High-temperature continuous flow synthesis of 1,3,4-oxadiazoles via N-acylation of 5-substituted tetrazoles

Article abstract of DOI:10.1016/j.tetlet.2011.12.043

Applying continuous flow processing in a high-temperature/high-pressure regime (200-220 °C, 11-14 bar) 2,5-disubstituted-1,3,4-oxadiazoles are prepared in high yields within 5-10 min residence time by treatment of 5-substituted-1H-tetrazoles with anhydrides or acid chlorides as electrophiles (Huisgen reaction).

Full text of DOI:10.1016/j.tetlet.2011.12.043

Tetrahedron Letters 53 (2012) 952–955
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
High-temperature continuous flow synthesis of 1,3,4-oxadiazoles
via N-acylation of 5-substituted tetrazoles
⇑
Benedikt Reichart, C. Oliver Kappe
Christian Doppler Laboratory for Microwave Chemistry, Institute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
Applying continuous flow processing in a high-temperature/high-pressure regime (200–220 °C, 11–14 bar)
2,5-disubstituted-1,3,4-oxadiazoles are prepared in high yields within 5–10 min residence time by treat-
ment of 5-substituted-1H-tetrazoles with anhydrides or acid chlorides as electrophiles (Huisgen reaction).
Ó 2011 Elsevier Ltd. All rights reserved.
Received 26 November 2011
Revised 6 December 2011
Accepted 9 December 2011
Available online 24 December 2011
Keywords:
Continuous flow synthesis
Heterocycles
Microreactors
Microwave-assisted synthesis
Process intensification
1,3,4-Oxadiazole derivatives display a broad spectrum of phar-
maceutical and biological activities including anti-inflammatory,
antimicrobial, anticonvulsant, and antiviral properties,1 and fur-
thermore have attracted interest in medicinal chemistry as surro-
gates (bioisosteres) of carboxylic acids, esters and carboxamides.2
A number of important pharmaceuticals including the HIV-integr-
ase inhibitor Raltegravir3 and the antihypertensive agents Tiodazo-
sin4 and Nesadipil5 possess the 1,3,4-oxadiazole nucleus. In
addition, the oxadiazole heterocyclic scaffold is found in a number
of important photosensitive6 and high-performance/high-tempera-
ture resistant polymers.7
The 1,3,4-oxadiazole ring system can be prepared using several
different methods, which include: (a) the introduction of a one-car-
bon fragment from acyl hydrazides and ortho esters, (b) the cyclode-
hydration of 1,2-diacylhydrazides, (c) the oxidative cyclization of
hydrazones and semicarbazones, and (d) the reaction of tetrazoles
with electrophiles.8 Interestingly, the last method, the synthesis of
1,3,4-oxadiazoles 2 by reaction of 5-substituted-1H-tetrazoles 1
with electrophiles (such as carboxylic acid anhydrides or acid chlo-
rides) has received comparatively little interest in the past few
years.9–11 Originally reported by Huisgen and co-workers in
1958,10 this transformation (now known as Huisgen reaction) can
provide 2,5-disubstituted-1,3,4-oxadiazoles in a very clean and effi-
cient manner via initial N-acylation of the tetrazole nucleus by the
electrophile, followed by extrusion of nitrogen and formation of a
1,5-dipole (nitrileimine) which subsequently cyclizes to the desired
1,3,4-oxadiazole (Fig. 1).9,10 The less frequent use of this method, in
particular on large scale, may be related to the known thermal insta-
bility of the tetrazole nucleus. Tetrazole derivatives are considered
high energy compounds and are used as propellants and explosives;
these heterocycles tend to release nitrogen under thermal stress,
and thus need to be handled with care.12
In addition to the thermal instability of the tetrazole nucleus it-
self, the synthesis of these heterocycles is not without complication
either and often involves potentially hazardous procedures requir-
ing the handling of inorganic or organic azide precursors.13 In recent
publications, we14 and others15 have reported the safe generation of
5-substituted-1H-tetrazoles 1 from organic nitriles and an inorganic
azide source using microreactor technology. As an extension to our
previous method,14 we now describe a safe and scalable continuous
flow method for the generation of 1,3,4-oxadiazoles 2 from
O
H
R2
X = Cl, OR2
X
N
R1
R1
N
N
R1
N
N
N
N
NH
N
N
N
N
O
1
R2
O
R1
R2
O
R1
C N N C
R2
- N2
N
N
2
⇑
Corresponding author. Tel.: +43 316 3805352; fax: +43 316 3809840.
