Regioselectivity studies of sydnone cycloaddition reactions of azine-substituted alkynes

Article abstract of DOI:10.1016/j.tetlet.2011.01.115

The synthesis of azine-substituted pyrazoles by a sydnone cycloaddition strategy is described. Incorporation of a 3-pyridyl moiety at the sydnone N-atom has little effect on either reactivity or regioselectivity, however, 2-ethynyl-pyridine and -pyrimidin

Full text of DOI:10.1016/j.tetlet.2011.01.115

Tetrahedron Letters 52 (2011) 1506–1508
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselectivity studies of sydnone cycloaddition reactions
of azine-substituted alkynes
Robert S. Foster a, Harald Jakobi b, Joseph P. A. Harrity a,
⇑
a Department of Chemistry, University of Sheffield, Sheffield S3 7HF, UK
b Bayer CropScience Aktiengesellschaft, BCS AG-R-DIS, 65926 Frankfurt, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of azine-substituted pyrazoles by a sydnone cycloaddition strategy is described. Incorpora-
tion of a 3-pyridyl moiety at the sydnone N-atom has little effect on either reactivity or regioselectivity,
however, 2-ethynyl-pyridine and -pyrimidine undergo cycloaddition with surprisingly poor levels of reg-
iocontrol. A rationale for the observed regiochemical trends and potential routes for improving selectiv-
ities are discussed.
Received 9 December 2010
Revised 19 January 2011
Accepted 25 January 2011
Available online 1 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Sydnones
Cycloadditions
Pyrazoles
Regioselectivity
Azine-substituted pyrazoles represent a common and versatile
class of heteroaromatic systems in organic chemistry. They have
been investigated for their biological properties both with respect
to the development of agrochemicals1 and therapeutic agents.2
Moreover, they are a common class of ligands for the preparation
of self-assembling co-ordination networks.3 Some examples are
illustrated in Figure 1. The cycloaddition reaction of alkynes with
sydnones provides a convenient and direct method for accessing
highly substituted pyrazoles,4 although this route has not been
extensively studied in connection with generating azine-substi-
tuted pyrazoles.5 Nonetheless, we anticipated that sydnone cyc-
loadditions would provide an attractive method for the synthesis
of a range of pyrazoles bearing N-heteroaromatic substituents,
and report herein our findings.
A very narrow range of N-azine-substituted sydnones have been
reported in the literature, and these have been based on N-2-pyri-
dyl 16 and N-3-pyridyl 27 substituted analogues (Fig. 2). In our
hands, we were readily able to prepare the latter sydnone, how-
ever, we were unable to generate the 2-pyridyl isomer 1. Our expe-
rience mirrors that of Ohta et al. who reported difficulties in
promoting the N-nitrosation step.6b Nonetheless, the literature
procedure provided sufficient quantities of 2 to be made available
and allowed us to study the suitability of this sydnone for N-pyr-
idylpyrazole formation. In this regard, recent studies in our labora-
tories have focused on the cycloaddition of sydnones with
alkynylboronates for the synthesis of pyrazole boronic acid deriv-
O
N
N
R2
Cl
Me
N
HO
R1
N
N
N
NR2
N
O
Herbicides and plant
growth regulators
CCR1 Receptor
antagonists
N
N
O
O
N
N
N
R
N
R
Ligands for
self-assembling
co-ordination networks
N
Figure 1.
O
O
O
N
O
N
N
N
1
2
N
N
⇑
Corresponding author. Tel.: +44 114 222 9496; fax: +44 114 222 9346.
E-mail address: j.harrity@shef.ac.uk (J.P.A. Harrity).
