Sydnone Methides—A Forgotten Class of Mesoionic Compounds for the Generation of Anionic N-Heterocyclic Carbenes

Article abstract of DOI:10.1002/anie.202107495

Sydnone methides are described from which only one single example has been mentioned in the literature so far. Their deprotonation gave anions which can be formulated as π-electron rich anionic N-heterocyclic carbenes. Sulfur and selenium adducts were stabilized as their methyl ethers, and mercury, gold as well as rhodium complexes of the sydnone methide carbenes were prepared. Sydnone methide anions also undergo C?C coupling reactions with 1-fluoro-4-iodobenzene under Pd(PPh₃)₄ and CuBr catalysis. ⁷⁷Se NMR resonance frequencies and ¹J_C4-Se as well as ¹J_C4-H coupling constants have been determined to gain knowledge about the electronic properties of the anionic N-heterocyclic carbenes. The carbene carbon atom of the sydnone methide anion 3 j resonates at δ=155.2 ppm in ¹³C NMR spectroscopy at ?40 °C which is extremely shifted upfield in comparison to classical N-heterocyclic carbenes.

Full text of DOI:10.1002/anie.202107495

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Heterocycles
Sydnone Methides— A Forgotten Class of Mesoionic Compounds for
the Generation of Anionic N-Heterocyclic Carbenes
Sebastian Mummel, Felix Lederle, Eike G. Hübner, Jan C. Namyslo, Martin Nieger, and
Andreas Schmidt*
Abstract: Sydnone methides are described from which only
one single example has been mentioned in the literature so far.
Their deprotonation gave anions which can be formulated as
p-electron rich anionic N-heterocyclic carbenes. Sulfur and
selenium adducts were stabilized as their methyl ethers, and
mercury, gold as well as rhodium complexes of the sydnone
methide carbenes were prepared. Sydnone methide anions also
synthesis of [18F]fluoroarenes,[9] and co-catalysts or ligands of
Pd catalysts for Suzuki–Miyaura reactions under acidic
conditions.[10] They are of ongoing interest as biologically
active compounds[11] from which the sydnone imine[12] Molsi-
domine[13] and Sydnocarb[14] are in clinical use.[15] Recently
they have been applied for in vitro bioconjugation of purified
proteins,[5] as sialic acid-substituted bioorthogonal reporters,[4]
as imaging reagents,[16] labeling and imaging tools in live
cells,[17] and fluorogenic compounds.[18] In view of this
remarkable career it is surprising that some members of the
sydnone family of compounds (Scheme 1) have remained
almost unknown to date. Thus, only one sydnone methide
(sydnone methanide) (2a) has been prepared,[19] examined by
17O,[20] 15N, and 14N NMR spectroscopy,[21] and repeatedly
mentioned in monographs.[15]
À
undergo C C coupling reactions with 1-fluoro-4-iodobenzene
under Pd(PPh3)4 and CuBr catalysis. 77Se NMR resonance
frequencies and 1JC4-Se as well as 1JC4-H coupling constants have
been determined to gain knowledge about the electronic
properties of the anionic N-heterocyclic carbenes. The carbene
carbon atom of the sydnone methide anion 3j resonates at d =
155.2 ppm in 13C NMR spectroscopy at À408C which is
extremely shifted upfield in comparison to classical N-hetero-
cyclic carbenes.
U
ndoubtedly, sydnones are the best known mesoionic
compounds. They are widely applied as masked nitrile imines
[1]
in 1,3-dipolar cycloadditions (“Huisgen reactions” ) which
proceed in a copper-catalyzed,[2] metal-free[3] or metal-free
strain-promoted click fashion[4,5] with sub-millisecond inter-
mediates,[6] as summarized in numerous review articles and
compilations about [2+3]-cycloadditions.[7] Recent develop-
ments include the synergistic combination of organocatalysis
and visible-light photocatalysis of cycloadditions of sydnones
to form pyrazoles.[8] Apart from cycloadditions, sydnones are
versatile precursors for nucleophilic radiofluorination for the
Scheme 1. Some members of the sydnone family of compounds.
