A simple and efficient synthesis of new mono- and bis([1,2,4]-oxadiazol)- benzaldehyde building blocks

Article abstract of DOI:10.1055/s-2007-990834

An efficient approach to bis([1,2,4]-oxadiazol)benzaldehydes as well as the corresponding mono-benzaldehyde derivatives has been developed starting from benzamidoxime, which is readily obtained from 4-cyanobenzaldehyde. All these new compounds were synthe

Full text of DOI:10.1055/s-2007-990834

3406
PAPER
A Simple and Efficient Synthesis of New Mono- and Bis([1,2,4]-oxadiazol)-
benzaldehyde Building Blocks
Synthesis of
N
r
ew Mon
a
o- and
B
is(
n
[1,2,4]-oxadi
ç
azol)benza
o
ldehydes is Crestey,a Cyril Lebargy,a Marie-Claire Lasne,a Cécile Perrio*a,b
a
Laboratoire de Chimie Moléculaire et Thioorganique, CNRS UMR 6507, ENSICAEN, Université de Caen Basse-Normandie,
6 Boulevard Maréchal Juin, 14050 Caen Cedex, France
b
Groupe de Développements Méthodologiques en Tomographie par Emissions de Positons, UMR CEA 2E,
Université de Caen Basse-Normandie, Centre Cyceron, 15 Boulevard Henri Becquerel, 14070 Caen Cedex, France
Fax +33(2)31470275; E-mail: perrio@cyceron.fr
Received 12 June 2007
which is probably the most used carbonyl protective
group.2 Thus, 4-cyanobenzaldehyde (1) was reacted with
four equivalents of ethyleneglycol, in the presence of a
catalytic amount of p-toluenesulfonic acid, in toluene, un-
Abstract: An efficient approach to bis([1,2,4]-oxadiazol)benzalde-
hydes as well as the corresponding mono-benzaldehyde derivatives
has been developed starting from benzamidoxime, which is readily
obtained from 4-cyanobenzaldehyde. All these new compounds
were synthesized in a high-yielding, five-step procedure with few der reflux conditions for three hours, to give the product 2
in 89% yield.3,4 The nitrile was easily transformed into the
and simple purifications.
corresponding amidoxime 3 in 90% yield, by treatment
with hydroxylamine hydrochloride (3.5 equiv) and sodi-
um carbonate (2 equiv) in aqueous ethanol at 100 °C.5 The
1,2,4-oxadiazole 6 was obtained quantitatively in two
steps as follows: O-acylation5,6 was realized by the addi-
tion of pyridine (2 equiv) and phenylacetyl chloride (1.2
equiv) to a solution of benzamidoxime 3 in dichloro-
methane at room temperature, to afford O-acylated benz-
amidoxime 4, which was cyclized and dehydrated7 by
heating in toluene for 15 hours. Deprotection of the acetal
was carried out by the use of pyridinium p-toluene-
sulfonate8 (PPTS, 0.3 equiv) in aqueous acetone at 75 °C,
to give the aldehydes 5 and 7, respectively, in 86% and
88% yield (Scheme 2). Thus, the desired mono-benzalde-
hyde was obtained in five steps with an overall yield of
70%.
Key words: mono- and bis-benzaldehyde, 1,2,4-oxadiazole, benz-
amidoxime, O-acylation, acetal deprotection
The development of general and simple synthetic path-
ways for the generation of new and original libraries of or-
ganic compounds is currently one of the most important
challenges in organic chemistry. In the course of our stud-
ies related to a new and selective route to the (Z,Z)-2,7-
bis(4-cyanobenzylidene)cycloheptan-1-one (BABCH),1
we discovered a simple and efficient method for the syn-
thesis of various new aromatic and aliphatic bis([1,2,4]-
oxadiazol)benzaldehydes of type I. To obtain these com-
pounds, we decided to synthesize benzamidoxime II,
which was reacted with a range of dicarboxylic acids and/
or acid dichlorides III (Scheme 1).
After these encouraging results, we decided to study these
reactions with various aromatic and aliphatic linkers in or-
der to obtain the desired dibenzaldehydes. To introduce
R
OH
N
O
O
N
H2N
N
N
N
X
X
R
O
+
O
O
Bn
III
OH
N
O
O
N
B
n
II
N
N
H2N
H2N
Y
CHO
CHO
CN
R
I
R = aromatic/aliphatic linker
X = Cl or OH
Y = protected aldehyde
ii
iii
v
Scheme 1 Considered strategy for the synthesis of bis([1,2,4]-
R
oxadiazol)benzaldehydes
R
R
3
O
O
O
1 R = CHO
4 R =
6 R =
With this in mind, we first wanted to apply our methodol-
ogy to the synthesis of a benzaldehyde with a 1,2,4-oxadi-
azole ring from 4-cyanobenzaldehyde (1), in order to test
this strategy (Scheme 2). Initially, the aldehyde function
of the starting material was protected as its 1,3-dioxolane,
O
i
O
2 R =
O
iv
vi
5 R = CHO
7 R = CHO
Scheme 2 Reagents and conditions: (i) PTSA (cat.), ethyleneglycol
(4 equiv), toluene, reflux, Dean–Stark, 3 h, 89%; (ii) NH2OH·HCl
(3.5 equiv), Na2CO3 (2 equiv), EtOH–H2O (2:1), 100 °C, 4.5 h, 90%;
(iii) BnCOCl (1.2 equiv), pyridine (2 equiv), CH2Cl2, r.t., 16 h, 100%;
(iv) PPTS (0.3 equiv), acetone–H2O (10:1), 75 °C, 2 h, 86%; (v)
toluene, reflux, Dean–Stark, 15 h, 100%; (vi) PPTS (0.3 equiv),
acetone–H2O (10:1), 75 °C, 24 h, 88%.
