Nitroethylenophanes - New class of novel cyclophanes

Article abstract of DOI:10.1081/SCC-100106213

Reaction of o-xylenyl dibromide with dipotassium salt of 2-nitro-1,1-ethanedithiol afforded nitroethylenophane 2. Similar strategy has been used for the synthesis of cyclophanes 7, 9 and 11.

Full text of DOI:10.1081/SCC-100106213

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NITROETHYLENOPHANES— NEW CLASS OF NOVEL
CYCLOPHANES
Perumal Rajakumar a , Muthialu Srisailas a & Manickam Dhanasekaran a
a Department of Organic Chemistry , University of Madras , Guindy Campus, Chennai,
600 025, India
Published online: 22 Aug 2006.
To cite this article: Perumal Rajakumar , Muthialu Srisailas & Manickam Dhanasekaran (2001) NITROETHYLENOPHANES—
NEW CLASS OF NOVEL CYCLOPHANES, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 31:22, 3517-3525, DOI: 10.1081/SCC-100106213
To link to this article: http://dx.doi.org/10.1081/SCC-100106213
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SYNTHETIC COMMUNICATIONS, 31(22), 3517–3525 (2001)
NITROETHYLENOPHANES—
NEW CLASS OF NOVEL
CYCLOPHANES
Perumal Rajakumar,* Muthialu Srisailas,
and Manickam Dhanasekaran
Department of Organic Chemistry,
University of Madras, Guindy Campus,
Chennai – 600 025, India
ABSTRACT
Reaction of o-xylenyl dibromide with dipotassium salt of 2-
nitro-1,1-ethanedithiol afforded nitroethylenophane 2. Similar
strategy has been used for the synthesis of cyclophanes 7, 9
and 11.
Synthesis of cyclophanes with heterocyclic building blocks resulting in
Pyridinophanes,1 Ureaphanes,2 Benzimidazolophanes,3 Piperazinophanes,4
Benzotriazolophanes5 has been recently reported. Such cyclophanes have
promising properties6 as molecular clefts and possesses favourable binding
sites for metal ions and guest molecules. Recently, the field of molecular
capsules has advanced to the stage where self-assembling through non-
covalent interactions such as hydrogen bonds7 and metal co-ordination8
*Corresponding author.
3517
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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RAJAKUMAR, SRISAILAS, AND DHANASEKARAN
has proved to be a reliable tool. Though the synthesis of dipotassium salt of
2-nitro-1,1-ethanedithiol and its utility for the synthesis of ranitidine9 and as
histenine receptor10 are known, its applicability for the synthesis of cyclo-
phane with non- collapsible cavity is not known so far. Therefore, we wish
to report herein the synthesis of new class of cyclophanes called nitroethyleno-
phanes, which has a highly functionalized appendage that could be a poten-
tial tethering unit for non-covalent interaction.
Reaction of dipotassium salt of 2-nitro-1,1-ethanedithiol with o-xyle-
nyl dibromide was carried out with a view to synthesize non-collapsible
microcavity cyclophane 2. The reaction mixture after stirring11 in methanol
and few drops of CH2Cl2 for 12 h and after usual workup gave cyclophane
2 in 40% yield. The benzylic protons are not equivalent and appeared as two
singlets at d 4.41 and 4.22 two protons each in 1H NMR. Further, the
olefinic proton appeared at d 7.65 in addition to aromatic protons at
d 7.05 to 7.18. In 13C NMR, also the two benzylic carbons are found to
be non-equivalent and appeared at d 37.5 and 39.2. One of the olefinic
carbon appeared at d 159.8 due to the deshielding effect of the nitro
group. In mass spectrum, the molecular ion appeared at m/z 239. Though
the spectral data can even account for the dimeric structure, the steel proof
for the structure was arrived at from single crystal XRD.12
The cyclophane 2 was then reduced with NaBH4 in ethanol with a
view to modify the receptor–tethering unit. Treatment of nitroethyleno-
phane 2 with NaBH4 in EtOH gave nitroethanophane 3 as a colourless
1
solid. In H NMR, benzylic protons appeared as AB quartet at d 4.40 and
3.81 and –CHCH2NO2 protons appeared as a multiplet at d 4.61. The
aromatic protons appeared as a multiplet at d 7.12. Nitroethanophane 3
was then reduced with LAH to give the aminoethanophane 4 as a pale
yellow liquid. The benzylic protons appeared along with the –CH– protons
as a multiplet at d 3.49 to 3.88 and the –CH2NH2 protons appeared as
doublet at d 3.04 in addition to the aromatic proton in 1H NMR. The
reaction sequence is shown in Scheme 1.
The above synthetic methodology has been applied for the synthesis of
the cyclophane 7. Nitroethylenophane 7 has been synthesized by two
methods as shown in Scheme 2. Structure 7 has been confirmed on the
1
basis of H NMR.
Similar synthetic sequence when applied on m-terphenyl dibromide13
resulted in the formation of nitroethylenophane 8 as a mixture of insepar-
able syn and anti isomers. The mixture was then reduced with NaBH4 to
yield the nitroethanophane 9 which is characterized by 1H NMR. Similarly,
the macrocyclic nitroethylenophane 10 was obtained as pale yellow solid in
30% yield from 2,6-bis(bromomethyl)-4-methylphenol14 and dipotassium
salt of 2-nitro-1,1-ethanedithiol (1). Cyclophane 10 was also found to be a

