Synthesis and cycloaddition chemistry of oxetanyl-substituted sydnones

Article abstract of DOI:10.1016/j.tetlet.2013.03.139

Oxetan-3-one reacts with 4-metallated sydnones to provide functionalised precursors to a variety of novel pyrazoles. Intermolecular cycloadditions were found to proceed in variable yield, but intramolecular cycloadditions were very efficient and provide an effective means to generate spiro-substituted heterocyclic intermediates. The potential of these compounds for further elaboration has been highlighted by cross-coupling reactions.

Full text of DOI:10.1016/j.tetlet.2013.03.139

Tetrahedron Letters 54 (2013) 3094–3096
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Tetrahedron Letters
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Synthesis and cycloaddition chemistry of oxetanyl-substituted sydnones
Anne-Chloé Nassoy a, Piotr Raubo b, Joseph P. A. Harrity a,
⇑
a Department of Chemistry, University of Sheffield, Sheffield S3 7HF, UK
b Research and Development, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 12 April 2013
Oxetan-3-one reacts with 4-metallated sydnones to provide functionalised precursors to a variety of
novel pyrazoles. Intermolecular cycloadditions were found to proceed in variable yield, but intramolec-
ular cycloadditions were very efficient and provide an effective means to generate spiro-substituted het-
erocyclic intermediates. The potential of these compounds for further elaboration has been highlighted
by cross-coupling reactions.
Keywords:
Sydnones
Oxetanes
Cycloadditions
Pyrazoles
Ó 2013 Elsevier Ltd. All rights reserved.
Regioselectivity
Oxetanes have recently received significant interest as struc-
tural units in biologically active molecules as they lend favourable
pharmacological properties whilst contributing little to overall
molecular weight.1 The growing interest in these compounds has
prompted the development of efficient synthetic routes for the
incorporation of oxetanes into a range of molecules.2 In particular,
Carreira, Rogers–Evans and Müller have reported a series of func-
tionalised oxetane cores that are easily elaborated to a diverse
range of structures through C–C/C–X bond forming reactions.
Studies in our laboratories have focused on alkyne cycloaddi-
tion reactions for the synthesis of small molecule scaffolds through
the use of a selection of dienes and dipolar reagents.3 We have
been particularly drawn to the chemistry of sydnones,4 and have
found this class of mesoionic reagents to be especially effective
for the synthesis of a diverse range of pyrazoles.5 We were intri-
gued by the notion of merging sydnone and oxetane chemistry
as we envisaged that it could provide a flexible approach to a vari-
ety of useful heteroaromatic scaffolds by offering the opportunity
to elaborate the mesoionic intermediate via alkylation or cycload-
dition reactions (Fig. 1). We report herein the successful realisation
of this idea and the scope and limitations of this chemistry as a
method for delivering oxetane-substituted pyrazoles.
a convenient access to a small selection of sydnones 2a–c in
acceptable overall yield. The compounds were found to be unstable
to chromatography on silica gel, but were routinely isolated by trit-
uration from EtOH.
With an effective means of generating oxetane-substituted syd-
nones in hand, we wanted to explore the use of these dipolar re-
agents in cycloadditions with
a selection of commercially
available alkynes.7 Our results are summarised in Table 1. Micro-
wave-promoted cycloaddition of 2a with electron deficient alkynes
proceeded rapidly to provide the corresponding products in high
Elaboration via
alkyne cycloaddition
O
O
FG
N
N
R
Functionalisation
O
Early stage incorporation
of N-substituent
Figure 1. Design of oxetanyl-substituted sydnones
We began our studies by developing a convenient and general
approach to oxetane-substituted sydnones. Specifically, we opted
to take advantage of the ready deprotonation of these mesoionic
reagents to form an organometallic intermediate6 that could be
added to commercially available oxetan-3-one. As highlighted in
Scheme 1, the low temperature deprotonation of sydnones 1a–c
with MeMgBr followed by addition of oxetan-3-one proved to offer
1. MeMgBr
THF, -15 o
2.
O
O
O
O
C
OH
N
N
O
N
R
N
R
O
O
1a
2a;
69%
R:R:4-MeOC6H4; 2b; 63%
R:Bn; 2c; 54%
R:Ph;
R:Ph;
R:4-MeOC6H4; 1b
R:Bn; 1c
⁄ Corresponding author. Tel.: +44 114 222 9496.
E-mail address: j.harrity@sheffield.ac.uk (J.P.A. Harrity).
