Copper-catalyzed dehydrogenative coupling of arenes with alcohols

Article abstract of DOI:10.1002/anie.201303702

What a couple! Arenes functionalized with donating groups undergo oxidative dehydrogenative coupling with alcohols in the presence of a copper/silver catalyst system. This intermolecular C-H alkoxylation provides a convenient synthetic route to the important class of aryl ethers. The catalyst system also allows the alkoxylation of benzylic C-H groups with formation of benzyl alkyl ethers. Copyright

Full text of DOI:10.1002/anie.201303702

Angewandte
Chemie
Communications
À
C H Activation
S. Bhadra, C. Matheis, D. Katayev,
L. J. Gooßen*
&&&& — &&&&
Copper-Catalyzed Dehydrogenative
Coupling of Arenes with Alcohols
What a couple! Arenes functionalized
with donating groups undergo oxidative
dehydrogenative coupling with alcohols
in the presence of a copper/silver catalyst
lation provides a convenient synthetic
route to the important class of aryl ethers.
The catalyst system also allows the
À
alkoxylation of benzylic C H groups with
À
system. This intermolecular C H alkoxy-
formation of benzyl alkyl ethers.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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DOI: 10.1002/anie.201303702
À
C H Activation
Copper-Catalyzed Dehydrogenative Coupling of Arenes with
Alcohols**
Sukalyan Bhadra, Christian Matheis, Dmitry Katayev, and Lukas J. Gooßen*
Dehydrogenative cross-couplings arguably represent the
most attractive strategy to introduce carbon- or heteroatom-
based groups into organic molecules.[1] Ideally, two different
ment of dehydrogenative alkoxylations of arenes is challeng-
ing. Alkanols easily dehydrate through cationic or radical
mechanisms[14] and are sensitive towards oxidation to the
corresponding ketones or carboxylic acids.[15] Moreover,
metal alkoxide intermediates are prone to b-hydride elimi-
nation.[16] Pioneering direct dehydrogenative alkoxylations of
arenes that involve the use of nitrogen-based directing groups
and palladium catalysts have been disclosed by the groups of
Sanford[17] and others.[18] A CuCl-catalyzed C2 alkoxylation of
imidazoles has been reported by Kanai et al.[19] However,
these methods have been applied only to a small number of
simple alcohol substrates.
Based on the Cu-catalyzed phenoxylation of arenes
developed by Yu and co-workers[13b] and the observation by
Ribas and Stahl that a macrocyclic copper ligand was
methoxylated on the addition of methanol,[20] we reasoned
that a copper catalyst might promote the desired direct
dehydrogenative cross-coupling between arenes and alco-
hols.[21,22] This was further supported by our recent discovery
of decarboxylative ipso-[23] and ortho-alkoxylations[24] of
benzoic acids with boron or silicon alkoxides.
À
molecules are each selectively activated at one specific C H
À
or heteroatom H group, and undergo regioselective cross-
coupling with one another. The hydrogen formally produced
is usually scavenged in an oxidative step, for example, with
formation of water, which significantly contributes to the
thermodynamic driving force of the reaction. Key advantages
of this approach are that functionalization occurs within
a single step rather than a resource- and waste-intensive
synthetic sequence consisting of the prefunctionalization of
substrates with leaving groups and traditional cross-coupling.
Tremendous progress has been made in recent years in this
field, and the feasibility of regioselective dehydrogenative
[1a,d]
À
cross-couplings has been demonstrated for various C C,
[2]
[3]
À
À
several C N, and a few C O bond-forming reactions.
However, the practical utility of existing protocols is often
limited by narrow substrate scopes, lack of selectivity or the
use of expensive metal catalysts, e.g., Pd,[4] Rh,[5] or Ru.[6]
Owing to the abundance of aryl ether moieties in
biologically active molecules and functional materials,[7]
their synthesis by the dehydrogenative coupling of arenes
and free alcohols is highly desirable (Scheme 1). It compares
To probe the viability of this approach, we investigated
the reaction between 1-butanol and 2-phenylpyridine, a sub-
À
strate widely employed for chelation-assisted C H function-
alizations.[25] Indeed, when a solution of 2-phenylpyridine in 1-
butanol was treated with stoichiometric amounts of Cu-
(OAc)2 under an O2 atmosphere at 1208C, the desired
butoxyarene (3ab) was obtained in visible amounts, along
with some doubly butoxylated product 4 (Table 1, entry 1).
