A novel and direct synthesis of 1,3,4-oxadiazoles or oxazolines from carboxylic acids using cyanuric chloride/indium

Article abstract of DOI:10.1016/j.tetlet.2009.07.032

Direct synthesis of various oxazolines and 1,3,4-oxadiazoles from carboxylic acids was achieved using cyanuric chloride/indium under very mild conditions.

Full text of DOI:10.1016/j.tetlet.2009.07.032

Tetrahedron Letters 50 (2009) 5332–5335
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A novel and direct synthesis of 1,3,4-oxadiazoles or oxazolines from
carboxylic acids using cyanuric chloride/indium
b
Cyrous O. Kangani a, , Billy W. Day
*
a Asta Tech, Inc., 2525 Pearl Buck Road, Bristol, PA 19007, USA
b Pharmaceutical Sciences and Chemistry, University of Pittsburgh, Pittsburgh, PA 15213, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Direct synthesis of various oxazolines and 1,3,4-oxadiazoles from carboxylic acids was achieved using
cyanuric chloride/indium under very mild conditions.
Received 11 June 2009
Revised 30 June 2009
Accepted 1 July 2009
Available online 10 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Five-membered heterocycles are privileged structures with util-
ity in synthetic and medicinal chemistries.1 In general, oxazoline
and oxadiazole building blocks have found widespread applica-
tions as synthetic intermediates, protecting groups, pharmaco-
phores, and ester and amide surrogates.2–4 They also possess a
wide spectrum of biological activities with antiinflammatory, anti-
hypertensive, anticonvulsant, and analgesic properties.5–7 Because
of the importance of oxazolines and oxadiazoles, the development
of simple and efficient protocols to prepare them using mild condi-
tions has received much attention. Oxazolines and oxadiazoles are
commonly prepared by a two-step method: coupling of carboxylic
acids with amino alcohols and/or acylhydrazides followed by a
dehydration step.8–11 There are, however, few one-pot methods re-
ported in the literature, with most being limited in substrate
scope.12 We recently reported an efficient, direct and common
method for the synthesis of oxazolines and oxadiazoles from vari-
ous carboxylic acids using the Deoxo-Fluor reagent.13 The reaction
was carried out in one-pot and was operationally simple and mild
giving the products in high yields and purity in a very short time.
For successful synthesis, it was necessary to use neat Deoxo-Fluor.
When the reaction was carried out using Deoxo-Fluor in solution
(such as THF and/or toluene), the efficiency, as well as yield, was
reduced. Since neat Deoxo-Fluor is available only in North America
and supplied only in solution (THF and toluene) in Europe and else-
where, we wished to develop a convenient one-pot method for the
synthesis of these useful heterocycles using reagents available to
researchers worldwide. We therefore investigated the possibility
of synthesizing oxazolines and oxadiazoles from carboxylic acids
using an inexpensive and readily available reagent, such as 2,4,6-
trichloro[1,3,5]triazine (cyanuric chloride, TCT). Cyanuric chloride
has been reported as an efficient coupling reagent in the prepara-
tion of amides, esters, and anhydrides.14 In this report, we describe
a new, simple, and efficient synthesis of oxazolines and oxadiaz-
oles directly from carboxylic acids using cyanuric chloride.
Recently, Bandgar and Pandit reported the use of 2-chloro-4,6-
dimethoxy-1,3,5-triazine as a simple, mild, and highly efficient
promoter for the synthesis of oxazolines.8a Their major product
was, however,
x
-hydroxyamides instead of oxazolines.15 We em-
ployed this procedure, but used cyanuric chloride instead of 2-
chloro-4,6-dimethoxy-1,3,5-triazine. Although the reaction times
were long and yields were modest, we were delighted to observe
that cyanuric chloride promoted coupling and cyclodehydration
at the same time (Scheme 1).
The use of cyanuric chloride as coupling reagent typically in-
volves the initial formation of an N-methylmorpholine: cyanuric
chloride complex in CH2Cl2 or CH3CN. Once this complex is formed,
a carboxylic acid is added to generate the activated carboxylic acid,
which upon further treatment with amine gives the corresponding
amides.16 After considerable experimentation with reaction of car-
boxylic acids with cyanuric chloride, we identified CH2Cl2 and pyr-
idine as the optimal solvent and base, respectively.17 In addition, to
ensure an elegant and efficient synthesis of target heterocycles un-
der very mild and shorter reaction times the addition of a catalytic
amount of indium (In) metal is necessary.18 Typically, the carbox-
ylic acid (0.43 mmol, 1 equiv) and cyanuric chloride (0.65 mmol,
1.5 equiv) were dissolved in CH2Cl2 (5 ml) in an open test tube.
Pyridine (1.3 mmol, 3 equiv) was added drop wise at 0 °C, and a
white suspension was formed after occasional vortex mixing. After
15 min, 2-amino-2-methyl-1-propanol (1.2 mmol, 3 equiv) was
added (portion wise), followed by addition of indium (0.065 mmol,
0.15 equiv) at room temperature. The reaction mixture was occa-
sionally shaken on a vortex mixer until oxazoline formation was
complete (monitored by TLC and GC–MS). Table 1 shows the
results obtained from the direct reaction of various carboxylic
acids with 2-amino-2-methyl-1-propanol. The products were
generally recovered in pure form and in high yields simply by
concentration of solvent extracts under reduced pressure. The
* Corresponding author. Tel.: +1 412 647 6796; fax: +1 412 692 2165.
E-mail address: cyrouskangani@gmail.com (C.O. Kangani).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.032

