Acyl Donor Intermediates in N-Heterocyclic Carbene Catalysis: Acyl Azolium or Azolium Enolate?

Article abstract of DOI:10.1002/anie.202010348

Azolium enolates and acyl azolium cations have been proposed as intermediates in numerous N-heterocyclic carbene (NHC) catalyzed transformations. Acetyl azolium enolates were generated from the reaction of 2-propenyl acetate with both saturated (SIPr) and

Full text of DOI:10.1002/anie.202010348

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Accepted Article
Title: Acyl Donor Intermediates in N-Heterocyclic Carbene Catalysis:
Acyl Azolium or Azolium Enolate?
Authors: Albrecht Berkessel, Animesh Biswas, Jörg M. Neudörfl, and
Nils E. Schlörer
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Acyl Donor Intermediates in N-Heterocyclic Carbene Catalysis:
Acyl Azolium or Azolium Enolate?
Animesh Biswas,[a] Jörg-M. Neudörfl,[a,b] Nils E. Schlörer,[a,c] and Albrecht Berkessel*[a]
[a]
Dr. A. Biswas, Dr. J.-M. Neudörfl, Dr. N.E. Schlörer, Prof. Dr. A. Berkessel
Department of Chemistry (Organic Chemistry), University of Cologne
Greinstraße 4, 50939 Cologne (Germany)
E-mail: berkessel@uni-koeln.de
[b]
[c]
X-Ray Crystallography
NMR Spectroscopy
Supporting information for this article is given via a link at the end of the document.
O
O
O
δ+
Abstract: Azolium enolates and acyl azolium cations have been
proposed as intermediates in numerous N-heterocyclic carbene
catalyzed transformations. Acetyl azolium enolates were generated
from the reaction of 2-propenyl acetate with both saturated (SIPr)
and aromatic (IPr) N-heterocyclic carbenes, isolated, and charac-
terized by NMR and XRD. Protonation with triflic acid gave the cor-
responding acetyl azolium triflates which were isolated and charac-
terized (NMR, XRD) as well. Acyl azolium cations have been
proposed as immediate precursors of the ester product e.g in the
redox esterification of α,β-enals. Our current studies, involving iso-
topically labeled d3-acetyl azolium triflate, suggest that ester
formation instead originates from an azolium enolate intermediate.
Furthermore, the acetyl azolium enolate was found to selectively
react with alcohol nucleophiles in the presence of amines. While the
acetyl azolium cation did not react with alcohols, an ester-selective
reaction could be induced by addition of base, via intermediate
formation of the acetyl azolium enolate.
R
N
H
R'
R'
δ+
LG
R'
H
(b)
activation of
carboxylic acid
derivatives
(c)
(a)
N
R
a3-d3 Umpolung
oxidative
NHC
catalysis
of α,β-enals
R
R
N
O
α
N
E
γ-protonation,
tautomerization
OH
δ−
α
δ+
δ−
R'
N
R
N
R
γ
β
R'
tautomerization,
γ-deprotonation
γ
β
acyl azolium cation
diamino dienol I
III
homoenolate chemistry
e.g. γ-lactones, γ-lactams,
spiro-lactones, cyclopentenes,
saturated esters
activated carboxylic acid chemistry
e.g. redox esterification,
transesterification
R
N
O
α
β
γ
N
R
OH-Cγ
proton
shift
δ−
R'
β-deproton-
ation
In recent years, the synthetic application of N-heterocyclic
carbenes (NHCs) has been extended beyond classical a1-d1
Umpolung of simple aldehydes:[1-4] As shown in Scheme 1 (a),
a3-d3-Umpolung of α,β-unsaturated aldehydes with NHCs opens
a pathway to homoenolate chemistry, through the formation of
the diaminodienols I.[5] Additionally, an OH-Cγ proton shift in the
diamino dienol I leads to the azolium enolate II. The latter
behaves as an enolate equivalent and serves as the source of
yet another broad spectrum of products.[6]
E
azolium enolate II
Cγ-OH
proton shift
β-protonation
enolate chemistry
e.g. chiral β-lactones,
γ,δ-unsaturated δ-lactones, γ,δ-unsaturated δ-lactams
Scheme 1. Manifold of intermediates formed from NHCs and α,β-enals (a),
activated carboxylic acid derivatives (b), through oxidative NHC catalysis (c),
and their interconversion by proton transfer steps.
chanism proposed by Scheidt and Bode for this transformation is
shown in Scheme 2, pathway A: As a key step, γ-protonation of
the initially formed diamino dienol I affords the azolium enol IV.
Tautomerization of the latter gives the acyl azolium cation III.
