A base-induced ring-opening process of 2-substituted-1,3,4-oxadiazoles for the generation of nitriles at room temperature

Article abstract of DOI:10.3184/174751914X14007780679741

A novel base-catalysed 1,3,4-oxadiazole fragmentation for the synthesis of nitriles at room temperature has been developed. This reaction is performed under transition-metal-free conditions, and provides a new ring cleavage reaction of 1,3,4-oxadiazoles in organic synthesis.

Full text of DOI:10.3184/174751914X14007780679741

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 JUNE, 371–374
RESEARCH PAPER 371
A base-induced ring-opening process of 2-substituted-1,3,4-oxadiazoles for
the generation of nitriles at room temperature
Guo-ping Lu* and Ya-mei Lin
College of Chemical Engineering, Nanjing University of Science and Technology, 200 Xiaoling Wei, Nanjing 210094, P.R. China
A novel base-catalysed 1,3,4-oxadiazole fragmentation for the synthesis of nitriles at room temperature has been developed. This
reaction is performed under transition-metal-free conditions, and provides a new ring cleavage reaction of 1,3,4-oxadiazoles
in organic synthesis.
Keywords: 2‑substituted‑1,3,4‑oxadiazole, heterocycle, ring cleavage, nitrile
Ring cleavage reactions of the 1,3,4‑oxadiazoles can lead to
new aliphatic nitrogen‑containing compounds or to other ring
systems. However, few reports mention the ring‑cleavage of
2‑substituted‑1,3,4‑oxadiazoles. We now describe a novel base‑
catalysed 1,3,4‑oxadiazole fragmentation for the formation of
nitriles at room temperature.
With the optimised conditions in hand, a series of 2‑aryl‑
1,3,4‑oxadizoles were chosen to establish the scope and
generality of the method (Table 2). Both electron‑rich and
electron‑defect 2‑aryl‑1,3,4‑oxadizoles gave good to excellent
yields. It should be noted that a poor yield of 2d was observed
even after longer reaction time, presumably due to the poor
solubility of 4‑(1,3,4‑oxadiazol‑2‑yl)phenol 1d in DMF.
Alternatively, the hydroxyl group enhance the electronic
density on the 1,3,4‑oxadizole ring by conjugative effects,
which may inhibit the ring‑opening process.
In order to examine the possibility for large‑scale operation,
we also scaled up the reaction to 10 mmol, and the reaction
proceeded well with 93% yield of 2c just by prolonging the
reaction time to 12 h. The outcome was also satisfactory
(2i, 2j) when sterically hindered substrates were employed.
Heteroaryl nitriles such as 2m and 2n, could be produced from
corresponding 2‑aryl‑1,3,4‑oxadiazoles. To our delight, the
scope of the protocol could be extended to the preparation of the
benzyl nitrile (2o) and the alkyl nitrile (2p). To further highlight
the potential of this chemistry, aromatic nitrile 4, a crucial
intermediate to L692,429 5, a non‑peptidyl growth hormone
secretagogue21 and losartan potassium 6, an angiotensin II
receptor antagonist,22 was synthesised from 1j and 3 through
a one‑pot reaction involving a Suzuki coupling and cyanation
reaction (Scheme 2).
The significance of the present chemistry is two‑fold: (1) It
is the first example of a direct transformation of 2‑substituted‑
1,3,4‑oxadiazoles to nitriles, which are useful in organic
synthesis.1–4 Although, there are many methods for the
preparation of nitriles from simpler substrates compared
to 2‑substituted‑1,3,4‑oxadiazoles, such as aryl halides,5,6
carboxylic acids7,8 and methyl arenes,9–11 the newly developed
protocol provide an alternative route for the cyanation in which
the cyano‑group could be formed via a ring cleavage process
of heterocycles.12 (2) The research not only reveals a new
ring cleavage route for 2‑subsitituted‑1,3,4‑oxadiazoles, but
also offers mechanistic insights into this reaction, which may
suggest new ring‑opening processes of other heteroarenes.
As a part of our interest in cyanation,13 we attempted to
synthesise 5‑phenyl‑1,3,4‑oxadiazole‑2‑carbonitrile through
the copper‑catalysed C–H activation of 2‑phenyl‑1,3,4‑
oxadiazole. However, the reaction failed to provide the desired
product, and instead yielded benzonitrile as the final product.
