[1,3]Oxazolo[3,2-b][1,2,4]triazoles: a versatile synthesis of a novel heterocycle

Article abstract of DOI:10.1016/j.tetlet.2010.05.100

An efficient one-pot microwave approach for the synthesis of novel [1,3]oxazolo[3,2-b][1,2,4]triazoles is described.

Full text of DOI:10.1016/j.tetlet.2010.05.100

Tetrahedron Letters 51 (2010) 3907–3909
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
[1,3]Oxazolo[3,2-b][1,2,4]triazoles: a versatile synthesis of a novel heterocycle
*
Catherine Ball, David K. Dean , Olivier Lorthioir, Lee W. Page, Charlotte L. Smith, Stephen P. Watson
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot microwave approach for the synthesis of novel [1,3]oxazolo[3,2-b][1,2,4]triazoles is
Received 6 April 2010
Revised 30 April 2010
Accepted 21 May 2010
Available online 26 May 2010
described.
Ó 2010 Elsevier Ltd. All rights reserved.
The synthesis of novel heterocycles is of ongoing interest to the
medicinal chemistry and pharmaceutical communities because
heterocycles are ubiquitous in drugs and biologically active mole-
cules. Indeed, a recent review by Pitt et al. at UCB1 highlighted the
large number of potential heterocycles that have to be yet exempli-
fied. In our laboratories we recently had need to prepare
compounds based on the hitherto unprecedented [1,3]oxazol-
o[3,2-b][1,2,4]triazole heterocyclic system for one of our drug
discovery programmes. Herein, we describe an expedient and
versatile one-pot synthesis of the novel [1,3]oxazolo[3,2-b]
[1,2,4]triazole template 1 from 3,5-dibromo-1,2,4-triazole (2).
strategy outlined in Scheme 2. The residual bromine atom could
then be removed (having functioned as a ‘dummy atom’) or
used for further functionalisation as appropriate. Furthermore,
N
R
Br
N
R
O
O
N
N
R2
N
N
R2
R1
R1
1
6
Hal
R2
R1
N
N
N
O
N
R
Br
4
Br
Br
O
R
R2
N
R
Br
O
N
N
N
N
N
N
N
H
R1
H
R2
R1
1
2
3
5
Scheme 1. [1,3]oxazolo[3,2-b][1,2,4]triazoles—retrosynthesis.
In designing
a
synthetic approach, we anticipated that
[1,3]oxazolo[3,2-b][1,2,4]triazoles 1 could be constructed by way
of a tandem alkylation-displacement reaction of 3-bromo-1,2,4-tri-
azoles 3 and a-haloketones 4, via intermediate enolate 6 (Scheme 1).
Hal
R2
R1
N
Br
Br
Whilst alkylation of 1,2,4-triazoles typically occurs at N-1(2) rather
than N-4, reflecting the higher nucleophilicity of N–N systems,2 the
envisaged synthetic scheme also required triazole alkylation on the
N-1(2) nitrogen atom adjacent to the bromine atom. However,
dependent on the nature of the other ring substituent, alkylation
of triazoles 3 could occur predominantly (or exclusively) at the
nitrogen remote from the bromine atom, which would preclude
cyclisation. We consequently reasoned that the use of symmetrical
3,5-dibromo-1,2,4-triazole (2) would overcome such regiochemi-
4
N
O
Br
Br
O
N
N
N
N
(i)
R2
H
R1
2
7
N
N
Br
Br
Br
O
O
N
N
R2
N
N
cal difficulties, by forcing alkylation adjacent to
atom and allowing subsequent cyclisation, to afford the overall
a bromine
R2
R1
R1
8
9
* Corresponding author. Tel.: +44 1279 627687; fax: +44 1279 622260.
E-mail addresses: david.k.dean@gsk.com, deandandr@aol.com (D.K. Dean).
Scheme 2. Reagents and conditions: (i) Base (see Table 1), 100 °C, microwave,
10–20 min.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.100

