Rhodium(III)-Catalyzed Selective Monoarylation of β or γ C(sp3)-H Bonds Assisted by a Trimethylpyrazole Group

Article abstract of DOI:10.1021/acs.orglett.6b03522

The selective arylation of unactivated β or challenging γ primary and secondary β-C(sp³)-H bonds has been developed with a Cp*Rh(III) catalyst assisted by a trimethylpyrazole group. A rarely reported six-membered rhodacycle has been identified in rhodium-catalyzed C(sp³)-H activation reactions. Preliminary mechanistic studies have revealed that a concerted metalation-deprotonation pathway might be involved in the C-H activation step.

Full text of DOI:10.1021/acs.orglett.6b03522

Letter
pubs.acs.org/OrgLett
3
Rhodium(III)-Catalyzed Selective Monoarylation of β or γ C(sp )−H
Bonds Assisted by a Trimethylpyrazole Group
Chunchen Yuan, Guangliang Tu, and Yingsheng Zhao*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, China
*
S Supporting Information
ABSTRACT: The selective arylation of unactivated β or
3
challenging γ primary and secondary β-C(sp )−H bonds has
been developed with a Cp*Rh(III) catalyst assisted by a
trimethylpyrazole group. A rarely reported six-membered rhoda-
3
cycle has been identified in rhodium-catalyzed C(sp )−H
activation reactions. Preliminary mechanistic studies have
revealed that a concerted metalation−deprotonation pathway
might be involved in the C−H activation step.
ver the past decades, transition-metal-catalyzed C−H
whereby a rarely reported six-membered Rh−C(alkyl)
intermediate may be invoked for the first time.
O
activation reactions have seen rapid development and
2
now provide straightforward approaches to many important
Although pyrazole-directed C(sp )−H functionalizations
1
−5
synthetic units.
Among the reported procedures, rhodium-
have been well explored and various transition metals such as
13
14
15
(
III)-catalyzed C−H functionalization has attracted consid-
Rh, Pd, and Ru have been demonstrated to be effective
erable attention in recent years due to its high selectivity, good
catalysts, there have been few examples of pyrazole-directed
6
3
functional group tolerance, and high efficiency. To date,
C(sp )−H activations. It is likely that the weak coordinating
2
16
numerous of Rh-catalyzed C(sp )−H functionalizations have
ability of pyrazole hinders C−H transformations. Recently,
1
7
been developed, leading to carbon−carbon and carbon−
Yu’s group has overcome this problem by employing
monoprotected amino acids as ligands, which are well-known
to promote C−H activation reactions with palladium catalysts.
On the basis of our experience in developing new directing
7
heteroatom bond formation. Despite these great achievements,
only limited reports have been concerned with the rhodium-
3
(
III)-catalyzed C(sp )−H functionalization, which may be due
18
to an incomplete understanding of pertinent mechanistic
aspects.
groups, the electron density is known to greatly influence the
efficacy of transition-metal-catalyzed C−H activations. We
speculate that the pyrazole skeleton may provide a perfect
In 2010, Glorius’ group reported pioneering work on the
3
3
rhodium(III)-catalyzed allylic C(sp )−H activation of enamines
coordinating center for C(sp )−H activation if its structure is
8
in coupling with alkynes to form pyrazoles. Later, Wang’s
slightly modified. Thus, 1-alkylpyrazole derivatives might be
3
group showed 8-methylquinolines to be suitable substrates for
suitable substrates for rhodium-catalyzed C(sp )−H activation
3
rhodium(III) catalysts in activating C(sp )−H for alkenylation
to form important synthetic units. Further investigation
indicated that these 1-alkylpyrazoles could be easily prepared
9
reactions. Since then, several examples of selective function-
1
9
20
3
from an alkyl bromide, an alcohol and a (trifluoromethyl)-
alization of C(sp )−H bonds with Cp*Rh(III) as catalyst have
21
10
11
12
sulfonyloxy-protected alcohol.
been developed by the groups of Glorius, You, and Li.
