N-Heterocyclic Carbene/Carboxylic Acid Co-Catalysis Enables Oxidative Esterification of Demanding Aldehydes/Enals, at Low Catalyst Loading

Article abstract of DOI:10.1002/anie.202104712

We report the discovery that simple carboxylic acids, such as benzoic acid, boost the activity of N-heterocyclic carbene (NHC) catalysts in the oxidative esterification of aldehydes. A simple and efficient protocol for the transformation of a wide range of sterically hindered α- and β-substituted aliphatic aldehydes/enals, catalyzed by a novel and readily accessible N-Mes-/N-2,4,6-trichlorophenyl 1,2,4-triazolium salt, and benzoic acid as co-catalyst, was developed. A whole series of α/β-substituted aliphatic aldehydes/enals hitherto not amenable to NHC-catalyzed esterification could be reacted at typical catalyst loadings of 0.02–1.0 mol %. For benzaldehyde, even 0.005 mol % of NHC catalyst proved sufficient: the lowest value ever achieved in NHC catalysis. Preliminary studies point to carboxylic acid-induced acceleration of acyl transfer from azolium enolate intermediates as the mechanistic basis of the observed effect.

Full text of DOI:10.1002/anie.202104712

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Accepted Article
Title: N-Heterocyclic Carbene/Carboxylic Acid Co-Catalysis Enables
Oxidative Esterification of Demanding Aldehydes/Enals,
at Low Catalyst Loading
Authors: Albrecht Berkessel, Wacharee Harnying, Panyapon Sudkaow,
and Animesh Biswas
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10.1002/anie.202104712
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COMMUNICATION
N-Heterocyclic Carbene/Carboxylic Acid Co-Catalysis Enables
Oxidative Esterification of Demanding Aldehydes/Enals,
at Low Catalyst Loading
Wacharee Harnying,*[a] Panyapon Sudkaow,[a] Animesh Biswas,[a] and Albrecht Berkessel*[a]
In memory of Professor Klaus Hafner
[a]
Dr. W. Harnying, Dr. P. Sudkaow, Dr. A. Biswas, Prof. Dr. A. Berkessel
Department of Chemistry (Organic Chemistry), University of Cologne
Greinstraße 4, 50939 Cologne (Germany)
E-mail: berkessel@uni-koeln.de
Supporting information for this article is given via a link at the end of the document.
Abstract: We report the discovery that simple carboxylic acids, such
as benzoic acid, boost the activity of N-heterocyclic carbene (NHC)
catalysts in the oxidative esterification of aldehydes. A simple and
efficient protocol for the transformation of a wide range of sterically
hindered α- and β-substituted aliphatic aldehydes/enals, catalyzed
by a novel and readily accessible N-Mes-/N-2,4,6-trichlorophenyl
1,2,4-triazolium salt, and benzoic acid as co-catalyst, was developed.
A whole series of α/β-substituted aliphatic aldehydes/enals hitherto
not amenable to NHC-catalyzed esterification could be reacted at
typical catalyst loadings of 0.02 - 1.0 mol %. For benzaldehyde, even
0.005 mol % of NHC catalyst proved sufficient - the lowest value
ever achieved in NHC catalysis. Preliminary studies point to carbox-
ylic acid-induced acceleration of acyl transfer from azolium enolate
intermediates as the mechanistic basis of the observed effect.
ous useful new reactions.[5] The most frequently used oxidant for
this transformation is the Kharasch reagent O1 (Scheme 2),[13]
pioneered by Studer et al. for NHC catalysis.[7l] The oxidation
Scheme 1. Acyl donor intermediates formed in NHC catalysis via internal
redox reaction (a), and external redox reaction (b).
