A facile route to a novel aza-crown ether incorporating three thiophene moieties

Article abstract of DOI:10.1016/S0040-4039(00)01033-9

The preparation of the first of a novel type of large thiophene-containing aza-crown ether is reported. The macrocycle is synthesised by linking a 3,4-dialkoxythiophene moiety with two 3-hydroxythiophene units and ring closure is effected by reaction with piperazine via the Mannich reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01033-9

Tetrahedron Letters 41 (2000) 6223±6226
A facile route to a novel aza-crown ether incorporating three
thiophene moieties
Joan Halfpenny,* Phillip B. Rooney and Zachary S. Sloman
Department of Chemistry and Physics, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK
Received 15 May 2000; accepted 20 June 2000
Abstract
The preparation of the ®rst of a novel type of large thiophene-containing aza-crown ether is reported.
The macrocycle is synthesised by linking a 3,4-dialkoxythiophene moiety with two 3-hydroxythiophene
units and ring closure is e€ected by reaction with piperazine via the Mannich reaction. # 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: aza-crown; thiophene; macrocycle; Mannich reaction.
The syntheses of non-aromatic and benzene-containing aza-crown ethers have been widely
reported.1 However, thiophene analogues are poorly represented in the literature.2 Aza-crown
ethers have complexing properties which are intermediate between those of crown ethers and
those of nitrogen donor macrocycles. They exhibit enhanced coordinating ability towards
ammonium salts and transition metals over crown ethers3,4 as well as having important
applications as synthetic receptors in molecular recognition processes.5 We report in this paper a
new route to the ®rst of a novel type of large aza-crown ether incorporating three thiophene rings.
The method of ring closure employed utilises the Mannich reaction, which gives selective
substitution of the 3-alkoxythiophene units over the 3,4-dialkoxythiophene unit. The synthetic
route is shown in Scheme 1.
To diethyl 3,4-dihydroxythiophene-2,5-dicarboxylate, 1, (1 equiv.) and anhydrous potassium
carbonate (1.2 equiv.) in DMF (1.0 cm3 mmol^1), heated at 100ꢀC, was added 5-tosyloxy-3-oxa-
pentan-1-ol (1.2 equiv.) in DMF (0.5 cm3 mmol^1) by means of a syringe pump. After the addition,
heating was continued for 12 h. The solvent was removed in vacuo and the crude mixture was
partitioned between water and EtOAc. The organic layer was dried (MgSO4) and evaporated.
Diethyl 3,4-bis(50-hydroxy-30-oxapentyloxy)thiophene-2,5-dicarboxylate, 2, was obtained in 56%
yield6 as an oil after column chromatography (silica: EtOAc). To crude 2 (5.10 g, 0.012 mol), in
dry DCM (45 cm3) and triethylamine (10 cm3), was added methanesulfonyl chloride (8.04 g, 0.07
* Corresponding author. Fax: +44 0115 9486636; e-mail: joan.halfpenny@ntu.ac.uk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01033-9

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Scheme 1. (i) K2CO3, 5-tosyloxy-3-oxapentan-1-ol, DMF, Á 100ꢀC. (ii) methanesulfonyl chloride, DCM/triethyl-
amine, 0ꢀC. (iii) methyl 3-hydroxythiophene-2-carboxylate, K2CO3, DMF, Á 100ꢀC. (iv) 2 M NaOH(aq), EtOH, Á
60ꢀC, 4 M HCl. (v) Cu2O, quinoline, Á 180ꢀC, under N2. (vi) 37% CH2O(aq), piperazine, g.AcOH.
mol) with ice cooling. The mixture was stirred at room temperature for 10 min, and then poured
into water (100 cm3). The organic layer was separated, washed with water, dried (Na2SO4) and
evaporated. The resulting oil was puri®ed by column chromatography, (silica: EtOAc±light petroleum,
2:1), to give diethyl 3,4-bis(50-methanesulfonyloxy-30-oxapentyloxy)thiophene-2,5-dicarboxylate,
3, as an oil (3.22 g, 47% yield).7 To add the end thiophene units, 3 (2.14 g, 3.64 mmol) was added
to a suspension of methyl 3-hydroxythiophene-2-carboxylate (1.25 g, 8.23 mmol) and potassium
carbonate (1.50 g, 10.87 mmol) in DMF (50 cm3) and stirred and heated (100ꢀC) for 12 h. Upon
cooling, the inorganic material was ®ltered o€ and the ®ltrate was evaporated to dryness in
vacuo. The resulting oil was dissolved in EtOAc (75 cm3) and washed with water. The organic
layer was dried (MgSO4), and evaporated to give an oil, which was subjected to column
chromatography, (silica: EtOAc±light petroleum, 3:1), to give diethyl 3,4-bis[50-(200-methoxy-
carbonyl-300-thienyloxy)-30-oxapentyloxy]-thiophene-2,5-dicarboxylate, 4, (1.93 g, 75%).8 Having

