Synthesis of 1,3,4-oxadiazoles using polymer-supported reagents

Article abstract of DOI:10.1055/s-2001-11404

The preparation of a novel polystyrene-supported dehydrating agent and its application to the synthesis of 1,3,4-oxadiazoles under thermal and microwave conditions is described. An alternative procedure using tosyl chloride and P-BEMP is also presented.

Full text of DOI:10.1055/s-2001-11404

382
LETTER
Synthesis of 1,3,4-Oxadiazoles Using Polymer-supported Reagents
Christopher T. Brain,* Shirley A. Brunton
Novartis Institute for Medical Sciences, 5 Gower Place, London, WC1E 6BN, UK
Fax +44(0)2073874116; E-mail: christopher.brain@pharma.novartis.com
Received 21 December 2000
O
Abstract: The preparation of a novel polystyrene-supported dehy-
O
O
1. ClSO2NCO, CH2Cl2
drating agent and its application to the synthesis of 1,3,4-oxadiaz-
oles under thermal and microwave conditions is described. An
S
OH
O
N
-
NR3
+
2. R3N
alternative procedure using tosyl chloride and P-BEMP is also pre-
sented.
1 NR3 = NEt3
2 NR3 = DMAP
Key words: oxadiazoles, polymer-supported reagents, cyclization,
microwaves
Scheme 1
It was anticipated that a more efficient leaving group on 1
may facilitate the cyclization, therefore the novel DMAP
variant 2 was prepared (Scheme 1). The resin loading of 2
was found to be quantitative by microanalysis (0.73
mmol/g).7 Reagent 2 was stable for long periods (>1
month) when stored in the refrigerator and could be
weighed out in air without decomposition. Treatment of
3a with 2 (5 eq, THF, reflux) gave clean conversion to the
oxadiazole 4a, although the reaction was incomplete after
18 h (20% conversion, LC-MS). Under microwave condi-
tions 4a was formed cleanly (66% conversion) after just
20 × 1 min (100 W).
The development of flexible methods for the clean and ef-
ficient synthesis of heteroaromatic analogues has received
considerable attention over the past few years.1 The appli-
cation of polymer-supported reagents2 to heterocycle con-
struction is particularly attractive since the need for
tedious work-up and purification procedures is eliminat-
ed.
In medicinal chemistry, oxadiazoles are important as ester
and amide bioisosteres for a number of biological targets.3
The synthesis of oxadiazoles usually involves harsh reac-
tion conditions, although some recent publications have
reported mild cyclization methods.4 We previously report-
ed a mild procedure for the synthesis of 1,3,4-oxadiazoles
by cyclodehydration of 1,2-diacylhydrazines5 using
Wipf’s soluble PEG-supported Burgess reagent6 under
microwave conditions. The oxadiazoles were obtained
cleanly and in excellent yields after passing the reaction
mixtures through a silica column to remove the spent
polymer.
It was considered that a basic additive might increase the
rate of cyclization by deprotonating the hydrazide NH.
The addition of DIEA (2 eq) did not improve the reaction
but the strong guanidine base 5 (2 eq) (Scheme 2) had a
dramatic effect: the reaction was complete after 4 hours
under thermal conditions9 and after 5 × 1 min (100 W) un-
der microwave conditions. In each case, the crude reaction
mixture was simply shaken with Amberlyst® 1510 to re-
move 5 and DMAP, producing 4a cleanly and in a near-
quantitative yield. This procedure was found to be suc-
cessful for the synthesis of a selection of 1,3,4-oxadiaz-
oles 4(a-p) (Scheme 2 and Table, Method A).11
We considered that synthesis of the Burgess reagent on a
polystyrene support would be an improvement on the
PEG reagent. This would give the practical advantage that
clean products could be obtained simply by filtration of
the reagent from the reaction mixture. We now report the
preparation of a novel polystyrene-supported dehydrating
agent and its application to the synthesis of 1,3,4-oxadi-
azoles.
In light of these encouraging results it was anticipated that
activation of 3a as a tosylate may effect the cyclization.
