Polyhalogenated heterocyclic compounds: Part 52. [1] Macrocycles from 3,5-dichloro-2,4,6-trifluoropyridine

Article abstract of DOI:10.1016/j.jfluchem.2005.01.018

Model studies show that displacement of fluorine, rather than chlorine, occurs upon reaction of 3,5-dichloro-2,4,6-trifluoropyridine with sodium methoxide and phenoxide. Subsequent hydro-dechlorination can be achieved by reaction with lithium aluminium hy

Full text of DOI:10.1016/j.jfluchem.2005.01.018

Journal of Fluorine Chemistry 126 (2005) 1002–1008
www.elsevier.com/locate/fluor
Polyhalogenated heterocyclic compounds
Part 52. [1] Macrocycles from 3,5-dichloro-2,4,6-trifluoropyridine
a
a
Richard D. Chambers a, , Ali Khalil , Christopher B. Murray ,
*
Graham Sandford a,1, Andrei S. Batsanov b, Judith A.K. Howard b
a Department of Chemistry, University of Durham, South Road, Durham DH13LE, UK
b Chemical Crystallography Group, Department of Chemistry, University of Durham, South Road, Durham DH13LE, UK
Received 30 November 2004; accepted 24 January 2005
Available online 9 March 2005
Dedicated to Professor Herbert W. Roesky on the occasion of his 70th birthday.
Abstract
Model studies show that displacement of fluorine, rather than chlorine, occurs upon reaction of 3,5-dichloro-2,4,6-trifluoropyridine with
sodium methoxide and phenoxide. Subsequent hydro-dechlorination can be achieved by reaction with lithium aluminium hydride whereas
reaction of sodium in iso-propanol leads to formation of the tri-iso-propoxy pyridine derivative, via nucleophilic substitution of the methoxy
group, rather than the dechlorinated products. Macrocycles can be synthesised by reactions of appropriate difunctional oxygen nucleophiles
with 3,5-dichloro-2,4,6-trifluoropyridine, one of which was characterised by X-ray crystallography.
# 2005 Elsevier B.V. All rights reserved.
Keywords: Heterocycle; Macrocycle; Perfluoroheterocycle; Nucleophilic aromatic substitution; Pyridine; X-ray structure
1. Introduction
3,5-Dichloro-2,4,6-trifluoropyridine 2 is directly avail-
able [7] from pentachloropyridine 3 and, in principle, a
variety of non-halogenated macrocyclic systems 4 could be
obtained from 2, by subsequent removal of chlorine from 5,
Scheme 3.
Nucleophilic displacement of fluorine in highly fluori-
nated pyridine and related heteroaromatic systems occurs
very readily because the heterocyclic ring is activated
strongly both by the presence of the nitrogen heteroatom and
by the activating influence of the fluorine substituents
themselves [2–4] (Scheme 1). The orientating influence of
the fluorine atom substituents for nucleophilic substitution
processes has also been well established [2–4].
Here, we first describe reactions of appropriate model
perhalogenated pyridine compounds to assess the feasibility
of this approach and then demonstrate the formation of
macrocycles corresponding to type 5.
Recently, pentafluoropyridine 1 and related derivatives
have been used as substrates for the construction of various
macrocycles [1,5,6] by exploiting this reactivity in reactions
involving appropriate difunctional nucleophiles, as illustrated
in Scheme 2.
2. Results and discussion
The results of reactions of 2 with both sodium methoxide
and phenoxide are collated in Table 1 and it is clear that
reactions of 2 with these nucleophiles are much less
selective than analogous reactions involving pentafluoro-
pyridine 1 which gives only a single mono-substituted
product arising from highly selective attack at the 4-position
[2,8].
* Corresponding author. Tel.: +44 191 3342039; fax: +44 191 3844737.
E-mail addresses: r.d.chambers@durham.ac.uk (R.D. Chambers),
graham.sandford@durham.ac.uk (G. Sandford).
1
Co-corresponding author. Tel.: +44 191 334 2020; fax: +44 191 384
4737.
