Copper-catalyzed formation of C-O bonds by direct α-C-H bond activation of ethers using stoichiometric amounts of peroxide in batch and continuous-flow formats

Article abstract of DOI:10.1002/chem.201200815

Peroxides and ethers in flow: 2-Carbonyl-substituted phenols and β-ketoesters react safely with ethers in a microreactor environment using a copper catalyst and an organic peroxide (TBHP). This protocol results in unsymmetrical acetal scaffolds not easily available otherwise (see scheme). Copyright

Full text of DOI:10.1002/chem.201200815

DOI: 10.1002/chem.201200815
À
À
Copper-Catalyzed Formation of C O Bonds by Direct a-C H Bond
Activation of Ethers Using Stoichiometric Amounts of Peroxide in Batch and
Continuous-Flow Formats
G. Sathish Kumar,[a] Bartholomꢀus Pieber,[b] K. Rajender Reddy,*[a] and
C. Oliver Kappe*[b]
Numerous synthetic strategies for the transition-metal cat-
sis of 2,3-dihydrobenzofurans via intramolecular oxidative
À
À
À
alyzed formation of C C as well as C–heteroatom bonds
C O coupling involving activation of an aromatic C H
have been advanced during the last decades.[1] Apart from
the well-established classical cross-coupling protocols involv-
ing prefunctionalized starting materials,[1] the direct func-
bond was recently described.[6] Similarly, intermolecular C
À
O couplings have been reported for the acetoxylation of ar-
À
omatic and aliphatic C H bonds using transition-metal cata-
tionalization of the C H bond (“C H activation”) for the
atom- and step-economical synthesis of functionalized mole-
cules has attracted significant interest in the synthetic com-
lysts.[7] These and related methods for the a-functionaliza-
À
À
À
tion of ethers via C H bond activation have recently been
reviewed.[8] In this context, CDC methods have demonstrat-
munity.[2] Among the many C H bond activation protocols
ed to be very efficient for the formation of C C bonds
À
À
which have been developed over the past few years, catalytic
cross-dehydrogenative-coupling (CDC) reactions have been
(Scheme 1, Method B).[9] However, the a-functionalization
À
of ethers toward the formation of a C O bond has rarely
shown to be particularly useful,[3] and have been extensively
been disclosed in the literature (Scheme 1, Method C).[10]
The only known example involves the Bu4NI-catalyzed for-
mation of esters from carboxylic acids and ethers requiring
20 mol% of the catalyst, 2.2 equivalents of tert-butyl hydro-
peroxide (TBHP) as oxidant, and a typical reaction time of
12 h at 808C.[10]
[4]
À
utilized in various C C bond forming protocols. The a-
functionalization of amines, for example, is a widely investi-
gated method for the formation of C C bonds using the
À
CDC approach under oxidative conditions (Scheme 1, Meth-
od A).[5] In addition, several methods involving the concept
À
À
À
of C H bond activation for the construction of C O bonds
Herein, we present a novel copper-catalyzed oxidative C
have appeared in the literature.[6–10] For example, the synthe-
O bond formation protocol in which 2-carbonyl-substituted
phenols and b-ketoesters are directly coupled with simple
ethers to generate hitherto undisclosed unsymmetrical
acetal scaffolds (Scheme 2). Under optimized conditions,
À
Scheme 1. Cross-dehydrogenative-coupling (CDC) approaches for C C
À
À
and C O bond formation via a-C H bond activation.
Scheme 2. Copper-catalyzed oxidative cross-dehydrogenative-coupling of
b-ketoesters or 2-carbonyl-substituted phenols with ethers.
[a] G. S. Kumar, Dr. K. R. Reddy
Inorganic and Physical Chemistry Division
Indian Institute of Chemical Technology
Tarnaka, Hyderabad-500 607 (India)
Fax : (+91)40-27160921
catalyst amounts as low as 1 mol% of CuACTHNUTRGENUG(N OAc)2 can be em-
ployed, resulting in high product yields within 20–30 min in
an elevated temperature regime. Since a key requirement to
E-mail: rajender@iict.res.in
rajenderkallu@yahoo.com
À
the success of this oxidative C O bond forming protocol is
[b] B. Pieber, Prof. Dr. C. O. Kappe
Christian Doppler Laboratory for Microwave Chemistry (CDLMC)
and Institute of Chemistry, Karl-Franzens-University Graz
Heinrichstrasse 28, 8010 Graz (Austria)
Fax : (+43)316-380-9840
the use of 2–3 equivalents of TBHP as oxidant, an obvious
safety issue results from the combination of a peroxide with
ethers at high temperatures. Therefore, the synthesis was
successfully translated to a continuous-flow/microreactor
protocol providing a means to safely scale this process to
synthetically useful quantities of acetal products, and to best
E-mail: oliver.kappe@uni-graz.at
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200815.
