Pyridine-enabled copper-promoted cross dehydrogenative coupling of C(sp2)-H and unactivated C(sp3)-H bonds

Article abstract of DOI:10.1039/c5sc02143j

The pyridine-enabled cross dehydrogenative coupling of sp² C-H bonds of polyfluoroarenes and unactivated sp³ C-H bonds of amides was achieved via a copper-promoted process with good functional group compatibility. This reaction showed great site-selectivity by favoring the sp² C-H bonds ortho to two fluoro atoms of arenes and the sp³ C-H bonds of α-methyl groups over those of the α-methylene, β- or γ-methyl groups of the aliphatic amides. Mechanistic studies revealed that sp³ C-H bond cleavage is an irreversible but not the rate-determining step, and the sp² C-H functionalization of arenes appears precedent to the sp³ C-H functionalization of amides in this process.

Full text of DOI:10.1039/c5sc02143j

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EDGE ARTICLE
Pyridine-Enabled Copper-Promoted Cross
Dehydrogenative Coupling of C(sp2)−H and
Unactivated C(sp3)−H Bonds †
Cite this: DOI: 10.1039/x0xx00000x
Xuesong Wu, Yan Zhao and Haibo Ge*
Received 00th January 2015,
Accepted 00th January 2015
The pyridine-enabled cross dehydrogenative coupling of sp2 C−H bonds of polyfluoroarenes and unactivated
sp3 C−H bonds of amides was achieved via a copper-promoted process with good functional group
compatibility. This reaction showed great site-selectivity by favoring the sp2 C−H bonds ortho to two fluoro
atoms of arenes and the sp3 C−H bonds of α-methyl groups over those of the α-methylene, β- or γ-methyl
groups of the aliphatic amides. Mechanistic studies revealed that sp3 C−H bond cleavage is an irreversible but
not the rate-determining step, and the sp2 C−H functionalization of arenes appears precedent to the sp3 C−H
functionalization of amides in this process.
DOI: 10.1039/x0xx00000x
www.rsc.org/
unactivated sp3 C−H bond activation process developed by
Daugulis’ group,7 we envisaged that attachment of a bidentate
Introduction
Transition metal-promoted direct functionalization of
unactivated C−H bonds is a highly valuable approach for the
selective construction of C−C bonds, and considerable efforts
have been devoted into this research area over the past couple of
decades.1 Within this reaction category, ligand-assisted cross
dehydrogenative coupling (CDC) is of current interest, and
significant progress has been achieved in recent years.2
Compared with the conventional cross coupling reactions, this
method enables the direct manipulation of aromatic and aliphatic
C−H bonds by obviating the pre-installation of the functional
groups. Moreover, the ligand acts as a directing group to ensure
the high site-selectivity. In the process, a noble metal species
such as palladium, rhodium, or ruthenium is often employed as
a catalyst. From an economical point of view, avoidance of the
use of the precious catalyst in the process would be highly
desirable. Towards this effort, Miura and co-workers reported
the first copper-promoted cross dehydrogenative coupling of 2-
phenylpyridines and benzoxazoles in 2011 (Scheme 1, a).3 It was
then found that azine-N-oxides, benzamides, indoles,
naphthylamines, and 2-pyridones were also effective substrates.4
Despite being a highly efficient method for the construction of
C−C bonds, this process does not allow for the site-selective
direct functionalization of unactivated sp3 bonds coupling with
an arene bearing a directing group, thus restricting the product
diversity.5,6 Inspired by the bidentate directing group-assisted
directing group to an aliphatic acid may potentially overcome
this drawback.8 With this design, we have examined and report
here the copper-promoted cross dehydrogenative coupling of
aliphatic amides9 and polyfluoroarenes10 (Scheme 1, b), which
provides an efficient access to alkyl-substituted perfluoroarenes,
an important structural motif in pharmaceuticals and
agrochemicals.11 It is worthy to mention that this is the first
example
of
ligand-directed
copper-promoted
cross
dehydrogenative
coupling
reactions by employing
polyfluoroarenes as the coupling partners.