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.01.018

R.D. Chambers et al. / Journal of Fluorine Chemistry 126 (2005) 1002–1008
1003
high yield and this provided a useful model compound for
studies concerning reductive displacement of chlorine.
Use of sodium in iso-propanol is a well-established
process for the dechlorination of saturated chlorocarbons
but, with 9 as the substrate, no significant dechlorination was
detected and, to our surprise, 9 had been converted to the
corresponding tri-iso-propyl derivative 10 (Scheme 4). This
clearly demonstrates that introduction of methoxy and other
alkoxy groups into heterocyclic ring systems can be
reversible in appropriate circumstances.
Scheme 1.
In 2, the 4-position is obviously more sterically hindered
towards nucleophilic attack by the presence of the adjacent
chlorine atoms. Consequently, mixtures of both derivatives 6
and 7 arising from attack at both 4- and 2-positions
respectively are present in the monosubstituted products and
disubstituted products 8 are formed from further nucleo-
philic attack at either of the remaining 2- and 4-carbon
fluorine sites, respectively. It is worth emphasising that some
disubstitution products 8 are obtained even when a
deficiency (0.6 equiv.) of nucleophile is used and this is
at first sight puzzling. However, this is a further manifesta-
tion of the fact that attack at the 4-position is inhibited by
steric effects and it is probable that most of 8a and 8b arise
from further attack at the 2-position in compound 6a and 6b,
respectively, in competition for the nucleophile with attack
at the crowded 4-position in 2. However, reaction of 2 with a
large excess of methoxide gave trisubstituted compound 9 in
In contrast, reduction of 9 with lithium aluminium
hydride occurred to give a mixture of 11 and 12. Although
we have not optimised this reductive dechlorination
reaction, the results are sufficient to demonstrate the
feasibility of the approach that we outlined in Scheme 2.
Subsequently, we carried out a series of reactions of 6a
with the difunctional oxygen nucleophiles generated from
the corresponding silyl derivatives 13, shown in Table 2, by
reaction with cesium fluoride in monoglyme following
methodology similar to that we reported previously [6]. The
two-step process is illustrated in Table 2 and the
macrocycles 15 shown were purified from the corresponding
bridged precursors 14 by a combination of column
chromatography and recrystallisation.
Scheme 2.
Scheme 3.

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R.D. Chambers et al. / Journal of Fluorine Chemistry 126 (2005) 1002–1008
Table 1
Reactions of 2 with sodium methoxide phenoxide
Rona
Conditions
Product mixture composition (%)
MeONa
MeONa
MeONa
PhONa
PhONa
0.6 equiv. MeOH
2 equiv. MeOH
20 equiv. MeOH
0.6 equiv. THF
2 equiv. THF
27
2
6a, 59
6a, 61
–
7a, 9
7a, 7
–
–
–
8a, 4
8a, 29
–
–
–
–
9, 99
–
–
44
–
6b, 44
6b, 37
8b, 12
8b, 63
Scheme 4.
Characterisation of macrocycles 15 was largely carried
out by NMR. but a full single-crystal X-ray analysis was
performed on 15c to reveal a 32-membered ring (Fig. 1)
formed from two units each of 13c and 14c. The molecule
has crystallographic C4 symmetry where the dihedral angles
between adjacent pyridine and benzene rings alternate
between 30.08 and 84.48, resulting in a tightly folded
molecular conformation.
1000 Spectrometer coupled with a Hewlett Packard 5890
series II gas chromatograph using a 25 m HP1 (methyl-
silicone) column. Elemental analyses were obtained on a
Exeter Analytical CE-440 elemental analyser. Melting
points and boiling points were recorded at atmospheric
pressure unless otherwise stated and are uncorrected. The
progress of reactions was monitored by either 19F NMR or
gas-chromatography on an Shimadzu GC8A system using
an SE30 column. Distillation was performed using a Fischer
Spaltrohr MS220 microdistillation apparatus. Column
chromatography was carried out on silica gel (Merck no.
109385, particle size 0.040–0.063 mm) and TLC analysis
was performed on silica gel TLC plates (Merck).
