Pd-catalyzed sp2 C-H hydroxylation with TFA/TFAA via weak coordinations

Article abstract of DOI:10.1055/s-0033-1339871

An efficient sp² C-H hydroxylation has been developed for the synthesis of a wide range of functionalized phenols with aryl ketones, benzoates, benzamides, acetanilides and sulfonamides through palladium(II) catalysis. A trifluoroacetic acid (TFA)/trifluoroacetic anhydride (TFAA) co-solvent system serves as the oxygen source and is the critical factor for weak coordination promoted C-H activation. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339871

2472▌
SYNPACTS
2
synpacts
Pd-Catalyzed sp C–H Hydroxylation with TFA/TFAA via Weak Coordina-
tions
Pd-Catalyzed sp2 C–H Hydroxylation
Yu Rao*
MOE Key Laboratory of Protein Sciences, Department of Pharmacology and Pharmaceutical Sciences, School of Medicine and School of Life
Sciences, Tsinghua University, Beijing 100084, P. R. of China
Fax +86(10)62783404; E-mail: yrao@tsinghua.edu.cn
Received: 14.06.2013; Accepted after revision: 30.08.2013
Abstract: An efficient sp2 C–H hydroxylation has been developed
for the synthesis of a wide range of functionalized phenols with aryl
ketones, benzoates, benzamides, acetanilides and sulfonamides
through palladium(II) catalysis. A trifluoroacetic acid (TFA)/triflu-
oroacetic anhydride (TFAA) co-solvent system serves as the oxy-
gen source and is the critical factor for weak coordination promoted
C–H activation.
Key words: phenol synthesis, C–H hydroxylation, palladium, oxy-
gen heterocycles
Functionalized phenols are highly valuable chemicals that
are used in pharmaceutical, agrochemical and polymer in-
dustries.1 Although tremendous progress has been made
Professor Yu Rao received his BA degree in 1999 from Shandong
towards the direct catalytic hydroxylation of arenes to
phenols, there are still many unmet challenges for the di-
rect hydroxylation in terms of regio- and chemoselectivity
and practicality of the prevalent methods (Scheme 1). For
example, 2-hydroxy aromatic ketones are an important
structural motif found in a diverse range of bioactive mol-
ecules from natural products to drugs. Moreover, they also
serve as versatile building blocks for the preparation of
various oxygen-containing heterocycles, such as benzofu-
ranone, chromanone, and dibenzooxazepine. Traditional
approaches to making 2-hydroxy aromatic ketones in-
clude oxidation of benzylic alcohol,2 Fries rearrangement
of esters,3 hydrolysis of aromatic halides,4 and demethyl-
ation of methyl phenyl ether.5 However, these approaches
always suffer some limitations such as tedious reaction
procedures, low yields, harsh reaction conditions or for-
mation of side products.
Medical University and his MS degree in 2002 under the supervision
of Prof. Jixiang Chen from Shenyang Pharmaceutical University. He
obtained his Ph.D. degree from the University of Georgia by working
on the synthesis of biologically important complex oligosaccharides
under the supervision of Prof. Geert-Jan Boons (2007). He then car-
ried out post-doctorial research work at Sloan-Kettering Cancer Cen-
ter under the supervision of Prof. Samuel J. Danishefsky (2007–
2010), focusing on the synthesis of bioactive natural products. He
joined Tsinghua University in 2010. Prof. Rao’s major research inter-
ests are heterocycle chemistry and medicinal chemistry.
of the starting materials and the high atom economy. Fur-
thermore, discovering a more general approach to regio-
and chemoselective C–H hydroxylation of a variety of
challenging arenes would be especially desirable for phe-
nol synthesis (Scheme 1).
Herein, our results on palladium(II)-catalyzed regio- and
chemoselective C–H hydroxylation of arenes and its ap-
plications in heterocycle synthesis and late-stage drug
modification are described.
OH
H
R
Pd(II) catalysts
In the past decade, transition metals6,7 such as palladium8
have been used to catalyze C–H bond activation by weak
coordination, and this has led to significant advances in
terms of reaction selectivity and atom economy. In our
studies of phenol synthesis, we proposed that palladi-
um(II) catalysts can cleave ortho C–H bonds through an
orthometalation process involving weak coordination of
the carbonyl group from aryl ketones, benzoates, benza-
mides, etc or even the sulfonyl oxygen from sulfon-
R
TFA/TFAA, oxidants
R = COR1, CO2Et, CONHR2, NHCOR3, SO2NHR4
Scheme 1 Developing a general strategy to functionalized phenols
Hence, direct transformation of aromatic ketones into 2-
hydroxylated products through transition-metal-catalyzed
C−H activation is attractive due to the ready availability
amides,9,10
under
suitably
acidic
conditions.