Ester formation is completed by attack of the alcohol nucleophile
on the latter. Note, however, that the occurrence of acyl azolium
cations III in redox esterification has not been substantiated by
isolation, or spectroscopically.[11] We have been wondering
Besides applications in Umpolung strategies, NHCs have
also served as nucleophilic catalysts, e.g. in the transesterifica-
tion of activated esters.[7-9] As shown in Scheme 1(b), the acyl
azolium cation III is believed to result from the interaction of the
NHC catalyst with an activated carboxylic acid derivative. Note
that a "cross-overs" exists between the two types of NHC-cata-
lysis shown in Scheme 1(a) and (b): γ-protonation/tautomeriza-
tion may equilibrate the diamino dienol I [pathway (a)] with the
acyl azolium cation III [pathway (b)]. Another "cross-over point"
is the azolium enolate II which is accessible from both the
diamino dienol I (by OH-Cγ proton shift) and the acyl azolium
cation III (by β-deprotonation). Finally, the acyl azolium cation III
can also be accessed by "oxidative NHC catalysis", i.e. from
aldehydes in the presence of a suitable oxidant [Scheme 1,
pathway (c)].[10]
OH
OH
O
tauto-
merization
R
R
R
γ-protonation
pathway A
N
N
N
R
R
R
N
N
N
R
R
R
azolium enol IV
diamino dienol I
acyl azolium cation
III
O
tauto-
merization
O
R
N
+ ROH
R
R
OR'
OR'
pathway B
In 2005, Scheidt et al.[11a-c] and Bode et al.[11d,e] reported the
NHC-catalyzed redox esterification of enals, leading from α,β-
unsaturated aldehydes to saturated esters (Scheme 2). The me-
N
saturated ester product
(+ NHC)
H
azolium enolate II
R
Scheme 2. Mechanistic alternatives for the redox esterification of enals.
1
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10.1002/anie.202010348
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whether ester formation may instead proceed through the
azolium enolate stage (II, Scheme 2, pathway B). From II, a
single-step reaction with the alcohol component to the product
ester can be formulated, with regeneration of the NHC catalyst.
In 2012, Chi et al. exploited a "reverse cross-over" and
reported that NHC catalysis can be used for the generation of
azolium enolates II from activated esters.[12] After reaction with
the NHC catalyst, β-deprotonation of the initially formed acyl
azolium cation III affords an azolium enolate II [Scheme 1 (b)].
The latter can be reacted with various electrophiles, affording
e.g. γ,δ-unsaturated δ-lactams with N-tosyl imines.[12] Again,
none of the intermediates postulated for such "reverse cross-
over" reactions had been characterized.
To probe the acyl transfer chemistry discussed above, we
envisaged the acetate-based azolium enolates 1-3ae (Scheme
3) and the acyl azolium cations 1,2aa (Scheme 4) as model
systems. This choice was based on the simplicity of the acyl
residue, and on our earlier experience that the use of SIPr, IPr
as the carbene component provides sufficient stability for the
characterization and even isolation of intermediates postulated
for NHC catalysis. This approach had enabled us earlier to
generate and probe Breslow intermediates involved in the NHC-
catalyzed Umpolung of simple aldehydes,[4] related intermed-
iates of α,β-enal Umpolung,[13] and even later stages of azolium
enolate chemistry.[13] In an elegant study by Maji and Mayr, azol-
ium enolates have been prepared earlier by the reaction of
NHCs with ketenes, and analyzed thoroughly with regard to their
structure and reactivity towards benzhydrylium ions.[14]
a typical azolium enolate feature,[13,14] the planar enolate moiety
and the imidazolinium ring are tilted relative to one another, by
ca. 47o. The C=C distance of the enolate moiety nicely reflects
its double bond character [1.356 (2) Å]. The SIPr-acetone ad-
duct 4 was clearly identified by NMR (see SI). A control ex-
periment revealed that the strongly basic[16] NHC SIPr reacts
smoothly with acetone in [D8]THF at RT, yielding exclusively the
1:1 adduct 4.
When the unsaturated imidazolin-2-ylidene IPr was reacted
with 2-propenyl acetate [Scheme 3, (ii)] in [D8]THF at room
temperature, acetone was liberated which, however, did not
react further with IPr. Again, the azolium enolate 2ae crystallized
from the reaction mixture. X-Ray diffraction (Scheme 3, bottom
right) confirmed the constitution of the azolium enolate. The
planar enolate moiety and the (planar) imidazolium ring are
strongly tilted relative to one another, by ca. 53o, and the C=C
distance [1.345(3) Å] within the enolate moiety proves its double
bond character. The solubility of 2ae in [D8]THF turned out to be
so low that the crystalline material had to be re-dissolved in
[D3]MeCN for NMR characterization. In the latter solvent, 2ae
1
displayed characteristic singlets in its H NMR at δ = 3.09 ppm
(s, 1H, H6) and 2.75 ppm (s, 1H, H7) and 13C NMR resonances
at δ = 77.7 (C10) and 132.7 (C9) ppm. When IMes was used as
the NHC component, NMR analogously indicated the formation
of the azolium enolate 3ae (see SI). Unfortunately, no crystals of
3ae suitable for XRD could be obtained as yet.