No reaction occurred using tosyl chloride alone, but the
cyclization was successful on addition of 5 under similar
conditions to those of Method A12 The oxadiazole 4a was
obtained cleanly in 98% yield (thermal or microwave) af-
ter the crude reaction mixture was shaken with Amberlyst
15 and polymer-supported carbonate to remove 5 and
TsOH respectively. The reaction also proceeded using ei-
ther P-TsCl13 (2 eq) with 5 (2 eq) or polymer-bound
1,3,4,6,7,8-hexahydro-1-methyl-2H-pyrimido[1,2-a]py-
rimidine (P-TBD)14 with TsCl (1.2 eq). The latter method,
however, required 20 eq of base with a longer reaction
time and gave a lower yield: 6 h at reflux gave a 65% yield
under thermal conditions and 20 × 1 min (100 W) gave a
53% yield using microwaves. Use of the polymer-bound
Polystyrene-supported Burgess reagent 1 was prepared by
treatment of hydroxymethyl polystyrenewith chlorosulfo-
nyl isocyanate followed by triethylamine (Scheme 1).7,8
The resin loading of 1 was found to be quantitative (0.74
mmol/g) by microanalysis. Treatment of 1,2-dibenzoyl-
hydrazine 3a with 1 (5 eq, THF, reflux 18 h) failed to pro-
duce any cyclized material and 3a was recovered
quantitatively. In an attempt to effect the cyclization, the
experiment was repeated under microwave conditions
(20 × 1 min, 100 W, 2450 MHz) in a monomode labora-
tory instrument. Similarly, 3a was recovered quantitative-
ly.
Synlett 2001, No. 3, 382–384 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of 1,3,4-Oxadiazoles using Polymer-supported Reagents
383
Table Data for the synthesis of oxadiazoles 4
aConditions: Pre-heated oil bath, THF, reflux, 4 h. bConditions: 5 × 1 min (100 W), THF. cYields are of crude products, characterised by 1H
NMR (400 MHz) and LC-MS. dDetermined by LC-MS, 254 nm detection. eReaction mixture irradiated for 10 × 1 min (100 W). f4f:3f, 1:5.
g4f:3f, 1:4. h4f:3f, 7:1. I4I:3I, 4:1. jPurity determined by 1H NMR. k4I:3I, 1:2. l4I:3I, 1:1.
phosphazene base P-BEMP14 (5 eq) as the basic additive The oxadiazoles in the Table were formed in excellent
(Scheme 2) was a great improvement on this and was the yields and purities using Method A or B, except for a few
method of choice with no Amberlyst 15 or polymer-sup- examples. Cyclization of the o-methoxyphenyl derivative
ported carbonate washes being required. This procedure 3f did not go to completion, even after prolonged reaction
proved to be successful for the synthesis of oxadiazoles times. Method B was favoured for this example, giving a
4(a-p) (Scheme 2 and Table, Method B),15 giving results higher conversion to 4f under both thermal and micro-
comparable to those of Method A under both thermal and wave conditions. The basic oxadiazole 4h was not isolat-
microwave conditions.
ed using Method A: the cyclized product was observed in
the crude reaction mixture by 1H NMR but was removed
by the Amberlyst 15 wash. The cyclization of 3o was also
unsuccessful using Method A, giving an unidentified
product that did not contain an ethyl group. A moderate
yield of 4o was obtained using Method B. The cyclization
of the phenylsulfone analogue 3i did not go to completion,
producing a mixture of 4i and 3i in varying ratios, with
Method A giving better conversions than Method B.