SYNTHESIS 2007, No. 21, pp 3406–3410
x
x.
x
x
.
2
0
0
7
Advanced online publication: 16.10.2007
DOI: 10.1055/s-2007-990834; Art ID: Z14607SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of New Mono- and Bis([1,2,4]-oxadiazol)benzaldehydes
3407
O
O
diacetic acids were then converted into the corresponding
acid dichlorides by reaction with oxalyl chloride and a
catalytic amount of dimethylformamide in dichloro-
methane10 and poured, without further purification, into a
solution of compound 3 in dichloromethane and pyridine,
to give the products 8 and 9 in a quantitative yield (method
B). With commercially available suberoyl and sebacoyl
chloride, the aliphatic bis-amidoximes 10 and 11 were ob-
tained in a quantitative yield (Scheme 3, Table 1).
OH
O
N
R
O
N
H2N
N
H2N
NH2
A or B
C or D
O
O
O
O
O
O
8–11
3
Depending on the solubility of the starting material in tol-
uene, the bis-oxadiazoles 12–15 were obtained by heating
either under reflux conditions (method C) or under sol-
vent-free conditions at 110 °C (method D), for 12–18
hours, from the corresponding bis-amidoximes 8–11 in
good to excellent yields (Scheme 3, Table 1).
R
O
O
R
N
O
N
N
N
O
N
N
N
N
E or F
Finally, deprotection of the acetal of the bis-oxadiazoles
was performed either with PPTS (0.6 equiv) in aqueous
acetone at 75 °C for 24 hours (method E) or with a cata-
lytic amount of concentrated hydrochloric acid11 in aque-
ous tetrahydrofuran at 65 °C for 18 hours (method F), to
give the desired dibenzaldehydes 16–19 in excellent
yields (Scheme 3, Table 1).
O
O
O
O
CHO
CHO
16–19
12–15
(
)
n
R =
In conclusion, we describe here a general and efficient
method for the synthesis of new mono- and bis([1,2,4]-
oxadiazol)benzaldehydes with aromatic and aliphatic
linkers, obtained from 4-cyanobenzaldehyde in five steps
with overall yields between 66% and 80%, employing
simple and convenient conditions and purification pro-
cesses. Moreover, this method has already been scaled up
for the synthesis of multigram amounts of the dibenzalde-
hydes. Many of these original compounds should prove to
be valuable building blocks in organic chemistry for a
wide range of applications. Further studies on this project
will be reported in due course.
n = 4, 6
Scheme 3 Reagents and conditions: Method A: R(CO2H)2 (0.5
equiv), EDC (1 equiv), CH2Cl2, reflux, 12 h; Method B: R(COCl)2
(0.7 equiv), pyridine (2 equiv), CH2Cl2, r.t., 16 h; Method C: toluene,
reflux, Dean–Stark, 12–18 h; Method D: 110 °C, 12–18 h; Method E:
PPTS (0.6 equiv), acetone–H2O (10:1), 75 °C, 24 h; Method F: HCl
(37%, cat.), THF–H2O (4:1), 65 °C, 18 h.
the linkers, two methodologies were studied: the use of a
dicarboxylic acid (method A) and the use of an acid
dichloride (method B).
All commercial reagents were used as received without further pu-
rification. Reaction mixtures were stirred magnetically and moni-
tored by TLC using 0.2 mm Macherey–Nagel Polygram SIL G/
UV254 precoated plates. Column chromatography was performed
using CarloErba-SDS 60A 70–200 mm silica gel. Melting points (re-
ported uncorrected) were determined on a Köfler melting point ap-
paratus. IR spectra were record with a Perkin–Elmer Spectrum
16PC FT-IR spectrometer. 1H NMR (250 MHz) and 13C NMR (62
MHz) spectra were recorded on a Brucker Avance DRX 250 instru-
ment. Chemical shifts (d) are expressed in ppm downfield from
TMS as an internal standard and the coupling constants are in hertz.
