A New Route to Phenols: Palladium-Catalyzed Cyclization and Oxidation of γ,δ-Unsaturated Ketones

Article abstract of DOI:10.1002/cctc.201600447

We report a new strategy for the synthesis of phenols from acyclic unsaturated ketones in one pot. The reaction proceeds by palladium-catalyzed carbopalladation of an alkene with the enol form of the tethered ketone, generating a substituted cyclohexanone. Upon introduction of a terminal oxidant a palladium-catalyzed oxidation ensues to give the desired phenol. This approach allows the programming of phenol substituents on the acyclic substrate and therefore circumvents the limitations inherent in traditional syntheses of phenols.

Full text of DOI:10.1002/cctc.201600447

DOI: 10.1002/cctc.201600447
Communications
A New Route to Phenols: Palladium-Catalyzed Cyclization
and Oxidation of g,d-Unsaturated Ketones
Sadaf Samadi and Arturo Orellana*[a]
We report a new strategy for the synthesis of phenols from
acyclic unsaturated ketones in one pot. The reaction proceeds
by palladium-catalyzed carbopalladation of an alkene with the
enol form of the tethered ketone, generating a substituted cy-
clohexanone. Upon introduction of a terminal oxidant a palladi-
um-catalyzed oxidation ensues to give the desired phenol. This
approach allows the programming of phenol substituents on
the acyclic substrate and therefore circumvents the limitations
inherent in traditional syntheses of phenols.
Polysubstituted phenols feature prominently as final products
or intermediates in the synthesis of pharmaceuticals, complex
natural products or functional materials.[1] The development of
efficient strategies for their preparation is therefore an endur-
ing challenge.[2] Depending on the substitution pattern pres-
ent, their synthesis can be straightforward or may involve
a considerable number of steps. Electrophilic aromatic substi-
tution of phenols exploits the inherent nucleophilicity of the
ortho- and para-positions (Scheme 1, a), and is therefore not
suitable for the installation of substituents at the meta-posi-
tion. Furthermore, it is possible to generate mixtures of com-
pounds through double substitution. Perhaps the most
Scheme 1. Strategies for the synthesis of functionalized phenols: a) electro-
philic aromatic substitution, b) directed ortho-metalation, c) oxidation of cy-
clohexanone to phenols, and d) palladium-catalyzed tandem cyclization and
oxidation.
common alternative to this approach is the directed ortho-met-
alation (DoM) strategy (Scheme 1b).[3] This is an effective
method for introducing substituents ortho to the hydroxyl
group of the phenol, but requires the introduction and remov-
al of directing groups, and is not suitable for the installation of
groups at the meta- or para-position. Methods that selectively
install meta-substituents on a phenol while leaving the ortho-
position intact are rare and require the introduction and re-
moval of cumbersome directing groups[4] or special reaction
conditions.[5,6] The oxidation of substituted cyclohexanones
with palladium has long been recognized as a method for the
preparation of phenols (Scheme 1c).[7] The need for environ-
mentally responsible synthesis, combined with more sophisti-
cated mechanistic understanding of palladium catalysis have
renewed interest in this reaction.[8,9] This approach to substitut-
ed phenols circumvents the selectivity and reactivity con-
straints imposed by the hydroxyl group because substituents
can be introduced at the cyclohexanone stage by conjugate
addition or enolate alkylation reactions.
We envisioned a conceptually different method for the prep-
aration of polysubstituted phenols. Specifically, we reasoned
that a single palladium catalyst could promote the redox-neu-
tral cyclization of g,d-unsaturated ketones and also catalyze
the oxidation of the resulting cyclohexanones to substituted
phenols upon the introduction of an oxidative switch
(Scheme 1d).[10,11] In this approach, the desired substituents on
the phenol can be preprogrammed into the acyclic g,d-unsatu-
rated ketones, which can be readily prepared using a variety of
methods, thereby circumventing some of the limitations inher-
ent in other approaches to phenols.
