Synthesis of cyclopenteno [c] fused 2,2'-bipyridine based cyclophane by ring - closing metathesis (RCM)1

Article abstract of DOI:10.3987/COM-08-11530

A route to cyclophane 7 incorporating mixed 2,2'-bipyridine 3, consisting of the two different heterocyclic units, i.e. uncondensed pyridine and cyclopenta[c]pyridine, using as a crucial step ring-closing metathesis is reported.

Full text of DOI:10.3987/COM-08-11530

HETEROCYCLES, Vol. 78, No. 2, 2009
457
HETEROCYCLES, Vol. 78, No. 2, 2009, pp. 457 - 462. © The Japan Institute of Heterocyclic Chemistry
Received, 19th August, 2008, Accepted, 19th September, 2008, Published online, 25th September, 2008.
DOI: 10.3987/COM-08-11530
SYNTHESIS OF CYCLOPENTENO [c] FUSED 2,2′-BIPYRIDINE BASED
CYCLOPHANE BY RING - CLOSING METATHESIS (RCM)1
Justyna Ławecka, Danuta Branowska, Zbigniew Karczmarzyk, and Andrzej
Rykowski*
Department of Chemistry University of Podlasie, 08-110 Siedlce, Poland
e-mail: rykowski@ap.siedlce.pl
Abstract – A route to cyclophane 7 incorporating mixed 2,2′-bipyridine 3,
consisting of the two different heterocyclic units, i.e. uncondensed pyridine and
cyclopenta[c]pyridine, using as a crucial step ring-closing metathesis is reported.
2,2′-Bipyridines (bpy) and their fused analogues are utilized as molecular hosts in bpy based macrocycles,
in particular crown macrocycles.2 Such chelating ligands possessing bpy subunit encapsulate specific
metal ions3 or various organic and inorganic substrates4 and have been successfully applied as building
blocks for larger supramolecular species.5 Recently, Kwong and coworkers reported a series of C2 –
symmetric bpy crown ethers.6 These macrocycles exhibited enantioselective binding towards the amino
acid derivatives and chiral organic ammonium salts. The similar interactions of bpy thiacrown ethers with
neutral and cationic substrates have never been investigated. In view of these interesting results and our
continuing interest in the synthesis of bpy thiacrown ethers,7 we began exploring the possibilities of
preparation of the monoannulated bpy cyclophane 7 (Scheme 1), consisting of the two different
heterocyclic units: uncondensed pyridine and cyclopenta[c]pyridine. Attachment of the cyclopentene into
one of the pyridine rings in 7 can result in a higher efficiency of a ligand field, since the basicity of this
ring nitrogen is enhanced.8
In an early report we have demonstrated the use of easily available 3,3′-bis(methylsulfanyl)-5,5′-bi-1,2,4-
triazine 1 as a convenient precursor for the preparation of monoannulated bpy derivative 3.9 This
approach is based on the regioselective intermolecular Diels-Alder/retro Diels-Alder reaction of 1 with 1-
vinylimidazole to give pyridotriazine 2 in good yield. The reaction of the latter with 1-pyrrolidino-1-
cyclopentene leads to unsymmetrical bpy derivative 3 with attached cycloalkene ring. On the basis of this
prior experience, we have elaborated a route to 7 starting from 3 and using as the key steps: (1) S-
transalkylation of 3 with ethyl bromoacetate, and (2) ring-closing metathesis of the resulting alkenyl ether
6. The essential features of the strategy are summarized in Scheme 1.

