Rh(III)-Catalyzed meta-C-H Olefination Directed by a Nitrile Template

Article abstract of DOI:10.1021/jacs.6b13269

A range of Rh(III)-catalyzed ortho-C-H functionalizations have been developed; however, extension of this reactivity to remote C-H functionalizations through large-ring rhodacyclic intermediates has yet to be demonstrated. Herein we report the first examp

Full text of DOI:10.1021/jacs.6b13269

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Communication
Rh(III)-Catalyzed Meta-C–H Olefination Directed by a Nitrile Template
Hua-Jin Xu, Yi Lu, Marcus E. Farmer, Huai-Wei Wang, Dan
Zhao, Yan-Shang Kang, Wei-Yin Sun, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b13269 • Publication Date (Web): 27 Jan 2017
Downloaded from http://pubs.acs.org on January 27, 2017
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Rh(III)-Catalyzed Meta-C–H Olefination Directed by a Nitrile Template
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HuaꢀJin Xu,† Yi Lu,*,† Marcus E. Farmer,‡ HuaiꢀWei Wang,† Dan Zhao,† YanꢀShang Kang,† WeiꢀYin
Sun,*,† JinꢀQuan Yu*,‡
† Coordination Chemistry Institute, State Key Laboratory of Coordination Chemistry, School of Chemistry and
Chemical Engineering, Nanjing National Laboratory of Microstructures, Collaborative Innovation Center of Advanced
Microstructures, Nanjing University, Nanjing 210023, China
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‡ Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037,
USA
RECEIVED DATE (automatically inserted by publisher); luyi@nju.edu.cn, sunwy@nju.edu.cn, yu200@scripps.edu
Scheme 1. Directed Meta-C–H Functionalization
Abstract:
A
range of Rh(III) catalyzed orthoꢀC–H
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functionalizations have been developed; however, extension of
this reactivity to remote C–H functionalizations through large ring
rhodacyclic intermediates has yet to be demonstrated. Herein, we
report the first example of utilizing a Uꢀshaped nitrile template to
direct Rh(III)ꢀcatalyzed remote metaꢀC–H activation via
a
postulated 12ꢀmembered macrocyclic intermediate. Considering
the ligands used for Rh(III) catalysts are significantly different
from those of Pd(II) catalysts, this offers new opportunities for
future development of ligandꢀpromoted metaꢀC–H activation
reactions.
In light of the recent and rapid development of Rh(III)ꢀ
catalyzed orthoꢀC–H functionalizations,1gꢀj,8 it is highly desirable
to extend the templating approach to Rh(III)ꢀcatalyzed metaꢀC–H
activation processes for a number of reasons. First, both substrate
and reaction type can be complementary to that of Pd(II)ꢀ
catalyzed metaꢀC–H functionalizations. Second, the ligands used
for Rh(III) and Pd(II) are often different which could offer new
opportunities for developing ligand controlled, enantioselective
remote C–H activation reactions. Third, the oxidation potentials
for the reoxidation of low valent metal species are different which
may lead to the use of more practical oxidants for closing the
catalytic cycle. Herein, we report the first example of using a
Rh(III) catalyst in the presence of a guiding template to provide a
metaꢀselective C–H olefination of hydrocinnamic acids. The use
of Cu(II) as the coꢀoxidant is an advantage compared to the Ag
oxidant required for the related Pd chemistry. The generality of
this approach is also demonstrated by accomplishing a metaꢀC–H
olefination of aniline and indoline substrates bearing templates
previously developed for Pd(II) catalysts.6b,c
Transition metal catalyzed C–H functionalization has been
an area of significant interest due to the enabling nature of these
reactions to convert previously considered inert C–H bonds into a
diverse range of carbonꢀcarbon and carbonꢀheteroatom bonds.
