Synthesis of 1,3,4-oxadiazoles from 1,2-diacylhydrazines using [Et 2NSF2]BF4 as a practical cyclodehydration agent

Article abstract of DOI:10.1039/c1ob06512b

The preparation of 1,3,4-oxadiazoles from 1,2-diacylhydrazines using XtalFluor-E ([Et₂NSF₂]BF₄) as cyclodehydration reagent is described. Various functionalized 1,3,4-oxadiazoles were synthesized and it was found that the use of acetic acid as an additive generally improved the yields.

Full text of DOI:10.1039/c1ob06512b

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PAPER
Synthesis of 1,3,4-oxadiazoles from 1,2-diacylhydrazines using [Et2NSF2]BF4
as a practical cyclodehydration agent†
Marie-France Pouliot, Laetitia Angers, Jean-Denys Hamel and Jean-Franc¸ois Paquin*
Received 2nd September 2011, Accepted 27th October 2011
DOI: 10.1039/c1ob06512b
The preparation of 1,3,4-oxadiazoles from 1,2-diacylhydrazines using XtalFluor-E ([Et2NSF2]BF4) as
cyclodehydration reagent is described. Various functionalized 1,3,4-oxadiazoles were synthesized and it
was found that the use of acetic acid as an additive generally improved the yields.
It is not surprising that a number of synthetic methods for
the preparation of 1,3,4-oxadiazoles have been developed over
Introduction
the years9 and among these, the cyclodehydration reaction of
1,2-diacylhydrazines is the most commonly encountered.10 To
promote this transformation, a number of cyclodehydration agents
have been used including SOCl2,11 POCl3,12 Burgess reagent,13 2-
chloro-1,3-dimethylimidazolinium chloride,14 as well as others.15
While some of these reagents are expensive and not available
on a large scale, most are either hygroscopic, moisture sensitive,
highly toxic or thermally unstable, which can sometimes impede
their use. Finally, some transformations require an excess of the
cyclodehydration agent (>2 equiv.) in order to obtain good yields
which generate, along the way, unnecessary waste.
N-containing heterocycles, especially five-membered rings, are of
great interest as they are found in natural products1 and used
frequently in medicinal chemistry.2 Amongst these heterocycles,
the 1,3,4-oxadiazole motif is of particular value in materials
science,3 agrochemistry4 and in pharmaceutical chemistry as it
can be used as a bioisosteric replacement of acid, ester, and amide
functionalities (Fig. 1).5,6,7,8
Recently, diethylaminodifluorosulfinium tetrafluoroborate
([Et2NSF2]BF4), XtalFluor-E,16 has been reported as a new,
crystalline deoxofluorinating agent with enhanced thermal
stability.17 It has been shown that this reagent is fluoride-deprived,
i.e. for the deoxofluorination reaction to proceed, an external
source of fluoride was required. In this context, we wondered if
this reagent could, in the absence of a fluoride source, be used as an
activating agent. We report herein the use of XtalFluor-E as a new
cyclodehydration agent for the preparation of 1,3,4-oxadiazoles
from 1,2-diacylhydrazines.
Results and discussion
Optimization was performed with 1,2-diacylhydrazine 1a and
initial results are reported in Table 1. Reaction of 1a with 1.5
equivalents18 of XtalFluor-E at low temperature resulted in a low
yield of the desired 1,3,4-oxadiazole (entry 1). A side-product was
isolated and identified as N,N-diethylcyclohexanecarboxamide
Fig. 1 Pharmaceuticals containing the 1,3,4-oxadiazole motif.