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HETEROCYCLES, Vol. 78, No. 2, 2009
N
N
N
N
N
N
N
N
N
N
N
N
N
heat
1
MeS
SMe
MeS
heat
SMe
2
LiAlH4
THF
R
Br
N
N
N
N
S
S
MeS
SMe
4
heat
3
R
R
4
R
a
b
Ph
CO2Et
Br
N
N
N
N
S
S
S
S
NaH
5
6
OH
HO
O
O
P(Cy)3
Cl
Ph
Ru
Cl
P(Cy)3
N
N
S
S
7
O
O
Scheme 1
The utility of S-transalkylation of bpy alkyl sulfides with alkylating agents for the synthesis of
functionalized bipyridines is well documented.10, 11 To establish optimal conditions for S-transalkylation
of annulated bipyridine 3, the reaction of this compound with benzyl bromide was first investigated. After
7 h stirring at reflux, the desired bis(benzylthio) derivative 4a was formed in 78% yield. As expected, the
1H NMR spectrum of 4a revealed two methylene peaks at 4.58 and 4.63 ppm, which suggest two
nonequivalent benzyl groups are present. The reaction of compound 3 and ethyl bromoacetate under the
same reaction conditions showed the generality of this process, since the bpy bis(carboxylate) 4b was
obtained as a single product in excellent yield. The latter was next reacted with lithium aluminium
hydride in THF under reflux for 6 h to provide the corresponding alcohol 5 as colorless solid. Reaction of
5 with allyl bromide in the presence of sodium hydride in DMF at room temperature for 30 min afforded

HETEROCYCLES, Vol. 78, No. 2, 2009
459
alkenyl ether 6. The conversion of 6 into 2,2′-bipyridine based cyclophane 7 could be easily achieved by
ring-closing metathesis. Treatment of 6 with Grubbs’ catalyst I (10 mol %) in a 0.01 M solution of
methylene chloride under reflux resulted in the formation of the olefin cyclophane 7 in 70% yields. The
ratio of the E/Z isomers in 7 was 10:1. The assignment of configuration in 7 was made by analyzing 13C
1
satellites in its H NMR spectrum.12 The structure of the predominant E-isomer (Figure 1) was
determined by energy minimization and optimization of all geometrical parameters using AM1
semiempirical method13 implemented in the program package HyperChem.14
Figure 1
The results of these calculations suggested that the pyridine rings are twisted relative to each other by
51.6º. This conformation is probably constrained by steric interactions of the methine hydrogen atoms in
both pyridine rings as well by the strain in the chain of the thioether crown caused by rigid vinyl bond.
Further studies on asymmetrical sulfoxidation of 7 with chiral oxidants are under investigations.
EXPERIMENTAL
1
Melting points were determined in open capillaries and are uncorrected. H NMR spectra were recorded
on a Varian Gemini 200MHz spectrometr using tetramethylsilane as the internal standard. The IR spectra
were measured with a Magna IR-760 spectrophotometr in KBr pellets. Mass spectra were measured on
AMD 604 spectrometr (electron impact, 70eV). Elemental analyses were obtained on Perkin-Elmer 2400-
CHN analyzer and the results for the indicated elements were within 0.3 % of the calculated values.