In order to compare the yields, benzamidoxime 3 was re-
acted with 1,3- and 1,4-phenylenediacetic acid with 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochlo-
ride (EDC) as a coupling agent. The basic advantage of
EDC was the water-solubility of the resulting urea, which
avoided the necessity for further purifications.9 Thus, the
coupling reaction in dichloromethane under reflux condi-
tions for 12 hours, afforded the desired aromatic bis-amid-
oximes 8 and 9, both in 53% yield (method A). These two
Table 1 Synthesis and Yields of Bis([1,2,4]-oxadiazol)benzaldehydes 16–19
n-Bu
n-Hex
R
Method (%)
8
A
(53)
9
A
(53)
10
B (100)
11
B (100)
B (100)
D (100)
E (100)
B (100)
Method (%)
Method (%)
12
16
13
17
D
F
(87)
(94)
14
18
C
(85)
15
19
C
(90)
F (100)
F (100)
Synthesis 2007, No. 21, 3406–3410 © Thieme Stuttgart · New York

3408
F. Crestey et al.
PAPER
MS and HRMS (EI) were obtained on a Waters Micromass Q-Tof
micro instrument and a JEOL JMS-AX500 spectrometer. Elemental
analyses were performed with a Thermoquest NA 2500 instrument.
IR (KBr): 2352, 1738, 1734, 1622, 1616, 1558 cm–1.
1H NMR (CDCl3): d = 3.84 (s, 2 H), 4.02–4.14 (m, 4 H), 4.94 (br s,
2 H), 5.82 (s, 1 H), 7.28–7.36 (m, 5 H), 7.51 (d, J = 8.3 Hz, 2 H),
7.68 (d, J = 8.3 Hz, 2 H).
13C NMR (CDCl3): d = 40.5, 65.3, 103.1, 126.8, 127.2, 128.6, 129.0,
131.8, 133.8, 141.0, 141.5, 156.3, 168.9.
MS (EI): m/z (%) = 326 (5) [M+], 308 (53), 307 (63), 263 (15), 208
(35), 191 (24), 136 (21), 119 (21), 104 (23), 91(100), 77 (10), 73
(34).
(4-[1,3]-Dioxolan-2-yl)benzonitrile (2)4
To a round-bottomed flask equipped with a Dean–Stark trap were
successively added 4-cyanobenzaldehyde (1; 7.68 g, 58.6 mmol), a
catalytic amount of p-TsOH and toluene (150 mL). After 5 min at
r.t., ethyleneglycol (13 mL, 234.3 mmol, 4 equiv) was added drop-
wise and the mixture was heated for 3 h under reflux conditions.
The organic solution was washed successively with sat. aq Na2CO3
(2 × 35 mL) and H2O (2 × 35 mL) and the combined aqueous layers
were extracted with CH2Cl2 (2 × 50 mL). The combined organic
layers were dried over MgSO4, filtered and concentrated in vacuo.
The orange oil obtained was triturated in n-pentane (20 mL) at
–5 °C to give the product 2.
Anal. Calcd for C18H18N2O4: C, 66.25; H, 5.56; N, 8.58. Found: C,
66.40; H, 5.48; N, 8.64.
a,a¢-Bis{(4-[1,3]-dioxolan-2-yl)-O-carboxybenzamidoximo}-
1,3-xylene (8)
Prepared from (4-[1,3]-dioxolan-2-yl)benzamidoxime (3; 2.20 g,
10.6 mmol), 1,3-benzenediacetyl dichloride (1.7 mL, 7.4 mmol)
and pyridine (1.6 mL, 21.2 mmol).
Yield: 9.12 g (89%); colorless solid; mp 45 °C; Rf = 0.35 (CH2Cl2).
1H NMR (CDCl3): d = 4.02–4.14 (m, 4 H), 5.85 (s, 1 H), 7.59 (d,
J = 8.3 Hz, 2 H), 7.68 (d, J = 8.3 Hz, 2 H).
13C NMR (CDCl3): d = 65.5, 102.4, 112.9, 118.6, 127.1, 132.2,
143.1.
Yield: 1.23 g (100%); colorless solid; mp 190 °C.
IR (KBr): 3354, 3346, 1734, 1618, 1084 cm–1.
1H NMR (DMSO-d6): d = 3.88 (s, 4 H), 4.01–4.12 (m, 8 H), 5.83 (s,
2 H), 6.96 (br s, 4 H), 7.28–7.40 (m, 4 H), 7.55 (d, J = 8.2 Hz, 4 H),
7.78 (d, J = 8.2 Hz, 4 H).
MS (EI): m/z (%) = 175 (15) [M+], 174 (27), 148 (41), 130 (100),
102 (38).
13C NMR (DMSO-d6): d = 41.0, 64.5, 101.9, 126.2, 126.3, 127.6,
130.0, 130.2, 131.9, 134.4, 140.0, 156.3, 168.9.
Anal. Calcd for C10H9NO2: C, 68.56; H, 5.18; N, 8.00. Found: C,
68.57; H, 5.21; N, 7.87.
MS (EI): m/z (%) = 575 (7) [M + 1], 235 (10), 209 (10), 193 (28),
191 (92), 171 (20), 157 (80), 104 (18), 93 (23), 79 (100), 73 (34).
