benzaldehyde Building Blocks

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PAPER

A Simple and Efficient Synthesis of New Mono- and Bis([1,2,4]-oxadiazol)benzaldehyde Building Blocks Synthesi ofNewMono-andBis([1,24]-oxadiazol)benzaldehydes Crestey,a Cyril Lebargy,a Marie-Claire Lasne,a Cécile Perrio*a,b François 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: [email protected] Received 12 June 2007

Abstract: 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 synthesized in a high-yielding, five-step procedure with few and simple purifications. Key words: mono- and bis-benzaldehyde, 1,2,4-oxadiazole, benzamidoxime, O-acylation, acetal deprotection

The development of general and simple synthetic pathways for the generation of new and original libraries of organic compounds is currently one of the most important challenges in organic chemistry. In the course of our studies related to a new and selective route to the (Z,Z)-2,7bis(4-cyanobenzylidene)cycloheptan-1-one (BABCH),1 we discovered a simple and efficient method for the synthesis of various new aromatic and aliphatic bis([1,2,4]oxadiazol)benzaldehydes of type I. To obtain these compounds, we decided to synthesize benzamidoxime II, which was reacted with a range of dicarboxylic acids and/ or acid dichlorides III (Scheme 1). R

O N

N

N

After these encouraging results, we decided to study these reactions with various aromatic and aliphatic linkers in order to obtain the desired dibenzaldehydes. To introduce

OH

O N

H2N

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, under reflux conditions for three hours, to give the product 2 in 89% yield.3,4 The nitrile was easily transformed into the corresponding amidoxime 3 in 90% yield, by treatment with hydroxylamine hydrochloride (3.5 equiv) and sodium 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 addition of pyridine (2 equiv) and phenylacetyl chloride (1.2 equiv) to a solution of benzamidoxime 3 in dichloromethane at room temperature, to afford O-acylated benzamidoxime 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-toluenesulfonate8 (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-benzaldehyde was obtained in five steps with an overall yield of 70%.

N X +

X

R O

O

O

Bn

III

OH

II CHO I

CHO

Y

H2N

CN

R = aromatic/aliphatic linker X = Cl or OH Y = protected aldehyde

N

H2N

ii

Scheme 1 Considered strategy for the synthesis of bis([1,2,4]oxadiazol)benzaldehydes

O

R

N

v

R

R

3

O N

N

iii

R

Bn

O

With this in mind, we first wanted to apply our methodology to the synthesis of a benzaldehyde with a 1,2,4-oxadiazole 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, SYNTHESIS 2007, No. 21, pp 3406–3410xx. 207 Advanced online publication: 16.10.2007 DOI: 10.1055/s-2007-990834; Art ID: Z14607SS © Georg Thieme Verlag Stuttgart · New York

1 R = CHO i

O 2 R=

O

4 R= iv

6 R= O

5 R = CHO

vi

O 7 R = CHO

O

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%.

PAPER

Synthesis of New Mono- and Bis([1,2,4]-oxadiazol)benzaldehydes O

OH H2N

O

N

H2N

R

O N

NH2

A or B

C or D

O

O

O

O

8–11 R

O

O

O

3

N

diacetic acids were then converted into the corresponding acid dichlorides by reaction with oxalyl chloride and a catalytic amount of dimethylformamide in dichloromethane10 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 obtained in a quantitative yield (Scheme 3, Table 1).

O

N

N

Depending on the solubility of the starting material in toluene, the bis-oxadiazoles 12–15 were obtained by heating either under reflux conditions (method C) or under solvent-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).

O N

N

R

O N

N

O N

N

E or F

O

O

O

O

CHO

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 catalytic amount of concentrated hydrochloric acid11 in aqueous tetrahydrofuran at 65 °C for 18 hours (method F), to give the desired dibenzaldehydes 16–19 in excellent yields (Scheme 3, Table 1).

