, 3539.
(13) (a) Clegg, W.; Dale, S. H.; Hevia, E.; Honeyman, G. W.; Mulvey, R. E.
Angew. Chem., Int. Ed. 2006, 45, 2370. (b) Clegg, W.; Dale, S. H.;
Harrington, R. W.; Hevia, E.; Honeyman, G. W.; Mulvey, R. E. Angew.
Chem., Int. Ed. 2006, 45, 2374.
(14) For full experimental details and X-ray crystallographic data, see the
Supporting Information.
(15) Imahori, T.; Uchiyama, M.; Sakamoto, T.; Kondo, Y. Chem. Commun.
2001, 2450.
(16) Andrikopoulos, P.; Armstrong, D. R.; Barley, H. R. L.; Clegg, W.; Dale,
S. H.; Hevia, E.; Honeyman, G. W.; Kennedy, A. R.; Mulvey, R. E. J.
Am. Chem. Soc. 2005, 127, 6184.
t
terminal Bu ligand, and in 3 by a terminal ortho-deprotonated
anisole ligand. The Li coordination is also trigonal planar, with
the terminal sites filled by THF in 2 and 3 and by a neutral anisole
ligand in 4. Formally, complex 4, with one non-deprotonated anisole
O-ligated to Li and one deprotonated anisole, can be considered a
pre-metalation complex (in a CIPE sense),10 or at least a key
intermediate in the reaction pathway to complex 3 with its two
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