As we had previously observed a beneficial effect of
silver(I) salts on the alkoxylation step of decarboxylative
Chan–Evans–Lam reactions, we next tested various silver
salts as additives, including AgOTf, Ag2CO3, AgOAc, and
Ag2O (see also the Supporting Information, Table S1).
Among them, silver(I) triflate proved to be particularly
effective and its use led to a sharp increase in the yield
(Table 1, entry 2). A reduction in the copper loading to
25 mol% and an increase in the temperature to 1408C further
enhanced the conversion and the selectivity for the mono-
alkoxylated product 3ab (Table 1, entries 3 and 4). 3ab was
obtained exclusively when less 1-butanol was used (Table 1,
entry 5). A reduction of the copper acetate loading to
10 mol% or the silver triflate loading to 1 equivalent led to
decreased yields (Table 1, entries 6 and 7). Addition of
various N or O donor and/or phosphine ligands to stabilize
the copper catalyst did not substantially influence the yields
(see the Supporting Information, Table S2). However, a com-
bination of Cu(OTf)2 with excess NaOAc is effective also at
10 mol% Cu loading. This is in agreement with findings by
Scheme 1. Dehydrogenative alkoxylation of arenes. DG=directing
group, FG=functional group, Alk=alkyl.
favorably with traditional approaches[8] and modern aryl
ether syntheses, for example, through Pd-catalyzed Buch-
wald–Hartwig[9] couplings and Cu-catalyzed Ullmann[10] or
Chan–Evans–Lam[11] reactions. However, whereas efficient
methods for direct hydroxylations,[12] acetoxylations,[13] and
even a phenoxylation[13b] have been reported, the develop-
[*] Dr. S. Bhadra, C. Matheis, Dr. D. Katayev, Prof. Dr. L. J. Gooßen
FB Chemie-Organische Chemie
Technische Universitꢀt Kaiserslautern
Erwin-Schrçdinger-Strasse Geb. 54
67663 Kaiserslautern (Germany)
E-mail: goossen@chemie.uni-kl.de
Homepage: http://www.chemie.uni-kl.de/goossen
[**] We thank the DFG (SFB/TRR-88, “3MET”), and the Swiss National
Foundation (fellowship to D.K.) for financial support, and Prof. Dr.
F. W. Patureau for helpful discussion.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303702.
2
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Table 1: Optimization of the reaction conditions.
Table 2: Scope of the dehydrogenative alkoxylation.
Entry
2b [mL]
Cu salt
[equiv]
Ag salt
[equiv]
T [8C]
3ab [%]
4 [%]
Product
Yield
[%]
Product
Yield
[%]
1
2
3
4
5
6
7
2
2
2
2
1
1
1
1
1
1
1
1
1
0
120
120
120
140
140
140
140
140
140
140
140
16
57
53
67
82
32
46
61
26
27
0
4
13
7
4
0
0
2
5
3
5
0
78
3aa
65
3ab
58[a]
76[b]
1.5
1.5
1.5
1.5
1.5
1
1.5
1.5
0.25
1.5
0.25
0.25
0.25
0.1
0.25
0.1
0.25
0.25
0
3ac
3ae
53
59
3ad
3af
57
65
8[a]
9[b]
10
11
3ag 54[c]
3ah
32
Reaction conditions: 1a (0.3 mmol), 2 (1–2 mL), Cu(OAc)2, AgOTf,
1 atm O2, 24 h. Yields determined by GC analysis using n-tetradecane as
internal standard. [a] Cu(OTf)2 (0.1 equiv), NaOAc (1 mmol). [b] Under
N2 atmosphere. Py=2-pyridyl, Tf=trifluoromethanesulfonyl.