(4-[1,3]-Dioxolan-2-yl)benzamidoxime (3)
Hydroxylamine hydrochloride (NH2OH·HCl; 18.61 g, 267.8 mmol,
3.5 equiv) and Na2CO3 (16.22 g, 153.0 mmol, 2 equiv) were succes-
sively added to a solution of benzonitrile 2 (13.39 g, 76.5 mmol) in
EtOH–H2O (2:1, 130 mL) at r.t. under stirring. The reaction mixture
was heated at 100 °C for 4.5 h then concentrated in vacuo. The
crude material was poured into H2O (80 mL), stirred for 30 min then
filtered to give the product 3.
Anal. Calcd for C30H30N4O8: C, 62.71; H, 5.26; N, 9.75. Found: C,
63.04; H, 5.53; N, 9.40.
a,a¢-Bis{(4-[1,3]-dioxolan-2-yl)-O-carboxybenzamidoximo}-
1,4-xylene (9)
Prepared from (4-[1,3]-dioxolan-2-yl)benzamidoxime (3; 2.20 g,
10.6 mmol), 1,4-benzenediacetyl dichloride (1.7 mL, 7.4 mmol)
and pyridine (1.6 mL, 21.2 mmol).
Yield: 14.27 g (90%); colorless solid; mp 150 °C; Rf = 0.3 (CH2Cl2–
MeOH, 9:1).
Yield: 1.23 g (100%); colorless solid; mp 202 °C.
IR (KBr): 1638, 1068 cm–1.
1H NMR (DMSO-d6): d = 3.81 (s, 4 H), 3.82–4.06 (m, 8 H), 5.77 (s,
2 H), 6.91 (br s, 4 H), 7.36 (s, 4 H), 7.50 (d, J = 8.2 Hz, 4 H), 7.73
(d, J = 8.2 Hz, 4 H).
13C NMR (DMSO-d6): d = 40.0, 63.1, 100.6, 124.8, 125.0, 127.7,
130.5, 131.4, 138.7, 154.9, 167.2.
1H NMR (DMSO-d6): d = 3.93–4.06 (m, 4 H), 5.74 (s, 1 H), 5.83 (br
s, 2 H), 7.42 (d, J = 8.3 Hz, 2 H), 7.68 (d, J = 8.3 Hz, 2 H), 9.68 (s,
1 H).
13C NMR (DMSO-d6): d = 65.3, 103.0, 125.8, 126.8, 134.5, 139.1,
151.1.
MS (EI): m/z (%) = 575 (33) [M + 1], 574 (31), 460 (100), 459 (88),
443 (22).
MS (EI): m/z (%) = 208 (96) [M+], 192 (55), 176 (35), 148 (45), 136
(33), 119 (27), 105 (37), 104 (33), 73 (100).
Anal. Calcd for C30H30N4O8: C, 62.71; H, 5.26; N, 9.75. Found: C,
62.71; H, 5.52; N, 9.62.
Anal. Calcd for C10H12N2O3: C, 57.69; H, 5.81; N, 13.45. Found: C,
57.65; H, 5.88; N, 13.11.
Bis{(4-[1,3]-dioxolan-2-yl)-O-carboxybenzamidoximo}-1,6-
hexane (10)
Prepared from (4-[1,3]-dioxolan-2-yl)benzamidoxime (3; 0.65 g,
3.1 mmol), suberoyl chloride (0.4 mL, 2.2 mmol) and pyridine (0.5
mL, 6.2 mmol).
Synthesis of Acylated Amidoximes 4 and 8–11; General Proce-
dure
Pyridine (2 equiv) and acid chloride (1.2 equiv) or acid dichloride
(0.7 equiv) were successively added dropwise, under nitrogen, to a
solution of benzamidoxime 3 in CH2Cl2 (40 mL) at r.t. under stir-
ring. The reaction mixture was stirred at r.t. for 16 h and then con-
centrated in vacuo. The crude material was poured into H2O (50
mL), stirred for 15 min then filtered to give the desired compound.
Yield: 0.95 g (100%); colorless solid; mp 169 °C.
1H NMR (DMSO-d6): d = 1.15–1.32 (m, 4 H), 1.48–1.65 (m, 4 H),
2.41 (t, J = 7.5 Hz, 4 H), 3.91–4.07 (m, 8 H), 5.73 (s, 2 H), 6.79 (br
s, 4 H), 7.56 (d, J = 8.3 Hz, 4 H), 7.79 (d, J = 8.3 Hz, 4 H).
13C NMR (DMSO-d6): d = 24.7, 28.6, 32.7, 65.2, 102.7, 126.9,
127.0, 132.8, 140.7, 156.5, 171.2.
(4-[1,3]-Dioxolan-2-yl)-O-phenylacetylbenzamidoxime (4)
Prepared from (4-[1,3]-dioxolan-2-yl)benzamidoxime (3; 4.43 g,
21.3 mmol), phenylacetyl chloride (3.4 mL, 25.6 mmol) and pyri-
dine (3.2 mL, 42.6 mmol).