6225
successfully coupled the three thiophene moieties, the tetraester, 4, was stirred with a 30% excess
of sodium hydroxide solution (2 M) and an equal volume of ethanol at 60ꢀC for 1 hour. The
cooled solution was acidi®ed with hydrochloric acid (4 M), and the subsequent slurry was stirred
for a further hour. The ethanol was removed in vacuo and the precipitate ®ltered o€ and recrystallised
from water to a€ord 3,4-bis[50-(200-carboxy-300-thienyloxy)-30-oxapentyloxy]thiophene-2,5-dicarboxylic
acid, 5, as a white solid, (92%).9 In order to decarboxylate the tetraacid, compound 5, quinoline
(3 cm3 g^1) and copper(I) oxide (0.25 mol per mol of CO2 expected) were heated (180ꢀC) for 45
min under nitrogen. Upon cooling, the mixture was ®ltered and the residue was washed with
diethyl ether. The combined ®ltrate and ethereal washings were extracted with hydrochloric acid
(4 M), water and sodium carbonate solution (10%). The diethyl ether layer was dried (Na2SO4)
and evaporated. The crude compound was puri®ed by centrifugal chromatography, (silica: light
petroleum-EtOAc, 1:1), to give 3,4-bis[50-(300-thienyloxy)-30-oxapentyloxy]thiophene, 6, as a white
solid (81%).10 In the ®nal step, 6 (0.67 g, 1.47 mmol) was added to glacial acetic acid (50 cm3),
piperazine (0.13 g, 1.51 mmol) and aqueous formaldehyde (37%, 0.24 cm3, 2.96 mmol) and stir-
red overnight. The solvent was removed in vacuo and the residue was basi®ed (4 M NaOH) and
extracted with dichloromethane, (3Â20 cm3). The combined organic layers were dried (MgSO4)
and evaporated to give the crude product which was puri®ed by column chromatography,
(alumina: light petroleum±EtOAc, 5:1), to give 2,5,8,14,17,20-hexaoxa-27,30-diaza-11,24,33-
trithia-27,30-ethylenpentacyclo[30.3.1,322.27,300.21,250.9,13]-pentatriaconta-1(32),9,12,21,(25),22,34-
hexene, 7, as a white crystalline solid (0.41 g, 49%).11
The macrocycle 7 was obtained as the sole product of the reaction. This was somewhat
surprising as cyclisation should also be possible between the 2-position of the 3,4-dioxy
substituted thiophene ring and the 2-position of one of the 3-oxy substituted thiophene rings.
However, this latter reaction clearly does not occur as no asymmetrically substituted product was
isolated from the column chromatography fractions.
References
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J. Chem. Soc., Dalton. Trans. 1984, 2281±2288. (c) Barker, J. M.; Chan, J. D. E.; Halfpenny, J.; Huddleston,
P. R.; Tseki, P. F. J. Chem. Soc., Chem. Commun. 1993, 1733±1734. (d) Miller, D. C.; Johnson, M. R.; Ibers, J. A.
J. Org. Chem. 1994, 59, 2877±2879.
3. Lehn, J. M.; Vierling, P. Tetrahedron Lett. 1980, 21, 1323±1326.
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6. ꢀmax (®lm) 3426, 2937, 2872 and 1717 cm^1; ꢁH (CDCl3) 1.37 (6H, t, J 7.3 Hz, CH3), 3.63±3.65 (4H, m, OCH2),
3.80±3.84 (8H, m, OCH2), 4.35 (4H, q, CO2CH2), 4.39±4.41 (4H, m, ArOCH2); ꢁC (CDCl3) 14.2 (CH3), 61.5
(CO2CH2), 61.7 (CH2OH), 70.2, 72.9 and 74.1 (OCH2), 119.7 (C2/C5), 153.2 (C3/C4), 160.5 (CˆO); (Found: C,
49.71; H, 6.72. C18H28O10S requires C, 49.53; H, 6.47%).
7. ꢀmax (®lm) 2960, 2910 and 1710 cm^1; ꢁH (CDCl3) 1.37 (6H, t, J 7.3 Hz, O2CH2CH3), 3.06 (6H, s, SO2CH3), 3.80±
3.87 (8H, m, OCH2), 4.34 (4H, q, J 7.3 Hz, CO2CH2), 4.36±4.39 (8H, m, OCH2); ꢁC (CDCl3) 14.2 (CH2CH3), 37.5
(SO2CH3), 61.4 (CO2CH2), 68.9, 69.3, 70.5 and 73.7 (OCH2), 119.6 (C2/C5), 153.0 (C3/C4), 160.4 (CˆO); (Found:
C, 40.62; H, 5.49. C20H32O14S3 requires C, 40.53; H, 5.44%).
8. ꢀmax (®lm) 3110, 2980, 2950 and 1710 cm^l; ꢁH (CDCl3) 1.36 (6H, t, J 7.3 Hz, O2CH2CH3), 3.81 (6H, s, CO2CH3),
3.87±3.92 (8H, m, OCH2), 4.24±4.39 (12H, m, CO2CH2 and OCH2), 6.85 (2H, d, J 5.6 Hz, ArH on C4), 7.37 (2H,