Consequently, C–O bond formation is possible through
reductive elimination to afford the corresponding phenols
with suitable acid reagents (Scheme 1).11
SYNLETT 2013, 24, 2472–2476
Advanced online publication: 30.09.2013
DOI: 10.1055/s-0033-1339871; Art ID: ST-2013-P0551-SP
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

SYNPACTS
Pd-Catalyzed sp2 C–H Hydroxylation
2473
Our model study started with aromatic ketone 1 in the a broad range of aromatic ketones were transformed into
presence of Pd(OAc)2 with oxidants such as PhI(OAc)2, the corresponding phenol derivatives in moderate to ex-
Selectfluor12 and K2S2O813 in AcOH/Ac2O solvent system cellent yields. The ortho-, meta- and para-substituted aryl
(Scheme 2). After many attempts, however, no desired groups, including electron-withdrawing and electron-do-
product was formed. Stronger acids such as trichloroace- nating functional groups, were well tolerated. For unsym-
tic acid/anhydride (TCA/TCAA) and trifluoroacetic ac- metrical diaryl ketone substrates, the more electron-rich
id/anhydride (TFA/TFAA) were then tested. To our parts were hydroxylated preferentially over less electron-
delight, the phenol product 2 was observed in these sol- rich parts (5, 8, and 9). To our delight, a remarkable regio-
vent systems (32% yield with TFA/TFAA after stirring and chemoselectivity was observed when ketones con-
for 10 h at 100 °C), which suggests that the strong acidity taining reactive α-protons were used (14, 15, and 16).
of TFA played a key role in this reaction. Further optimi- During our investigation, it was noticed that actually aryl
zation studies were performed with a range of oxidants, ketone substrates can be converted into the desired phenol
TFA/TFAA ratios, and palladium catalysts. It was found products effectively at ambient temperature under these
that, generally, 0.05 equivalent of Pd(OAc)2 was suffi- conditions (yields given in the parentheses in Scheme 3),
cient to effectively promote the reaction to completion albeit in longer time (typically 24–48 h). For instance, di-
within 3–4 hours at 90 °C.
oxybenzone 20, an organic compound broadly used in
sunscreen to block UVB and short-wave UVA (ultravio-
let) rays,14 was readily prepared by using our new method
at room temperature without protecting the free hydroxyl
group of 19 (Scheme 4), which proved both the practical-
ity and effectiveness of this novel approach. It is also
noteworthy that this protocol was conducted without the
need for air- or moisture-proof conditions.
After establishing these optimal conditions, the scope of
this new reaction was examined. As shown in Scheme 3,
OH
O
H
O
Pd(OAc)2, (5 mol%)
various conditions
yield up to 80%
1
2
Scheme 2 A model study with aromatic ketone 1
OH
O
H
O
R2
Pd(OAc)2 (5 mol%), TFA/TFAA, K2S2O8
50–90 °C or r.t.
R2
R1
R1
R1
O
R2
R1
O
R2
OH
O
Cl
F
F
Cl
4a R1 = H, R2 = OH, 63%
4b R1 = R2 = OH, 16%
5a R1 = OH, R2 = H, 77%
5b R1 = H, R2 = OH, 11%
3 87%
R1
O
R2
OH
O
OH
O
R
CHO
NO2
8a R1 = OH, R2 = H, 58%
8b R1 = H, R2 = OH, 12%
6 R = CO2Et, 47%
7 R = NHCOCF3, 57%
9 83%
OH
O
OH
O
OH
O
t-Bu
t-Bu
Me
R
R
Me
10 R = Cl, 88% (50%)
11 R = H, 84% (65%)
12 R = Me, 94%
13 R = F, 51%
14 R = Me, 58% (78%)
OH
O
OH
O
OH
O
Et
Me
Me
Et
16 65% (72%)
Me
15 R = H, 50% (51%)
Me
R
17 R = F, 31%
18 R = OMe, 30%
Scheme 3 The scope of the reaction with aryl ketones
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2472–2476

2474
Y. Rao
SYNPACTS
Pd(OAc)2, (5 mol%)
TFA/TFAA (9:1)
K2S2O8
Besides aryl ketones, the scope of the reaction was further
explored (Scheme 5). For example, substrates including
benzoates, benzamides, acetanilides and sulfonamides
were also successfully converted into the corresponding
phenol products in modest to good yields. Considering
that aromatic ketones, esters, amides and sulfonamides
are common scaffolds in drugs and natural products, this
method can potentially provide a facile way for rapid ac-
cess to hydroxylated analogues of a broad range of sub-
strates.