Our strategy for developing this reaction was to first identify
practical conditions for the cyclization and aromatization reac-
tions independently, and then combine them in a one-pot pro-
cess. In a series of reports, Widenhoefer[12] and coworkers
showed that g,d-unsaturated ketones could be converted to
cyclohexanones using a PdII catalyst.[13] The proposed mecha-
nism involves carbopalladation[14] of the alkene with the enol
form of the ketone, a series of b-hydride elimination and inser-
tion steps, and protonation of a palladium enolate (Scheme 2).
These reactions required a high loading (10%) of palladium
[a] S. Samadi, Prof. A. Orellana
Department of Chemistry
York University
4700 Keele Street, Toronto ON, M3J 1P3 (Canada)
E-mail: aorellan@yorku.ca
Supporting information for this article can be found under http://
dx.doi.org/10.1002/cctc.201600447.
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Scheme 2. a) Key steps in the palladium-catalyzed cyclization of g,d-unsatu-
rated ketones, and b) summary of optimized conditions.
Scheme 3. a) Key steps in the palladium-catalyzed oxidation of cyclohexa-
catalyst, and very low substrate concentrations owing to the
formation of off-cycle substrate-bound polymeric palladium
complexes at high concentration.[12] Furthermore, the addition
of an acid was required to promote the formation of the enol
tautomer of the ketone.
nones to phenols, and b) summary of optimized conditions.
dation step (Scheme 3, entry 4). Finally, removal of the palladi-
um catalyst from the mixture does not lead to phenol, demon-
strating that it is required for the aromatization step (entry 5).
We wondered if the chelating ability of the product could in-
terfere with the oxidation reaction, and therefore tested other
substrates. If a-phenyl cyclohexanone is subjected to the same
reaction conditions for oxidation, the corresponding phenol is
obtained in high yield. A similar result is obtained if a cyclic ke-
toester is used, however the yield is diminished significantly if
2-methylcyclohexanone is used. This last observation may re-
flect the low enol concentration for this substrate.
At the outset of our studies we aimed to identify a robust
catalytic system that would allow us to run reactions at higher
concentration and avoid the formation of unproductive palla-
dium complexes. We thus evaluated a number of palladium(II)
salts in combination with bidentate pyridine-like ligands. De-
spite extensive exploration, however, we were unable to iden-
tify a better catalyst than the PdCl2·2CH3CN complex previous-
ly employed (see ESI). Nevertheless, we established that the re-
action could be conducted with a lower catalyst loading
(Scheme 2, entry 2). Using a combination CuCl2 and HCl ap-
peared to have a subtle but beneficial effect on the reaction
(entry 3).[15] Furthermore, the reaction could be conducted in
both dioxane and toluene as solvents (entry 4), but more polar
solvents, such as DMF and DMSO, were not suitable (entry 5).
We also observed that the desired phenol was formed along
with the expected cyclohexanone.
Having identified suitable conditions for the cyclization and
oxidation steps, we prepared a number of substrates that
would lead to substituted phenols (Scheme 4). To demonstrate
the flexibility of this strategy towards phenol synthesis, we em-
ployed a variety of routes to g,d-unsaturated ketones, includ-
ing addition of Grignard reagents to morpholine amides (a
and b, substrates 1a–8a), Weiler alkylation of dienolates (c,
substrates 9a–11 a), alkylation and decarboxylation of b-ke-
toesters (d, substrate 12a), alkylation of ketone enolates (e,
substrates 13a and 14a), or a combination of these steps (f,
substrate 15a).
Finally, we subjected these substrates to optimized condi-
tions for the palladium-catalyzed cyclization and oxidation
steps (Scheme 5). Substrates bearing a methylene flanked by
a carbonyl group and an aryl group generated the desired
phenols in uniformly good yields (1b–7b, 71–90%). If the reac-
tion is conducted without CuCl2 the yield of phenol 1b was re-
duced from 80 to 50%, and therefore all other reactions were
conducted using CuCl2. The uniformly high yields for this sub-
strate class may reflect the fact that a conjugated nucleophilic
We then explored a variety of oxidants and reaction condi-
tions for the oxidation step. We initially employed an atmos-
phere of oxygen as the terminal oxidant, but this proved inef-
fective. Similarly, the use of additives such as H2O, which is re-
quired for oxidation of Cu in the Wacker process, and a range
of electron transfer mediators (ETMs)[16] provided unsatisfactory
results (see ESI for details). On the other hand, the use of stoi-
chiometric amounts of quinone oxidants led to the expected
product in good yield (Scheme 3). Reducing the catalyst load-
ing from 10% to 5% (entry 2), or the amount of quinone oxi-
dant from two to one equivalent (entry 3) led to a reduced
yield. Although toluene was shown to be effective for the ini-
tial cyclization step (Scheme 2) it was not suitable for the oxi-
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Scheme 5. One-pot palladium-catalyzed cyclization and oxidation of g,d-un-
saturated ketones to phenols. [a] Reaction conducted without CuCl2.