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3519
Scheme 1. Reagents and conditions: i. CH3OH/CH2Cl2, r.t., 12 h, 40%; ii. NaBH4,
EtOH, r.t. 6 h, 85%; iii. LiAlH4, THF, r.t. 6 h, 30%.
Scheme 2. Reagents and conditions: i. a) K2CO3/acetone, 48 h, 85%. b) LiAlH4,
THF, 6 h, 90%. c) PBr3, CH2Cl3, r.t. 6 h, 95%; ii. MeOH/CH2Cl2, r.t, 24 h, 30%;
iii. MeOH/CH2Cl2, r.t, 24 h, 63%; iv. m-xylenyl dibromide, K2CO3/acetone, r.t,
24 h, 25%.

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RAJAKUMAR, SRISAILAS, AND DHANASEKARAN
mixture of syn and anti isomers, which on reduction with NaBH4 gave the
nitroethanophane 11 as a colourless solid, characterized by spectral data.
The reaction sequences are shown in Scheme 3.
Further studies on nitroethylenophanes as organic receptors are under
investigation.
Scheme 3. Reagents and conditions: i. MeOH/CH2, r.t. 24 h, 22%, ii. NaBH4,
EtOH, r.t, 12 h, 53%, iii. MeOH/CH2Cl2, r.t. 24 h, 30%; iv. NaBH4, EtOH, r.t.
12 h, 45%.

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3521
EXPERIMENTAL
General
All the melting points are uncorrected. The IR spectra were recorded
1
using Shimadzu FT-IR 8300 instrument. The H and 13C NMR spectra of
all compounds in CDCl3 were recorded using Brucker (200 MHz) or Jeol
(90 MHz) NMR spectrometer. The mass spectra were recorded using
Hewlett–Packard 5985 (70 eV). The column chromatography was performed
using silica gel (100–200 mesh).
Preparationof Dipotassium Salt of
Nitroethenedithioacetate (1)
To a cooled and well stirred solution of carbon disulfide (20.8 mL,
0.37 mol) and nitromethane (17.6 mL, 0.32 mol), well dissolved potassium
hydroxide (36.0 g) in 90 mL of dry methanol was added drop by drop over
40 min using a pressure equalizing funnel. The temperature was maintained
at ꢀ5ꢁC to 0ꢁC using ice salt mixture. Then the stirring was continued for
3 h. The brown colour solid formed was filtered though Buckner funnel as
much as quickly to avoid the absorption of moisture. The residue was
washed three times with dry methanol and three times with ether. The prod-
uct was quickly transferred into a sample bottle, which was covered by a
black paper to avoid the light decomposition of the sample. The yield of
product obtained was 18.33 g, (27%). mp 210–211ꢁC.
General Procedure for Preparation of Cyclophanes
To a well stirred solution of dipotassium salt of 2-nitro-1,1-ethane-
dithiol (1) (0.212 g, 1 mmol) in 20 mL of 50% aq. MeOH, corresponding
dibromide (1 mmol) was added and the reaction mixture was stirred at room
temperature for 24 h. Then, the reaction mixture was concentrated to a
minimum volume and water was added to form residue from which was
extracted using CH2Cl2 (4 ꢂ 50 mL). The organic layer was thoroughly
washed with water (3 ꢂ 100 mL); brine and dried over anhyd. Na2SO4.
The dichloromethane was filtered and evaporated at reduced pressure to
give the crude product, which was purified by column chromatography
over silica gel.

