Mesoionic oxides: Facile access from triazolium salts or triazolylidene copper precursors, and catalytic relevance

Article abstract of DOI:10.1039/c2cc32843g

Reaction of CsOH with triazolium salts affords mesoionic compounds containing an exocyclic oxygen; the same product is obtained by reaction of the corresponding Cu(i) triazolylidenes with CsOH and represents an unusual reactivity pattern of N-heterocyclic

Full text of DOI:10.1039/c2cc32843g

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Mesoionic oxides: facile access from triazolium salts or triazolylidene
copper precursors, and catalytic relevancew
Ana Petronilho, Helge Muller-Bunz and Martin Albrecht*
¨
Received 21st April 2012, Accepted 8th May 2012
DOI: 10.1039/c2cc32843g
Reaction of CsOH with triazolium salts affords mesoionic
compounds containing an exocyclic oxygen; the same product
is obtained by reaction of the corresponding Cu(I) triazolylidenes
with CsOH and represents an unusual reactivity pattern of
N-heterocyclic carbene precursors that has implications for
carbene copper-catalyzed reactions.
Mesoionic compounds,1 in particular sydnones (A, Fig. 1),2
are of considerable interest due to their pharmacological
relevance, as established e.g. in Feprosidnin or Molsidomine.3
In an attempt to broaden the sydnone family, recent focus has
been directed towards aza-versions and specifically towards
1,2,3-triazolium-4-olates as structural analogues (B, Fig. 1).4
Investigation of these mesoionic compounds is thwarted however
by their restricted synthetic accessibility.5 Here we present a short
and convenient route to this class of compounds, which involves
the reaction of CsOH with either a triazolium salt or the corres-
ponding triazolylidene copper complex. The straightforward
access entails an unexpected reaction pathway of heterocyclic
azolium salts with a base, providing the oxo-adduct6 rather than
the free N-heterocyclic carbene (NHC).7 Analysis of the bonding
in these mesoionic compounds has direct implications for
describing the bonding situation in related free and metal-
complexed triazolylidenes.8
Scheme 1 Direct and indirect syntheses of mesoionic 2 from the
triazolium salt 1 and ORTEP representation of 2c (50% probability).
isolated in 20–30% yield as white solids. Higher purities and
yields (up to 90% overall from 1) were accomplished when
applying an indirect protocol involving first the synthesis of
the corresponding triazolylidene copper(I) complex 3 via an
established transmetalation methodology,9 followed by treat-
ment of this complex with CsOH (2 mol equiv.).10 For
compound 3c, which in contrast to 3a,b is air- and moisture
sensitive, a sequential one-pot synthesis from 1c involving
Ag2O, CuCl and CsOH was found to give pure 2c in good
yields. Notably, decomposition of 3c in a moist environment
in the absence of CsOH gave mixtures of 1c (major product)
and minor quantities of 2c.
Compounds 2a–c were synthesized via two different routes,
both starting from the corresponding triazolium salts 1a–c
(Scheme 1). Direct reaction with 1 or 2 mol equiv. CsOH
afforded compounds 2 as major products (70–90%) together
with demethylated 1,4-substituted triazole. After column chromato-
graphic purification of this mixture, analytically pure 2a–c were
Unambiguous confirmation of the formation of 2a was
obtained from a single crystal X-ray diffraction analysis
(Scheme 1).w The unit cell of 2a lacks any anion and identifies 2a
as an overall neutral compound. As a key feature, the molecular
structure reveals a C–O bond distance of 1.243(2) A, which is
characteristic for a CQO double bond. The heterocycle is
essentially planar, indicating charge delocalization as observed
in related mesoionic compounds.11 It is particularly instructive
to compare the bond lengths and angles of 2a with those in
related triazolium salts.12 In the latter, the heterocycle is bound
to a hydrogen, representing the extreme case of a C–E single
bond of a triazolium adduct, whereas 2a displays the CQE
double bond limit of a triazolylidene fragment. Comparison of
these two extremes reveals that the exocyclic double bond
induces an elongation of both adjacent heterocyclic bonds
C5–N1 and C5–C4.w This diagnostic structural feature allows free
and metal-bound triazolylidenes to be classified. Accordingly, the
bond elongation in the free carbene is about 70% compared to 2a
Fig. 1 Generic structure of sydnone A and its aza-derivative B.
School of Chemistry & Chemical Biology, University College Dublin,
Belfield, Dublin 4, Ireland. E-mail: martin.albrecht@ucd.ie;
Fax: +353 1716 2501; Tel: +353 1716 2504
w Electronic supplementary information (ESI) available: Synthetic
and catalytic procedures, IR data, and crystallographic data in CIF
format. CCDC 870677. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2cc32843g
c
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Chem. Commun., 2012, 48, 6499–6501 6499

