Synthesis of some new macrocyclic bis-sulfonamides by fast addition method

Article abstract of DOI:10.1080/00397910802219171

Novel macrocyclic bis-sulfonamides that structurally related to the proton-ionizable crown compounds have been synthesized. These compounds were obtained in the macrocyclization step by the fast addition method, and the results were compared with both hig

Full text of DOI:10.1080/00397910802219171

Synthetic Communications1, 38: 2540–2547, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802219171
Synthesis of Some New Macrocyclic
Bis-sulfonamides by Fast Addition Method
Hossein Eshghi
Department of Chemistry, Ferdowsi University of Mashhad, Mashhad, Iran
Abstract: Novel macrocyclic bis-sulfonamides that structurally related to the
proton-ionizable crown compounds have been synthesized. These compounds
were obtained in the macrocyclization step by the fast addition method, and
the results were compared with both high dilution and solvent-free conditions.
Keywords: Fast addition, high dilution technique, macrocyclization, proton-
ionizable, solvent-free conditions, sulfonamides
Various modifications have been made to the basic crown ether structure
to enhance the sensing and selectivity of these ligands and the stability of
the complex formed.[1] Among these modifications are the substitutions
of ligand donor atoms with nitrogen or sulfur atoms or the inclusion
of ester and amide linkages in the polyether ring.[2] There has been much
attention paid to the chemistry of proton-ionizable crown ethers.[3] The
nature of the proton-ionizable group, particularly its acidity, controls
the metal ion complexation properties of such ligands. Arylsulfonamides
offer an advantage over other proton-ionizable crown compounds by
increasing the acidity of the amide protons by stabilizing the nitrogen
anions.[4] Bradshaw et al.[4,5] have reported bis-sulfonamide crown com-
pounds as excellent alkali metal cation carriers in bulk liquid membranes.
These macrocycles have been prepared mainly by the reaction of bis-
sulfonyl chlorides and diamines in high dilution conditions, which suffer
from disadvantages such as long reaction time, low yields, tedious proce-
dures, and use of high volumes of organic solvents.
Received in the U.K. August 22, 2007
Address correspondence to Hossein Eshghi, Department of Chemistry,
Ferdowsi University of Mashhad, Mashhad 91775-1436, Iran. E-mail: heshghi@
ferdowsi.um.ac.ir
2540

New Macrocyclic Bis-sulfonamides
2541
Scheme 1. New macrocyclic bis-sulfonamides.
Herein, we report the synthesis of novel macrocyclic bis-sulfonamides
1–8 (Scheme 1), in which the acidity of these proton-ionizable macrocycles
are increased by electronegative chloride substituents. As shown in
Scheme 2, these compounds were prepared by reacting the bis-sulfonyl
chlorides 13 and 14 and diamines in the fast addition method.
The reaction of p-chlorophenol with dichlorides 9 and 10 in N,N-
dimethylformamide (DMF) using potassium carbonate as a base gave
podands 11 and 12 in 76 and 64% yields, respectively. Bis-sulfonyl chlor-
ides 13 and 14 were obtained by chlorosulfonation of podands in 86 and
73% yields, respectively. The cyclization was carried out with vigorously
stirring and fast addition of a mixture of the diamine and triethylamine
into a suspension of bis-sulfonyl chlorides 13 and 14 in tetrahydrofuran
(THF) over 5 s at 25 ꢀC (Scheme 2).
A typical preparation of macrocyclic bis-sulfonamides is as follows: a
solution of 1,3-diaminopropane (2 mmol) and triethylamine (4 mmol) in
THF (20 ml) was added rapidly (5 s.) into a vigorously stirred suspension
of bis-sulfonyl chlorides 13 (2 mmol) in THF (20 ml) at 25 ꢀC. After the
usual workup and purification, bis-sulfonamide macrocyle 1 was
Scheme 2. Synthesis of macrocyclic bis-sulfonamides.