1
(3).19 The crude H NMR for this reaction indicated a ratio of
33 : 67 between the oxadiazole and the amide. Performing the
reaction at higher temperature slightly improved the isolated yield
of 2a and the ratio 2a : 3 (entries 2–3). It is interesting to note
that using the structurally related reagents DAST or Deoxo-
Canada Research Chair in Organic and Medicinal Chemistry, Department
of Chemistry, 1045 avenue de la Me´decine, Universite´ Laval, Que´bec,
Canada. E-mail: jean-francois.paquin@chm.ulaval.ca; Fax: +1-418-656-
7916; Tel: +1-418-656-2131 ext. 11430
† Electronic supplementary information (ESI) available: Experimental
procedures for the synthesis of the starting 1,2-diacylhydrazines or 1-
thio-1,2-diacylhydrazine and NMR spectra for all the new compounds
prepared. See DOI: 10.1039/c1ob06512b
◦
R
Fluorꢀ (1.5 equivalents in CH2Cl2, 0 C to rt, 12 h) led to lower
isolated yields (<15%) and the crude mixture showed a significant
portion of the side-product (ratio 2a : 3 = 10 : 90).20,21 The fact that
988 | Org. Biomol. Chem., 2012, 10, 988–993
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Scheme 1 Proposed mechanism for the formation of the 1,3,4-oxadiazole 2a and side-product 3.
Table 1 Initial results and optimizationa
In order to improve both the yield and the selectivity in favour
of the oxadiazole, we next investigated the use of additives. Of
the ones tested, acetic acid (AcOH) was revealed to be the best.27
Indeed, without acid, 2a was isolated in 61% yield with a 2a : 3 ratio
of 66 : 34; however, using 1.5 equivalents of AcOH28 allowed the
desired product to be isolated in an improved yield of 77% with
a better selectivity in favour of the oxadiazole (2a : 3 = 80 : 20).
Finally, it was discovered that if XtalFluor-E and acetic acid
were stirred together in DCE for 20 min at rt before adding
the 1,2-diacylhydrazine, additional improvement of the yield and
selectivity could be obtained, as 2a was isolated in 84% yield and
no trace of the amide 3 could be detected in the crude mixture
(Scheme 2). A possible explanation for the effect of added AcOH
is that the acid would react with XtalFluor-E to form an activated
acid.29,30,31,32 The most nucleophilic carbonyl group of the 1,2-
diacylhydrazine would attack the activated acid which would,
upon expulsion of diethylaminosulfinyl fluoride (6), generate
intermediate 11. As opposed to intermediate 4 (Scheme 1), this
Entry
Solvent
T/◦C
Ratio 2a : 3b
Yield (%)c
1
2
3
4
5
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
DCE
-78 to rt
0 to rt
rt
45
85
33 : 67
43 : 57
43 : 57
45 : 55
47 : 53
66 : 34
25
39
38
48
47
61
90
a See the Experimental section for details concerning the reaction con-
ditions. b Estimated ratio between 2a and 3 by 1H NMR spectroscopic
analysis of the crude product after work-up. c Isolated yield of 2a after
purification by flash chromatography.
R
XtalFluor-E is thermally stable,17 unlike DAST or Deoxo-Fluorꢀ,
allowed us to perform the reaction at higher temperature. Thus,
in CH2Cl2 at 45 ◦C, a 45 : 55 ratio of 2a : 3 was observed and the
oxadiazole was isolated in 48% yield (entry 4). A similar result
was obtained in EtOAc at 85 ◦C (entry 5). Finally, using 1,2-
dichloroethane (DCE) at 90 ◦C, the desired oxadiazole 2a was
isolated in 61% yield with an improved selectivity (entry 6).
With respect to the reaction mechanism, the formation of 2a
would most likely proceed with a mechanism similar to that
which occurs when other activating agents are used for the cy-
clodehydration of 1,2-diacylhydrazines (Scheme 1).15a Hence, the
most nucleophilic carbonyl group would first attack [Et2NSF2]BF4
at the electrophilic sulfur which would generate intermediate 4.
Cyclization would then occur leading to intermediate 5. Nitrogen-
assisted expulsion of diethylaminosulfinyl fluoride (6)22 would
generate 2a in addition to HF and HBF4. The production of
side-product 3 could be potentially obtained from intermediate
4 by an intramolecular attack of the nitrogen to generate the
oxathiazetidine derivative 8.23 Here again, with the assistance of
the nitrogen atom, fragmentation would produce HBF4, thionyl
fluoride, a gas with a bp of ca. -45 ◦C that would proba-
bly escape from the reaction mixture,24 and amidine derivative
9.25 The latter would, upon aqueous work-up, produce N,N-
diethylcyclohexanecarboxamide (3)26 and benzhydrazide (10).