Azolium enolates 1-3ae: NMR-Monitoring revealed that the add-
ition of 2-propenyl acetate to a solution of the saturated imid-
azolidin-2-ylidene SIPr in [D8]THF at room temperature resulted
in the smooth formation of the azolium enolate 1ae, together
with the acetone adduct of SIPr, 4 as a 1:1 mixture [Scheme 3,
(i)]. In [D8]THF, the azolium enolate 1ae displayed two charac-
teristic singlets in its 1H NMR at δ = 3.03 (s, 1H, H6) and 2.65 (s,
1H, H7), and 13C NMR resonances at δ = 76.5 (1C, C10) and
153.2 (1C, C9) ppm. The azolium enolate 1ae crystallized from
the reaction mixture, and single crystals suitable for X-ray
crystallography could be obtained (Scheme 3, bottom left).[15] As
Scheme 4. Preparation and X-ray crystal structures of the acyl azolium
triflates 1aa•OTf and 2aa•OTf.[19]
As summarized in Scheme 4, the acetyl azolium cations 1aa and
2aa were prepared, as triflates, from the azolium enolates 1ae
and 2ae by protonation with trifluoromethanesulfonic acid (TfOH).
In [D2]DCM, the instantaneous disappearance of the enolate
proton resonances and appearance of a new singlet at δ = 1.95
1
ppm (3H, H10) in the H NMR, and of new 13C resonances at
186.4 (1C, C9) and 29.3 (1C, C10) ppm in the 13C NMR
indicated the formation of the acetyl azolium salt 1aa•OTf. Its
unsaturated counterpart 2aa•OTf shows almost identical new
resonances. We succeeded in crystallizing both acetyl azolium
triflates 1aa•OTf and 2aa•OTf, and their X-ray crystal structures
are shown in Scheme 4. In both cases, the acetyl moiety is
again significantly tilted relative to the heterocyclic ring. In the
case of the saturated acetyl azolium salt 1aa•OTf, the dihedral
angle O1–C9–C8–N1 amounts to ca. – 57.4o, and somewhat
Scheme 3. Preparation and X-ray crystal structures of the azolium enolates 1-
3ae.[19]
2
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1
smaller, yet significant, in the case of the aromatic azolium salt
changed for a proton (see Supporting Information for H NMR
2aa•OTf [O1–C9–C8–N2= 31.42(19)o].
spectral data). As depicted in Scheme 6, this formation of benzyl
acetate-d2 is compatible only with deprotonation of the acetyl
azolium cation (to the azolium enolate 1ae-d2; pathway A), and
not with alcohol deprotonation (pathway B). In the latter case,
full D-retention, i.e. formation of benzyl acetate-d3 should have
been expected. NMR monitoring showed that no concomitant
H/D-exchange occurs at the acetyl group's α-position in the
course of the ester formation. Another control experiment, in the
absence of benzyl alcohol, confirmed that treatment with DBU
cleanly and instantaneously converts the acetyl azolium triflate
1aa-d3•OTf to the azolium enolate 1ae-d2.
Redox esterification: ester formation from acyl azolium cations -
or from azolium enolates? When exposed to benzyl alcohol (1
equiv) in [D8]THF (1H NMR observation) at RT, the azolium
enolate 1ae was instantaneously converted to benzyl acetate
(Scheme 5). The adduct of benzyl alcohol with SIPr (5) was
formed as by-product. The analogous reaction of 2ae with
benzyl alcohol was studied in [D2]DCM, for solubility reasons.
Again, ester formation was instantaneous, with IPr (as its DCl
salt)[17] being formed as by-product.
