Tetrahedron Letters
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
⇑
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0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.