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and thus in full agreement with the mesoionic assignment.12a
The heterocyclic bonds in the triazolylidene metal complexes
are typically similar,8,9a which suggests partial MQC double
bond character in these complexes.
The 1H and 13C NMR data of compounds 2a–c are remarkably
similar to those of the corresponding copper complexes 3a–c. For
example the carbonyl resonance in 2a was observed at 155.6 ppm,
a mere 5 ppm upfield compared to the resonance in 3a (dC–Cu
1
161.3 ppm).9a In the H NMR spectrum, the most characteristic
Scheme 2 Expansion of CsOH mediated oxidation to C2-alkylated
and unsubstituted imidazolium salts.
shift pertains to the N–CH3 group, which appears at dH 4.12 ppm
in 2a and at 4.21 ppm in 3a, and to para-positioned aryl
protons. All other signals differ by less than 0.05 ppm and are
thus not diagnostic for distinguishing 2 from 3.13
Demethylation increased with higher CsOH, and was more
pronounced with 1c than with the aryl-substituted triazolium
salts 1a,b. Substitution of Cs+ by K+ produced 2c but the
yield is lower, probably due to the limited solubility of KOH in
THF. With Bu4NOH as a base, 1c gave a mixture of products
and only traces of 2c. Ag2O represents a special case; in
CH2Cl2, 1 affords selectively the corresponding silver carbene
complex, while in THF, exclusive formation of the mesoionic
compound 2 was observed, presumably mediated by transiently
formed Ag(OH). Hence, appropriate solvatization of the M(I)
salt, a critical parameter for stabilizing free carbenes,19 is also
pivotal for generating mesoionic 2. Attempts to isolate the
free carbene to further support this hypothesis have been
unsuccessful thus far.
The pertinent IR data reveal a stretch vibration around
1640 cmꢀ1 (CHCl3) and thus provide unambiguous spectro-
scopic evidence for the presence of a carbonyl unit in 2. The
wavelength of this vibration is slightly solvent dependent and
shifts between 1660 cmꢀ1 (Et2O, er = 4.42) and 1640 cmꢀ1
(CH2Cl2, er = 9.02), though the shift does not correlate with
the relative permittivity of the solvent (cf. nCO = 1641 cmꢀ1 in
MeCN, er = 35.94).w This independence suggests that the
crystallographically identified keto resonance form of 2 prevails
in solution. In contrast, solid state IR measurements in KBr
with a substantially higher polarity lowers the energy of the
C–O bond to 1603 cmꢀ1, in line with a larger enolate resonance
contribution (cf. 20 in Scheme 1).
The scope of this oxygenation reaction was probed with the
imidazolium salts 4 and 5 comprised of a methyl-functionalized
and an unsubstituted C2 position, respectively (Scheme 2).
When treated with CsOH, both types of imidazolium salts
formed the cyclic urea 6. While the reactivity patterns of the
unsubstituted imidazolium salts 5 and the triazolium salts 1
are probably mutually related and may involve a Cs-stabilized
carbene, the C2-demethylation of 4 is less trivial. Formation of
a mesoionic compound analogous to 2 may be prevented
because of the pKa mismatch between the C4/5-bound proton
(pKa around 30) and CsOH. Such C2–Calkyl bond cleavage has
been observed previously with Ag2O in an oxidative process,20
though the drastic difference in standard redox potentials of
AgI and CsI (0.80 V vs. 2.92 V) tends to suggest that methyl
group dissociation may be related to the observed demethyla-
tion of 1 in the presence of a large excess of CsOH.
Related oxo-adducts of NHCs have recently been observed
as thermally induced decomposition products from imidazol-
2-ylidene copper complexes,14 and from direct interaction of
an imidazolinium salt with Cu2O, affording cyclic urea.13 In
the former case, elegant work provided direct evidence for O2
as the oxygen source. The methodology presented here appears to
be complementary, since the copper complex 3a is air-stable within
the timeframe of the reaction (24 h). 3a decomposes only very
gradually and after 3 days, a mixture of 1a and the mesoionic
compound 2a (40% and 32% by 1H NMR integration,
respectively) were observed together with unreacted 3a
