Full text of DOI:10.1016/j.tetlet.2018.04.034

Accepted Manuscript
Experimental and Theoretical Studies on Rhodium-Catalyzed Direct C-H Ben-
zoxylation Reaction
Chen Jin, Guimin Wang, Xueyan Yang, Weiliang Zhu, Yaxi Yang
PII:
S0040-4039(18)30492-1
https://doi.org/10.1016/j.tetlet.2018.04.034
TETL 49897
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
16 March 2018
11 April 2018
16 April 2018
Please cite this article as: Jin, C., Wang, G., Yang, X., Zhu, W., Yang, Y., Experimental and Theoretical Studies on
Rhodium-Catalyzed Direct C-H Benzoxylation Reaction, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.04.034
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Experimental and Theoretical Studies on
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Benzoxylation Reaction
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a,b,†
c,d,†
a,*
c,d,*
b,d,*
Chen Jin, Guimin Wang,
Xueyan Yang, Weiliang Zhu,
Yaxi Yang,

1
Tetrahedron Letters
Experimental and Theoretical Studies on Rhodium-Catalyzed Direct C-H
Benzoxylation Reaction
a,b,†
c,d,†
a,*
c,d,*
b,d,*
Chen Jin,
Guimin Wang,
Xueyan Yang, Weiliang Zhu, Yaxi Yang,
a
Key Lab for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, PR
China. E-mail: yxy@ecust.edu.cn
b
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China. Fax: (+)86-21-50807288. E-mail:
yangyaxi@simm.ac.cn; spyyx@163.com
Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. E-mail:
c
wlzhu@mail.shcnc.ac.cn
d
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
These authors contributed equally.
†
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient Rh(III)-catalyzed, chelation assisted C-H benzoxylation reaction has been
developed, releasing H O as the single byproduct. The reaction proceeded under mild
2
Received in revised form
Accepted
Available online
conditions, with controllable mono- and dioxygenation selectivity, thus providing a good
complement to previous C-H oxygenation reactions. DFT calculations support that a
nucleophilic addition pathway is most likely involved in the current reaction system.
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Rh(III)-catalyzed
C-H benzoxylation
DFT calculations
Introduction
The selective oxidation of unactivated C-H bonds is an
important research goal due to its importance in synthesis and the
1
chemical industry. In this context, the recent years have
witnessed remarkable progress on the C-H oxygenation
2
reactions by using various transition-metal catalysts such as
3
palladium, copper, ruthenium, rhodium and iridium. Despite
Scheme 1. Transition-matal-catalyzed C-H functionalization.
these significant progresses, stoichiometric amounts of external
oxidants are required in these reactions, thus inevitably
generating stoichiometric amounts of hazardous reduced oxidant
Results and discussion
2,3
byproducts (Scheme 1a). Moreover, these protocols lack the
selectivity for mono and bis-oxygenation. Therefore, the
development of environmentally benign and mild C-H
oxygenation methods, selective for mono and bis-oxygenation, is
highly desirable.
We started our model study by investigating the direct C-H
oxygenation of 2-phenylpyridine (1a) with hypervalent iodine-
hydroxyl reagent (2a) in the presence of (Cp*RhCl
2
)
2
(2.5 mol
) at 55 C (Table 1). We were rather pleased to find that
treatment of 1a with hypervalent iodine reagent 2a in the
presence of (Cp*RhCl (2.5 mol %) and AgSbF (10 mol %) in
o
%
)
2 2
6
Recently, Rh(III)-catalyzed C−H activation has evolved to be a
mild and redox-economic strategy for constructing various
structurally diverse organic molecules under external oxidant-
DCE at 55 °C, provided the oxygenation product 3a in 32%
yield, also with dioxygenation product 4a in less than 5% yield
(entry 1). Next, some additives such as acid, base and metal salt,
were screened (entries 2-7). Changing to other silver salts or an
addition of acids, which are known to be involved in the key step
of C-H cleavage in many reported C-H functionalizations, did not
improve the yield (entries 2-4). An addition of base completely
4,5
free conditions. In this context, we report the first example of
2
rhodium-catalyzed C(sp )-H benzoxylation reaction with the
2
hypervalent iodine-oxygen reagent releasing H O as the single
byproduct (Scheme 1b). Moreover, this method exhibits
2
controllability of mono and bis C(sp )-H benzoxylation under
inhibited the reaction (entry 5). Using Zn(OTf)
further increased the yield (entry 6). To our delight, introduction
of Cu(OTf) as an additive significantly improved the yield to
2
as an additive
relatively mild reaction conditions, thus affording a good
complement to current C-H oxygenation reactions.