At this point, however, we have been unable to apply the
reduction process efficiently, largely due to the low order of
solubility of the macrocycles 15.
3. Experimental
X-ray diffraction experiment was carried out on a
Siemens 3-circle diffractometer with a SMART 1K CCD
area detector, using graphite-monochromated Mo Ka
All starting materials were obtained commercially
(Aldrich, Lancaster or Fluorochem) All solvents were dried
using literature procedures. NMR spectra were recorded in
deuteriochloroform, unless otherwise stated, on a Varian
VXR 400S NMR spectrometer operating at 400 MHz (1H
NMR), 376 MHz (19F NMR) and 100 MHz (13C NMR) with
tetramethylsilane and trichlorofluoromethane as internal
standards. Mass spectra were recorded on a Fisons VG-Trio
˚
¯
radiation (l = 0.71073 A) and a Cryostream (Oxford
Cryosystems) open-flow N2 cryostat. The structure was
solved by direct methods and refined by full-matrix least
squares (non-H atoms refined in anisotropic, all H atoms in
isotropic approximation) against F2 of all reflections, using
SHELXTL software (version 6.12, Bruker AXS, Madison,
WI, USA, 2001).

R.D. Chambers et al. / Journal of Fluorine Chemistry 126 (2005) 1002–1008
1005
Table 2
Synthesis of macrocycles from 2
13
14
15
3.1. Model reactions of 2 with oxygen nucleophiles
3.1.2. Reaction with sodium methoxide
3.1.2.1. 0.6 equivalents. Compound 2 (2.0 g, 9.9 mmol)and
sodium methoxide (0.32 g, 5.9 mmol) in methanol (30 ml)
gave the crude product as a straw-coloured oil (0.77 g).
Characterisation by GC/MS and 19F NMR showed 2, 6a, 3,5-
dichloro-2-methoxy-4,6-difluoropyridine 7a [dF ꢀ72.7 (1F, d,
3.1.1. General procedure
A three-necked flask was charged with sodium alkoxide
and the appropriate solvent and heated to reflux temperature
with continual stirring. 3,5-Dichloro-2,4,6-trifluoropyridine
2 was added rapidly and the mixture heated to reflux for
18 h. The reaction mixture was poured into an equal volume
of water, extracted with dichloromethane and dried
(MgSO4). The solvent was evaporated to afford the crude
product, which could be purified by column chromatography
if required.
F-6), ꢀ98.6 (1 F, d, F-4)] and 8a in the ratio 27:59:9:4 by 19
F
NMR. Spectral and physical data of products below.
3.1.2.2. 2 equivalents. Compound 2 (2.0 g, 9.9 mmol) and
sodium methoxide (1.06 g, 19.8 mmol) in methanol (30 ml)
gave the crude product as a pale yellow oil (2.27 g). Analysis

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R.D. Chambers et al. / Journal of Fluorine Chemistry 126 (2005) 1002–1008
8a (0.27 g, 12.1%) as pale straw coloured needles; mp 66.9–
67.1 8C (from dichloromethane) (lit., [8] 65–67 8C); RF
0.18. (Found: C, 37.2; H, 2.7; N, 6.1. C7H6Cl2FNO2
requires: C, 37.2; H, 2.7; N, 6.2%); dH 3.96 (3H, s, CH3),
4.02 (3H, s, CH3); dF ꢀ74.1 (s); dC {H} 55.2 (s, 4-OMe),
2
4
61.2 (s, 2-OMe), 102.9 (d, JCF 34.70, C-5), 108.4 (d, JCF
8.05, C-3), 156.2 (d, 1JCF 238.05, C-6), 157.2 (d, 3JCF 15.99,
3
C-2), 163.4 (d, JCF 4.63, C-4); m/z (EI+) 225 (M+, 100%),
227 (M++2, 64.06%), 229 (M++4, 10.94%).