Scheme 2 Effect of AcOH on the selectivity and mechanistic proposal
for the role of AcOH.
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Table 2 Synthesis of 1,3,4-oxadiazolesa
Yield (%)b
Entry
1
Substrate
Product
Without AcOH
With AcOH
84
61
83
2
92
3
4
5
6
7
trace
69
92
90
82
70c
83
45
58
59
8
72
44
56
19
54c
92
9
10
a See the Experimental section for details concerning the reaction conditions. b Isolated yield after purification by flash chromatography. c AcOH was
added at 90 ◦C without prior mixing with XtalFluor-E, see the experimental section for details.
new iminium species can only cyclize via the attack of the other
carbonyl to produce 12. The latter would then generate 2a in
addition to HF and AcOH.
These conditions were used to examine the scope of this
transformation (Table 2). Interestingly, in all cases, except one
(entry 8), the addition of acetic acid proved beneficial. In
particular, in the case of 1,2-diacylhydrazine 1c (entry 3) without
using acid, only traces of 2c could be observed while with 1.5
equivalents of AcOH, the desired oxadiazole was isolated in 92%
yield. A wide range of functionalized 1,3,4-oxadiazoles could be
obtained in good to excellent yield. For example, a 2-substituted-5-
trifluoromethyl-1,3,4-oxadiazole was obtained in 72% yield (entry
8).33 Interestingly in this case, addition of AcOH considerably
1
slows down the reaction. Indeed, after 12 h, H NMR analysis
indicates a conversion of 23%34 and an isolated yield of 19% was
obtained. The reason for this behavior is not understood at the
moment. 1-Thio-1,2-diacylhydrazines 1i could also be cyclized
to give 2-aminooxadiazole 2i albeit in a moderate yield (entry
9).10e Finally, a 2-substituted-1,3,4-oxadiazole (2j) could likewise
be prepared in 92% yield (entry 10). The latter is an interesting class
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of oxadiazoles since they have been shown to be good substrates
for copper-mediated direct cross-coupling with terminal alkynes.35
ethyl acetate/hexane (10/90). Spectral data for 3 were identical to
those previously reported.19
2-(1,1-Dimethylethyl)-5-phenyl-1,3,4-oxadiazole (2b). Follow-
ing the general procedure on a 0.23 mmol scale of N¢-benzoyl-
1,1-dimethylethylhydrazide, the desired product (42 mg, 92%)
was isolated as a yellow oil by flash chromatography using
acetone/hexane (10/90). IR (neat) n = 2973, 2934, 1562, 1553,
1158, 1083, 1069, 747, 704, 690 cm-1; 1H NMR (300 MHz, CDCl3)
d 8.06–8.03 (m, 2H), 7.51–7.49 (m, 3H), 1.49 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 173.3, 164.7, 131.6, 129.1, 126.9, 124.4, 32.6,
28.4; HRMS-ESI calcd for C12H15N2O [M + H]+ 203.1179, found
203.1182.
Conclusions
In conclusion, we have demonstrated that XtalFluor-E is a
practical cyclodehydration reagent for the synthesis of various
1,3,4-oxadiazoles. In addition, we have shown that the use of acetic
acid as an additive generally resulted in increased yields. Further
expansion of the scope, mechanistic studies and application of
this methodology for the synthesis of bioactive compounds are
currently underway and will be reported in due course.
2-Methyl-5-phenyl-1,3,4-oxadiazole (2c). Following the gen-
Experimental
eral procedure on
a 0.28 mmol scale of N¢-benzoyl-
General
methylhydrazide, the desired product (41 mg, 92%) was isolated
as a beige solid by flash chromatography using ethyl acetate/
hexane (30/70). mp 65–67 ◦C; IR (neat) n = 3053, 2931, 1714,
All reactions were carried out under a nitrogen or argon at-
mosphere with dry solvents under anhydrous conditions. 1H,
13C, and 19F NMR spectra were recorded on a VARIAN Inova
400 MHz or BRUKER Avance 300 MHz in CDCl3 at ambient
temperature using tetramethylsilane (1H NMR) or residual CHCl3
or DMSO (1H and 13C NMR) as the internal standard, or
CFCl3 (19F NMR) as the external standard. Infrared spectra were
recorded on a Thermo Scientific Nicolet 380 FT-IR spectrometer.