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RAJAKUMAR, SRISAILAS, AND DHANASEKARAN
Synthesis of Nitroethylenophane 2
Following the general procedure, the nitroethylenophane 2 was
obtained from o-xylylene dibromide. Yield: m.p. 96–98ꢁC, IR (KBr) 3095,
1
1531, 1458, 1309, 1265, 1105, 769, 704 cmꢀ1; H NMR (200 MHz, CDCl3):
d 4.22 (s, 2H), 4.41 (s, 2H), 7.05–7.18 (m, 4H), 7.65 (s, 1H); 13C NMR
(75 MHz, CDCl3): d 37.4, 39.1, 128.1, 128.3, 129.6, 130.4, 133.5, 159.8;
m/z 239 (mþ); Anal. Calcd. for C10H9NO2S2: C. 50.19, H, 3.79; N, 5.85.
Found: C, 50.21, H, 3.82; N, 5.89.
Reduction of Nitroethylenophane 2 to
Nitroethanophane 3 Using NaBH4
The nitroethylenophane 2 (0.276 g, 1.1 mmol) was stirred with NaBH4
(0.022 g, 0.6 mmol) in ethanol at room temperature for 6 h. Then the sol-
ution was acidified and evaporated to dryness. The solid mass obtained was
purified by column chromatography over silica gel using 40% CHCl3 in
hexane to afford the nitroethanophane 3 in 85% yield. mp 107ꢁC; IR
(KBr) 3006, 2922, 1591, 1546, 1427, 1371, 1259, 1184, 765, 688 cmꢀ1
,
1H NMR (200 MHz): d 3.81 and 4.40 (dd, 4H), 4.61 (m, 3H), 7.12 (m,
4H); 13C NMR (50 MHz): d 34.55, 56.02, 108.75, 127.24, 128.24, 129.20;
m/z 241 (Mþ); Anal. Calcd. for C10H11NO2S2: C, 49.77; H, 4.59; N, 5.80.
Found: C, 49.87; H, 4.64; N, 5.84.
Reduction of Nitroethanophane 3 to
Aminoethanophane 4 Using LAH
The nitroethanophane 2 (0.135 g, 0.55 mmol) was refluxed with
LiAlH4 (0.021 g, 0.56 mmol) in dry THF for 6 h. The reaction mixture
was then treated with hydrated Na2SO4. The inorganic mass was filtered
off and washed several times with THF. The THF was evaporated to afford
the aminoethanophane 4 in 30% yield as a pale yellow liquid. IR (CHCl3)
3354, 2923, 1654, 1444, 1043, 754 cmꢀ1, 1H NMR (200 MHz): d 3.04 (d, 2H),
3.49 and 3.88 (m, 5H), 7.19 (m, 4H); 13C NMR (50 MHz): d 24.88,
48.92, 71.65, 127.21, 128.24, 128.88; Anal. Calcd. for C10H13NS2: C, 56.83;
H, 6.20; N, 6.63. Found: C, 56.90; H, 6.24; N, 6.67.
Synthesis of Dibromide 5
The m-xylylene dibromide (2.64 g, 10 mmol) was treated p-hydroxy-
methylbenzoate (3.34 g, 22 mmol) in DMF and K2CO3 at 60ꢁC for 48 h.

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3523
Then the reaction mixture was diluted using large volume of water; the
precipitated solid was extracted with CH2Cl2 (3 ꢂ 200 mL); washed with
water and dried over anhyd. Na2SO4. The organic layer was filtered and
evaporated to dryness to afford diester as a white solid in 85% yield. The
diester (2.03 g, 5 mmol) was then treated with LiAlH4 (0.265 g. 7 mmol) in
THF at reflux for 8 h. The reaction mixture was treated with 20.0 g of
hydrated Na2SO4. The reaction mixture was then filtered and the inorganic
solid was washed with THF several times. All the THF was collected and
evaporated to dryness to yield diol in 90%. The diol (0.7 g, 2 mmol) in
CH2Cl2 was treated with PBr3 (0.2 mL, 2 mmol) at room temperature for
8 h to afford the dibromide 5 in 95% yield.
Synthesis of Nitroethylenophane 7 from Dibromide 5
The nitroethylenophane 7 was obtained by following the general pro-
cedure from the dibromide 5 in 30% yield. mp 128ꢁC; IR (KBr) 2931, 1604,
1512, 1450, 1303, 1228, 1172, 1091, 1016, 823 cmꢀ1, 1H NMR (200 MHz): d
3.36 (s, 4H), 4.41 (s, 2H), 5.10 (s, 2H), 7.11 (ABq 8 Hz, 8H), 7.40 (m, 4H),
7.52 (s, 1H); Anal. Calcd. for C24H21NO4S2: C, 63.84; H, 4.69; N, 3.10.
Found: C, 63.91; H, 4.82; N, 3.19.
Alternative Procedure for the Synthesis of 7
The p-hydroxybenzylbromide (1.87 g, 10 mmol) was treated with the
nitroethylene dithioacetate (2.12 g, 10 mmol) in MeOH (60 mL) at room
temperature for 24 h. The reaction mixture was then evaporated to dryness.
The solid obtained was then purified over silica gel using 1:1 CHCl3: hexane
to give the diol 6 in 30% yield. The diol 6 (0.349 g, 1 mmol) was then treated
with the m-xylylene dibromide (0.264 g, 1 mmol) in dry acetone (100 mL) at
room temperature for 24 h. The reaction mixture upon usual work up
afforded the nitroethylenophane 7 in 25% yield.
Synthesis of Cyclophane 8
Following the general procedure, the nitroethylenophane 8 was
obtained from m-terphenyl dibromide in 22% yield. m.p. 131ꢁC; IR (KBr)
2931, 1608, 1517, 1307, 1099, 1085, 790, 706, 466 cmꢀ1
,
1H NMR
(200 MHz): d 4.26 (s, 4H), 4.33 (s, 4H), 7.23–7.77 (m, 24H), 7.95 (s, 2H);
13C NMR (50 MHz); d 30.58, 57.80, 73.99, 105.78, 125.67, 126.79, 127.88,