Moreover, benzonitrile was also obtained in the absence of
copper (Scheme 1). The surprising finding prompted us to
investigate the reaction in more detail in order to possibly
optimise the reaction conditions and to understand the
mechanism of the reaction.
Table 1 Optimisation of the reaction conditionsa
N
N
Base
CN
solvent, rt, 2 h
O
1a
2a
N N
O
Cu(OAc)2, t-BuONa
TM N DMF 130 o
Ph
CN
SC
C
,
,
N N
O
Entry
Base
Solvent
Yield/%b
1
2
3
4
3
4
5
6
7
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
NaOH
DMF
H2O
99, 81c
NR
NR
4
NR
NR
NR
84
92
Ph
t-BuONa
Ph
N
C
DMF 130 o
C
,
DMF/H2O (v/v=1/1)
DMF/H2O (v/v=2/1)
EtOAc
Scheme 1
Further investigations indicated the reaction could be
completed even at room temperature in DMF using t‑BuONa
as the base (Table 1, entry 1). Water proved to have a negative
effect on the process (entries 2–4). After screening different
solvents and bases, the results indicated the necessity of both
a strong base and a polar aprotic solvent. No desired product
was detected in the absence of either of them. The combination
of DMF and t‑BuONa provided the best results (entry 1). The
amount of t‑BuONa was also optimised, and 1.0 equiv. t‑BuONa
proved to be the best selection for the reaction (entry 12).
MeCN
Diglyme
DMSO
DMAc
8
DMF
21
9
K2CO3
DMF
NR
10
11
12
K3PO4
NEt3
t-BuONa
DMF
DMF
DMF
NR
NR
99d, 36e, 3f
aReaction condition: 1a 0.5 mmol, base 1.0 mmol, solvent 1 mL, room
temperature, 2 h. bGC yields. cThe reaction time is 1 h. d1.0 equiv. t-BuONa
was used. e0.50 equiv. t-BuONa was used. f0.25 equiv. t-BuONa was used.
NR, No reaction.
* Correspondent. E‑mail: glu@njust.edu.cn
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372 JOURNAL OF CHEMICAL RESEARCH 2014
Table 2 The synthesis of nitriles from 2-substituted-1,3,4-oxadiazolea
N
N
t-BuONa
Ar
Ar CN
DMF, rt
O
1
2
Entry
Ar
1
Time/h
a
Yield/%b
M.p./oC
Lit. m.p./oC
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph
3-CH3C6H4
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
4
4
4
24
8
4
4
8
4
4
8
8
8
8
4
4
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
90
95
97, 93c
45d
89
98
94
84
95
88
84
99
93
91
87
92
Oil
Oil
56–58
110–112
36–38
92–94
Oil14
Oil15
61–6214
110–11314
39–4115
90–9315
4-MeOC6H4
4-HOC6H4
4-F3CC6H4
4-ClC6H4
4-O2NC6H4
4-FC6H4
145–147 148–15014
32–34
108–110
192–194
64–66
92–94
48–50
Oil
32–3415
107–10916
194–19517
63–6814
91–9418
50–5119
26–2820
Oil18
2-O2NC6H4
2-BrC6H4
2-Naphthyl
3,4,5-Trimethylphenyl
3-Pyridyl
2-Pyridyl
Benzyl
2-Phenylethyl
Oil
Oil
Oil18
aReaction condition: 1 0.5 mmol, t-BuONa 0.5 mmol, DMF 1 mL, room temperature. b Isolated yields. c Reaction condition:
1c 10.0 mmol, t-BuONa 10.0 mmol, DMF 10 mL, room temperature, 12 h. dThe reaction was performed in DMSO.
N
B(OH)2
N
Pd(OAc)2, t-BuONa
+
DMF, 80 oC, 8 h
O
Br
N
4
C
3
O
1j
, 83%
l
C
NH2
N
NH
H
O
N N
N
N N
N
O
N
NK
N
NH
5
6
Scheme 2
The synthesis of letrozole 8, which is an oral non‑steroidal
aromatase inhibitor for the treatment of hormonally‑responsive
breast cancer after surgery,23 was also achieved with our
present transformation as the key step (Scheme 3). Initially,
we intended to prepare 2q by the cyanation of 1q under basic
conditions, but the reaction failed to provide the desired
product. Alternatively, the formation of 2q could be realised
using 1r as the starting material via cyanation, bromination and
electrophilic substitution. In the last step, 2q was reacted with
1h under optimised conditions to afford letrozole 8 in a one‑pot
cyanation and nucleophilic substitution (Scheme 3).
