Selective oxidative homo-and cross-coupling of phenols with aerobic catalysts

Article abstract of DOI:10.1021/ja500183z

Simple catalysts that use atom-economical oxygen as the terminal oxidant to accomplish selective ortho-ortho, ortho-para, or para-para homo-couplings of phenols are described. In addition, chromium salen catalysts have been discovered as uniquely effective in the cross-coupling of different phenols with high chemo-and regioselectivity.

Full text of DOI:10.1021/ja500183z

Communication
pubs.acs.org/JACS
Selective Oxidative Homo- and Cross-Coupling of Phenols with
Aerobic Catalysts
Young Eun Lee, Trung Cao, Carilyn Torruellas, and Marisa C. Kozlowski*
Penn Merck High Throughput Experimentation Laboratory, Department of Chemistry, University of Pennsylvania, Philadelphia,
Pennsylvania 19104-6323, United States
S
* Supporting Information
Chart 1. Phenolic Coupling Natural Products
ABSTRACT: Simple catalysts that use atom-economical
oxygen as the terminal oxidant to accomplish selective
ortho−ortho, ortho−para, or para−para homo-couplings of
phenols are described. In addition, chromium salen
catalysts have been discovered as uniquely effective in
the cross-coupling of different phenols with high chemo-
and regioselectivity.
ince the groundbreaking work by Barton and Erdtmann
Sthat phenol oxidation is a key step in the biosynthesis of
several natural product classes,1 chemists have been inspired to
develop laboratory analogues of these important processes.2
Numerous natural products can be constructed via different
oxidative phenol couplings including homo-coupling at the
same site, homo-coupling at different sites, and cross-coupling
of different phenols (Chart 1).2c−f Due to the vast array of
useful biological activities associated with these compounds,
especially their antibacterial and antifungal properties, these
compounds remain the subject of intense interest.2c−f While
many stoichiometric phenolic oxidations have been studied,2a,3
the coupling selectivities are typically low when multiple
coupling sites are available (see red arrows in Chart 1).
Furthermore, the use of superstoichiometric reagents is
undesirable.4 Herein, we disclose simple catalysts that use
atom-economical oxygen as the terminal oxidant to accomplish
selective ortho−ortho, ortho−para, or para−para homo-
couplings of phenols. In addition, chromium salen catalysts
have been found to be exceptional in cross-coupling two
different phenols with high selectivity.
Few nonenzymatic catalytic systems have been reported for
the oxidative coupling of the parent phenols, even though there
are many for 2-naphthols.5 Due to the difference in oxidation
potentials (naphthol = 1.87 eV, phenol = 2.10 eV),6 the
oxidation of phenols is more difficult. In addition diverse
product mixtures are observed due to similar stabilities of the
different radical resonance forms relative to naphthol (Scheme
1).5a In addition, direct oxygenation of the aromatic ring to
quinones and further adducts becomes competitive.
Our strategy to explore this challenging transformation
centered on metal catalysts that are reoxidized readily by O2.
Based on prior experience with 2-naphthol coupling, we elected
to examine Cr, Cu, Fe, Mn, Ru, and V.5 An appropriate ligand
framework that stabilizes the metal, is tuned easily and is
oxidatively stable was crucial. For phenol coupling, the salen/
salan scaffold7−9 proved superior. Due to the large number of
variables (36 catalysts, Chart 2, R = H; solvent; additives;
substrates), parallel microscale screening10 was used to rapidly
identify trends (Figure 1). To test the premise that these
catalysts are appropriate for phenol oxidation and that O2 was
being effectively introduced into the reaction microvials, a
substrate (Table 1, entry 1) that readily undergoes phenolic
coupling to a single ortho−ortho product was tested first.
Gratifyingly, almost all the catalysts were effective to some
degree with this substrate (Figure 1, entry 1). Further bench
Received: January 10, 2014
Published: May 5, 2014
© 2014 American Chemical Society
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Scheme 1. Possible Outcomes in 2-Naphthol vs Phenol
Oxidation
Table 1. Selective Phenol Homo-Couplings
Chart 2. Catalyst Library
scale optimization revealed a Ru catalyst as highly effective with
oxygen for this substrate (Table 1, entry 1).
With substrates that are not effectively coupled even with
stoichiometric oxidants, the initial screen (Figure 1, bottom
four entries) showed lower yields. However, the trends
narrowed the focus for further optimization. By examining
temperature, solvents, and additives,5e ortho−ortho coupling of
a range of substrates was achieved (Table 1, entries 2−4, 7). To
improve reactivity for reluctant substrates, we theorized that an
electron-withdrawing substituent NO2 (R2, Chart 2) would
improve the oxidizing power of the Ru-Salen-H. With this
second generation catalyst, higher yields were seen for entries 9
and 11. Overall, Ru salens are the most general for ortho−ortho
coupling, but some substrates respond better to V or Cu
catalysts.