Figure 2.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.115

R. S. Foster et al. / Tetrahedron Letters 52 (2011) 1506–1508
1507
Table 1
found that the reactions again proceeded efficiently, but with sur-
prisingly lower levels of regiocontrol [Eq. 2]. Finally, we employed
2-ethynylpyrimidine in these cycloaddition reactions and once
again found this process to deliver an almost equal mixture of 3-
and 4-azine-substituted pyrazoles [Eq. 3].10
Our earlier work on DFT investigations of the cycloaddition of
sydnones and alkynylboronates8b allows us to put forward an
explanation for the contrasting regioselectivities observed in the
cycloadditions of phenylacetylene and 2-ethynyl-pyridine and
-pyrimidine (Scheme 2). Specifically, ab initio studies suggest that
arylacetylenic boronates prefer to react via the orbital that is per-
R
B
PinB
R
R
BPin
O
O
N
N
N
reflux
16 h
N
N
N
+
O
O
N
N
N
2
3-6
7a-10a
7b-10b
pendicular to the aromatic
p-system, accordingly, the transition
state leading to the minor 4-arylpyrazole regioisomer is disfa-
voured by destabilizing steric interactions between the ortho-aryl
proton and the sydnone C4 H-atom (I). Assuming a similar transi-
tion state for the cycloaddition of simple arylacetylenes, this model
accounts for the high levels of regiocontrol in the formation of
3-phenylpyrazoles 12 and 13. Moreover, as azineacetylenes can
avoid such an interaction (II), one would expect a smaller differ-
ence in the activation energies of the two competing regiochemical
modes. In order to gather some evidence for this, we prepared a
2-ethynylpyridinium salt that we envisaged would be isosteric
with phenylacetylene. Indeed, the cycloaddition of this alkyne with
11 proceeded with high levels of regioselectivity, albeit in low
yield.11,12
These studies raised the question as to whether or not useful
levels of regiocontrol could be observed in the cycloaddition reac-
tions of sydnones with azine-substituted alkynes. In this context,
we have shown that the incorporation of substituents at the
sydnone C4-position, together with the incorporation of a p-nitro-
phenyl group at nitrogen results in optimal yields and regioselec-
tivities in alkyne cycloaddition reactions.8a,8b,13 Therefore, we
decided to employ sydnones 18 and 19 in the cycloaddition of
2-ethynyl-pyridine and -pyrimidine to establish whether more
synthetically useful levels of regiocontrol could be achieved, our
results are highlighted in Scheme 3. Pleasingly, heating an
o-dichlorobenzene solution of 2-ethynylpyridine with sydnones
18 and 19 provided the corresponding pyrazoles 20 and 21 in high
yield and with useful levels of regiocontrol. Moreover, this trend
could be extended to 2-ethynylpyrimidine, providing the pyrazole
22 in high yield as a 7:2 mixture of regioisomers. Finally, we could
exploit the apparent low steric volume of the azine ring to carry
out a regioselective cycloaddition of unsymmetrical disubstituted
alkyne 23. In the event, pyrazoles 24a,b were generated in high
yield and with good selectivity for 24a.
Entry
R
Solvent
Yield (a:b)
1
2
3
4
Ph; 3
Xylenes
Xylenes
Mesitylene
Mesitylene
7; 60% (>98:2)
8; 70% (1.3:1)
9; 56% (2.5:1)
10; 84% (1:8)
Me3Si; 4
Bun; 5
H; 6
atives,8 largely because of the associated versatility of the boronate
motif.9 Accordingly, we investigated the potential of this strategy
for the synthesis of N-azine-substituted pyrazole boronic esters
and our results are highlighted in Table 1. The cycloaddition of 2
with a selection of alkynylboronates proved to be successful, pro-
viding the corresponding pyrazoles 7–10 in moderate to high yield.
The reactions were generally found to be regioselective for the 4-
boronate isomer (entries 1–3), with the exception of the terminal
alkyne which gave high selectivity for the 3-boronate (entry 4).
