A facile synthesis of 3-trifluoromethyl-1,2,4-oxadiazoles from cyanamides

Article abstract of DOI:10.1016/j.tetlet.2014.06.019

A safe and facile method for the formation of 3-trifluoromethyl-5-amino-1, 2,4-oxadiazoles, via a reversed addition of hydroxylamine to cyanamides, is reported. This two-pot procedure is suitable to scale-up and avoids the hazards associated with trifluor

Full text of DOI:10.1016/j.tetlet.2014.06.019

Tetrahedron Letters 55 (2014) 4433–4436
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Tetrahedron Letters
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A facile synthesis of 3-trifluoromethyl-1,2,4-oxadiazoles
from cyanamides
⇑
Kristin Goldberg , David S. Clarke, James S. Scott
AstraZeneca, Cardiovascular & Gastrointestinal Innovative Medicines Unit, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A safe and facile method for the formation of 3-trifluoromethyl-5-amino-1,2,4-oxadiazoles, via a reversed
addition of hydroxylamine to cyanamides, is reported. This two-pot procedure is suitable to scale-up and
avoids the hazards associated with trifluoromethyl amidoxime synthesis.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 15 February 2014
Revised 19 May 2014
Accepted 5 June 2014
Available online 12 June 2014
Keywords:
3-Trifluoromethyl-1,2,4-oxadiazoles
Cyanamides
N-Boc-hydroxylamine
1,2,4-Oxadiazoles
Oxadiazoles are becoming increasingly important in the phar-
maceutical industry.1 As part of a medicinal chemistry programme
investigating the development of GPR119 agonists,2 we required a
safe, efficient and high yielding route for the synthesis of 500 g of
3-trifluoromethyl-1,2,4-oxadiazole (1) (Fig. 1).
N
N
O
N
N
N
OBn
N
F3C
1
A review of the literature3 showed that the majority of 1,2,
4-oxadiazoles are made from one of two methods (Scheme 1),
either (i) a 1,3-dipolar cycloaddition of a nitrile with a nitrile oxide,
or more commonly, (ii) the reaction of an amidoxime with a car-
boxylic acid or nitrile followed by acid-catalysed cyclization. In
addition, isomerization of a 1,2,4-oxadiazole into its regioisomer
Figure 1. Oxadiazole 1 needed for our studies.
(i)
R
O
N
N
1,3-dipolar
N
via
a nucleophilic ring-opening, ring-closing rearrangement
R
R
cycloaddition
N
O
N
N
R'
(ANRORC) has been achieved on a variety of fluorinated 1,2,
R'
R'
4-oxadiazoles (iii).4
N
O
(ii)
OH
Our initial route2a to deliver oxadiazole 1 proceeded via known
trifluoromethyl amidoxime 3,5 (Scheme 2). Trifluoromethyl ami-
doxime synthesis becomes problematic on large scale, the main
issue being the difficulty in detecting the amount of unreacted
hydroxylamine remaining in solution. Any hydroxylamine remain-
ing in the mixture can react with the cyanamide 4. This results in
undesired amidoxime 7 and decreased yields of desired oxadiazole
1. In addition, trifluoroacetonitrile (2) is a toxic gas. For these rea-
sons we decided to investigate alternative methods for the large
scale synthesis of oxadiazole 1.
O
N
or
1.
R
OH
R
R'
NH2
2. H+
Amidoxime
(iii)
O
N
N
N
H2NOH
N
O
R
R
ANRORC
R'
R'
Scheme 1. Methods for the synthesis of 1,2,4-oxadiazoles.
We subsequently turned our attention to the 1,3-dipolar cyclo-
addition of 1,1,1-trifluoromethyl nitrile oxide5 and cyanamide 4,
but found difficulty generating the required trifluoroacetonitrile
oxide in situ.6 The ANRORC rearrangement4 was also investigated
⇑
Corresponding author. Tel.: +44 07798618771.
E-mail addresses: Kristin.Goldberg@CRUK.manchester.ac.uk (K. Goldberg),
davidsclarke@hotmail.com (D.S. Clarke), Jamie.Scott@Astrazeneca.com (J.S. Scott).
http://dx.doi.org/10.1016/j.tetlet.2014.06.019
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

