Mechanosynthesis of sydnone-containing coordination complexes

Article abstract of DOI:10.1039/c9cc04673a

N-Phenyl-4-(2-pyridinyl) sydnone was shown to act as a four-electron donor N,O-ligand in unprecedented coordination complexes featuring three different metallic centers (Co, Cu, and Zn). Starting with various anilines, the use of a ball-mill efficiently enabled the synthesis of N-arylglycines, subsequent nitrosylation and cyclization into sydnones, and further metalation.

Full text of DOI:10.1039/c9cc04673a

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Mechanosynthesis of Sydnone-containing Coordination
Complexes
Received 00th January 20xx,
Accepted 00th January 20xx
Nicolas Pétry,a Thibaut Vanderbeeken,a Astrid Malher,a Yoan Bringer,a Pascal Retailleau,b Xavier
Bantreila and Frédéric Lamaty a,*
DOI: 10.1039/x0xx00000x
www.rsc.org/
N-Phenyl-4-(2-pyridinyl) sydnone was shown to act as a four-
electron donor N,O-ligand in unprecedented coordination
complexes featuring three different metallic centers (Co, Cu, Zn).
Starting from various anilines, the use of ball-mill enabled
efficiently the synthesis of N-arylglycines, subsequent
nitrosylation and cyclization into sydnone, and further metalation.
Known structures
O
N
N
O
O
N
O
N
N
O
N
PR2
O
Cl
R
Pd
MeO
[Pd]
N
N
PPh2
S
Ph2P
Pd
Cl
NHPh
Cl
1
Sydnones, mesoionic heterocyclic compounds, are versatile
building blocks for heterocyclic chemistry, for example in the
formation of pyrazoles through copper-catalyzed 1,3-dipolar
cycloaddition.1 They also display interesting biological
activities, e.g., as antibacterial, antineoplastic and anti-
inflammatory agents.2 Sydnone synthesis from α-amino acids
involves a nitrosylation step, using sodium nitrite in highly
acidic media or isoamyl nitrite,3 and subsequent cyclization
using acetic or trifluoroacetic anhydride (TFAA).4 In 2014, Shih
et al. showed that palladium complexes featuring a sydnone-4-
carbaldehyde N(4)-phenylthiosemicarbazone ligand exhibited
higher anticancer activities than 5-fluorouracil (Figure 1).5 To
date, this is the only reported example in which the exocyclic
oxygen of the sydnone is shown to coordinate a metal. Indeed,
in the literature, sydnones have been modified as phosphine
ligands for palladium complexation (Figure 1),6 directly
metalated at C4,7 through deprotonation or carbon-halogen
insertion, or modified at N3 with a 3-pyridine for iron
coordination.8 In this context, we wondered if the presence of
a 2-pyridine at C4 would enable the access to unprecedented
coordination structures featuring sydnones as N,O-ligands.9
Given our expertise in mechanochemistry for organic and
2
O
5
N
O
N
3
R
4
This work
O
N
O
O
O
N
N
N
H
R
[M]
O
N
NH2
R
OH
R
N
R
• Novel structures • Reagentless mechanosynthesis
•
Figure 1. Coordination complexes featuring sydnone–based polydentate ligands
During our study, we realized that accessing sydnone
precursors could also benefit from mechanochemistry in terms
of reaction time and yield. N-arylglycines were thus prepared
via solvent-free mechanochemistry, using a 15 mL Teflon jar
(filled with one 1 cm diameter stainless steel ball) agitated at
25 – 30 Hz in a vibratory ball-mill (Scheme 1), through either
alkylation of substituted anilines with ethylbromoacetate and
subsequent saponification (one-pot two-step, Method A) or
reductive amination involving glyoxylic acid and sodium
cyanoborohydride (Method B). N-arylglycines featuring in para
position electron-donating groups such as methyl (1b) or
methoxy (1c) could be isolated in 95% and 80% yield over the
two steps, respectively, using method A. When a bromine
atom was either in meta or para position, method A was also
found efficient, giving corresponding glycines in 85% (1h) and
76% (1d) yield, respectively. Mesitylamine, even though
extremely sterically hindered reacted using method A to
furnish the expected glycine 1i in 37% yield. Even if modest,
this yield is four-fold higher than the 10% yield reported in
literature.12 When using anilines bearing electron-withdrawing
groups such as NO2, CF3 or CN, method B was found more
organometallic synthesis,10 we envisioned
a solvent-free
mechanochemical approach11 for an efficient access to
sydnones and to unprecedented coordination complexes.
a. Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université
de Montpellier, ENSCM, Campus Triolet, Place Eugène Bataillon, 34095
Montpellier cedex 5, France. E-Mail: frederic.lamaty@umontpellier.fr
b. Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-
Saclay, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Electronic Supplementary Information (ESI) available: Synthetic procedures,
characterization of compounds, crystallographic data and copies of 1H and 13C
NMR and IR spectra. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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case come from the amine and acid functions of 1a.
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DOI: 10.1039/C9CC04673A
Gratifyingly, milling 1a and NaNO2 in stoichiometric quantity
for 5 min resulted in full conversion of 1a into N-nitroso-N-
phenylglycinate. Subsequent addition of TFAA to the crude
mixture and milling for 30 min yielded sydnone 2a in 54% yield
(Table 1, entry 2). Increasing the milling time of the second
step to 1 h enabled an excellent 95% yield (Table 1, entry 3).
Notably, changing the stoichiometry of TFAA did not improve
the final yield (Table 1, entries 4 and 5).
Milling conditions were then applied to N-arylglycines 1a-i
(Scheme 2). Reaction time and milling frequency were
modulated to obtain in each case fast and full conversion,
which enabled the avoidance of chromatography on silica gel.
In all cases, total reaction time did not exceed 120 min with
yields comparable to those obtained in solution.13 Sydnones
featuring methyl (2b) and methoxy (2c) groups in para position
of the phenyl moiety were produced in 91% and 54% yield,
respectively. With a bromine atom either in para or meta
position, corresponding sydnones 2d and 2h could be obtained
in 91% and 81% yield, respectively. Sydnones 2e-g, featuring
NO2, CN and CF3 electron-withdrawing groups were isolated in
lower yields of 34 – 46%. Even though full conversion was
reached, a recrystallization step (for 2e-f) or a chromatography
on silica gel (only for 2g) that reduced the final yield was
required to furnish pure compounds. The same remark applies
to sydnone 2i, featuring sterically hindered mesityl group,
which was yielded in 53%. To the best of our knowledge, it is
the first time that sydnone 2i is synthesized and fully
characterized.15, 7f
Scheme 1. Mechanosynthesis of N-arylglycines 1a-i
efficient, giving corresponding products in 53-74% yield (1e-g).
In all the cases, yields obtained using the mechanochemical
approaches were similar if not better compared to literature
conditions in solution.13 In addition, reaction time was limited
to 2 – 3 h, and a simple extraction/precipitation procedure was
required to isolate pure compounds.
Using N-phenylglycine 1a as model substrate, the synthesis of
corresponding sydnone in a mechanochemical one-pot two-
step approach was next investigated. Recently, the Taran
group developed a one-pot procedure using tert-butyl nitrite
and TFAA under solvent-free conditions and magnetic stirring,
but sydnones were not isolated and directly engaged in a
cycloaddition step.14 Under mechanochemical activation,
tBuONO was found to be efficient and nitrosylation was
complete within 5 min, as confirmed by HPLC analysis (Table 1,
entry 1). Addition of trifluoroacetic anhydride (2.5 equiv.) to
the reaction mixture in the same jar furnished sydnone 2a in
51% yield. Even though this method is sodium nitrite and acid
free, tBuONO has to be prepared from tert-butanol using these
reagents. We reasoned that sodium nitrite, without the
addition of concentrated HCl, could furnish the nitrosylated
intermediate. Indeed, the two hydrogen atoms necessary for
water release in the nitrosylation mechanism would in this
The introduction of a pyridine at C4 of the sydnone was next
performed to obtain
a putative bidendate ligand. N-
Phenylsydnone 2a was reacted with 2-bromopyridine in the
presence of Pd(PPh3)4 or Pd(OAc)2/XPhos as catalytic systems
according to literature methods.16 However, yields obtained
were not reproducible and separation of XPhos ligand revealed
complicated. Although other palladium-catalysed cross-
couplings were successful in the ball-mill,17 attempts to
perform the coupling reaction with 2a under
mechanochemical conditions failed. A quick study showed that
this coupling could be performed using Pd(OAc)2/PPh3 (1:2) in
DMC (dimethylcarbonate), an environmentally friendly
solvent, giving corresponding 3-phenyl-4-(2-pyridine)sydnone
3a in 55% yield, with a facilitated purification (Scheme 3).