3bb 80
3db 64
3cb
3eb
82
58[d]
Stahl and co-workers, who reported that copper(II) catalysts
with non-coordinating anions can be activated by NaOAc.[26]
Control experiments revealed that an oxygen atmosphere
is essential, even when a stoichiometric amount of silver
triflate is used (Table 1, entries 9 and 10). Without copper
acetate, no reaction takes place (Table 1, entry 11). This
finding confirms that the main role of the silver is to transfer
the alkoxy group to the copper catalyst. The presence of water
in the alkoxylation reactions is tolerated but results in
a decrease in the reaction rate. Even when the alcohols are
completely replaced with water, no hydroxylation of the
arene occurred (see Supporting Information, Table S3).
Having, thus, found an effective protocol for the dehy-
drogenative alkoxylation, we next investigated its scope and
found that it has broad applications (Table 2). Both linear and
branched alcohols were successfully coupled with 2-phenyl-
pyridine to give products 3aa–3af. Chiral alcohols reacted
with retention of their configuration (see 3ag–3ah). The
reactions of methanol, as well as allylic and benzylic alcohols
did not give good yields, presumably they are sensitive to
oxidation.[15a] Phenols are also unsuitable as substrates
because they undergo oxidative self-coupling under the
reaction conditions. 2-(Hetero)arylpyridines with diversely
substituted aryl/heteroaryl and pyridine rings were butoxy-
lated in good to moderate yields to give products 3bb–3kb,
and 3mb. Even bromide substituents remained largely intact
(see 3eb). As well as 2-pyridyl, other N-chelating directing
groups, for example, pyrimidine, benzoquinoline, and pyra-
zole, can be used (see 3na–3qb). The alkoxylation was
regiospecific in all cases, and no bis(alkoxylation) product was
obtained. The reactions proceeded cleanly with regard to the
phenylpyridines. The differences between the isolated and
expected product yields were due to incomplete conversion;
by-products originating from these starting materials were
detected only in trace amounts. Typical side reactions of the
alcohols include the formation of symmetrical ethers (up to
3 fb
61
3gb
3ib
56
54
69
3hb 68
3jb
3lb
41
58
3kb
3mb 76
3na 51
3pb 67
3ob
3qb
62
55
Reaction conditions: 1 (1.00 mmol), 2 (3 mL), Cu(OAc)2 (0.25 mmol),
AgOTf (1.50 mmol), 1 atm O2, 1408C, 24 h. [a] with 0.1 mmol of
Cu(OTf)2 and 1 mmol of NaOAc. [b] with 0.25 mmol of Cu(OTf)2 and
1 mmol of NaOAc. [c] 1.8 mL of (S)-(+)-2-BuOH. [d] Along with 13% 2-
(4-butoxyphenyl)pyridine.
30% based on the alcohol) and dialkyl acetals (ca. 2%). For
the example of 3ab, the alkoxylation reaction was successfully
carried out also in the pesence of 10 mol% of Cu(OTf)2 and
1 equivalent of NaOAc.[26]
This strategy can also be used for the alkoxylation of
benzylic C H groups (Scheme 2). When 2-benzylpyridine
(1r) was reacted with 1-butanol, the butoxy group was
installed selectively in the benzylic position rather than on the
aromatic ring. This shows that regioselective dehydrogenative
alkoxylations are not limited to Csp2 H bonds.
Further studies were performed to obtain insight into
mechanism of the dehydrogenative alkoxylation (see the
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À
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the arene ring[31] can be excluded, as they would have resulted
in a low kinetic isotope effect. The possibility of a proton-
coupled electron-transfer (PCET) mechanism cannot be
excluded as it is also in agreement with the observed KIE
value.[32]
The intermediacy of a hydroxy- or acetoxyarene resulting
from an attack of (per)oxo/copper species to the arene ring
was excluded on the basis that neither 2-(2-hydroxyphenyl)-
pyridine nor 2-(2-acetoxyphenyl)pyridine were converted
into 3ab under the reaction conditions (Scheme 4).