position of 1,3,4‑oxadiazole ring may be necessary for the ring‑
opening process.12
The role of the DMF in the reaction can be explained since
the solvation of the sodium ion in DMF enhances the basicity
of t‑BuONa. This has a positive effect on the formation of
a carbanion intermediate. Based on these results above,
a proposed mechanism for the reaction was illustrated in
Scheme 5. A corresponding carbanion intermediate is formed
by removal of a proton from the 5 position of the 2‑substituted‑
1,3,4‑oxadiazole with strong base. This is followed by a ring‑
opening transformation to yield the nitrile.
In order to study the mechanism, several control experiments
were carried out. First, the cyanation of 1a gave benzonitrile
2a in DMSO (Table 1, entry 6), showing that the cyano‑group
originated from the 1,3,4‑oxadiazole ring, and benzonitrile
2a aroseby 1,3,4‑oxadiazole fragmentation. Second, the
reaction proceeded smoothly in the presence of 1.2 equiv. of
TEMPO (Scheme 4). Moreover, the reaction was not sensitive
to moisture and oxygen, because the reaction could took place
under air atmosphere in DMF which was used directly without
drying. It could be concluded that the transformation do not
proceed through a radical intermediate.24–26 Subsequently,
2,5‑diphenyl‑1,3,4‑oxadiazole 9 was employed in the protocol,
but no reaction occurred indicating that the hydrogen on 5
In conclusion, we have discovered and optimised a novel,
methodology for the synthesis of nitriles from 2‑substituted‑
1,3,4‑oxadiazoles via a base‑induced ring‑opening process
at room temperature under transition‑metal‑free conditions.
Although 2‑substituted‑1,3,4‑oxadiazoles compared to other
starting materials of cyanation have no advantage from
synthetic point of view, the transformation offers another
approach to cyanation in which nitriles can be formed by a
heterocyclic ring cleavage process. In addition, it is an efficient
protocol for the fragmentation of 1,3,4‑oxadiazole ring, due to
its mild conditions, high yields and simple work‑up procedures,
offering potential for applications in organic synthesis.
JCR1402514_FINAL.indd 372
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JOURNAL OF CHEMICAL RESEARCH 2014 373
N
N
N
C
t-BuONa
N
N
O
N
N
N
r
DMF
t
,
N
1
q
2
q
N
N
N
C
N
C
NBS, (PhCO2)2
t-BuONa
DMF, rt, 8 h
O
r
B
CHCl3, reflux, 24 h
r
1
r
94
,
2
7
%
, 89%
N
N
N
N
N
F
HN
N
N
C
N
1h
O
N
N
K2CO3, KI, acetone
reflux, 16 h
N
t-BuOK, DMF, rt, 9 h
2q
, 97%
N
C
N
C
8
, 64%
Scheme 3
t-BuONa
t-BuOH
t-BuONa 1 equiv
TEMPO 1.2 equiv
N N
O
N
O
N
O
Ph
N
C
N
N
Ph
Ph
DMF, rt, 2 h
Ar
Ar
2a
1a
GC yield 99%
H
2O
N N
t-BuONa
no reaction
Ph
DMF, rt, 24 h
H2O
O
9
CO2 + NH3
HN
C O
OH-
Ar CN
Scheme 4
Scheme 5
Experimental
4′-Methylbiphenyl-2-carbonitrile (4): A mixture of 1j (0.5 mmol),
3 (0.6 mmol), Pd(OAc)2 (0.01 mmol), t‑BuONa (1.0 mmol) and DMF
(1 mL) was stirred at 80 °C for 8 h. When the reaction completed,
EtOAc (5 mL) and petroleum ether (5 mL) were added, and the mixture
was washed by water (3×10 mL) to remove DMF. The organic layer
was collected and filtered through a bed of silica gel layered over
Celite. The volatiles were removed under reduced pressure, and further
column chromatography on silica gel was needed to afford the pure
desired product 4 (83%), white solid, m.p. 46–48 °C (lit.19 49–50 °C).
Letrozole (8): 2r was prepared by the general procedure for the
synthesis of nitriles from 2‑substituted‑1,3,4‑oxadiazoles in 94% yield,
colourless oil, m.p.<30 °C (lit.15 26–28 °C).
