Aerobic synthesis of N-sulfonylamidines mediated by N-heterocyclic carbene copper(I) catalysts

Article abstract of DOI:10.3762/bjoc.16.43

A new catalytic strategy for the one-pot synthesis of N-sulfonylamidines is described. The cationic copper(I) complexes were found to be highly active and efficient under mild conditions in air and in the absence of solvent. A copper acetylide is proposed as key intermediate in this transformation.

Full text of DOI:10.3762/bjoc.16.43

Aerobic synthesis of N-sulfonylamidines mediated by
N-heterocyclic carbene copper(I) catalysts
Faïma Lazreg1, Marie Vasseur1, Alexandra M. Z. Slawin1 and Catherine S. J. Cazin*2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 482–491.
1School of Chemistry, University of St Andrews, St Andrews, KY16
9ST, UK and 2Centre for Sustainable Chemistry and Department of
Chemistry, Ghent University, Krijgslaan 281-S3, 9000 Ghent, Belgium
doi:10.3762/bjoc.16.43
Received: 13 December 2019
Accepted: 04 March 2020
Published: 24 March 2020
Email:
Catherine S. J. Cazin* - catherine.cazin@ugent.be
This article is part of the thematic issue "Copper-catalyzed reactions for
organic synthesis".
* Corresponding author
Keywords:
Guest Editor: G. Evano
catalysis; copper; copper catalysis; N-heterocyclic carbene;
solvent-free; sulfonylamidines
© 2020 Lazreg et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A new catalytic strategy for the one-pot synthesis of N-sulfonylamidines is described. The cationic copper(I) complexes were found
to be highly active and efficient under mild conditions in air and in the absence of solvent. A copper acetylide is proposed as key
intermediate in this transformation.
Introduction
Amide derivatives represent a ubiquitous molecular construct in ever, the presence of additives and high catalyst loading (CuI
chemistry [1-3]. This structural motif favours rearrangements 10 mol %) were required for the synthesis of N-sulfonylimi-
that lead to high reactivity and associated bioactivity [4,5]. dates (Scheme 1, left).
Indeed, the presence of an N-atom in the amidine structure leads
to opportunities as ligands and organocatalysts [6-8]. Over the last two decades, NHCs (NHC = N-heterocyclic
N-Sulfonylamidines and N-sulfonylimidates are members of a carbene) have become ligands of choice to permit the stabilisa-
specific class of these amidines. One initial methodology de- tion and formation of highly reactive transition metal species
veloped for the formation of sulfonylamidines was based on the [14]. Thus, significant advances have been achieved using this
cleavage of the bond between the N-4 and C-benzene in thiadi- supporting ligand family [15-19]. Recently, our group contrib-
azine ring-type molecules [9]. To date, only few examples of uted to this area, reporting on the synthesis of the first
copper-based catalysts have been reported to enable access to heteroleptic bis-NHC and mixed NHC/phosphine copper(I)
such compounds [10-13]. Chang and co-workers were pioneers complexes [20-22]. Interestingly, these new copper-based com-
in this area [10-12]. A three-component reaction between plexes have shown excellent activity in the [3 + 2] cycloaddi-
alkyne, sulfonyl azide and amine/alcohol was described as a tion reaction of azides/sulfonyl azides and alkynes (Scheme 1,
synthetic route to generate sulfonyltriazole intermediates. How- right) [22]. Based on these earlier results, the reactivity of these
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Beilstein J. Org. Chem. 2020, 16, 482–491.
Scheme 1: Formation of sulfonyltriazoles and sulfonamidines.
catalysts was investigated in the context of achieving formation [Cu(IPr)(Pyr)]OTf (4) was obtained by the reaction of the iso-
of the challenging sulfonamide derivatives.
lated hydroxide derivative [Cu(IPr)(OH)] [29] with pyridinium
trifluoromethanesulfonate, while the biscarbene complexes 5
Herein, we report the high efficiency of cationic copper(I) com- and 6 were obtained from the corresponding [Cu(NHC)Cl]
plexes for the formation of N-sulfonylamidines via a three-com- through the in situ formation of the corresponding hydroxide
ponent reaction performed in air, using solvent-free conditions complex [Cu(NHC)(OH)] [20] which deprotonates the tri-
and in the absence of any additive.
azolium salt (Scheme 2).
