Ni-catalyzed reduction of inert C-O bonds: A new strategy for using aryl ethers as easily removable directing groups

Article abstract of DOI:10.1021/ja106943q

An efficient Ni-catalyzed protocol for the reductive cleavage of inert C-O bonds has been developed. The method is characterized by its simplicity and wide scope, thereby allowing the use of aryl ethers as easily removable directing groups in organic synthesis.

Full text of DOI:10.1021/ja106943q

Published on Web 09/15/2010
Ni-Catalyzed Reduction of Inert C-O Bonds: A New Strategy for Using Aryl
Ethers as Easily Removable Directing Groups
´
Paula Alvarez-Bercedo and Ruben Martin*
Institute of Chemical Research of Catalonia (ICIQ), AV. Pa¨ısos Catalans 16, 43007, Tarragona, Spain
Received August 3, 2010; E-mail: rmartinromo@iciq.es
outcome. Indeed, the use of ethoxy, acetoxy, mesylate, tosylate, or
Abstract: An efficient Ni-catalyzed protocol for the reductive
cleavage of inert C-O bonds has been developed. The method
is characterized by its simplicity and wide scope, thereby allowing
the use of aryl ethers as easily removable directing groups in
organic synthesis.
pivalate groups gave lower conversions to products, thus indicating
the subtleties of our catalyst system.15 At present we do not have
an explanation for this marked difference in reactivity.
Table 1. Ni-Catalyzed Reductive Cleavage of Aryl Methyl Ethersa b
,
The pivotal role of aryl ethers as synthetic intermediates has
attracted the attention of chemists for decades. The utility of methyl
aryl ethers is mainly attributed to their ability to act as directing
groups, thus maximizing the reactivity and selectivity of a wide
variety of transformations such as ortho-metalation,1 electrophilic
aromatic substitution,2 or Friedel-Crafts-type reactions,3 among
others (Scheme 1, path a).4 Despite the attractiveness of directing
groups in organic synthesis, however, their selective cleavage still
constitutes a tremendous challenge.5 Ideally, catalytic techniques
that could readily replace the C-O bond of readily available methyl
aryl ethers by hydrogen6 would be highly desirable (Scheme 1,
path b), thus constituting a powerful alternative for arene func-
tionalization as electronically unbiased arenes often lead to unse-
lective chemical processes (Scheme 1, path c).7
Scheme 1
Prompted by the seminal work of Wenkert,8 recent studies have
demonstrated the formidable potential of aryl ethers in catalytic
C-C and C-N bond-forming reactions.9 Despite the advances
realized, these methods are still at their infancy compared with the
use of aryl halides as substrates. As part of our program aimed at
activating inert molecules,10 we present herein the first catalytic
reductive cleavage of inert C-O bonds as a means to use aryl
methyl ethers as remoVable directing groups.11,12 This method is
characterized by its simplicity, wide preparative scope, and the
availability of the substrates employed. Remarkably, this study does
not require the use of toxic halogenated or tin-based compounds,
thus representing an additional bonus when compared with related
dehalogenation or Stille-reduction protocols, respectively.13
We began our investigations by examining the reactivity of
2-methoxynaphthalene (1a) with several hydride sources using
nickel catalysts.14 After extensive experimentation, we found that
the use of PCy3 as the ligand and tetramethyldisiloxane (TMDSO)
as the hydride source was critical for obtaining the desired arenes
in good yields.15 Control experiments in which the metal was
omitted resulted in no product formation.15 Notably, the nature of
the aryl ether employed had a pronounced influence on the reaction
a ArOMe (0.5 mmol), Ni(COD)2 (5 mol %), PCy3 (10 mol %),
TMDSO (0.5 mmol), PhMe (1 mL) at 110 °C. b Isolated yields, average
of two runs. c Ni(COD)2 (10 mol %). d TMDSO (1.0 mmol). e TMDSO
(0.23 mmol).
Encouraged by these results, we set out to explore the scope of
the Ni-catalyzed reductive cleavage of aryl methyl ethers (Table
1). Regardless of the substrates used, we found that silyl groups
(entries 2 and 19), esters (entries 4, 9, 13, and 21-25), amides
(entry 25), or acetals (entry 20) could all be tolerated. Equally
striking is the fact that tertiary amines (entries 5 and 24) or nitrogen-
containing heterocycles (entries 6, 8, 10, 15-20, and 22) do not
interfere, indicating the low Lewis acidity of the operating catalyst.
Interestingly, while the reduction of naphthalene derivatives invari-
ably resulted in good yields of products (entries 1-13), the coupling
of simple anisoles proved to be more difficult.9g We hypothesized
that a suitable ortho-directing group might facilitate the C-O bond
oxidative addition step within the catalytic cycle.16 To our delight,
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17352 J. AM. CHEM. SOC. 2010, 132, 17352–17353
10.1021/ja106943q  2010 American Chemical Society