2

2
Tetrahedron
8
6% (entry 7). A screening of solvents indicated that other
solvents provided inferior results (entries 8-10). Control
experiments revealed that both (RhCp*Cl and Cu(OTf) are
)
2 2
2
necessary for this transformation (entries 11 and 12). Finally, we
were pleased to find that bis benzoxylation product 4a could be
obtained in 85% yield as the sole product by simply increasing
o
the reaction temperature to 90 C and using 3 equivalents of 2a
(entry 13). Lowering the catalyst loading to 1.5 mol% did not
aff ect the reaction outcome too much (entry 14).
a
Table 1. Reaction Optimization.
Scheme 2. Rh(III)-catalyzed C-H benzoxylation reaction.
Conditions: 1 (0.2 mmol), 2a (0.24 mmol), (Cp*RhCl (2.5 mol%),
(5 mol%), DCE (2 mL), 55 C, 12 h. Isolated yield.
yield of
yield of
entry
additive (x mol %)
solvent
2 2
)
3
a
4a
o
Cu(OTf)
2
1
2
3
4
5
6
7
8
9
AgSbF
6
(10)
(10)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
DCM
MeOH
DCE
DCE
DCE
DCE
32
36
35
38
<5
60
86
50
70
<10
0
<5
<5
<5
<5
0
Next, the scope of the C-H dibenzoxylation reaction was
also examined (Scheme 3). A variety of substrates
containing both electron-donating and electron-withdrawing
groups at the para-position of the phenyl ring were
successfully coupled with 2a, providing dioxidized adducts
AgBF
4
AgOTf (10)
AgSbF (10)/AcOH
AgSbF (10)/CsOAc
Zn(OTf)
6
6
(
4a-e) in good to excellent yields. Notably, meta-substituted
substrate 4f and 4g successfully provided
difunctionalization products, enabling the preparation of
,2,3,4-tetrasubstituted benzene derivatives. Gratifyingly,
(
)
2
(5)
(5)
(5)
(5)
(5)
5
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
-
2
2
2
2
<5
0
1
pyrimidine (4h) also worked well as a directing group in the
present C-H dibenzoxylation reaction.
<5
0
1
1
0
1
0
b
1
2
3
4
Cu(OTf)
Cu(OTf)
Cu(OTf)
2
2
2
(5)
(5)
(5)
0
0
c
1
1
<5
78
85
d
<5
a
Reactions were carried out by using (RhCp*Cl
2
)
2
(2.5 mol%),
additive (5-10 mol%), 2-phenylpyridine 1a (0.2 mmol) and
hypervalent iodine reagent 2a (0.24 mmol) in a solvent (2 mL)
Scheme 3. Rh(III)-catalyzed C-H dibenzoxylation reaction.
o
b
at 55 C for 12 h; lsolated yield. No rhodium catalyst was used.
Conditions: 1 (0.2 mmol), 2a (0.6 mmol), (Cp*RhCl
2
)
2
(2.5 mol%),
c
o
o
The reaction was carried out by using 0.6 mmol of 2a at 90 C
Cu(OTf)
2
(5 mol%), DCE (2 mL), 90 C, 12 h. Isolated yield.
d
for 12 h. 1.5 mol% [Cp*RhCl
2
]
2
was used.