Results and Discussion
The reactivity of a series of cationic copper(I) complexes (1–6)
[Cu(ICy)2]BF4 (1), [Cu(IPr)(ICy)]BF4 (2) and [Cu(IPr)(Pt- was evaluated at 0.5 mol % loading using tosyl azide, phenyl-
Bu3)]BF4 (3) were initially selected as optimum candidates acetylene and diisopropylamine as benchmark substrates
[22]. This class of catalysts was expanded through the synthe- [31,32]. Various solvents were evaluated at room temperature
sis of the pyridine derivative 4, of the heteroleptic normal/ under aerobic conditions (see Supporting Information File 1 for
mesoionic carbene complex 5, and of the homoleptic mesoionic details). Tetrahydrofuran (THF), 1,2-DCE, 1,4-dioxane and
triazole derivative 6 (Figure 1). This special class of ligands acetonitrile proved to be the most suitable solvents for this
presents unique electronic and steric properties and lead to transformation (Table 1). Interestingly, similar results were ob-
unusual reactivity [23-28].
tained for complexes 1–5, while 6 displayed superior activity.
Figure 1: Catalytic systems used in this study.
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Beilstein J. Org. Chem. 2020, 16, 482–491.
Scheme 2: Synthetic access to complexes 4–6 [30].
Table 1: Catalyst and solvent optimisation.a,b
Entry
Complex
Solvent
Conv.c (%)
1
2
3
4
5
6
7
8
1
2
3
4
5
6
6
6
6
6
1
2
5
THF
THF
THF
THF
THF
THF
neat
1,2-DCE
water
1,4-dioxane
neat
neat
neat
49
47
42
42
46
71
65
63
41
58
30
58
55
9
10
11
12
13
aReaction conditions: phenylacetylene (0.5 mmol), tosyl azide (0.6 mmol), diisopropylamine (0.6 mmol), [Cu] (0.5 mol %), solvent (1 mL), 16 hours.
bSee Supporting Information File 1 for full optimisation. cConversion was determined by GC analysis based on phenylacetylene using mesitylene
(42 µL) as internal standard.
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Indeed, 71% conversion to the desired product was observed 10a–g). The presence of an activating/deactivating group in
using the homoleptic cationic MIC (mesoionic carbene) com- para-position of the aryl ring was evaluated in order to assess
plex 6 (Table 1, entry 6). For complexes 1–5, the conversion the substrate tolerance. Electron-donating groups, such as
proved modest and ranged between 42 and 49% (Table 1, methyl, methoxy or naphthyl enhanced considerably the reac-
entries 1–5).
tivity leading to quantitative conversion with respectively 96%
(10a), 95% (10c) and 93% (10g) isolated yields, in reaction
Subsequently, solvent-free conditions were investigated times of 3 to 4.5 hours. Regarding the 2,4,6-triisopropylsul-
(Table 1, entries 7 and 11–13). Interestingly, the absence fonyl azide, a slight decrease in the reactivity was observed
of solvent proved to be highly effective, except for (66%, 10f), presumably due to the steric hindrance of the sub-
[Cu(ICy)2]BF4 1 (Table 1 entry 11). An encouraging 65% strate. Electron-withdrawing groups such as bromo (10d) or
conversion was obtained using [Cu(Triaz)2]BF4 6 (Table 1, cyano (10e) appeared to disfavour the reaction resulting in
entry 7), while complexes 2 and 5 showed comparable results lower yields. Indeed for the cyanosulfonyl azide, under solvent-
(Table 1, entries 12 and 13). Complex 6 was also shown free conditions, only 38% of the desired product was obtained
to be active in water and in 1,4-dioxane. Based on these after 24 hours. This lower yield could also be due to the starting
results, a reaction scope was conducted under solvent-free material being a solid which leads to poorer mixing and mass
conditions, in air, using 1 mol % of [Cu(Triaz)2]BF4 6 transport issues. Interestingly, when conducted in THF, an
(Scheme 3).