3.1.2.3. 20 equivalents. A mixture consisting of 2 (11.3 g,
0.05 mol) and sodium methoxide (5.4 g, 0.1 mol) in
methanol (50 ml) was heated under reflux with continual
stirring. After 48 h, the resulting material was poured into
cold water and the white solid was precipitated which was
extracted into methylene dichloride. The organic layer was
separated, dried (MgSO4), and evaporated to give a crude
product which was shown by gc/ms to consist of one
component. Recrystallisation from light petroleum gave 3,5-
dichloro-2,4,6-trimethoxypyridine 9 (11.7 g, 99%) as white
crystals; m.p. 99–100 8C (lit., [9] 97.8–98 8C). (Found: C,
40.4; H, 3.8; N, 5.8. C8H9Cl2NO3 requires C, 40.3; H, 3.8; N,
5.88%); dH 3.93 (3H, s, CH3), 3.95 (6H, s, CH3); dC 54.32 (s,
CH3), 60.7 (s, CH3), 103.0 (s, C-3), 156.5 (s, C-2), 161.8 (s,
C-4); m/z (EI+) 240 (10%, M+), 239 (62%, M+), 238 (41,
M+), 237 (100, M+), 208 (59), 194 (28), 144 (24), 87 (27).
3.1.3. Reaction with sodium phenoxide
3.1.3.1. 0.6 equivalents. Sodium (0.13 g, 5.6 mmol), phe-
nol (0.70 g, 7.4 mmol), 2 (2.0 g, 9.9 mmol) in THF (50 ml)
gave the crude product as an extremely viscous bright yellow
oil (1.455 g). Analysis of the crude product revealed 2, 6b
and 8b in the ratio 44:44:12 by 19F NMR. Spectral and
physical data of products below.
3.1.3.2. 2 equivalents. Sodium metal (0.39 g, 16.9 mmol),
phenol (1.9 g, 20.2 mmol), 2 (2.0 g, 9.9 mmol) in THF
(50 ml) gave the crude product as an extremely viscous
bright yellow oil (2.94 g). Analysis of the crude product by
GC/MS and 19F NMR revealed 6b and 8b in the ratio of 1:2
by 19F NMR. Column chromatography on silica gel using
hexane-10% DCM as eluant gave 3,5-dichloro-4-phenoxy-
2,6-difluoropyridine 6b (0.57g, 6%) as translucent white
crystals; RF 0.28. (Found C, 47.7; H, 1.7; N, 5.0.
C11H5Cl2F2NO requires C, 47.8; H, 1.8; N, 5.1); dH 6.8–
7.4 (m, Ar-H); dF ꢀ70.4 (s); dC 109.6 (m, C-3), 115.7 (s, Ar),
Fig. 1. X-ray crystal structure of 15c; (above) viewed down the four-fold
axis, (below) side view (four-fold axis vertical).
by GC/MS and 19F NMR revealed 2, 6a, 7a and 8a in the
ratio 2:61:7:29 by 19F NMR. Column chromatography of the
crude product on silica gel (25 g) using hexane-10% DCM
as eluant gave 3,5-dichloro-4-methoxy-2,6-difluoropyridine
6a (0.70 g, 33%) as a very pale yellow liquid; b.p. 217–
219 8C (Siwoloboff) (lit., [8] 213–214 8C); RF 0.22. (Found:
C, 33.6; H, 1.4; N, 6.7. C6H3Cl2F2NO requires C, 33.7; H,
1.4; N, 6.5%); dH 4.13 (m, OCH3); dF ꢀ71.5 (s, F-2); dC 61.7
(s, OMe), 108.2 (dd, 2JCF 24.04, 4JCF 16.39, C-3), 155.4 (dd,
1
124.2 (s, Ar), 130.0 (s, Ar), 155.3 (s, Ar), 155.6 (dd, JCF
245.7, 3JCF 17.2, C-2), 160.2 (t, 3JCF 4.6, C-4); m/z (EI+) 275
(M+, 33%), 277 (M++2, 17 %), 279 (M++4, 3%); and, 3,5-
dichloro-2,4-diphenoxy-6-fluoropyridine 8b (1.81 g, 18%)
as a viscous bright yellow oil, which slowly yielded an
amorphous white solid on standing (1–2 weeks); mp 65–
68 8C; RF 0.14. (Found C, 58.6; H, 2.8; N, 4.1.
