The use of a Mitsunobu reagent for the formation of heterocycles: A simple method for the preparation of 3-alkyl-5-aryl-1,3,4-oxadiazol-2(3H)-ones from carboxylic acids

Article abstract of DOI:10.1039/c4cc01971g

The reaction of carboxylic acids with Mitsunobu reagents, prepared by the reaction of triphenylphosphine with dialkyl azodicarboxylates, followed by heating at 180-190 °C under solvent-free conditions, afforded 3-alkyl-5-aryl-1,3,4-oxadiazol-2(3H)-ones. This facile and convenient method readily provides the 1,3,4-oxadiazolone ring systems in good yields using a one-pot protocol starting from the corresponding carboxylic acids. It was also demonstrated that the presence of a catalytic base facilitates the final ring closure forming the 1,3,4-oxadiazol-2(3H)-one.

Full text of DOI:10.1039/c4cc01971g

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The use of a Mitsunobu reagent for the formation
of heterocycles: a simple method for the
preparation of 3-alkyl-5-aryl-1,3,4-oxadiazol-
2(3H)-ones from carboxylic acids†
Cite this: Chem. Commun., 2014,
50, 7314
Received 17th March 2014,
Accepted 14th May 2014
Osamu Sugimoto,* Tomoyo Arakaki, Hiroka Kamio and Ken-ichi Tanji*
DOI: 10.1039/c4cc01971g
www.rsc.org/chemcomm
The reaction of carboxylic acids with Mitsunobu reagents, prepared by the
reaction of triphenylphosphine with dialkyl azodicarboxylates, followed by
heating at 180–190 8C under solvent-free conditions, afforded 3-alkyl-5-
aryl-1,3,4-oxadiazol-2(3H)-ones. This facile and convenient method
readily provides the 1,3,4-oxadiazolone ring systems in good yields
using a one-pot protocol starting from the corresponding carboxylic
acids. It was also demonstrated that the presence of a catalytic base
facilitates the final ring closure forming the 1,3,4-oxadiazol-2(3H)-one.
The Mitsunobu reaction1–3 is a useful method for the esterification
of carboxylic acids under neutral conditions. A Mitsunobu reagent is
used as an activating agent and is prepared by the reaction of
phosphines with azodicarboxylic acid diesters. Hughes et al.4 have
reported that the reaction of a carboxylic acid with triphenylphos-
phine (PPh3) and diisopropyl azodicarboxylate in the absence of an
alcohol leads to the formation of the corresponding 1-acylhydrazine-
1,2-dicarboxylates 1 as the major product. During the course of our
Scheme 1 One-pot formation of 5-aryl-1,3,4-oxadiazol-2(3H)-ones (2).
was prepared by the reaction of PPh3 with diethyl azodicarbox-
ylate (PPh3–DEAD) (Table 1).
studies, the observation that heating a reaction mixture containing 1 Table 1 Preparation of 2a under various conditions
under solvent-free conditions afforded 3-alkyl-5-aryl-1,3,4-oxadiazol-
2(3H)-ones 2 (Scheme 1) was made.
The development of an efficient method for preparing
3-substituted 5-aryl-1,3,4-oxadiazol-2(3H)-ones is desirable as these
compounds exhibit a variety of biological activities including maxi-K
channel opening,5 MAO inhibition,6 and fungicidal activity.7 Some
progress has been made in developing procedures for the synthesis
of 5-aryl-1,3,4-oxadiazol-2(3H)-ones.5–14 However, these procedures
involve many steps and require the use of hazardous reagents. In
this communication we report a facile one-pot synthesis of 3-alkyl-5-
aryl-1,3,4-oxadiazol-2(3H)-ones arising from the corresponding
Yields (%)
Amount of
PPh3–DEAD (equiv.)
carboxylic acids under solvent-free conditions. In the initial
studies, the reaction of benzoic acid was explored with respect
to the equivalents (1–3 equiv.) of the Mitsunobu reagent, which
Entry
Condition
1a
2a
3
1
2
3
4
5
6
7
8
9
1.2
1.2
1
1.2
1.5
2
3
1.2
1.2
Room temperature
140–150 1C, 24 h
180–190 1C, 24 h
180–190 1C, 24 h
180–190 1C, 24 h
180–190 1C, 24 h
180–190 1C, 22 h
180–190 1C, 6 h
180–190 1C, 2 h
72
0
0
0
0
0
0
0
0
0
55
65
71
77
73
50
70
69
0
8
6
3
0
0
0
0
0
Laboratory of Organic Chemistry, School of Food and Nutritional Sciences,
University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
E-mail: osamu@u-shizuoka-ken.ac.jp; Fax: +81 54 264 5542; Tel: +81 54 264 5545
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc01971g
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The reaction of benzoic acid with PPh3–DEAD (1.2 equiv.) in the di-t-butyl azodicarboxylate (PPh3–DtBAD) was employed (entry 7).