The ester functional group is encountered ubiquitously in organic
molecules.[1] As a consequence, the development of mild and
efficient strategies for the synthesis of esters continues to be an
important objective. Classical esterification methods involve the
stoichiometric activation of carboxylic acids (as acid halides,
anhydrides, or activated esters) amenable to subsequent coup-
ling with alcohol nucleophiles.[1] Over the past decade, the direct
oxidative coupling of aldehydes with alcohols as a one-pot pro-
cedure (oxidative esterification) has emerged as a conceptually
and economically attractive alternative approach.[2] In this
context, various metal-based and metal-free catalytic systems
employing mild oxidants have been developed. Among those, as
an elegant organocatalytic process, the use of N-heterocyclic
carbenes (NHCs) has gained considerable interest as a mild
acylation strategy. The latter transformation can be achieved
either by incorporating a redox-active functionality into the
substrates, such as α-reducible aldehydes or enals (NHC-redox
catalysis, Scheme 1a),[3,4] or by using external stoichiometric
oxidants (oxidative NHC catalysis, Scheme 1b).[5] For the latter,
various oxidants, including MnO2,[6] organic oxidants (nitroben-
zene, PhSSPh, TEMPO, diphenoquinone, flavins, azobenzene,
phenazine, CCl3CN),[7] electrochemistry,[8] and transition metal
catalysis in combination with O2/air,[9] have been reported.
a) Previous work
N
N
I
tBu
tBu
N
O
O
Me
Me
A
O
O
R1
H
R1
OR
+ ROH
oxidant
tBu
tBu
O1
Scheidt:[6a-b] A (10 mol%), DBU (1 equiv), MnO2 (5 equiv), rt
Studer:[7p] A (7.5 mol%), Rb2CO3 (2 equiv), O1 (1 equiv), 60 ¡C
Cl
b) This work
O
O
O
Cl
C1 (0.02-1 mol%)
BzOH (cat.)
with or w/o DMAP
Cl
R2
OR
R2
R2
H
H
N
N
N
R1
R1
+ ROH
Cl
O1 (1 equiv)
R3
O
R3
Ph
Mes
C1
R2
OR
R1, R2, R3 = H, alkyl
R1
Mes = 2,4,6-trimethylphenyl
R1
Scheme 2. NHC-catalyzed oxidative esterification of aliphatic aldehydes/enals.
process with O1 works most efficiently for aromatic aldehydes/
enals as substrates.[7l-t] With aliphatic aldehydes, the transform-
ation is comparatively sluggish, requires 7.5 mol% of the triazol-
ium catalyst A (Scheme 2a) at elevated temperature, and 2
equiv of Rb2CO3 as base.[7p] Scheidt et al. reported the use of
MnO2 (5 equiv) as oxidant in combination with the triazolium
iodide A (10 mol%). In the presence of DBU (1.1 equiv), oxid-
ative esterification of unbranched aliphatic aldehydes, and of
some α- and β-methyl substituted aldehydes was achieved.[6a-b]
Mechanistically, oxidative NHC catalysis relies on a two-
electron oxidation of the Breslow intermediate (diamino enol
I)[10,11] (Scheme 1) with an external oxidant to afford the acyl
azolium intermediate III,[12] which has been exploited in numer-
1
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10.1002/anie.202104712
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COMMUNICATION
It is a general observation that sterically demanding aliphatic
aldehydes and α,β-alkyl enals are challenging substrates for
NHC catalysis. On the other hand, we had shown earlier for
redox esterifications of enals[4j] that NHC catalysts with low
basicity, and carrying dispersion energy donors[14,15] can
overcome the above limitations. Key to success is superior
catalyst stability, together with the ability to promote the form-
ation of the Breslow intermediate. We reasoned that NHCs of
the above type may just as efficiently catalyze aldehyde ester-
ifications under oxidative conditions. Herein, we introduce the
novel and readily accessible triazolium salt C1 as a new and
highly efficient catalyst for oxidative esterification (Scheme 2b;
see SI for synthesis details). A whole series of sterically deman-
ding aliphatic aldehydes and alkyl enals, hitherto not amenable
to the known NHC-catalyzed transformation using O1 as oxidant,
could smoothly be converted to esters (Scheme 2b). We
furthermore discovered that simple benzoic acid (BzOH) co-
catalyzes this transformation, allowing NHC catalyst loadings as
low as 0.005 mol%.[16]
may also play a role in assisting the reduction of diquinone O1
by H-bonding/protonation.[18] In summary, the use of C1 (0.5
mol%), DMAP (1 mol%) and BzOH (10 mol%) proved most
practical for the co-catalyzed transformation of 1a and 2a to 3aa.
