Synthesis of new di- and tetraazadibenzosulfoxide macrocycolic compounds

Article abstract of DOI:10.1002/jhet.5570450204

(Chemical Equation Presented) Novel macrocyclic di and tetraamide compounds have been synthesized by the reaction of 2-2′-sulfoxide-bis-(4-methyl phenoxy) aceticester or aceticacid chloride) (obtained from corresponding bisphenol) with appropriate diamine

Full text of DOI:10.1002/jhet.5570450204

Mar-Apr 2008
319
Synthesis of New Di- and Tetraazadibenzosulfoxide Macrocycolic
Compounds
Abbas Shockravi1*, Ali Yousefi1, Samad Bavili Tabrizi1, Masoomeh Zakeri1,
Ebrahim Abouzari-Lotf1, Hashem Sharghi2
1Faculty of Chemistry, Tarbiat Moallem University, Mofatteh Ave. No.49, Postal Code 15614, Tehran, Iran.
2Department of Chemistry, Shiraz University, Shiraz, 71457, Iran.
Fax No.009888825580. e-mail: abbas_shockravi@yahoo.co.uk
Received January 22, 2007
O
O
O
Z
Z
O
S O
O
O CH2COG
O
NH
O
S O
O
NH
HN
O
NH2
Z
H2N
Z
S
and/or
O
S
O CH2COG
NH
O
NH
O
HN
O
O
G = OCH3 (methhod 1 (A and B)) or = Cl (method 2)
Z
(CH2)2
(CH2)3
(CH2)4
CH2*CHCH3
CH2CH2NHCH2CH2
CH2CH2OCH2CH2OCH2CH2
(e)
(a)
(b)
(c)
(d)
(f)
Novel macrocyclic di and tetraamide compounds have been synthesized by the reaction of 2-2'-
sulfoxide-bis-(4-methyl phenoxy) aceticester or aceticacid chloride) (obtained from corresponding
bisphenol) with appropriate diamines. Also the results of the presence of base as template are discussed
and compared.
J. Heterocyclic Chem., 45, 319 (2008).
areas of research, by providing efficient access to
compounds that are otherwise hard to synthesize using
step-wise syntheses [23]. In this route, the rate of
formation of the macrocycles is intimately tied to the
nature of the cation that is present [24]. If it can fit snugly
in the incipient crown, the reaction rate and the yield will
be much greater than in the parallel experiment in which
an ill-fitting cation is present [23].
INTRODUCTION
Due to their selective cationic binding affinities and
their adjustable hydrophobicities, crown ethers [1] have
found increasing applications as a phase transfer reagents
[2,3], catalysts [2-4], membrane transports [5,6], sensors
[7,8], and in separation technologies [9] such as the
removal of cesium from the alkaline nuclear waste
[10,11].
Activated dicarboxylic acid derivatives have also been
used for the preparation of macrocyclic diamides in
excellent yields under normal reaction conditions [25].
In the previous work, we have described the syntheses of
new macrocycles 8 and 11 (Table 1) [25]. The compelex-
ation reactions between 7,10,13-triaza-1-sulfoxo-4,16-
dioxa-20,24-dimethyl-2,3;17,18-dibenzo-cyclooctadecane-
6,14-dione (11) macrocycles with Ag+, Cd2+, Cu2+, Pb2+,
Sr2+, Tl+ and Zn2+ ions have been studied by our research
teams. The stability constants of the resulting complexes
were determined and found to decrease in the order Tl+ >
Zn2+> Cd2+> Pb2+ >Cu2+ > Ag+> Sr2+ [26]. These results
encouraged us to synthesis a variety of corresponding
macrocycle derivatives with different sizes. Here in
continuation of previous works [25,27], we report the
preparation of set of new di- and tetraazadibenzosulfoxide
macrocyclic compounds via different techniques: a diester,
a metal template and an activated diacid dichloride. Also
the results of methods are discussed and compared.
