Synthesis of 2-acylphenol and flavene derivatives from the ruthenium-catalyzed oxidative c-h acylation of phenols with aldehydes

Article abstract of DOI:10.1002/ejoc.201403518

The cationic ruthenium hydride complex [(C₆H₆)(PCy₃)(CO)RuH]⁺BF₄^- has been found to be an effective catalyst for the oxidative C-H coupling reaction of phenols with aldehydes to give 2-acylphenol compounds. The coupling of phenols with α,β-unsaturated aldehydes selectively gives the flavene derivatives. The catalytic method mediates direct oxidative C-H coupling of phenol and aldehyde substrates without using any metal oxidants or forming wasteful byproducts. A cationic ruthenium hydride complex catalyzes the oxidative C-H coupling of phenols with aldehydes to form 2-acylphenol and flavene derivatives.

Full text of DOI:10.1002/ejoc.201403518

Job/Unit: O43518
/KAP1
Date: 16-02-15 13:32:12
Pages: 7
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403518
Synthesis of 2-Acylphenol and Flavene Derivatives from the Ruthenium-
Catalyzed Oxidative C–H Acylation of Phenols with Aldehydes
Hanbin Lee[a] and Chae S. Yi*[a]
Keywords: Acylation / Phenol / Aldehydes / Ruthenium / Flavene
The cationic ruthenium hydride complex [(C6H6)(PCy3)(CO)-
with α,β-unsaturated aldehydes selectively gives the flavene
derivatives. The catalytic method mediates direct oxidative
C–H coupling of phenol and aldehyde substrates without
using any metal oxidants or forming wasteful byproducts.
RuH]+BF4 has been found to be an effective catalyst for the
–
oxidative C–H coupling reaction of phenols with aldehydes
to give 2-acylphenol compounds. The coupling of phenols
Introduction
Results and Discussion
We recently discovered that the well-defined cationic
2-Acylphenols are a common core structure present in
many biologically active natural products and pharmaceuti-
cal agents.[1] Traditionally, Friedel–Crafts-type acylation re-
actions have been used to form acylated phenol com-
pounds,[2] but these methods have been found to be prob-
lematic in controlling product regioselectivity, tolerating
common functional groups as well as in forming wasteful
byproducts. Pd-catalyzed arene carbonylative coupling
methods have greatly advanced synthetic potency for form-
ing acyl-substituted arene compounds.[3] However, these
catalytic methods typically require prefunctionalization of
substrates, which lead to the formation of salt byproducts.
More recently, transition-metal-catalyzed C–H coupling
methods have emerged as step-efficient, environmentally
compatible ways to form aryl ketone compounds.[4–8] Che-
late-assisted oxidative C–H acylation methods have been
shown to be particularly effective in promoting regioselec-
tive introduction of acyl groups to indoles, benzamides and
other functionalized arene compounds.[5] Intramolecular
catalytic C–H coupling methods,[6] catalytic oxidative bond
cleavage reactions,[7] multicomponent coupling reactions of
arenes with CO/olefins,[8] and arene hydroxylation meth-
ods[9] have also been successfully applied to form 2-acylar-
ene products. While these catalytic C–H coupling methods
directly install acyl groups to arene substrates, the methods
are mostly limited to aromatic aldehydes and often require
stoichiometric metal oxidants. A broadly applicable oxidat-
ive C–H acylation method on phenol substrates is desired
to enhance its synthetic efficacy toward the synthesis of bio-
active acyl-substituted phenol compounds.