With these conditions in mind, we initially treated 1-
isopropyl-1H-pyrazole (1a) with a triarylboroxine (2) in the
However, the substrates have been limited to 8-methylquion-
line-type benzylic C−H bonds or oxime-directed β-Me C−H
bonds. There have been few examples of functionalization of
presence of [Cp*RhCl ] (5 mol %), Ag CO (2 equiv), and
2 2
2
3
3
AgSbF (0.2 equiv) in toluene for 24 h (Scheme 1, 3a).
unactivated primary and secondary C(sp )−H bonds. In
6
Unfortunately, the arylated product 3a was only observed by
LC−MS in <3% yield. Next, pyrazoles bearing electron-
withdrawing functional groups were tested (3a). However,
these did not give the desired products, and only the starting
material was recovered. It is probable that weakly coordinating
pyrazoles have no assisting ability in promoting C−H
activation. Monomethyl-substituted pyrazoles were further
particular, to the best of our knowledge, there has been no
3
example of rhodium-catalyzed γ-C(sp )−H bond functionaliza-
tion, presumably because an unstable six-membered rhodacycle
would need to be formed during the catalytic cycle. Herein, we
report a rhodium(III)-catalyzed selective monoarylation of
3
C(sp )−H bonds assisted by a trimethylpyrazole group.
Preliminary results have revealed that rhodium(III) can not
only promote functionalization of β-Me C−H bonds but also of
3
less activated methylene C(sp )−H bonds. Further study has
Received: November 28, 2016
3
revealed that primary γ-C(sp )−H bonds are compatible,
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03522
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3
Scheme 1. Scope of Rhodium-Promoted C(sp )−H
Scheme 2. Scope of Arylboron Reagents in the Rhodium-
Catalyzed C(sp )−H Arylation*
a
3
Activation
a
FG: functional group.
screened. As we expected, monoarylated products were
obtained in up to 18% yields (3b,c). Encouraged by these
results, 1-isopropyl-3,5-dimethylpyrazole (1d) was tested. To
our great delight, the arylated product 3d was obtained in 38%
yield. The 1-isopropyl-3,4,5-trimethylpyrazole was further
explored, affording the monoarylated product 3e in a rather
good yield of 56%. When substrate 1h was scanned, less than
*
Reactions were performed with 1 (0.2 mmol) and 2 (2 equiv) in 1
a
b
mL of toluene. [Cp*RhCl ] (10 mol %). 150 °C
2
2
10% of the arylated product (3f) was obtained.
With these preliminary results in hand, we next explored
various oxidants, solvents, and additives to accomplish this β-
well, providing the corresponding products in good yields
(3s,u,v).
3
C(sp ) arylation reaction (see the Table S1). The results
revealed that the additives NaOAc, PivOH, (n-BuO) PO H,
We next investigated various 1-alkyl-TMPs under the optimal
conditions (Scheme 3). The substrates 4a and 4b were both
selectively arylated at the β-Me position, providing the
monoarylated products (5a,b) in good yields. 1-Ethyl-TMP
also reacted smoothly, leading to monoarylated product 5c in
78% yield. Moreover, 1-cyclobutyl-TMP, 1-cyclopentyl-TMP,
and 1-cyclohexyl-TMP all gave the monoarylated products in
moderate to good yields, although methylene units are
generally less reactive in C−H activation. However, the
substrates of n-propyltrimethylpyrazole (4g) could not be
tolerated under standard reaction conditions, and only starting
material was recovered. The product of 5c, which contained β-
secondary benzylic C−H bonds, was treated with triarylborox-
ine 2a, but it failed to give any β-arylated product. The
substrate 4h was unreactive in the reaction, affording the
arylated products in less than 10% yield.
2
2
and 1-Ad-OH all had a promoting effect. A satisfactory isolated
yield of 3g of 85% was achieved when PivOH was used as the
additive. In regard to the role of these additives in palladium-
3
catalyzed C(sp )−H activation, a concerted metalation−
deprotonation (CMD) pathway might be involved in activating
3
22
the C(sp )−H bonds. Several oxidants, such as Cu(OAc)2,
BQ, K S O , and O , were screened in place of Ag CO .
