A facile method for the synthesis of benzothiacrown ether formyl derivatives

Article abstract of DOI:10.1081/SCC-120004088

A facile route to the formyl derivatives of benzothiacrown ethers with different combinations of O and S heteroatoms in the macrocycle involving ring closure reactions of substituted benzaldehydes with dithiols was developed. The effects of alkali metal cations and solvent were studied.

Full text of DOI:10.1081/SCC-120004088

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A FACILE METHOD FOR THE SYNTHESIS OF
BENZOTHIACROWN ETHER FORMYL DERIVATIVES
Olga A. Fedorova a , Artem I. Vedernikov a , Olga V. Yescheulova a , Yulia V. Pershina a , Pavel
V. Tsapenko a & Sergey P. Gromov a
a Photochemistry Center of the Russian Academy of Sciences , Novatorov str., 7a, Moscow,
117421, Russia
Published online: 17 Oct 2011.
To cite this article: Olga A. Fedorova , Artem I. Vedernikov , Olga V. Yescheulova , Yulia V. Pershina , Pavel V. Tsapenko &
Sergey P. Gromov (2002) A FACILE METHOD FOR THE SYNTHESIS OF BENZOTHIACROWN ETHER FORMYL DERIVATIVES, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:12, 1909-1915, DOI:
10.1081/SCC-120004088
To link to this article: http://dx.doi.org/10.1081/SCC-120004088
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SYNTHETIC COMMUNICATIONS, 32(12), 1909–1915 (2002)
A FACILE METHOD FOR THE
SYNTHESIS OF BENZOTHIACROWN
ETHER FORMYL DERIVATIVES
*
Olga A. Fedorova, Artem I. Vedernikov,
Olga V. Yescheulova, Yulia V. Pershina,
Pavel V. Tsapenko, and Sergey P. Gromov
Photochemistry Center of the Russian Academy of
Sciences, Novatorov str., 7a, Moscow 117421, Russia
ABSTRACT
A facile route to the formyl derivatives of benzothiacrown
ethers with different combinations of O and S heteroatoms
in the macrocycle involving ring closure reactions of substi-
tuted benzaldehydes with dithiols was developed. The effects
of alkali metal cations and solvent were studied.
There exist lots of macrocycles containing one or more sulfur atoms
including crown ethers,[1] cryptates,[2] cyclophanes,[3] and ligands of a defi-
nite shape.[4] Macrocyclic sulfur compounds present considerable interest
due to their ability to bind selectively heavy and transition metal cation.[5]
A wide range of macrocyclic polythioethers are known; they are prepared by
the route developed by Ochrymowycs and coworkers.[6] The formation of
macrocycles from thiolates was found to proceed in remarkably good yields
*Corresponding author.
1909
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1910
FEDOROVA ET AL.
when cesium is used as the counterion in the nucleophile and DMF is used
as the solvent.[7] However, only a few macrocyclic polythioethers have been
prepared using another alkali metal cation to coordinate the sulfur atoms in
the reaction of thiols with dihalides;[8] the template requirement has not
been established.[9]
A number of O,S-mixed benzocrown ethers have been prepared.[10]
Substitution is considered to be of great importance because it provides
reactive sites for the attachment of other functions[11a–c] or polymer sup-
ports.[12] Syntheses of the substituted benzothiacrown ethers have not been
well developed by now, although some of the possible methods have been
[13a,b]
presented in our publications.
The methods described are multistep
procedures relatively difficult to perform in practice (low temperatures,
anhydrous solvents, inert atmosphere).
Here we propose a facile process for the preparation of macrocyclic
benzopolythiacrown ethers. Compounds 3a–e were obtained in 42–90%
yields by refluxing substituted benzaldehydes 1b, c and dithiols 2a–e in
organic or aqueous organic solvents in the presence of alkali metal carbo-
nates (Scheme 1). The roles of the alkali metal cation and the solvent in the
synthesis of the crown ethers 3a–e were studied.
The dithiols 2a–c required for the experiments were commercially
available, compounds 2d,
e were prepared according to known
methods. [14a,b] The substituted benzaldehyde 1b, c were prepared according
Scheme 2 (see Experimental).
The results obtained demonstrate that various organic solvents and
their mixtures with water (organic solvent/water ¼ 1/1) are suitable for the
synthesis of the macrocycles 3a–e. Thus the yields of 3c in the condensation
reaction between 1b and 2c in the presence of Cs2CO3 were: 61%
(EtOH/H2O); 88% (MeCN); 81% (MeCN/H2O); 90% (DMF); and 90%
(DMF/H2O). The aliphatic components 2b–d containing O and S atoms
1 : b, X ¼ Cl; c, X ¼ l ; 2, 3: a,n ¼ 0; b, Y ¼ O, n ¼ 1; c, Y ¼ O, n ¼ 2; d, Y ¼ O, n ¼ 3; e,
Y ¼ S, n ¼ 2, M ¼ Li, Na, K, Cs.
Scheme 1.