–
ruthenium hydride complex [(C6H6)(PCy3)(CO)RuH]+BF4
(1) is a highly effective catalyst precursor for a number of
dehydrative C–H coupling reactions of phenols with
alcohols to form 2-alkylphenol and benzofuran products.[10]
In light of the recent reports on coupling reactions of
alcohols,[11] one of the key mechanistic questions is whether
the alcohol substrate undergoes dehydrogenation to form
an aldehyde prior to the dehydrative coupling reactions. We
have been probing this possibility by exploring the reacti-
vity of phenols toward aldehydes. Here, we report a highly
regioselective oxidative C–H coupling of phenols with
aldehydes to form 2-acylphenol and flavene products. The
catalytic method mediates direct C–H activation of both
phenol and aldehyde substrates without using any metal
oxidants or resorting to prefunctionalization of phenol sub-
strates.
Initially, we had chosen the coupling reaction of 3-meth-
oxyphenol with benzaldehyde to probe the selectivity be-
tween acylation and alkylation products. The treatment of
3-methoxyphenol with benzaldehyde and the catalyst 1
(3 mol-%) under the previously reported dehydrative cou-
pling reaction conditions led to the formation of a 1:1 mix-
ture of the acylated phenol product 2a along with the alkyl-
ated product, but with only ca. 20% of the combined yield
[Equation (1)].[10] Suspecting that the aldehyde substrate
might have been reduced to benzyl alcohol in leading to the
alkylation product, we screened additive effects to optimize
for the acylation product 2a. Among screened additives and
selected ruthenium catalysts, complex 1 with base additives,
[a] Department of Chemistry, Marquette University
Milwaukee, Wisconsin 53201-1881, USA
E-mail: chae.yi@marquette.edu
www.marquette.edu/chem/Yi.shtml
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403518.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O43518
/KAP1
Date: 16-02-15 13:32:12
Pages: 7
H. Lee, C. S. Yi
SHORT COMMUNICATION
K2CO3 and PPh3, was found to be the most effective in ficient benzaldehydes gave significantly higher yields than
promoting the acylation product 2a (Table S1, Supporting the ones with electron-releasing group (Entries 10–18). The
Information).
coupling of 1-naphthol with both aliphatic and aryl-substi-
We explored the scope of the coupling reaction by using tuted aldehydes gave the 2-acylated products 2s–2x (En-
the optimized catalytic system (Table 1). Both aliphatic and tries 19–24), while the analogous coupling of 2-naphthol se-
aryl-substituted aldehydes readily reacted with 3-meth- lectively yielded 1-acylnaphthol products 2y and 2z (En-
oxyphenol to form the 2-acylphenol products 2 (Entries 1– tries 25 and 26). Although the crude mixture typically con-
9). For the coupling of 3,5-dimethoxyphenol, electron-de- tained a small amount of the alkylation product as well as
Table 1. Oxidative C–H acylation of phenols with aldehydes.[a]
[a] Reaction conditions: phenol (0.5 mmol), aldehyde (1.0 mmol), 1 (5 mol-%), PPh3 (20 mol-%), K2CO3 (30 mol-%), C6H5Cl (2–3 mL),
110 °C.
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43518
/KAP1
Date: 16-02-15 13:32:12
Pages: 7
Synthesis of 2-Acylphenol and Flavene Derivatives
unidentified oligomeric side products (5–10% combined), thetic utility of the catalytic method, we next surveyed the
analytically pure acylated products were readily isolated af- coupling reaction of phenol substrates with α,β-unsaturated
ter column chromatography on silica gel. In most cases, aldehydes to form flavonoid derivatives (Table 2). The cou-
2 equiv. of aldehyde is required for the optimum yield of pling reaction of 3-methoxyphenol with both aliphatic and
coupling products, as the second equivalent of aldehyde is aryl-substituted enals smoothly occurred to give the substi-
acting as a hydrogen acceptor.[12] The catalytic method tuted flavene derivatives (Entries 1–6). A substantially
achieves regioselective acylation of phenol substrates with- higher product yield was obtained from the coupling of 3,5-
out using any stoichiometric metal oxidants or reactive dimethoxyphenol substrate with disubstituted enals (En-
reagents.