4434
K. Goldberg et al. / Tetrahedron Letters 55 (2014) 4433–4436
N
O
N
N
N
N
OH
CF3
a
b
N
F3C
N
N
OBn
N
N
N
OBn
+
NH2
N
F3C
NH2
N
2
H
3
4
5
+
N
N
HO
N
N
N
O
N
c
N
N
OBn
N
N
OBn
N
H2N
F3C
1
7
Scheme 2. Trifluoromethyl-1,2,4-oxadiazole synthesis via trifluoromethyl amidoxime. (a) H2NOH.HCl, NaOMe (1 eq.), MeOH, 0 °C then trifluoroacetonitrile (1.2 eq.). (b)
ZnCl2 (2.2 eq.), THF, 20 °C. (c) 2 M HCl (aq), EtOH, reflux
N
N
N
N
O
N
N
N
N
O
N
N
OBn
N
N
OBn
F3C
F3C
1
8
H2NOH
-H2NOH
OBn
OH
OH N
N
N
N
N
N
NH
F3C
Scheme 3. Synthesis of (1) via ANRORC.
(Scheme 3): the success of this method depends upon two factors,
firstly the presence of an electrophilic centre for hydroxylamine
attack, and secondly, the absence of a competing leaving group,
as highlighted by Buscemi et al.4b Unfortunately, this method gave
consistently poor yields starting from the regioisomeric oxadiazole
8. This is perhaps due to the fact that in the final ring-closing step,
the piperazine is competitive with hydroxylamine as a leaving
group.
The difficulties with these traditional methods, exemplified
above, highlighted the need for an improved process and led us
to develop novel chemistry suitable for the large scale synthesis
of oxadiazole 1 (Scheme 4). It is well documented that hydroxyl-
amine adds to nitriles through nitrogen. As hydroxylamine poten-
tially has ambident reactivity we reasoned that if we could
deactivate the nitrogen sufficiently we could invert the reactivity.
We hypothesized that the presence of a Boc group would decrease
N
a
b
N
N
N
OBn
N
4
Boc
H
N
N
O
N
N
OBn
OBn
HN
N
9
N
O
N
N
N
N
N
F3C
1
Scheme 4. Synthesis of 1 via a non-classical hydroxylamine addition using N-Boc-
hydroxylamine. (a) BocN-OH (1.2 eq), ZnCl2 (2.2 eq.), THF, 20 °C, 16 h. (b) TFAA (1.2
eq), TFA (5 eq.), CH2Cl2, 20 °C, 2 h, 66% over 2 steps.
Table 1
Reaction scopea
a) BocHN OH,
ZnCl2, THF
O
R'
N
R'
R
N
N
N
N
F3C
R
b) TFA/TFAA,
CH2Cl2
Entry
1
Cyanamide
Product
Yieldb (%)
66
N
N
N
N
O
N
N
N
N
N
N
N
OBn
N
N
N
OBn
N
O
F3C
N
N
N
N
2
3
4
64
55
40
N
O
F3C
N
Ph
Ph
Ph
Ph
N
N
N
N
N
O
F3C
N
O
O
O
O
N
F3C

K. Goldberg et al. / Tetrahedron Letters 55 (2014) 4433–4436
4435
Table 1 (continued)
Entry
Cyanamide
Product
Yieldb (%)
O
N
N
N
O
N
O
5
6
48
40
N
F3C
F3C
O
N
N
N
NH
NH
N
N
N
N
O
S
O
S
O
O
O
N
N
N
N
7
47
NH
N
N
N
NH
N
N
O
F3C
F3C
F3C
F3C
N
N
N
N
8
9
73
0
N
O
N
N
N
O
10
0
N
a
Standard reaction conditions: (a) BocN-OH (1.2 equiv), ZnCl2 (2.2 equiv), THF, 20 °C, 16 h. (b) TFAA (1.2 equiv), TFA (5 equiv), CH2Cl2, 20 °C, 2 h.
Isolated yield.
b
suitably the nucleophilicity of the hydroxylamine nitrogen. We
chose to investigate the use of N-Boc-hydroxylamine as a commer-
cially available, inexpensive reagent for introduction of the
hydroxylamine moiety into our cyanamides. However, we found
no examples in the literature of N-Boc-hydroxylamine addition to
a nitrile or alkyne, reacting through oxygen.
Acknowledgments
We would like to thank our AstraZeneca colleagues Sue Bowker,
Julian Hudson, Paul Schofield, Nathaniel Martin, Ed Griffin, Stuart
Wells and Joseph Sweeney (Huddersfield University) for helpful
discussions. We would also like to thank Paul Davey and Peter Bar-
ton for providing accurate mass analysis and Howard Beeley and
Sarah-Kate Cantlie for NMR support.
Zinc chloride is commonly used to catalyse the addition of ami-
doximes to nitriles and cyanamides.7 We applied similar conditions
to the reaction of N-Boc-hydroxylamine with cyanamide 4 and
found that in the presence of zinc chloride, N-Boc-hydroxylamine
reacted with cyanamide 4 exclusively through oxygen to give the
required regioisomer 9 (Scheme 4). Subsequent addition of TFAA
and TFA resulted in rapid acylation, deprotection and cyclization
to give oxadiazole 1 in 66% yield. This protocol proved suitable for
scale-up and allowed the required 500 g of 1 to be synthesized.
We then investigated the scope of the reaction (Table 1) and
found that both cyclic and acyclic cyanamides (entries 1–4) are tol-
erated, as was a morpholine (entry 5). Functional groups such as a
sulfone (entry 7) and ester (entry 4) were compatible, though care
must be taken as N-Boc-hydroxylamine reacted with the ester dur-
ing prolonged reaction times. This chemistry worked with second-
ary cyanamides (entries 6 and 7), and heterocycles such as
pyrimidine (entry 1) and pyrazole (entry 6) were compatible.
We were surprised to find that under these conditions the addi-
tion of N-Boc-hydroxylamine to aromatic and alkyl nitriles did not
occur (entries 9 and 10). However, this enabled us to perform
selective ring syntheses (entry 8) where N-Boc-hydroxylamine
reacted exclusively with the cyanamide, leaving the aryl nitrile
untouched. This can be rationalized by the decreased electrophilic-
ity and reactivity of nitriles relative to cyanamides.8
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.06.
019.
References and notes
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In conclusion, we have developed a safe, mild and an efficient
method for the formation of 3-trifluoromethyl-1,2,4-oxadiazoles from
cyanamides. The two-pot synthesis proceeds via a zinc-catalysed,
reversed addition of a hydroxylamine moiety using N-Boc-hydroxyl-
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