increase to 68% isolated yield was observed after 4 hours, sup-
porting our inhomogeneity/transport hypothesis. In the case of
Functionalised azides were reacted with phenylacetylene and the bromosulfonyl azide, a 73% conversion was obtained after
diisopropylamine resulting in good to high yields (Scheme 3, 4 hours at 40 °C.
Scheme 3: Variation of sulfonylazides. Reaction conditions: phenylacetylene (0.5 mmol), sulfonyl azide (0.6 mmol), diisopropylamine (0.6 mmol), 6
(1 mol %). Conversion determined by 1H NMR based on alkyne using mesitylene (42 µL) as internal standard. Isolated yield in parentheses. aSolvent-
free conditions, rt. bSolvent-free conditions, 40 °C. cTHF (1 mL), rt.
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Beilstein J. Org. Chem. 2020, 16, 482–491.
Various terminal aryl/alkyl-substituted alkynes were investigat- and/or the use of THF as reaction solvent. Interestingly, ortho-
ed in the presence of tosyl azide and diisopropylamine and meta-substitution of the aryl rings are well tolerated
(Scheme 4). Under standard conditions, good to excellent yields (11e–i). In the case of 9-ethynylphenanthrene, which is a solid
were obtained. The presence of functional groups in para-posi- substrate, solvent-free conditions lead to 78% isolated yield at
tion of the aryl ring leads to a decrease of the conversion to 40 °C. Diynes were also investigated and excellent isolated
approximately 50% (11a, 11b, 11c and 11d). The reactivity was yields were achieved (92% and 85% for 11j and 11k, respec-
considerably enhanced by increasing the temperature to 40 °C tively). Regarding the alkyl-alkynes, longer reactions times as
Scheme 4: Variation of alkynes. Reaction conditions: alkyne (0.5 mmol), tosyl azide (0.6 mmol), diisopropylamine (0.6 mmol), 6 (1 mol %). Conver-
sion determined by 1H NMR based on alkyne using mesitylene (42 µL) as internal standard. Isolated yield in parenthesis. aSolvent-free conditions, rt.
bSolvent-free conditions, 40 °C. cTHF (1 mL), rt.
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Beilstein J. Org. Chem. 2020, 16, 482–491.
well as higher temperature were required to reach high conver- ative [33], resulting from a [3 + 2] cycloaddition of azide and
sion. Interestingly, in the case of 11r, the desired product was alkyne (Scheme 6).
obtained in 67% isolated yield.
The catalytic system was also shown applicable to phosphoryl
The effect of the amines was also investigated. Amongst the azides; and reaction of phenylacetylene with diisopropylamine
amines evaluated, dicyclohexylamine (for 12a) and isopropyl- and diphenylphosphoryl azide leads to the formation of the cor-
amine (for 12b) lead to good isolated yields (64% and 72%, responding phosphorylamidine product [34] in good yield
Scheme 5). In contrast, with diphenylamine, only 20% of the (Scheme 7), using 2 mol % of catalyst under mild conditions
desired product was observed (12c).
(solvent-free, room temperature).
Interestingly, with benzyl azide, a substrate not containing a A proposed reaction mechanism occurring via formation of a
sulfonyl moiety, the product obtained is the 1,2,3-triazole deriv- copper-acetylide species is proposed and illustrated in
Scheme 5: Variation of the amine substrate. Reaction conditions: phenylacetylene (0.5 mmol), tosyl azide (0.6 mmol), amine (0.6 mmol), 6 (1 mol %).