The utility of the direct C−H oxygenation reaction as a
tool for late-stage modification of bioactive complex
With the optimal reaction conditions in hand, we explored
the scope with respect to the 2-phenylpyridine derivatives
molecules such as estrone derivative
affording the corresponding benzoxylation product
yield (eq 1). In addition, treatment of 4a with K
6
was also carried out,
in 77%
CO in
(Scheme 2). 2-Phenylpyridines bearing donating as well as
7
withdrawing groups in the phenyl ring reacted smoothly
with 2a to give the corresponding products 3a-3l in 64-90%
yield. Notably, excellent reactivity was observed when a
methyl group was present on the phenyl ring at the ortho-
positon (3b) or on the pyridine ring at the 3-position (3m),
thus showing high tolerance for steric hindrance. Meta-
2
3
MeOH provide dihydroxyl compound 9a which can be used
6
for the synthesis of chiral organocatalyst (eq 2).
substituted derivatives
(
3c-i
)
showed an excellent
regioselectivity through functionalization of the less
congested C-H bond. Furthermore, the halogen (3e and 3f),
ester (3l), nitrile (3h) and even carboxaldehyde (3i) groups
were all well tolerated, enabling further functionalization.
Extension of the C-H substrate to other N-based
heterocycles such as pyrimidine (3n) or pyrazole (3o
)
proved successful.
A series of preliminary experiments have been performed
to probe the mechanism. Significant H–D exchange was
observed in the presence of D O and hypervalent iodine
2

3
reagent 2d, indicative of the reversibility of the ortho-
C(sp )-H bond cleavage process (Scheme 4a). A significant
kcal/mol exothermicity. Subsequent intramolecular
nucleophilic addition type reaction occurs to give via
transition state TS-C1D. Ligand substitution of generates
3a and , with 12.5 kcal/mol endothermicity. In comparison
2
D
primary kinetic isotope effect (k
an intermolecular competitive coupling of 2a with a 1:1
mixture of 1a and 1a-d at a low conversion, indicating that
H
/k
D
= 3.3) was observed for
D
E
5
with the data in pathway a, the calcuated free energy of TS-
C1D is 26.1 kcal/mol, which is lower than TS-CF and TS-
F3a. Therefore, the pathway b is much feasible.
the C-H bond cleavage is likely involved in the turnover-
7
limiting step (Scheme 4b). To further understand the
reaction process, cyclometalated Rh(III) complex 11 was
prepared and 11 successfully catalyzed the benzoxylation
reaction to give 3a in high yield (Scheme 4c). Moreover, a
stoichiometric reaction of 11 with 2a also afforded 3a
(Scheme 4d). Both of the results suggested the plausible
intermediacy of a cyclometalated complex in the catalytic
cycle.
Scheme 4. Preliminary Mechanistic Studies.
Reaction Mechanism
Figure 1. Energy profiles and geometry information for the
mechanistic pathways from compound A to 3a.
Based on the above observed data, a mechanistic pathway is
proposed in Scheme 5. First, treatment of the (Cp*RhCl
2 2
)
Conclusion
precursor with Cu(OTf) additive affords a cationic Rh(III)
2
species, which facilitates the C−H activation to generate a five-
membered rhodacyclic intermediate A. In path a, oxidation of A
with the hypervalent iodine reagent 2a generates the Rh(V)
complex F, which undergoes a reductive elimination to afford the
product 3a and an active Rh(III) catalyst which may react with
substrate 1a to regenerate A. Alternatively, in path b, the Cu
cation probably activate the hypervalent iodine species, thus the
rhodacyclic A can undergo a nucleophilic addition type reaction
to B to directly lead to product 3a.