A mixture of p‑toluonitrile 2r (5 mmol), N‑bromosuccinimide
(5 mmol) and benzoyl peroxide (10 mg) was refluxed in chloroform
(15 mL) for 24 h. The completion of reaction was detected by TLC. The
solvent was evaporated under reduced pressure and then ethyl acetate
and H2O was added. The organic layer was extracted and washed
3 times with brine. After evaporation of ethyl acetate, compound
7 was obtained as a white solid (yield 89%), m.p. 112–114 °C (lit.29
113–115 °C). The product was used for the next step without any further
purification.
2‑Subsituted‑1,3,4‑oxadiazoles were prepared from corresponding
carboxylic acids according to previous literature27,28 (see Electronic
Supplementary Information, ESI). All other chemical reagents
were obtained from commercial suppliers and used without further
purification. All the products were known compounds, which were
1
identified by appropriate technique such as H NMR, and 13H NMR
and compared with previously reported data. Analytical TLC was
performed on glass plates precoated with silica gel impregnated with
a fluorescent indicator (254 nm), and the plates were visualised by
exposure to UV light. Mass spectra were taken on a Finnigan TSQ
Quantum‑MS instrument in the electrospray ionisation mode. 1H
NMR and 13C NMR spectra were recorded on an Avance 500 Bruker
spectrometer operating at 500 MHz and 125 MHz in CDCl3 or
DMSO‑d6, respectively. Chemical shifts were reported in ppm. GC
analyses are performed on an Agilent 7890A instrument (Column:
Agilent 19091J-413: 30 m×320 μm×0.25 μm, carrier gas: H2, FID
detection. GC/MS data were obtained by using a Saturn2000 GC/MS
series. HP 5890 GC was equipped with a CPSTIL‑8CB mass selective
detector.
Synthesis of nitriles from 2‑substituted‑1,3,4‑oxadiazoles; general
procedure
A
mixture of methyl 4‑(bromomethyl)benzoate 7 (3 mmol),
1H‑1,2,4‑triazole (4.5 mmol), K2CO3 (4.5 mmol), KI (0.15 mmol) and
acetone (10 mL) was stirred under reflux for 16 h. Then, water (20 mL)
was added to the mixture. The product was extracted with ethyl acetate
(3×5 mL). The organic phase was dried over Na2SO4, and the solvent
was evaporated under vacuum affording the product 2q (methyl
4‑((1H‑1,2,4‑triazol‑1‑yl)methyl)benzoate, 97%), white solid, m.p.
78–80 °C, (lit.30 77–79 °C).
At –5 °C and under argon atmosphere, t‑BuOK (3 mmol) was
suspended in anhydrous DMF (2.5 mL) with vigorous stirring. Over
a period of 1 h, 2q (0.75 mmol) dissolved in 1 mL DMF was added
A mixture of 2‑substituted‑1,3,4‑oxadiazole (0.5 mmol), t‑BuONa
(0.5 mmol) and DMF or DMSO (1 mL) was stirred at room temperature
for an appropriate time. When the reaction completed, EtOAc (5 mL)
and petroleum ether (5 mL) were added, and the mixture was washed
by water (3×10 mL) to remove DMF or DMSO. The organic layer was
collected and filtered through a bed of silica gel layered over Celite.
The volatiles were removed under reduced pressure to afford the final
product. In a few cases, further column chromatography on silica gel
was needed to afford the pure desired product.
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374 JOURNAL OF CHEMICAL RESEARCH 2014
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dropwise to the reaction mixture, followed by dropwise addition of
2‑(4‑fluorophenyl)‑1,3,4‑oxadiazole 1h (1.09 mmol) in 0.5 mL DMF
over 30 min. After 7.5 h, the mixture was quenched with 3 M HCl until
acidic (pH<5), neutralised with NaHCO3, diluted with 50 mL water
and then extracted with 3×15 mL EtOAc. The organic fraction was
washed with brine, dried over Na2SO4, filtered and concentrated. The
residue was purified by silica gel column chromatography to yield the
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Electronic Supplementary Information
The ESI is available through
stl.publisher.ingentaconnect.com/content/stl/jcr/supp‑data.
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Received 10 March 2014; accepted 25 April 2014
Paper 1402514 doi: 10.3184/174751914X14007780679741
Published online: 10 June 2014
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