Scheme 1. Synthesis of oxetanyl-substituted sydnones
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.139

A.-C. Nassoy et al. / Tetrahedron Letters 54 (2013) 3094–3096
3095
Table 1
X
X
O
Intermolecular sydnone cycloadditions
xylenes, 140 o
µW, 15-30 min
C
O
N
O
O
R2
R3
R3
R2
N
O
N
N
R
R2
R3
R
O
N
OH
OH
OH
O
N
N
O
µW
N
N
N
R1
R1
R1
2a-2c
O
O
O
X
X
3a-9a
3b-9b
N
O
N
N
O
N
Ph
PMP
Entry
R1
R2
R3
Time
Yield (a:b)d
O
O
1
2
3
4
5
6
7
Ph; 2a
Ph; 2a
Ph; 2a
CO2Me
CO2Et
Ph
Me3Si
CO2Me
CO2Et
CO2Et
CO2Me
5 minb
30 minc
6 hc
3; 92%
X:H; 12; 98%
13;
X:H; 14; 93%
X:Br; 15; 89%
H
H
H
4; 66% (7:1)
5; 51% (>98:2)
6; 17% (>98:2)
7; 60%
8; 44% (5:1)
9; 21% (2:1)
X:Br;
94%
Ph; 2a
3.5 hc
Scheme 3. Intramolecular sydnone cycloadditions
PMP; 2ba
PMP; 2ba
Bn; 2c
CO2Me
20 minb
1 hc
H
H
30 minb
pyrazole products, we decided to carry out the conversion of these
substrates into the corresponding bromoalkynes. We were pleased
to find that this chemistry proceeded quite efficiently to give syd-
nones 11a,b in high yields.
In studying the intramolecular cycloaddition of alkynes 10a,b
and 11a,b, we opted to employ microwave irradiation so as to be
able to make a direct comparison with the reactions shown in Ta-
ble 1. Pleasingly, we found that all substrates formed the corre-
sponding pyrazoles 12–14 in excellent yield and within a short
reaction time (Scheme 3).
The spiro-oxetane intermediates 14 and 15 represent interest-
ing fragments for drug discovery as they have a low molecular
weight, low clogP and nonplanar polar moiety.9 In order to employ
these pyrazoles as fragments however, we recognized the need to
remove the PMP-group to access the free pyrazole. We therefore
investigated the CAN deprotection of 14 and our results are shown
in Scheme 4. The deprotection reaction was surprisingly challeng-
ing and provided an unexpected by-product 17 that appears to de-
rive from oxidation and hydrolysis of the 5-membered heterocycle
ring. The product distribution was found to be dependent on water
concentration, and after significant optimisation we were able to
uncover conditions for the selective synthesis of both pyrazoles, al-
beit in modest yield.
a
b
c
PMP: 4-MeOC6H4.
Reaction conducted in 1,2-Cl2C6H4 at 180 °C.
Reaction conducted in xylenes at 140 °C.
d
Regioselectivities determined by 400 MHz 1H NMR spectroscopy.
yield, and with good regiocontrol in the case of 4a (entries 1 and 2).
In contrast, phenyl- and trimethylsilyl-acetylene were found to be
rather sluggish and afforded the products in significantly lower
yield, but with excellent regioselectivity for isomer a in each case
(entries 3 and 4). PMP-substituted sydnone 2b was found to be less
reactive than 2a and afforded products in reduced yield (entries 5
and 6), however, Bn-substituted sydnone 2c proved to be signifi-
cantly less effective in cycloaddition reactions and appeared to un-
dergo substantial decomposition returning poor yields of pyrazole
products (entry 7).
As only a narrow set of substrates participated adequately in
the key cycloaddition step, we decided to explore the potential of
an intramolecular variant in the hope that improved yields could
be realised. Accordingly, we subjected sydnones 2a–c to propargy-
lation reactions and our results are shown in Scheme 2. In the
event, sydnones 2a,b underwent a smooth base-mediated addition
to propargyl bromide to give alkynes 10a and 10b in good yield.