2
2
8
2
2
3
However, none of them gave the desired products in good
yields. It is worth mentioning that the monoarylated product 3g
was the only arylated product. We surmise that the rhodium-
(
III) complex interacted weakly with the arenes, which
precluded secondary C−H activation, while the steric effect is
also a possible reason for the absence of a secondary arylation.
In addition, palladium acetate was also tested in combination
with aryl iodides as coupling partners. However, mono- and
diarylated products were obtained unselectively, highlighting
the unique properties of the rhodium(III) catalyst system in the
C−H activation.
3
In all previously reported rhodium(III)-catalyzed C(sp )−H
activations, a five-membered Rh−C(alkyl)-cyclic intermediate
has been invoked. To the best of our knowledge, a six-
membered Rh−C(alkyl)-cyclic intermediate has not hitherto
A wide range of triarylboroxines were treated with 1-
isopropyl-3,4,5-trimethylpyrazole (1-isopropyl-TMP) (1g) to
explore the functional group tolerance of this rhodium-
3
been observed in a Cp*Rh(III)-catalyzed C(sp )−H activation
reaction. Inspired by palladium-catalyzed C−H activation
reactions, in which a six-membered Pd−C(alkyl)-cycle is
readily formed when the C−H activation step proceeds by a
CMD pathway, we speculated that the modified pyrazole-
3
catalyzed C(sp )−H arylation (Scheme 2). Arylboron reagents
(2) bearing para or meta substituents gave the corresponding
products in moderate to good yields (53−85%). A wide variety
3
of functional groups, such as MeO, F, Cl, Br, CF , and CO Me,
directed rhodium-catalyzed C(sp )−H activation may also
3
2
3
were well tolerated in this transformation (3g−p). Multiply
substituted arylboron reagents also reacted well, affording the
corresponding monoarylated products in good yields (3q,r,t).
Importantly, condensed-ring boron reagents also performed
facilitate γ-C(sp )−H arylation. Thus, 2,2-dimethylpropane-
TMP was examined under the standard conditions. As
expected, the monoarylation reaction proceeded well with
different triarylboroxine reagents (6a,b). For example, both
B
DOI: 10.1021/acs.orglett.6b03522
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Scope of Arylboron Reagents in Rhodium-
Catalyzed C(sp )−H Arylation Reactions*
only can various pyrazole derivatives be prepared from simple
alkyl halides but also a facile approach to alkenes from alkyl
halides via a transitive directing center has also been developed.
Because mono- and diarylated products were inevitably
obtained when we treated 1g with aryl iodides in the presence
of a palladium catalyst, the product 5c was further treated with
the aryl iodide using the palladium catalyst to form the
heterodiarylated product. To our delight, the arylation occurred
3
3
selectively at the β-C(sp )−H position rather than at the δ-
2
C(sp )−H position, indicating that a five-membered Pd−
C(alkyl) intermediate is more stable than a seven-membered
Pd−C(arene) intermediate. We also treated 5c with triarylbor-
oxine 2a under the optimal reaction conditions, but it proved to
be completely unreactive, which explains why the diarylate
3
could not be observed in the Cp*Rh-catalyzed C(sp )−H
arylation and is a clear reason why a diarylated product was not
obtained under the Rh(III)-catalyzed conditions. We proposed
that the rhodium(III) complex might have interacted weakly
with the arenes, which prevented secondary C−H activation. In
addition, steric effects might also be a reason for the absence of
a secondary arylation.
Several experiments were performed to gain more insight
into the mechanism. Hydrogen−deuterium-exchange experi-
ments were explored with the rhodium catalyst or palladium
acetate. A deuterated product was never observed, indicating
3
that C(sp )−H bond activation is irreversible (see the SI).
Intermolecular kinetic isotope effect (KIE) experiments were
carried out (Scheme 5a), which gave a consistent KIE of 2.3.
*
Reactions were performed with 4 and (ArBO) (2 equiv) in 1 mL of
3
a
toluene. [Cp*RhCl ] (10 mol %), 150 °C.