C17H10Cl2FNO2 requires C, 58.3; H, 2.9; N, 4.0); dH 6.9–
3
3
1JCF 244.49, JCF 17.60, C-2), 164.8 (t, JCF 4.6, C-4); m/z
(EI+) 213 (M+, 100%), 215 (M++2, 69.70%), 217 (M++4,
11.88%), and 3,5-dichloro-2,4-dimethoxy-6-fluoropyridine
2
7.5 (m, ArH); dF ꢀ71.2 (s); dC 105.7 (d, JCF 35.40, C-5),
110.5 (d, 4JCF 7.64, C-3), 115.5 (s, Ar), 121.3 (s, Ar), 123.7

R.D. Chambers et al. / Journal of Fluorine Chemistry 126 (2005) 1002–1008
1007
(s, Ar), 125.8 (s, Ar), 129.7 (s, Ar), 129.9 (s, Ar), 152.5 (s,
4. Synthesis of bridged oxygen derivatives 14
Ar), 155.6 (s, Ar), 155.9 (d, 1JCF 241.1, C-6), 156.2 (d, 3JCF
15.3, C-2), 158.9 (d, 3JCF 4.6, C-4); m/z (EI+) 349 (M+, 19%),
351 (M++2, 12%), 353 (M++4, 2%).
4.1. General procedure
A mixture consisting of 6a, bis-silyl derivative 13 and
CsF in monoglyme (50 ml) was heated at reflux temperature
and stirred for 3 days. The resulting mixture was poured into
cold water and extracted with dichloromethane. The organic
layer was separated, dried (MgSO4) and the solvent removed
under reduced pressure to give a crude product which was
purified by either distillation, recrystallisation or column
chromatography on silica gel.
3.2. Reactions of 3,5-dichloro-2,4,6-trimethoxypyridine 9
3.2.1. 3,5-Dichloro-2,4,6-triisopropoxypyridine 10
A mixture consisting of 9 (6 g, 0.025 mol) and sodium
(4.6 g, 0.2 mole) in isopropanol (50 ml) was heated under
reflux with continual stirring. After 6 days, the resulting
material was poured into cold water and extracted into
methylene dichloride. The organic layer was separated, dried
(MgSO4), and evaporated to give crude material (5.7 g)
which was shown by gc/ms to consist of three components in
the ratio 0.5:1.5:17.5. Column chromatography on silica gel
using light petroleum:CH2Cl2 (8:2) as eluent, gave 3,5-
dichloro-2,4,6-tri-isopropoxypyridine 10 (5.1 g, 89%) as a
colourless liquid; b.p. 259–260 8C, Rf 0.52. (Found C, 52.5;
H, 6.7; N, 4.5 C14H21Cl2NO3 requires: C, 52.2; H, 6.5; N,
4.3%); dH 1.3 (6H, d, 3JHH 6.0, CH3), 1.3 (12H, d, 3JHH 6.4,
CH3, C-8), 4.7 (1H, sept, 3JHH 6.0, CH at C-4), 5.1 (2H, sept,
3JHH 6.0, CH at C-7); dC 22.0 (s, CH3), 22.5 (s, CH3), 69.9
(s, CH), 77.5 (s, CH), 103.6 (s, C-3), 155.9 (s, C-2), 160.3 (s,
C-4); m/z (EI+) 323 (10%, M++2) 321 (15%, M+), 239 (10),
237 (16), 197 (59), 195 (100), 43 (51).