Method A
1) 2,
N
, THF
N
N
5
O
O
O
2) Amberlyst 15
R1
R2
R1
R2
N
H
N
H
N
N
Method B
TsCl,
3a-p
4a-p
In summary, we have prepared a novel polystyrene-sup-
ported dehydrating agent and shown its effectiveness in
producing 1,3,4-oxadiazoles by the cyclodehydration of
1,2-diacylhydrazines. The reaction proceeds in high
yields and purities under both thermal and microwave
, THF
N
N
P
NtBu
Et2N
P-BEMP
Scheme 2
Synlett 2001, No. 3, 382–384 ISSN 0936-5214 © Thieme Stuttgart · New York

384
C. T. Brain, S. A. Brunton
LETTER
for 10 minutes. Filtration of the resin and removal of THF in
vacuo provided the oxadiazole 4, which required no further
purification; (b) General procedure under microwave
conditions: A mixture of 3 (0.1 mmol), 2 (5 eq) and 5 (2 eq) in
THF (3 ml) in a screw-top Pyrex tube (16 × 100 mm) fitted
with a PTFE septum was irradiated in a Labwell MW10
microwave apparatus (Personal Chemistry, Uppsala, Sweden)
for 5 × 1min (100 W) with 2 min cooling between each run
(CAUTION: PRESSURE DEVELOPS). After cooling to
room temperature in the microwave cavity, the reaction
mixture was washed with Amberlyst 15 (excess) followed by
filtration of the resin and removal of THF in vacuo to provide
4, which required no further purification. Selected data: 4l,
white solid; mp 98-100 °C; 1H NMR (400 MHz, CDCl3) 8.03
(2 H, dd, J 7.6, 1.2, ArH), 7.50-7.52 (3 H, brm, ArH), 5.15
(0.25 H, brs, Pro-CH), 5.05 (0.75 H, brs, Pro-CH), 3.58-3.67
(2 H, brm, Pro-CH2), 1.94-2.19 (4 H, brm, 2 × Pro-CH2) 1.43
(3 H, s, tBu) 1.25 (6 H, s, tBu); m/z (ES+) 316 (M++1, 100%).
4m, white solid; mp 53-57 °C; 1H NMR (400 MHz, CDCl3)
7.23-7.29 (4 H, brm, ArH+NH), 7.10 (2 H, d, J 6.9, ArH), 5.10
(0.5 H, brs, NCH), 5.23 (0.5 H, brs, NCH), 3.27 (1 H, dd, J
13.9, 6.4, CH2), 3.18-3.19 (1 H, brm, CH2), 2.48 (2.5 H, s,
CH3), 2.27 (0.5 H, s, CH3), 1.36 (9 H, s, tBu); m/z (ES+) 304
(M++1, 100%). 4n, waxy solid; 1H NMR (400 MHz, CDCl3)
8.15 (1 H, brs, Indole 2-H), 7.40-7.45 (1 H, brm, ArH), 7.32-
7.36 (6 H, brm, ArH+amide NH), 7.17 (1 H, t, J 8.0, Indole 6-
H), 7.08 (1 H, t, J 7.4, Indole 5-H), 6.95 (1 H, brs, ArH), 5.39-
5.43 (1 H, brs NCH), 5.09-5.10 (2 H, m, OCH2), 3.42-3.43 (2
H, m, CH2), 2.40 (3 H, brs, CH3); m/z (ES+) 377 (M++1,
100%).
conditions with no conventional purification required.
The use of microwave technology clearly provided a prac-
tical advantage over thermal heating with the reaction
times being dramatically reduced. An alternative proce-
dure, using tosyl chloride and P-BEMP, was also success-
ful under similar conditions to provide 1,3,4-oxadiazoles
with comparable yields and purities.
References and Notes
(1) Collins, I. J. Chem. Soc., Perkin Trans. 1 2000, 2845-2861.
(2) For a comprehensive review see: Ley, S.V.; Baxendale, I.R.;
Bream, R.N.; Jackson, P.S.; Leach, A.G.; Longbottom, D.A.;
Nesi, M.; Scott, J.S.; Storer, R.I.; Taylor, S.J. J. Chem. Soc.,
Perkin Trans. 1 2000, 3815-4195.
(3) (a) Ladduwahetty, T.; Baker, R.; Cascieri, M.A.; Chambers,
M.S.; Haworth, K.; Keown, L.E.; MacIntyre, D.E.; Metzger,
J.M.; Owen, S.; Rycroft, W.; Sadowski, S.; Seward, E.M.;
Shepheard, S.L.; Swain, C.J.; Tattersall, F.D.; Watt, A.P.;
Williamson, D.W.; Hargreaves, R.J. J. Med. Chem. 1996, 39,
2907-2914; (b) Tully, W.G.; Gardner, C.R.; Gillespie, R.J.;
Westwood, W. J. Med. Chem. 1991, 34, 2060-2067; (c)
Swain, C.J.; Baker, R.; Kneen, C.; Saunders, J.; Seward, E.M.;
Stevenson, G.S.; Beer, M.; Stanton, J.; Watling, K. J. Med.