A) Effect of bases: C1 (1.0 mol%), BzOH (10 mol%), base (2 mol%)
As a touchstone substrate, we chose 2-ethyl hexanal (1a)
which is unreactive in the presence of known NHC catalysts. O1
was chosen as oxidant, as it can easily be recovered and
recycled.[14] Key results from extensive optimization (see Sup-
porting Information) are shown in Figure 1. Among the NHC
catalysts examined (see SI, Figure S3), the new triazolium salt
C1 was identified as the most effective one. Initially, treatment of
1a with benzyl alcohol (BnOH, 2a, 1.5 equiv) in the presence of
C1 (1 mol%), DIPEA (1 mol%), and O1 (1.1 equiv) in tetrahydro-
furan (THF) afforded only trace amounts of 3aa (8% yield) after
24h at rt. We discovered that BzOH (10 mol%) as co-catalyst
significantly enhances the catalytic efficiency of C1 (1 mol%),
even in the absence of added base, affording the desired ester
3aa in 96% yield after a reaction time of only 5h (Figure 1A, line
a).[17] The reaction was further accelerated upon addition of a
catalytic amine base (2 mol%), including DIPEA, DABCO, N-
methylmorpholine (NMM), N,N-dimethylaminopyridine (DMAP),
and pyridine (Figure 1A). Among those, DMAP gave the best
performance, completing the esterification within 3h (Figure 1A,
line d), presumably promoting NHC turnover as proton shuttle
and as an acyl-transfer catalyst. No reaction occurred in the
absence of the triazolium salt, regardless of whether or not
base/BzOH was present. The loading of C1 in the presence of
BzOH could be decreased further to 0.5 mol% without com-
promising the product yield, albeit at somewhat longer reaction
time (5h) for full conversion. The efficiency of co-catalysis was
found to be strongly dependent on the type of acid. Different
carboxylic acids were evaluated and simple BzOH provided best
activity (see SI, Figure S2).
The effect of BzOH and DMAP on the kinetics of the
reaction is compared in Figure 1B. The initial rates of reactions
with added BzOH (lines c,d) were significantly higher than those
without (lines a,b). In the absence of BzOH as co-catalyst, the
reactions stalled at very low conversion (lines a,b). Varying the
loadings of the BzOH and DMAP co-catalysts revealed that
higher BzOH concentrations accelerate the reactions further,
with the accelerating effect approaching saturation at some point
(around 10 mol%, Figure 1C). At the same time, increasing the
ratio of DMAP to C1 above ca. 1:5 resulted in a less pronounced
acceleration by BzOH (see SI, Figure S4). These results indicate
that external BzOH is crucial for promoting the NHC catalyst
turnover, and/or preventing catalyst deactivation. Clearly, BzOH
B) Effect of DMAP/BzOH: C1 (0.5 mol%), DMAP (2 mol%), BzOH (10 mol%)
C) Effect of BzOH: C1 (0.5 mol%), DMAP (0.5 mol%), BzOH (X mol%)
Figure 1. Kinetic studies on the effect of (a) base, (b) DMAP/BzOH, and (c)
BzOH, as the co-catalysts of C1 in the reaction of 1a and 2a. Yields were
determined by GC using dodecane as internal standard.
We next investigated the practicality and generality of this
transformation (Figure 2). The oxidative esterification of the al-
dehydes 1 with the alcohol component 2 was performed on
gram scale (5-15 mmol of substrate) under operationally simple
conditions, i.e. at room temperature and under air, unless other-
wise stated. Simple Kugelrohr distillation was applied to isolate
the ester from the crude product after evaporation of the THF
solvent. Under these experimental conditions, O1-H2/O1 could
be readily recovered, recycled to O1 (97% purity),[14] and reused.