E-mail address: oliver.kappe@uni-graz.at (C.O. Kappe).
Figure 1. Mechanism of the Huisgen 1,3,4-oxadiazole synthesis.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.043

B. Reichart, C. O. Kappe / Tetrahedron Letters 53 (2012) 952–955
953
to the requirement of reaction homogeneity in continuous flow
processing, solubility issues before, during, and after the reaction
were carefully evaluated using microwave batch technology before
starting the optimization studies. Different aprotic polar solvents
(e.g., DMF, NMP, DME, pyridine, MeCN and mixtures thereof) were
screened and ultimately 1,2-dimethoxyethane (DME, bp. 85 °C)
was used as the solvent of choice for reactions involving anhy-
drides, while in the case of acid chlorides a 1:9 (v/v) mixture of
pyridine and acetonitrile (pyr/MeCN) provided best results.
As a starting point for the Huisgen reaction with acetic anhy-
dride we employed 5 equiv of the anhydride and screened different
temperatures in order to obtain reliable data on the influence of
temperature on reaction speed and product purity (Table 1, entries
1–3, see also Fig. S2 in the Electronic Supplementary data). Raising
the temperature to 240 °C (18 bar) allowed a reduction of the reac-
tion time to just 1 min, still providing a very pure product accord-
ing to HPLC-UV monitoring. In the next phase we attempted to
reduce the excess of acetic anhydride as far as possible retaining
full conversion at high temperatures (Table 1, entries 4–8). An opti-
mum set of conditions for the Huisgen reaction was ultimately ob-
tained by applying 2 equiv of acetic anhydride, 5 min reaction time
and 220 °C (14 bar) reaction temperature (Table 1, entry 9). This
set of conditions provided full conversion to the desired 1,3,4-oxa-
diazole 2a, no major byproducts, and a 93% isolated product yield
after an extractive work-up. Compared to the classical conditions
reported for these transformations in the literature where the reac-
tion solvent is typically the reagent (Ac2O) and reaction times of
several hours are required,9–11 these intensified high-T/p condi-
tions constitute a significant improvement.
For the second method employing benzoyl chloride as the elec-
trophile reagent, our initial optimization regime employed anhy-
drous pyridine (pyr) as the solvent as previously suggested in the
literature by Huisgen and co-workers (Table 2, entries 1–6).10 In-
deed, applying high-T/p conditions in combination with 1.15 equiv
of PhCOCl full conversion could be achieved within only one min at
140 °C (entry 6). As the use of pyridine as solvent is not desirable on
larger scale, we subsequently started to reduce the amount of pyr-
idine using acetonitrile (MeCN, bp.81 °C) as a more benign co-sol-
vent (Table 2, entries 7–11). Gratifyingly, the amount of pyridine
base could ultimately be reduced to 10% (v/v) with full conversion
being achieved at 200 °C (10 bar) within 8 min (entry 12). The iso-
lated yield of pure 2,5-diphenyl-1,3,4-oxadiazole (2a) using these
Table 1
Optimization of Huisgen reaction conditions using acetic anhydride as electrophilea
N
N
HN
N
N
Ac2O (1.05-5 equiv), DME
MW, 120-220 °C, 1-20 min
Me
O
N
1a
2a
Entry
Ac2O (equiv)
Time (min)
T (°C)
Conversionb (%)
1
2
3
4
5
6
7
8
9
5
5
5
1.5
1.5
1.5
1.05
1.05
2
20
10
1
10
5
120
180
240
140
200
220
140
220
220
55
100
100
12
89
97
5
10
10
5
6
92
100 (93)c
a
Conditions: 0.3 mmol of 1a, 1.05–5.0 equiv of Ac2O in anhydrous DME (3 mL).