C. O. Kangani, B. W. Day / Tetrahedron Letters 50 (2009) 5332–5335
5333
O
O
CH Cl , Pyridine
OH
2
o
2
+
R
N
H
R
0
C
RT
N
15%
O
Cl
N
Cl
85%
NH2
HO
+
N
+
R
OH
N
O
CH Cl , Pyridine,
Cl
2
2
o
R
In, 0
C
RT
N
Scheme 1. Effect of Indium on oxazoline cyclization.
Table 1
Direct cyclization of carboxylic acids to oxazolines using cyanuric chloride/indium
Entry
Substrate
Product
Yielda (%)
Time (h)
35
O
COOH
1
88
N
O
COOH
2
3
4
5
6
7
8
9
90
80
88
92
86
90
85
90
90
35
20
20
30
40
30
30
35
30
N
Me
Br
Me
Br
O
COOH
COOH
N
O
N
O2N
O2N
O
COOH
OH
N
OH
O
COOH
N
N
N
O
COOH
N
O
COOH
N
O
O
COOH
COOH
N
N
10
a
Yields of pure, isolated products (characterized by GC–MS, and 1H and 13C NMR).
triazine byproducts were easily removed by simple aqueous work-
up. Both aromatic (Table 1, entries 1–5) and aliphatic (entries 6–
10) carboxylic acids converted efficiently to the corresponding
oxazoles. All reactions resulted in high isolated yields, and conver-

5334
C. O. Kangani, B. W. Day / Tetrahedron Letters 50 (2009) 5332–5335
sion of carboxylic acid was complete as determined by GC–MS.
This method was also applicable to ortho-substituted carboxylic
acids, such as salicylic acid to give 2-(4,4-dimethyl-4,5-dihydroox-
azol-2-yl)-phenol (entry 4) along with 610% of the 2-(2-chloro-
phenyl)-4,4-dimethyl-4,5-dihydrooxazole.
These encouraging results motivated us to speculate that a one-
pot process for the synthesis of oxadiazoles under very mild condi-
tion might be possible. Fortunately, following the above protocol,
we were able to prepare 1,3,4-oxadiazoles very efficiently at room
temperature, simply by increasing the amount of indium catalyst
to 0.30 equiv. Moreover, the best results were obtained using 3 equiv
of TCT and 2 equiv of pyridine. This one-pot method was found to be
quite general and worked well for a variety of alkyl and aryl carbox-
ylic acids, as well as alkyl and aryl acid hydrazides (Table 2). Both
aromatic and aliphatic carboxylic acids were smoothly converted
to 1,3,4-oxadiazoles. Benzoic acids with electron-withdrawing
Table 2
Direct cyclization of carboxylic acids to oxadiazoles using cyanuric chloride/indium
R2
O
O
O
Cl
N
Cl
CH2Cl2, Pyridine,
NH2
N
+
In, 0 o
C
RT
R2
N
H
+
N
R1
R1
OH
N
N
Cl
Entry
1
Substrate
Product
Yielda (%)
Time (h)
O
Ph
COOH
N
89
6
N
O
Ph
COOH
COOH
COOH
N
2
3
4
5
6
7
8
9
85
80
85
87
82
86
85
85
92
6
2
2
3
4
3
4
8
2
N
Me
Br
Me
Br
O
Ph
N
N
O
Ph
N
N
O2N
O2N
O
Ph
N
COOH
OH
N
N
OH
O
N
COOH
Ph
N
N
Ph
O
COOH
N
N
O
COOH
Ph
Ph
N
N
O
COOH
COOH
N
N
CH3
N
O
10
N
a
Yields of pure, isolated products (characterized by GC–MS, and 1H and 13C NMR).