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Compound 3 was synthesized according to literature procedure.15
Synthesis of 1-(benzylthio)-3-(6-(benzylthio)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine
(4a).
A stirred solution of 3 (130 mg, 0.45 mmol) in benzyl bromide (0.5 mL, 4.21 mmol) was heated under
reflux for 7 h. After this time the reaction mixture was cooled and Et2O was added. The precipitate 4a
was filtered off and the crude product was purified by column chromatography using CH2Cl2/hexane
(10:3) as the eluent. Analytically pure compound, white solid, was recrystallized from MeOH, to provide
154 mg (78%) of 4a. mp 228 ˚C; 1H NMR (CDCl3) δ: 2.14 (qui, 2H, J = 7.4 Hz), 2.85 (t, 2H, J = 7.4 Hz),
2.99 (t, 2H, J = 7.4 Hz), 4.58 (s, 2H), 4.63 (s, 2H), 7.15 (d, 1H, J = 7.8 Hz), 7.27 – 7.48 (m, 10H), 7.57 (t,
1H, J = 7.8 Hz), 8.05 (s, 1H), 8.15 (d, 1H, J = 7.8 Hz); 13C NMR (CDCl3) δ: 24.2, 30.1, 33.0, 33.5, 34.4,
113.4, 116.8, 121.5, 126.9, 127.0, 128.4, 128.7, 128.8, 136.7, 137.2,138.3, 138.7, 152.9, 153.4 154.0,
155.9, 157.5; IR (KBr) cm-1: 1598; 1137; HRMS (m/z) for C27H24N2S2: 440.1376 [M+]; Calcd. 440.1380.
Synthesis of ethyl 2-(6-(1-(2-ethoxy-2-oxoethylthio)-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)-
pyridin-2-ylthio)acetate (4b).
A stirred solution of 3 (6 g, 20.8 mmol) in ethyl bromoacetate (25 mL, 226 mmol) was heated under
reflux for 10 h. After this time the reaction mixture was cooled and Et2O was added. The precipitate 4b
was filtered off and the crude product was purified by column chromatography using CH2Cl2 as the eluent.
Analytically pure compound, white solid, was recrystallized from a mixture of CH2Cl2/hexane, to provide
1
8.1 g (90%) of 4b. mp 123 - 125 ˚C; H NMR (CDCl3) δ: 1.22 (t, 3H, J=7.2Hz), 1.25 (t, 3H, J=7.1Hz),
2.16 (qui, 2H, J = 7.7 Hz), 2.85 (t, 2H, J = 7.5 Hz), 2.99 (t, 2H, J = 7.7 Hz), 4.02 (s, 2H), 4.03 (s, 2H),
4.17 (q, 2H, J = 7.2 Hz), 4.18 (q, 2H, J = 7.2 Hz), 7.19 (dd, 1H, J = 0.8 Hz, J = 7.9 Hz), 7.58 (t, 1H, J =
13
7.8 Hz), 8.1 (s, 1H) 8.15 (dd, 1H, J = 0.7 Hz, J = 7.7 Hz); C NMR (CDCl3) δ: 14.1, 24.34, 29.9, 32.1,
32.5, 32.9, 61.4, 113.6, 117.0, 121.4, 136.7, 137.2, 151.2, 153.4, 154.2, 155.7, 155.8, 169.6, 169.8; IR
(KBr) cm-1: 1744, 1731, 1175, 1144; HRMS (m/z) for C21H24N2S2O4: 432.1173 [M+]; Calcd. 432.1177;
Anal. Calcd for C21H24N2S2O4: C, 58.34; H, 5.56; N, 6.48. Found C, 58.50; H, 5.69; N, 6.60.
Synthesis of 2-(6-(1-(2-hydroxyethylthio)-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)pyridin-2-
ylthio)ethanol (5).
To a suspension of LiAlH4 (250 mg, 6.58 mmol) in THF (14 mL) was added 4b (1.5 g, 3.47 mmol) in
THF (40 mL). The reaction mixture was heated under reflux for 4 h under nitrogen. After cooling, THF
saturated with water (4 mL), water (4 mL) and KOH 15% aqueous solution (28 mL) was added. The
whole was extracted with THF (4 × 15 mL). The combined organic layers were dried over MgSO4. The