OH
O
OH
OH
O
H
r.t.
MeO
MeO
19
20 82%
Scheme 4 C–H hydroxylation of aromatic ketone at room tempera-
ture
OH
H
As illustrated in Scheme 6, a variety of biologically im-
portant O-containing heterocycles, such as benzofuran-
3(2H)-one 29 and xanthone 30, were prepared from 2-hy-
droxylated aryl ketone derivatives, which demonstrates
the synthetic utility of this C–H hydroxylation reaction.
R
R
Pd(OAc)2 (5 mol%), TFA/TFAA, K2S2O8
R = COOEt, CONHR1, NHCOR2, SO2NHR3
OH
O
OH
O
In Scheme 7, we show the feasibility of our new reaction
in late-stage modification of drug candidates. By perform-
ing a regio- and chemoselective C–H hydroxylation, ibu-
profen ethyl ester (a representative nonsteroidal anti-
inflammatory drug) was directly converted into a novel
hydroxylated ibuprofen analogue 32.
OEt
OEt
R
F
Br
21 R = H, 51%
22 R = Me, 83%
23 82%
OH
O
F
O
Preliminary studies were conducted to gain some insight
into the reaction mechanism (Scheme 8). Crystals of the
reaction intermediate 34 (the identity of which was con-
firmed by X-ray analysis, with our results being consist
with those reported previously9b) prepared with a stoi-
chiometric amount of Pd(OAc)2, can undergo oxidation
by K2S2O8 to afford phenol product 35. Moreover, triflu-
oroacetate product 37 was obtained from the reaction of
aryl ketone 36, which was then transformed into the or-
tho-hydroxylated product 13 after workup and purifica-
tion. These results suggest a two-fold effect of
TFA/TFAA: (1) the system is an essential factor for weak
coordination promoted C–H activation, and (2) it serves
NHPr
NH
OH
Me
Me
F
25 52%
24 71%
O
O
OH
S
H
N
NH
CF3
Et
Me
OH
27 66%
O
26 66%
Scheme 5 The scope of the reaction with other substrates
O
O
OH
O
Cl
OH
O
a
c
Me
O
Ph
O
28 85%
30 95%
OH
O
OH
O
O
Me
Me
Me
d
b
Me
O
O
29 81%
31 60%
Scheme 6 Transforming 2-hydroxy aromatic ketones into oxygen-containing heterocycles. Reagents and conditions: (a) benzaldehyde, NaOH,
EtOH, r.t., 12 h, 72%; I2, DMSO, reflux, 1 h, 85%; (b) Tf2O, pyridine, CH2Cl2, –78 °C to r.t., 2 h, 83%; DBU, DMF, 0.2 h, 81%; (c) KOH, H2O,
100 °C, 15 h, 95%; (d) CuOAc, K2CO3, 8-hydroxyquinoline, O2, DMA, 140 °C, 24 h, 60%.
HO
Me
H
Me
Pd(OAc)2 (5 mol%)
TFA/TFAA (3:2)
OEt
OEt
Me
Me
O
O
K2S2O8, 2–3 h
Me
Me
ibuprofen ethyl ester
32 60%
hydroxylated derivative
Scheme 7 Regio- and chemoselective modification of ibuprofen
Synlett 2013, 24, 2472–2476
© Georg Thieme Verlag Stuttgart · New York

SYNPACTS
Pd-Catalyzed sp2 C–H Hydroxylation
2475
as the oxygen source in the reaction. Based on the above selectivity, good functional group tolerance and high
investigations, we propose that TFA/TFAA can be used as yields. Current work is focused on broadening the scope
a general reagent for Pd-catalyzed C–H hydroxylation of of the reaction and conducting further mechanistic stud-
arenes in phenol synthesis.15
ies.
2
Acknowledgment
O
TFA Pd
O
OH
OH
O
This work was supported by the national ‘973’ grant (grant
2011CB965300), NSFC grant (grant 21142008) and Tsinghua Uni-
versity 985 Phase II funds and Tsinghua University Initiative Scien-
tific Research Program.