CHO

16–19

12–15

()

n

R=

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). In order to compare the yields, benzamidoxime 3 was reacted with 1,3- and 1,4-phenylenediacetic acid with 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (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 conditions for 12 hours, afforded the desired aromatic bis-amidoximes 8 and 9, both in 53% yield (method A). These two

Table 1

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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 processes. Moreover, this method has already been scaled up for the synthesis of multigram amounts of the dibenzaldehydes. 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. All commercial reagents were used as received without further purification. Reaction mixtures were stirred magnetically and monitored 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 (reported uncorrected) were determined on a Köfler melting point apparatus. 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 instrument. Chemical shifts (d) are expressed in ppm downfield from TMS as an internal standard and the coupling constants are in hertz.

Synthesis and Yields of Bis([1,2,4]-oxadiazol)benzaldehydes 16–19

n-Bu

R

n-Hex

Method (%)

8

A (53) B (100)

9

A (53) B (100)

10

B (100)

11

B (100)

Method (%)

12

D (100)

13

D (87)

14

C (85)

15

C (90)

Method (%)

16

E (100)

17

F (94)

18

F (100)

19

F (100)

Synthesis 2007, No. 21, 3406–3410

© Thieme Stuttgart · New York

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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. (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 dropwise 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. Yield: 9.12 g (89%); colorless solid; mp 45 °C; Rf = 0.35 (CH2Cl2). 1 H 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). 13

C NMR (CDCl3): d = 65.5, 102.4, 112.9, 118.6, 127.1, 132.2, 143.1. MS (EI): m/z (%) = 175 (15) [M+], 174 (27), 148 (41), 130 (100), 102 (38). Anal. Calcd for C10H9NO2: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.57; H, 5.21; N, 7.87. (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 successively 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. Yield: 14.27 g (90%); colorless solid; mp 150 °C; Rf = 0.3 (CH2Cl2– MeOH, 9:1).

IR (KBr): 2352, 1738, 1734, 1622, 1616, 1558 cm–1. 1 H 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). 13

C 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). 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: 1.23 g (100%); colorless solid; mp 190 °C. IR (KBr): 3354, 3346, 1734, 1618, 1084 cm–1. 1

H 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).

13

C 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. 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). 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: 1.23 g (100%); colorless solid; mp 202 °C.

IR (KBr): 1638, 1068 cm–1.

1

1

H 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).

H 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). 13

C NMR (DMSO-d6): d = 65.3, 103.0, 125.8, 126.8, 134.5, 139.1, 151.1.

C 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.

MS (EI): m/z (%) = 208 (96) [M+], 192 (55), 176 (35), 148 (45), 136 (33), 119 (27), 105 (37), 104 (33), 73 (100).

MS (EI): m/z (%) = 575 (33) [M + 1], 574 (31), 460 (100), 459 (88), 443 (22).

Anal. Calcd for C10H12N2O3: C, 57.69; H, 5.81; N, 13.45. Found: C, 57.65; H, 5.88; N, 13.11.


13

Synthesis of Acylated Amidoximes 4 and 8–11; General Procedure 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 stirring. The reaction mixture was stirred at r.t. for 16 h and then concentrated in vacuo. The crude material was poured into H2O (50 mL), stirred for 15 min then filtered to give the desired compound. (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 pyridine (3.2 mL, 42.6 mmol). Yield: 6.94 g (100%); pale-brown solid; mp 130 °C; Rf = 0.6 (CH2Cl2–MeOH, 9:1).

Synthesis 2007, No. 21, 3406–3410


Bis{(4-[1,3]-dioxolan-2-yl)-O-carboxybenzamidoximo}-1,6hexane (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). Yield: 0.95 g (100%); colorless solid; mp 169 °C. 1

H 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).

13

C 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. HRMS (ESI): m/z [M + H]+ calcd for C28H35N4O8: 555.2455; found: 555.2436.

PAPER

Synthesis of New Mono- and Bis([1,2,4]-oxadiazol)benzaldehydes

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1

Bis{(4-[1,3]-dioxolan-2-yl)-O-carboxybenzamidoximo}-1,8-octane (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).