Once again however, we found Bn-substituted sydnone 2c to be
unstable and the corresponding alkyne 10c could only be isolated
in very low yield from a complex mixture. The instability of 4-
substituted Bn-sydnone 2c in comparison to the N-aryl analogues
is notable and is in line with similar observations made by Padwa
and co-workers.8 Nonetheless, with efficient routes to 10a,b in
hand, and looking ahead to the formation of functionalised
CHO
CAN (3 equiv)
N
O
N
O
N
+
OH
N
N
H
N
PMP
PMP
O
O
O
16
MeCN:H2O (1:5) 42%
MeCN:H2O (5:1) --
17
6%
61%
Scheme 4. CAN oxidation of 14
O
O
O
O
KH, 10 mol% TBAI
OH
O
ArB(OR)2
N
N
Br
N
Ar
, THF
Br
18 19
or
N
R
N
R
5 mol% Pd(PPh3)4
O
O
O
N
O
K3PO4, 90 o
C
2a
10a;
79%
R:4-MeOC6H4; 10b; 75%
R:Bn; 10c; <10%
R:Ph;
R:Ph;
N
N
R
R
H2O, 1,4-dioxane (1:4)
R:4-MeOC6H4; 2b
R:Bn; 2c
O
O
Me
N
PhN
X
X
4-MeC6H4B(OH)2
SiMe3
18
O
O
F3C
O
N
N
O
O
O
O
Me3Si
BPin
CF3
N
O
O
N
N
O
O
N
N
R
Ph
O
PMP
N
R
N
N
Ph
X:H; 10a
X:Br; 11a; 84%
X:H; 10b
11% AgNO3
NBS, acetone
10% AgOAc
NBS, CH2Cl2
R:Ph; 20; 96%
R:PMP; 21; 88%
R:Ph; 22; 94%
R:PMP; 23; 77%
19
X:Br; 11b; 94%
Scheme 2. Synthesis of substrates for intramolecular cycloaddition
Scheme 5. Cross-coupling reactions

3096
A.-C. Nassoy et al. / Tetrahedron Letters 54 (2013) 3094–3096
Vivat, J. F.; Browne, D. L.; Harrity, J. P. A. Org. Biomol. Chem. 2009, 7, 4052; (d)
In addition, we envisaged that 3-bromopyrazoles 13 and 15
Browne, D. L.; Taylor, J. B.; Plant, A.; Harrity, J. P. A. J. Org. Chem. 2009, 74, 396;
(e) Browne, D. L.; Taylor, J. B.; Plant, A.; Harrity, J. P. A. J. Org. Chem. 2010, 75,
984.
would provide a convenient means for conducting Suzuki cross-
coupling reactions. We employed boronic acid 18 and more heavily
substituted pinacol ester 1910 to highlight the scope of this chem-
istry. Pleasingly, both substrates underwent clean and high yield-
ing coupling to provide the corresponding biaryl products
(Scheme 5).
In conclusion, we have shown that oxetane-substituted sydnon-
es offer an effective vehicle for generating a range of pyrazole
intermediates via alkyne cycloaddition processes. In particular,
the intramolecular cycloaddition provides an efficient means of
generating spiro-fused intermediates that have the potential for
exploitation as low molecular weight polar fragments in lead
discovery.11
6. Tien, H.-J.; Fang, G.-M.; Lin, S.-T.; Tien, L.-L. J. Chin. Chem. Soc. 1992, 39, 107.
7. (a) Huisgen, R.; Grashley, R.; Gotthardt, H.; Schmidt, R. Angew. Chem. Int. Ed.
1962, 1, 48; (b) Wu, C.; Fang, Y.; Larock, R. C.; Shi, F. Org. Lett. 2010, 12, 2234; (c)
Delauney, T.; Geux, P.; Es-Sayed, M.; Vors, J.-P.; Monteiro, N.; Balme, G. Org.
Lett. 2010, 12, 3328; (d) Fang, Y.; Wu, C.; Larock, R. C.; Shi, F. J. Org. Chem. 2011,
76, 8840.
8. Padwa, A.; Burgess, E. M.; Gingrich, H. L.; Roush, D. M. J. Org. Chem. 1982, 47,
786.
9. The low molecular weight and lipophilicity of compound 16 offers the
opportunity to incorporate
a range of fragments for lead discovery
(estimated clogP = À1.3; ChemBioDraw Ultra™ version 12.0 Nadin, A.;
Hattotuwagama, C.; Churcher, I. Angew. Chem. Int. Ed. 2012, 51, 1114.