Convenient methods for preparation of aza-crowns
have been extensively reviewed [12-16]. Among these
methods, the high-dilution technique [17], the route based
on template effect [18], the high pressure approach [19],
high concentration technique [20], and diester methods
[21] are frequently used as the most versatile procedures.
Using a diester allows the reaction to take place under
normal conditions without using the high dilution or high
pressure techniques. For application purposes the
availability of efficient synthetic methods are everything.
Consequently any route that represents a more efficient
alternative to a long and tedious process is always
welcome. Templating is one such route that engenders,
among other things, mass production and the construction
of countless architectural designs. In chemical terms,
templation involves the use of molecule or ion to promote
the formation of one compound from a reaction that
would otherwise from a complex mixture [22]. Using a
molecular or ionic scaffold in this manner opens up new

320
A. Shockravi, A. Yousefi, S. Bavili Tabrizi, M. Zakeri, E. Abouzari-Lotf, H. Sharghi
Vol 45
Scheme II
RESULTS AND DISCUSSION
Z
Dibenzosulfoxide 1 was synthesized based on
a
O
G
O
O
G
O
O
NH
O
HN
O
O
reported procedure [28] in 65% yield. Treatment of 1 with
chloroacetonitrile and methylchloroacetate in the presence
of K2CO3 and KI at refluxed in dry acetone afforded
dinitrile 2 in 90% yield and dimethyl ester 5 in 95% yield,
respectively. Basic hydrolysis of dinitrile 2 in refluxing
basic alcoholic solution followed by acidification afforded
the diacid 3 in 95% yields [29]. The diacid 3 was
converted to diacid dichloride 4 in 90% yield by reaction
with oxalyl chloride in the presence of DMF (cat.) in
CH2Cl2 and used without purification (Scheme I).
S
O
O
O
O
S
O
S
NH2
Z
H2N
O
NH
HN
O
O
and/or
O
Z
Z
NH
O
HN
O
G = OCH3 (methhod 1 (A and B)) or = Cl (method 2)
Z
O
S
(CH2)2
(a)
(CH2)3
(b)
(CH2)4
(c)
CH2*CHCH3
(d)
CH2CH2NHCH2CH2
(e)
CH2CH2OCH2CH2OCH2CH2
(f)
Scheme I
differences for these different alkali metal ions. Because
these cations are able to interact with the reacting
functional groups in a manner that keeps them together
during the macrocyclization step, higher yields of
cyclocondensation reaction were expected.
O CH2COCl
S O
O CH2COCl
O CH2CO2H
O
O CH2CN
S O
O CH2CN
(c)
(b)
S
O CH2CO2H
4
2
3
In the macrocyclization reaction with diamine a a
“dimerization” reaction was observed in which a 30
membered macrocyclic tetraamide (7) was isolated as the
main product in method 1-A, and by-product in method 1-B,
while in method 2 only regular macrocyclization was
occurred (6) and no dimerization was observed (Scheme III).
(a)
O CH2CO2Me
O
OH
S O
OH
(d)
S
O CH2CO2Me
Scheme III
1
O
O
5
O
O
S O
O
HN
O
S O
O
N
H
O
N
H
a) ClCH2CN / K2CO3 / KI, CH3COCH3, Reflux
b) KOH / EtOH / H2O, Reflux
c) (COCl)2 / DMF, CH2Cl2 d) ClCH2CO2Me / K2CO3 / KI, CH3COCH3, Reflux
O S
O
H
N
H
N
HN
O
Our first attempts toward the synthesis of aza
macrocycles (method 1-A) generally afforded low to
moderate yields of macrocyclic products and long
reaction time (up to 3 day) (Scheme 2). These moderate
yields were because of factors such as the competition
between the formation of linear oligomers and desired
macrocycles. There is no restriction of bond rotations in
both diacid dichloride, diesters and condensing diamines
in these cases. Hence, not much loss in entropy during the
cyclization step is expected. This factor does affect the
final yields and reaction times in the ring closure
processes.