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RAJAKUMAR, SRISAILAS, AND DHANASEKARAN
129.25, 137.17, 165.88; Anal. calcd. for C44H34N2O4S4: C, 67.49; H, 4.38; N,
3.58. Found: C, 67.51; H, 4.48; N, 3.69.
Reduction of Nitroethylenophane 8 Using
Sodium Borohydride
The nitroethylenophane 8 (0.1 g, 0.16 mmol) was stirred with NaBH4
(0.012 g, 0.317 mmol) in ethanol at room temperature for 6 h. Then the sol-
ution was acidified and evaporated to dryness. The solid mass obtained was
purified by column chromatography over silica gel using 40% CHCl3 in
hexane to afford the nitroethanophane 9 in 30% yield. m.p. 142ꢁC; IR
(KBr) 2932, 1606, 1517, 1458, 1312, 1230, 1171, 1098, 1017, 823,
1
790 cmꢀ1; H NMR (200 MHz): d 4.11 (s, 4H), 4.21 (s, 4H), 4.42–4.54 (m,
6H), 7.10–7.62 (m, 24H); Anal. Calcd. for C44H38N2O4S4: C, 67.15; H, 4.87;
N, 3.56. Found: C, 67.21; H, 4.89; N, 3.61.
Synthesis of Cyclophane 10
Following the general procedure, the nitroethylenophane 10 was
obtained from 2,6-(bromomethyl)4-methylphenol in 30% yield. m.p. 91ꢁC;
IR (KBr) 3396, 2942, 1526, 1458, 1309, 1265, 1162, 1105, 770, 708 cmꢀ1
;
1H NMR (200 MHz): d 2.28 (s, 6H), 3.35 (s, 4H), 4.52, (s, 4H), 6.98 (s, 2H),
7.52 (s, 2H); 13C NMR (50 MHz): d 29.70, 58.28, 71.86, 117.88, 123.28,
128.69, 129.02, 165.50; Anal. Calcd. for C22H22N2O6S4: C, 49.05; H, 4.12;
N, 5.20. Found: C, 49.08; H, 4.15; N, 5.24.
Reduction of Nitroethylenophane 10 Using
Sodium Borohydride
The nitroethylenophane 10 (0.107 g, 0.2 mmol) was stirred with
NaBH4 (0.015 g, 0.4 mmol) in ethanol at room temperature for 6 h. Then
the solution was acidified and evaporated to dryness. The solid mass
obtained was purified by column chromatography over silica gel using
40% CHCl3 in hexane to afford the nitroethanophane 11 in 45% yield.
m.p. 108ꢁC; IR (KBr) 3386, 2934, 1606, 1517, 1456, 1312, 1222, 1171,
;
1091, 1017, 823, 790 cmꢀ1 1H NMR (200 MHz): d 2.26 (s, 6H), 3.99
(s, 4H), 4.11, (s, 4H), 4.66–4.71 (m, 6H), 6.92 (s, 4H); Anal. Calcd.
for C22H26N2O6S4: C, 48.69; H, 4.83; N, 5.16. Found: C, 48.72; H, 4.84;
N, 5.19.

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3525
ACKNOWLEDGMENT
MS thanks CSIR, New Delhi for the SRF and UGC for Special Assi-
stance Programme and Mr. S. Baktharaman for the synthesis of few starting
materials. The authors thank Dr. G. Geetha, SPIC Science Foundation,
Chennai, for recording NMR spectra for some of the cyclophanes.
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Received in the Netherlands January 25, 2001

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