tries 7–12). The coupling with β-phenylcinnamaldehyde af-
Flavonoids, a common group of polyphenol compounds forded the 2,2-disubstituted flavene product 3m (Entry 13).
in fruits and vegetables, have been shown to exhibit a wide The analogous treatment of 1-naphthol and 9-phenanthrol
range of pharmacological effects including anti-inflamma- with enals gave the corresponding polycyclic enol ether
tory, anti-aging and anticancer activities.[13] To extend syn- products 3n–3t (Entries 14–20). The formation of these
Table 2. Oxidative C–H acylation and dehydrative annulation of phenols with α,β-unsaturated aldehydes.[a]
[a] Reaction conditions: phenol (0.5 mmol), aldehyde (1.0 mmol), 1 (5 mol-%), PPh3 (20 mol-%), C6H5Cl (2–3 mL).
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O43518
/KAP1
Date: 16-02-15 13:32:12
Pages: 7
H. Lee, C. S. Yi
SHORT COMMUNICATION
flavene products 3 can be readily rationalized by ortho-C–
To discern the rate-limiting step of the coupling reaction,
H acylation followed by conjugate addition and dehydrative we next measured the deuterium isotope effect of the
annulation sequences. The structure of 2-acylphenol and aldehyde substrate. Thus, the reaction rate of 3,5-dimeth-
flavene products 2 and 3 was completely established by oxyphenol with PhCHO and PhCDO at 110 °C was
standard spectroscopic methods. The molecular structures measured separately [Equation (3)]. The kobs value for each
of 2v and 3t were also determined by X-ray crystallography substrate was obtained from the first-order plots of the for-
(Figures S3 and S4). Recently, a number of intermolecular mation of 2j, which led to a normal deuterium isotope
and intramolecular coupling and annulation catalytic meth- effect of kH/kD = 3.3Ϯ0.3 (Figure S2). The observation of
ods have been reported to form flavene derivatives, but a relatively high normal deuterium isotope effect is consis-
these typically require prefunctionalization of substrates tent with the rate-limiting aldehyde C–H activation step.
and multiple reaction steps.[14]
The chemoselectivity of the coupling method has been
explored by using bioactive phenol substrates (Scheme 1).
For example, estrone reacted smoothly with both aliphatic
and aryl-substituted aldehydes, 4-chlorobenzaldehyde and
cyclohexanecarbaldehyde, to give the 1:2 coupling products
4a and 4b, respectively. In this case, both arene C–H acyl-
ation and aldol-type couplings occurred on the estrone sub-
To probe electronic influence on the aldehyde substrate,
strate. Several attempts to form 1:1 coupling products were
we constructed a Hammett plot by comparing the rate of
unsuccessful, as mixtures of both C–H acylation and aldol-
3,5-dimethoxyphenol with a series of para-substituted benz-
aldehydes p-X–C6H4CHO (X = CH3, H, F, Cl, CF3). A
type coupling products resulted from using less than
1.5 equiv. of aldehyde substrate. The structure of 4b, as es-
linear correlation from the relative rate vs. Hammett σp led
tablished by X-ray crystallography, clearly showed the (E)-
to a positive ρ value of +0.69Ϯ0.05 (Figure 1). A strong
enone configuration (Figure S5).
promotional effect by the electron-withdrawing group
suggests a substantial cationic character build-up on the
carbonyl carbon atom in the transition state, which may
be facilitated by the formation of Ru–acyl species. Similar
Hammett ρ values have been observed in the catalytic cou-
pling reactions of benzaldehyde and related arenes.[15]
Scheme 1. Oxidative C–H acylation and aldol-type coupling of
estrone with aldehydes.