Our interest in mesomeric betaines[22] and their relation-
ship to neutral[12a,b, 23,24] as well as anionic N-heterocyclic
carbenes[25] in combination with the introduction of an
energy-based quantitative index of the ease of NHC forma-
tion from precursors by deprotonation (carbene relative
energy of formation, CREF)[26] stimulated initial calculations
which suggested that sydnone methides are interesting
precursors for the generation of unique p-electron-rich
anionic N-heterocyclic carbenes. This index supplements
other measures of s-donor and/or p-properties of NHCs such
as molecular electrostatic potentials (MESP),[27] computa-
tionally derived ligand electronic parameters (CEP),[28] Tol-
man parameters (TEP),[29] HOMO energies,[30,31] calculated
[*] M. Sc. S. Mummel, Dr. F. Lederle, Prof. Dr. E. G. Hübner,
Dr. J. C. Namyslo, Prof. Dr. A. Schmidt
Clausthal University of Technology, Institute of Organic Chemistry
Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld (Germany)
E-mail: schmidt@ioc.tu-clausthal.de
Dr. F. Lederle, Prof. Dr. E. G. Hübner
Fraunhofer Heinrich Hertz Institute HHI, Fiber Optical Sensor
Systems
Am Stollen 19H, D-38640 Goslar (Germany)
1
1
proton affinities,[30,32] JCH and JCSe coupling constants[33] of
precursor salts and Se adducts, respectively, and Huynh
electronic parameters (HEP)[34] of Pd complexes (review[35]).
We calculated the CREF value of sydnone methide 2a to be
0.534 (B3LYP/6-311 ++ G**) which seemed to be a promising
value in comparison to other mesomeric betaines as carbene
precursors like 1,3-dimethylimidazolium-4-olate and its 4-
Dr. M. Nieger
University of Helsinki, Department of Chemistry
P.O. Box 55, FIN-00014 Helsinki (Finland)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202107495.
ꢀ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
aminide,
and
1,3-dimethyl-6-oxo-pyrimidinium-4-olate
(CREFs = 0.576, 0.557, 0.547, resp.).[24,25] We therefore report
here on the syntheses of a series of sydnone methides, their
18882
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conversion into anionic NHCs by deprotonation, and trapping
resonance structures three of which are shown in Scheme 2. It
reactions with sulfur, selenium, C-electrophiles, mercury,
is interesting to note that carbon atom C4 is a site of negative
charge according to the rules of resonance as indicated by
mesomeric structure 2a–lB, although it is a site of deproto-
nation for the formation of anionic N-heterocyclic carbenes.
Correspondingly, the C4 carbon atoms resonate at high field
between d = 108.2 ppm (2j) and 110.9 ppm (2 f) in 13C NMR
spectroscopy. Further DFT calculations predict that the E
isomer of 2e is by DGvac = 4.6 kJmolÀ1 more stable in vacuo
than the corresponding Z isomer and that the rotation barrier
is DEvac = 82.7 kJmolÀ1 (PBE0-d3/ 6-31G**). We also calcu-
lated the solvent dependence. In THF, dichloromethane
(DCM) and DMSO the rotation barriers decrease to
À
gold, and rhodium as well as C C coupling reactions under
Pd0/CuI-catalysis.
We first developed a reliable synthetic method which lead
to a series of sydnone methides 2a–l (Scheme 2, Table 1).
Thus, we started from the sydnones 1a–l which we treated
with Tf2O to obtain a mixture of inseparable bis-sydnone
ethers and sydnone 5-triflates which proved to be very
sensitive towards minute traces of water. Trapping with in situ
generated malodinitrile anions for the synthesis of 2b–d,
methyl 2-cyanoacetate anions for 2e–h, and 2-(methylsulfo-
nyl)acetonitrile anions for the preparation of 2i–l gave the
desired sydnone methides, respectively. These compounds are
stable, brilliant yellow to orange in color and slightly
fluorescent (see Supporting Information for fluorescence
spectra). Sydnone methides can be represented by several
DETHF = 65.8 kJmolÀ1, DEDCM = 65.0 kJmolÀ1, and DEDMSO
=
61.6 kJmolÀ1, respectively (see Supporting Information).
These results are in agreement with the fact that the bonds
C5-C6 of 2e and 2i [crystallographic numbering, Figure 1]
display a considerable double bond character, as determined
by single crystal X-ray analyses. As N2 resonates considerably
more upfield in 15N NMR spectroscopy than N3, the
mesomeric structures 2a-lC can be identified as the most
suitable representation for sydnone methides. In the elemen-
tal cells, the phenyl ring is twisted by À52.65(17)8 (2e) and
À12.74(17)88 (2i) out of the plane of the sydnone rings. As
1
determined by HMBC measurements, the JC4-H coupling
constants of 2a,e,i are 214 Hz, 220 Hz, and 219 Hz, respec-
tively, and these values are between those of 1,3-dimesityli-
midazolium and 1,3-dimesitylimidazolidinium (1JCH = 225 Hz
and 206 Hz) as precursors of normal N-heterocyclic carbenes,
respectively, thus indicating strong s-donor capacities of the
Scheme 2. Syntheses of sydnone methides 2a–l and generation of
anionic N-heterocyclic carbenes 3a–l derived thereof (for substitution
patterns, see Table 1). Selected mesomeric structures A–C. Several Li
species detectable by 7Li NMR due to rapid decomposition of the
anions.