The selectivities in all cases mirrored those observed for N-phenyl
derived sydnones (as well as substituted phenyl derivatives), pro-
viding further evidence that the sydnone N-moiety has little effect
on the reaction regiocontrol.8
We next turned to the investigation of the cycloadditions of
azine-substituted alkynes with sydnones to demonstrate their po-
tential for the synthesis of 3- and/or 4-substituted pyrazoles
(Scheme 1). The cycloaddition of phenylacetylene with sydnones
11 and 2 proceeded in good yield and with high levels of regiocon-
trol for the 3-phenylpyrazole isomers of 12 and 13, respectively
[Eq. 1]. Upon extending this chemistry to 2-ethynylpyridine, we
O
Ph Ph
+
Ph
O
1,2-Cl2C6H4
(1)
µw, 200 oC, 2 h
N
N
N
N
N
N
In conclusion, we have demonstrated that alkyne/sydnone
cycloaddition reactions provide a direct and convenient method
to prepare a range of azine-substituted pyrazoles.14,15 These stud-
ies also provide further evidence that the high regioselectivities
observed in the reactions of arylalkynes originate from a preferred
trajectory of addition where the aryl ring lies perpendicular to the
plane of the sydnone.
Ar
Ar
Ar
Ar: Ph (11)
Ar: 3-Py (2)
Ar: Ph (12); 66% (10:1)
Ar: 3-Py (13); 84% (8:1)
N
O
O
N
N
1,2-Cl2C6H4
(2)
+
N
N
µw, 200 oC, 2 h
N
N
N
N
PinB
O N
NPh
(I)
O N
NPh
(II)
Ar
Ar
Ar
Ar: Ph (11)
Ar: 3-Py (2)
Ar: Ph (14); 85% (3:2)
Ar: 3-Py (15); 80% (2:1)
O
O
H
H
H
N
o
1.5A
N
N
N
O
O
N
N
N
1,2-Cl2C6H4
µw, 200 oC, 2 h
O
N
NH
(3)
+
N
N
N
N
O
OTs
N
N
N
N
Ar
Ar
Ar
ethylene glycol
N
N
Ph
Ph
Ar: Ph (11)
Ar: 3-Py (2)
Ar: Ph (16); 86% (3:2)
Ar: 3-Py (17); 84% (3:2)
reflux, 16 h;
3 (aq)
11
14; 14%; 10:1
NaHCO
Scheme 1.
Scheme 2.

1508
R. S. Foster et al. / Tetrahedron Letters 52 (2011) 1506–1508
Haeuser-Hahn, I.; Kehne, H.; Rosinger, C. H. WO 2009152995, 2009; Chem.
O
Abstr. 2009, 152, 57307.
N
O
2. Zhang, P.; Pennell, A. M. K.; Chen, W.; Greenman, K. L.; Sullivan, E. J.; Li, L. WO
2007044885; Chem. Abstr. 2007, 146, 421980.
N
N
N
R
3. Fenton, H.; Tidmarsh, I. S.; Ward, M. D. Dalton Trans. 2010, 39, 3805.
4. Browne, D. L.; Harrity, J. P. A. Tetrahedron 2010, 66, 553.
5. Huisgen, R.; Gotthardt, H.; Grashey, R. Chem. Ber. 1968, 101, 536.
6. (a) Chadra, T.; Bhati, S. K.; Yadav, P.; Agarwal, R. C.; Agarwal, T. P.; Kumar, A.
Orient. J. Chem. 2008, 24, 229; (b) Ohta, M.; Masaki, M. Bull. Chem. Soc. Jpn. 1960,
33, 1392.
N
+
1,2-Cl2C6H4
N
N
R
R
N
N
reflux, 20 h
PNP
PNP
R: Me (20); 87% (4:1)
R: iPr (21); 78% (6:1)
NO2
7. Tien, J. M.; Hunsberger, I. M. J. Am. Chem. Soc. 1955, 77, 6604.
8. (a) Browne, D. L.; Helm, M. D.; Plant, A.; Harrity, J. P. A. Angew. Chem., Int. Ed.
2007, 46, 8656; (b) Browne, D. L.; Vivat, J. F.; Plant, A.; Gomez-Bengoa, E.;
Harrity, J. P. A. J. Am. Chem. Soc. 2009, 131, 7762; (c) Foster, R. S.; Huang, J.;
Vivat, J. F.; Browne, D. L.; Harrity, J. P. A. Org. Biomol. Chem. 2009, 7, 4052.
9. Boronic Acids; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2005.
10. The reactions were run under microwave irradiation for convenience;
however, reactions conducted in refluxing xylenes over 16 h gave similar
yields and identical regioisomer ratios.