Directed C–H functionalization has been of particular interest as
the preꢀcoordination of a given functional group to the transition
metal catalyst enables highly selective C–H activation in a general
and predictable manner.1 This strategy has been demonstrated to
be a useful tactic with a wide variety of metals and has been
shown to be particularly versatile when using Pd(II), Ru(II),and
Rh(III) as catalysts.1 The use of other catalysts including Cu(II)
and Ir(III) has also been demonstrated.1 Directed C–H activation
typically proceeds via five or sixꢀmembered cyclometalation
processes which precludes the functionalization of remote metaꢀ
or paraꢀC–H bonds. As one of several approaches towards metaꢀ
C–H functionalization of aromatics,2ꢀ5 the development of a Uꢀ
shaped directing template has successfully achieved a number of
remote C–H activation reactions with several different classes of
substrates.6 Key to the success of this approach was the use of a
nitrile embedded in the template which serves as a linear endꢀon
directing group. The linearity of the nitrile group prevents the
assembly of the classical cyclic preꢀtransition state required for
orthoꢀC–H activation and instead, positions the palladium catalyst
near the remote metaꢀC–H bond. This allows for a macrocyclic
cyclophaneꢀlike transition state to be preferentially assembled
which results in a metaꢀC–H functionalized product. Such precise
recognition of distance and geometry has proven to be rather
general in terms of substrate and reaction type.6ꢀ7 Furthermore,
this approach has been demonstrated to be compatible with both
Pd(II)/(0) and Pd(II)/(IV) catalysis6 and has been utilized to
achieve paraꢀC–H activation by modification of the template.7
Based on previous Pd(II)ꢀcatalyzed metaꢀselective C–H
bond activation studies using a nitrileꢀcontaining template,6a we
initiated efforts to develop a [RhCp*Cl2]2ꢀcatalyzed metaꢀC–H
olefination of hydrocinnamic acid (Scheme 1). We selected
hydrocinnamic acid derived compound 1’ (Table 1) as our initial
substrate for optimization as this is a benchmark substrate for the
analogous Pd(II) chemistry. Our studies began using Cu(OAc)2 as
a terminal oxidant for the reaction in dry toluene under an
atmosphere of O2 at 100 °C. With these conditions, we were
delighted to find our desired product in trace quantities. A
thorough solvent screen was undertaken and DCE was found to be
optimal, allowing formation of the desired product in 18% yield.
A brief study of the temperature dependence of this reaction
indicated that at 120 °C, 25% yield could be obtained. Though
o
140 C provided a higher yield, the reaction profile was not as
clean and we therefore decided to move forward with the
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o
optimization using 120 C. No distinct difference was observed
when the reaction time was extended to 48 hours, indicating that
the catalyst was no longer functional after 36 hours. A wide
variety of oxidants were evaluated and Cu(O2CCF3)2·xH2O was
found to be far superior to the others, enhancing the yield to 50%
with 5% being diꢀsubstituted product. Interestingly, when we
decreased the equivalence of Cu(O2CCF3)2·xH2O to one
equivalent, a significant increase of the total yield to 77% was
obtained. Presumably, excess Cu(II) species could outcompete the
Rh(III) for coordination with the nitrile template. We next
examined the role of the oxidants in this transformation. First,
since O2 can potentially turn over copper oxidation catalysts, we
attempted the reaction under an atmosphere of oxygen with only
0.5 equivalents of Cu(O2CCF3)2·xH2O and found that the yield
decreased to 44%. This led us to evaluate the reaction under a
nitrogen atmosphere in the presence of one equivalent of
Cu(O2CCF3)2•xH2O; however, the yield of the desired products
under these conditions was a mere 13% indicating O2 is also
necessary for this transformation (see supporting information).
Further optimization of additives revealed that addition of one
equivalent of CF3CO2H improved the yield to 89%. The use of a
Cu(II) oxidant is a practical advantage over Pd(II) methods as
Ag(I) salts are often needed in Pd(II)ꢀcatalyzed remote C–H
functionalizations using nitrile templates.6
Since the diꢀsubstituted product was nonꢀnegligible in the
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standard conditions, we endeavored to search for a suitable
directing group which can inhibit the generation of diꢀsubstituted
product. A brief evaluation of templates revealed that use of T3
containing a single nitrile group (Table 2) could slightly improve
the mono:di ratio, enabling the monoꢀsubstituted product to be
obtained in 68% yield and the diꢀsubstituted product in 22%.
Based on these results, we selected template T3 as our final
template. Importantly, the nitrile is key to achieving high
selectivity as indicated by the mixture of products obtained when
using T4. At this point, we attempted to lower the reaction
temperature. As can be seen in Table 2, using the optimized
conditions and template at 100 oC provided a comparable yield of
the desired product. Under these milder conditions, the catalyst
was active for over 36 hours and the optimal reaction time was
extended to 48 hours.
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Table 3. Rh(III)-catalyzed meta-C–H olefination of
hydrocinnamic acid derivatives.a,b
T3
T3
[RhCp*Cl2]2
O
H
Cu(CO2CF3)2 xH2O
O
F
OEt
+
R
R
N
T3
=
O
CF3CO2H, DCE
O2, 100oC, 48 h
CO2Et
NC
1
2a
3
T3
Me
T3
T3
T3
O
O
Me
O
MeO
O
Table 1. Optimization of reaction conditions.a
CO2Et
CO2Et
3bmono 67%
m:others = 94:6
3bdi 23%
CO2Et
CO2Et
3amono 65%
m:others = 95:5
3adi 23%
3c 81%
= 93:7
3d 87%
m:others
= 91:9
m:others
m:others = 93:7
m:others = 94:6
T3
T3
T3
T3
F
O
Cl
O
Br
O
F3C
O
CO2Et
CO2Et
CO2Et
CO2Et
3e 75%
3f 76%
3g 78%
3h 55%
m:others = 91:9
m:others = 95:5
m:others = 93:7
m:others = 90:10
T3
T3
T3
T3
O
O
O
O
Me
CO2Et MeO
CO2Et
F
CO2Et Cl
CO2Et
3i 85%
3j 81%
3k 60%
3l 67%
m:others = 92:8
m:others = 95:5
m:others = 93:7
m:others = 94:6
T3
T3
T3
T3
O
O
O
O
CO2Et
CO2Et
aReaction conditions: 1’ (0.1 mmol), 2a (0.6 mmol), [RhCp*Cl2]2 (5 mol %), oxidant
(0.2 mmol), additive (0.1 mmol), dry DCE (2 mL), O2, 36 h, 120 °C. Yield was
determined by 1H NMR analysis using CH2Br2 as the internal standard.
