N-Heterocyclic carbene catalyzed synthesis of oxime esters

Article abstract of DOI:10.1039/c2ob26974k

A triazolium salt derived N-heterocyclic carbene catalyzes the redox esterification reaction between α-β-unsaturated aldehydes and oximes. The resulting saturated oxime esters were obtained in very good yields for a broad range of aliphatic, aromatic and heteroaromatic substrates. The Royal Society of Chemistry.

Full text of DOI:10.1039/c2ob26974k

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N-Heterocyclic carbene catalyzed synthesis of oxime
esters†
Cite this: Org. Biomol. Chem., 2013, 11,
138
Dieter Enders,* André Grossmann and David Van Craen
Received 18th September 2012,
Accepted 15th October 2012
A triazolium salt derived N-heterocyclic carbene catalyzes the redox esterification reaction between
α–β-unsaturated aldehydes and oximes. The resulting saturated oxime esters were obtained in very good
yields for a broad range of aliphatic, aromatic and heteroaromatic substrates.
DOI: 10.1039/c2ob26974k
www.rsc.org/obc
When designing a synthesis strategy for a complex target mole-
cule through retrosynthetic analysis, the concept of umpolung
has turned out to be very useful allowing non-traditional dis-
connections.1 In this context N-heterocyclic carbenes have
evolved into a very successful class of catalysts for the umpo-
lung of aldehydes over the past few decades.2 Among the vast
number of publications on NHC organocatalysis, Chow and
Bode3a and Rovis et al.3b independently reported on the conju-
gate umpolung of α-reducible aldehydes in 2004 (Scheme 1).
Thereby, N-heterocyclic carbenes react with aldehydes bearing
a double bond equivalent or a leaving group in the alpha posi-
tion to the carbonyl group forming an acyl azolium salt, which
subsequently reacts with an alcohol leading to saturated esters
via internal redox esterification.3,4
In comparison with the classic preparation methods of
esters via substitution reaction of carboxylic acid derivatives5
this catalytic or sub-stoichiometric approach has, theoretically,
the advantage of avoiding stoichiometric amounts of salt
waste and/or coupling reagents, therefore being atom6 and
Scheme 1 Examples of NHC catalyzed redox esterifications; an alcohol is the
nucleophile in all three literature cases.
redox economical.7 In reality, all reports on intermolecular triazolium salt 12a (5 mol%) and potassium acetate as a base
redox esterifications so far do not fulfill these advantages by (30 mol%) in chloroform for 24 h. Although crotonaldehyde is
applying stoichiometric amounts of base, protic additives or thought to be a poor substrate for the redox esterification,3j we
large excesses of the O-nucleophile (Scheme 1). We now would could successfully isolate the corresponding oxime ester 13a in
like to report a highly efficient redox esterification reaction 69% yield with 72% converted starting material (Table 1, entry
between α–β-unsaturated aldehydes and oximes under very 1). It is noteworthy that no typical by-products via the benzoin
mild, nearly equimolar conditions where no protic additives reaction or dimerization of the aldehyde were observed in the
are necessary. All starting materials and reagents are commer- crude reaction mixture. From the range of the tested bases
cially available and the resulting oxime esters are very useful (Table 1, entries 2–8) strong bases such as KOtBu or DBU
biologically active molecules for fragrance,8 medical9 and agri- showed no activity in this reaction while weaker ones, such as
cultural industries.10
amino or acetate bases, could promote the reaction albeit less
We started our investigations by utilizing crotonaldehyde effectively as compared to potassium acetate. Therefore, in
(11a) and p-tolylaldoxime (10a) in the presence of the agreement with the literature, only bases whose corresponding
acid is strong enough for the protonation of the extended
Breslow intermediate II (Scheme 2) led to a measurable conver-
sion of the starting material.3d
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074
Aachen, Germany. E-mail: enders@rwth-aachen.de; Fax: (+49) 241-809-2127
In order to improve the reaction rate we increased the cata-
†Electronic supplementary information (ESI) available: Experimental procedures
lyst loading to 10 mol% and tested different solvents (Table 1,
entries 9–16). Aprotic solvents and especially chlorinated ones
and full spectroscopic data for all isolated compounds. See DOI:
10.1039/c2ob26974k
138 | Org. Biomol. Chem., 2013, 11, 138–141
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Table 1 Optimization studies of the reaction conditionsa
gave the best results, while ethers, esters and primary alcohols
led to poor conversion rates. Interestingly, the catalytic system
was highly selective concerning the choice of the nucleophile.