O
O
[1+1]
[2+2]
Template effect caused an increase in the [1+1] product
(6) and a decrease in the [2+2] product (7), which may be
the result of a stabilizing interaction in the incipient
hetromacrocycle in the [1+1] product. Also we observed a
more enhanced template effect for diamine f, likely due to
the existence of two highly electron pair donating oxygen
atoms [Table 1].
Results indicate that the diacid dichloride method
shows better macrocylization yields than the diester
method and template effect but this method also has some
difficulties such as diacid dichloride instability.
To minimize these difficulties, we have used different
conditions including high-concentration method (method
2), as well as the presence of variety of alkali metal
cations to evaluate the “template” and “salt” effects in the
macrocyclization step (method 2-B) (Scheme II).
EXPERIMENTAL
The “template effects” of different cations (Na+, K+ and
Cs+) were studied by using their carbonate salts. The
study proved that these salts are effective in
macrocyclization steps in both the yields (~60%) and the
length of times (~12 h), but did not indicate considerable
The reactions were carried out in an efficient hood. All the
materials purchased from Merck, Fluka and Aldrich chemical
companies and used without further purification. CH2Cl2 was
dried over P2O5 and then distilled from CaH2. Both CH3CN and
CH3OH were dried over CaH2 and then distilled. Triethylamine

Mar-Apr 2008
Synthesis of New Di- and Tetraazadibenzosulfoxide Macrocycolic Compounds
321
Table 1
Synthesis of different macrocyclic compounds by three methods
Macrocycle
Z
Yield (%)
Method 1
Method 2
A
B
6
7
CH2CH2 [1+1]
CH2CH2 [2+2]
25%
40%
45%
40%
45%
50%
40%
50%
20%
55%
50%
60%
65%
70%
80%
-----
a
8
CH2CH2CH2
65%
75%
65%
80%
80%
b
9
CH2*CHCH3
10
11
12
CH2CH2CH2CH2
a
CH2CH2NHCH2CH2
CH2CH2OCH2CH2OCH2CH2
aSee reference [26].
bThe only isolated product is [2+2].
bThe only isolated product is [2+2].
was distilled from CaH2 and stored over 4 Å molecular sieves.
The melting points (uncorrected) were measured by an
Electrothermal engineering LTD 9100 apparatus. Ir spectra were
2.28(s, 6H), 3.29-3.34(m, 4H), 4.53-4.69(m, 4H), 6.54-7.27(m,
8H) ppm; 13C nmr (CDCl3) δ 167.2, 153, 134.4, 133.5, 131.5,
121.6, 112.5, 68.2, 38.5, 20.6 ppm; MS (EI) m/z 402(M+), 386,
355, 337, 331, 281, 151, 149, 105, 91, 77, 71, 45, 30.
1
recorded on a Perkin-Elmer model 543, the H nmr and 13C nmr
spectra were obtained using BRUKER AVANCE DRX 500 and
BRUKER AVANCE DPX 250 MHz apparatus and mass spectra
were obtained by an electron ionization Varian Incos 50 and
JEOL JMS-700 and the MULDI spectra BRUKER Biflex.
7,10,22,25-Tetraaza-1,16-disulfoxo-4,13,19,28-tetraoxa-32,
36,41,44-tetramethyl-2,3;14,15;17,18;29,30-tetrabenzo-cyclo-
triacontane-6,11,21,26-tetraone (7). This compound was
purified by column chromatography on silica gel using EtOAc/
MeOH (4:1) as eluent and then recrystallized from CH2Cl2/n-
hexane to afford white powder, mp 322-324 °C; ir (KBr): 3410,
3250, 2955, 1685, 1535, 1495, 1430, 1285, 1245, 1230, 1160,
1035, 1045, 1025, 810, 725 cm-1; 1H nmr (CDCl3) δ 2.24(s, 6H),
2.28(s, 6H), 3.46-3.71(m, 8H), 4.42-4.53(m, 8H), 6.69-6.7(m,
4H), 7.12-7.14(d, J=10Hz, 4H), 7.21-7.37(m, 4H), 8.85(s, 2H),
9.02(s, 2H) ppm; 13C nmr (CDCl3) δ 168.1, 168, 153.4, 133.8,
133.6, 131.5, 131.4, 128.4, 128.2, 128, 127.7, 112.7, 112.6, 68.2,
68, 39.5, 39.3, 20.6 ppm; MS m/z 804.1 (M+), 805.1 (M+1)+,
806.1 (M+2)+, 536.2, 331, 298, 151, 122, 105, 91, 71, 69, 56, 45.