11. Sydnones are known to be acid sensitive, and as 11 was completely consumed
in this reaction, we attribute the low yield to the decomposition of this
compound.
12. Subjecting a 2:1 mixture of pyrazole regioisomers 14 to TsOH in refluxing
ethylene glycol over 16 h did not result in a change of regioisomer ratios. This
experiment confirms that the selectivity observed in the cycloaddition of
ethynylpyridinium and 11 is not the result of selective decomposition of a 3-
substituted pyrazole isomer.
13. Browne, D. L.; Taylor, J. B.; Plant, A.; Harrity, J. P. A. J. Org. Chem. 2010, 75, 984.
14. Cycloaddition regioselectivities were estimated using 1H NMR spectroscopy
and GC–MS techniques. Regiochemical assignments were made on the basis of
diagnostic 1H NMR shift patterns,8,13 and confirmed in the case of compound
24 by NOE spectroscopy. Regiosiomer ratios were estimated on crude reaction
mixtures and confirmed by chromatographic separation in the case of
compounds 12, 16, 17, 22 and 24.
R: Me; (18)
R: iPr; (19)
O
O
N
N
N
N
N
iPr
N
N
N
+
1,2-Cl2C6H4
iPr
iPr
N
N
N
N
reflux, 20 h
PNP
PNP
19
22a; 66%
22b; 19%
NO2
O
O
N
N
N
SiMe
3
Me3Si
SiMe3
N
N
N
N
23
1,2-Cl2C6H4
µw, 200 oC, 2 h
N
+
N
N
Ph
N
N
11
Ph
24a; 55%
Ph
24b; 9%
15. Representative experimental procedure and spectroscopic data for 14: A solution
of N-phenylsydnone (11) (81 mg, 0.5 mmol) and 2-pyridylacetylene (103 mg,
1 mmol) in o-dichlorobenzene was added to a microwave vial. The vial was
sealed and placed in a CEM Discover SP Microwave Reactor and heated at
200 °C for 2 h, before the volatiles were removed in vacuo. Compound 14 was
purified by column chromatography on silica gel (30:70 EtOAc/petroleum
ether) and the product isolated as a brown solid (94 mg, 85%; 3:2 regioisomeric
mixture). 1H NMR (400 MHz, CDCl3): d 8.69–8.67 (m, 0.6H), 8.63–8.61 (m,
0.4H), 8.55 (s, 0.4H), 8.21 (s, 0.4H), 8.16–8.14 (m, 0.6H), 8.01 (d, J = 2.5 Hz.,
0.6H), 7.82–7.69 (m, 3H), 7.58–7.56 (m, 0.4H), 7.52–7.48 (m, 2H), 7.36–7.31
(m, 1H), 7.26–7.24 (m, 0.6H), 7.19–7.15 (m, 1H); 13C NMR (63 MHz, CDCl3): d
153.2, 152.0, 151.4, 149.7, 149.4, 140.2, 139.9, 139.2, 136.8, 136.6, 129.5, 129.4,
129.0, 128.3, 126.8, 126.6, 125.3, 122.7, 121.5, 120.3, 119.8, 119.3, 119.2,
106.5; FTIR: 3050 (w), 2919 (w), 1741 (w), 1594 (s), 1567 (w), 1503 (s), 1459
(m), 1412 (m), 1370 (m), 1267 (m), 1050 (w), 962 (m), 756 (s) cmÀ1; HRMS:
m/z [M+H]+ calcd for C14H12N3: 222.1031, found: 222.1031.
Scheme 3. PNP = 4-O2NC6H4.
Acknowledgements
We are grateful to Bayer CropScience and the University of
Sheffield for financial support.
References and notes
1. (a) Lamberth, C. Heterocycles 2007, 71, 1467; (b) Jakobi, H.; Ort, O.; Hills, M.;
Kehne, H.; Rosinger, C.; Feucht, D. WO2008080504; Chem. Abstr. 2008, 149,
121249.; (c) Jakobi, H.; Martelletti, A.; Tiebes, J.; Dittgen, J.; Feucht, D.;