In summary, we have developed an efficient Rh(III)-
catalyzed benzoxylation of C(sp )-H bonds. The reaction
requires no external oxidants and releases H O as the single
2
2
byproduct, thus offering an environmentally benign C−H
oxygenation procedure. Moreover, this protocol shows a
controllable mono- and di-oxygenation selectivity through
adjustment of the ratio of reactants and temperature, thus
providing a good complement to current C-H oxygenation
reactions. DFT calculations support that different with
traditional oxidative addition/reductive elimination pathway,
a nucleophilic addition pathway is most likely involved in
the current reaction system.
Acknowledgments
Youth innovation promotion association (2017333) of the
Chinese Academy of Sciences are gratefully acknowledged.
Scheme 5. Plausible mechanistic pathway.
To further understand the mechanism, DFT calculations
were performed with Gaussian 09 (Figure 1). In path a,
Supplementary Material
8
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
coordination of reagent 2a to five-membered rhodacyclic
intermediate
addition occurs to give intermediate
A
forms C2 or C3, and subsequent oxidative
via transition state
F
TS-CF which has an unfeasibly high free energy of 32.6
kcal/mol. After formation of Rh(V) species, the subsequent
intramolecular reductive elimination of
transition state TS-F3a with an activation energy barrier of
2.6 kcal/mol. (pathway a). In path b, coordination of
F produce 3a via
References and notes
3
1.
a) Buckingham, J. Dictionary of Natural Products; University
+
Press: Cambridge, MA, 1994; b) Czarnik, A. W. Acc. Chem. Res.
cationic
B, formed by reaction of 2a and H with 24.9
1
996, 29, 112; c) Theil, F. Angew. Chem., Int. Ed. 1999, 38, 2345;
9
kcal/mol exothermicity, to
A
produces C1 with 33.6

4
Tetrahedron
d) Sawyer, J. S. Tetrahedron 2000, 56, 5045; e) Thomas, A.W.;
Ley, S. V. Angew. Chem., Int. Ed. 2003, 42, 5400; f) Cristau, P.;
Vors, J. P.; Zhu, J. Tetrahedron 2003, 59, 7859; g) Muci, A. R.;
Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131.
2
3
.
.
Reviews on metal-catalyzed C-O bond forming reactions: a)
Enthaler, S.; Company, A. Chem. Soc. Rev. 2011, 40, 4912; b)
Alonso, D. A.; Najera, C.; Pastor, I. M.; Yus, M. Chem. Eur. J.
2
1
010, 16, 5274; c) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010,
10, 1147.
For selected examples: a) Dick, A. R.; Hull, K. L.; Sanford, M. S.
J. Am. Chem. Soc. 2004, 126, 2300; b) Desai, L. V.; Malik, H. A.;
Sanford, M. S. Org. Lett. 2006, 8, 1141; c) Dick, A. R.; Kampf, J.
W.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 12790; 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.
2
005, 44, 7420; e) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-
Q. J. Am. Chem. Soc. 2006, 128, 6790; f) Shan, G.; Yang, X.; Ma,
L.; Rao, Y. Angew. Chem., Int. Ed. 2012, 51, 13070; g) Yan, Y.;
Feng, P.; Zheng, Q.-Z.; Liang, Y.-F.; Lu, J.-F.; Cui, Y.; Jiao, N.
Angew. Chem., Int. Ed. 2013, 52, 5827; h) Chen, X.; Hao, X.-S.;
Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790; i)
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.;
Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 12068; j) Wendlandt, A.
E.; Suess, A. M.; Stahl, S. S.; Angew. Chem. Int. Ed. 2011, 50,
1
1062; k) Bhadra, S.; Matheis, C.; Katayev, D.; Gooßen, L. J.
Angew. Chem. Int. Ed. 2013, 52, 9279; l) Yang, F. Z.; Rauch, K.;
Kettelhoit, K.; Ackermann, L. Angew. Chem., Int. Ed. 2014, 53,
1
2
1
1285; m) Thirunavukkarasu, V. S.; Ackermann, L. Org. Lett.
