Cooperative N-Heterocyclic Carbene (NHC) and Ruthenium Redox Catalysis: Oxidative Esterification of Aldehydes with Air as the Terminal Oxidant

Article abstract of DOI:10.1002/adsc.201300034

The paper describes a cooperative NHC (N-heterocyclic carbene) and ruthenium-based redox catalysis for the mild aerobic oxidative esterification of various aromatic and heteroaromatic aldehydes. The ruthenium(II) complex Ru(bpz)₃(PF₆)₂ (bpz=2,2′-bipyrazine) as catalyst is shown to be compatible with free NHCs. The NHC is used in these cascade reactions for the umpolung of the aldehyde to form the corresponding Breslow intermediate which in turn gets oxidized to an acylazolium ion by the ruthenium redox catalyst. Air is used as a terminal oxidant for oxidation (regeneration) of the ruthenium catalyst. In addition, we will show that in the absence of the ruthenium redox catalyst and alcohol, NHC-catalyzed aerobic oxidation of aldehydes delivers the corresponding acids in good to excellent yields. Mechanistic studies and DFT calculations supporting our suggested mechanisms are provided. Copyright

Full text of DOI:10.1002/adsc.201300034

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DOI: 10.1002/adsc.201300034
Cooperative N-Heterocyclic Carbene (NHC) and Ruthenium
Redox Catalysis: Oxidative Esterification of Aldehydes with Air
as the Terminal Oxidant
Junfeng Zhao,a Christian Mꢀck-Lichtenfeld,a and Armido Studera,*
a
Westfꢁlische Wilhems-University, Institute of Organic Chemistry, Corrensstrasse 40, 48149 Mꢀnster, Germany
Fax : (+49)-251-833-6523; e-mail: studer@uni-muenster.de
Received: January 15, 2013; Revised: February 15, 2013; Published online: April 8, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300034.
Abstract: The paper describes a cooperative NHC oxidant for oxidation (regeneration) of the rutheni-
(N-heterocyclic carbene) and ruthenium-based redox um catalyst. In addition, we will show that in the ab-
catalysis for the mild aerobic oxidative esterification sence of the ruthenium redox catalyst and alcohol,
of various aromatic and heteroaromatic aldehydes. NHC-catalyzed aerobic oxidation of aldehydes deliv-
The ruthenium(II) complex RuACHTNURGTENN(UG bpz)3ACHTUNTGERN(NUGN PF6)2 (bpz= ers the corresponding acids in good to excellent
2,2’-bipyrazine) as catalyst is shown to be compatible yields. Mechanistic studies and DFT calculations sup-
with free NHCs. The NHC is used in these cascade porting our suggested mechanisms are provided.
reactions for the umpolung of the aldehyde to form
the corresponding Breslow intermediate which in
turn gets oxidized to an acylazolium ion by the Keywords: carbenes; cooperative catalysis; organo-
ruthenium redox catalyst. Air is used as a terminal catalysis; oxidation; ruthenium
Introduction
of acylazolium ions can be achieved by employing
substrates able to undergo internal redox processes.[6,9]
Cooperative catalysis using an organocatalyst and It was also found that MnO2,[10] azobenzene,[11] ribo-
a transition metal-based catalyst may offer novel reac- flavin,[12] phenazine,[13] TEMPO[14] and quinones[15] are
tivity which cannot be achieved by either of them in- effective external oxidants for oxidation of the
dividually.[1] NHCs have attracted great attention in Breslow intermediate to give the corresponding reac-
the past decade and various NHC-catalyzed reactions tive acylazolium ion intermediate.[5] However, the in-
have been developed.[2] However, the successful ternal redox active substrates need to be specially de-
merger of NHC catalysis with transition metal cataly- signed and the necessity to add an organic or inorgan-
sis is still a challenging topic. This is due to the fact ic stoichiometric external oxidant in the latter pro-
that NHCs act as good ligands for most transition cesses lead to an increase of costs and chemical waste
metals and their coordination to the metal generally which will hamper application of these strategies on
results in the loss of their reactivity as organocatalysts a larger scale. We therefore envisioned that this
(organocatalyst poisoning).[3] Therefore, only few ex- chemistry would be more attractive if air could be
amples on successful cooperative NHC- and metal- used as cheap terminal oxidant for the oxidation of
based catalysis have appeared to date.[4] Herein, we the Breslow intermediate.[16] Indeed, O2 has already
report the oxidative esterification of aldehydes by been successfully applied as terminal oxidant to
using cooperative NHC and Ru(II) redox catalysis NHC-catalyzed esterifications. However, reactive nu-
with air as the terminal oxidant under mild reaction cleophiles such as boronic acids[4h] and phenols[4i] are
conditions. During the course of these studies we also required or esterification occurs via oxidation to the
developed a protocol for the mild NHC-catalyzed acid and subsequent trapping with an alkyl halide.[17]
aerobic oxidation of aldehydes to carboxylic acids.