Ada
a
b
Ada
Ada
92%
96%
Me
35
33
34
Me
Me
O
CF3C(O)O
O
O
References and Notes
aqueous
workup
t-Bu
t-Bu
c
t-Bu
(1) (a) Tyman, J. H. P. Synthetic and Natural Phenols; Elsevier:
New York, 1996. (b) Rappoport, Z. The Chemistry of
Phenols; Wiley-VCH: Weinheim, 2003. (c) Bedford, R. B.;
Coles, S. J.; Hursthouse, M. B.; Limmert, M. E. Angew.
Chem. Int. Ed. 2003, 42, 112. (d) Dorta, R.; Togni, A. Chem.
Commun. 2003, 760. (e) Boebel, T. A.; Hartwig, J. F. J. Am.
Chem. Soc. 2008, 130, 7534.
37
(confirmed by 1H, 13C, 19F NMR)
F
F
36
13
F
Scheme 8 Studies of the mechanistic pathway. Reagents and condi-
tions: (a) 100% Pd(OAc)2, TFA, r.t.; (b) K2S2O8, r.t., TFA/TFAA;
(c) 5% Pd(OAc)2, K2S2O8, TFA/TFAA, r.t.
(2) Alaimo, P. J.; Knight, Z. A.; Shokat, K. M. Bioorg. Med.
Chem. 2005, 13, 2825.
(3) Miller, J. A. J. Org. Chem. 1987, 52, 322.
(4) Xu, H.; Liang, Y.; Cai, Z.; Qi, H.; Yang, C.; Feng, Y. J. Org.
Chem. 2011, 76, 2296.
(5) Yadav, J. S.; Reddy, B. V. S.; Madan, Ch.; Hashim, S. R.
Chem. Lett. 2000, 29, 738.
Additionally, the result of parallel competition experi-
ments showed that electron-rich aromatic rings react
much faster than their electron-poor counterparts. More-
over, consistent and significant KIE values were observed
from both intra- (kH/kD = 5.6) and intermolecular
(kH/kD = 5.0) isotope effect studies, which suggested that
the C–H bond cleavage step might be the rate-limiting
step of this reaction.
(6) For general reviews on transition-metal-catalyzed C–H
activation of arenes, see: (a) Kakiuchi, F.; Chatani, N. Adv.
Synth. Catal. 2003, 345, 1077. (b) Dick, A. R.; Sanford, M.
S. Tetrahedron 2006, 62, 2439. (c) Godula, K.; Sames, D.
Science 2006, 312, 67. (d) Yu, J. Q.; Giri, R.; Chen, X. Org.
Biomol. Chem. 2006, 4, 4041. (e) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. Rev. 2007, 107, 174. (f) Ackermann, L.;
Vicente, R.; Kapdi, A. R. Angew. Chem. Int. Ed. 2009, 48,
9792. (g) Daugulis, O.; Do, H. Q.; Shabashov, D. Acc.
Chem. Res. 2009, 42, 1074. (h) Colby, D. A.; Bergman, R.
G.; Ellman, J. A. Chem. Rev. 2010, 110, 624.
(7) For illustrative transition-metal-catalyzed C–H activation of
arenes, see: (a) Enthaler, S.; Company, A. Chem. Soc. Rev.
2011, 40, 4912. (b) Dick, A. R.; Hull, K. L.; Sanford, M. S.
J. Am. Chem. Soc. 2004, 126, 2300. (c) Chernyak, N.;
Dudnik, A. S.; Huang, C.; Gevorgyan, V. J. Am. Chem. Soc.
2010, 132, 8270. (d) Desai, L. V.; Malik, H. A.; Sanford, M.
S. Org. Lett. 2006, 8, 1141. (e) Gou, F. R.; Wang, X. C.;
Huo, P. F.; Bi, H. P.; Guan, Z. H.; Liang, Y. M. Org. Lett.
2009, 11, 5726. (f) Zheng, X.; Song, B.; Xu, B. Eur. J. Org.
Chem. 2010, 4376. (g) Wang, G. W.; Yuan, T. T. J. Org.
Chem. 2010, 75, 476.
(8) (a) Dick, A. R.; Kampf, J. W.; Sanford, M. S. J. Am. Chem.
Soc. 2005, 127, 12790. (b) Kalberer, E. W.; Whitfield, S. R.;
Sanford, M. S. J. Mol. Catal. A: Chem. 2006, 251, 108.
(c) Deprez, N. R.; Sanford, M. S. Inorg. Chem. 2007, 46,
1924. (d) Neufeldt, S. R.; Sanford, M. S. Org. Lett. 2010, 12,
532. (e) Jintoku, T.; Nishimura, K.; Takaki, K.; Fujiwara, Y.
Chem. Lett. 1990, 19, 1687. (f) Xiao, B.; Gong, T. J.; Liu, Z.