We conducted the following preliminary experiments to
gather mechanistic features. First, we examined the reaction
of a phenol with a deuterium-labeled aldehyde to probe the
possible H/D exchange pattern on both the phenol sub-
strate and the products. A mixture of 3,5-dimethoxyphenol
(0.5 mmol) with PhCDO (Ͼ 95% D, 1.0 mmol) in the pres-
ence of 1 (5 mol-%), PPh3 (20 mol-%), and K2CO3 (30 mol-
%) in chlorobenzene (2 mL) was heated at 110 °C for 12 h,
which led to 86% conversion as analyzed by both GC–MS
1
2
and NMR analysis [Equation (2)]. The H and H NMR
analysis showed exclusive deuterium incorporation on the
benzyl position (83% D) of the isolated benzyl alcohol by-
product, but no deuterium incorporation was observed on
either the starting material or the product 2j (Figure S1).
The presence of Ͼ80% of deuterium at the α-CH2 group
of benzyl alcohol byproduct suggests that the aldehyde sub-
strate serves as both the hydrogen acceptor and the reagent
for the coupling product.
Figure 1. Hammett plot from the reaction of 3,5-dimethoxyphenol
with p-X–C6H4CHO (X = CH3, H, F, Cl, CF3).
On the basis of these results, we compiled a plausible
mechanistic repertoire for the oxidative C–H acylation reac-
tion (Scheme 2). We propose that the initial displacement
of the benzene ligand with the phenol substrate and depro-
tonation of the Ru–H complex would generate a catalyti-
cally active neutral Ru–arene species 5. In support of this
notion, we previously observed a facile arene exchange re-
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43518
/KAP1
Date: 16-02-15 13:32:12
Pages: 7
Synthesis of 2-Acylphenol and Flavene Derivatives
action of 1 at room temperature.[16] The observed H/D ex-
change pattern on both the coupling product as well as the
recovered benzyl alcohol byproduct suggests a facile ortho-
C–H activation of the phenol substrate to form a metallated
species 6. Hydrogenation of the first equivalent of aldehyde,
coupled with the C–H activation of the second aldehyde
substrate, can be envisioned to rationalize the formation of
the Ru–acyl intermediate 7. Both the deuterium isotope ef-
fect and Hammett studies signify that the aldehyde C–H
activation is the turnover limiting step of the catalytic cycle.
The subsequent reductive elimination of the coupling prod-
uct 2 and the binding of another phenol substrate would
complete the catalytic cycle.
Acknowledgments
Financial support from the US National Science Foundation
(CHE-1358439) and the National Institute of Health General Med-
ical Sciences (R15GM109273) is gratefully acknowledged. The au-
thors thank Dr. Sergey Lindeman for the X-ray crystal structure
determination of 2v, 3t and 4b.
[1] a) Z. Rappoport, The Chemistry of Phenols, Wiley, Weinheim,
2003; b) M. G. Charest, C. D. Lerner, J. D. Brubaker, D. R. Sie-
gel, A. G. Myers, Science 2005, 308, 395; c) C. González-Bello,
L. Castedo, Sci. Synth. 2007, 31a, 319.
[2] a) P. H. Gore, Chem. Rev. 1955, 55, 229; b) G. A. Olah, Friedel–
Crafts Chemistry, Wiley Interscience, New York, 1973.
[3] a) A. Suzuki, Acc. Chem. Res. 1982, 15, 178; b) N. Miyaura,
A. Suzuki, Chem. Rev. 1995, 95, 2457.
[4] Recent reviews: a) T. W. Lyons, M. S. Sanford, Chem. Rev.
2010, 110, 1147; b) C. S. Yeung, V. M. Dong, Chem. Rev. 2011,
111, 1215; c) P. B. Arockiam, C. Bruneau, P. H. Dixneuf, Chem.
Rev. 2012, 112, 5879; d) V. S. Thirunavukkarasu, S. I. Kozhush-
kov, L. Ackermann, Chem. Commun. 2014, 50, 29.
[5] a) X. Jia, S. Zhang, W. Wang, F. Luo, J. Cheng, Org. Lett.
2009, 11, 3120; b) C.-W. Chan, Z. Zhou, A. S. C. Chan, W.-Y.