C. O. Kangani, B. W. Day / Tetrahedron Letters 50 (2009) 5332–5335
5335
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groups (entries 3 and 4) were significantly better candidates than
their electron-rich or neutral carboxylic acids (entries 1 and 2).
To demonstrate the efficiency of this method, we also reacted
cinnamic acid as well as salicylic acid (entries 5 and 6) with acid
hydrazides to give the corresponding oxadiazoles, which were
not easily accessible by previous methods, in high yields. As can
be seen from the Table 2, aliphatic carboxylic acids were also con-
verted in good yields to the corresponding oxadiazoles (entries 8
and 10). In addition, the optically active oxadiazoles were also pre-
pared (entry 9) by this method, with no racemization being ob-
served by chiral GC analysis.19
In conclusion, we have developed an inexpensive, efficient,
straightforward, and common method for the synthesis of oxazo-
lines and oxadiazoles from various carboxylic acids using cyanuric
chloride. The reaction is carried out in one-pot and is operationally
simple and gives products with high yields and purity. Moreover,
this process is amenable to scale-up.
Acknowledgment
We thank Professor Paul Floreancig, University of Pittsburgh, for
helpful discussions.
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19. In a typical procedure, the carboxylic acid (0.43 mmol, 1 equiv) and cyanuric
chloride (1.3 mmol, 3 equiv) were dissolved in CH2Cl2 (5 ml) in an open test
tube. Pyridine (0.86 mmol, 2 equiv) was added dropwise, a white suspension
was formed on vortexing occasionally. After 15 min acid hydrazide (1.2 mmol,
3 equiv) was added (portionwise) followed by indium (0.13 mmol, 0.30 equiv)
at room temperature. The reaction mixture was occasionally shaken on a
vortex mixer at room temperature until formation of oxadiazoles was
completed as determined by TLC and GC–MS analysis. (S)-2-Phenyl-5-(2-
phenylpropyl)-[1,3,4]oxadiazole (Table 2, entry 9). 1H NMR (600 MHz, CDCl3):
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d
7.98(d, J = 7.4 Hz, 2H), 7.54–7.48 (m, 3H), 7.34–7.28 (m, 4H), 7.25(t,
J = 7.4 Hz, 1H), 3.42(m, 1H), 3.22 (dd, J = 12.0 Hz, 2H), 1.43(d, J = 6.0 Hz, 3H);
TM
GC–FID: (Chiraldex , 50 °C, 5 min, 2 °C/min to 160 °C, 10 min.), tR: 16.81 min
(99% ee). ½a D
260 °C, 5 min, 40 °C/min to 300 °C, 10 min), tR: 11.95 min. MS (EI) m/z
(relative intensity): 264 (M+ꢀ
52), 249 (24), 160 (60), 105 (100).2-(2,2-
ꢀ
+8.23 (c 0.10, EtOH); GC: (HP-5, 50 °C, 2 min, 20 °C/min to
,
Diphenylethyl)-5-methyl-[1,3,4]oxadiazole (Table 2, entry 10). 1H NMR
(600 MHz, CDCl3): d 7.38–7.18 (m, 10H), 4.52 (m, 1H), 3.05 (d, J = 6.0 Hz,
2H), 2.45 (s, 3H); GC: (HP-5, 50 °C, 2 min, 20 °C/min to 260 °C, 5 min, 40 °C/
min to 300 °C, 10 min), tR: 11.85 min. MS (EI) m/z (relative intensity): 264
(M+ꢀ, 45), 180 (10), 167 (100), 152 (25).2-(2,2-Diphenylethyl)-4,4-dimethyl-4,5-
dihydrooxazole (Table 1, entry 10). 1H NMR (600 MHz, CDCl3): d 7.30–7.18 (m,
10H), 4.51 (m, 1H), 3.93 (s, 2H), 3.04 (d, J = 6.0 Hz, 2H), 1.05 (s, 6H); GC: (HP-
5, 50 °C, 2 min, 20 °C/min to 260 °C, 5 min, 40 °C/min to 300 °C, 10 min), tR:
11.20 min. MS (EI) m/z (relative intensity): 279 (M+ꢀ, 8), 264 (35), 167 (100),
152 (25), 77 (10).
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