4.2. 6-[2-(3,5-Dichloro-6-fluoro-4-methoxy(2-
pyridyloxy))ethoxy]-3,5-dichloro-2-fluoro-4-
methoxypyridine 14a
6a (6.5 g, 30 mmol), 13a (3 g, 12 mmol) and CsF (3.5 g,
23 mmol) in monoglyme (50 ml), after recrystallisation
from n-hexane, gave 6-[2-(3,5-dichloro-6-fluoro-4-meth-
oxy(2-pyridyloxy))ethoxy]-3,5-dichloro-2-fluoro-4-methox-
ypyridine 14a (6.0 g, 90%) as a white solid; m.p. 146–
148 8C. (Found: C, 37.4; H, 2.2; N, 6.2. C14H10Cl4F2N2O4
requires C, 37.3; H, 2.2; N, 6.2%); dH 4.0 (3H, s, OCH3),
4.7 (2H, s, CH2); dF ꢀ74.0 (s); dC 61.2 (s, CH3), 65.5 (s,
2
4
CH2), 103.3 (d, JCF 34.2, C-3), 108.7 (d, JCF 7.6, C-5),
156.1 (d, 3JCF 15.9, C-4), 155.7 (d, 1JCF 237, C-2), 163.3 (d,
3JCF 4.6, C-6); m/z (EI+) 454 (M+, 1%), 452 (M+, 3%),
450 (M+, 5%), 448 (M+, 4%), 242 (11), 240 (65), 239(10),
238 (100).
3.2.2. 3-chloro-2,4,6-trimethoxypyridine 11 and 2,4,6-
trimethoxypyridine 12
To cold (0 8C), stirred solution of 9 (5 g, 24 mmol) in
ether was added 0.32 N LiAlH4 in ether (32 gm in 40 ml).
On completion of addition the reaction mixture was heated
under reflux with continually stirring. After 6 h, cooled
(0 8C) and 2N H2SO4 acid (10 ml) was added slowly. The
resulting material was poured into cold water and extracted
into methylene dichloride. The organic layer was separated,
dried (MgSO4) and evaporated to give a crude product (2 g)
which was shown by gc/ms to consist of two compounds
(ratio 1:1). Column chromatography on silica gel using
hexane:dichloromethane ratio (8:2) as eluent, gave 3-chloro-
2,4,6-trimethoxypyridine 11 (0.5 g, 27%) as a colourless
liquid; b.p. 65–66 8C, Rf 0.28. (Found: C, 47.1; H, 4.9; N,
6.8. C8H10ClNO3 requires C 47.2; H, 4.9; N, 6.9%); dH 3.9
4.3. 6-{2-[2-(3,5-Dichloro-6-fluoro-4-methoxy(2-
pyridyloxy)) ethoxy]ethoxy}-3,5-dichloro-
2-fluoro-4-methoxypyridine 14b
6a (6.5 g, 30 mmol), 13b (3 g, 12 mmol) and CsF
(3.5 g, 23 mmol) in monoglyme (50 ml), after recrystallisa-
tion from petroleum ether 40–60, gave 6-{2-[2-(3,5-
dichloro-6-fluoro-4-methoxy(2-pyridyloxy))ethoxy]ethoxy}-
3,5-dichloro-2-fluoro-4-methoxy pyridine 14b (6.6 g, 90%)
as white solid; m.p. 98–100 8C. (Found: C, 38.9; H, 2.8; N,
5.7. C16H14Cl4F2N2O5 requires C, 38.9; H, 2.8; N, 5.7%); dH
3.9 (2H, m, CH2OCH2), 4.0 (3H, s, OCH3), 4.4 (2H, m, Ar-
OCH2); dF ꢀ74.1(s); dC 61.2 (s, CH3), 67.4 (s, CH2OCH2),
69.2 (s, Ar-OCH2), 103.0 (d, 2JCF 34.2, C-3), 108.5 (d, 4JCF
8.0, C-5), 155.8 (d, 1JCF 237, C-2), 156.4 (d, 3JCF 15.6, C-4),
163.2 (d, 3JCF 5.0, C-6); m/z (EI+) 496 (3%, M+), 494 (6%,
M+), 492 (4%, M+), 242 (11), 240(65), 239(11), 238 (100),
213 (18), 212 (13), 211(28).