À
Scheme 2. Dehydrogenative alkoxylation of an Csp3 H bond.
Supporting Information). The presence of radical quenchers,
such as 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) or p-
benzoquinone (1.5 equiv in each case), completely suppressed
product formation; this finding suggests that the reaction
involves radical steps. In the presence of TEMPO, the
reaction exclusively produces butyraldehyde dibutyl acetal,
whereas no reaction takes place in the presence of p-
benzoquinone.
Scheme 4. Evidence against the formation of hydroxyarene intermedi-
ates.
The intermediacy of alkoxy radicals is more likely than
that of acyl radicals because no competing acylations[27] or
hydroxyalkylations[28] were observed. Silver is likely to be
involved in the formation of the alkoxy radicals because in the
absence of silver, only low yields of the alkoxylated product
3ab are obtained.[29] Treatment of 1-butanol with Cu(OAc)2,
AgOTf, and TEMPO affords butyraldehyde dibutyl acetal in
high yield, whereas this product is formed at best in traces in
the presence of only the copper catalyst.[15a] In GC–MS
analyses of the copper/silver-catalyzed butoxylations of 2-
phenylpyridine, traces of butyraldehyde dibutyl acetal were
always detected. Moreover, the formation of metallic silver is
observed in all reactions. These findings further support the
intermediacy of alkoxy radicals, which would readily form
from silver alkoxides. The generation of large quantities of di-
n-butyl ether can be rationalized by the addition of butoxy
radicals to 1-butene formed through thermal dehydration of
1-butanol.[14a]
Based on the above mechanistic investigations, we
tentatively propose the catalytic cycle outlined in Scheme 5.
À
The arene 1 initially undergoes chelation-assisted C H
activation in the presence of the CuII catalyst to form
intermediate B. The alcohol 2 is converted into the transient
silver alkoxide species C by reaction with AgOTf.[30] In
Unfortunately, control experiments starting from pre-
formed silver alkoxides, that would unambiguously prove
their intermediacy, have so far been precluded by their
instability.[30]
In the reaction of 2-phenylpyridine (1a) and 2-phenyl-
[D5]pyridine ([D5]-1a) with 1-butanol, a high kinetic isotope
effect of 3.3 was observed (Scheme 3). When 2-phenylpyr-
idine was ethoxylated with ethanol-d1, no proton scrambling
in the starting material was detected. These findings indicate
Scheme 5. Proposed dehydrogenative alkoxylation mechanism.
a redox process, the alkoxy radical that is formed by
fragmentation of C is transferred to the CuII/arene species B
to give the CuIII-intermediate D together with metallic silver.
Reductive elimination of the alkoxyarene product furnishes
CuI-species E, which is reoxidized in the presence of
molecular oxygen to the initial CuII-species A.
In conclusion, a bimetallic copper/silver catalyst has been
discovered that allows the regiospecific dehydrogenative
cross-coupling of arenes substituted with donating groups
and alcohols. This constitutes an expedient synthetic route to
aryl and benzyl ethers. Ongoing research is directed towards
À
that the C H activation of the arene is irreversible and rate
limiting (see the Supporting Information). The process thus
À
involves a directed C H activation. Single-electron-transfer
(SET) pathways as found by Yu and co-workers in copper-
mediated chlorination reactions[13b] and mechanisms involv-
ing the attack of copper-coordinated oxide or peroxide onto
À
extending this dehydrogenative alkoxylation to Csp3 H groups
of aliphatic substrates.
Scheme 3. Determination of the kinetic isotope effect.
4
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General procedure for the dehydrogenative alkoxylation: A 70 mL
Schlenk tube was charged with the arene (1a–r, 1.00 mmol),
copper(II) acetate (0.25 mmol) and silver triflate (1.5 mmol). Anhy-
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Published online: && &&, &&&&
À
À
Keywords: C H activation · C O coupling · copper ·
.
dehydrogenative cross-coupling · homogeneous catalysis
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