2
2
Scheme 5. Preliminary Mechanism Study
electron-rich and electron-deficient substituted triarylboroxine
reagents were tolerated in the transformation, indicating the
potentially wide scope of these reagents. Isopentyl-TMP gave
monoarylted 6c in 58% yield.
Gram-scale reactions were easily performed with a range of
triarylboroxine reagents under the standard reaction conditions
(Scheme 4a). More importantly, we demonstrated that the
trimethylpyrazole coordinating center could be easily removed
from product 3j under basic conditions at room temperature,
affording the important product anethole, which is widely used
as a flavoring agent (Scheme 4b). This result implied that not
Scheme 4. Further Study on This Rhodium-Catalyzed
3
C(sp )−H Arylation Reaction
Control experiments revealed that the additives AgSbF and
6
PivOH both had a promoting effect (Scheme 5b). To
understand the role of these additives, a catalyst precursor
was prepared by the reaction of [Cp*RhCl ] , AgSbF , and
2
2
6
NaOAc in acetonitrile, affording a complex in the form of deep-
red prisms. Its structure was confirmed by single-crystal X-ray
diffraction analysis (Scheme 5c). Complex A was further
utilized as the catalyst instead of [Cp*RhCl ] , AgSbF , and
2
2
6
PivOH, and the desired product 3g was obtained in 61% yield
C
DOI: 10.1021/acs.orglett.6b03522
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Scheme 5d). This result implied that complex A is an active
Letter
(
(10) Wang, X.-M.; Glorius, F. Angew. Chem., Int. Ed. 2015, 54, 10280.
11) Huang, X.-L.; You, J.-S. Angew. Chem., Int. Ed. 2015, 54, 9404.
12) (a) Wang, H.; Li, X.-W. Angew. Chem., Int. Ed. 2015, 54, 13049.
b) Yu, S.-j.; Li, X.-W. ACS Catal. 2016, 6, 7744. (c) Yu, S.-J.; Li, X.-W.
Angew. Chem., Int. Ed. 2016, 55, 8696.
13) (a) Zhou, B.; Chen, Z.-Q.; Li, Y.-C. Angew. Chem., Int. Ed. 2015,
4, 12121. (b) Xie, F.; Li, X.-W. J. Am. Chem. Soc. 2014, 136, 4780.
c) Asaumi, T.; Chatani, N. J. Org. Chem. 2004, 69, 4433. (d) Wang,
(
(
species in the catalytic cycle.
In conclusion, we have developed a rhodium-catalyzed site-
selective monoarylation of both methyl and methylene at either
the β or γ position by employing a modified pyrazole as a
transitive coordinating center. Preliminary mechanistic studies
have revealed that a CMD pathway might be involved in the
C−H activation step. This may pave the way for a
(
(
5
(
H.; Glorius, F. Angew. Chem., Int. Ed. 2013, 52, 5386.
comprehensive understanding of the mechanism of rhodium-
(14) (a) Dick, A. R.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126,
2300. (b) Testa, C.; Hierso, J. Adv. Synth. Catal. 2015, 357, 2913.
15) (a) Hashimoto, Y.; Miura, M. J. Org. Chem. 2013, 78, 638.
(b) Schinkel, D.-M.; Ackermann, L. Angew. Chem., Int. Ed. 2013, 52,
977.
3
(
III)-promoted C(sp )−H activation.
(
ASSOCIATED CONTENT
* Supporting Information
■
3
(
S
16) Yang, W-B.; Yu, J.-Q. Angew. Chem., Int. Ed. 2015, 54, 2501.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03522.
(17) Yang, W.-B.; Yu, J.-Q. Chem. - Eur. J. 2016, 22, 7059.
(18) (a) Han, J.; Zhao, Y.-S. Org. Lett. 2014, 16, 5682. (b) Guo, K.;
Zhao, Y.-S. Org. Lett. 2015, 17, 1802.
(19) Papernaya, L.; Levkovskaya, G. Heteroat. Chem. 2015, 26, 5.