To the best of our knowledge, only one paper describ-
Acylazolium ions[5] are reactive intermediates ing an NHC-catalyzed esterification between alde-
which can be trapped by different nucleophiles in hydes and aliphatic alcohols with air as the terminal
a range of NHC-catalyzed reactions such as esterifica- oxidant showing very limited substrate scope was pub-
tion,[6] amidation[7] and Michael addition.[8] Formation lished.[18] Since alcohols are known to react efficiently
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Cooperative N-Heterocyclic Carbene (NHC) and Ruthenium Redox Catalysis: Oxidative Esterification
Scheme 1. NHC-catalyzed oxidative esterifications of alde-
hydes via cooperative NHC/metal-based catalysis.
with acyl
oxidative esterifications must lie in the generation of
the acylazolium ion. Importantly, NHC-catalyzed oxi-
ACHTUNGTRENNUNGazolium ions the problem in these aerobic
ACHTUNGTRENNUNG
dation of aldehydes to the corresponding acids with
air as the terminal oxidant is documented.[19,20,21] How-
ever, these oxidations do not necessarily need to pro-
ceed via acylazolium ions. Oxidation of the Breslow
intermediate with O2 can lead via single electron
transfer and in cage recombination to the peroxy
adduct without formation of the acylazolium ion
(Scheme 1). Proton transfer and carbene fragmenta-
tion will provide the corresponding peracid which
upon reaction with the aldehyde will eventually
afford two equivalents of the acid. Hence the chal-
lenge was to identify a catalyst which (i) does not
react with the carbene by ligation (NHC poisoning),
(ii) reacts with the Breslow intermediate faster than
O2 does (to suppress peracid formation), and (iii) can
after successful oxidation of the Breslow intermediate
be regenerated by air oxidation (Scheme 1).
Figure 1. Various carbene precursors tested in the oxidation
of benzaldehyde to benzyl benzoate (yields are given in
brackets).
Results and Discussion
and Cp2FePF6 afforded the targeted ester in 55%
yield (entries 5 and 6). In agreement with a recent
As a test reaction we chose oxidation of benzalde- Rovis study we found that Ru-based catalysts are
hyde in the presence of benzyl alcohol to benzyl ben- compatible with free NHCs.[4g] Whereas Ru
AHCTUNGTRENNUNG
zoate. Initial screening of the reaction conditions re- did not show any catalyst activity (entry 7, compare
vealed that promising results could be obtained in with the background esterification in entry 1; bpy=
acetonitrile with carbene precursor 1 (5 mol%, see 2,2’-bipyridine) significant activity was achieved with
Figure 1) and triazabicyclodecene (TBD, 1.2 equiv.) as Ru
ACHTUNGTNERU(NGN bpm)3Cl2 and RuACHUTNRGTEN(NU bpz)3ACUTNGHTR(NUNENG PF6)2 [entries 8 and 9; all
a stoichiometric base (Table 1). In the absence of any further studies were conducted with Ru
N
CHTUNGTRENNUNG
metal-based cocatalyst we isolated the benzyl ester in for structures see Figure 1]. Interestingly, at lower
24% yield along with benzoic acid (72%, entry 1; NHC catalyst loading (2.5 mol%) the yield further in-
studies on acid formation will be discussed below). creased to 76% (entry 10). Reactions were run by
We tested various redox active catalysts and found leaving the reaction vessel open to the air atmosphere
the ester in traces upon using Cu-based salts (en- and esterifications performed under an O2 atmos-
tries 2–4). Pleasingly, the ferrocenium salts Cp2FeBF4 phere (balloon technique, around 1 bar) delivered
Adv. Synth. Catal. 2013, 355, 1098 – 1106
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Junfeng Zhao et al.
Table 1. Oxidative esterification of benzaldehyde under various conditions.
Entry
Metal catalyst (mol%)
none
1 (mol%)
Base
Time [h]
Yield [%][a,b]
1
5
TBD
2
4
4
4
2
2
4
2
2
2
2
2
2
2
2
1
1
1
1
2
2
2
2
24
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Cu
CuBr2 (5)
CuCl2 (5)
Cp2FeBF4 (5)
Cp2FePF6 (5)
G
5
5
5
5
5
5
5
5
2.5
2.5
2.5
5
5
5
5
5
5
5
TBD
TBD
TBD
TBD
TBD
TBD
TBD
TBD
TBD
TBD
TBD
DBU
MTBD
Cs2CO3
Rb2CO3
tBuOK
KHMDS
TBD[c]
K2CO3
DIEA
DABCO
Et3N
traces
traces
traces
55
55
26
67
70
76
66
78
53
76
57
50
50
67
38
Ru
Ru
Ru
Ru
Ru
Ru
Ru
Ru
Ru
Ru
Ru
Ru
Ru
Ru
Ru
Ru
Ru
5
5
5
5
–
–
–
–
[a]
Reactions were carried out on a 0.25-mmol scale of aldehyde with 10 equiv. of benzyl alcohol (2.5 mmol) in 1 mL acetoni-
trile at room temperature.