Conversion determined by 1H NMR based on alkyne using mesitylene (42 µL) as internal standard. Isolated yield in parenthesis. aSolvent-free condi-
tions, 40 °C. bTHF (1 mL), rt.
Scheme 6: Reactivity of “non-sulfonyl” azide [33]. Reaction conditions: phenylacetylene (0.5 mmol), benzyl azide (0.6 mmol), diisopropylamine
(0.6 mmol), 24 h.
Scheme 7: Reactivity of diphenylphosphoryl azide. Reaction conditions: phenylacetylene (0.5 mmol), diphenylphosphoryl azide (0.6 mmol), diiso-
propylamine (0.6 mmol), [Cu] (2 mol %), 24 h. Conversion determined by GC based on phenylacetylene using mesitylene (42 µL) as internal stan-
dard. Isolated yield in parentheses.
487

Beilstein J. Org. Chem. 2020, 16, 482–491.
Scheme 8. The bis-NHC copper(I) complex 6 reacts with the tion of A, [Cu(Triaz)Cl] was reacted with phenylacetylene and
alkyne leading to the formation of an acetylide derivative A sodium hydroxide (4 equiv), in toluene for 24 hours under an
(left hand side, Scheme 8), with concomitant loss of a NHC inert atmosphere. The independent synthesis of A was success-
ligand through the formation of the corresponding triazolium fully achieved in this manner (Scheme 10). The latter was then
salt B. The intermediate A can then react with the azide sub- reacted with tosyl azide. An immediate colour change resulted
strate to form a triazolyl–copper complex C. The latter can and based on 1H NMR data, two new species were formed.
liberate the amidine product and regenerate either catalyst 6 (tri- They were identified as the sulfonyltriazole and an unstable
azolium salt B is source of proton) or directly the acetylide organometallic compound, presumably the triazolylcopper(I)
complex A (phenylacetylene is source of proton).
complex C. These results corroborated the proposed hypothesis
regarding the formation of a triazole intermediate during the
In order to support this mechanism, a number of stoichiometric catalytic cycle.
reactions were conducted (see Supporting Information File 1).
In a first instance, 6 was reacted with phenylacetylene at room To support the relevance of the Cu-acetylide species in cataly-
temperature. This led to the rapid formation of the copper sis, the benchmark reaction was conducted at 1 mol % catalyst
acetylide complex A with concomitant loss of the triazolium of the isolated acetylide complex (Scheme 11). After
salt Triaz.HBF4 (B, Scheme 9). To further confirm the forma- 45 minutes, 80% conversion into the sulfonamidine product was
Scheme 8: Proposed mechanism for the formation of sulfonamidine.
Scheme 9: Stoichiometric reaction between 6 and 8.
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Beilstein J. Org. Chem. 2020, 16, 482–491.
Scheme 10: Synthesis of copper-acetylide intermediate A via [Cu(Cl)(Triaz)].
Scheme 11: Catalytic reaction involving copper-acetylide complex A.
observed. Of note, the presence of sulfonyltriazole was also ob- CD2Cl2, 298 K, TMS) δ (ppm) 23.5 (s, CHCH3 (Triaz)), 24.8
served (10%).
(s, CHCH3 (Triaz)), 28.8 (s, 2 CHCH3 (Triaz)), 124.4 (s,
CArH), 124.5 (s, CArH), 131.0 (s, CArH), 134.2 (s, CArH), 140.8
(s, CIV), 145.8 (s, CH (IPr)), 148.9 (s, CIV), 177.5 (s, Ccarbene);
19F{1H} NMR (282 MHz, CDCl3, 298 K) δ (ppm) −78.6 (s);
anal. calcd for C33H41CuF3N3O3S: C, 58.26; H, 6.07; N, 6.18;
found: C, 58.39; H, 6.16; N, 6.08.