HRMS (ESI): m/z [M + H]+ calcd for C28H35N4O8: 555.2455;
found: 555.2436.
Yield: 6.94 g (100%); pale-brown solid; mp 130 °C; Rf = 0.6
(CH2Cl2–MeOH, 9:1).
Synthesis 2007, No. 21, 3406–3410 © Thieme Stuttgart · New York

PAPER
Synthesis of New Mono- and Bis([1,2,4]-oxadiazol)benzaldehydes
3409
Bis{(4-[1,3]-dioxolan-2-yl)-O-carboxybenzamidoximo}-1,8-oct-
ane (11)
Prepared from (4-[1,3]-dioxolan-2-yl)benzamidoxime (3; 0.65 g,
3.1 mmol), sebacoyl chloride (0.4 mL, 2.2 mmol) and pyridine (0.5
mL, 6.2 mmol).
1H NMR (CDCl3): d = 4.05–4.15 (m, 8 H), 4.28 (s, 4 H), 5.86 (s,
2 H), 7.39–7.25 (s, 4 H), 7.58 (d, J = 8.3 Hz, 4 H), 8.08 (d, J = 8.3
Hz, 4 H).
13C NMR (CDCl3): d = 32.7, 65.4, 103.2, 126.9, 127.5, 129.6, 133.0,
141.0, 168.3, 177.8.
Yield: 0.95 g (100%); colorless solid; mp 184 °C.
MS (EI): m/z (%) = 539 (75) [M + 1], 366 (20), 193 (63), 176 (100).
HRMS (ESI): m/z [M + H]+ calcd for C30H27N4O6: 539.1931; found:
539.1947.
1H NMR (DMSO-d6): d = 1.08–1.27 (m, 8 H), 1.35–1.61 (m, 4 H),
2.41 (t, J = 7.5 Hz, 4 H), 3.84–3.96 (m, 8 H), 5.66 (s, 2 H), 6.70 (br
s, 4 H), 7.39 (d, J = 8.3 Hz, 4 H), 7.62 (d, J = 8.3 Hz, 4 H).
13C NMR (DMSO-d6): d = 24.9, 28.9, 29.0, 32.8, 65.3, 102.8, 126.9,
127.1, 132.9, 140.8, 156.6, 171.3.
Bis{5-(4-[1,3]-dioxolan-2-ylphenyl)-[1,2,4]oxadiazol-3-yl}-1,6-
hexane (14)
Obtained by method C, starting from bis{(4-[1,3]-dioxolan-2-yl)-
O-carboxybenzamidoximo}-1,6-hexane (10; 0.85 g, 1.5 mmol).
HRMS (ESI): m/z [M + H]+ calcd for C30H39N4O8: 583.2767; found:
583.2770.
Yield: 0.68 g (85%); orange solid; mp 123 °C.
Synthesis of 1,2,4-Oxadiazoles 6 and 12–15; General Procedure
Method C: In a round-bottomed flask equipped with a Dean–Stark
trap, the corresponding acylated benzamidoxime dissolved in tolu-
ene (50–80 mL), was heated for 12–18 h under reflux conditions
and then concentrated under vacuo. The orange oil obtained was
triturated in n-pentane (20 mL) at 0 °C for 30 min and then filtered
to give the desired 1,2,4-oxadiazole.
1H NMR (CDCl3): d = 1.48–1.53 (m, 4 H), 1.88–1.94 (m, 4 H), 2.96
(t, J = 7.5 Hz, 4 H), 4.03–4.15 (m, 8 H), 5.87 (s, 2 H), 7.59 (d,
J = 8.3 Hz, 4 H), 8.11 (d, J = 8.3 Hz, 4 H).
HRMS (ESI): m/z [M + H]+ calcd for C28H31N4O6: 519.2165; found:
519.2163.
Bis{5-(4-[1,3]-dioxolan-2-ylphenyl)-[1,2,4]oxadiazol-3-yl}-1,8-
octane (15)
Obtained by method C, starting from bis{(4-[1,3]-dioxolan-2-yl)-
Method D: The desired acylated benzamidoxime was heated for 12–
18 h at 110 °C without solvent. The crude material was taken up in
CH2Cl2 (30 mL) and the mixture was stirred for 15 min then filtered.
The resulting solution was concentrated in vacuo to give the desired
1,2,4-oxadiazole.
O-carboxybenzamidoximo}-1,8-octane (11; 0.85 g, 1.5 mmol).
Yield: 0.72 g (90%); pale-orange solid; mp 108–110 °C.
1H NMR (CDCl3): d = 1.34–1.48 (m, 8 H), 1.82–1.90 (m, 4 H), 2.94
(t, J = 7.5 Hz, 4 H), 4.03–4.18 (m, 8 H), 5.87 (s, 2 H), 7.59 (d,
J = 8.3 Hz, 4 H), 8.11 (d, J = 8.3 Hz, 4 H).