Table 1. Optimization of the reaction conditions of sydnone mechanosynthesisa
Entry
NO source
(equiv.)
TFAA (equiv.)
t2 (min)
Yield 2a (%)
1
2
3
4
5
tBuONO (1.2)
NaNO2 (1.0)
NaNO2 (1.0)
NaNO2 (1.0)
NaNO2 (1.0)
2.5
2.5
2.5
2
30
30
60
60
60
51
54
95
77
92
3
a
Total mass of the reagents was calculated to obtain a milling load (ML) of 20
mg.mL-1. Reactions were performed in a vbm at 25 Hz.
Scheme 2. Mechanochemical synthesis of N-arylsydnones 2a-i
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X-ray structures, the pyridine and sydnone rinVgieswwArteicrleeOnnlionet
DOI: 10.1039/C9CC04673A
found in the same plane and a twist of 22 – 35° was observed
in the complexes. This non-planarity was also witnessed in the
X-ray structure of 3a.13 Such observation tends to indicate that
pyridine and sydnone rings may not be conjugated.
Additionally, the exocyclic C-O bond was measured at 1.21 –
1.24 Å, which is consistent with a double bond character.
Bidentate sydnone 3a may thus act as a four-electron rather
than a three-electron donor ligand.
In conclusion, the use of ball mills enabled the efficient
reagent-less preparation of a series of N-aryl glycines and of
corresponding sydnones. N-Phenyl-4-(2-pyridinyl) sydnone 3a
was used for the first time as ligand to coordinate metals,
leading to unprecedented compounds via a mechanochemical
solvent-free approach. Such results pave the way for the
development of novel families of coordination complexes.
Conflicts of interest
There are no conflicts to declare.
Scheme 3. Synthesis of coordination complexes with sydnone 3a as N,O-ligand
Bidentate compound 3a was then reacted, using a vibratory
ball-mill, with various metallic salts (CoCl2, CuCl2, Cu(OTf)2 and
ZnCl2) under solvent-free conditions. We were pleased to
observe that after 1h of milling corresponding complexes were
obtained in yields of 66-74%. Conversion was followed in the
solid state using IR spectroscopy, as the C=O stretching band in
3a (ν = 1757 cm-1) shifts to lower wave numbers upon
coordination (ν = 1660 – 1726 cm-1). The structure of the
complexes [Co(µ-Cl)(3a)2]2.COCl4, [CuCl2(3a)2], [Cu(OTf)2(3a)2]
and [ZnCl2(3a)] were confirmed by single crystal X-ray
diffraction after crystallisation (Figure 2).13 Interestingly, cobalt
complex possesses a dimeric structure with two sydnone
ligands on each metallic center, and bridging chloride atoms.
This kind of arrangement was rarely observed in literature with
bidentate N,O ligands.18 For copper containing species, an
octahedral geometry with two sydnone ligands and with a
trans-arrangement between the two chloride (or triflate)
ligands was observed. On the other hand, reaction with zinc(II)
chloride provided the complex with only one sydnone ligand
and a tetrahedral geometry. In all the
Acknowledgements
This work was funded by the University of Montpellier, CNRS
and the French Government through the program
‘‘Investissements d’Avenir” ANR-10-LABX-05-01 managed by
Agence Nationale pour la Recherche (TV). We thank Quentin
Garnier for his contribution to the design of the graphical
abstract.
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DOI: 10.1039/C9CC04673A
Mechanochemistry provides a powerful approach to the multistep synthesis of novel
coordination complexes, featuring sydnones as ligands, starting with N-arylglycines.