Single-mode microwave heating (Biotage Initiator 2.5) with magnetic stirring.
b
Conversion based on HPLC-UV analysis (215 nm).
Isolated yield (see Electronic Supplementary data for details).
c
5-aryl-1H-tetrazoles via Huisgen reaction. The use of a high-temper-
ature/high-pressure flow regime allows a drastic intensification of
this transformation leading to a reduction of the required reaction
times to 5–10 min.
As a starting point in our investigations we have employed
sealed vessel batch microwave technology in order to rapidly ac-
cess high-temperature/pressure (high-T/p) process windows on
small scale (3 mL). This was required since most of the original
experimental procedures for these transformations report reaction
times of several hours, unsuitable for efficient continuous flow pro-
cessing.9–11,16 In a subsequent step the optimized conditions were
then translated from batch to continuous flow following the
‘microwave-to-flow’ paradigm.17 Owing to the high surface-to-vol-
ume ratio in conventionally heated microreactors of this type, heat
transfer to the reaction mixture is very efficient, thus mimicking
the advantages of using microwave dielectric heating on small
scale, but gaining the beneficial aspects of safety and scalability.17
Our initial optimization studies focused on two model transfor-
mations involving 5-phenyl-1H-tetrazole (1a): its reaction with
acetic anhydride (Table 1) and benzoyl chloride (Table 2), leading
to the corresponding 2,5-disubstituted-1,3,4-oxadiazoles 2. Owing
Table 2
Optimization of Huisgen reaction conditions using benzoyl chloride as the electrophilea
N
N
HN
N
N
PhCOCl (1.15-1.25 equiv)
pyr/MeCN (1:0-1:9)
O
N
MW, 80-200 °C, 1-10 min
2r
1a
Entry
PhCOCl (equiv)
Solvent (v:v)
Time (min)
T (°C)
Conversionb (%)
1
2
3
4
5
6
7
8
1.15
1.15
1.15
1.15
1.15
1.15
1.15
1.15
1.15
1.15
1.15
1.25
pyr
pyr
pyr
pyr
pyr
pyr
10
2.5
1
1
1
1
1
1
5
140
140
100
80
120
140
160
120
180
180
180
200
100
100
79
25
96
100
100
95
99
pyr/MeCN (1:1)
pyr/MeCN (1:1)
pyr/MeCN (1:2)
pyr/MeCN (1:3)
pyr/MeCN (1:6)
pyr/MeCN (1:9)
9
10
11
12
5
5
8
100
100
100 (90)c
a
Conditions: 0.3 mmol of 1a, 1.15–1.25 equiv of PhCOCl in anhydrous pyridine/acetonitrile mixture (3 mL). Single-mode microwave heating (Biotage Initiator 2.5) with
magnetic stirring.
b
Conversion based on HPLC-UV analysis (215 nm).
Isolated yield (see Electronic Supplementary data for details).