Isolated yields.
0.6 equiv. of TBD were used.
[b]
[c]
lower yields. Increasing the RuACHTNURGTENN(UG bpz)3ACHTUNGTREN(NUGN PF6)2 concentra- (entries 13–18). Decreasing the amount of TBD to
tion (10 mol%) did not give a better result but de- 0.6 equiv. had a detrimental effect on the yield
creasing Ru loading to 3 mol% led to a lower yield (entry 19) and no reaction occurred with K2CO3,
(entries 11 and 12). The major side product in all DIEA (diethylamine), DABCO (1,4-diazabicyclo-
these transformations was benzoic acid. Importantly,
ACHTUNGTRENN[NUG 2.2.2]octane) and Et3N (entries 20–23). Other sol-
such Ru(II) complexes have been extensively used in vents such as THF, DMSO, and DMF provided worse
visible light photoredox catalysis.[22] However, control results (solvent screening was conducted with DBU
experiments demonstrated that irradiation with visible as base, see the Supporting Information).
light is not necessary in our case. In fact we noted
slightly diminished yields upon running the esterifica- 5 mol% of Ru
tion under irradiation. This result clearly showed that under air)[25] we tested various carbene precursors 2–8
Ru(bpz)3A
(PF6)2 (E1/2 =1.98)[23] in its ground state is in the oxidative esterification of benzaldehyde with
Under the optimized conditions (1.2 equiv. TBD,
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
a strong enough oxidant to oxidize the Breslow inter- benzylalcohol. Surprisingly, only the electron-rich
mediate. Further control experiments revealed that bulky triazolium salt 2[26] provided a good yield (76%,
the NHC 1, TBD, and air are all crucial for successful Figure 1). Less bulky triazolium salts such as 3, 4 and
esterification.
the electron poorer congener 5 gave only traces of
We found that the nature of the base has a strong the targeted ester. Imidazolium salt 6, salt 7 and the
influence on the reaction outcome. Along with TBD, thiazolium salt 8 did not show high activity in the oxi-
other bases such as DBU (1,8-diazabicycloundec-7- dative esterification and products were identified in
ene), MTBD (7-methyl-1,5,7-triazabicyclo
ene, pKa >24 in CH3CN),[24] Cs2CO3, Rb2CO3, t-
BuOK, KHMDS showed activity in the esterification substrate scope of this methodology by varying the al-
ACHTUNGTRENNUNG
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Cooperative N-Heterocyclic Carbene (NHC) and Ruthenium Redox Catalysis: Oxidative Esterification
hydes provided lower yields and heteroaromatic alde-
hydes containing a furan, pyrrole or a thiophene
moiety were good substrates for this esterification.
Additionally, other alcohols such as methanol, ethanol
and propargyl alcohol also work well for this reaction.
However, aliphatic aldehydes turned out to be not
good substrates for this oxidative esterification. 3-
Phenylpropanal provided only traces of the targeted
ester and cyclohexylcarbaldehyde in the reaction with
benzylalcohol gave only 15% yield of the correspond-
ing benzyl ester. The major product formed was cy-
clohehexanecarboxylic acid which was obtained in
70% yield.
A possible mechanism for the cooperative NHC/
RuACHTUNGRTENN(UG bpz)3ACHTUNGTREN(NUNG PF6)2-catalyzed cascade reaction is depicted
in Scheme 3. The Breslow intermediate 9 generated
upon reaction of the carbene with the aldehyde gets
oxidized by RuACHTNUTRGENNUG(bpz)3AHCUTNGTREN(NUGN PF6)2 through a single electron
transfer (SET) process to afford the radical cation
10.[27] Oxygen acts as the terminal oxidant by oxida-
tion of the intermediate Ru(I) complex to give the
++
RuACTHNUTRGEN(UGN bpz)3 complex along with the superoxide radical
anion. Reaction of 9 with dioxygen initiates a process
eventually leading to the acid as will be discussed
below. Deprotonation of 10 with the base or with the
superoxide radical anion will provide the tertiary radi-
cal 11, which will be further oxidized to the acylazoli-
um ion 12. This oxidation can be achieved with
++
RuACTHNUTRGEN(UGN bpz)3 or with the hydroperoxyl radical. Trap-
ping of the acylazolium ion 12 by the alcohol will
eventually provide the ester thereby releasing the
NHC catalyst. This step is catalyzed by the NHC.[15a]
We assume that the base is not only used to release
the NHC catalyst but also likely involved in the for-
mation of the Breslow intermediate.
As mentioned above, the major side product identi-
fied in these oxidative esterifications was the acid,
Scheme 2. Substrate scope.
dehyde as well as the alcohol component. As shown
in Scheme 2, aromatic aldehydes were converted to
the corresponding benzyl esters in good to excellent
yields. As expected, sterically more shielded alde- Scheme 3. Suggested mechanism for oxidative esterification.
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