Yu, Org. Lett. 2010, 12, 3926; c) M. Li, H. Ge, Org. Lett. 2010,
12, 3464; d) O. Baslé, J. Bidange, Q. Shuai, C.-J. Li, Adv. Synth.
Catal. 2010, 352, 1145; e) C. Li, L. Wang, P. Li, W. Zhou,
Chem. Eur. J. 2011, 17, 10208; f) J. Park, E. Park, A. Kim, Y.
Lee, K.-W. Chi, J. H. Kwak, Y. H. Jung, I. S. Kim, Org. Lett.
2011, 13, 4390; g) V. S. Thirunavukkarasu, M. Donati, L. Ack-
ermann, Org. Lett. 2012, 14, 3416; h) S. Sharma, J. Park, E.
Park, A. Kim, M. Kim, J. H. Kwak, Y. H. Jung, I. S. Kim, Adv.
Synth. Catal. 2013, 355, 332; i) H. Li, P. Li, L. Wang, Org.
Lett. 2013, 15, 620; j) Q. Zhang, C. Li, F. Yang, J. Li, Y. Wu,
Tetrahedron 2013, 69, 320; k) Z. Wang, Q. Tian, X. Yu, C.
Kuang, Adv. Synth. Catal. 2014, 356, 961; l) S. Han, S. Sharma,
J. Park, M. Kim, Y. Shin, N. K. Mishra, J. J. Bae, J. H. Kwak,
Y. H. Jung, I. S. Kim, J. Org. Chem. 2014, 79, 275.
[6] a) B.-X. Tang, R.-J. Song, C.-Y. Wu, Y. Liu, M.-B. Zhou, W.-
T. Wei, G.-B. Deng, D.-L. Yin, J.-H. Li, J. Am. Chem. Soc.
2010, 132, 8900; b) P. Álvarez-Bercedo, A. Flores-Gaspar, A.
Correa, R. Martin, J. Am. Chem. Soc. 2010, 132, 466.
[7] a) C.-J. Li, Acc. Chem. Res. 2009, 42, 335; b) H. Rao, C.-J. Li,
Angew. Chem. Int. Ed. 2011, 50, 8936; Angew. Chem. 2011, 123,
9098; c) J. Yao, R. Feng, Z. Wu, Z. Liu, Y. Zhang, Adv. Synth.
Catal. 2013, 355, 1517.
[8] a) F. Kakiuchi, S. Murai, Acc. Chem. Res. 2002, 35, 826; b) F.
Kakiuchi, N. Chatani, Adv. Synth. Catal. 2003, 345, 1077.
[9] a) G. Shan, X. Yang, L. Ma, Y. Rao, Angew. Chem. Int. Ed.
2012, 51, 13070; Angew. Chem. 2012, 124, 13247; b) F. Mo,
L. J. Trzepkowski, G. Dong, Angew. Chem. Int. Ed. 2012, 51,
13075; Angew. Chem. 2012, 124, 13252; c) V. S. Thirunavukkar-
asu, L. Ackermann, Org. Lett. 2012, 14, 6206; d) P. Y. Choy,
F. Y. Kwong, Org. Lett. 2013, 15, 270; e) F. Yang, K. Rauch,
K. Kettelhoit, L. Ackermann, Angew. Chem. Int. Ed. 2014, 53,
11285; Angew. Chem. 2014, 126, 11467.
Scheme 2. Mechanistic hypothesis for the C–H oxidative acylation
of phenol with an aldehyde.
Conclusions
We successfully devised an ortho-selective C–H acylation
protocol for phenol substrates. The Ru catalytic system ex-
pedites the direct oxidative coupling of simple phenol and
aldehyde substrates to give 2-acylphenol and flavene prod-
ucts without using any external oxidants or resorting to
multistep synthetic manipulations. Efforts to utilize the
catalytic coupling method to synthesize bioactive flavene
molecules are currently underway in our laboratory.