c

954
B. Reichart, C. O. Kappe / Tetrahedron Letters 53 (2012) 952–955
conditions after precipitation with 2 N HCl was 90%, comparing
favorable with literature data.10
digm).17 The reaction times obtained in the batch microwave syn-
theses were identical to the residence times used in the continuous
flow protocols (Tables 3 and 4). As in our recent tetrazole synthe-
sis,14 flow experiments were performed in a FlowSyn reactor
(Uniqsis Ltd) equipped with a 20 mL (1.0 mm i.d.) stainless steel
coil (Fig. S1 in the Electronic Supplementary data). Thus, the reac-
tion mixture (one feed concept) was pumped through the coil reac-
tor heated to the appropriate temperature (200–220 °C) and left
the reactor via the heat exchanger and a 34 bar back-pressure reg-
ulator. The entire reaction mixture was collected (plus a 4 mL pre
collection and 8 mL post collection volume) and the desired prod-
ucts were subsequently isolated in similar high yields and excel-
lent purities as achieved using microwave batch conditions
(Tables 3 and 4).18 The only change in comparison to the batch
experiments relates to the use of acid chlorides in these reactors
(Table 4): in order to protect the stainless steel coil from corrosion
during the continuous flow experiments with acid chlorides at
high temperatures (corrosive action of free HCl), 2.5 equiv of tri-
ethylamine were added to the reaction mixture.19
With optimized conditions for both types of tetrazole to oxadi-
azole transformations in hand, we next evaluated the scope and
limitations of these processes using a collection of 12 of our previ-
ously synthesized14 5-aryl-1H-tetrazoles 1a–l as starting materials,
in combination with a small set of electrophiles (acetic, propionic
and pivalic anhydride; benzoyl and propionyl chloride). As shown
in Tables 3 and 4, in all instances the expected 2,5-disubstituted-
1,3,4-oxadiazoles were obtained in good to excellent yields using
microwave batch technology after an extractive work-up (see Elec-
tronic Supplementary data for details). For pivalic anhydride (Table
3), the reaction time was extended to 10 min in order to provide
complete conversion of the starting material. In a few cases, the sol-
vent was changed from DME to DMF to increase the solubility of the
tetrazole starting materials (Table 3, 1b, 1c, 1h, 1i). For oxadiazole
syntheses involving acid chlorides (Table 4) a prolongation of the
reaction time to 10 min was required for propionyl chloride. Apart
from these minor changes, the originally optimized conditions
worked well for all the tested tetrazole/electrophile combinations.
Finally, both sets of conditions were translated from the micro-
wave batch runs to high-T/p continuous flow processing without
changing any of the key parameters (‘microwave-to-flow’ para-
In terms of productivity, taking the preparation of 2-(1,1-
diphenylethyl)-5-methyl-1,3,4-oxadiazole (2m, Table 3) as an
example, a throughput of approximately 85 g of oxadiazole prod-
uct per day can be obtained using this method.
Table 3
a
Batch and continuous flow synthesis of 2,5-substitued-1,3,4-oxadiazoles 2 using anhydride electrophiles
(R2CO)2O (2 equiv), DME
HN
N
N
N
R1
N
R1
R2
N
O
MW or Flow, 220 °C, 5-10 min
2a-q
1a-l
Tetrazole 1
(R2CO)2O
R2 = Me
Method
Timeb (min)
Yieldc (%)
1a: R1 = C6H5
MW
Flow
MW
Flow
MW
Flow
MW
Flow
MW
Flow
MW
Flow
MW
Flow
MW
Flow
MW
Flow
MW
Flow
MW
Flow
MW
Flow
MW
Flow
MW
Flow
MW
Flow
MW
Flow
MW
Flow
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
—
5
—
5
—
5
—
5
5
5
5
5
—
10
10
10
—
10
10
93
84
93
93
87
86
91
92
79
86
99
93
83
80
55
—
61
—
85
—
84
—
95
92
90
95
74
—
81
78
86
—
1b:d R1 = 4-(Br)C6H4
1c:d R1 = 4-(Me)C6H4
1d: R1 = 4-(CF3)C6H4
1e: R1 = 3-(NO2)C6H4
1f: R1 = 3-(MeO)C6H4
1g: R1 = 2-furanyl
1h:d R1 = 2-pyrazinyl
1i:d R1 = 2-pyridinyl
1j: R1 = 4-ClC6H4
R2 = Me
R2 = Me
R2 = Me
R2 = Me
R2 = Me
R2 = Me
R2 = Me
R2 = Me
R2 = Me
R2 = Me
R2 = Me
R2 = Me
R2 = Et
1k: R1 = 4-(Cl)-benzyl
1l: R1 = (Ph)2CH
1m: R1 = Me(Ph)2C
1a: R1 = C6H5
1a: R1 = C6H5
R2 = tBu
R2 = tBu
R2 = tBu
1b: R1 = 4-BrC6H4
1l: R1 = (Ph)2CH
92
90
a
Conditions MW: see Table 1, entry 9; continuous flow: one feed concept using 1.2 mmol of 1, 2.4 mmol of (R2CO)2O dissolved in 15 mL of dry DME pumped through a
20 mL stainless steel coil (FlowSyn, Uniqsis Ltd).