(28%). In the presence of CsOH and under an atmosphere
of dry N2, exclusive formation of the mesoionic compound 2a
in high yields was observed without any thermal induction
(RT, 24 h), perhaps via CuCl dissociation involving the transient
formation of a free carbene,15 or more likely by a redox pathway
comprising a Cu(II)–OH intermediate that undergoes reductive
C–O bond formation.16 These observations suggest that CsOH
rather than O2 or water is initiating the formation of 2.
The mesoionic compounds 2 are excellent ligands for CuCl,
and the corresponding complexes catalyze the [3+2] dipolar
cycloaddition of alkynes and azides (‘click’ reaction). Thus,
addition of catalytic quantities of 2a and CuCl to a mixture
of phenylacetylene and benzyl azide (3% catalyst loading)
afforded, after 30 min, the corresponding 1-benzyl-4-phenyl-
triazole in essentially quantitative yield (eqn (1)).w In the
absence of added CuCl, 2a is catalytically silent in this
cycloaddition reaction. It is interesting to note that copper
complexes comprising bulky carbene ligands (1,2,3-triazol-5-
ylidenes akin to 3 or imidazol-2-ylidenes) were reported to
show excellent catalytic activity in this reaction.9a,21 Indeed,
when using complex 3a as catalyst precursor, full conversion
was observed with the same time frame as for the 2a–CuCl
mixture. In light of these results we are not confident in
attributing the catalytic activity to the carbene complex 3a.
Instead, the catalytically active species may ensue from a
coordination compound 2aꢁCuCl that readily forms in situ
The direct formation of 2 from the triazolium salt 1 in the
absence of copper lends further support to a hydroxide-
mediated pathway. A putative mechanism may entail either
triazolium deprotonation and subsequent nucleophilic–
electrophilic interaction of the free carbene with water,6a or
nucleophilic addition of hydroxide to the C5 position followed
by (formal) H2 elimination.17 While our data do not allow to
confidently discard one of these pathways, experiments have
been performed to better understand this reaction. Reaction of
1 with overstoichiometric quantities of CsOH (2–8 mol equiv.)
led, in addition to some formation of mesoionic 2, to partial
N–CH3 bond cleavage (Hoffman elimination) of the triazo-
lium salt as a competitive process and afforded the corre-
sponding 1,4-disubstituted triazole as a further product.18
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from 3 as detailed above. Similar decomposition or indeed
catalyst activation pathways may also be relevant in related
carbene copper-catalyzed reactions that involve a base.
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ð1Þ
In summary, we have disclosed a rapid synthesis of mesoionic
compounds starting from synthetically versatile triazolium salts and
CsOH. Identical products are formed while treating the corre-
sponding triazolylidene cuprous salt with CsOH. Formation of the
mesoionic compound directly from the triazolium salt likely
involves the transient formation of a free carbene, while the reaction
from the copper complex presumably occurs via reductive carbene
hydroxide elimination from a putative [Cu(triazolylidene)(OH)]
intermediate. The low stability of this latter complex, e.g. when
compared to the analogous normal imidazole-derived NHC
congeners, provides further support for a more reactive M–Ccarbene
bond in mesoionic complexes.22 The smooth oxygen transfer may
have direct implications in using Cu-triazolylidene complexes as
catalysts. Perhaps more relevant, the synthetic methodology is
remarkably general and provides facile access to a wide range of
mesoionic compounds that have potential in their own right, e.g. as
new structural motifs in active pharmacological ingredients, and
also as a new class of ligands with a high degree of electronic
flexibility (cf. limiting resonance structures of 2).
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a cationic
[Cu(triazolylidene)2]+ complex as a minor product were detected.
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6499–6501 6501