Scheme 4. Strategies for the preparation of substituted g-unsaturated acyclic
We have developed the first method for the direct conver-
sion of acyclic, g,d-unsaturated ketones to phenols. In this
method, the palladium catalyst serves to first cyclize the g,d-
unsaturated ketone and then to oxidize the resulting cyclohex-
anone to the corresponding phenol upon the addition of a ter-
minal oxidant. This strategy allows the pre-installation of multi-
ple phenol substituents on the acyclic substrate and therefore
circumvents the limitations inherent in other strategies. One
current limitation of this method is the need for stoichiometric
amounts of quinone oxidants for the aromatization step, and
therefore further work will focus on identifying better catalyst
systems and atom economical oxidants. Nevertheless, this
strategy should streamline the preparation of phenols bearing
difficult to access substitution patterns.
ketones.
enol is readily formed prior to cyclization, and similarly during
the first oxidation step. In contrast, substrate 8a provides
a poor yield of phenol 8b, which may reflect the diminished
acidity of the ketones, resulting in low concentration of the
enols required for cyclization and oxidation. This result is con-
sistent with the previous observations during our optimization
studies (Scheme 3). Substrates bearing a 1,3-dicarbonyl group
provided the desired phenols (9b–11 b) in modest yields,
which are also consistent with those observed in our optimiza-
tion experiments. The reasons for these diminished yields are
unclear, however, we note that ortho-acyl phenols are often
used as chelating ligands on transition metal complexes, and
may indeed remain bound to the catalysts (Pd or Cu) in this re-
action. Substrate 12a, bearing a methyl ketone group (see
Scheme 4), allows the direct formation of a meta-substituted Acknowledgements
phenol, which can be hard to access. Under optimized reaction
conditions this substrate yields the expected meta-phenol in
modest yield, which again may reflect the low concentration
of the enol tautomer required for both steps. Finally, substrates
13a–15a provide trisubstituted products in good yields.
We gratefully acknowledge support of our work by the Natural
Science and Engineering Research Council of Canada (NSERC)
through a Discovery grant, and Boehringer-Ingelheim Canada
through an unrestricted grant. We thank Professor Michael
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78, 5923; i) R. N. Lacey, J. Chem. Soc. 1960, 1625; j) Z. Horii, S. Yamamura,
H. Hakusui, T. Nishikado, T. Momose, Chem. Pharm. Bull. 1968, 16, 2456;
k) T. T. Wenzel, J. Chem. Soc. Chem. Commun. 1989, 932.
Organ of York University for generous sharing of resources, and
Dr. Howard Hunter of York University for assistance with NMR ex-
periments.
[8] Palladium-catalyzed oxidations of cyclohexanones to phenols: a) M. F.
Oldfield, L. Chen, N. P. Botting, Tetrahedron 2004, 60, 1887; b) Y. Izawa,
D. Pun, S. S. Stahl, Science 2011, 333, 209–213; c) T. Diao, T. J. Wadzinski,
S. S. Stahl, Chem. Sci. 2012, 3, 887–891; d) M. T. Kessler, M. H. G. Prechtl,
ChemCatChem 2012, 4, 326; e) Y. Izawa, C. Zheng, S. S. Stahl, Angew.