20) (a) Zarubaev, V.; Kiselev, O. Bioorg. Med. Chem. 2010, 18, 839−
48. (b) Beria, I.; Ferguson, R. J. Med. Chem. 2010, 53, 3532.
21) (a) Katz, J. D.; Jewell, J. P. J. Med. Chem. 2011, 54, 4092.
b) Yuya, O.; Shinichi, I. Bioorg. Med. Chem. 2010, 18, 7150.
Experimental procedures and 1H and 13C NMR spectra
for new compounds (PDF)
X-ray data for rhodium catalyst precursor (CIF)
(
8
(
(
AUTHOR INFORMATION
Corresponding Author
(22) (a) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
■
*
1
6496. (b) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc.
2
007, 129, 14570. (c) Huang, Q.; Fazio, A.; Dai, G.-X.; Campo, M. A.;
E-mail: yszhao@suda.edu.cn.
Larock, R. C. J. Am. Chem. Soc. 2004, 126, 7460.
ORCID
Yingsheng Zhao: 0000-0002-7977-5284
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the Natural
Science Foundation of China (No. 21572149) and the Young
National Natural Science Foundation of China (Nos. 21402133
and 21403148). The PAPD Project is also gratefully acknowl-
edged.
REFERENCES
■
(
1) (a) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. (b) Giri,
R.; Shi, B.-F.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38, 3242. (c) Lyons, T.
W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(
2) Wencel-Delord, W.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740.
e) Rouquet, G.; Chatani, N. Angew. Chem., Int. Ed. 2013, 52, 11726.
3) (a) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc. 2005, 127,
3154. (b) Zhang, S.-Y.; Li, Q.; Chen, G. J. Am. Chem. Soc. 2013, 135,
2135. (c) He, G.; Chen, G. Angew. Chem., Int. Ed. 2011, 50, 5192.
(
(
1
1
(
d) Chan, K. S. L.; Yu, J.-Q. Nat. Chem. 2014, 6, 146. (e) Wang, C.;
Chen, C.; Zhao, Y.-S. Angew. Chem., Int. Ed. 2014, 53, 9884.
4) (a) Ren, Z.; Dong, G.-B. J. Am. Chem. Soc. 2012, 134, 16991.
b) Guo, K.; Zhao, Y.-S. Chem. - Eur. J. 2015, 21, 17474.
5) (a) Kozhushkov, S. I.; Ackermann, L. Chem. Sci. 2013, 4, 886.
b) He, G.; Wang, B.; Chen, G. Acc. Chem. Res. 2016, 49, 635.
6) (a) Colby, D. A.; Tsai, A. S.; Ellman, J. A. Acc. Chem. Res. 2012,
5, 814. (b) Song, G.; Li, X. Acc. Chem. Res. 2015, 48, 1007. (c) Ye, B.;
Cramer, N. Acc. Chem. Res. 2015, 48, 1308.
7) (a) Stuart, D. R.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 18326.
(
(
(
(
(
4
(
(b) Lian, Y.; Ellman, J. A. J. Am. Chem. Soc. 2013, 135, 7122.
(c) Dateer, R. B.; Chang, S. J. Am. Chem. Soc. 2015, 137, 4908.
(d) Zhang, X.-S.; Shi, Z.-J. Angew. Chem., Int. Ed. 2015, 54, 5478.
(
8) (a) Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc.
010, 132, 9585. (b) Cochet, T.; Bellosta, V.; Roche, D.; Ortholand, J.-
Y.; Greiner, A.; Cossy, J. Chem. Commun. 2012, 48, 10745.
9) (a) Liu, B.; Zhou, T.; Li, B.; Wang, B. Angew. Chem., Int. Ed.
2
(
2
014, 53, 4191. (b) Liu, B.-X.; Wang, B.-Q. Angew. Chem. 2014, 126,
4275. (c) Wang, N.; Li, R.; Wang, B. J. Org. Chem. 2014, 79, 5379.
D
DOI: 10.1021/acs.orglett.6b03522
Org. Lett. XXXX, XXX, XXX−XXX