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BENZOTHIACROWN ETHER FORMYL DERIVATIVES
1911
Scheme 2.
are reactive towards both dichloro (1b) and diiodo (1c) substituted benzalde-
hydes. However, aliphatic oxygen-free components 2a, e are able to react only
with diiodide 1c.
All the alkali metal carbonates studied can be used effectively in the
þ
synthesis of the formylderivatives of the benzothiacrown ethers. The Li
,
Naþ and Kþ cations demonstrated the template effect, which implies that
the yield of the product reaches its maximum when the cation perfectly fits
into the cavity of the crown ether: 3b—81% (Liþ); 3c—75% (Naþ); 3d—
74% (Kþ) (see Table 1).
In the presence of cesium carbonate, all the prepared compounds
underwent successfully the ring-closure reaction; the yields of the products
did not depend on the size or composition of the macrocycle formed, for
instance, 3b—61%, 3c—61%, 3d—53%, 3e—68% (solvent EtOH/H2O). As
has been shown previously,[15] intramolecular cyclization does not involve
the formation of template complex but occurs on the surface of the highly
polarizable cesium ion. A detailed mechanistic study will be reported in full
paper.
The methodology described herein provides an acceptable synthetic
basis for the preparation of a large variety of sulfur-containing formyl
derivatives of the benzocrown ethers otherwise difficulty accessible. A wide
range of structural types have been prepared in this way in good to excellent
yields.
Table 1. The Yield (in %) of 3a–e in Reaction Condensation of 1b, c with 2a–e in
EtOH/H2O
Crown
Ether
3a
(From 1c)
3b
(From 1b)
3c
(From 1b)
3d
(From 1b)
3e
(From 1c)
Liþ
Naþ
Kþ
42
0
–
44
81
30
30
61
69
75
41
61
58
67
74
53
62
33
–
Csþ
68

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1912
FEDOROVA ET AL.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker DRX-500 spectrometer
in CDCl3 using tetramethylsilane as the internal standard. Chemical shifts
were measured with an accuracy of 0.01 ppm and spin–spin coupling con-
stants were determined with an accuracy of 0.1 Hz. Mass spectra were run
on a Varian MAT 311A instrument at an ionization energy of 70 eV with
direct sample injection into the ionization area. IR spectra were measured
on Shimadzu IR-435 and Bruker IFS-113v spectrophotometers in thin films
or in pellets with KBr. The reactions were monitored by TLC on
DC-Alufolien Kieselgel 60 F254, plates (Merck). Dehydration of DMF
needed for the reactions was performed by distilling the solvent
from BaO in vacuo. Commercialanhydrous ethanol(Adlrich), MeCN
(Aldrich), 1,2-bis(2-hydroxyethoxy)benzene (Aldrich), and 3,4-dihydroxy-
benzaldehyde (Merck) were used.
3,4-bis(2-Hydroxyethoxy)benzaldehyde (1a). A solution of 2-chloro-
ethanol (21.7 ml, 0.33 mol) in 60 ml of n-BuOH was added over a period of
1 h to a boiling solution of 3,4-dihydroxybenzaldehyde (15.0 g, 0.109 mol)
and NaOH (13.2 g, 0.33 mol) in a mixture of 300 ml of n-BuOH and 25 ml
of water. The reaction mixture was refluxed for an additional12 h, the solvent
was evaporated in vacuo, and the residue was chromatographed on a column
with silica gel (Kieselgel 60, 0.063–0.100 mm, elution with benzene–EtOH,
20 : 1) to give 20.4 g of product 1a (86%). 1H NMR (500 MHz, CDCl3–CCl4)
ꢀ 2.79 (br, s, 2H, 2OH), 3.95 (m, 4H, 2CH2OH), 4.19 (m, 4H, 2CH2O), 7.02 (d,
1H, H-6, J ¼ 8.1 Hz), 7.45 (m, 2H, H-3, H-5), 9.85 (s, 1H, CH¼O); Anal.
calcd for C11H14O5: C, 58.40; H, 6.24. Found: C, 58.13; H, 6.19.
3,4-bis(2-Chloroethoxy)benzaldehyde (1b).
A solution of SOCl2
(19.7 ml, 0.27 mol) in 30 ml of dry benzene was added with vigorous stirring
over a period of 1 h to a boiling solution of 1a (20.4 g, 0.09 mol) and anhy-
drous pyridine (21.8 ml, 0.27 mol) in 120 ml of anhydrous benzene. The
reaction mixture was refluxed for 5 h and cooled, and 100 ml of 15% HCl
was added. The organic layer was separated and the aqueous layer was
extracted with CHCl3 (2 ꢀ 50 ml). The extracts were combined, the solvent
was evaporated in vacuo, and the residue was chromatographed on silica gel
(Kieselgel 60, 0.063–0.200 mm, elution with benzene–MeCO2Et, 10 : 1) to
give 1.26 g of dichloride 1b (53%). 1H NMR (500 MHz, CDCl3–CCl4)
ꢀ 3.86 (m, 4H, 2CH2Cl), 4.35 (m, 4H, 2CH2O), 7.02 (d, 1H, H-6, J ¼
8.1 Hz), 7.43 (s, 1H, H-3), 7.47 (d, 1H, H-5, J ¼ 8.1 Hz), 9.85 (s, 1H, CH¼O);
Anal. calcd for C11H12Cl2O3: C, 50.21; H, 4.60. Found: C, 50.72; H, 4.61.
3,4-bis(2-Iodoethoxy)benzaldehyde (1c). A mixture of dichloride 1b
(5.8 g, 0.022 mol), anhydrous NaI (12.3 g, 0.082 mol), and 30 ml of anhydrous
acetone was refluxed with vigorous stirring for 120 h. The precipitate was