6226
d, J 5.6 Hz, ArH on C5); ꢁC (CDCl3) 14.2 (O2CH2CH3), 51.6 (CO2CH3), 61.4 (CO2CH2), 69.6, 70.8, 71.7 and 73.8
(OCH2), 110.0 (C20), 117.5 (C40), 119.5 (C2/C5), 130.5 (C50), 153.2 (C3/C4), 160.6 (CO2Et), 161.1 (CO2Me), 162.0
(C30); (Found: C, 50.62; H, 4.91. C30H36O14S3 requires C, 50.27; H, 5.06%).
9. M.p. 150±152ꢀC. ꢀmax (KBr) 3100, 2920, 2600, 1710 and 1690 cm^1; ꢁH (CDCl3/DMSO-d6) 3.84±3.88 (8H, m,
CH2OCH2), 4.26±4.30 (4H, m, ArOCH2), 4.36±4.40 (4H, m, ArOCH2), 6.90 (2H, d, J 5.6 Hz, ArH on C40), 7.45
(2H, d, J 5.6 Hz, ArH on C50), (no signal observed for CO2H); ꢁC (CDCl3/DMSO-d6) 69.3, 70.3, 71.4 and 73.5
(OCH2), 111.0 (C20), 117.6 (C40), 120.6 (C2/C5), 130.7 (C50), 152.3 (C3/C4), 160.4 (C30), 162.1 and 163.2 (CˆO);
(Found: C, 43.25; H, 4.09. C24H24O14S3 requires C, 45.57; H, 3.82%, C24H24O14S3.2H2O requires C, 43.11; H,
4.22%).
10. M.p. 98.5±100ꢀC. ꢀmax (KBr) 3100, 3090, 2920, 2895, 2850 and 1575 cm^1; ꢁH (CDCl3) 3.87±3.92 (8H, m,
CH2OCH2), 4.09±4.18 (8H, m, ArOCH2), 6.23±6.25 (4H, m, ArH on C2/C5 and C20), 6.75±6.78 (2H, m, ArH on
C40), 7.14±7.17 (2H, m, ArH on C50); ꢁC (CDCl3) 69.6, 69.7, 69.9 and 70.0 (OCH2), 97.6 (C20), 98.1 (C2/C5), 119.6
(C40), 124.7 (C50), 147.1 (C3/C4), 157.5 (C30); (Found: C, 52.33; H, 5.35. C20H24O6S3 requires C, 52.61; H, 5.30%).
11. M.p. 94±96ꢀC. ꢀmax (KBr) 3110, 2930, 2890, 1570 and 1555 cm^1; ꢁH (CDCl3-DMSO-d6) 2.49 (8H, s, NCH2), 3.61
(4H, s, ArCH2N), 3.81±3.90 (8H, m, CH2OCH2), 4.09±4.15 (8H, m, ArOCH2), 6.25 (2H, s, ArH), 6.79 (2H, d, J
5.3Hz, ArH on C40), 7.08 (2H, d, J 5.6Hz, ArH on C50); ꢁC (CDCl3 DMSO-d6) 51.8 (ArCH2N), 52.0 (NCH2),
69.6, 70.0, 70.1 and 71.6 (OCH2), 98.2 (C2/C5), 117.7 (C40), 118.0 (C20), 122.4 (C50), 147.0 (C3/C4), 154.1 (C30);
(Found: C, 55.27; H, 6.16; N, 4.74. C26H34N2O6S3 requires C, 55. 10; H, 6.05; N, 4.94%); mle 566 (M+, 100%).