7,10,22,25-Tetraaza-1,16-disulfoxo-4,13,19,28-tetraoxa-8,
23,32,36,41,44-hexamethyl-2,3;14,15;17,18;29,30-tetrabenz-
ocyclotriacontane-6,11,21,26-tetraone (9). This compound
was purified by column chromatography on silica gel using
EtOAc / MeOH (5:1) as eluent, mp 211-213 °C; ir (KBr): 3430,
3345-3290, 2990, 2950, 1690, 156, 1505, 1450, 1300, 1270,
General procedure for the preparation of macrocyclic
diamides.
Diester method (1-A). A mixture of diamine a-f (1 mmol)
and dimethyl esters 5 (1 mmol, 0.406 g) in dry methanol (80
mL) was refluxed for 3 days. Then the solvent was evaporated
under reduced pressure and the crude product was purified by
column chromatography on silica gel and/or recrystallization.
Diester Method and Salt Effect (1-B). A mixture of diamine
a-f (1 mmol), dimethyl esters 5 (1 mmol, 0.406 g) and K2CO3 or
Cs2CO3 (0.5 mmol) in dry methanol (80 mL) was refluxed for 12
h. Then the resulting precipitate was filtered off and the solvent
was evaporated under reduced pressure to give crude product
that was purified by column chromatography on silica gel and/or
recrystallization.
Method (2). A solution of diamine a-f (2 mmol) and
triethylamine (4 mmol, 0.55 mL) in dry CH2Cl2 (50 mL) was
added quickly (5 sec.) to a vigorously stirred solution of diacid
chloride 4 (2 mmol, 0.993 g) in dry CH2Cl2 (50 mL) at 0 °C. The
reaction mixture was stirred at room temperature for 30 min.
The precipitate was filtered off and the filtrate was washed with
water (2×50 mL), 10% aqueous NaOH solution (50 mL) and
then with water (100 mL). The organic layer was dried
(Na2SO4), and evaporated to afford a solid product that was
purified by recrystallization or column chromatography.
1
1230, 1170, 1080, 1050, 1030, 830, 615 cm-1; H nmr (CDCl3):
1
Crowded spectrum is obtained for H nmr, but selected data are
reported as following; δ 0.63 (b, 3H), 1.17 (b, 3H), 2.34 (b,
12H), 2.23-3.41(b, 2H), 4.11 (b, 2H), 4.28 (b, 2H), 4.54-4.93 (m,
8H), 6.69-7.44 (m, 12H), 7.71 (b, 1H), 8.94 (b, 1H) ppm; 13C
nmr (CDCl3): 168.5, 168, 166.4, 154.6, 151.9, 135.4, 134.3,
132.2, 131.1, 129.8, 128.7, 127.8, 129.6, 125.8, 114.7, 113.8,
113.4, 112, 68.6, 68, 67.7, 45.5, 44.7, 43.4, 42.5, 41.9, 21, 20.7,
20.6, 20.5, 17.7, 17.4 ppm; MS m/z 831.1 (M+), 832.1 (M+1)+,
833.1 (M+2)+,552.2, 536.2, 523.2, 417.2, 154.1.