Even when the reaction was performed in methanol only the
desired oxime ester was observed without any by-products
such as methylesters resulting from the redox esterification
reaction with the solvent. Subsequently, we tested different
azolium salts for their catalytic activity (Table 1, entries 9,
17–22). While thiazolium (14) and imidazolium salts 15 were
catalytically inactive, the triazolium catalyst precursors 12 gave
varying results strongly dependent on the aromatic N-substitu-
ent. Thereby, only the azolium salts 12a and 12e bearing ortho-
substituents on the N-phenyl moiety produced reasonable
oxime conversions with triazolium salt 12a being far superior
to 12e. Finally, using 12a as a catalyst precursor and increasing
the potassium acetate loading to 0.5 equivalents raised the
conversion of oxime to 91% and the yield of isolated product
to 90% (Table 1, entry 23).
With the optimized conditions in hand we turned our atten-
tion to the scope of the oxime and aldehyde substrates. Ali-
phatic esters of aromatic aldoximes have recently attracted
special attention due to their distinct and characteristic aroma
of berries making them interesting to the fragrance and food
industries.8 Therefore we prepared a range of these com-
pounds varying the aromatic moiety and utilizing our protocol
(Table 2, entries 1–10). Indeed, irrespective of their electronic
or steric properties, all these aldoximes performed well with
high yields (78–90%). Sole limitations were the solubility and/
or the basicity of the aldoxime leading to slightly lower yields
for 3,4-dimethoxyphenyl and 4-dimethylaminophenyl substi-
tuted aldoximes (Table 2, entries 8, 10). Similarly, hetero-
aromatic aldoximes gave good results (Table 2, entries 11–13)
although their low solubility required a change of solvent in
the case of R1 = 2-pyridinyl and 3-indolyloxime (Table 2,
entries 11–12). Since even ortho-substituted aldoximes do not
inhibit the reaction (Table 2, entry 9), we envisaged that ketox-
imes could be good substrates as well (Table 2, entries 14–19).
In fact, ketoximes irrespective of their aromatic or aliphatic
substituents reacted to give the corresponding oxime esters in
synthetically useful yields (56–95%). Only some methyl-substi-
tuted ketoximes gave moderate results (Table 2, entries 14, 16).
Finally, different α–β-unsaturated aldehydes were tested in
this reaction. In comparison to crotonaldehyde the longer
chained or bulkier aliphatic aldehydes were all equally active
resulting in high yields of 74–90% (Table 2, entries 20–24).
Similarly, aromatic aldehydes such as cinnamaldehyde are
good substrates as well. The oxime ester formed from cinna-
maldehyde and p-tolyloxime was isolated in 85% yield
(Table 2, entry 25).
Base
(mol%) (mol%)
Precatalyst
Conversionb
(%)
Entry Solvent Base
1
2
3
4
5
6
7
8
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
KOAc
30
30
30
30
30
12a (5)
12a (5)
12a (5)
12a (5)
12a (5)
12a (5)
12a (5)
12a (5)
12a (10)
12a (10)
12a (10)
12a (10)
12a (10)
12a (10)
12a (10)
12a (10)
12b (10)
12c (10)
12d (10)
12e (10)
14 (10)
15 (10)
12a (10)
72 (69)
53
51
Trace
Trace
43
32
Trace
86
83
73
65
34
43
13
55
13
13
10
NaOAc
CsOAc
DBU
KOtBu
(iPr)2NEt 30
NEt3
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
50
Cs2CO3
KOAc
KOAc
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23c
Toluene KOAc
Et2O KOAc
Acetone KOAc
iPrOH
MeOH
EtOAc
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
52
Trace
Trace
91 (90)
a Reaction conditions: 10a (1.0 mmol), 11a (1.0 mmol), solvent
(2.0 mL), 24 h, rt, under air. b Conversion of the oxime 10a in the
crude reaction mixture was determined via 1H NMR spectroscopy;
values in brackets are yields of isolated product 13a. c Excess aldehyde
11a (1.1 equiv.) was used.