10. Foster, R. S.; Jakobi, H.; Harrity, J. P. A. Org. Lett. 2012, 14, 4858.
11. General procedure for the synthesis of 4-(3-hydroxyoxetan-3-yl)-N-substituted-
sydnones 2:
(1.1 equiv) was added dropwise to
A
3 M solution of methyl magnesium bromide in hexane
solution of sydnone (1 equiv) in
a
1
Acknowledgments
anhydrous THF at À15 °C. After stirring at this temperature for 1 h 3-oxetanone
(1.1 equiv) was added and the resulting mixture was allowed to warm to room
temperature, and left to stir for 5 h. The mixture was quenched by addition of a
saturated aqueous solution of NH4Cl, and the volatiles were removed in vacuo.
The residue was extracted with CH2Cl2 and the combined organic fractions
were dried over MgSO4, and concentrated in vacuo. The resulting oil was then
triturated with EtOH and the product collected by filtration to afford the title
compound 2. 4-(3-Hydroxyoxetan-3-yl)-3-phenyl-3H-1,2,3-oxadiazol-1-ium-5-
olate (2a): Following the general procedure using N-phenylsydnone (1a)
(1.00 g, 6.17 mmol) in THF (10 mL), the product 2a was isolated as a yellow
solid (1.01 g, 69%). Mp 126–128 °C; 1H NMR (400 MHz, CDCl3) d 7.88–7.84 (m,
2H, ArH), 7.76–7.70 (m, 1H, ArH), 7.69–7.63 (m, 2H, ArH), 4.90 (s, 1H, OH), 4.75
(d, J = 7.5 Hz, 2H, CH2), 4.61 (d, J = 7.5 Hz, 2H, CH2); 13C NMR (101 MHz, CDCl3)
d 167.2, 134.4, 132.9, 130.2, 124.1, 108.5, 80.6, 67.8; FTIR: 3289 (br), 2950 (w),
2882 (w), 1721 (s), 1476 (m), 1267 (m), 1187 (m), 1140 (w), 1156 (w), 1018
(m), 982 (m), 773 (m), 690 (m); HRMS: m/z [MH]+ calcd for C11H11N2O4:
235.0719, found: 235.0709. 4-(3-Hydroxyoxetan-3-yl)-3-(4-methoxyphenyl)-
3H-1,2,3-oxadiazol-1-ium-5-olate (2b): Following the general procedure with
N-p-methoxyphenylsydnone (1b) (2.07 g, 10.75 mmol) in THF (20 mL), the
product 2b was isolated as a beige solid (1.80 g, 63%). Mp 126–128 °C; 1H NMR
(400 MHz, CDCl3) d 7.78 (d, J = 9.0 Hz, 2H, ArH), 7.10 (d, J = 9.0 Hz, 2H, ArH),
4.86 (s, 1H, OH), 4.77 (d, J = 7.5 Hz, 2H, CH2), 4.62 (d, J = 7.5 Hz, 2H, CH2), 3.93
(s, 3H, CH3); 13C NMR (101 MHz, CDCl3) d 167.2, 162.7, 127.0, 125.5, 115.2,
108.3, 80.7, 67.8, 55.8; FTIR: 3343 (m), 2878 (w), 1721 (s), 1606 (m), 1512 (s),
1469 (m), 1306 (w), 1256 (s), 1173 (m), 1115 (w), 1021 (m), 982 (m), 837 (m);
HRMS: m/z [MH]+ calcd for C12H13N2O5: 265.0824, found: 265.0819. 3-Benzyl-
4-(3-hydroxyoxetan-3-yl)-3H-1,2,3-oxadiazol-1-ium-5-olate (2c): Following the
general procedure with N-benzylsydnone (1c) (0.300 g, 1.70 mmol) in THF
(5 mL), the product 2c was isolated as a beige solid (0.228 g, 54%). Mp 82–
84 °C; 1H NMR (400 MHz, CDCl3) d 7.47–7.37 (m, 3H, ArH), 7.33 (d, J = 3.5 Hz,
2H, ArH), 5.60 (s, 2H, CH2), 4.93–4.63 (m, 3H, CH2 and OH), 4.40 (d, J = 6.0 Hz,
2H, CH2); 13C NMR (101 MHz, CDCl3) d 167.2, 130.4, 130.0, 129.4, 128.2, 106.1,
80.8, 69.2, 56.5; FTIR: 3317 (m), 2955 (w), 2881 (w), 1724 (s), 1495 (m), 1456
(m), 1328 (w), 1185 (m), 980 (m), 868 (w), 737 (m), 700 (m); HRMS: m/z [MH]+
calcd for C12H13N2O4:249.0864, found: 249.0875.
We are grateful to AstraZeneca and the University of Sheffield
for financial support. We also thank Robert Foster for providing a
sample of boronate ester 19.
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