7,12-Diaza-1-sulfoxo-4,15-dioxa-19,23-dimethyl-2,3;16,17-
dibenzo-cycloheptadecane-6,13-dione (10). This compound
was purified by column chromatography on silica gel using
EtOAc/MeOH (5:1) as eluent, mp 285-288 °C; ir (KBr): 3425,
3285, 3240, 3080, 2955, 2880, 1690, 1550, 1450, 1440, 1285,
1250, 1215, 1155, 1070, 1045, 1010, 885, 820, 740, 560cm-1; 1H
7,10-Diaza-1-sulfoxo-4,13-dioxa-17,21-dimethyl-2,3;14,15-
dibenzocyclopentadecane-6,11-dione (6). This compound was
purified by column chromatography on silica gel using petroleum
ether/EtOAc (1:5) as eluent and then recrystallized from CH2Cl2/
n-hexane to afford white powder, mp 245-248 °C; ir (KBr): 3400,
3050, 2965, 2935, 1705, 1600, 1530, 1485, 1440, 1255, 1215,
1070, 1040, 960, 890, 835, 820, 545, 500 cm-1; 1H nmr (CDCl3) δ

322
A. Shockravi, A. Yousefi, S. Bavili Tabrizi, M. Zakeri, E. Abouzari-Lotf, H. Sharghi
Vol 45
[10] Bonnesen, P. V.; Delmau, L. H.; Haverlock, T. J.; Levitskaia,
T. G.; Sachleben, R. A.; Sloop, F. V. J.; Moyer, B. A. Spectrum 2002:
Explor. Sci. Based Solutions. Technol. Bienn. Int. Conf. Nucl. Hazard.
Waste Manage. 9th, 2002, 840.
[11] Leonard, R. A.; Connor, C.; Liberator, M. A.; Sedlet, J.;
Aase, S. B.; Vandergrift, G. F.; Delmau, L. H.; Bonnesen, P. V.; Moyer,
B. A. Sep. Sci. Technol. 2001, 36, 743.
[12] Golel, G. W.; Korzeniowski, S. H. Macrocyclic Polyether
Synthesis, Springer, Berlin, 1982.
[13] Krakowiak, K. E.; Bradshaw, J. S.; Zamecka-Krakowiak, D.
J. Chem. Rev. 1989. 89, 929.
[14] Jurczak, J.; Ostaszewski, R. J. Coord. Chem. 1992, 27, 201.
[15] Blanita, G.; Bucsa, M.; Vlassa, M. Synth. Commun. 2006. 11,
1569.
[16] Krakowiak, K. E.; Bradshaw, J. S.; Izatt, R. M. Synlett. 1993.
611.
[17] Dietrich, B.; Lehn, J. M., Sauvage, J. P. Tetrahedron Lett.
1969, 10, 2885.
[18] Kulstand, S.; Malmsten, L. A. Acta Chim. Scand. 1970, b33, 469.
[19] Jurczak, J.; Pietraszkiewicz, M .Topics. Curr. Chem. 1985,
130, 183.
nmr (CDCl3) 1.62-1.63(m, 4H), 2.29(s, 6H), 3.193-3.198(m,
4H), 4.51-4.52(m, 4H), 7.239-7.241(m, 2H), 7.269-7.273(m,
4H), 8.3(s, 2H) ppm; 13C nmr (CDCl3) δ 167.6, 155, 134.7,
132.5, 129.8, 128.1, 113.9, 68, 38.3, 26, 20.7 ppm; MS (EI) m/z
430 (M+), 331, 298, 271, 248, 151, 122, 106, 84, 78, 71, 56, 40.