High-resolution mass spectra were obtained on a LC/MS-TOF
Agilent 6210 using electrospray ionization (ESI). Melting points
were recorded on a Stanford Research System OptiMelt capillary
melting point apparatus and are uncorrected. Synthesis of the
starting 1,2-diacylhydrazines and 1-thio-1,2-diacylhydrazine are
described in the ESI.†
1
1581, 1483, 1247, 780, 706, 692, 662 cm-1; H NMR (400 MHz,
CDCl3) d 8.04–8.02 (m, 2H), 7.53–7.48 (m, 3H), 2.63 (s, 3H);
13C NMR (100 MHz, CDCl3) d 165.0, 163.8, 131.7, 129.1, 126.8,
124.1, 11.3; HRMS-ESI calcd for C9H9N2O [M + H]+ 161.0709,
found 161.0713.
2-Pentyl-5-phenyl-1,3,4-oxadiazole (2d). Following the gen-
eral procedure on a 0.21 mmol scale of N¢-benzoylpentylhydrazide,
the desired product (42 mg, 90%) was isolated as a yellow oil
by flash chromatography using ethyl acetate/hexane (10/90). IR
(neat) n = 2957, 2930, 2861, 1572, 1553, 1450, 775, 731, 708, 689
cm-1; 1H NMR (400 MHz, CDCl3) d 8.05–8.02 (m, 2H), 7.52–7.48
(m, 3H), 2.93 (t, J = 7.6 Hz, 2H), 1.86 (quint, J = 7.2 Hz, 2H),
1.44–1.36 (m, 4H), 0.92 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 167.2, 164.8, 131.6, 129.1, 126.9, 124.3, 31.3, 26.4, 25.6,
22.3, 13.9; HRMS-ESI calcd for C13H17N2O [M + H]+ 217.1335,
found 217.1343.
General procedure for the synthesis of 1,3,4-oxadiazoles from
1,2-diacylhydrazines with AcOH as an additive
To a stirred solution of XtalFluor-E (69 mg, 0.3 mmol) in
dichloroethane (2 mL) at room temperature was added acetic acid
(17 mL, 0.3 mmol) and the resulting solution was stirred for 20 min
under argon. Then, 1,2-diacylhydrazide (0.2 mmol) was added and
the solution was stirred for 12 h at 90 ◦C. The reaction mixture was
cooled down to room temperature and quenched by a 5% sodium
carbonate aqueous solution. The aqueous phase was extracted
with dichloromethane (3¥). The combined organic extracts were
dried over anhydrous MgSO4, filtered, and concentrated in vacuo.
The crude material was purified with flash chromatography to give
the desired product.
2-Phenylmethyl-5-phenyl-1,3,4-oxadiazole (2e). Following the
general procedure on a 0.20 mmol scale of N¢-benzoyl-2-
phenylmethylhydrazide, the desired product (39 mg, 82%) was
isolated as a colorless solid by flash chromatography using ethyl
acetate/hexane (30/70). mp 102–103 ◦C; IR (neat) n = 3035,
2930, 1565, 1549, 1492, 1450, 1008, 729, 692, 982 cm-1; 1H NMR
(400 MHz, CDCl3) d 8.00 (d, J = 6.8 Hz, 2H), 7.50–7.45 (m, 3H),
7.36–7.29 (m, 5H), 4.28 (s, 2H); 13C NMR (100 MHz, CDCl3) d
165.4, 165.3, 134.0, 131.8, 129.1, 129.1, 128.9, 127.7, 126.9, 124.0,
32.0; HRMS-ESI calcd for C15H13N2O [M + H]+ 237.1022, found
237.1025.