CH2Cl2 under reflux for 1 h provided diethyl 1-benzoylhydrazine- These results may suggest that steric hindrance of the alkyl group on
1,2-dicarboxylate (1a) in 72% yield (entry 1); this result was identical the ester moiety affects the reactivity of the cyclization. With smaller
to that reported by Hughes et al.4 In contrast, heating at 140–150 1C alkyl groups (i.e., ethyl, methyl, and benzyl) the reaction proceeded
for 24 h under solvent-free conditions afforded 3-ethyl-5-phenyl- smoothly to afford the 5-phenyl-1,3,4-oxadiazol-2(3H)-ones (2a–2c) in
1,3,4-oxadiazol-2(3H)-one (2a) and 5-phenyl-1,3,4-oxadiazol-2(3H)- good yields.
one (3) in 55% and 8% yields, respectively (entry 2). It was
The scope of the reaction was next explored by varying the
subsequently found that the yield of 2a could be increased by aromatic carboxylic acid in combination with the Mitsunobu
heating the reaction mixture containing 1a at 180–190 1C. Varying reagents (Table 3). 4-Iodobenzoic acid (entries 1–6), 3,4,5-
the equivalents of the Mitsunobu reagent (1, 1.2, 1.5, and 2 equiv. trimethoxybenzoic acid (entries 7–11), 1-naphthoic acid (entries
of PPh3–DEAD) in CH2Cl2 under reflux for 1 h followed by heating 12–17), 2-naphthoic acid (entries 18 and 19), 2-pyridinecarboxylic
at 180–190 1C for 24 h afforded 2a in 65%, 71%, 77%, and 73% acid (entries 20–24), 2-chloropyridine-5-carboxylic acid (entries 25
yields, respectively (entries 3–6). However, when 3 equiv. of PPh3– and 26), 4-pyridinecarboxylic acid (entry 27), and 2-quinoline-
DEAD was used, the yield of 2a was slightly diminished (entry 7). carboxylic acid (entries 28–32) were tested as substrates with the
It was found that the reactions at 180–190 1C for a shorter time
(6 h and 2 h) compared to the reaction for 24 h (entry 4) gave
Table 3 Preparation of 3-alkyl-5-aryl-1,3,4-oxadiazol-2(3H)-ones (2)
similar yields (70% and 69%; entries 8 and 9).‡
Next, the reactions of benzoic acid with various Mitsunobu
reagents, PPh3–DMAD (dimethyl ester), PPh3–DBAD (dibenzyl
ester), PPh3–DIAD (di-i-propyl ester), and PPh3–DtBAD (di-t-butyl
ester), were carried out to test the effect of the alkyl substituent on
Yields (%)
Mitsunobu
reagent
Time
(h)
the cyclization event (Table 2). A mixture of benzoic acid was
treated with 1.2 equiv. of the respective Mitsunobu reagent in
CH2Cl2 under reflux for 1 h, followed by heating under solvent-free
conditions at 180–190 1C for the time period depicted in Table 2.
