Synthesis of aminopyrazoles from sydnones and ynamides

Article abstract of DOI:10.1039/c6ob02518h

Aminopyrazoles are prepared from readily accessible sydnones and sulfonyl ynamides using either a copper-mediated sydnone alkyne cycloaddition (CuSAC) or in situ generated strained cyclic ynamides.

Full text of DOI:10.1039/c6ob02518h

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Synthesis of aminopyrazoles from sydnones and
ynamides†
Cite this: DOI: 10.1039/c6ob02518h
T. Wezeman,a J. Comas-Barceló,b M. Nieger,c J. P. A. Harrityb and S. Bräse*a,d
Received 17th November 2016,
Accepted 16th January 2017
DOI: 10.1039/c6ob02518h
www.rsc.org/obc
Aminopyrazoles are prepared from readily accessible sydnones and amidative cross-coupling processes.35–43 The sydnones could
sulfonyl ynamides using either a copper-mediated sydnone alkyne be accessed via a two-step procedure consisting of the nitrosa-
cycloaddition (CuSAC) or in situ generated strained cyclic tion and cyclodehydration of N-arylglycines, as extensively
ynamides.
reported in the literature.1 Further functionalisation of the C4
position of the sydnone scaffold was achieved by Pd-catalysed
direct arylation44 or lithiation followed by quenching with elec-
trophiles, affording a range of 4-substituted sydnones with
different properties.
Sydnones are considered to be one of the most popular
members of the family of meso-ionic heteroaromatic
compounds.1–6 They are known to participate as 1,3-dipoles in
cycloaddition reactions, particularly with alkynes, as Huisgen
described in the 1960s.7,8 These cycloadditions tend to give
better results when electron-deficient dienophiles are used,
usually require high reaction temperatures and long reaction
times, and the regioselectivity of the pyrazole products is often
substrate-dependent.1 Previously reported attempts to try to
address these issues include the use of alkynylboronates9,10 or
copper promoters to direct the regioselectivity of the sydnone–
alkyne cycloaddition reactions.11–13 Due to the high interest
towards new routes to fully functionalised pyrazoles, which are
known to possess biological activities,14,15 we were interested
in expanding the scope of the sydnone–alkyne cycloaddition
reaction to increase the tolerance for activated and electron-
rich alkynes. To do so, we developed the synthesis of 4-amino-
pyrazoles from cycloaddition reactions between sydnones and
ynamides, which have not been reported to date.15–32
In order to improve the performance of the cycloaddition
reactions between sydnones and alkynes, different strategies
have been reported in the literature in the past few years. A
popular approach is the use of Lewis acids, since via coordi-
nation to the sydnone, the reaction is favoured and the regio-
selectivity of the pyrazole products can be affected.12,45 The
use of copper promoters has also been shown to affect regio-
selectivity and facilitate the cycloaddition reaction, commonly
referred to as a Cu-mediated Sydnone Alkyne Cycloaddition
(CuSAC).11,13 Based on these reports, we decided to undertake
a screening of readily available copper catalysts and study their
effect on the cycloaddition between ynamides and sydnones.
Although it is known that terminal sulfonyl ynamides are
water sensitive, this was not a major concern during previous
studies on metal-free systems, as the desired reactions out-
paced any side-reactions.34 However, during our copper cata-
lyst screen, we found that the presence of the copper promo-
ters facilitated the hydrolysis of the terminal sulfonyl ynamide
1a to sulfonyl amide 2 (Scheme 1).
First we proceeded with the preparation of the sulfonyl
ynamides via the dichloroenamide approach reported by
Anderson and co-workers,33 which allowed a convenient large
scale synthesis of the ynamide substrates.34 Alternative
popular synthetic routes to ynamides include copper-catalysed
The addition of copper(II) acetate to the ynamide-based
CuSAC was expected to result in the facile formation of 1,4-
pyrazole 4, but only trace amounts of pyrazole products
could be identified by LCMS, together with large quantities of
aInstitute of Organic Chemistry (IOC), Karlsruhe Institute of Technology (KIT),
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany. E-mail: braese@kit.edu
bDepartment of Chemistry, The University of Sheffield, Brook Hill, Sheffield, S3 7HF,
UK. E-mail: j.harrity@sheffield.ac.uk
cDepartment of Chemistry, University of Helsinki, Finland
dInstitute of Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT),
Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
†Electronic supplementary information (ESI) available. CCDC 1484278 (4a) and
1484279 (6). For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c6ob02518h
Scheme 1 Hydrolysis of the sulfonyl ynamide substrates.