Conclusion
Cationic bis-carbene copper(I) complexes were shown to
promote the formation of N-sulfonamidines in a Click reaction
[35,36]. The new developed mesoionic NHC copper(I) com-
plexes were found highly efficient under solvent-free and
aerobic conditions. Stoichiometric reactions support the release 1-{2,6-(Diisopropyl)phenyl}-3-methyl-4-(4-tert-butylphenyl)-
of one NHC and the formation of a copper(I) acetylide as key 1,2,3-triazol-5-ylidene-(N,N’-bis{2,6-(diisopropyl)-
elements in the catalytic cycle.
phenyl}imidazol-2-ylidene)copper(I) tetrafluoroborate,
[Cu(IPr)(Triaz)]BF4 (5). In a glovebox, a microwave vial was
charged with [Cu(Cl)(IPr)] (200.0 mg, 0.41 mmol), NaOH
Experimental
N,N’-Bis{2,6-(diisopropyl)phenyl}imidazol-2-ylidene(pyri- (66.0 mg, 4 equiv, 1.64 mmol), Triaz.HBF4 (190.0 mg, 1 equiv,
dine)copper(I) triflate, [Cu(IPr)(Pyr)]OTf (4). In a glovebox, 0.41 mmol) and acetonitrile (2 mL). The reaction mixture was
a vial was charged with [Cu(OH)(IPr)] (200 mg, 0.41 mmol), stirred during 2 h at 80 °C in a microwave. The solution was
pyridinium trifluoromethanesulfonate (94.0 mg, 1 equiv, concentrated and diethyl ether (10 mL) was added. The precipi-
0.41 mmol) and THF (2 mL). The reaction mixture was stirred tate was collected by filtration and washed with diethyl ether
at room temperature for 15 hours. The solution was concen- (3 × 5 mL). The desired compound was obtained as a colour-
trated and diethyl ether (10 mL) was added. The precipitate was less solid (346 mg, 92%). 1H NMR (400 MHz, CD2Cl2, 298 K)
collected by filtration and washed with diethyl ether (3 × 5 mL). δ (ppm) 0.77 (d, 3JHH = 6.9 Hz, 6H, CHCH3 (Triaz)), 0.82 (d,
The desired compound was obtained as a colourless solid 3JHH = 6.9 Hz, 12H, CHCH3 (IPr)), 0.96 (d, 3JHH = 6.9 Hz, 6H,
(201 mg, 92%). 1H NMR (400 MHz, CD2Cl2, 298 K) δ (ppm) CHCH3 (Triaz)), 1.01 (d, 3JHH = 6.9 Hz, 12H, CHCH3 (IPr)),
0.82 (d, 3JHH = 6.9 Hz, 12H, CHCH3 (IPr)), 1.01 (d, 3JHH = 1.44 (s, 9H, C(CH3)3) 1.99 (septet, 3JHH = 6.9 Hz, 2H, CHCH3
6.9 Hz, 12H, CHCH3 (IPr)), 1.44 (s, 9H, C(CH3)3), 2.36 (septet, (Triaz)), 2.36 (septet, 3JHH = 6.9 Hz, 4H, CHCH3 (IPr)), 3.98
3JHH = 6.9 Hz, 4H, CHCH3 (IPr)), 3.98 (s, 3H, CH3), 7.06 (s, (s, 3H, CH3), 6.98 (d, 3JHH = 8.3 Hz, 2H, CArH (Triaz)), 7.06
2H, H4 and H5), 7.19 (d, 3JHH = 7.8 Hz, 4H, CArH (IPr)), 7.50 (s, 2H, H4 and H5), 7.10 (d, 3JHH = 7.9 Hz, 2H, CArH (Triaz)),
(t, 3JHH = 7.8 Hz, 2H, CArH (IPr)); 13C{1H} NMR (100 MHz, 7.19 (d, 3JHH = 7.8 Hz, 4H, CArH (IPr)), 7.36 (d, 3JHH =
489

Beilstein J. Org. Chem. 2020, 16, 482–491.