Table 1: Substitution pattern and numbering of the sydnone methides
2a–l
Compd.
Ar
Z
Yield
2a
2b
2c
2d
2e
2 f
2g
2h
2i
Ph
CN
CN
CN
CN
COOMe
COOMe
COOMe
COOMe
SO2Me
SO2Me
SO2Me
SO2Me
53%
38%
28%
33%
61%
65%
71%
17%
63%
37%
12%
9%
4-C6H4Me
4-C6H4OMe
4-C6H4Cl
Ph
4-C6H4Me
4-C6H4OMe
4-C6H4Cl
Ph
Figure 1. Molecular drawing of sydnone methide 2e (above) and 2i
(below) (displacement parameters are drawn at 30% (2e) and 50%
(2i) probability level). Selected bond lengths of 2e [pm] (crystallo-
graphic numbering): N3–C4: 134.12(15), C4-C5: 138.91(15), C5–C6:
139.87(16), C6–C7: 143.83(17), C7–O7: 121.05(15), C9–N9: 114.51-
(18) pm. Selected torsion angles of 2e [8]: N2-N3-C10-C15: 128.96(13),
C4-C5-C6-C7: À1.8(2) 8. Selected bond lengths of 2i [pm]: N3–C4:
135.00(17), C4–C5: 138.10(17), C5–C6: 139.80(18), C6–S7: 172.16(13),
S7–O9: 144.04(10), C11–N12: 115.02(18) pm. Selected torsion angles
of 2i [8]: N2-N3-C13-C18: À12.74(17), C4-C5-C6-S7: 11.6(2) 8.[46]
2j
2k
2l
C6H4Me
4-C6H4OMe
4-C6H4Cl
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corresponding N-heterocyclic carbenes.[33] We next per-
formed a base screening which revealed that deprotonation
of the sydnone methides 2a–l can best be accomplished by
LiHMDS in THF at À108C. According to the rules of
resonance, the resulting anions 3a–l can be represented by
a number of canonical forms, among those the mesomeric
structures of abnormal N-heterocyclic carbenes 3a-lA, as
structures possessing two formal negative charges at C4 3a-lB,
and as normal anionic N-heterocyclic carbenes 3a-lC
(Scheme 2).
Although the anions 3a–l are instable and decompose
rapidly even at low temperatures, we successfully generated
3j quantitatively at À508C and immediately measured NMR
1
spectra at À408C. The H NMR spectra show the absence of
the proton at C4. In the 13C NMR spectra the signal of C4 of
the precursor shifted considerably from 108.2 ppm (2j) to
155.2 ppm (3j). The carbeneꢀs resonance frequency is thus
extremely shifted upfield in comparison to other NHCs. All
chemical shift differences are summarized in Table S2 (Sup-
porting Information). Moreover, the mass of the sydnone
methide anion 3j was confirmed by high resolution electro-
spray ionization mass spectrometry in the anion detection
mode on spraying a cooled in situ prepared sample of 3j. To
gain insight into the electronic properties of the sydnone
methide anions we performed DFT calculations (B3LYP/6-
311 ++ G**). In contrast to 1,3-dimesitylimidazol-2-ylidene
and 1,3-dimesitylimidazolidin-2-ylidene which we chose as
examples, the highest occupied molecular orbitals (HOMOs)
of the sydnone methide carbenes 3a, 3e and 3i are p-orbitals
with significant atomic orbital coefficients on C4 as legacy of
their origin from mesoionic compounds (Figure 2 and Sup-
porting Information). Vice versa, the HOMOs-1 display the
characteristic geometries of N-heterocyclic carbenes. Their
energies are considerably higher than those of the aforemen-
tioned N-heterocyclic carbenes of imidazole, but slightly
lower than those of N-phenylsydnone (Figure 3). Concerning
the substituent effects, the different electron-withdrawing
capacities of the COOMe group (Hammett constants[36] sm =
0.37; sp = 0.45), CN group (sm = 0.56; sp = 0.66) and SO2Me
group (sm = 0.60; sp = 0.72) correlates with the HOMO
energies within the series of sydnone methide anions.
Figure 3. Comparison of selected molecular orbital energies in vacuo
of imidazole-2-ylidene, imidazolidin-2-ylidene (left) and members of
the sydnone family of carbenes (right) which are p-electron-rich N-
heterocyclic carbenes calculated on B3LYP/ 6-311+ +G** level. Pic-
tures of selected orbitals and HOMO/LUMO energies in THF are
presented in the Supporting Information (see Table S1).