2-Cyclohexyl-5-phenyl-1,3,4-oxadiazole (2a). Following the
general procedure on a 0.12 mmol scale of N¢-benzoyl-2-
cyclohexylhydrazide, the desired product (23 mg, 84%) was
isolated as a white solid by flash chromatography using ethyl
acetate/hexane (10/90). mp 104–105 ◦C; IR (neat) n = 3057,
2922, 2855, 1564, 1551, 1485, 1447, 1021, 697, 685 cm-1; 1H NMR
(400 MHz, CDCl3) d 8.05–8.03 (m, 2H), 7.54–7.49 (m, 3H), 3.02–
2.97 (m, 1H), 2.16–2.13 (m, 2H), 1.89–1.87 (m, 2H), 1.77–1.64 (m,
3H), 1.49–1.25 (m, 3H); 13C NMR (100 MHz, CDCl3) d 170.1,
164.5, 131.5, 129.1, 126.9, 124.3, 35.4, 30.3, 25.7, 25.5; HRMS-
ESI calcd for C14H17N2O [M + H]+ 229.1335, found 229.1343. The
side product 3 was also isolated by flash chromatography using
2,5-Diphenyl-1,3,4-oxadiazole (2f). Following the general pro-
cedure with the exception that acetic acid was added directly
to a 90 ◦C solution of N¢-benzoylbenzohydrazide (0.13 mmol)
and XtalFluor-E in DCE. The desired product (19 mg, 70%)
was isolated as a white solid by flash chromatography using
ethyl acetate/hexane (10/90). mp 139–140 ◦C; IR (neat) n =
2957, 2924, 1727, 1551, 1484, 1445, 1068, 782, 709, 687 cm-1;
1H NMR (300 MHz, CDCl3) d 8.17–8.14 (m, 4H), 7.56, 7.54
(m, 6H); 13C NMR (75 MHz, CDCl3) d 164.8, 131.9, 129.2, 127.1,
124.1; HRMS-ESI calcd for C14H11N2O [M + H]+ 223.0866, found
223.0831.
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2-(4-Chlorophenyl)-5-phenyl-1,3,4-oxadiazole (2g). Following
the general procedure on a 0.18 mmol scale of N¢-benzoyl-4-
chlorobenzohydrazide, the desired product (39 mg, 83%) was
isolated as a beige solid by flash chromatography using ethyl
acetate/hexane (10/90). mp 162–163 ◦C; IR (neat) n = 2922,
1605, 1547, 1477, 1089, 1071, 1011, 838, 702, 686 cm-1; 1H NMR
(400 MHz, CDCl3) d 8.16–8.08 (m, 4H), 7.56–7.51 (m, 5H); 13C
NMR (75 MHz, CDCl3) d 164.9, 163.9, 138.1, 132.0, 129.6, 129.3,
128.3, 127.1, 123.9, 122.5; HRMS-ESI calcd for C14H10ClN2O
[M + H]+ 257.0476, found 257.0480.
P. Jones, O. Kinzel, R. Laufer, E. Monteagudo, E. Muraglia, E. Nizi, F.
Orvieto, P. Pace, G. Pescatore, R. Scarpelli, K. Stillmock, M. V. Witmer
and M. J. Rowley, J. Med. Chem., 2008, 51, 5843–5855.
7 Nesapidil: R. Schlecker and P. C. Thieme, Tetrahedron, 1988, 44, 3289–
3294.
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Antibiot., 1971, 24, 443–451.
ˇ
9 Review: Z. Jakopin and M. S. Dolenc, Curr. Org. Chem., 2008, 12,
850–898.
10 For other approaches not starting directly from isolated 1,2-
diacylhydrazines, see: (a) R. Natero, D. O. Koltun and J. A. Zablocki,
Synth. Commun., 2004, 34, 2523–2529; (b) C. O. Kangani, D. E. Kelley
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2-Trifluoromethyl-5-phenyl-1,3,4-oxadiazole (2h). Following
the general procedure on a 0.13 mmol scale of N¢-benzoyl-
trifluoromethylhydrazide with the exception that acetic acid was
not added, the desired product (20 mg, 72%) was isolated as
a yellow solid by flash chromatography using acetone/hexane
(10/90). mp 51–52 ◦C; IR (neat) n = 1608, 1452, 1400, 1201, 1141,
1
1159, 1080, 1067, 735, 705 cm-1; H NMR (300 MHz, CDCl3) d
8.13 (d, J = 7.3 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.57 (t, J = 7.8 Hz,
2H); 13C NMR (75 MHz, CDCl3) d 166.7, 155.0 (q, JC–F = 44.7 Hz),
133.3, 129.5, 127.7, 122.4, 116.5 (q, JC–F = 273.4 Hz); 19F NMR
(376 MHz, CDCl3) d -65.5; HRMS-ESI calcd for C9H6F3N2O
[M + H]+ 215.0427, found 215.0425.