2542
H. Eshghi
Table 1. Comparison of the macrocyclization methods for the synthesis of
bis-sulfonamides 1 and 2
1
2
Entrya
Solvent (ml) Time
Yieldc Solvent (ml) Time
Yieldc
Fast addition
Solvent free
High dilutionb
40
0
400
5 s
10 min
4 h
45
18
25
40
0
400
5 s
10 min
4 h
35
15
19
aAll reactions were carried out using 2 mmol of bis-sulfonyl chloride 13 or 14,
2 mmol of 1,3-diaminopropane, and 4 mmol of triethylamine in THF (except the
solvent-free entry).
bAccording to Ref. 4.
cYields refer to isolated yield.
obtained in 45% yield. As shown in Scheme 1, a series of macrocyclic bis-
sulfonamides was obtained by this procedure in 18–45% yields. As
pointed in our previous study,[6] the less-reactive substrates in a sol-
vent-presence procedure failed in solvent-free reaction conditions. To test
this opinion and possibly increase the isolated yield, we treated the 1,3-
diaminopropane (2 mmol) and bis-sulfonyl chlorides 13 and 14 (2 mmol)
in the presence of triethylamine (4 mmol) in solvent-free conditions by sim-
ply grinding the mixture for 10 min. The corresponding bis-sulfonamide
macrocyles 1 and 2 were obtained in low yields, 18 and 15%, respectively.
The results are summarized in Table 1 and are compared with the corres-
ponding results obtained in both high dilution and fast addition methods.
As shown in Table 1, yields of macrocyclization with the fast addition
method are quite good. However, bis-sulfonyl chlorides 13 and 14 are
solid, bulky, and much less reactive than dicarboxylic acid dichlorides,
which decreased the yields in all procedures, especially in the solvent-free
condition. On the other hand, these sulfonamide-containing crowns with
high melting points and so low solubility in common solvents were recrys-
tallized in acetic acid, which seriously decreased the isolated yields.
The structures proposed for the macrocyclic compounds are cons-
1
istent with data derived from IR and HNMR spectra and molecular
weights determined by mass spectrometric analysis. The proton-ionizable
properties and ion recognition ability of these novel compounds are in
progress in our laboratories.
EXPERIMENTAL
Melting points were recorded in open capillary tubes in an Electrother-
mal IA 9100 melting-point apparatus. IR spectra were recorded on a

New Macrocyclic Bis-sulfonamides
2543
Shimadzu IR 470 spectrophotometer. 1HNMR spectra were recorded on
a Bruker 100-MHz instrument using tetramethylsilane (TMS) as an inter-
nal standard. Mass spectra were determined on a Shimadzu GCMS-QP
1000 EX instrument at 70 eV. All chemicals were purchased from Merck
and Fluka Co. and used without further purification.
Preparation of Podands 11 and 12
A mixture of p-chlorophenol (0.1 mol, 12.8 g) and potassium carbonate
(0.1 mol, 14 g) in DMF (60 mL) was refluxed for 30 min. Then a solution
of dichlorides 9 or 10 (0.05 mol) in DMF (20 mL) was added dropwise
over a period of 30 min. The reaction mixture was stirred under reflux
for 20 h. After cooling, the mixture was poured into water (200 mL)
and extracted with chloroform (2 ꢁ 75 mL). The organic layer was
washed with brine (6 ꢁ 100 mL) and dried over calcium chloride. The sol-
vent was evaporated to give a bright white solid of the corresponding
podands 11 and 12 after recrystallization from ethanol.
Data
1-Chloro-4-(2-[2-(4-chlorophenoxy)ethoxy]ethoxy)benzene (11): yield
12.4 g (76%); mp ¼ 88–90 ꢀC; IR (KBr): 740, 840, 1062, 1125, 1440,
1
1490, 1580, 2920, 3070 cmꢂ1; HNMR (CDCl3, 100 MHz) d 7.2 (d, 4 H,
J ¼ 8.5 Hz), 6.8 (d, 4 H, J ¼ 8.5 Hz), 4.1 (m, 4H), 3.9 (m, 4H). MS m=z
330 (Mþ þ 4), 328 (Mþ þ 2), 327 (Mþ þ 1), 326(Mþ ), 218,170, 157,
140, 128 (base peak), 106.
1-Chloro-4-(2-[2-(2-[4-chlorophenoxy]ethoxy)ethoxy]ethoxy)benzene (12):
yield 11.85 g (64%); mp ¼ 78–80 ꢀC; IR (KBr): 760, 870, 1050, 1120,
1
1510, 1595, 2960, 3070 cmꢂ1; HNMR (CDCl3, 100 MHz) d 7.8 (d, 4
H, J ¼ 8.5 Hz), 7.35 (d, 4 H, J ¼ 8.5 Hz), 4.16 (m, 4 H), 3.7 (m, 4 H),
3.6 (s, 4 H). MS m/z 374 (Mþ þ 4), 372 (Mþ þ 2), 371 (Mþ þ 1), 370
(Mþ , base peak), 356, 342, 313, 299, 279, 243, 231, 198,172, 159, 140, 128.
Preparation of Bis-sulfonyl Chlorides 13 and 14
Podands 11 or 12 (0.01 mol) were added to a string chlorosulfonic acid
solution (5 mL) at 0 ꢀC over a 45-min period. The resulting mixture was
stirred at 0 ꢀC for an additional 5 h. The mixture was then diluted with
chloroform (30 mL) and poured onto crushed ice. The mixture was saturated
with sodium chloride. The separated organic layer was washed with
saturated sodium bicarbonate (2 ꢁ 15 mL) and dried over anhydrous
magnesium sulfate. The solvent was evaporated to give a white solid of