Using PPh3–DMAD as the Mitsunobu reagent (180–190 1C, 2 h)
provided 3-methyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one (2b) in 66%
yield (entry 1). When the reaction time was extended to 24 h, the
yield dropped to 62% (entry 2). With PPh3–DBAD, 3-benzyl-5-
phenyl-1,3,4-oxadiazol-2(3H)-one (2c) was likewise obtained, in
52% yield (entry 3). In contrast, the PPh3–DIAD system did not
provide 3-isopropyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one (2d) in
appreciable yield (entries 4–6). This result was mirrored when
Entry Ar
R
2
3
1
2
3
4
5
6
PPh3–DMAD CH3
2
5
24
2
77
43
50
72
25
24
0
PPh3–DEAD CH2CH3
PPh3–DEAD CH2CH3
PPh3–DBAD CH2Ph
PPh3–DIAD
PPh3–DIAD
23
24
0
48
14
CH(CH3)2 24
CH(CH3)2 48
7
8
9
10
11
PPh3–DMAD CH3
PPh3–DEAD CH2CH3
PPh3–DBAD CH2Ph
PPh3–DIAD
PPh3–DIAD
2
4
2
80
64
64
21
9
0
0
0
19
39
CH(CH3)2 24
CH(CH3)2 48
12
13
14
15
16
17
PPh3–DMAD CH3
PPh3–DMAD CH3
PPh3–DEAD CH2CH3
PPh3–DEAD CH2CH3
PPh3–DBAD CH2Ph
2
24
2
5
2
42
64
54
48
61
8
5
0
0
0
0
Table 2 Preparation of 2b–2e using a variety of Mitsunobu reagents
PPh3–DIAD
CH(CH3)2 24
48
18
19
PPh3–DEAD CH2CH3
PPh3–DEAD CH2CH3
2
24
70
57
7
4
20
21
22
23
24
PPh3–DMAD CH3
PPh3–DEAD CH2CH3
PPh3–DBAD CH2Ph
2
4
2
76
62
76
21
12
0
0
0
0
0
PPh3–DIAD
PPh3–DIAD
CH(CH3)2 24
CH(CH3)2 48
25
26
PPh3–DEAD CH2CH3
PPh3–DEAD CH2CH3
2
19
38
25
0
0
Yields (%)
Mitsunobu
reagent
Time
(h)
Entry
R
2b–2e
3
1
27
28
62 29
30
PPh3–DEAD CH2CH3
19
40
0
1
2
3
4
5
6
7
PPh3–DMAD
PPh3–DMAD
PPh3–DBAD
PPh3–DIAD
PPh3–DIAD
PPh3–DIAD
PPh3–DtBAD
CH3
CH3
CH2Ph
CH(CH3)2
CH(CH3)2
CH(CH3)2
C(CH3)3
2
24
2
66 (2b)
62 (2b)
52 (2c)
0 (2d)
10 (2d)
5 (2d)
5
4
13
0
34
29
7
PPh3–DMAD CH3
PPh3–DEAD CH2CH3
PPh3–DBAD CH2Ph
2
2
2
79
70
63
13
8
0
0
14
27
0
2
24
48
19
31
32
PPh3–DIAD
PPh3–DIAD
CH(CH3)2 24
CH(CH3)2 48
0 (2e)
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Table 4 Conversion of 1a into 2a
also promoted the cyclization (entries 7 and 8). The use of
OQPPh3 promoted the reaction slightly, affording 2a in 11%
yield (entry 9). However, heating 1a with 0.2 equiv. of
EtO2CNHNHCO2Et at 180–190 1C for 24 h did not lead to the
formation of 2a (entry 10). It was speculated that reaction of
benzoic acid with PPh3–DEAD first provides 1a, which is sub-
sequently converted into 2a. This conversion is facilitated by
the presence of a base and heating. To test this hypothesis, a
mixture of 1a and one of several bases such as EtONa (entries
11 and 12), NaH (entries 13 and 14), and DBU (entry 15), was
heated at 180–190 1C, effecting the formation of 2a. It was also
Yields (%)
Table
5
Formation of 1,3,4-oxadiazol-2(3H)-ones using an aliphatic
Entry Additive or solvent
Condition
2a
3
1a
carboxylic acid
1
2
3
4
5
6
7
8
None
None
Diglyme
Mesitylene
PPh3–DEAD (1 equiv.)
PPh3–DEAD (1 equiv.)
PPh3–DEAD (0.2 equiv.)
PPh3–DEAD (0.05 equiv.)
OQPPh3 (1 equiv.)
180–190 1C, 5 h
180–190 1C, 24 h
Reflux, 17 h
0
0
0
0
0
0
0
0
41
0
49
24
0
0
0
0
0
0
0
Reflux, 17 h
180–190 1C, 5 h 54 12
180–190 1C, 18 h 39 23
180–190 1C, 23 h 51 20
180–190 1C, 19 h 49 17
9
180–190 1C, 5 h 11
0
0
10
11
12
13
14
15
EtO2CNHNHCO2Et (0.2 equiv.) 180–190 1C, 24 h
0
EtONa (0.1 equiv.)
EtONa (0.03 equiv.)
NaH (1 equiv.)
NaH (0.1 equiv.)
DBU (0.07 equiv.)
180–190 1C, 4 h 15 21
180–190 1C, 2 h 42 27
180–190 1C, 5 h 16
180–190 1C, 2 h 48 15
180–190 1C, 2 h 64
0
0
0
0
0
Yields (%)
4
Entry
Base
Condition
4
5
1
2
3
4
5
None
180–190 1C, 24 h
180–190 1C, 4 h
140–150 1C, 6 h
180–190 1C, 24 h
180–190 1C, 6 h
17
32
32
40
26
0
EtONa (0.05 equiv.)
DBU (0.09 equiv.)
DBU (0.09 equiv.)
DBU (1 equiv.)
25
28
14
21
PPh3–DMAD, PPh3–DEAD, PPh3–DBAD, and PPh3–DIAD Mitsu-
nobu reagents.