3908
C. Ball et al. / Tetrahedron Letters 51 (2010) 3907–3909
nucleophilic substitution is fast at the 5-position of 1-alkyl-1H-
[1,2,4]triazoles and very slow at the 3-position,3 therefore the
alkylation at N-1 was also anticipated to activate the triazole to facil-
itate the subsequent intramolecular nucleophilic substitution/
cyclisation.
N
O
(i)
N
N
N
Br
O
10
N
N
(ii)
To implement this strategy we first alkylated 3,5-dibromo-
1,2,4-triazole (2) to afford intermediate 7 and, in preliminary
experiments, were gratified to find substantial amounts of the
spontaneously cyclised [1,3]oxazolo[3,2-b][1,2,4]triazole final
product 9. Rapid optimisation of the reaction conditions trans-
formed this two-step scheme into a convenient one-pot reaction,
made even more expeditious by the use of microwave heating
(Scheme 2).
9d
F
N
O
N
N
11
Scheme 3. Reagents and conditions: (i) H2, 10% Pd/C, Et3N (2 equiv), MeOH, (61%);
(ii) 4-FC6H4B(OH)2, Pd(PPh3)2Cl2, Na2CO3, DME, H2O 100 °C (67%).
Detailed investigation revealed this tandem alkylation/cyclisa-
tion reaction (Scheme 2) to be versatile and tolerant of diverse
activation towards enolisation, using 3-bromo-2-butanone (4d) as
a model substrate. Thus, reaction of 3,5-dibromo-1,2,4-triazole (2)
with 4d in the presence of 3 equiv of DBU at 100 °C in a microwave
reactor gave 2-bromo-5,6-dimethyl[1,3]oxazolo[3,2-b][1,2,4]tria-
zole(9d)as theexclusive reactionproduct(60%). Theregiochemistry
of compound 9d was confirmed by X-ray crystallography.4 Alkyl-
ation of 3,5-dibromo-1,2,4-triazole (2) with DBU and 4d at room
temperature allowed isolation of the intermediate ketone (7d,
R1 = R2 = Me) in 75% yield and subsequent microwave heating with
DBU at 100 °C afforded 9d as the exclusive product (69%). DBU is
required in this step to facilitate enolisation and subsequent cyclisa-
tion to the [1,3]oxazolo[3,2-b][1,2,4]triazole ring system.
functionalities (Table 1). While
by an additional -carbonyl group, underwent cyclisation to 9a,b
in the presence of DIPEA, reaction of -haloketone 4c required
a-haloketones 4a and 4b, activated
a
a
a stronger base, presumably to facilitate the formation of a less-
stabilized enolate intermediate 8.
In view of the apparent ease of the ring formation we further
investigated the scope of this procedure and were interested in
whether it could be extended to
a-haloketones lacking further
Table 1
Synthesis of [1,3]oxazolo[3,2-b][1,2,4]triazoles5
The results in Table 1 indicate that the tandem alkylation/cyclisa-
tion reaction has a good generic scope and functional group compat-
a
-Haloketone
Base
Product
Yield (%)
81
O
O
N
N
ibility. A range of commercially available
a-haloketone synthons
Br
O
gave [1,3]oxazolo[3,2-b][1,2,4]triazoles substituted with trifluoro-
methyl, aryl, ester or amido groups in moderate to good yields.
Finally, the remaining ‘dummy’ bromine atom in compound 9d
was readily removed by catalytic hydrogenation6 to afford the ex-
pected [1,3]oxazolo[3,2-b][1,2,4]triazole 10. The typical reactivity
of the bromo group in 9d for further functionalisation was demon-
strated by Suzuki coupling with 4-fluorobenzene boronic acid
giving the corresponding 2-aryl[1,3]oxazolo[3,2-b][1,2,4]triazole
11 (Scheme 3).
In summary, we have developed an expedient synthesis of
[1,3]oxazolo[3,2-b][1,2,4]triazoles via a tandem alkylation/cyclisa-
tion reaction, exploiting a facilitating ‘dummy’ bromine atom. The
synthesis affords easy entry into a previously unreported fused
heterocyclic system and allows for subsequent elaboration of the
template via the 5-Br atom or other functionalities (such as esters)
of which the synthesis is tolerant.
N
N
N
DIPEA
4a
Cl
O
9a
O
O
Br
O
MeO
N
DIPEA
68
Cl 4b
9b
MeO
N
O
O
O
Br
O
O
O
OEt
O
NaH
DBU
60
60
N
N
N
N
N
N
Br
Br
O
4c
9c
OEt
N
N
Br
4d
9d
Br
O
Acknowledgements
CF3
DIPEA
DIPEA
43
39
CF3
We thank Professor W. Clegg and Dr. L. Russo (University of
Newcastle) for the GSK-funded X-ray crystallographic analysis.
Br
9e
Br
4e
O
O
N
References and notes
O
Me2N
N
N
1. Pitt, W. R.; Parry, D. M.; Perry, B. G.; Groom, C. R. J. Med. Chem. 2009, 52, 2952–
Cl 4f
2963.
9f
2. So called ‘
a effect’, see: Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.;
Me2N
N
O
Blackwell Publishing, 2000. p 506.
3. Zumbrunn, A. Synthesis 1998, 1357–1361.
O
Br
O
4. X-ray crystallography of 9d confirmed that regioisomer
obtained exclusively, as predicted on steric and electronic (
X and not Y was
a
-effect) grounds
Ph
4g
N
N
DBU
DBU
9
Ph
Ph
Br
N
N
9g
Br
Br
O
N
O
O
N
N
N
N
Me
Me
O
Br
29
Ph
N
N
Me
Me
Br
4h
9h
X (9d)
Y