bCu(CO2CF3)2·xH2O (0.1 mmol). cAir was used instead of O2.
Br
CO2Et F3
C
CO2Et
OCH3
F
3m 69%
3n 49%
3o 85%
3p 75%
m:others = 94:6
m:others =91:9
m:o = 93:7
m:o = 95:5
aReaction conditions: 1 (0.1 mmol), 2a (0.6 mmol), [RhCp*Cl2]2 (5 mol %),
Cu(CO2CF3)2·xH2O (0.1 mmol), CF3CO2H (0.1 mmol), dry DCE (2 mL), O2, 48 h,
100 °C. bIsolated yield
Table 2. Investigation of templates.a,b
T
T
[RhCp*Cl2]2
O
H
Cu(CO2CF3)2 xH2O
O
OEt
+
With the optimized conditions in hand, we examined the
scope of hydrocinnamic acid derivatives using ethyl acrylate (2a)
as the coupling partner (Table 3). Unsubstituted compounds 1a
and 1b provided the highest total yields of 88% and 90%
respectively. It is worth noting that there were no diꢀsubstituted
products for the substrates with substituents at the orthoꢀ, metaꢀ,
or paraꢀpositions. For orthoꢀsubstituted substrates, both electronꢀ
donating groups (3c, 3d) and halogens (3eꢀ3g) were well
tolerated, with the desired products being obtained in good yield.
Substrate 1h containing an orthoꢀtrifluoromethyl group could be
coupled to provide the desired product in a modest, although
synthetically useful yield of 55%. For metaꢀsubstituted substrates,
those bearing electronꢀdonating groups at the metaꢀposition (1i,
1j) worked well in the reaction and the desired products were
cleanly afforded in 85% (3i) and 81% (3j) yield with good metaꢀ
selectivity. Substitution of the metaꢀposition with halogens
(entries 3k – 3m, Table 3) provided a slight depreciation of the
yield, though the selectivity remained high. Metaꢀtrifluoromethyl
substituted substrate 1n gave the desired product 3n in a modest
yield of 49%. Either methoxy or fluoride substitution at the para
O
CF3CO2H, DCE
O2, 120oC, 36 h
CO2Et
1
2a
3
OMe
NC
NC
N
N
N
OMe
NC
T1
NC
T4
T2
20% conversation
multiple products
63% mono, 26% di
48% mono, 34% di
F
Me
N
N
N
NC
NC
NC
T3
T5
T6
68% mono, 22% di
65% mono, 22% dic
55% mono, 19% di
49% mono, 22% di
aReaction conditions: 1 (0.1 mmol), 2a (0.6 mmol), [RhCp*Cl2]2 (5 mol %),
Cu(CO2CF3)2·xH2O (0.1 mmol), CF3CO2H (0.1 mmol), dry DCE (2 mL), O2, 36 h,
120 °C. bYield was determined by 1H NMR analysis using CH2Br2 as the internal
standard. cIsolated yield of reaction run at 100 oC, 48h.
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position does not hamper this reaction (3o, 3p). However, it is
elimination yields the desired product and a Rh(III) hydride 4.
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noteworthy that this reaction is somewhat sensitive to both sterics
and electronics at the 4ꢀposition of the aromatic. We have
attempted reactions using 4ꢀtertꢀbutylꢀ and 4ꢀnitroꢀhydrocinnamic
acid derived substrates, but neither provided significant quantities
of olefination products.
Reductive elimination, followed by reoxidation of [Rh(I)] to
[Rh(III)] by Cu(O2CCF3·xH2O) and O2 would restore the active
catalyst, completing the catalytic cycle. In an attempt to probe
whether C–H activation is rate determining in this catalytic cycle,
we conducted experiments to determine the kinetic isotope effect
(KIE) for parallel experiments. The KIE (kH/kD = 1.8) revealed
that the metaꢀC–H bond cleavage may be the rate determining
step (see supporting information for details).