2544
H. Eshghi
the corresponding bis-sulfonyl chlorides 13 and 14 after recrystallization
from ethyl acetate.
Data
5-Chloro-2-(2-[2-(4-chloro-2-chlorosulfonylphenoxy)ethoxy]ethoxy)-1-
benzenesulfonyl chloride (13): yield 4.5 g (86%); mp ¼ 118–120 ꢀC; IR
(KBr): 760, 830, 920, 1080, 1120, 1160, 1180, 1205, 1290, 1330, 1440,
1470, 1500, 1620, 2960, 3070 cmꢂ1; 1HNMR (DMSO-d6, 100 MHz) d 7.65
(d, 2 H, J ¼ 1.5 Hz), 7.35 (dd, 2 H, J1 ¼ 8.0 Hz, J2 ¼ 2.0 Hz), 7.05 (d, 2
H, J ¼ 8.0 Hz), 4.15 (m, 4 H), 3.90 (m, 4 H). MS m=z 526 (Mþ þ 4),
524 (Mþ þ 2), 523 (Mþ þ 1), 522 (Mþ ), 519, 426, 333, 326, 296, 282,
252, 235, 217, 198, 126, 107 (base peak).
5-Chloro-2-(2-[2-(2-[4-chloro-2-chlorosulfonylphenoxy]ethoxy)ethoxy]ethoxy)-
1-benzenesulfonyl chloride (14): yield 4.12 g (73%); mp ¼ 105 ꢀC; IR (KBr):
760, 850, 940, 1050, 1120, 1250, 1290, 1340, 1450, 1500, 1620, 2960,
1
3070 cmꢂ1; HNMR (DMSO-d6, 100 MHz) d 7.70 (d, 2 H, J ¼ 1.5 Hz),
7.40 (dd, 2 H, J1 ¼ 8.0 Hz, J2 ¼ 2.0 Hz), 7.10 (d, 2 H, J ¼ 8.0 Hz), 4.25
(m, 4 H), 3.75 (m, 4 H), 3.6 (s, 4 H). MS m=z 567 (Mþ þ 1), 566 (Mþ ),
564, 562, 499, 466, 370, 342, 325, 296, 252, 234, 216 (base peak), 188,
160, 128.
General Procedure for the Synthesis of Macrocyclic Bis-sulfonamides (1–8)
by Fast Addition Method
A solution of diamine (2 mmol) and triethylamine (0.41 g, 4 mmol) in
THF (20 mL) was added quickly (5 s) to a vigorously stirring suspension
of bis-sulfonyl chlorides 13 or 14 (2 mmol) in THF (20 mL) at 25 ꢀC. The
reaction mixture was stirred at room temperature for 30 min. The precipi-
tate was filtered off, and the filtrate was washed with water (2 ꢁ 50 mL),
saturated aqueous sodium bicarbonate solution (2 ꢁ 50 mL), and water
(100 mL). The organic layer was dried with anhydrous magnesium sul-
fate, and the solvent was evaporated to give a solid product. The crude
product was purified by recrystallization from acetic acid and subsequent
washing with water.
Data
3,13-Dichloro-7,8,9,10,17,18,20,21-octahydro-5H-5k6,11k6-dibenzo[b,k][1,
13,16,4,10,5,9]trioxadithiadiazacyclooctadecine-5,5,11,11,(6H)-tetraone (1):
45% yield; white solids; mp ¼ 285 ꢀC (decomposed); IR (KBr): 760,
1
850, 940, 1050, 1250, 1500, 1620, 2960, 3260 cmꢂ1. HNMR (DMSO-