H 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).

Yield: 0.95 g (100%); colorless solid; mp 184 °C.

MS (EI): m/z (%) = 539 (75) [M + 1], 366 (20), 193 (63), 176 (100).

1

H 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).

13

C 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. HRMS (ESI): m/z [M + H]+ calcd for C30H39N4O8: 583.2767; found: 583.2770.

13

C NMR (CDCl3): d = 32.7, 65.4, 103.2, 126.9, 127.5, 129.6, 133.0, 141.0, 168.3, 177.8. HRMS (ESI): m/z [M + H]+ calcd for C30H27N4O6: 539.1931; found: 539.1947. Bis{5-(4-[1,3]-dioxolan-2-ylphenyl)-[1,2,4]oxadiazol-3-yl}-1,6hexane (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). 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 toluene (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. 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.

1

H 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}-1,8octane (15) Obtained by method C, starting from bis{(4-[1,3]-dioxolan-2-yl)O-carboxybenzamidoximo}-1,8-octane (11; 0.85 g, 1.5 mmol). Yield: 0.72 g (90%); pale-orange solid; mp 108–110 °C. 1

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)-Ophenylacetylbenzamidoxime (4; 5 g, 15.3 mmol). Yield: 9.12 g (100%); beige solid; mp 62 °C; Rf = 0.35 (CH2Cl2). 1 H 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). 13

C 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). Anal. Calcd for C18H16N2O3: C, 70.12; H, 5.23; N, 9.09. Found: C, 70.16; H, 5.63; N, 8.59. 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-2yl)-O-carboxybenzamidoximo}-1,3-xylene (8; 1.23 g, 2.1 mmol). Yield: 1.15 g (100%); orange solid. 1 H 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).

MS (EI): m/z (%) = 539 (100) [M + 1], 493 (45), 366 (25), 193 (39), 176 (85). HRMS (ESI): m/z [M + H]+ calcd for C30H27N4O6: 539.1931; found: 539.1947. 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-2yl)-O-carboxybenzamidoximo}-1,4-xylene (9; 0.73 g, 1.3 mmol). Yield: 0.60 g (87%); orange solid.

H 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. Synthesis of Benzaldehydes 5, 7 and 16–19; General Procedure Method E: PPTS (0.3 equiv per acetal function) was added to a solution 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. Method F: HCl (37%, 10 drops) was added to a solution of the corresponding 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. 4-Formyl-O-phenylacetylbenzamidoxime (5) Obtained by method E, starting from (4-[1,3]-dioxolan-2-yl)-Ophenylacetylbenzamidoxime (4; 1 g, 3.1 mmol) and PPTS (0.23 g, 0.9 mmol). 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. 1

H 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). 13

C 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.

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


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PAPER

F. Crestey et al. 1


H 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]-dioxolan2-ylphenyl)-[1,2,4]oxadiazole (6; 0.69 g, 2.2 mmol) and PPTS (0.17 g, 0.7 mmol).


Yield: 0.51 g (88%); beige solid; mp 86 °C; Rf = 0.5 (CH2Cl2).

Acknowledgment

1

H 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). 13 C 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.

MS (EI): m/z (%) = 264 (100) [M+], 263 (36), 236 (12), 146 (42), 133 (19), 118 (14), 104 (34), 91 (25), 65 (14). 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]-dioxolan2-ylphenyl)-[1,2,4]oxadiazol-3-yl}-1,3-xylene (12; 1.15 g, 2.1 mmol). Yield: 0.96 g (100%); orange solid. 1

H 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. 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]-dioxolan2-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. 1 H 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).

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-2ylphenyl)-[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. 1

H 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-2ylphenyl)-[1,2,4]oxadiazol-3-yl}-1,8-octane (15; 0.50 g, 1.0 mmol). Yield: 0.42 g (100%); pale-yellow solid; mp 89 °C.

Synthesis 2007, No. 21, 3406–3410


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.

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