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BENZOTHIACROWN ETHER FORMYL DERIVATIVES
1913
filtered off, the mother liquor was concentrated in vacuo, and the residue was
dissolved in 50 ml of ethyl acetate and washed successively with 5% aqueous
solutions of Na2SO3 and Na2CO3 and with water. The solvent was evapo-
rated in vacuo and the residue was chromatographed on a column with silica
gel(Kieselgel60, 0.063–0.100 mm, elution with benzene–MeCO 2Et, 20 : 1) to
give 8.3 g of diiodide 1c (85%). 1H NMR (500 MHz, CDCl3–CCl4): ꢀ 3.49 (m,
4H, 2CH2I), 4.38 (m, 4H, 2CH2O), 7.00 (d, 1H, H-6, J ¼ 8.1 Hz), 7.43 (s, 1H,
H-3), 7.47 (d, 1H, H-5, J ¼ 8.1 Hz), 9.86 (s, 1H, CH¼O); Anal. calcd for
C11H12I2O3: C, 29.62; H, 2.71. Found: C, 30.07; H, 2.69.
Preparation of crown compounds 3a–e (General procedure). At
75–85ꢁC, solutions of dihalide 1b,c (4.24 mmol) and dithiol 2a–e
(4.66 mmol), each in 10 ml of a solvent (EtOH/H2O, MeCN, MeCN/H2O,
DMF, DMF/H2O), were added simultaneously with stirring over a period
of 1 h to a mixture of M2CO3 (M ¼ Li, Na, K, Cs) (21.2 mmol) in 200 ml of a
solvent. The reaction mixture was kept at the specified temperature for
13–20 h, the solvent was evaporated, 100 ml of water was added to the
residue, and the products were extracted with a benzene–CHCl3 mixture
(10 : 1). The extracts were concentrated in vacuo and the residue was chro-
matographed on a column with silica gel (Kieselgel 60, 0.063–0.100 mm); the
products were eluted successively with benzene and a benzene–MeCO2Et
mixture (20 : 1).
3a: 1H NMR: ꢀ 2.98 (m, 4H, 2CH2S), 3.07 (s, 4H, 2CH2S), 4.42
(m, 4H, 2CH2O), 6.92 (d, 1H, H-6, J ¼ 8.1 Hz), 7.36 (s, 1H, H-3), 7.47
(d, 1H, H-5, J ¼ 8.1 Hz), 9.85 (s, 1H, CH¼O); Anal. calcd for C13H16O3S2:
C, 54.90; H, 5.67. Found: C, 54.78; H, 5.61; b) 3b, 3c were published in
1
Ref. [13]; c) 3d: H NMR, ꢀ 2.95 (m, 4H, 2CH2S), 3.05 (s, 4H, 2CH2S),
3.66 (m, 8H, 4CH2O), 3.78 (m, 4H, 2CH2O), 4.27 (m, 4H, 2CH2O), 6.96
(d, 1H, H-6, J ¼ 8.2 Hz), 7.39 (s, 1H, H-3), 7.45 (d, 1H, H-5, J ¼ 8.2 Hz),
9.85 (s, 1H, CH¼O); Anal. calcd for C19H28O6S2: C, 54.78; H, 6.78.
1
Found: C, 54.56; H, 6.81; d) 3e: H NMR ꢀ 2.81–2.94 (m, 6H, 3CH2S),
2.97–3.15 (m, 10H, 5CH2S), 4.27–4.39 (m, 4H, 2CH2O), 6.98 (d, 1H, H-6,
J ¼ 8.2 Hz), 7.41 (s, 1H, H-3), 7.47 (d, 1H, H-5, J ¼ 8.2 Hz), 9.86 (s, 1H,
CH¼O); Anal. calcd for C17H24O3S4: C, 50.46; H, 5.98. Found: C, 50.65;
H, 6.04.
ACKNOWLEDGMENT
The study was supported by the INTAS (96-1142), DFG (Grant
436RUS 113/56/0), RFBR-DFG (Grant 98-03-04137) and the Ministry
for Science and Technologies of Russia.

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1914
FEDOROVA ET AL.
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BENZOTHIACROWN ETHER FORMYL DERIVATIVES
1915
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Received in the Netherlands June 27, 2001