Scheme 1. Copper-promoted cross dehydrogenative coupling (CDC) reactions
Results and discussion
Our investigation commenced with cross dehydrogenative
coupling of 2-ethyl-2-methyl-N-(quinolin-8-yl)pentanamide
Department of Chemistry and Chemical Biology, Indiana University-Purdue University
Indianapolis, Indianapolis, Indiana 46202 (USA). E-mail: geh@iupui.edu
† Electronic Supplementary Information (ESI) available: Experimenta ldetails including
characterization data, copies of 1H, 13C NMR and NOESY spectra. See
DOI: 10.1039/b000000x/
(
1a) and pentafluorobenzene (2a) in 1,4-dioxane with
stoichiometric amounts of Cu(OAc)2 under atmospheric oxygen
(Table 1). After an extensive screening of the bases, pyridine has
proven to be optimal, affording the desired product 3a in 22%
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Table 1. Optimization of reaction conditionsa
yield, while all inorganic bases failed in the reaction (entries 1-
7). Considering that pyridine could also act as a ligand in the
process, and thus promotes the reaction, a screening on nitrogen-
containing potential bidentate ligands was further carried out. As
shown in Table 1, several ligands such as TMEDA, 2,2’-
bipyridine, and 1,10-phenanthroline could promote the process,
but none of these molecules is as effective as pyridine (entries 8-
10). Next, different copper sources were examined, and it was
found that CuOAc was the only other species, but with less
efficiency (entry 13). Then, the effects of an oxidant towards the
reaction were examined, and it turned out that di-tert-butyl
peroxide was optimal, providing 3a in 44% yield (entry 17). It
was also noticed that a higher yield could be obtained under
atmospheric nitrogen (entry 18). Following the above
investigation, we carried out an extensive screening of the
solvents, and the reaction was significantly improved with the
solvent mixture of DME and 1,4-dioxane (entry 22).
Furthermore, an excellent yield was observed with increased
amounts of pyridine (entry 24). It was also noted that the reaction
yield was dramatically decreased with reduced amounts of the
copper species (entry 25), presumably due to the competitive
coordination of pyridine or tert-butanolate released from di-tert-
butyl peroxide to copper. Moreover, it is clear that pyridine is
required for this process since no apparent product formation
occurred in the absence of pyridine (entry 26). As expected, a
high site-selectivity was observed with the preference on C−H
bond of the α-methyl over that of the α-methylene, β- or γ-methyl
group,9 which is believed to be arisen from the steric effect and
a Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), Cu salt (0.3 mmol),
oxidant (0.75 mmol), additive, 1.0 mL of solvent, 140 oC, 16 h. b Yields and
conversions are based on 1a, determined by 1H-NMR using dibromomethane
as the internal standard. Isolated yield is in parenthesis. c Under N2
atmosphere. d Cu(OAc)2 (0.15 mmol). Q = 8-quinolinyl.
preference of the formation of
a five-membered ring
intermediate over the six- or seven-membered ring intermediate
in the cyclometalation step.
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bonds.10 Furthermore, fluoropyridines were also effective
coupling partners for this process (3m and 3n). Unfortunately,
other heteroaromatic substrates such as benzoxazoles,
thiophenes, indoles etc. failed to provide any desired products
under the current conditions.
Table 2. Scope of fluoroarenesa,b
Table 3. Scope of amidesa,b
a Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), Cu(OAc)2 (0.3 mmol),
(tBuO)2 (0.75 mmol), Py (0.9 mmol), DME/1,4-dioxane (v:v = 7:3, 1.0 mL),
140 oC, 16 h. b Isolated yield. c 2 (1.2 mmol), run at 160 oC.
a Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), Cu(OAc)2 (0.3 mmol),
(tBuO)2 (0.75 mmol), Py (0.9 mmol), DME/1,4-dioxane (v:v = 7:3, 1.0 mL),
140 oC, 16 h. b Isolated yield. c run at 160 oC.
Under the optimized conditions, the scope with respect to
fluoroarenes was examined. As shown in Table 2,
tetrafluorobenzenes bearing a methoxyl, bromo, cyano, or
trifluoromethyl group were compatible with the process (3b-e).
Additionally, higher yields were observed with substrates
substituted by an electron-withdrawing group, presumably due
to the increased reactivity of the aromatic C−H bonds from the
increased acidity of these bonds and/or increased
electronegativity of a copper intermediate which facilitates the
Next, the substrate scope study of aliphatic amides was carried
out (Table 3). As expected, 2,2-disubstituted propanamides
bearing either the linear or cyclic chains provided the
corresponding desired products in good yields with good
functional group compatibility. In addition, a predominant
preference of functionalizing the C−H bonds of the α-methyl
over those of the α-methylene, β- or γ-methyl groups, was
observed in all cases, presumably due to the steric effect.9
Notably, both mono- and di-pentafluoro-substituted coupling
products were obtained with 2,2-dimethyl butanamide and
trifluropropanamide (3w and 3x). Interestingly, only the mono-
coupling products were observed with α-phthalimide and α-
sulfone-substituted amides, which is believed to be due to the
steric effects (3y and 3z). Not surprisingly, both mono- and bis-
coupling products were isolated with N-(quinolin-8-
yl)pivalamide (3aa). Moreover, it was found that a tertiary α–
sp3
C−H
bond
activation.4
1,2,4,5-tetrafluorobenzene,
Furthermore,