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Table 1 Catalyst screening
Entry
R
[Cu] source
Time
Temp [°C]
Resulte
a
1
2
3
4
5
6
7
8
9
10
Cu(OAc)2 b
3–16 h
15 min
3 days
16 h
16 h
16 h
16 h
16 h
16 h
16 h
100–140
RT
60–100
80
100
80
100
100
80
100
Traces 3/4, mostly 2
Only 2
Traces 3/4, mostly 2
2 : 1 mix of 4 : 2
Traces 3/4
Traces 3/4
Degradation
Traces 3/4
Cu(OTf)2
CuIc
CuSO4·5H2Od
a
Cu(OAc)2
CuSO4·5H2Od
b
Cu(OTf)2
Cu(OAc)2
a
CuSO4·5H2Od
Traces 3/4
Degradation
b
Cu(OTf)2
a 0.2 equiv. of Cu(OAc)2, 0.2 M in o-DCB. b 1.0 equiv. of Cu(OTf)2, 0.2 M in o-DCB. c 0.2 equiv. of CuI, 0.2 equiv. 1,10-phenanthroline, 1.0 equiv.
Et3N, 0.1 M in DMF, activated 4 Å molecular sieves. d 0.2 equiv. of CuSO4·5·H2O, 0.2 equiv. 1,10-phenanthroline, 2.0 equiv. of Na-ascorbate, 1.0
equiv. Et3N, 0.1 M in tBuOH : H2O (1 : 1). e The isolation of trace amounts of pyrazole products did not allow for determination of obtained regio-
isomer, e.g. 3 or 4.
unreacted sydnone and hydrolysed ynamide 2 (Table 1, entry lack of formation of key Cu(I) acetylides. Attempts to use
1). Both the anhydrous and the monohydrate salt of copper(II) copper(II) triflate, that was previously reported to activate the
acetate were found to degrade the ynamide. Even more surpris- sydnone, resulted in the degradation of the internal ynamides,
ing results were obtained when copper(II) triflate was added to likely due to the elevated temperatures required (Table 1,
the terminal sulfonyl ynamide 1a. Where the copper(II) acetate entries 7 and 10).
reaction took several hours at elevated temperatures to hydro-
Next we decided to investigate the scope of the CuSAC reac-
lyse the ynamide, the copper(II) triflate-promoted degradation tion in terms of suitable sydnones (Scheme 2). Using the term-
of the ynamide was complete in several minutes at room temp- inal sulfonyl ynamide 1a and the copper(II) sulphate method a
erature (Table 1, entry 2). In a futile attempt to prevent hydro- variety of sydnones were screened. To our delight all the C4-
lysis, we decided to perform the reaction under strict an- unsubstituted 3-arylsydnones we had in hand reacted readily,
hydrous conditions by adding activated molecular sieves and resulting in the isolation of 4-aminopyrazoles in a moderate
using dry copper(I) iodide (Table 1, entry 3). We found that yields (Scheme 2), but regioselective manner, as confirmed by
under these conditions the amide formation was reduced, but 1H and 13C NMR as well as with X-ray crystallographic analysis
the desired reaction still yielded mere traces of product, even (Fig. 1). However, it appears that the ynamide CuSAC reaction
when elevated temperatures and prolonged reaction times is limited to C4-unsubstituted sydnones, as all attempts to use
were employed.
C4-substituted sydnones failed.
Satisfactorily, when the copper(II) sulphate-mediated
click chemistry-like conditions reported by Taran11,12 were
attempted (Table 1, entry 4), we were pleased to see full conver-
sion of the ynamide and the formation of a 2 : 1 mixture of pyr-
azole and sulfonyl amide. Fortunately, isolation of the desired
pyrazole product could be achieved by simple recrystallisation
from hot methanol.
