Rhodium(III)-Catalyzed Selective C-H Acetoxylation and Hydroxylation Reactions

Article abstract of DOI:10.1021/acs.orglett.7b01494

An efficient Cp?Rh(III)-catalyzed, chelation-assisted C(sp²)-H acetoxylation and hydroxylation reaction has been developed for the first time. The reaction proceeds under mild conditions and allows for selective preparation of C-H acetoxylation

Full text of DOI:10.1021/acs.orglett.7b01494

Letter
pubs.acs.org/OrgLett
Rhodium(III)-Catalyzed Selective C−H Acetoxylation and
Hydroxylation Reactions
Yunxiang Wu and Bing Zhou*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai
201203, China
University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: An efficient Cp*Rh(III)-catalyzed, chelation-
assisted C(sp2)−H acetoxylation and hydroxylation reaction
has been developed for the first time. The reaction proceeds
under mild conditions and allows for selective preparation of
C−H acetoxylation and hydroxylation products, thus provid-
ing a good complement to previous C−H oxygenation reactions and expanding the field of Cp*Rh(III)-catalyzed C−H
functionalizations.
−O bonds are ubiquitous in natural products, pharma-
Continuing our research efforts in the development of novel
Rh(III)-catalyzed C−H functionalization,10 we herein report the
first Cp*Rh(III)-catalyzed C−H oxygenation reaction (Scheme
1b). Notably, the optimized catalytic system allowed for selective
C−H acetoxylation or hydroxylation reaction under mild
reaction conditions, providing a good complement to previous
C−H oxygenation reactions and expanding the field of Rh(III)-
catalyzed C−H functionalizations.6
We started our model study by investigating the direct C−H
oxygenation of 2-phenylpyridine (1a) with PhI(OAc)2 as the
oxidant in the presence of (Cp*RhCl2)2 (5 mol %) and AgSbF6
(20 mol %) in various solvents (Table 1). We found that HOAc
as the solvent could indeed efficiently catalyze the reaction and
give the desired acetoxylation product 2a in 48% yield (entry 4).
To our delight, using HOAc/Ac2O (10:1) as the solvent further
improved the yield to 83% (entry 6).3a,d,11 A screening of additive
indicated that other additives provided inferior results (entries
7−11). More gratifyingly, hydroxylation product 3a could be
selectively obtained in 82% yield when 10 equiv of H2O was
added (entry 12). Control experiments indicated that no desired
product was generated in the absence of either rhodium catalyst
or PhI(OAc)2 (entries 13 and 14).
With the optimal reaction conditions in hand, we explored the
scope with respect to the 2-phenylpyridine derivatives (Scheme
2). The benzene ring with electron-donating and electron-
withdrawing groups at the ortho-, meta-, or para-position
proceeded well (2a−h). Substrates with a methyl group on the
phenyl ring at the ortho-position (2b) and on the pyridine ring at
the 3-position (2i) also reacted well, thus indicating high steric
tolerance of this system. The substrates containing a halogen
(2f), ester (2g), and even carboxaldehyde (2h) group were also
compatible and allow additional substrate modification. Notably,
the arene ring can also be extended to a pyrrole (2l) and
C
ceuticals, biologically active compounds, fragrances, and
polymers.1 As a consequence, there is a continued interest in the
development of new methods to construct C−O bonds. In view
of green and sustainable chemistry as well as in economic terms,
it is desirable and attractive to take advantage of chelation-
assisted C(sp2)−H activation, leading to C−O bond formation.2
However, in the past decade, only limited examples of chelation-
assisted C−H oxygenation have been reported by using
palladium,3 less commonly, copper,4 and ruthenium.5 Despite
these attractive processes, there is still a need for complementary
methods to attain a broader utility of this transformation.
Recently, Cp*Rh(III) complexes have recently stood out as
efficient catalysts for the chelation-assisted C(sp2)−H function-
alizations, with high activity, selectivity, broad substrate scope,
and high functional group tolerance.6 Despite these attractive
processes, all the reactions are limited to C−C,6 C−N,7 less
commonly, C−S(Se),8 and C−Hal9 bond formation (Scheme
1a). There have been no reports on the Rh(III)-catalyzed C−O
bond-forming reactions before now, presumably because the
strong binding ability of very electronegative O atoms (Pauling
electronegativity, 3.44) to the active Rh catalyst inhibits the
effective reductive elimination.
Scheme 1. Cp*Rh(III)-Catalyzed C−Heteroatom-Forming
Reaction
Received: May 17, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01494
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Organic Letters
Letter
a
worked well as a directing group to facilitate the acetoxylation
reaction.