To investigate the generality of this reaction, the scope of
olefin coupling partners was evaluated. As can be seen in Table 4,
a wide range of olefin coupling partners can be employed in this
transformation. Methyl acrylate, butyl acrylate, dimethyl
acrylamide, ethyl vinyl ketone, acrolein, and diethylvinyl
phosphonate could all be effectively coupled providing the
desired products in good yield. A βꢀsubstituted enone and styrene
derivatives were also compatible with this reaction, with electron
withdrawing groups on the aromatic ring of styrene being favored.
Phenyl vinyl sulfone also coupled well in this reaction.
We next attempted to scale the reaction to gram scale. By
refluxing the reaction mixture in toluene for 48 h under O2
(balloon), 75% yield (55% mono, 20% di, isolated) of the desired
product could be obtained (see supporting information for details).
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Scheme 2. Meta-C–H olefination of aniline and indoline
Given the generality of this templating approach with Pd(II)
catalysis, we sought to examine whether this Rh(III) system can
be extended to other types of substrates. A brief examination of
templates that have previously been utilized for Pd(II) catalysis6b,c
indicated
that
indeed,
Rh(III)
catalyzed
metaꢀC–H
functionalization using this strategy will likely prove to be highly
general. As can be seen in Scheme 2, both indoline and aniline
were successfully olefinated at the metaꢀC–H bond using a
template originally designed for Pd(II) catalyzed olefination of
indolines.6e Interestingly, it was found that in these cases, the
addition of TFA to the reaction hampered the reactivity of the
catalyst. Further work on improving the scope and efficiency of
this transformation using Rh(III), as well as other transition metal
catalysts, is currently underway and will be reported in due
course.
Table 4. Scope of olefin coupling partners.a,b
In summary, we have developed a Rh(III)ꢀcatalyzed metaꢀ
C–H olefination of hydrocinnamic acid derivatives using a
modified monoꢀnitrile template. The identification of
Cu(O2CCF3·xH2O) as oxidant was crucial for this reaction. These
results pave the way for further development of new ligands for
Rh(III)ꢀcatalyzed remote C–H functionalizations
T3
T3
[RhCp*Cl2]2
Cu(CO2CF3)2 xH2O
O
H
O
+
R
CF3CO2H, DCE
O2, 100oC, 48 h
MeO
MeO
R
1
2
3
T3
T3
T3
O
O
O
Me
N
Scheme 3. Simplified mechanism for the olefination reaction.
MeO
CO2Me MeO
CO2n-Bu
MeO
Me
T
O
3q 77%
3r 68%
3s 85%
O
m:others = 94:6
m:others = 95:5
m:others = 97:3
LnRh(III)
H
T3
T3
T3
1
H-X Reductive Elim./
O
O
O
Reoxidation
C-H Activation
OEt
MeO
COEt
MeO
CHO
MeO
Ar
N
Me
3v 65%
O
3tc 70%
3uc 64%
m:others = 93:7
Rh(III)/(I) Catalysis
m:others = 96:4
m:others = 94:6
O
N
2
LnRh(III)-H
4
T3
T3
T3
Rh
(III)Ln
O
O
O
CO2Me
Me
Ar
N
MeO
MeO
CO2Me
CO2Me
3x 68%
MeO
OEt
O
Me
O
CO2Me
3y 47%
T
3wc 60%
O
-H Elim.
1,2-Migratory Insertion
O
m:others = 98:2
m:others = 96:4
m:others = 94:6
N
3
CO2Et
T3
T3
T3
EtO2C
Rh(III)Ln
O
O
O
OEt
O
OEt
MeO
S
Acknowledgements. We gratefully acknowledge the National
Natural Science Foundation of China (grant no. 21201100, 21671097
and 21331002) and National Science Foundation (CHEꢀ1465292) for
financial support.
MeO
MeO
P
O
O
3z 80%
F
3
67%
3
68%
m:others = 96:4
m:others = 91:9
m:others = 93:7
aReaction conditions: 1 (0.1 mmol),
2 (0.6 mmol), [RhCp*Cl2]2 (5 mol %),
Cu(CO2CF3)2·xH2O (0.1 mmol), CF3CO2H (0.1 mmol), dry DCE (2 mL), O2, 48 h,
Supporting Information Available: Experimental procedures and
spectral data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
100 °C. bIsolated yield. cThe reaction was run in the absence of the TFA additive.
A plausible reaction mechanism for this reaction is proposed
in Scheme 3. Coordination of the nitrile to the [Rh(III)] catalyst is
followed by metaꢀC–H bond activation to give the corresponding
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12ꢀmembered
rhodacyclic
intermediate
2.
Subsequent
coordination to the olefin coupling partner followed by 1,2ꢀ
migratory insertion would yield intermediate 3. βꢀHydride
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