Chem. Int. Ed. 2013, 52, 3672–3675; Angew. Chem. 2013, 125, 3760–
3763; f) T. Diao, D. Pun, S. S. Stahl, J. Am. Chem. Soc. 2013, 135, 8205–
8212; g) D. Pun, T. Diao, S. S. Stahl, J. Am. Chem. Soc. 2013, 135, 8213–
8221; h) J. H. Park, C. Y. Park, M. J. Kim, M. U. Kim, Y. J. Kim, G.-H. Kim,
C. P. Park, Org. Process Res. Dev. 2015, 19, 812; i) J. Zhang, Q. Jiang, D.
Yang, X. Zhao, Y. Dong, R. Liu, Chem. Sci. 2015, 6, 4674.
[9] Reviews on aerobic oxidations with Pd: a) S. S. Stahl, Angew. Chem. Int.
Ed. 2004, 43, 3400–3420; Angew. Chem. 2004, 116, 3480–3501; b) S. S.
Stahl, Science 2005, 309, 1824–1826; c) K. M. Gligorich, M. S. Sigman,
Chem. Commun. 2009, 3854–3867; d) A. N. Campbell, S. S. Stahl, Acc.
Chem. Res. 2012, 45, 851–853.
Keywords: oxidation · palladium · phenol
[1] J. H. P. Tyman, Synthetic and Natural Phenols, Vol. 52, Elsevier, Amster-
dam, 1996.
[2] D.-G. Yu, F. de Azambuja, F. Glorius, Angew. Chem. Int. Ed. 2014, 53,
7710–7712; Angew. Chem. 2014, 126, 7842–7845.
[3] a) E. J.-G. Anctil, V. Snieckus in Metal-Catalyzed Cross-Coupling Reactions,
Vol. 2, 2nd ed. (Eds.: A. De Meijere, F. Diederich), Wiley-VCH, Chichester,
2004, pp. 761–813; b) V. Snieckus, Chem. Rev. 1990, 90, 879–993.
[4] a) L. Wan, N. Dastbaravardeh, G. Li, J.-Q. Yu, J. Am. Chem. Soc. 2013, 135,
18056–18059; b) H.-X. Dai, G. Li, X.-G. Zhang, A. F. Stepan, J.-Q. Yu, J.
Am. Chem. Soc. 2013, 135, 7567. For expert commentary on these li-
gands, see: M. O. Kitching, V. Snieckus, Nature 2012, 486, 478.
[5] For the direct synthesis of meta-substituted phenols using high pres-
sures of CO2 to install a directing group, see: a) J. Luo, S. Preciado, I.
Larrosa, J. Am. Chem. Soc. 2014, 136, 4109–4112. For the related use of
salicylic acids in the synthesis of meta-substituted phenols, see: c) J.
Luo, S. Preciado, I. Larrosa, Chem. Commun. 2015, 51, 3127–3130.
[6] Selected recent strategies for the synthesis of meta-substituted aryls:
a) J.-Y. Cho, M. K. Tse, D. Holmes, R. E. Maleczka, Jr., M. R. Smith, III, Sci-
ence 2002, 295, 305; b) T. Ishiyama, J. Takagi, K. Ishida, N. Miyaura, N. R.
Anastasi, J. F. Hartwig, J. Am. Chem. Soc. 2002, 124, 390; c) R. J. Phipps,
M. J. Gaunt, Science 2009, 323, 1593–1597; d) O. Saidi, J. Marafie,
A. E. W. Ledger, P. M. Liu, M. F. Mahon, G. K. Kçhn, M. K. Whittlesey, C. G.
Frost, J. Am. Chem. Soc. 2011, 133, 19298; e) L. Zhou, W. Lu, Organome-
tallics 2012, 31, 2124; f) N. Hofmann, L. Ackermann, J. Am. Chem. Soc.
2013, 135, 5877; g) S. Lee, H. Lee, K. L. Tan, J. Am. Chem. Soc. 2013, 135,
18778–18781; h) A. J. Martꢁnez-Martꢁnez, A. R. Kennedy, R. E. Mulvey,
C. T. O’Hara, Science 2014, 346, 834; i) C. Cheng, J. F. Hartwig, Science
2014, 343, 853; j) G. Yang, P. Lindovska, D. Zhu, J. Kim, P. Wang, R.-Y.
Tang, M. Movassaghi, J.-Q. Yu, J. Am. Chem. Soc. 2014, 136, 10807–
10813; k) Z. Dong, J. Wang, G. Dong, J. Am. Chem. Soc. 2015, 137,
5887–5890; l) M. Bera, A. Maji, S. K. Sahoo, D. Maiti, Angew. Chem. Int.