To our delight, in the presence of catalyst C1 (0.5 mol%), a va-
riety of benzylic, heterobenzylic, allylic and primary alcohols with
different chain lengths could be reacted with unbranched, α- and
β-branched aliphatic aldehydes 1a-f, affording the corresponding
esters 3aa-3fa in excellent yields (Figure 2). This method proved
2
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10.1002/anie.202104712
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COMMUNICATION
compatible with various substrate types and functional groups,
such as furan, thiophene, acetyl- and Boc-protected amines,
pyridine, and indole. The reaction rates were rather sensitive to
steric effects. For example, while the reaction of ethanol and
less nucleophilic trifluoroethanol with 1a was completed within
5h and 32h, respectively (giving the esters 3ag-3ah), trichloro-
ethanol and neo-pentanol required 9-10 days for complete con-
version (products 3ai-3aj). Similarly, the reaction of 1a with
secondary alcohols required higher catalyst loadings (C1/DMAP/
BzOH = 1:2:20 mol%) to complete the esterification within
reasonable time (products 3ar-3av). The tertiary alcohol t-BuOH
failed to give the ester 3aw, only starting material was recovered.
We next addressed the question of what the minimal
catalyst loading required for the oxidative esterification of more
reactive aromatic aldehydes might be. To our delight, as little as
0.005 mol% (50 ppm) of C1 and 0.05 mol% of BzOH were
sufficient to transform benzaldehyde (1p) to methyl benzoate
(3px) in 93 % yield, at room temperature, within 3h (Figure 3e).
Note that for operating at such extremely low NHC concentration,
inert atmosphere had to be applied. Although several successful
examples of NHC−acid co-catalysis have been reported,[19] the
50 ppm of C1 disclosed here represent the lowest-ever NHC
loading in the presence of an external Brønsted acid co-catalyst.
O
C1/BzOH
O
+
MeOH
O1 (1.1 equiv)
THF [2.5M], rt
R
OMe
R
H
O
O
C1/DMAP/BzOH
2x
+
R'OH
2a-w
(1.2 equiv)
3
1a-q (5-10 mmol) (1.5 equiv)
O1 (1.1 equiv)
THF [2.5M], rt
R
OR'
R
H
[a] C1 (0.05 mol%), BzOH (2 mol%).
1a-f (5-15 mmol)
3
O
O
O
O
[a] C1 (0.5 mol%), DMAP (1 mol%), BzOH (10 mol%)
OMe
OMe
Ph
OMe
OMe
H15C7
OMe
X
O
O
3aa, X = H (97%, 6h)
3gx (95%; 50 ¡C, 1h)
3dx (93%; 50 ¡C, 1h)
3ab, X = p-CF3 (95%, 8h)
3ac, X = p-OMe (90%, 8h)
3ad, X = m-OMe (95%,8h)
3hx (94%, 6h)
O
OR'
3ax (94%, 6h)
X
3ae, X = O (95%, 6h)
3af, X = S (93%, 8h)
O
O
O
O
HO
OMe
OMe
OMe
C8H17
O
X
O
3lx(95%, 24h)
O
O
3kx (97%, 16h)
3jx (94%, 6h)
3ag, X = CH3 (97%, 5h)
3ah, X = CF3 (90%, 32h)
3ai, X = CCl3 (84%, 9d)
3aj, X = CMe3 (83%,10d)
3ak (90%, 8h)
3am (92%, 8h)
3al (90%, 8h)
3ix (93%; 50 ¡C, 1h)
NH
[d] C1 (1 mol%),
BzOH (20 mol%).
O
[b] C1 (0.02 mol%),
BzOH (2 mol%).
[c] C1 (0.1 mol%),
BzOH (2 mol%).