HRMS (ESI): m/z [M + H]+ calcd for C30H35N4O6: 547.2557; found:
547.2565.
5-Benzyl-3-(4-[1,3]-dioxolan-2-ylphenyl)-[1,2,4]oxadiazole (6)
Obtained by method C, starting from (4-[1,3]-dioxolan-2-yl)-O-
phenylacetylbenzamidoxime (4; 5 g, 15.3 mmol).
Yield: 9.12 g (100%); beige solid; mp 62 °C; Rf = 0.35 (CH2Cl2).
1H NMR (CDCl3): d = 4.04–4.14 (m, 4 H), 4.29 (s, 2 H), 5.86 (s,
1 H), 7.15–7.38 (m, 5 H), 7.58 (d, J = 8.2 Hz, 2 H), 8.08 (d, J = 8.2
Hz, 2 H).
13C NMR (CDCl3): d = 33.4, 65.8, 103.6, 127.3, 127.9, 128.0, 129.0,
129.3, 130.5, 133.8, 141.4, 168.6, 178.4.
MS (EI): m/z (%) = 308 (100) [M+], 307 (39), 263 (15), 217 (37),
191 (38), 174 (11), 146 (9), 119 (18), 118 (15), 104 (18), 91 (43), 73
(24), 65 (16).
Synthesis of Benzaldehydes 5, 7 and 16–19; General Procedure
Method E: PPTS (0.3 equiv per acetal function) was added to a so-
lution of the corresponding acetal in acetone–H2O (10:1, 22 mL) at
r.t. under stirring. The reaction mixture was stirred at 75 °C for 2–
24 h then concentrated in vacuo. The crude material was taken up in
CH2Cl2 (50 mL) and the organic layer was washed successively
with a sat. aq NaHCO3 (2 × 25 mL), H2O (2 × 25 mL) and brine
(2 × 25 mL), dried over MgSO4, filtered and concentrated in vacuo
to give the desired benzaldehyde.
Anal. Calcd for C18H16N2O3: C, 70.12; H, 5.23; N, 9.09. Found: C,
70.16; H, 5.63; N, 8.59.
Method F: HCl (37%, 10 drops) was added to a solution of the cor-
responding acetal in THF–H2O (4:1, 50 mL) at r.t. under stirring.
The reaction mixture was stirred at 65 °C for 18 h then concentrated
in vacuo. The crude material was taken up in CH2Cl2 (50 mL) and
the organic layer was washed successively with H2O (2 × 30 mL)
and brine (2 × 30 mL), dried over MgSO4, filtered and concentrated
in vacuo to give the desired benzaldehyde.
a,a¢-Bis{5-(4-[1,3]-dioxolan-2-ylphenyl)-[1,2,4]oxadiazol-3-yl}-
1,3-xylene (12)
Obtained by method D, starting from a,a¢-bis{(4-[1,3]-dioxolan-2-
yl)-O-carboxybenzamidoximo}-1,3-xylene (8; 1.23 g, 2.1 mmol).
Yield: 1.15 g (100%); orange solid.
1H NMR (CDCl3): d = 3.91–4.03 (m, 8 H), 4.19 (s, 4 H), 5.76 (s,
2 H), 7.09–7.25 (m, 3 H), 7.31 (s, 1 H), 7.49 (d, J = 8.3 Hz, 4 H),
8.00 (d, J = 8.3 Hz, 4 H).
4-Formyl-O-phenylacetylbenzamidoxime (5)
Obtained by method E, starting from (4-[1,3]-dioxolan-2-yl)-O-
phenylacetylbenzamidoxime (4; 1 g, 3.1 mmol) and PPTS (0.23 g,
0.9 mmol).
MS (EI): m/z (%) = 539 (100) [M + 1], 493 (45), 366 (25), 193 (39),
176 (85).
Yield: 0.74 g (86%); pale-yellow solid; mp 156 °C; Rf = 0.6
(CH2Cl2–MeOH, 9:1).
IR (KBr): 1742, 1708, 1628, 1610, 1598, 1556, 1214, 1146 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C30H27N4O6: 539.1931; found:
539.1947.
1H NMR (CDCl3): d = 3.85 (s, 2 H), 5.03 (br s, 2 H), 7.28–7.36 (m,
5 H), 7.83 (d, J = 8.3 Hz, 2 H), 7.90 (d, J = 8.3 Hz, 2 H), 10.04 (s,
1 H).
13C NMR (CDCl3): d = 40.9, 127.7, 127.8, 129.2, 129.7, 130.3,
134.1, 136.9, 138.4, 155.8, 168.4, 191.9.
a,a¢-Bis{5-(4-[1,3]-dioxolan-2-ylphenyl)-[1,2,4]oxadiazol-3-yl}-
1,4-xylene (13)
Obtained by method D, starting from a,a¢-bis{(4-[1,3]-dioxolan-2-
yl)-O-carboxybenzamidoximo}-1,4-xylene (9; 0.73 g, 1.3 mmol).