J.; Liu, J. H.; Luo, D. F.; Xu, J.; Liu, L. J. Am. Chem. Soc.
2011, 133, 9250. (g) Huang, C. H.; Ghavtadze, N.;
Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem. Soc. 2011,
133, 17630.
On the basis of our studies, a possible mechanism for this
reaction is proposed in Scheme 9. In the first step, chelate-
directed C–H activation of the substrate could afford a
five-membered cyclopalladium(II) dimeric intermediate.
Then, Pd(II) can be oxidized into a Pd(IV) intermediate in
the following step. The final step (iii) involves carbon–ox-
ygen bond-forming reductive elimination to provide the
trifluoroacetate product and reduces Pd(IV) back into
Pd(II). The trifluoroacetate product is transformed into the
phenol derivatives upon subsequent workup.
2
O
(ii)
TFA Pd
O
(i)
oxidants
t-Bu
t-Bu
TFA
TFA Pd
O
Pd(II)
t-Bu
CF3C(O)O
[H+]
O
OH
O
(iii)
Pd(IV)
t-Bu
t-Bu
Pd(II)
Scheme 9 A possible reaction mechanism
In summary, a Pd(II) catalyzed regio- and chemoselective
phenol synthesis has been developed for the synthesis of
a broad range of functionalized phenols from aryl ketones,
benzoates, benzamides, acetanilides and sulfonamides.16
The reaction proceeds with excellent reactivity, ortho-
(9) (a) Gandeepan, P.; Parthasarathy, K.; Cheng, C. J. Am.
Chem. Soc. 2010, 132, 8569. (b) Xiao, B.; Gong, T.; Xu, J.;
Liu, Z.; Liu, L. J. Am. Chem. Soc. 2011, 133, 1466. (c) Dai,
H.-X.; Stepan, A. F.; Plummer, M. S.; Zhang, Y.-H.; Yu, J.-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2472–2476

2476
Y. Rao
SYNPACTS
Q. J. Am. Chem. Soc. 2011, 133, 7222. (d) Zhang, Y.-H.; Yu,
J.-Q. J. Am. Chem. Soc. 2009, 131, 14654.
135, 9350. (l) Sun, X.; Shan, G.; Sun, Y.; Rao, Y. Angew.
Chem. Int. Ed. 2013, 52, 4440.
(10) For C–H activation through weak coordination, see:
(a) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc.
Chem. Res. 2012, 45, 788. (b) Engle, K. M.; Thuy-Boun, P.
S.; Dang, M.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 18183.
(c) Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14082.
(d) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem. Int.
Ed. 2009, 48, 6097. (e) Thirunavukkarasu, V. S.; Hubrich,
J.; Ackermann, L. Org. Lett. 2012, 14, 4210.
(11) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006,
8, 1141.
(12) For bystanding F+ oxidants, see: (a) Engle, K. M.; Mei, T.-
S.; Wang, X.; Yu, J.-Q. Angew. Chem. Int. Ed. 2011, 50,
1478. (b) Wang, X.; Lu, Y.; Dai, H. X.; Yu, J. Q. J. Am.
Chem. Soc. 2010, 132, 12203.
(13) Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134, 134.
(14) Kishida, S.; Kawasaki, Y.; Yakupcin, R. U. S. Patent US
20110250250 A1 20111013, 2011.
(15) For methane C–H oxygenation examples, see: (a) Basickes,
N.; Hogan, T. E.; Sen, A. J. Am. Chem. Soc. 1996, 118,
13111. (b) Kao, L.; Hutson, A. C.; Sen, A. J. Am. Chem. Soc.
1991, 113, 700.
(f) Thirunavukkarasu, V. S.; Ackermann, L. Org. Lett. 2012,
14, 6206. (g) Yang, F.; Ackermann, L. Org. Lett. 2013, 15,
718. (h) Choy, P.; Kwong, F. Org. Lett. 2013, 15, 270.
(i) Liu, Q.; Wu, P.; Yang, Y.; Zeng, Z.; Liu, J.; Yi, H.; Lei,
A. Angew. Chem. Int. Ed. 2012, 4666. (j) Li, Y.; Ding, Y.;
Wang, J.; Su, Y.; Wang, X. Org. Lett. 2013, 15, 2574.
(k) Gallardo-Donaire, J.; Martin, R. J. Am. Chem. Soc. 2013,
(16) Shan, G.; Yang, X.; Ma, L.; Rao, Y. Angew. Chem. Int. Ed.
2012, 51, 13070.
Synlett 2013, 24, 2472–2476
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.