O
[e] C1 (0.005 mol%),
BzOH (0.05 mol%)
(Ar atmosphere)
O
X
O
O
N
O
3an, X = CH2NHBOC (92%,15h)
3ao, X = NHAc (86%, 32h)
O
3ap (95%, 10h)
3aq (91%, 4d)
O
TBSO
OMe
OMe
H11C5
OMe
O
O
O
O
Ph
OMe
OBn
3ba (99%, 2h)
3mx (89%, 3h)
3nx (95%, 64% ee, 4h)
3ox (0%)
3px (93%, 3h)
OBn
OBn
H15C7
OBn
OBn
3ca (99%, 1h)
3da (96%, 2h)
3ea (96%, 2h)
3fa (95%, 6h)
Figure 3. Scope of the oxidative esterification of aldehydes with methanol as
alcohol component. Yields refer to isolated products.
[b] C1 (1.0 mol%), DMAP (2 mol%), BzOH (20 mol%)
O
Ph
O
CF3
O
O
O
O
Ph
*
3au (85%, 90h)
3aw (0%)
O
CF3
rac-3av (85%,
d.r. = 1:1, 65h)
3as (95%, 40h)
R3
O
R3
O
3ar (95%, 30h)
3at (82%, 4d)
C1/BzOH
+
MeOH
R2
OMe
R2
H
O1 (1.1 equiv)
THF [2.5M], rt
2x
R1
R1
4a-l (10 mmol)
Figure 2. Substrate scope of the oxidative esterification: aliphatic aldehydes
and alcohol nucleophiles. Yields refer to isolated products.
(1.5 equiv)
5
[b] C1 (2x0.2 mol%),
BzOH (10 mol%).
O
[a] C1 (0.02 mol%),
BzOH (2 mol%).
[d] C1 (0.1 mol%), BzOH (2 mol%).
O
O
5ex (74%, 2h)*
When methanol (2x) was used as the nucleophile, the
esterification proceeded very fast, and the addition of DMAP
was not necessary (Figure 3). We found that the catalyst loading
could be drastically reduced to only 0.05 mol% of C1 and 2
mol% of BzOH for co-catalyzing the esterification of 1a to give
3ax in 94% isolated yield. The same conditions were applied to
the synthesis of esters 3dx and 3gx-3lx. For the aldehydes
1d ,1g, and 1i, the reaction with MeOH stalled after 2-3h at room
temperature, even at higher catalyst loadings. Nevertheless, full
conversion could be accomplished by either performing the re-
action at 50 °C, or at room temperature by adding an extra batch
of C1 (0.05 mol%) after 2-3h. For small unbranched aldehydes,
such as hexanal (3m), 0.02 mol% loading of C1 was sufficient to
complete the esterification within 3h (product 3mx). As an alde-
hyde substrate with an α-stereogenic center, prone to racemiza-
tion, enantiopure 1n (99% ee) was esterified in the presence of
0.1 mol% of the catalyst C1. Complete conversion to the ester
3nx (64% ee) occured within 4h. The partial loss of stereochemi-
cal integrity, also observed under the conditions reported by
Scheidt[6a-b] and Studer,[7p] can be accounted for by the form-
ation of the azolium enolate intermediate (II, Scheme 1) under
oxidative conditions.[12a] Sterically more demanding pivaldehyde
(1o) remained unchanged and did not react to yield the desired
methyl pivalate (3ox), even at catalyst loadings up to 15 mol%.
OMe
Ph
OMe
C5H11
5bx (98%, 6h)
Ph
OMe
[e] C1 (0.5 mol%), DMAP (0.5 mol%)
BzOH (10 mol%),
n-PrOH (1.2 equiv, instead of MeOH).
5ax (98%, 5h)
[c] C1 (0.2 mol%), BzOH (10 mol%).
O
O
O
5ey (93%, 8h)
n-Pr
OMe
OMe
On-Pr
5cx (80%, 5h) 5dx (84%, E/Z = 68:32, 8h)
[f] C1 (0.5 mol%), BzOH (10 mol%).
[g] C1 (1.0 mol%), BzOH (20 mol%).
O
O
O
H13C6
OMe
OMe
5hx (98%, 5h)
Ph
OMe
5fx (85%, 2h)
5gx (90%, 5h)
[g] C1 (1.0 mol%), BzOH (20 mol%).