HETEROCYCLES, Vol. 78, No. 2, 2009
461
solvent was evaporated under reduced pressure and the crude product 5 was purified by column
1
chromatography using CH2Cl2/acetone (30:1) as the eluent to give 725 mg (60%) of 5. mp 101 ˚C; H
NMR (CDCl3) δ: 2.15 (qui, 2H, J = 7.4 Hz), 2.85 (t, 2H, J = 7.5 Hz), 2.95 (t, 2H, J = 7.7 Hz), 3.42 -3.49
(m, 4H), 3.90 – 4.01 (m, 4H), 4.8 – 5.0(brs, 2H) 7.24 (d, 1H, J = 8.4 Hz), 7.59 (t, 1H, J = 7.8 Hz), 7.78 (s,
1H), 7.84 (d, 1H, J = 7.6 Hz); 13C NMR (CDCl3) δ: 24.1, 30.3, 32.7, 33.0, 33.2, 62.7, 63.3, 114.3, 117.4,
122.3, 137.0, 138.0, 153.4, 153.6, 154.5, 155.7, 158.0; IR (KBr) cm-1: 3355.2, 1554,6 1143.9; Anal. Calcd
for C17H20N2S2O2: C, 58.62; H, 5.75; N, 8.04. Found C, 58.58; H, 5.93; N, 8.03.
Synthesis
of
1-(2-(allyloxy)ethylthio)-3-(6-(2-(allyloxy)ethylthio)pyridin-2-yl)-6,7-dihydro-5H-
cyclopenta[c]pyridine (6).
To a mixture of 5 (1.16 g, 3.3 mmol) and NaH (0.46 g, 19.2 mmol) in dry DMF (50 mL), allyl bromide
(1.4 mL, 16.2 mmol) in DMF (10 mL) was added. The mixture was stirred at rt for 6 h. The reaction
mixture was poured into ice/H2O and acidified with AcOH. For 6 the water layer was extracted with Et2O.
The organic layers were dried over MgSO4 and evaporated in vacuo. The crude product 6 was purified by
column chromatography using CH2Cl2/acetone (100:1) as the eluent to provide 0.772 g (54%) of 6 as a
white oil; 1H NMR (CDCl3) δ: 2.15 (qui, 2H, J = 7.7 Hz), 2.84 (t, 2H, J = 7.4 Hz), 2.92 (t, 2H, J = 7.6 Hz),
3.48 – 3.59 (m, 4H), 3.75 – 3.82 (m, 4H), 4.04 – 4.08 (m, 4H), 5.14 – 5.34 (m, 4H), 5.87 – 6.00 (m, 2H),
7.16 (dd, 1H, J = 0.7 Hz, J = 7.8 Hz), 7.57 ( t, 1H, J = 7.8 Hz), 8.04 (s, 1H), 8.11 (dd, 1H, J = 0.8 Hz, J =
13
7.7 Hz); C NMR (CDCl3) δ: 24.2, 28.6, 29.1, 30.0, 33.0, 69.1, 69.2, 71.9, 113.1, 116.5, 117.0, 121.7,
134.5, 134.6, 136.6, 137.5, 152.4, 153.4, 153.9, 159.0,157.0; IR (KBr) cm-1: 1094, 1142; HRMS (m/z) for
C23H28N2S2O2: 428.1603 [M+]; Calcd. 428.1592.
Synthesis
of
3,4,6,9,11,12,22,23-octahydro-21H-18,14:19,1-diepiazenocyclopenta[f]-
[1,18,4,15]dioxadithiacyclodocosine (7)
A solution each of the substrate 6 (150 mg, 0.35 mmol) in CH2Cl2 (c = 0.01M) and Grubbs’ catalyst I (80
mg, 10 mol %) was heated under reflux for 6 h. The solvent was removed in vacuo and the crude product
was separated by column chromatography, using CH2Cl2/hexane (100:1) as the eluent. Analytically pure
compound 6 was recrystallized from EtOH as white solid to provide 98 mg (70%) of 7. mp 204 – 206 ºC;
1H NMR (CDCl3) δ: 2.10 (qui, 2H, J = 7.2 Hz), 2.84 (t, 2H, J = 7.6 Hz), 2.99 (t, 2H, J = 7.8 Hz), 3.34 –
3.43 (m, 4H), 3.55 – 3.66 (m, 4H), 3.88 – 4.10 (m, 4H), 5.63 – 5.86 (m, 2H), 7.04 (dd, 1H, J = 0.7 Hz, J =
7.4 Hz), 7.48 (t, 1H, J = 7.8 Hz), 7.95 (s, 1H), 8.01 (dd, 1H, J = 0.7 Hz, J = 7.2 Hz); 13C NMR (CDCl3) δ:
24.23, 26.8, 29.3, 33.0, 51.2, 59.2, 68.9, 70.0, 70.5, 70.6, 70.7, 113.1, 116.5, 121.6, 129.5, 138.4, 137.5,
153.9, 154.3, 155.8, 157.5; IR (KBr) cm-1: 1104, 1142; HRMS (m/z) for C21H24N2S2O2: 400.1273 [M+];
Calcd. 400.1226.

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