Table 1. Reaction Optimization
Extension of the acetoxylation reaction to direct C−H
hydroxylation reaction proved successful (Scheme 3). 2-
a
Scheme 3. Rh(III)-Catalyzed C−H Hydroxylation Reaction
a
Reaction conditions: 1 (0.2 mmol), PhI(OAc)2 (0.24 mmol),
(Cp*RhCl2)2 (5 mol %), AgSbF6 (20 mol %), H2O (2 mmol),
AcOH/Ac2O (2 mL/0.2 mL), 80 °C, 12 h. Isolated yield.
a
Conditions: 1a (0.2 mmol), PhI(OAc)2 (0.24 mmol), (Cp*RhCl2)2
(5 mol %), additive (20 mol %), solvent, 80 °C, 12 h. Isolated yield.
Phenylpyridines bearing donating as well as withdrawing groups
in the phenyl ring reacted smoothly with PhI(OAc)2 to give the
corresponding products 3a−3h in 65−85% yield. Substrates with
a methyl group on the phenyl ring at the ortho-position (3b) and
on the pyridine ring at the 3-position (3i) were well-tolerated,
thus indicating high steric tolerance of this system. Under
modified reaction conditions, the direct hydroxylatoin of arenes
assisted by pyridine (3a−i), pyrimidine (3j), and azobenzene
(3k) all proceeded smoothly in good to high yields.
b
c
10 equiv of H2O was added. The reaction was carried out in the
d
absence of rhodium catalyst. The reaction was carried out in the
absence of PhI(OAc)2.
a
Scheme 2. Rh(III)-Catalyzed C−H Acetoxylation Reaction
Synthetic applications of this C−H oxygenation have been
demonstrated. The hydroxylation products, 2-(pyridin-2-yl)-
phenols, are important synthetic intermediates for the synthesis
of various biologically active compounds and organic light-
emitting materials (eq 1).12 A series of preliminary experiments
have been performed to probe the mechanism. Significant H−D
exchange was observed when treating 2-phenylpyridine in
AcOD/Ac2O in the absence of PhI(OAc)2 (eq 2). Moreover,
in the presence of PhI(OAc)2, the deuteration was also observed
in the reisolated 1a (eq 3). Both results indicate the reversibility
of the ortho-C(sp2)−H bond cleavage process. In the reaction of
2-phenylpyridine (1a) and 2-phenyl-[d5]pyridine (1a-d5) with
PhI(OAc)2, a kinetic isotope effect of 1.2 was observed (eq 4).
Moreover, a kinetic isotopic effect of 1.28 was also obtained from
two side-by-side reactions using 1a and 1a-d5 (eq 5). Both results
indicated that the C−H bond cleavage might not be involved in
the rate-determining step.13 To further understand the reaction
process, cyclometalated Rh(III) complex 4 was prepared, and 4
successfully catalyzed the acetoxylation reaction, suggesting the
plausible intermediacy of a cyclometalated complex in the
catalytic cycle (eq 6). Treatment of 2a under the standard
reaction condition did not give 3a, indicating that the
hydroxylation products are not formed by hydrolysis of
acetoxylation products (eq 7).
a
Reaction conditions: 1 (0.2 mmol), PhI(OAc)2 (0.24 mmol),
(Cp*RhCl2)2 (5 mol %), AgSbF6 (20 mol %), AcOH/Ac2O (2 mL/
0.2 mL), 80 °C, 12 h. Isolated yield.
thiophene (2m). In addition to pyridine, pyrazole (2j),
pyrimidine (2k−m), ketoxime (2n), and azobenzene (2o) also
Based on the above observed data, we propose the catalytic
cycle to involve an initial reversible C−H activation to form five-
B
DOI: 10.1021/acs.orglett.7b01494
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Letter
products has been demonstrated in subsequent functional group
transformations. The relatively mild reaction conditions, the
tolerance of various synthetically useful functional groups, and
the selective preparation of acetoxylation and hydroxylation
products may allow for synthetic application opportunities.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01494.
Experimental procedures, characterization of products,
and copies of 1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zhoubing@simm.ac.cn or zhoubing2012@hotmail.
com.
ORCID
Bing Zhou: 0000-0003-1813-8035
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the 1000-Youth Talents Plan, the
CAS Pioneer Hundred Talents Program, Shanghai Rising-Star
Program (Grant No. 17QA1405000) and Personalized Medi-
cinesMolecular Signature-based Drug Discovery and Devel-
opment, and Strategic Priority Research Program of the Chinese
Academy of Sciences (Grant No. XDA12020333).