O
O
O
O
β
OMe
OMe
α
γ
OMe
OMe
5lx (0%)
5jx (81%, 24h,
5kx (95%, 48h,
α,β-/β,γ-unsaturation α,β-/β,γ-unsaturation = 73:21)
5ix
(82%, 28h)
= 87:13)
Figure 4. Scope of the oxidative esterification of enals. Yields refer to isolated
products. *The lower yield of the isolated methyl ester 5ex (74%) is due to its
volatility, as the prenal substrate 5e was completely consumed with clean
conversion. When changing to n-propanol, the resulting ester 5ey could be
isolated in 93% yield.
3
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COMMUNICATION
We finally evaluated the oxidative esterification of α,β-
enals 4, with MeOH (2x) as the alcohol component, using the
substrate library shown in Figure 4. We were delighted to find
that a diverse array of enals, including α- and β- substituted
aromatic and aliphatic ones, reacted smoothly to give the cor-
responding esters 5 (Figure 4). Gratifyingly, even α-substitued
acroleins were successfully oxidized to the esters 5fx-5hx in
yields ranging from 80% to 98%, indicating the absence of NHC
deactivation by Michael addition.[4j] In the case of citral (5d; E/Z
= 50:50), we observed E/Z-isomerization, as the dienoate 5dx
was obtained with an E/Z ratio of 68:32. Additionally, partial
isomerization of the α,β-unsaturation to the β,γ-position was
observed with 5j and 5k, giving the products 5jx and 5kx,
respectively. Sterically congested β-cyclocitral (5l) was unreact-
ive when the same experimental conditions were applied, and
no product 5lx was observed.
salt C1, with low-basicity and carrying dispersion energy donors.
Furthermore, the introduction of benzoic acid as co-catalyst was
the key to success. The resulting cooperative catalytic system
effects oxidative esterification at very low catalyst loadings
(down to 50 ppm for benzaldehyde).
Acknowledgements
Support by the Deutsche Forschungsgemeinschaft (priority
program 1807 “Control of London Dispersion Interactions in Mo-
lecular Chemistry”, grant nos. BE 998/14-1,2) and by the Fonds
der Chemischen Industrie is gratefully acknowledged. We thank
Kevin Zühlke, Alicia Köcher and Marvin Naase for experimental
support.
Initial kinetic experiments were performed to shed light on
the mechanism of the BzOH co-catalysis. We have recently sug-
gested that ester formation from aliphatic aldehydes proceeds
via the azolium enolate state (such as 7, Scheme 3), while
esterification of aromatic aldehydes must proceed through an
acyl azolium intermediate (such as 6a,b, Scheme 3).[12a] The
SIPr-derived acetyl azolium triflate 6a, the analogous benzoyl
azolium chloride 6b[20] and the acetyl azolium enolate 7 were
exposed to BnOH (2a) or methanol (2x) in the presence of
Keywords: Carbene • cooperative catalysis • acylation •
esterification • oxidation
[1]
[2]
J. Otera, J. Nishikido, Esterification: Methods, Reactions, and Applica-
tions, 2nd ed., Wiley-VCH, Weinheim, 2010.
For reviews, see: a) K. Ekoue-Kovi, C. Wolf, Chem Eur. J. 2008, 14,
6302–6315; b) S. Gaspa, A. Porcheddu, L. De Luca, Tetrahedron Lett.
2016, 57, 3433–3440.
1
[3]
For reviews on NHC-redox catalysis, see: a) V. Nair, Menon, R. S.;
Biju, A. T.; Sinu, C. R.; Paul, R. R.; Jose, A.; Sreekumar, V. Chem. Soc.
Rev. 2011, 40, 5336−5346; b) P.-C. Chiang, J. W. Bode, TCI MAIL
2011, 149, 2−17; c) Z.-Q. Rong, W. Zhang, G.-Q. Yang, S.-L. You, Curr.
Org. Chem. 2011, 15, 3077 – 3090; d) H. U. Vora, P. Wheeler, T. Rovis,
Adv. Synth. Catal. 2012, 354, 1617−1639; e) J. Mahatthananchai, J. W.