C. Ball et al. / Tetrahedron Letters 51 (2010) 3907–3909
3909
.
layer was extracted with CH2Cl2 (2 Â 25 mL). The organic layers were combined,
dried and evaporated. The crude product was purified by silica gel
chromatography eluting with 0–70% EtOAc in isohexane to give the title
compound 9d as a white solid (284 mg, 60%). Mp 72–74 °C. 1H NMR (400 MHz,
CDCl3) d 2.34 (s, 3 H), 2.37 (s, 3 H). 13C NMR (100 MHz, CDCl3): 7.1, 11.0, 117.3,
141.5, 144.0, 158.4. LC/MS [M+H]+ 216/218.
Crystallographic data (excluding structural factors) for compound 9d have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 771885. Copies of the data can be obtained free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44
(0)1223 336033 or email: deposit@ccdc.cam.ac.uk).
5. Preparation of 1-(2-bromo-5-methyl[1,3]oxazolo[3,2-b][1,2,4]triazol-6-yl)eth-
anone (9a). To a stirred suspension of 3,5-dibromo-1,2,4-triazole (2) (1.134 g,
5.0 mmol) in MeCN (20 mL) were added DIPEA (1.75 mL, 10 mmol) and 3-
chloro-2,4-pentanedione (4a) (0.57 mL, 5.0 mmol), and the reaction mixture
was heated for 20 min at 100 °C in a microwave reactor (Biotage Initiator 2.5).
The solvent was evaporated and the residue was partitioned between CH2Cl2
(100 mL) and aqueous 1 M HCl (100 mL). The layers were separated and the
organic phase was evaporated to dryness. The crude product was purified by
silica gel chromatography eluting with 0–70% EtOAc in isohexane to give the
title compound 9a as a white solid (980 mg, 81%). Mp 120–122 °C. 1H NMR
(400 MHz, CDCl3) d 2.765 (s, 3H), 2.759 (s, 3H). 13C NMR (100 MHz, CDCl3): 13.4,
3-(3,5-Dibromo-1H-1,2,4-triazol-1-yl)-2-butanone (7d). A suspension of 3,5-
dibromo-1,2,4-triazole (2) (567 mg, 2.5 mmol) in MeCN (5 mL) was stirred at
room temperature, DBU (0.415 mL, 2.75 mmol) was added, and the resulting
solution was stirred for 10 min.
A solution of 3-bromo-2-butanone (4d)
(0.29 mL, 2.75 mmol) in MeCN (1 mL) was added dropwise and the reaction
mixture was stirred at room temperature for 2 h. The reaction mixture was
diluted with EtOAc (30 mL) and 2 M HCl (15 mL). The organic layer was
separated and the aqueous layer was extracted with EtOAc (20 mL). The organic
extracts were combined and the solution was washed with 2 N HCl (15 mL), H2O
(20 mL) and brine (20 mL), dried and evaporated. The residue was triturated
with cold Et2O/isohexane (1:4) and the resulting solid was collected and dried to
give the title compound 7d as a white solid (554 mg, 75% yield). Mp 82–83 °C.
1H NMR (400 MHz, CDCl3) d 1.66 (3H, d, J = 7.2 Hz), 2.18 (s, 3 H), 5.43 (1H, q,
J = 7.2 Hz). 13C NMR (100 MHz, CDCl3): 14.9, 26.3, 63.7, 131.8, 139.3, 202.2. LC/
30.0, 121.9, 142.5, 155.7, 157.9, 187.2. LC/MS [M+H]+ 244/246. IR (solid):
m
1701 cmÀ1
.
2-Bromo-5,6-dimethyl[1,3]oxazolo[3,2-b][1,2,4] triazole (9d). To a suspension
of 3,5-dibromo-1,2,4-triazole (2) (500 mg, 2.20 mmol) in MeCN (8 mL) were
added DBU (0.33 mL, 2.20 mmol) and then 3-bromo-2-butanone (4d) (0.29 mL,
2.76 mmol). The mixture was stirred at room temperature for 10 min and then
heated for 5 min at 100 °C in a microwave reactor. Additional DBU (0.66 mL,
4.4 mmol) was added and the mixture was heated for 10 min at 100 °C in the
microwave. The solvent was evaporated, CH2Cl2 (25 mL) and 1 M HCl (25 mL)
were added to the residue, and the organic layer was separated. The aqueous
MS [M+H]+ 296/298/300. IR (solid):
m .
1715 cmÀ1
5,6-Dimethyl[1,3]oxazolo[3,2-b][1,2,4]triazole (10). White solid. Mp 68–70 °C.
1H NMR (400 MHz, CDCl3) d 2.36 (3H, s), 2.37 (3H, s), 7.88 (1H, s). 13C NMR
(100 MHz, CDCl3): 7.2, 11.1, 117.0, 144.5, 154.0, 159.6. LC/MS [M+H]+ 138.
6. Libnow, S.; Wille, S.; Christiansen, A.; Hein, M.; Reinke, H.; Kockerling, M.;
Miethchen, R. Synthesis 2006, 496–508.