Ed. 2015, 54, 8515–8519; Angew. Chem. 2015, 127, 8635–8639.
[10] This type of catalysis is termed ‘Assisted Tandem Catalysis’. D. E. Fogg,
E. N. Dos Santos, Coord. Chem. Rev. 2004, 248, 2365–2379.
[11] For an example of quinones as the oxidative trigger in assisted tandem
catalysis with palladium, see: B. M. Trost, D. A. Thaisrivongs, M. M. Hans-
mann, Angew. Chem. Int. Ed. 2012, 51, 11522–11526; Angew. Chem.
2012, 124, 11690–11694.
[12] a) T. Pei, R. A. Widenhoefer, J. Am. Chem. Soc. 2001, 123, 11290–11291;
b) T. Pei, R. A. Widenhoefer, Chem. Commun. 2002, 650–651; c) H. Qian,
R. A. Widenhoefer, J. Am. Chem. Soc. 2003, 125, 2056–2057; d) X. Wang,
T. Pei, X. Han, R. A. Widenhoefer, Org. Lett. 2003, 5, 2699–2701; e) X.
Han, X. Wang, T. Pei, R. A. Widenhoefer, Chem. Eur. J. 2004, 10, 6333–
6342; f) C. Liu, X. Wang, T. Pei, R. A. Widenhoefer, Chem. Eur. J. 2004, 10,
6343–6352; g) H. Qian, T. Pei, R. A. Widenhoefer, Organometallics 2005,
24, 287–301; h) X. Han, R. A. Widenhoefer, Organometallics 2007, 26,
4061–4065.
[13] For related lanthanide assisted cyclizations see: D. Yang, J.-H. Li, Q. Gao,
Y. L. Yan, Org. Lett. 2003, 5, 2869; K.-T. Yip, J.-H. Li, O.-Y. Lee, D. Yang,
Org. Lett. 2005, 7, 5717.
[14] R. I. McDonald, G. Liu, S. S. Stahl, Chem. Rev. 2011, 111, 2981–3019.
[15] Although the effect of CuCl2 in the cyclization reaction is minimal, re-
moving the CuCl2 from the two-step, one-pot process results in dimin-
ished yields. See Scheme 5.
[7] a) L. Ruzicka, E. Morgeli, Helv. Chim. Acta 1936, 19, 377; b) E. Mosettig,
H. M. Duvall, J. Am. Chem. Soc. 1937, 59, 367; c) R. P. Linstead, K. O. A.
Michaelis, J. Chem. Soc. 1940, 1134; d) R. P. Linstead, K. O. A. Michaelis,
S. L. S. Thomas, J. Chem. Soc. 1940, 1139; e) J. W. Cook, R. Schoental, J.
Chem. Soc. 1945, 288; f) C. D. Gutsche, W. S. Johnson, J. Am. Chem. Soc.
1946, 68, 2239; g) E. C. Kornfeld, E. J. Fornefeld, G. B. Kline, M. J. Mann,
D. E. Morrison, R. G. Jones, R. B. Woodward, J. Am. Chem. Soc. 1956, 78,
3087; h) R. B. Turner, D. E. Nettleton, R. Ferebee, J. Am. Chem. Soc. 1956,
[16] Use of ETMs: J. Piera, J.-E. Bꢂckvall, Angew. Chem. Int. Ed. 2008, 47,
3506–3523; Angew. Chem. 2008, 120, 3558–3576.
Received: April 18, 2016
Published online on && &&, 0000
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S. Samadi, A. Orellana*
&& – &&
A New Route to Phenols: Palladium-
Catalyzed Cyclization and Oxidation of
g,d-Unsaturated Ketones
2-in-1: A new strategy for the synthesis
of substituted phenols from acyclic un-
saturated ketones is described. The re-
action features sequential redox-neutral
palladium-catalyzed cyclization and pal-
ladium-catalyzed oxidation steps. This
approach to phenols enables pre-pro-
gramming of substituents on the acyclic
system, and circumvents selectivity
issues frequently encountered in the
functionalization of phenols.
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