With entries 7 and 9 from Table 1, an additional major peak
was seen in the HPLC spectra from the initial screening. Re-
examination of the data rapidly identified catalysts selective for
this compound (beige highlights in Figure 2). This material was
ultimately determined to be the tricyclic Pummerer ketone1,2a
(PK), which forms via ortho−para coupling followed by a 1,4-
addition (Scheme 2). Optimized conditions provided this PK
with high efficiency (Table 1, entries 8, 10, 12). Notably, this
a
Parenthetical yields are based on recovered substrate. Bracketed
yields are unoptimized parallel screening results.
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Table 2. Cross-Coupling of Different Monomers
Figure 1. 36 catalysts (20−30 mol %, 40−80 °C, DCE, 1 d) with five
substrates in oxidative phenolic coupling using O2. For each substrate:
top row = salan, bottom row = salen. Conversion is for the ortho−
ortho products.
Scheme 2. Formation of PK
a
1.2 equiv of red coupling partner used. All others used 2.0 equiv.
Parenthetical yields based on recovered substrate.
b
Scheme 3. Proposed Mechanism of the Cross-Coupling
Figure 2. Amounts of ortho−ortho (o−o) and PK products from Table
1, entry 7 with 36 catalysts using O2. Beige shading indicates PK is the
major product.
generated (entry 5). Notably, different catalysts permit control
of ortho−ortho vs ortho−para coupling (Table 1, entries 4/5, 7/
8, 9/10).
The next challenge was identifying catalysts for para−para
coupling. When there is competition between ortho- and para-
sites, selective catalysts were found (Table 1, entries 6, 13, 14),
but yields were modest due to low reactivity, a challenge that
motif is found in several natural products such as the
galanthamines and usnic acids.11 On the other hand, when
the para-position is unsubstituted, ortho−para bisphenols are
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Communication
remains to be addressed. When the ortho-positions are blocked,
the expected para-product is obtained (Table 1, entries 15−
17). Most interestingly, selective catalysts for ortho−ortho,
ortho−para, and para−para coupling of 2,3,5-trimethylphenol
have been identified (Table 1, entries 4−6) showing the
versatility of this catalytic aerobic coupling.
At this juncture, the question of cross-coupling different
phenols arose, a very difficult venture since any catalyst must
promote the cross-coupling much faster than either of the
corresponding homo-couplings.2,12,13 Initially, phenols with
only one open coupling site were used limiting the outcome to
three coupling products (Table 2, entries 1−2). Remarkably, a
Cr catalyst affected cross-coupling with high efficiency (75−
85%) with only a 1.2:1 reactant stoichiometry.
(1S10RR022442) and the NSF for X-ray (CHE 0840438).
T.C. thanks the Vietnam Education Foundation for a
fellowship.
REFERENCES
■
(1) (a) Barton, D. H. R.; Cohen, T. In Festschrift Prof. Dr. Arthur Stoll
zum Siebzigsten Geburstag; Birkhauser: Basel, 1957; p 117. (b) Erdtman,
H.; Wachtmeister, C. A. In Festschrift Prof. Dr. Arthur Stoll zum
̈
Siebzigsten Geburstag; Birkhauser: Basel, 1957; p 144.
̈
(2) (a) Whiting, D. A. Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I., Pattenden, G., Eds.; Pergamon: Oxford, 1991; Vol. 3, p
659. (b) Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski,
M. C. Chem. Rev. 2013, 113, 6234. (c) Pal, T.; Pal, A. Curr. Sci. 1996,
71, 106. (d) Keseru, G. M.; Nogradi, M. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, F. R. S., Ed.; Elsevier: New York, 1998;
Venturing to substrates where six products are possible led to
the discovery that Cr-salen-Cy is broadly effective for cross-
coupling (entries 3−10). A 2:1 stoichiometry of the coupling
partners was well tolerated. Notably, selective cross-coupling
was seen for many substrates (yellow highlights, Table 2) where
selective homo-coupling had been achieved in Table 1.
Selective cross-coupling requires a 2,6-disubstituted partner
(Type I), which is postulated to add at the para-site to a metal
bound radical or radical cation of the complementary partner
(Type II or III), which has a less hindered phenol for metal
binding (Scheme 3). Site selectivity occurs at the sterically least
hindered site of this metal bound phenol (Type II ortho, Type
III para). To date, no other substitution patterns have been
found effective for the Type I partner.
The degree of selectivity control in the catalysts described
herein suggests significantly different mechanisms are operat-
ing. Further, preliminary studies with radical inhibitors reveal
complex effects (see Supporting Information). For example,
TEMPO inhibited reaction of the Cr catalyst with O2.
Combined with the lack of reactivity of the Cr catalyst without
O2 and the formation of product under N2 with a pregenerated
Cr(IV) species,14 the data support the mechanism shown in
Scheme 3 for the cross-coupling.
Vol. 20, p 263. (e) Bringmann, G.; Gunther, C.; Ochse, M.; Schupp,
̈
O.; Tasler, S. Prog. Chem. Org. Nat. Prod. 2001, 82, 1. (f) Bringmann,
G.; Gulder, T.; Gulder, T. M.; Breuning, M. Chem. Rev. 2011, 111,
563.