C O M M U N I C A T I O N S
this was indeed the case, as pyridines (entry 15), oxazolines (entries
16-17), pyrazoles (entries 18-20), or esters (entries 21-25) could
be efficiently coupled.17 Remarkably, the presence of such groups
in either metha or para position resulted in little conversion to
products, indicating that electronic effects might not be the only
factor coming into play.15 On the basis of these results, we
anticipated that high levels of site selectivity could be achieved
based on subtle steric and electronic differences among multiple
C-O bonds. Indeed, while exhaustive reduction was observed for
simple substrates (entry 11), site selectivity was possible when using
appropriate ortho-directing groups (entries 13 and 18), providing
an additional handle for further manipulation. Similarly, sp2 C-O
bonds were selectively activated in the presence of multiple sp3
C-O bonds (entries 12, 19, and 20); note, however, that activated
benzylic C-O bonds18 could also be coupled with equal efficiency
(entry 14).18,19
In summary, a highly efficient Ni-catalyzed reduction of aryl
ethers has been developed. The ready availability of the substrates
and the remarkable substrate scope observed make this method
attractive to synthetic chemists. Further investigations into related
processes and the identification of reactive intermediates are ongoing
in our laboratories.
Acknowledgment. We thank the ICIQ Foundation, Consolider
Ingenio 2010 (CSD2006-0003), and MICINN (CTQ2009-13840)
for financial support. Johnson Matthey, Umicore, and Nippon
Chemical Industrial are acknowledged for a gift of metal and ligand
sources.
Supporting Information Available: Experimental procedures and
spectral data for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Scheme 2. Synthetic Applicability
References
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The usefulness of our methodology is nicely illustrated in Scheme
2. Thus, structurally related 3-5 could be selectively prepared from
2-naphthol.15 We believe this demonstrates the flexibility in
synthetic design when employing temporary directing groups. The
preparation of 5 is particularly noteworthy; to the best of our
knowledge, the Ni-catalyzed activation of inert C-O bonds with
substrates containing two ortho substituents has no precedent in
the literature. In view of the high ubiquity of aryl ethers in many
pharmaceutically relevant molecules,20 we envisioned that a late-
stage, site-selective, C-O bond activation could be used as a
manifold for natural product diversity. Gratifyingly, quinine and
estradiol derivatives (6 and 7) could be obtained in 63 and 62%
yield.
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J. Am. Chem. Soc. 2008, 130, 14422, and references therein.
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(14) No conversion to products was observed when using Pd catalysts.
(15) For full experimental details, see Supporting Information.
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Scheme 3. Mechanistic Considerations
(17) We note that all our attempts to couple 1-methoxy-2-(methoxymethyl)ben-
zene were unsuccessful, thus ruling out the ortho-directing ability of a
proximal CH2OMe group.
Next, we performed deuterium-labeling experiments to gather
evidence about the reaction mechanism (Scheme 3). Interestingly,
2a and 2a-D were exclusively obtained when using Et3SiH(D),21
thus ruling out a mechanistic scenario via ꢀ-hydride elimination
from preformed arylnickel(II) alkoxy intermediates.22 These results
clearly indicate that our protocol can be used for introducing
deuterium atoms23 in unbiased arene backbones from readily
aVailable precursors. Although further mechanistic studies are
needed, we tentatively propose a pathway consisting of C-O
oxidative addition, σ-bond metathesis with the Si-H bond, and
reductive elimination from a nickel(II) hydride intermediate.24
(18) Guan, B.-T.; Xiang, S.-K.; Wang, B.-Q.; Sun, Z.-P.; Wang, Y.; Zhao, K.-
Q.; Shi, Z.-J. J. Am. Chem. Soc. 2008, 130, 3268.
(19) Less activated 1-(methoxymethyl)naphthalene as well as simple alkyl or
benzyl methyl ethers gave no conversion to products.
(20) Rao, A. V. R.; Gurjar, M. K.; Reddy, K. L.; Rao, A. S. Chem. ReV. 1995,
95, 2135.
(21) Et3SiH(D) and TMDSO gave comparable results. See ref 15.
(22) Bryndza, H. E.; Tam, W. Chem. ReV. 1988, 88, 1163.
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(24) Li, Z.; Zhang, S.-L.; Fu, Y.; Guo, Q.-X.; Liu, L. J. Am. Chem. Soc. 2009,
131, 8815.
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