New Macrocyclic Bis-sulfonamides
2545
d6, 100 MHz): d 7.65 (d, 2 H, J ¼ 1.5 Hz), 7.40 (dd, 2 H, J1 ¼ 8.0 Hz,
J2 ¼ 2.0 Hz), 7.20 (d, 2 H, J ¼ 8.0 Hz), 6.60 (br s, 2 H, NH), 4.20 (m,
4 H), 3.90 (m, 4 H), 3.0 (m, 4 H), 1.70 (m, 2 H). MS m=z 528
(Mþ þ 4), 526 (Mþ þ 2), 524 (Mþ ), 521, 459, 427, 324, 306, 283, 256
(base peak), 217, 199, 173, 143, 128, 108.
2,17-Dichloro-6,7,9,10,12,13,21,22,23,24-decahydro-19H-19k6,25k6-dibenzo
[b,k]
[1,13,16,19,4,10,5,9]tetraoxadithiadiazacyclohenicosine-19,19,25,25,
(20H)-tetraone (2): 35% yield; white solids; mp ¼ 280 ꢀC (decomposed);
IR (KBr): 760, 950, 1050, 1250, 1450, 1500, 1600, 2960, 3240cmꢂ1
.
1HNMR (DMSO-d6, 100 MHz): d 7.70 (d, 2 H, J ¼ 1.5 Hz), 7.40 (dd,
2 H, J1 ¼ 8.0 Hz, J2 ¼ 2.0 Hz), 7.10 (d, 2 H, J ¼ 8.0 Hz), 6.60 (br s, 2 H,
NH), 4.20 (m, 4 H), 3.80 (m, 4 H), 3.60 (s, 4 H), 3.10 (m, 4 H), 1.60 (m,
2 H). MS m=z 572 (Mþ þ 4), 570 (Mþ þ 2), 568 (Mþ ), 486, 369, 339,
264, 230 (base peak), 200, 149, 136, 107.
3,12-Dichloro-7,7-dimethyl-6,7,8,9,16,17,19,20-octahydro-5k6,10k6-dibenzo
[b,j][1,12,15,4,9,5,8]trioxadithiadiazacycloheptadecine-5,5,10,10-tetraone (3):
45% yield; white solids; mp ¼ 295 ꢀC (decomposed); IR (KBr): 760, 850,
950, 1150, 1450, 1500, 1620, 2920, 2960, 3280 cmꢂ1. 1HNMR (DMSO-d6,
100 MHz): d 7.70 (m, 2 H), 7.40 (m, 2 H), 7.10 (m, 2 H), 6.60 (br s, 2 H,
NH), 4.10 (m, 8 H), 3.90 (m, 2 H), 1.25 (s, 6 H). MS m=z 539 (Mþ þ 1),
538 (Mþ ), 536, 533, 453, 356, 340, 325, 296, 256, 244 (base peak), 217,
200, 173, 121.
2,17-Dichloro-21,21-dimethyl-6,7,9,10,12,13,20,21,22,23-decahydro-19k6,
24k6-dibenzo[b,j][1,12,15,18,4,9,5,8]tetraoxadithiadiazacycloicosine-19,19,
24,24-tetraone (4): 18% yield; white solids; mp ¼ 283 ꢀC (decomposed);
IR (KBr): 800, 900, 1050, 1150, 1200, 1350, 1485, 1600, 3200 cmꢂ1
.
1HNMR (DMSO-d6, 100 MHz): d 7.62 (m, 2 H), 7.35 (m, 2 H), 7.05
(m, 2 H), 6.70 (br s, 2 H, NH), 4.30 (m, 8 H), 4.10 (s, 4 H), 3.85 (m,
2 H), 1.20 (s, 6 H). MS m=z 582 (Mþ ), 552, 536, 530, 457, 359, 345,
320, 291, 255, 243 (base peak), 217, 199, 176, 121.
7,21-Dichloro-11,14,17-trioxa-4k6,24k6-dithia-3,25-diazatetracyclo[25.2.2.05,10
.
018,23]hentriaconta-1(29),5,7,9,18(23),19,21,27,30-nonaene-4,4,24,24-tetraone
(5): 40% yield; white solids; mp ¼ 263 ꢀC; IR (KBr): 750, 800, 850, 1095,
1
1180, 1265, 1485, 1600, 3400 cmꢂ1. HNMR (DMSO-d6, 100MHz): d 7.55
(m, 2 H), 7.25 (m, 2 H), 7.05 (m, 2 H), 6.90 (s, 4H), 6.80 (br s, 2 H, NH),
4.20 (m, 4 H), 4.05 (m, 4 H), 3.70 (m, 4 H). MS m=z 587 (Mþ þ 1), 586
(Mþ ), 585, 581, 451, 413, 336, 296, 282, 253, 236, 217, 200, 172, 136, 104,
64 (base peak).