012, 14, 6206; n) Yang, F. Z.; Ackermann, L. Org. Lett. 2013,
5, 718; o) Okada, T.; Nobushige, K.; Satoh, T.; Miura, M. Org.
Lett. 2016, 18, 1150; p) Yu, W.; Chen, J.; Gao, K.; Liu, Z.; Zhang,
Y. Org. Lett. 2014, 16, 4870; q) Wu, Y.; Zhou, B. Org. Lett. 2017,
1
9, 3532; r) Li, C.-X.; Zhang, H.-Y.; Wong, T.-Y.; Cao, H.-J.;
Yan, H.; Lu, C.-S. Org. Lett. 2017, 19, 5178; s) Zhou, M.; Schley,
N. D.; Crabtree, R. H. J. Am. Chem. Soc. 2010, 132, 12550; t)
Zhou, M.; Hintermair, U.; Hashiguchi, B. G.; Parent, A. R.;
Hashmi, S. M.; Elimelech, M.; Periana, R. A.; Brudvig, G. W.;
Crabtree, R. H. Organometallics 2013, 32, 957.
4
.
For reviews on Cp*Rh(III) catalyzed C-H activation, see: a)
Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010,
1
10, 624; b) Satoh, T.; Miura, M. Chem. Eur. J. 2010, 16, 11212;
c) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc.
Chem. Res. 2012, 45, 814; d) Song, G.; Wang, F.; Li, X. Chem.
Soc. Rev. 2012, 41, 3651; 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; g) Song, G.;
Li, X. Acc. Chem. Res. 2015, 48, 1007; h) Ye, B.; Cramer, N. Acc.
Chem. Res., 2015, 48, 1308.
5
.
Selected examples for Rh(III)-catalyzed redox-neutral C−H
activation: a) Kim, J. Y.; Park, S. H.; Ryu, J.; Cho, S. H.; Kim, S.
H.; Chang, S. J. Am. Chem. Soc. 2012, 134, 9110; b) Shi, J.; Zhou,
B.; Yang, Y.; Li, Y. Org. Biomol. Chem. 2012, 10, 8953; c) Ryu,
J.; Shin, K.; Park, S. H.; Kim, J. Y.; Chang, S. Angew. Chem., Int.
Ed. 2012, 51, 9904; d) Zhou, B.; Yang, Y.; Shi, J.; Feng, H.; Li, Y.
Chem. Eur. J. 2013, 19, 10511; e) Ng, K.-H.; Zhou, Z.; Yu, W.-Y.
Org. Lett. 2012, 14, 272; h) Grohmann, C.; Wang, H.; Glorius, F.
Org. Lett. 2012, 14, 656; j) Grohmann, C.; Wang, H.; Glorius, F.
Org. Lett. 2013, 15, 3014; k) Yu, S.; Wan, B.; Li, X. Org. Lett.,
2
013, 15, 3706.
6
7
8
.
.
.
Pignataro, L.; Benaglia, M.; Annunziata, R.; Cinquini, M.; Cozzi,
F. J. Org. Chem. 2006, 71, 1458.
Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed., 2012, 51,
3
066.
Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.;
Mennucci, B.; Petersson, G. A. Gaussian 09, Revision C.01.;
Gaussian, Inc. Wallingford, CT, 2009.
9
.
a)
; also see the
following references: b) Kalyanashis, J.; Tusar, B.; Bishwajit, G.
J. Phys. Chem. B, 2016, 120, 13031; c) Magill, A. M.; Cavell, K.
J.; Yates, B. F. J. Am. Chem. Soc., 2004, 126, 8717.

5



Cp*Rh(III)-catalyzed selective mono or bis C-H
benzoxylation reaction
Good functional group tolerance, mild reaction
conditions and late-stage functionalization
Green Chemistry, water as the sole byproduct