b
Reaction times refer to hold times at 220 °C in the microwave experiments, and to residence times in the continuous flow experiments in the 20 mL stainless steel coil
(flow rate 2.0–4.0 mL/min).
c
Isolated yields. For work-up protocols, see the Electronic Supplementary data.
Dimethylformamide (DMF) was used as the solvent.
d

B. Reichart, C. O. Kappe / Tetrahedron Letters 53 (2012) 952–955
955
Table 4
Batch and continuous flow synthesis of 2,5-substitued-1,3,4-oxadiazoles 2 using acid chloride electrophilesa
R2COCl (1.25 equiv), Et3N (2.5 equiv)
HN
N
N
N
N
pyr/MeCN (1:9)
R1
R1
R2
N
O
MW or Flow, 200 °C, 8-10 min
2n, 2r-u
1a 1d 1k 1m
,
,
,
b
c
Tetrazole 1
a: R1 = C6H5
R2COCl (1.25 equiv)
R2 = C6H5
Method
Time (min)
Yield (%)
MW
Flow
MW
Flow
MW
Flow
MW
Flow
MW
Flow
8
8
8
8
8
8
10
10
10
10
91
92
88
87
75
76
80
81
75
80
1k: R1 = 4-(Cl)-benzyl
1m: R1 = Me(Ph)2C
1a: R1 = C6H5
R2 = C6H5
R2 = C6H5
R2 = Et
1d: R1 = 4-(CF3)-C6H4
R2 = Et
a
Conditions MW: see Table 2, entry 12; continuous flow: one feed concept using 1.2 mmol of 1, 1.25 mmol of R2COCl and 2.5 equiv of Et3N dissolved in 15 mL of 1:9
pyridine/acetonitrile (v/v) pumped through a 20 mL stainless steel coil (FlowSyn, Uniqsis Ltd).
b
Reaction times refer to hold times at 200 °C in the microwave experiments, and to residence times in the continuous flow experiments in the 20 mL stainless steel coil
(flow rate 2.0–2.5 mL/min).
c
Isolated yields. For work-up protocols, see the Electronic Supplementary data.
9. (a) Ostrovskii, V. A.; Koldobskii, G. I.; Trifonov, R. E. In Comprehensive
In conclusion, we have demonstrated that 2,5-disubstituted-
1,3,4-oxadiazoles of type 2 can be synthesized with very high
Heterocyclic Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V.,
Taylor, R. K., Eds.; Elsevier: Amsterdam, 2008; vol. 6, pp 257–423; (b)
Hetzheim, A., 4th ed. In Methoden der Organischen Chemie (Houben-Weyl);
Schaumann, E., Ed.; Thieme: Stuttgart, 1994; Vol. 8c, p 526; (c) Koldobskii, G. I.;
Ivanova, S. E. Russ. J. Gen. Chem. 1994, 64, 1512–1517; (d) Moderhack, D. J. Prakt.