2546
H. Eshghi
7,24-Dichloro-11,14,17,20-tetraoxa-4k6,27k6-dithia-3,28-diazatetracyclo
[28.2.2.05,10.021,26]tetratriaconta-1(32),5,7,9,21(26),22,24,30,33-nonaene-4,4,
27,27-tetraone (6): 25% yield; white solids; mp ¼ 245 ꢀC; IR (KBr):
750, 850, 950, 1100, 1150, 1350, 1500, 1600, 3400 cmꢂ1 1HNMR
.
(DMSO-d6, 100 MHz): d 9.30 (br s, 2 H, NH), 7.60 (m, 2 H),
7.30 (m, 2 H), 6.90 (s, 4H), 6.80 (m, 2 H), 4.25 (m, 4 H), 4.0
(m, 4 H), 3.80 (m, 4 H), 3.60 (s, 4 H). MS m=z 631 (Mþ þ 1), 630
(Mþ ), 629, 401, 368, 334, 325, 290, 246, 230, 200, 134, 124, 86, 64, 56
(base peak).
3,18-Dichloro-7,8,10,11,14,15,22,23,25,26-decahydro-5k6,16k6-dibenzo[b,p]
[1,8,11,18,21,4,15,5,14]pentaoxadithiadiazacyclotricosine-5,5,16,16(6H,13H)-
tetraone (7): 35% yield; white solids; mp ¼ 270 ꢀC; IR (KBr): 750, 850,
1
1050, 1150, 1250, 1350, 1500, 1600, 3350 cmꢂ1. H-NMR (DMSO-d6,
100 MHz): d 7.60 (d, 2 H, J ¼ 1.5 Hz), 7.35 (dd, 2 H, J1 ¼ 8.0 Hz,
J2 ¼ 2.0 Hz), 7.05 (d, 2 H, J ¼ 8.0 Hz), 6.20 (br s, 2 H, NH), 4.15 (m,
4 H), 3.90 (m, 4 H), 3.50 (m, 4 H), 3.4 (s, 4 H), 3.05 (m, 4 H). MS m=z
602 (Mþ þ 4), 600 (Mþ þ 2), 598 (Mþ ), 457, 425, 407, 348, 333, 291,
278, 250, 234, 217, 200, 174, 131, 126 (base peak).
3,18-Dichloro-7,8,10,11,14,15,22,23,25,26,28,29-dodecahydro-5k6,16k6-
dibenzo[b,p][1,8,11,18,21,24,4,15,5,14]hexaoxadithiadiazacyclohexacosine-
5,5,16,16(6H,13H)-tetraone (8): 23% yield; white solids; mp ¼ 256 ꢀC;
IR (KBr): 750, 800, 1050, 1190, 1300, 1520, 1600, 3300 cmꢂ1. 1HNMR
(CDCl3, 100 MHz): d 7.85 (m, 2 H), 7.50 (m, 2 H), 6.95 (d, 2 H,
J ¼ 8.0 Hz), 6.10 (br s, 2 H, NH), 4.30 (m, 4 H), 3.95 (m, 4 H), 3.80
(s, 4 H), 3.50 (m, 8 H), 3.0 (m, 4 H). MS m=z 642 (Mþ ), 641, 620,
598, 550, 457, 425, 407, 350, 330, 295, 278, 258, 234, 217, 200, 174,
131, 126 (base peak).
General Procedure for the Solvent-Free Synthesis of Macrocyclic
Bis-sulfonamides (1 and 2)
A mixture of 1,3-diaminopropane (0.15 g, 2 mmol), triethylamine (0.4 g,
4 mmol), and bis-sulfonyl chloride 13 or 14 (2 mmol) was grinded in a
mortar and pestle for 10 min. The reaction mixture was treated with
water (500 ml), and the precipitate was filtered off. The crude product
was purified by recrystallization from acetic acid and subsequent washing
with water. Compounds 1 and 2 were obtained by this procedure in 18
and 15% yields, respectively, with the same characterization as reported
previously for the fast addition procedure.

New Macrocyclic Bis-sulfonamides
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