Due to the high sensitivity of terminal sulfonyl ynamides
towards the copper-promoted hydrolysis, we decided to explore
the use of two internal ynamides: 1b (R = Me) and 1c (R =
CO2Et). As these are more stable, treatment of 1b and 1c with
copper(II) acetate or copper(II) sulphate did not lead to degra-
dation (Table 1, entries 5 & 6 and 8 & 9). However, only traces
of the desired pyrazoles could be detected, likely due to the Scheme 2 Cycloaddition between sydnones and terminal ynamide 1a.
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ditions with sodium bromide and oxone47 also proved to be
unsuccessful and unreacted starting material was recovered.
In pursuit of reaction conditions that could tolerate C4-
substituted sydnones and thus would allow access to a wider
substrate scope, we decided to perform the reaction under
copper-free conditions. Inspired by the strain-promoted alkyne
azide cycloaddition (SPAAC),48–52 which is well-known for its
efficacy despite its lack of copper, we set out to investigate the
synthesis of strained cyclic ynamides as recently conceptualised
by Danheiser et al.53 Additionally, it was recently shown that
sydnones are suitable substrates for strain-promoted cycloaddi-
tions.54 In four steps the N-tosyl-azacyclohexyne precursor 10
can be prepared with relative ease following Danheiser’s work
(Scheme 4). Subsequently the strained cyclic ynamide 11 can be
generated in situ by addition of caesium fluoride, a procedure
best known from the preparation of arynes.55–63
To our delight, the strain-promoted sydnone ynamide cyclo-
addition tolerated a wide range of substitutions on the C4
position of the sydnone, as shown in Scheme 4. Reaction
optimization revealed that slight excess of the sydnone pro-
vided best results, since when activated ynamides were used in
excess, complex reaction mixtures were obtained, presumably
due to side reactions.
Fig. 1 Molecular structure of 4-aminopyrazoles 4a (left) and 6 (right).
Displacement parameters are drawn at 50% probability level, in 6 the
minor disordered part is omitted for clarity.
In order to increase the synthetic versatility for the
4-amino-pyrazoles, the removal of the tosyl and benzyl groups
was investigated (Scheme 3). It was found that, although the
tosyl group could be removed in moderate yield using potas-
sium diphenyl-phosphanide,46 the benzyl group was surpris-
ingly resistant to hydrogenation. Even when a pressure of
10 bar of hydrogen was applied, no conversion was observed.
Attempts to remove the benzyl group using oxidative con-
Although in most cases complete conversion was reached
after a few hours, the regioselective outcome of the reactions
turned out to be rather inconsistent. Initial results showed
that 4-unsubstituted sydnones favour the 4,3-disubstituted
product 20a–27a (Scheme 4). However, when 4-aryl-substituted
sydnones were employed, no clear preference was observed
over the product ratio. Interestingly, from these preliminary
results it seemed that C-4 amide substituted sydnones
tend to produce the 3,4-regio-isomer 20b–27b preferentially.
Scheme 3 Successful removal of the N-tosyl group.
Scheme 4 Scope for the strained ynamide-sydnone cycloaddition process. For clarity, only the “a” isomer is shown.
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Additional experiments, molecular modelling and DFT calcu- 21 J. Kempson, Knorr pyrazole synthesis, in Name Reactions in
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under investigation.
Heterocyclic Chemistry II, John Wiley & Sons, Inc., 2011.
22 S. Kumari, S. Paliwal and R. Chauhan, Synth. Commun.,
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In conclusion, we successfully achieved the synthesis of
(fused) amino-substituted pyrazole scaffolds by means of 23 G. Molteni, ARKIVOC, 2007, 224–246.
cycloaddition reactions between sydnones and ynamides, 24 R. J. Mullins, Pechmann pyrazole synthesis, in Name
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CCDC 1484278 (4a), and 1484279 (6) contain the supple-
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25 S. Rajappa, Heterocycles, 1977, 7, 507–527.
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