7,16-Diaza-1-sulfoxo-4,10,13,19-tetraoxa-23,27-dimethyl-2,3;
20,21-dibenzo-cyclouneicosane-6,17-dione (12). This compound
was purified by column chromatography on silica gel using
EtOAc/MeOH (10:1) as eluent, mp 196.5-198 °C; ir (KBr): 3430,
3330, 3115, 2960, 2940, 2870, 1700, 1615, 1580, 1540, 1500,
1440, 1315, 1295, 1235, 1150, 1055, 1030, 830, 820, 735, 610, 580
1
cm-1; H nmr (CDCl3) δ 2.32(s, 6H), 3.55-3.61(m broad, 12H),
4.51-4.56(m, 4H), 6.88-6.91(m, 2H), 7.30(s, 2H), 7.51-7.55(m, 2H)
ppm; 13C nmr (CDCl3) 167.7, 153.1, 133.9, 132.9, 131.7, 127.2,
113.2, 70.3, 68.7, 68.1, 39.2, 20.7 ppm; MS m/z 490.2 (M+), 491.2
(M++1), 371.2, 298.2, 271.1, 248.2, 211.1, 162.1.
Acknowledgement. We wish to thank the Ministry of
Science, Research and Technology (Nano section) and Ministry
of Research at Tarbiat Moallem University for financial support.
Also we wish to thank Prof. R. Gleiter and Ms. Birgit Esser,
from Heidelberg (Germany) for FAB-MASS analysis.
[20] a) Sharghi, H.; Niknam, Kh.; Massah, A. R. J. Heterocyclic
Chem. 1991, 36, 601. b) Sharghi, H.; Massah, A. R.; Niknam, Kh. J.
Org. Chem. 1998, 63, 913.
[21] Gryko, D. T.; Piatek, P.; Jurczak, J. Tetrahedron. 1997, 53,
7966.
REFERENCES
[22] Template organic synthesis (Eds.: Diederich, F.; Stang, P. J.),
Wiley VHC, Weinheim, 2000.
[23] Gibb, B. C. Chem. Eur. J. 2003, 9, 5180.
[24] Illuminate, G.; Mandolini, L.; Masci, B. J. Am. Chem. Soc.
1983, 105, 555.
[25] Shockravi, A.; Bavili-T, S.; Rostami, E.; Yousefi, A.;
Dehjurian, A.; Tohidi, R. J. Inclusion Phenomena and Macrocyclic
Chemistry. 2004, 49, 163.
[1] Pedersen, C. J. J. Am. Chem. Soc. 1967, 89, 7017.
[2] Ruiter, C.; Lingeman, H. Handbook of Phase-Transfer
Catalysis (Eds.: Y. Sasson, R. Newmann) Kluver Academic, London,
1997, 405.
[3] Steed, J. W.; Atwood, J. L. Supramolecular chemistry,
Wiley, Chichester, 2000.
[4] Hossain, M. A.; Schnieder, H. J. J. Am. Chem. Soc. 1998,
120, 11208.
[26] Mozaffari, S.; Chaloosi, M.; Divsar, F.; Abouzari-Lotf, E.;
Bavili-T, S.; Yousefi, A.; Shockravi. A. Phosphorus, Sulfur and Silicon
and the Related Elements. 2007, 182, 2439.
[27] Shockravi,A.; Bavili-T, S. J. Incl. Phenom. 2005, 52, 223.
[28] Shockravi, A.; Alizadeh, R..; Moghimi, A.; Rostami E.;
Bavili-T, S. Phosphorus, Sulfur and Silicon and the Related Elements.
2003, 178, 2519.
[5] Gokel, G. W. Chem Commun. 2000, 1.
[6] Smith, B. D.; Gardiner, S. J.; Munro, T. A.; Paugam, M. F.;
Riggsa, J. A. J Inclusion Phenom. Mol. Recognit. Chem. 1998, 32, 121.
[7] McFarland, S. A.; Finney, N. S. J. Am. Chem. Soc. 2001,
123, 1260.
[8] Prodi, L.; Bargossi, C.; Montalti, M.; Zaccheroni, N.; Su, N.;
Bradshow, J. S.; Izatt, R. M.; Savage, P. B. J. Am. Chem. Soc. 2000,
122, 6769.
[29] Shockravi, A.; Mehdipour-Ataei, S.; Abouzari-Lotf, E.;
Yousefi, A. Eur Polym J. 2006, 42, 133.
[9] Gutsche, C. D. ACS Symp. Ser. 2000, 757, 2.