Bode, Acc. Chem. Res. 2014, 47, 696−707.
BzOH (1 equiv), and the reaction progress was monitored by H
NMR (see SI, Figures S10-16, Tables S1,2). In the presence of
BzOH, the azolium enolate 7 reacted with BnOH ca. 11 times
faster to benzyl acetate than in the absence of BzOH. This result
suggests that for aliphatic aldehyde substrates (such as 1a,
Figure 1B,C), BzOH co-catalysis involves interaction with the
azolium enolate intermediate.[21] In contrast, neither the acetyl
azolium triflate 6a nor the benzoyl azolium chloride 6b reacted
with BnOH (2a) or methanol (2x), regardless of whether or not
BzOH was present. This result is in line with our observation that
BzOH effects at best a slight acceleration in the case of
benzaldehyde (1p), where ester formation can proceed only via
an acyl azolium intermediate, and not an azolium enolate (see
SI, Figure S9). While rate acceleration may be negligible, the
presence of the BzOH co-catalyst is still necessary for achieving
extremely low catalyst loadings in benzaldehyde esterification
(Figure 3e). We conclude that BzOH also prevents, or at least
retards, deactivation of the NHC catalyst. An obvious mechan-
istic option for this may be reversible protonation to the azolium
cation.
[4]
For selected examples of NHC-catalyzed redox esterification, see: a) K.
Y.-K. Chow, J. W. Bode, J. Am. Chem. Soc. 2004, 126, 8126–8127; b)
N. T. Reynolds, J. Read de Alaniz, T. Rovis, J. Am. Chem. Soc. 2004,
126, 9518–9519; c) A. Chan, K. A. Scheidt, Org. Lett. 2005, 7, 905–
908; d) S. S. Sohn, J. W. Bode, Org. Lett. 2005, 7, 3873–3876; e) K.
Zeitler, Org. Lett. 2006, 8, 637–640; f) S. S. Sohn and J. W. Bode,
Angew. Chem., Int. Ed., 2006, 45, 6021–6026; Angew. Chem. 2006,
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[5]
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Dipp
Dipp
N
R
O
BnOH (2 equiv)
with and w/o BzOH (1 equiv)
N
O
O
X
N
Dipp
H3C
OBn
[D]8THF
N
Dipp
BnOAc
k
with BzOH ≈ 11xkw/o BzOH
6a, R = CH3, X = OTf
6b, R = Ph, X = Cl
7
No reaction
Scheme 3. SIPr-derived acetyl azolium triflate 6a, benzoyl azolium chloride 6b,
acetyl azolium enolate 7, and the effect of BzOH on the reaction of 7 with
BnOH (2a) or methanol (2x) [Dipp: 2,6-di(2-propyl)phenyl].
[6]
[7]
In summary, we disclose an efficient and practical method
for the NHC-catalyzed oxidative coupling of alcohols with a wide
range of sterically hindered α/β-substituted aliphatic aldehydes
and enals, hitherto recalcitrant to this type of transformation. Our
method hinges on the novel and readily accessible triazolium
4
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10.1002/anie.202104712
Angewandte Chemie International Edition
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5
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Entry for the Table of Contents
Ph
Cl
N
N
N
Mes
Cl
Cl
Cl
NHC (0.005-1 mol%)
BzOH (cat.)
R3
O
R3
O
ROH
R2
H
R2
OR
oxidant
R1
R1
Oxidative NHC Catalysis
R1, R2, R3 = H, alkyl
While N-heterocyclic carbene (NHC) catalyzed oxidative esterification of aldehydes/enals is a synthetically highly attractive method, it
is plagued by poor conversions/yields for sterically demanding substrates. The novel and readily accessible triazolium catalyst shown,
with benzoic acid as co-catalyst, overcomes this deficiency. A variety of hitherto recalcitrant aldehydes/enals are efficiently converted
to esters, and very low catalyst loadings (down to 50 ppm) can be applied.
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