REFERENCES
■
(1) (a) Buckingham, J. Dictionary of Natural Products; University Press:
Cambridge, MA, 1994. (b) Czarnik, A. W. Acc. Chem. Res. 1996, 29,
112−113. (c) Theil, F. Angew. Chem., Int. Ed. 1999, 38, 2345−2347.
(d) Sawyer, J. S. Tetrahedron 2000, 56, 5045−5065. (e) Thomas, A. W.;
Ley, S. V. Angew. Chem., Int. Ed. 2003, 42, 5400−5449. (f) Cristau, P.;
Vors, J.-P.; Zhu, J. Tetrahedron 2003, 59, 7859−7870. (g) Muci, A. R.;
Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131−209.
membered complex A and release 1 equiv of proton (H+)
(Scheme 4).6 Oxidation of A with PhI(OAc)2 generates the
Rh(V) complex B, which undergoes a reductive elimination to
afford the product 2a and regenerate the active Rh(III) catalyst.
In summary, we have reported the first Rh(III)-catalyzed C−H
oxygenation reaction under chelation assistance. This protocol
shows an excellent tolerance of functional group and allows for
selective preparation of acetoxylation and hydroxylation
products, thus providing a good complement to current C−H
oxygenation reactions. The synthetic utility of these oxygenation
(2) Reviews on metal-catalyzed C−O bond-forming reactions:
(a) Enthaler, S.; Company, A. Chem. Soc. Rev. 2011, 40, 4912−4924.
(b) Alonso, D. A.; Najera, C.; Pastor, I. M.; Yus, M. Chem. - Eur. J. 2010,
16, 5274−5284. (c) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110,
1147−1169.
(3) (a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004,
126, 2300−2301. (b) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett.
2006, 8, 1141−1144. (c) Dick, A. R.; Kampf, J. W.; Sanford, M. S. J. Am.
Chem. Soc. 2005, 127, 12790−12791. (d) Giri, R.; Liang, J.; Lei, J.-G.; Li,
J.-J.; Wang, D.-H.; Chen, X.; Naggar, I. C.; Guo, C.; Foxman, B. M.; Yu,
J.-Q. Angew. Chem., Int. Ed. 2005, 44, 7420−7424. (e) Chen, X.; Hao, X.-
S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790−6791.
(f) Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 14654−14655.
(g) Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134, 134−137.
(h) McMurtrey, K. B.; Racowski, J. M.; Sanford, M. S. Org. Lett. 2012,
14, 4094−4097. (i) Mo, F.; Trzepkowski, L. J.; Dong, G. Angew. Chem.,
Int. Ed. 2012, 51, 13075−13079. (j) Shan, G.; Yang, X.; Ma, L.; Rao, Y.
Angew. Chem., Int. Ed. 2012, 51, 13070−13074. (k) Yan, Y.; Feng, P.;
Zheng, Q.-Z.; Liang, Y.-F.; Lu, J.-F.; Cui, Y.; Jiao, N. Angew. Chem., Int.
Ed. 2013, 52, 5827−5831.
Scheme 4. Plausible Mechanistic Pathway
(4) (a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 6790−6791. (b) King, A. E.; Huffman, L. M.; Casitas, A.;
Costas, M.; Ribas, X.; Stahl, S. S. J. J. Am. Chem. Soc. 2010, 132, 12068−
12073. (c) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464−
3484. (d) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem., Int.
C
DOI: 10.1021/acs.orglett.7b01494
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Ed. 2011, 50, 11062−11807. (e) Bhadra, S.; Matheis, C.; Katayev, D.;
Gooßen, L. J. Angew. Chem., Int. Ed. 2013, 52, 9279−9283.
(5) (a) Yang, F. Z.; Rauch, K.; Kettelhoit, K.; Ackermann, L. Angew.
Chem., Int. Ed. 2014, 53, 11285−11288. (b) Thirunavukkarasu, V. S.;
Ackermann, L. Org. Lett. 2012, 14, 6206−6209. (c) Thirunavukkarasu,
V. S.; Hubrich, J.; Ackermann, L. Org. Lett. 2012, 14, 4210−4213.
(d) Yang, F. Z.; Ackermann, L. Org. Lett. 2013, 15, 718−720. (e) Liu, W.
P.; Ackermann, L. Org. Lett. 2013, 15, 3484−3486. (f) Okada, T.;
Nobushige, K.; Satoh, T.; Miura, M. Org. Lett. 2016, 18, 1150−1153.
(6) For reviews on Cp*Rh(III)-catalyzed C−H activation, see:
(a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110,
624−655. (b) Satoh, T.; Miura, M. Chem. - Eur. J. 2010, 16, 11212−
11222. (c) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc.