The proposed mechanism of the reaction is shown in
Scheme 2. First, the triazolium salt 12 is deprotonated by pot-
assium acetate. Considering the low basicity of acetate bases
and previous labeling experiments by Sohn and Bode3d the
concentration of the free carbene 12′ is probably low and the
protonation is reversible. Subsequently, the resulting carbene
12′ attacks the aldehyde 11 forming the tetrahedral
Scheme 2 Proposed mechanism of the NHC catalyzed redox esterification of
oximes 10 with enals 11.
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Table 2 Scope of the aldehyde and oxime substratesa
oximes. The reaction worked well for all tested aliphatic, aro-
matic and heteroaromatic substrates with the only limitation
being substrate solubility and basicity. In fact, the presented
methodology is a good alternative to the classical transesterifi-
cation processes of carboxylic acid derivatives leading to
industrially valuable oxime esters in good to excellent yields.
Entry
R1
R2
R3
13
Yieldb (%)
1
2
3
4
5
6
7
8
4-MeC6H4
Ph
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
90
81
93
90
90
83
90
79
88
85
73
84
87
56
92
68
92
95
83
82
80
90
74
79
85
General procedure for the NHC catalyzed
redox esterification
1-Naphthyl
4-BrC6H4
3-ClC6H4
4-(CF3)C6H4
3,4,5-F3C6H2
4-(Me2N)C6H4
2-(MeO)C6H4
3,4-(MeO)2C6H3
2-Pyridinyl
3-Indolyl
2-Furanyl
Me
Oxime 10 (2 mmol) and aldehyde 11 (2.2 mmol) were mixed in
a flask and subsequently dissolved in chloroform (8 mL). The
clear solution was treated with triazolium salt 12a (0.2 mmol)
and potassium acetate (1 mmol). The heterogeneous reaction
mixture was stirred at ambient temperature.16 After 24 h the
reaction mixture was transferred onto a small amount of silica
gel and purified by column chromatography.
9
10c
11c
12d
13
14
15
16
17
18e
19
20
21
22
23
24
25
H
Me
Me
Me
Ph
Et
Ph
Ph
Acknowledgements
1-Indanonyl
–(CH2)5–
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
s
t
u
v
w
x
We thank the German Research Foundation for support (scho-
larship for A. G., International Research Training Group
H
H
H
H
H
H
nPr
iPr
CH2OTIPS
Bn
“Selectivity in Chemo- and Biocatalysis”
– SeleCa). The
donation of chemicals by the former Degussa AG and BASF SE
is gratefully acknowledged.
Ph
y
a Reaction conditions: 10 (2.0 mmol), 11 (2.2 mmol), solvent (4.0 mL),
24 h, rt, under air. b Yields of isolated product 13. c CH2Cl2 (4.0 mL)
was used as solvent. d A mixture of CHCl3–CH2Cl2–Et2O 2 : 1 : 1
(8.0 mL) was used as solvent. e A mixture of CHCl3–CH2Cl2 1 : 1 (8 mL)
was used as solvent.
Notes and references
1 D. Seebach, Angew. Chem., 1979, 91, 259–278, (Angew.
Chem., Int. Ed. Engl., 1979, 18, 239–258).
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II. Recent DFT calculations showed that such proton transfers
are protonation–deprotonation processes more than symmetry
forbidden intramolecular [1,2]-H-shifts.12 In the current case,
the acetate base and the corresponding acetic acid predomi-
nantly take the role of the proton shuttle agent. Indeed, when
the reaction was performed with triethylamine as a base,
addition of 30 mol% acetic acid improved the conversion of
oxime significantly, up to around 50% (previously 32%, see
Table 1 entry 7). The important regioselective step is the sub-
sequent protonation of the Breslow intermediate II to the
azolium-enol IV and its tautomeric acyl-azolium V. Taking into
account that no significant amounts of by-products were
observed, the protonation of the Breslow intermediate occurs
faster than the reaction with an additional molecule of the
aldehyde 11 preventing C–C bond formation leading to lac-
tones 1613 or the oxidation leading to α–β-unsaturated acyl-
azolium III.3j,14,15 Finally, the oxime 10 performs a nucleophi-
lic substitution on the carboxyl surrogate V yielding the oxime
ester 13 and liberating the carbene catalyst 12′ together with
acetic acid.
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140 | Org. Biomol. Chem., 2013, 11, 138–141
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