Dipp
O
N
BnOH
OBn
Mechanistic implications for the redox esterification of α,β-enals
(and related aldehydes): We conclude from the above studies
that for the acetyl system 1,2aa•OTf/1,2ae - and analogously for
other acyl azolium ions carrying at least one α-proton - ester
formation most likely proceeds via the azolium enolate state. For
the redox esterification of α,β-enals, a modified, and in fact
simplified mechanistic picture results (Scheme 7): In the first
step, the diamino dienol I is generated from the substrate enal
and the NHC catalyst. Tautomerization of the latter by OH-Cγ-
shift gives the azolium enolate II which can react directly with the
alcohol component to the saturated ester product, with regen-
eration of the catalyst. We are well aware that this simple
scheme does not explain the often complex influence of the
nature and amount of base used for transforming azolium pre-
catalysts to their active form. It is clear, however, that the equi-
libria NHC/NHC-H+ and I/II alone bear sufficient potential for pro-
nounced influence by acids and bases.
O
N
Dipp
CH3
pathway A
Dipp
1,2aa
Ph
O
+
CH3
H
O
N
Dipp
N
Dipp
N
O
pathway B
IPr or
Dipp
N
BnOH
N
Dipp
O
Bn
1,2ae
5
BnO
N
Dipp: 2,6-di(2-propyl)phenyl
H
Dipp
Scheme 5. Mechanistic alternatives for the esterification of BnOH by the
azolium enolates 1,2ae.
Mechanistically, the ester formation may proceed either via a
discrete proton transfer from the alcohol to 1,2ae, affording the
acyl azolium cation 1,2aa as intermediate (Scheme 5, pathway
A). Our NMR monitoring did not indicate accumulation of any
intermediate which, however, does not exclude this possibility,
as the formation of 1,2aa may be rate-limiting. Alternatively, a
concerted proton/acyl-transfer may be envisaged (Scheme 5,
pathway B). When 1ae was exposed to BnOD instead of BnOH,
a moderate kinetic isotope effect of ca. 1.4 was observed (see
Supporting Information, Tables S1 and S2 for kH/kD data).
O
R
H
OH
R
N
NHC
R
diamino enol
I
N
O
R
O
R
R
While neither one of the two results above allows for a clear
distinction, the following set of experiment advocates for the
azolium enolate as the immediate ester precursor: We first
established that in the absence of base, the acetyl azolium salt
1aa•OTf does not react with benzyl alcohol (or other alcohols).
Stoichiometric addition of DBU, however, results in instantan-
eous ester formation. Again, it may be argued whether the base
deprotonates the alcohol, or converts the acetyl azolium salt
1aa•OTf to the azolium enolate 1ae (as in Scheme 5). We ad-
dressed the latter question by using the trideuterated acetyl
R
O-R'
HO-R'
OH-Cγ-
proton shift
N
R
N
azolium enolate II
Scheme 7. Simplified mechanistic proposal for the NHC-catalyzed redox
esterification of α,β-enals.
Chemoselectivity of ester/amide formation from azolium enol-
ates and acyl azolium cations: In 2010, Studer et al. reported
their intriguing observation that alcohols can selectively be
cinnamoylated, in the presence of amines, under conditions of
oxidative NHC-catalysis.[10,18,19] With this in mind, we decided to
evaluate the ester/amide selectivity of our azolium enolate/acetyl
azolium pair 1ae/1aa•OTf. We studied their reactivity towards
benzyl alcohol (BnOH) and benzyl amine (BnNH2) by 1H NMR in
[D2]DCM, the results are summarized in Table 1. Exposure of
the azolium enolate 1ae to BnOH (Table 1, entry 1) and BnNH2
(Table 1, entry 2) resulted in smooth and quick ester formation,
and sluggish amide formation, respectively. When 1ae was
exposed to an equimolar mixture of BnOH and BnNH2, formation
of benzyl acetate was favored by a factor of 5.5 over amidation
(Table 1, entry 3). Control experiments established that there is
no secondary ester-to-amide transformation (see SI). Therefore,
the ester-to-amide ratio reflects the kinetic preference for ester-
ification. On the basis of the proposed single-step conversion of
the azolium enolate (Scheme 5, pathway B), its preference for
1
azolium triflate 1aa-d3•OTf (Scheme 6). H NMR monitoring of
this transformation clearly showed that in the resulting benzyl
acetate, exactly one of the three acetyl deuterons had been ex-
DBU
DBUD
Dipp
O
O
N
BnOH
D2HC
OBn
N
CD2
pathway A
benzyl acetate-d2
Dipp
Dipp
1ae-d2
BnOH
DBU
O
N
N
CD3
=
Dipp
N
OTf
O
Dipp
O
pathway B
OTf
OBn
D3C
OBn
1aa-d3•OTf
N
CD3
benzyl acetate-d3
Dipp
DBUH
BnO
Dipp:
DBU
1aa-d3•OTf
2,6-di(2-propyl)phenyl
Scheme 6. H/D-Exchange in the esterification of BnOH by the acetyl azolium
salt 1aa-d3•OTf, in the presence of DBU.
3
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