(3) (a) Armstrong, D. R.; Cameron, C.; Nonhebel, D. C.; Perkins, P.
G. J. Chem. Soc. Perk. Trans. 2 1983, 563. (b) Noshino, H.; Itoh, N.;
Nagashima, M.; Kurosawa, K. Bull. Chem. Soc. Jpn. 1992, 65, 620.
(c) Morimoto, K.; Sakamoto, K.; Ohnishi, Y.; Miyamoto, T.; Ito, M.;
Dohi, T.; Kita, Y. Chem.Eur. J. 2013, 19, 8726.
(4) Catalytic oxidative phenol coupling where only a single coupling
site is open: (a) Liao, B.-S.; Liu, Y.-H.; Peng, S.-M.; Liu, S.-T. Dalton
Trans. 2012, 41, 1158. (b) Jiang, Q.; Sheng, W.; Tian, M.; Tang, J.;
Guo, C. Eur. J. Org. Chem. 2013, 1861. (c) Feng, J.; Yang, X.-B.; Liang,
S.; Zhang, J.; Yu, X.-Q. Tetrahedron Lett. 2013, 54, 355.
(5) (a) Kozlowski, M. C.; Morgan, B. J.; Linton, E. C. Chem. Soc. Rev.
2009, 38, 3193. (b) Irie, R.; Masutani, K.; Katsuki, T. Synlett 2000,
1433. (c) Guo, Q.-X.; Wu, Z.-J.; Luo, Z.-B.; Liu, Q.-Z.; Ye, J.-L.; Luo,
S.-W.; Cun, L.-F.; Gong, L.-Z. J. Am. Chem. Soc. 2007, 129, 13927.
(d) Takizawa, S.; Katayama, T.; Sasai, H. Chem. Commun. 2008, 4113.
(e) Yan, P.; Sugiyama, Y.; Takahashi, Y.; Kinemuchi, H.; Temma, T.;
Habaue, S. Tetrahedron 2008, 64, 4325. (f) Egami, H.; Katsuki, T. J.
Am. Chem. Soc. 2009, 131, 6082. (g) Egami, H.; Matsumoto, K.;
Oguma, T.; Kunisu, T.; Katsuki, T. J. Am. Chem. Soc. 2010, 132, 13633.
(6) Bordwell, F. G.; Cheng, J. P. J. Am. Chem. Soc. 1991, 113, 1736.
(7) (a) Katsuki, T. Chem. Soc. Rev. 2004, 33, 437. (b) Cozzi, P. G.
Chem. Soc. Rev. 2004, 33, 410.
In summary, catalytic amounts of simple salen/salan
complexes using O2 as the terminal oxidant provide access to
phenolic dimers unattainable via conventional oxidants. The PK
exemplifies oxidative coupling as a powerful strategy to rapidly
build complexity without using leaving groups. The Cr salens,
which have not been reported previously in oxidative phenolic
coupling, exhibit unique cross-coupling activity enabling access
to many unknown adducts. Further studies on the mechanisms
to tailor catalysts for reactivity and selectivity are under way.
(8) Nonselective salen oxidative phenolic coupling: (a) Tonami, H.;
Uyama, H.; Kobayahsi, S. Macromolecules 2004, 37, 7901. (b) Bassoli,
A.; Di Gregorio, G.; Rindone, B.; Tollari, S. J. Mol. Catal. 1989, 53,
173. (c) Haikarainen, A.; Sipila, J.; Pietikainen, P.; Pajunen, A.;
̈
̈
Mutikainen, I. Biorg. Med. Chem. Lett. 2001, 9, 1633.
(9) Although effective catalytic oxidants, Co salens were not studied
due a strong tendency toward oxygenation. See ref 2a.
(10) Schmink, J. R.; Bellomo, A.; Berritt, S. Aldrichimica Acta 2013,
46, 71.
(11) (a) Pelish, H. E.; Westwood, N. J.; Feng, Y.; Kirchhausen, T.;
Shair, M. D. J. Am. Chem. Soc. 2001, 123, 6740. (b) Cocchietto, M.;
Skert, N.; Nimis, P. L.; Sava, G. Naturwissenschaften 2002, 89, 137.
(c) Elo, H.; Matikainen, J.; Pelttari, E. Naturwissenschaften 2007, 94,
465.
(12) Bird, C. W.; Chauhan, Y.-P. Tetrahedron Lett. 1978, 19, 2133.
(13) For an alternate cross-coupling that appeared after this
submission: Elsler, B.; Schollmeyer, D.; Dyballa, K. M.; Franke, R.;
Waldvogel, S. R. Angew. Chem. Int. Ed. 10.1002/anie.201400627.
(14) McGarrigle, E. M.; Gilheany, D. G. Chem. Rev. 2005, 105, 1563.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
marisa@sas.upenn.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the NSF (CHE1213230, CHE0848460) for
financial support. Partial instrumentation support was provided
by the NIH for MS (1S10RR023444) and NMR
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