Scheme 3. Chemistry of sydnone methide anionic carbenes with sulfur,
selenium, and acyl chlorides, respectively.
nance frequencies of the selenium ethers 5a–c were detected
at d = 86 ppm, 101 ppm and 109 ppm, respectively, and these
values correspond to those measured for Molsidomine [that
is, N-(ethoxycarbonyl)-3-(4-morpholino)sydnone imine; d =
97 ppm].[37] As expected they are considerably more upfield
than those of the selenium ethers of 1,3-dimesitylimidazol-2-
ylidene and its imidazolidine derivative which are cations and
which resonate at d = 199 ppm and 271 ppm, respectively.
Treatment of 3a,e,i with acetyl chloride (R = Me) and benzoyl
chloride (R = Ph) gave 6a–e which slowly reconstitute the
corresponding sydnone methides on exposure to water. The
acetyl derivative of 6 f (Z = SO2Me, R = Me) could not be
isolated as it is unstable under ambient conditions. These
reactions correspond to rare trapping reactions of normal[38,39]
as well as abnormal imidazolylidenes with acyl chlorides.[39]
Mesoionic compounds such as 1,3-dimesitylimidazolium-4-
olates, however, undergo electrophilic heteroaromatic sub-
stitutions to give these structures.[40]
Reaction of the in situ generated anionic sydnone methide
carbenes 3a,e,i with sulfur and selenium gave the thioethers
4a–c and selenium ethers 5a–c after methylation as stable
compounds, respectively (Scheme 3). The 77Se NMR reso-
The reaction of 3e,f with 0,5 equiv of mercury(II)-
chloride lead to the predominant formation of the dimeric
mercury complexes 72(a,b), whereas 3–4 equiv of HgCl2
yielded the monomeric complexes 7a,b from 3b,f.
Figure 2. Calculated frontier orbital profile of the anion of sydnone
methide 3a.
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Chloro(triphenylphosphine)gold(I) converted the sydnone
methide carbenes 3c,f,i into the gold(I) complexes 8a–c as
yellow solids (Scheme 4). We also reacted the sydnone
methide carbenes 3a,f,i with RhCO(PPh3)Cl which resulted
in the formation of the rhodium complexes 9a–c as pale
yellow solids.
À
Scheme 5. Copper-catalysed C C coupling reactions.
X-ray analyses[44,45] of new stable members of the substance
class of syndone methides from which only one single
example had been described in 1984. Deprotonation yielded
sydnone methide anions which can be formulated by a number
of resonance forms, among those mesomeric structures of
anionic N-heterocyclic carbenes. The frontier orbital profile
sets these N-heterocyclic carbenes apart from other examples
of this class of compounds, as their highest occupied
molecular orbitals are p-orbitals with considerable atomic
orbital coefficients on the carbene carbon atom, and ex-
tremely upfield shifted 13C NMR resonance frequencies of the
carbene carbon atom (3j: d = 155.2 ppm). The sydnone
methide anions can be reacted with sulfur and selenium,
respectively, and stabilized by S- and Se-methylation. Reac-
tion with acyl chlorides gave sydnone methide ketones, and
trapping reactions with mercury, gold, and rhodium gave the
corresponding complexes. Finally, we presented a Pd0/CuI-
Scheme 4. Trapping of the sydnone methide anionic carbenes with as
mercury, gold, and rhodium complexes, respectively.
À
catalyzed C C coupling reaction at C4 of the sydnone
Single crystals of the gold complex 8a were subjected to
an X-ray analysis (Figure 4). The results show that complex
formation does not influence the starting mesoionꢀs geometry
(2a) significantly.
methide. Our results supplement the knowledge about the
sydnone family of compounds as well as about anionic N-
heterocyclic carbenes.
À
Concerning C C coupling reactions, treatment of 3a,e,i
with CuBr gave in situ generated, non-isolable copper
compounds, which coupled with 4-fluoro-1-iodobenzene in
the presence of Pd(PPh3)4 in acceptable yields (Scheme 5).
These reactions proceed in analogy to those of sydnones.[41]
In summary, we present the syntheses, spectroscopic
characterizations, results of calculations[42,43] and single crystal
Acknowledgements
The Deutsche Forschungsgemeinschaft (DFG) is acknowl-
edged for financial support. Open access funding enabled and
organized by Projekt DEAL.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: betaines ·carbenes ·heterocycles ·rhodium ·
selenium
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Manuscript received: June 5, 2021
Accepted manuscript online: June 21, 2021
Version of record online: July 14, 2021
Angew. Chem. Int. Ed. 2021, 60, 18882 –18887 ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH www.angewandte.org 18887