Chem. 1988, 340, 687–709.
efficiency (5–10 min) using
a high-temperature/high-pressure
(high-T/p) microreactor approach. Employing microwave batch
technology as an optimization tool, optimum reaction conditions
were rapidly identified and subsequently translated to a continuous
flow protocol. This method now allows the safe conversion of ther-
mally compromised 1H-tetrazoles into thecorresponding 1,3,4-oxa-
diazoles (Huisgen reaction).
10. (a) Huisgen, R.; Sauer, J.; Sturm, H. J. Angew. Chem. 1958, 70, 272–273; (b)
Sauer, J.; Huisgen, R.; Sturm, H. J. Tetrahedron 1960, 11, 241–251; (c) Huisgen,
R.; Sauer, J.; Sturm, H. J.; Markgaf, J. H. Chem. Ber. 1960, 93, 2106–2124; (d)
Huisgen, R.; Sturm, H. J.; Seidel, M. Chem. Ber. 1961, 94, 1555–1562; (e)
Huisgen, R.; Sauer, J.; Seidel, M. Chem. Ber. 1961, 94, 2503–2509.
11. For more recent applictions of the Huisgen oxadiazole synthesis, see: (a) Jursic,
B. S.; Zdravkovski, Z. Synth. Commun. 1994, 24, 1575–1582; (b) Fürmeier, S.;
Metzger, J. O. Eur. J. Org. Chem. 2003, 885–893; (c) Obushak, N. D.; Pokhodylo,
N. I.; Matiichuk, V. S. Russ. J. Org. Chem. 2008, 44, 1522–1527; (d) Vereshchagin,
L. I.; Petrov, A. V.; Proidakov, A. G.; Pokatilov, F. A.; Smirnov, A. I.; Kizhnyaev, V.
N. Russ. J. Org. Chem. 2004, 42, 912–917; (e) Tóth, M.; Kun, S.; Bokor, E.; Benltifa,
M.; Tallec, G.; Vidal, S.; Docsa, T.; Gergely, P.; Somsák, L.; Praly, J. P. Biorg. Med.
Chem. 2009, 17, 4773–4785.
Acknowledgments
This work was supported by a Grant from the Christian Doppler
Research Foundation (CDG). We thank Bernhard Gutmann for his
contributions to this work.
12. (a) Lesnikovich, A. I.; Levchik, S. V.; Balabanovich, A. I.; Ivaskevich, O. A.;
Gaponik, P. N. Thermochim. Acta 1992, 200, 427–441; (b) Klapötke, T. M. In High
Energy Density Materials; Klapötke, T. M., Ed.; Springer: Heidelberg, 2007; Vol.
125, pp 36–52.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.043.
13. (a) Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379–3383; (b) Wittenberger, S. J.
Org. Prep. Proced. Intl. 1994, 26, 499–531.
14. (a) Gutmann, B.; Roduit, J. P.; Roberge, D.; Kappe, C. O. Angew. Chem., Int. Ed.
2010, 49, 7101–7105; See also: (b) Cantillo, D.; Gutmann, B.; Kappe, C. O. J. Am.
Chem. Soc. 2011, 133, 4465–4475; (c) Gutmann, B.; Glasnov, T. N.; Razzaq, T.;
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15. Palde, B. P.; Jamison, T. F. Angew. Chem., Int. Ed. 2011, 50, 3525–3528.
16. For recent publications involving the use of microwave heating in the Huisgen
reaction, see: (a) Macheno, O. G.; Bolm, C. Org. Lett. 2007, 9, 2951–2954; (b)
Lukyanov, S. M.; Bliznets, I. V.; Shorshnev, S. V.; Aleksandrov, G. G.; Stepanow,
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reaction mixture was collected (plus 4 mL pre collection and 8 mL post
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details see the Electronic Supplementary data).
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19. This method has been used previously in our laboratories for high-temperature
continuous flow transformations involving HCl in stainless steel coils, see:
Obermayer, D.; Glasnov, N. T.; Kappe, C. O. J. Org. Chem. 2011, 76, 6657–6669.
See also Ref. 14c.
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