Overall, the generation of the desired product, 2, proceeded
smoothly when Mitsunobu reagents with smaller alkyl groups
such as methyl, ethyl, and benzyl were used. As was previously
the case, the reaction using PPh3–DIAD as the reagent afforded
2 in a low yield. These results are consistent with those depicted
in Table 2, and highlight the structure–reactivity relationship of
the Mitsunobu reagent with respect to the size of the alkyl
group on the azodicarboxylate.
The conversion of purified intermediate 1a under several
conditions was carried out next in order to identify whether the
cyclization event was occurring thermally, or was perhaps
facilitated by the reaction conditions (Table 4).
Interestingly, heating 1a at 180–190 1C without additives did
not provide the desired product 2a (entries 1 and 2). Similarly,
heating 1a in the neutral organic solvents, diglyme (bp. 162 1C)
or mesitylene (bp. 163–166 1C), under reflux for 17 h did not
lead to the formation of 2a (entries 3 and 4). It was surmised
that the conversion of 1a into 2a not only requires heating, but
is also facilitated by the Mitsunobu reaction conditions. It can
be presumed that the presence of a reagent used in this
reaction, such as PPh3–DEAD, or the by-products triphenylpho-
sphine oxide (OQPPh3) or diethyl 1,2-hydrazinedicarboxylate
(EtO2CNHNHCO2Et), may accelerate the formation of 2a. As
expected, when a mixture of 1a and 1 equiv. of PPh3–DEAD was
heated at 180–190 1C, 2a was obtained in 54% (for 5 h) and 39%
(for 18 h) yield, respectively (entries 5 and 6). It should be noted
that a catalytic amount of PPh3–DEAD (0.2 equiv. or 0.05 equiv.)
Scheme 2 Proposed mechanism for the generation of 3-alkyl-5-(hetero)-
aryl-1,3,4-oxadiazol-2(3H)-ones and 5-(hetero)aryl-1,3,4-oxadiazol-2(3H)-
ones 2 and 3.
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found that the yield of 2a was increased by using a catalytic that a catalytic amount of a basic additive is required to convert
amount of base. the intermediate alkyl 1-aroylhydrazine-1,2-dicarboxylates into the
Reactions using an aliphatic carboxylic acid as a substrate corresponding 3-alkyl-5-aryl-1,3,4-oxadiazol-2(3H)-ones at 180–190 1C.
were examined (Table 5). A mixture of 3-phenylpropionic acid
and PPh3–DEAD (1.2 equiv.) in CH2Cl2 was heated to reflux for
Notes and references
1 h, followed by removal of CH2Cl2 and heating with or without
‡ All yields shown in the tables are isolated yields. Typical experimental
a base. The reaction in the absence of a base afforded the
procedure: azodicarboxylic acid ester was added dropwise to a mixture
corresponding cyclized product (4) in 17% yield (entry 1). On
the other hand, the yield of 4 was increased by using a catalytic
amount of base such as EtONa (entry 2) or DBU (entries 3 and
4). The use of a stoichiometric amount of base (1 equiv. DBU)
resulted in a lower yield (entry 5). In one-pot cyclizations using
an aromatic carboxylic acid as a substrate (e.g., Tables 1 and 3),
the Mitsunobu reagent (e.g., excess PPh3–DEAD) acts as a base,
so the addition of exogenous base is not required.
A reasonable mechanism for the cyclization/alkyl group
migration is depicted in Scheme 2. Two different routes are
possible for the generation of 2 and 3. When an alkyl group R2
is non-hindered (methyl, ethyl, and benzyl), the NH proton in 1
is deprotonated to generate an isocyanate A, which is cyclized
(C). Rearrangement of R2 then proceeds to form 2. On the other
hand, when R2 is hindered, as is the case of an isopropyl group,
1 cannot be deprotonated due to hindrance by R2. Therefore,
cyclization proceeds and forms B, followed by decomposition of
an ester moiety to give 3. The generated R2OÀ shown in this
mechanism acts as a base catalytically.
of carboxylic acid and PPh3 in CH2Cl2 at rt, then the mixture was heated
to reflux for 1 h. After CH2Cl2 was removed at atmospheric pressure, the
residue was heated at 180–190 1C, followed by purification using silica
gel column chromatography to give the desired product.
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In summary, an efficient and operationally simplified method
for the preparation of 3-alkyl-5-aryl-1,3,4-oxadiazol-2(3H)-ones
from carboxylic acids has been developed. These studies revealed 14 M. Golfier and M. G. Guillerez, Bull. Soc. Chim. Fr., 1991, 127, 71.
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