8.4 Hz, 2H, CArH (Triaz)), 7.43 (t, 3JHH = 7.9 Hz, 1H, CArH
(Triaz)), 7.50 (t, 3JHH = 7.8 Hz, 2H, CArH (IPr)); 13C{1H}
NMR (75 MHz, CD2Cl2, 298 K) δ (ppm) 23.4 (s, CHCH3
(Triaz)), 24.8 (s, CHCH3 (IPr)), 24.4 (s, CHCH3 (IPr)), 24.7 (s,
CHCH3 (Triaz)), 28.4 (s, CHCH3 (Triaz)), 28.6 (s, CHCH3
(IPr)), 31.3 (s, CCH3), 35.0 (s, CIV), 37.6 (s, CH3), 123.4 (s,
CIV), 123.9 (s, CArH), 124.2 (s, C4 and C5), 124.4 (s, CArH),
126.6 (s, CArH), 129.4 (s, CArH), 130.5 (s, CArH), 130.9 (s,
CArH), 134.3 (s, CIV), 144.8 (s, CIV), 145.2 (s, CIV), 152.0 (s,
CIV), 152.8 (s, CIV), 179.4 (s, Ccarbene); 19F{1H} NMR
(282 MHz, CDCl3, 298 K) δ (ppm) −155.0 (s, BF4), −155.1 (s,
BF4); anal. calcd for C52H69BCuF4N5: C, 68.30; H, 7.61; N,
7.66; found: C, 68.15; H, 7.72; N, 7.68.
Supporting Information
Supporting Information File 1
Experimental and characterisation data.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-43-S1.pdf]
Supporting Information File 2
Crystal data for 4.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-43-S2.cif]
Supporting Information File 3
Crystal data for 5.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-43-S3.cif]
Bis{1-{2,6-(diisopropyl)phenyl}-3-methyl-4-(4-tert-
butylphenyl)-1,2,3-triazol-5-ylidene}copper(I) tetrafluoro-
borate, [Cu(Triaz)2]BF4 (6). In a glovebox, a vial was charged
with [Cu(Cl)(Triaz)] (150.0 mg, 0.32 mmol), NaOH (50 mg,
4 equiv, 1.28 mmol), Triaz.HBF4 (148 mg, 1 equiv, 0.32 mmol)
and acetonitrile (2 mL). The reaction mixture was stirred during
2 h at 80 °C in a microwave. The solution was concentrated
(0.5 mL) and diethyl ether (10 mL) was added. The precipitate
was collected by filtration and washed with diethyl ether
Supporting Information File 4
Crystal data for 6.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-43-S4.cif]
(3 × 5 mL). The desired compound was obtained as a colour- Acknowledgements
less solid (281 mg, 97%). 1H NMR (400 MHz, CDCl3, 298 K, The authors gratefully acknowledge the ESPRC National Mass
TMS) δ (ppm) 0.79 (d, 3JHH = 6.8 Hz, 12H, CHCH3 (IPr)), 1.08 Spectroscopy Facilities for the HMRS analysis at the Univer-
(d, 3JHH = 6.8 Hz, 12H, CHCH3 (IPr)), 1.38 (s, 18H, C(CH3)3), sity of Swansea.
2.10 (septet, 3JHH = 6.8 Hz, 4H, CHCH3 (IPr)), 4.20 (s, 6H,
ORCID® iDs
CH3), 7.19 (d, 3JHH = 7.8 Hz, 4H, CArH (IPr)), 7.34 (m, 8H,
CArH), 7.49 (t, 3JHH = 7.7 Hz, 2H, CArH (IPr)); 13C{1H} NMR
(75 MHz, CDCl3, 298 K, TMS) δ (ppm) 23.8 (s, CHCH3
Alexandra M. Z. Slawin - https://orcid.org/0000-0002-9527-6418
Catherine S. J. Cazin - https://orcid.org/0000-0002-9094-8131
(Triaz)), 24.2 (s, CHCH3 (Triaz)), 28.4 (s, CHCH3 (Triaz)),
References
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