Chem. Res. 2012, 45, 814−825. (d) Song, G.; Wang, F.; Li, X. Chem. Soc.
Rev. 2012, 41, 3651−3678. (e) Patureau, F. W.; Wencel-Delord, J.;
Glorius, F. Aldrichimica Acta 2012, 45, 31. (f) Kuhl, N.; Schroder, N.;
Glorius, F. Adv. Synth. Catal. 2014, 356, 1443−1460. (g) Song, G.; Li, X.
Acc. Chem. Res. 2015, 48, 1007−1020.
(7) For rhodium(III)-catalyzed C−N bond-forming reaction, see:
(a) Kim, J. Y.; Park, S. H.; Ryu, J.; Cho, S. H.; Kim, S. H.; Chang, S. J. Am.
Chem. Soc. 2012, 134, 9110−9113. (b) Ryu, J.; Shin, K.; Park, S. H.; Kim,
J. Y.; Chang, S. Angew. Chem., Int. Ed. 2012, 51, 9904−9908. (c) Shi, J.;
Zhou, B.; Yang, Y.; Li, Y. Org. Biomol. Chem. 2012, 10, 8953−8955.
(d) Ng, K.-H.; Zhou, Z.; Yu, W.-Y. Org. Lett. 2012, 14, 272−275.
(e) Lian, Y.; Hummel, J. R.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2013, 135, 12548−12551. (f) Yu, S.; Wan, B.; Li, X. Org. Lett. 2013,
15, 3706−3709. (g) Grohmann, C.; Wang, H.; Glorius, F. Org. Lett.
2013, 15, 3014−3017. (h) Zhou, B.; Yang, Y.; Shi, J.; Feng, H.; Li, Y.
Chem. - Eur. J. 2013, 19, 10511−10515. (i) Tang, R.-J.; Luo, C.-P.; Yang,
L.; Li, C.-J. Adv. Synth. Catal. 2013, 355, 869−873. (j) Xie, F.; Qi, Z.; Li,
X. Angew. Chem., Int. Ed. 2013, 52, 11862−11866. (k) Zhou, B.; Du, J.;
Yang, Y.; Feng, H.; Li, Y. Org. Lett. 2013, 15, 6302−6305. (l) Yu, D.-G.;
Suri, M.; Glorius, F. J. Am. Chem. Soc. 2013, 135, 8802−8805. (m) Park,
S. H.; Kwak, J.; Shin, K.; Ryu, J.; Park, Y.; Chang, S. J. Am. Chem. Soc.
2014, 136, 2492−2502. (n) Shi, J.; Zhao, G.; Wang, X.; Xu, H. E.; Yi, W.
Org. Biomol. Chem. 2014, 12, 6831−6836.
(8) (a) Yang, Y.; Hou, W.; Qin, L.; Du, J.; Feng, H.; Zhou, B.; Li, Y.
Chem. - Eur. J. 2014, 20, 416−420. (b) Yu, S.; Wan, B.; Li, X. Org. Lett.
2015, 17, 58−61.
(9) (a) Schroder, N.; Wencel-Delord, J.; Glorius, F. J. Am. Chem. Soc.
̈
2012, 134, 8298−8301. (b) Schroder, N.; Lied, F.; Glorius, F. J. Am.
̈
Chem. Soc. 2015, 137, 1448−1451.
(10) Selected examples: (a) Zhou, B.; Chen, Z.; Yang, Y.; Ai, W.; Tang,
H.; Wu, Y.; Zhu, W.; Li, Y. Angew. Chem., Int. Ed. 2015, 54, 12121−
12126. (b) Yang, Y.; Wang, X.; Li, Y.; Zhou, B. Angew. Chem., Int. Ed.
2015, 54, 15400−15404. (c) Zhou, B.; Yang, Y.; Tang, H.; Du, J.; Feng,
H.; Li, Y. Org. Lett. 2014, 16, 3900−3903. (d) Wu, Y.; Zhou, B. ACS
Catal. 2017, 7, 2213−2217.
(11) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004,
126, 9542.
(12) (a) Riggio, G.; Hopff, W. H.; Hofmann, A. A.; Waser, P. G. Helv.
Chim. Acta 1983, 66, 1039. (b) a) Kim, N. J.; Shin, C. H.; Lee, M. H.;
Do, Y. J. Organomet. Chem. 2009, 694, 1922−1928. (c) Kim, H.; Eum, S.
J.; Cho, Y. J.; Kwon, H. J.; Kim, B. O.; Kim, S. M.; Yoon, S. S. European
Patent Appl. EP 2080795A1, 2009.
(13) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51,
3066−3072.
D
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