1,2,3,5-
and
tetrafluorobenzene,
trifluorobenzenes with an additional electron-withdrawing group
were effective substrates (3f-i). Not surprisingly, low reactivity
was
observed
with
1,3,5-trifluorobenzene,
1,2,4-
trifluorobenzene, and 3,5-difluorobenzonitrile. Delightfully,
successfully couplings of these substrates were achieved at an
elevated reaction temperature (3j-l). Interestingly, a high
regioselectivity was also observed in these cases by favoring the
C−H bonds between the two C−F bonds, the most acidic C−H
carbon is necessary for this reaction since amides
4 and 5 failed
to provide the corresponding desired products. Unfortunately,
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functionalization of secondary β–sp3 carbons was not successful (Scheme 4). It is believed that this process begins with the
and ). reversible C−H cupration of fluoro(hetero)arene with
To gain some mechanistic insights of this reaction, a series of Cu(OAc)2 in the presence of pyridine. Coordination of amide
(6
7
a
1
deuterium-labeling experiments were carried out (Scheme 2). to this CuII species followed by a ligand exchange step gives rise
Considering that tBuOH is generated from (tBuO)2 as a to the CuII intermediate
B
. Subsequent oxidation of the CuII
B C, which undergoes an
t
byproduct in the process, stoichiometric amounts of BuOD was species
generates the CuIII intermediate
added into the reaction system for this study. It was noticed that intramolecular cyclometalation step to provide the CuIII complex
an apparent H/D exchange occurred with pentafluorobenzene . Reductive elimination of this intermediate followed by a
2a
and a CuI
D
(
)
with or without 2-ethyl-2-methyl-N-(quinolin-8- ligand dissociation process affords the product 3
yl)butanamide (1b), indicating that C−H bond cleavage of species. Oxidation of the CuI species by (tBuO)2 regenerates the
fluorobenzene is a reversible step. Furthermore, either a small or CuII species. Alternatively, on the basis of the observations in
trace amount of [D]-2a was observed in the absence of Cu(OAc)2 Scheme 2, the cupration of fluoro(hetero)arene
2 could take
or pyridine, while the obvious H-D scrambling occurred without place with the CuI species, providing the CuI intermediate
F
(tBuO)2. It should be mentioned that H-D scrambling could also which could then be oxidized to the CuII intermediate
be promoted by CuOAc instead of Cu(OAc)2 in the absence of (tBuO)2.
(tBuO)2. These results suggest that the copper species promotes
the sp2 C−H bond cleavage with the pyridine as a base and ligand
to facilitate the process, and a pyridine-coordinated aryl copperII
or aryl copperI intermediate may be involved in the reaction.4e-i
In the study, it was found that H/D exchange did not happen with
1b in the absence of 2a, indicating that an aryl copper
intermediate may be involved in the sp3 C−H bond cleavage step
of the amide.
A
by
Scheme 2. Deuterium labeling experiments.
Scheme 4. Plausible reaction mechanism.
We further carried out the deuterium-labeling experiments
with [D3]-1b. As shown in Scheme 3, a H/D exchange was not
observed with either this substrate or the product, suggesting that
sp3 C−H bond cleavage is an irreversible step. In addition, a
Conclusions
In summary, copper-promoted pyridine-enabled cross
dehydrogenative coupling of aromatic sp2 C−H bonds and
unactivated aliphatic sp3 C−H bonds was developed with high
efficiency and good functional group tolerance. In this process,
high regioselectivity was observed with sp2 C−H bond
functionalization, favoring an sp2 C−H bond between two C−F
bonds of (hetero)arenes. In addition, a predominant preference
of functionalizing the sp3 C−H bonds of α-methyl groups over
those of the α-methylene, β- or γ-methyl groups was observed
with aliphatic amides. Mechanistic studies suggested that sp2
C−H bond cleavage is a reversible step while sp3 C−H bond
cleavage is an irreversible but not the rate-limiting step.
Interestingly, it was also found that sp3 C−H bond cleavage is
dependent on sp2 C−H bond cleavage. The detailed mechanistic
studies and potential synthetic applications of this process are
currently under investigation in our laboratory.
second order kinetic isotope effect was observed with 1b in the
process, indicating that cyclometalation of the amide is not the
rate-limiting step.
Scheme 3. Deuterium labeling experiments of amides.
On the basis of the above observed results and the previous
reports,4,9,12 a plausible mechanism of this reaction is proposed
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Ed., 2013, 52, 4457; (g) R. Odani, K. Hirano, T. Satoh and M. Miura,
J. Org. Chem., 2013, 78, 11045; (h) R. Odani, K. Hirano, T. Satoh
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For Cu-catalyzed and/or promoted CDC between sp2 and sp2/sp C-H
Acknowledgements
We gratefully acknowledge Indiana University Purdue
University Indianapolis for financial support. We would also like
to acknowledge Nanjing University for financial support. The
Bruker 500 MHz NMR was purchased using funds from an NSF-
MRI award (CHE-0619254).
5
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6 | J. Name., 2015, 00, 1-3
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Chemical Science
ARTICLE
Table of Contents
Pyridine-enabled cross dehydrogenative coupling of sp2 C−H
bonds of polyfluoroarenes and unactivated sp3 C−H bonds of
amides was achieved.
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