Yield: 0.60 g (87%); orange solid.
MS (EI): m/z (%) = 282 (3) [M+], 264 (20), 136 (21), 118 (25), 104
(13), 92 (20), 91 (100), 77 (12), 65 (18).
Synthesis 2007, No. 21, 3406–3410 © Thieme Stuttgart · New York

3410
F. Crestey et al.
PAPER
Anal. Calcd for C16H14N2O3: C, 68.08; H, 5.00; N, 9.92. Found: C,
68.04; H, 5.40; N, 9.52.
1H NMR (CDCl3): d = 1.41–1.51 (m, 8 H), 1.89–1.94 (m, 4 H), 2.98
(t, J = 7.5 Hz, 4 H), 7.97 (d, J = 8.2 Hz, 4 H), 8.24 (d, J = 8.2 Hz,
4 H), 10.06 (s, 2 H).
4-(5-Benzyl-[1,2,4]oxadiazol-3-yl)benzaldehyde (7)
Obtained by method E, starting from 5-benzyl-3-(4-[1,3]-dioxolan-
2-ylphenyl)-[1,2,4]oxadiazole (6; 0.69 g, 2.2 mmol) and PPTS
(0.17 g, 0.7 mmol).
Anal. Calcd for C26H26N4O4: C, 68.11; H, 5.72; N, 12.22. Found: C,
68.10; H, 6.10; N, 12.08.
Acknowledgment
Yield: 0.51 g (88%); beige solid; mp 86 °C; Rf = 0.5 (CH2Cl2).
1H NMR (CDCl3): d = 4.32 (s, 2 H), 7.31–7.39 (m, 5 H), 7.99 (d,
J = 8.4 Hz, 2 H), 8.25 (d, J = 8.4 Hz, 2 H), 10.04 (s, 1 H).
13C NMR (CDCl3): d = 33.1, 127.8, 128.1, 128.9, 129.0, 130.1,
132.2, 133.2, 138.0, 167.7, 178.6, 191.6.
We thank Myriam Segou and Gaëtan Leboucher for their technical
support on the project, Karine Jarsale for the mass spectrometry
measurements and Margareth Lemarié for the elemental analyses.
MS (EI): m/z (%) = 264 (100) [M+], 263 (36), 236 (12), 146 (42),
133 (19), 118 (14), 104 (34), 91 (25), 65 (14).
References
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Soc., Perkin Trans. 1 2001, 690. (b) Poulain, N.; Dez, I.;
Perrio, C.; Lasne, M.-C.; Prud’homme, M.-P.; Nakache, E.
J. Controlled Release 2003, 92, 27. (c)Grandeury, A.; Petit,
S.; Coste, S.; Coquerel, G.; Perrio, C.; Gouhier, G. Chem.
Commun. 2005, 4007.
(2) Greene, T. W.; Wuts, P. G. M. In Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley and Sons Inc.: New
York, 1999, 312–322.
Anal. Calcd for C16H12N2O2: C, 72.12; H, 4.58; N, 10.60. Found: C,
72.51; H, 4.79; N, 10.13.
a,a¢-Bis[5-(4-formylphenyl)-[1,2,4]oxadiazol-3-yl]-1,3-xylene
(16)
Obtained by method E, starting from a,a¢-bis{5-(4-[1,3]-dioxolan-
2-ylphenyl)-[1,2,4]oxadiazol-3-yl}-1,3-xylene (12; 1.15 g, 2.1
mmol).
(3) Dahnke, K. R.; Paquette, L. A. J. Org. Chem. 1994, 59, 885.
(4) Ouari, O.; Polidori, A.; Pucci, B.; Tordo, P.; Chalier, F. J.
Org. Chem. 1999, 64, 3554.
(5) (a) Eloy, F.; Lenaers, R. Chem. Rev. 1962, 62, 155.
(b) Robertson, G. M. In Comprehensive Organic Functional
Group Transformations, Imines and their N-Substituted
Derivatives: Oximes and their O-R Substituted Analogues,
Vol. 3; Katritzky, A. R.; Meth-Cohn, O.; Rees, C. W., Eds.;
Pergamon: Oxford, 1995, 425–441.
Yield: 0.96 g (100%); orange solid.
1H NMR (CDCl3): d = 4.34 (s, 4 H), 7.36–7.44 (m, 4 H), 7.99 (m,
4 H), 8.25 (m, 4 H), 10.09 (s, 2 H).
MS (EI): m/z (%) = 451 (100) [M + 1], 367 (13), 323 (21), 192 (16),
149 (45), 132 (19).
HRMS (ESI): m/z [M + H]+ calcd for C26H19N4O4: 451.1406; found:
451.1377.
(6) (a) Bell, C. L.; Nambury, C. N. V.; Bauer, L. J. Org. Chem.