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COMMUNICATION
of our knowledge represents the first application of continu-
ly full substrate conversion and a 81% isolated yield of the
desired acetal 3a (Table 1, entry 10, see also Table S1). The
lack of product formation in control experiments without
oxidant clearly underlines the importance of both metal cat-
alyst and oxidant (Table 1, entries 11 and 12).
Encouraged by the results obtained in the optimization
experiments described above, a number of analogous CDC
transformations varying both reaction partners were studied
(Table 2). Cyclic ethers such as 1,4-dioxane (2a) and THF
(2b) reacted smoothly with different 2-carbonyl-substituted
phenol derivatives (1a–e) to provide the corresponding
acetal products (3a–j) in moderate to excellent yields.
Linear, unsymmetrical ethers such as 1,2-dimethoxyethane
(DME; 2c) furnished a mixture of products resulting from
[11]
À
ous-flow processing to C H activation chemistry.
Previous investigations from our laboratory on the
copper-catalyzed CDC reaction of b-dicarbonyl derivatives
or 2-carbonyl-substituted phenols with N,N’-disubstituted
formamides mediated by stoichiometric amounts of TBHP
have indicated that the carbonyl group adjacent to the hy-
droxy moiety acts as directing group, and therefore consti-
tutes an essential functionality for efficient coupling reac-
tions.[12] To explore the ability of these substrates in a puta-
tive CDC reaction with ethers, the coupling behavior of 2-
hydroxyacetophenone (1a) and 1,4-dioxane (2a) under dif-
ferent conditions was evaluated (Table 1). Gratifyingly, the
À
competitive C H activation of the internal methylene and
Table 1. Optimization of reaction conditions.[a]
the terminal methyl group, respectively (3k–3n). Methyl
tert-butyl ether (MTBE; bp. 568C) as well as simple Et2O
(bp. 358C) remained completely unreactive under these re-
action conditions operating at the reflux temperature of the
solvent (3p–3q). Subsequently, without further reoptimiza-
tion, the substrate scope was further extended to b-keto-
Entry Catalyst [mol%]
Oxidant [equiv]
T [8C] 3a [%][b]
AHCTUNGTRENNUNG
1
2
3
4
5
6
7
8
9
Cu
(OAc)2 (10)
TBHP in water (1.5)
80
80
80
80
80
80
80
80
100
29
24
–
24
–
–
–
31
69
81
–
CuN
volving a peroxide/ether mixture to a safe and scalable con-
tinuous-flow regime,[13] we first attempted to reduce the ini-
tially optimized reaction time of 3 h under reflux conditions
(Table 1) to something more suitable for a continuous pro-
CuCl2 (10)
CuCl (10)
TBHP in water (1.5)
TBHP in water (1.5)
H2O2 (1.5)
Cu
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (5)
Cu(OAc)2 (5)
A
R
NaOCl (1.5)
DTBP[c] (1.5)
AHCTUNGTREGcNNUN essing approach (<30 min). Therefore the CDC of 2-hy-
ACHTUNGTRENNUNG
N
TBHP in decane (1.5)
TBHP in water (2.2)
TBHP in decane (2.2) 100
TBHP in decane (2.2) 100
R
10
11
12
R
Table 2. Substrate scope in the Cu
ACHTUNGRTEN(NUNG OAc)2-catalyzed coupling of 2-car-
bonyl-substituted phenols with ethers.[a]
–
CuN
–
100
–
[a] Reaction conditions: 1a (1 mmol), 2a (2 mL), 3 h, unless noted other-
wise. [b] Yields isolated after chromatograhpy. [c] Di-tert-butyl hydro-
ACHTUNGTRENNUNGperoxide.
Entry
1
2
Product
3a
Yield
[%][b]
use of 10 mol% of CuACHTNUGTRNEUNG(OAc)2 as catalyst in combination
with aqueous (70%) TBHP at 808C for 3 h did indeed
afford the desired acetal (3a) in moderate yield (Table 1,
entry 1). Surprisingly, all other tested CuII species, with the
1
2
3
4
5
79
80
55
85
28
exception of CuACHTUNGTRENNUNG(OAc)2 hydrate, were completely inactive
3b
(Table 1, entries 2 and 3, see also Table S1 in the Supporting
Information), whereas several CuI catalysts showed moder-
ate catalytic activity (Table 1, entry 4 and Table S1). The
nature of the oxidant was also found to be a crucial factor in
this transformation; no desired product was observed by re-
placing TBHP with a variety of other common oxidants
(Table 1, entries 5–7, see also Table S1). Moving from aque-
ous TBHP to a commercially available solution of TBHP in
decane (5–6m), the product yield could be slightly increased
(Table 1, entry 8) and further experiments at elevated tem-
perature clearly demonstrated a reaction enhancement using
the water-free variant (Table 1, entries 9 and 10). A system-
atic reaction optimization using both increased temperatures
and higher amounts of oxidant in combination with a signifi-
cantly reduced catalyst loading ultimately resulted in virtual-
3c
3d
3e
6
7
8
9
1a
1b
1c
1d
1e
3 f
3g
3h
3i
74
66
39
82
45
10
3j
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C. O. Kappe, K. R. Reddy et al.