Experimental Section
General Procedure for the C–H Acylation of Phenol with Aldehyde:
In a glove box, phenol (0.5 mmol), aldehyde (1.0 mmol), K2CO3
(30 mol-%), PPh3 (20 mol-%) and complex 1 (14 mg, 5 mol-%) were
dissolved in chlorobenzene (2 mL) in a 25 mL Schlenk tube
equipped with a Teflon stopcock and a magnetic stirring bar. The
tube was brought out of the glove box, inserted into an oil bath set
at 110 °C, and the mixture was stirred for 8–16 h. The reaction tube
was taken out of the oil bath and cooled to room temperature.
After the tube was open to air, the solution was filtered through a
short silica gel column by eluting with CH2Cl2 (10 mL), and the
filtrate was analyzed by GC–MS. Analytically pure product was
isolated by a simple column chromatography on silica gel (280–
400 mesh, hexanes/EtOAc). The product was completely charac-
terized by NMR and GC–MS analysis.
[10] D.-H. Lee, K.-H. Kwon, C. S. Yi, J. Am. Chem. Soc. 2012, 134,
7325.
[11] a) C. Gunanathan, D. Milstein, Acc. Chem. Res. 2011, 44, 588;
b) Y. Obora, ACS Catal. 2014, 4, 3972.
[12] Using more than 2 equiv. of aldehyde did not improve the
product yields, as excess aldehydes were found to form homo-
coupling products.
[13] a) E. Middleton Jr., C. Kandaswami, T. C. Theoharides,
Pharm. Rev. 2000, 52, 673; b) A. W. Boots, G. R. M. M. Ha-
enen, A. Bast, Eur. J. Pharmacol. 2008, 585, 325.
[14] a) S. J. Pastine, S. W. Youn, D. Sames, Org. Lett. 2003, 5, 1055;
b) W. A. L. van Otterlo, E. L. Ngidi, S. Kuzvidza, G. L. Mor-
gans, S. S. Moleele, C. B. de Koning, Tetrahedron 2005, 61,
9996; c) A. Aponick, B. Biannic, M. R. Jong, Chem. Commun.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O43518
/KAP1
Date: 16-02-15 13:32:12
Pages: 7
H. Lee, C. S. Yi
SHORT COMMUNICATION
2010, 46, 6849; d) S. Madabhushi, R. Jillella, K. R. Godala,
K. K. R. Mallu, C. R. Beeram, N. Chinthala, Tetrahedron Lett.
2012, 53, 5275.
2085; c) M. S. Sigman, E. W. Werner, Acc. Chem. Res. 2012,
45, 874.
K.-H. Kwon, D. W. Lee, C. S. Yi, Organometallics 2010, 29,
[16]
[15] Selected recent examples: a) P. Fristrup, M. Kreis, A. Palme-
lund, P.-O. Norrby, R. Madsen, J. Am. Chem. Soc. 2008, 130,
5206; b) L. Koren-Selfridge, H. N. Londino, J. K. Vellucci, B. J.
Simmons, C. P. Casey, T. B. Clark, Organometallics 2009, 28,
5748.
Received: November 24, 2014
Published Online: ᭿
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43518
/KAP1
Date: 16-02-15 13:32:12
Pages: 7
Synthesis of 2-Acylphenol and Flavene Derivatives
Oxidative Coupling
H. Lee, C. S. Yi* .............................. 1–7
Synthesis of 2-Acylphenol and Flavene De-
rivatives from the Ruthenium-Catalyzed
Oxidative C–H Acylation of Phenols with
Aldehydes
Keywords: Acylation / Phenol / Aldehydes /
Ruthenium / Flavene
A
cationic ruthenium hydride complex
phenols with aldehydes to form 2-acyl-
phenol and flavene derivatives.
catalyzes the oxidative C–H coupling of
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7