1964, 29, 2873. (b) Korbonits, D.; Horvath, K. Heterocycles
1994, 37, 2051. (c) Andersen, K. E.; Lundt, B. F.;
Joergensen, A. S.; Braestrup, C. Eur. J. Med. Chem. 1996,
31, 417. (d) Gangloff, A. R.; Litvak, J.; Shelton, E. J.;
Sperandio, D.; Wang, V. R.; Rice, K. D. Tetrahedron Lett.
2001, 42, 1441.
a,a¢-Bis{5-(4-formylphenyl)-[1,2,4]oxadiazol-3-yl}-1,4-xylene
(17)
Obtained by method F, starting from a,a¢-bis{5-(4-[1,3]-dioxolan-
2-ylphenyl)-[1,2,4]oxadiazol-3-yl}-1,4-xylene (13; 0.44 g, 0.8
mmol) and PPTS (0.12 g, 0.5 mmol).
Yield: 0.35 g (94%); yellow solid.
1H NMR (CDCl3): d = 4.30 (s, 4 H), 7.40 (s, 4 H), 7.98 (d, J = 8.4
Hz, 4 H), 8.24 (d, J = 8.4 Hz, 4 H), 10.08 (s, 2 H).
(7) (a) Palazzo, G.; Strani, G.; Tavella, M. Gazz. Chim. Ital.
1961, 91, 1085. (b) Ooi, N. S.; Wilson, W. S. J. Chem. Soc.,
Perkin Trans. 2 1980, 1792. (c) LaMattina, J. L.; Mularski,
C. J. J. Org. Chem. 1984, 49, 4800. (d) Korbonits, D.;
Kanzel-Svoboda, I.; Gönczi, C.; Simon, K.; Kolonits, P.
Chem. Ber. 1989, 122, 1107. (e) Menzler, S.; Bikker, J. A.;
Horwell, D. C. Tetrahedron Lett. 1998, 39, 7619.
(f) Srivastava, R. M.; Oliveira, F. J. S.; Machado, D. S.;
Souto-Maior, R. M. Synth. Commun. 1999, 29, 1437.
(g) Kayukova, L. A. Pharm. Chem. J. 2005, 39, 539.
(8) Walz, A. J.; Sundberg, R. J. J. Org. Chem. 2000, 65, 8001.
(9) (a) Kawashima, E.; Tabei, K. J. Heterocycl. Chem. 1986, 23,
1657. (b) Payne, R. J.; Daines, A. M.; Clark, B. M.; Abell,
A. D. Bioorg. Med. Chem. 2004, 12, 5785. (c) Montalbetti,
C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827.
(d) Shinada, T.; Umezawa, T.; Ando, T.; Kozuma, H.;
Ohfune, Y. Tetrahedron Lett. 2006, 47, 1945. (e) Klutchko,
S. R.; Zhou, H.; Winters, R. T.; Tran, T. P.; Bridges, A. J.;
Althaus, I. W.; Amato, D. M.; Elliott, W. L.; Ellis, P. A.;
Meade, M. A.; Roberts, B. J.; Fry, D. W.; Gonzales, A. J.;
Harvey, P. J.; Nelson, J. M.; Sherwood, V.; Han, H.-K.;
Pace, G.; Smaill, J. B.; Denny, W. A.; Showalter, H. D. H. J.
Med. Chem. 2006, 49, 1475.
MS (EI): m/z (%) = 451 (100) [M + 1], 323 (13), 175 (14), 149 (16).
HRMS (ESI): m/z [M + H]+ calcd for C26H19N4O4: 451.1406; found:
451.1416.
Bis{5-(4-formylphenyl)-[1,2,4]oxadiazol-3-yl}-1,6-hexane (18)
Obtained by method F, starting from bis{5-(4-[1,3]-dioxolan-2-
ylphenyl)-[1,2,4]oxadiazol-3-yl]-1,6-hexane (14; 0.50 g, 1.0
mmol).
Yield: 0.42 g (100%); pale-yellow solid; mp 95 °C.
1H NMR (CDCl3): d = 1.41–1.51 (m, 4 H), 1.89–1.94 (m, 4 H), 2.98
(t, J = 7.5 Hz, 4 H), 7.97 (d, J = 8.2 Hz, 4 H), 8.24 (d, J = 8.2 Hz,
4 H), 10.06 (s, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C24H23N4O4: 431.1779; found:
451.1702.
Bis{5-(4-formylphenyl)-[1,2,4]oxadiazol-3-yl}-1,8-octane (19)
Obtained by method F, starting from bis{5-(4-[1,3]-dioxolan-2-
ylphenyl)-[1,2,4]oxadiazol-3-yl}-1,8-octane (15; 0.50 g, 1.0
mmol).
(10) Kluger, R.; Shen, L.; Xiao, H.; Jones, R. T. J. Am. Chem.
Yield: 0.42 g (100%); pale-yellow solid; mp 89 °C.
Soc. 1996, 118, 8782.
(11) Inagaki, M.; Matsumoto, S.; Tsuri, T. J. Org. Chem. 2003,
68, 1128.
Synthesis 2007, No. 21, 3406–3410 © Thieme Stuttgart · New York