Table 2. (Continued)
Entry
1
2
Product
Yield
[%][b]
65
12
11
1a
41
18
12
1b
Scheme 3. Substrate scope in the Cu
toesters with dioxane.
ACHTUNGERTN(NUNG OAc)2-catalyzed coupling of ß-ke-
13
1c
35
64
higher temperatures.[16] However, further optimization at
1358C showed almost full conversion within only 15 min
when the amount of TBHP oxidant was increased to
3 equivalents, and was added portionwise (3ꢁ1 equiv).[16] In
addition, under these intensified conditions it was possible
14
15
1d
1a
to decrease the amount of CuACHTNUGRTENUNG(OAc)2 catalyst to 1 mol% at
20
76
the expense of a 30 min reaction time. Ultimately, keeping
the desire of throughput in the flow process in mind, a cata-
lyst loading of 2.5 mol% and a reaction time of 20 min were
chosen.[16] Under these high-temperature conditions in the
sealed microwave vial, substrate 1a was also successfully
coupled not only with THF (2b) providing a 96% isolated
yield of acetal 3b, but also with MTBE (2e) and diethyl
ether (2 f), furnishing the desired target molecules 3p and
3q in moderate yields (Table S5 in the Supporting Informa-
tion).
The optimized microwave batch protocols were then
translated to a continuous-flow regime (“microwave-to-
flow” paradigm)[17] in a Uniqsis FlowSyn reactor equipped
with a 20 mL internal volume stainless steel coil (i.d.=
1.0 mm) operating at 1308C coil temperature.[18] To avoid
large volumes of ether/peroxide mixtures, a two-feed strat-
egy as shown in Figure 1 was devised. Therefore, a solution
of the Cu catalyst and 2-hydroxyacetophenone substrate
(1a) in 1,4-dioxane (Feed A, flow rate: 0.8 mLminÀ1), and
commercially available TBHP in decane (Feed B, flow rate
0.2 mLminÀ1) were passed through a glass static mixer (M)
and subsequently heated in the above-mentioned coil reac-
tor (RC). Within the 20 min residence time of this flow ex-
periment, conversion/yields similar to those obtained under
microwave batch conditions were obtained, considering that
3o
16
17
1a
1a
3p
3q
–
–
[a] Reaction conditions: 1a–e (1 mmol), 2a–d (2 mL), reflux temperature
of the respective ether. [b] Yields isolated after chromatography.
[c] Amount of terminal coupling product too low for isolation.
droxyacetophenone (1a) and 1,4-dioxane (2a) was reevalu-
ated more closely under sealed-vessel microwave conditions
paying particular attention to the reaction time.[14] An initial
temperature screen using accurate internal temperature
monitoring[15] indicated that the optimum temperature
window for the oxidative coupling is between 120 and
1358C. At lower, as well as higher temperatures, a drop in
conversion was observed (see Table S2 and Figure S1 in the
Supporting Information). We presume that the decomposi-
tion of TBHP is faster than the desired CDC reaction at
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Copper-Catalyzed Formation of C O Bonds
COMMUNICATION
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periment.[16]
In summary, we have demonstrated the efficient construc-
À
À
tion of C O bonds via a-C H bond activation of simple
ethers using an inexpensive copper catalyst in combination
with a commercially available decane solution of TBHP as
stoichiometric oxidant. This protocol allows the generation
of unsymmetrical acetal scaffolds not easily available by
other methods. To make this potentially hazardous synthetic
protocol scalable, a two-feed high-temperature/pressure mi-
croreactor approach was developed that provided the de-
sired acetals in yields similar to those obtained in the batch
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General procedure for the acetal synthesis (3a–3o) in a standard oil
bath: (Table 2 and Scheme 3).
phenol (1a–e) or b-keto ester (4a–h) (1.0 mmol), CuAHCTUNGTRENNUNG
A
solution of 2-carbonyl-substituted
(OAc)2 (9 mg,
5 mol%) in 2 mL of the respective ether 2 was stirred at room tempera-
ture. To the same solution, a 5–6m TBHP solution in decane (2.2 mmol)
was added dropwise before the mixture was heated at the reflux temper-
ature of the respective ether (oil bath) for 3 h. After cooling to room
temperature, the reaction mixture was extracted with ethyl acetate and
dried over anhydrous Na2SO4. Removal of the solvent under reduced
pressure afforded the crude product, which was purified by preparative
column chromatography on silica gel (hexane/ethyl acetate=9:1).
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Acknowledgements
This work was supported by a grant from the Christian Doppler Society
(CDG). G. S. K and K. R. R. thank the Council of Scientific and Indus-
trial Research (CSIR), India for financial support and a Raman Research
Fellowship to K. R. R.
À
Keywords: C H activation · continuous-flow reactions ·
copper · ethers · oxidative coupling
Chem. Eur. J. 2012, 18, 6124 – 6128
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C. O. Kappe, K. R. Reddy et al.
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Received: March 10, 2012
Published online: April 11, 2012
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