Chem. 1991, 34, 140-151; (d) Saunders, J.; Cassidy, M.;
Freedman, S.; Harley, E.A.; Iverson, L.L.; Kneen, C.;
Macleod, A.; Merchan, K.; Snow, R.J.; Baker, R. J. Med.
Chem. 1990, 33, 1128-1138.
(4) (a) Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6989; (b)
Lutun, S.; Hasaik, B.; Couturier, D. Synth. Commun. 1999,
29, 111; (c) Brown, B.J.; Clemens, I.R.; Neesom, J.K. Synlett
2000, 1, 131-133.
(5) Brain, C.T.; Paul, J.M.; Loong, Y.; Oakley, P.J. Tetrahedron
Lett. 1999, 40, 3275-3278.
(12) Procedure similar to reference (11) (1.1 eq of TsCl and 2 eq of
5 were required). The crude reaction mixture was shaken with
a large excess of Amberlyst 15for 10 min, filtered and shaken
with 5 eq of PS-carbonate (Argonaut Technologies) for 1 h.
The product was obtained after filtration of the resin and
evaporation of THF in vacuo. No further purification was
required.
(13) P-TsCl (1.45 mmol/g) was purchased from Argonaut Tech-
nologies.
(14) P-TBD (2.6 mmol/g) and P-BEMP (2.2 mmol/g) were
purchased from Fluka.
(15) (a) General procedure under thermal conditions: A mixture of
3 (0.1 mmol), tosyl chloride (1.2 eq) and P-BEMP (5 eq) in
THF was heated under reflux in a pre-heated oil bath for 4 h.
The reaction mixture was filtered and the THF was removed
in vacuo to give the oxadiazole 4, which required no further
purification; (b) General Procedure under microwave
conditions: To a solution of 3 (0.1 mmol) in THF (3 ml) was
added tosyl chloride (1.2 eq) and P-BEMP (5 eq). The reaction
mixture was irradiated for 5 × 1 min (100 W).11 After cooling
to room temperature in the microwave cavity, the reaction
mixture was filtered and the THF was removed in vacuo to
give 4, which required no further purification.
(6) Wipf, P.; Venkatraman, S.; Tetrahedron Lett. 1996, 37, 4659-
4662.
(7) General Procedure: Hydroxymethyl polystyrene resin (5 g,
Novabiochem, 0.87 mmol/g) was allowed to swell in the
minimum volume of dichloromethane with shaking.
Chlorosulfonyl isocyanate (20 eq) was added dropwise at RT
and the resulting mixture was shaken for 18 h. The resin was
filtered and washed with dichloromethane. The resin was
suspended in dichloromethane and the amine (20 eq) was
added at RT. The mixture was shaken for 18 h, after which
time the resin was filtered, washed with dichloromethane and
dried under high vacuum to give pale yellow beads. Elemental
analysis. 1. Found: S, 2.29%. Required: S, 2.37%; 2. Found:
S, 2.46%. Required: S, 2.32%.
(8) Wipf was unsuccessful in attaching Burgess reagent to a
modified Merrifield resin.6
(9) The reaction does not proceed in the presence of 5 alone.
(10) Amberlyst® 15 was purchased from Acros and washed
thoroughly with methanol before use.
(11) (a) General procedure under thermal conditions: A mixture of
3 (0.1 mmol), 2 (5 eq) and 5 (2 eq) in THF (3 ml) was heated
under reflux in a pre-heated oil bath for 4 h. The reaction
mixture was filtered and shaken with Amberlyst® 15 (excess)
Article Identifier:
1437-2096,E;2001,0,03,0382,0384,ftx,en;L22800ST.pdf
Synlett 2001, No. 3, 382–384 ISSN 0936-5214 © Thieme Stuttgart · New York