Acknowledgements
This work was supported by the Canada Research Chair Program,
the Natural Sciences and Engineering Research Council of
Canada, the Canada Foundation for Innovation, the Fonds de
recherche sur la nature et les technologies (FQRNT), FQRNT
Centre in Green Chemistry and Catalysis (CGCC), FQRNT
Research Network on Protein Function, Structure and Engi-
neering (PROTEO), and the Universite´ Laval. OmegaChem is
acknowledged for a generous gift of XtalFluor-E. We thank
Alexandre l’Heureux and Michel A. Couturier (OmegaChem) for
useful discussions and suggestions.
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16 The reagent [Et2SF2]BF4 is commercially available under the trademark
of XtalFluor-EꢀR .
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18 Using 1.5 equivalents of XtalFluor-E was found to be optimal. Using
less or more of the reagent resulted in lower yields.
19 S. D. Burke, R. W. Driver and J. J. Hans, J. Org. Chem., 2000, 65,
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20 In the case of Deoxo-FluorꢀR , the side-product is not N,N-
diethylcyclohexanecarboxamide (3), but rather N,N,-bis(2-
methoxyethyl)cyclohexanecarboxamide.
21 The same transformation using POCl3, a standard cyclodehydration
agent, resulted in only 25% yield of 2a.
22 (a) D. H. Brown, K. D. Crosbie, J. I. Darragh, D. S. Ross and D. W. A.
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26 Alternatively, attack of diethylamine on 4 would release intermediate 9
along with 6, HF and HBF4. In this scenario, free diethylamine would
originate from the decomposition of [Et2NSF2]BF4, see J. M. White,
A. R. Tunoori, B. J. Turunen and G. I. Goerg, J. Org. Chem., 2004, 69,
2573–2576. Mechanistic studies to explore these possible pathways are
ongoing.
27 Other acidic additives (CF3CO2H, Et3N·3HF), Lewis acid (BF3·Et2O)
or basic additives (DBU, Et3N, K2CO3) were less efficient providing
lower conversions and inferior selectivities.
30 Since no external source of fluoride is present, the conversion of the
activated acid to an acyl fluoride is slow. See ref. 17b.
31 A related alkoxy-N,N-dialkylaminodifluorosulfane has been isolated
and characterized, see: A. Sutherland and J. C. Vederas, Chem.
Commun., 1999, 1739–1740.
32 The use of another activated acid such as acetic anhydride instead of the
XtalFluor/AcOH combinaison resulted in no reaction, see: S. Cesarini,
N. Colombo, M. Pulici, E. R. Felder and W. K.-D. Brill, Tetrahedron,
2006, 62, 10223–10236.
33 For other synthetic approaches to this class of 1,3,4-oxadiazoles, see:
(a) L. I. Vereshchagin, O. N. Verkhozina, F. A. Pokatilov and V.
N. Kizhnyaev, Russ. J. Org. Chem., 2007, 43, 1575–1576; (b) L. I.
Vereshchagin, O. N. Verkhozina, F. A. Pokatilov, S. K. Strunevich,
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1
28 Using 1.0 or 2.0 equivalents of AcOH led to slightly lower yields and
selectivities.
29 A similar intermediate has been proposed before, see: T. B. Patrick and
Y.-F. Poon, Tetrahedron Lett., 1984, 25, 1019–1022.
34 Only 1h and 2h are observed in the crude mixture by H NMR. The
corresponding carboxamide side-product is not observed.
35 M. Kitahara, K. Hirano, H. Tsurugi, T. Satoh and M. Miura, Chem.–
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The Royal Society of Chemistry 2012
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