5
5
(3H, d, JHH 2, C-8), 3.9 (3H, d, JHH 2, C-9), 4.0 (3H, d,
5
5JHH 2, C-7), 5.9 (1H, d, JHH 2.8, C-5); dC 53.5 (s, C-9),
54.1 (s, C-7), 56.3 (s, C-8), 86.3 (s, C-5), 96.4 (s, C-3), 158.4
(s, C-6), 161.5 (s, C-2), 164.3 (s, C-4); m/z (EI+) 205 (28%,
M++3), 204 (36%, M++2), 203 (89%, M++1), 202 (100%,
M+), 174 (33), 173 (27), 160 (14), 110 (11), 69 (18), 53 (20);
and, 2,4,6-trimethoxypyridine 12 (0.4 g, 25%) as colourless
liquid; b.p. 45–47 (lit., [10] 47–48 8C), Rf 0.18. (Found: C,
53.6; H, 6.1; N, 7.8. C8H11NO3 requires C, 56.8; H, 6.5; N,
8.2%); dH 3.8 (3H, m, C-8), 3.9 (6H, m, C-7), 5.9 (2H, m, C-
3); dC 53.6 (s, 2-OMe), 55.3 (s, 4-OMe), 87.3 (s, C-3), 164.3
(s, C-2), 170.1 (s, C-4); m/z (EI+) 170 (7%, M++1), 168
(65%, M+), 169 (100%, M+-1), 140 (16), 139 (29), 69 (21).
4.4. 6-[3-(3,5-Dichloro-6-fluoro-4-methoxy(2-pyridyloxy))
5-methylphenoxy]-3,5-dichloro-2-fluoro-4-
methoxypyridine 14c
6a (5.35 g, 25 mmol), 1-methyl-3,5-bis-trimethylsilany-
loxy-benzene 13c (2.68 g, 10 mmol) and CsF (2.28 g,

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15 mmol) in monoglyme (50 ml), after recrystallisation
from dichloromethane, gave 6-[3-(3,5-dichloro-6-fluoro-4-
methoxy(2-pyridyloxy))5-methylphenoxy]-3,5-dichloro-2-
fluoro-4-methoxypyridine 14c (5.7 g, 90%) as a straw yellow
solid; m.p. 55–56 8C. (Found: C, 44.2; H, 2.3; N, 5.4.
C19H12Cl4F2N2O4 requires C, 44.5; H, 2.3; N, 5.4%); dH 2.4
(3H, s, Ar-CH3), 4.1 (6H, s, OCH3), 6.7 (1H, m, H-20), 6.8
(2H, m, H-40); dF ꢀ74.8 (s); dC 21.5 (s, Ar-CH3), 61.4
hexaoxatricyclo [19.3.1.1<9,13>]hexacosa-1(24),9,11,
13(26),21(25), 22-hexaene 15b (1.4 g, 25%) as a white
solid; mp 186–187 8C. (Found: C, 43.1; H, 4.1; N, 4.9.
C20H22Cl4N2O8 requires C, 42.9; H, 4.9; N, 5.0); dH 4.5
(8H, t, 3JHH 5.6, 2CH2, C-8), 3.9 (6H, s, OCH3), 3.8 (4H, t,
3JHH 5.6, 2CH2, C-8); dC 60.7 (s, CH3), 65.4 (s, C-9), 69.1
(s, C-8), 103.5 (s, C-1), 155.8 (s, C-2), 162.2 (s, C-6); m/z
(EI+) 564 (4%, M++2), 562 (16%, M++2), 560 (34%, M+),
558 (25), 264(10), 262(16), 240 (12), 239 (16), 238 (61),
237 (62), 236 (100), 223 (35), 137 (18), 132(14), 103 (16).
2
4
(s, OCH3), 105.2 (d, JCF 34.5, C-3), 109.8 (d, JCF 7.6,
C-5), 111.7 (s, C-20), 119.0 (s, C-40), 140.9 (s, C-50), 153.2
3
1
(s, C-10), 155.5 (d, JCF 15.5, C-4), 155.7 (d, JCF 239.0
C-2), 163.9 (d, 3JCF 4.5, C-6); m/z (EI+) 516 (M+, 12%), 515
(M+, 11), 514 (M+, 50), 513 (M+, 24), 512 (M+, 100), 511
(M+, 21), 510 (M+, 78), 302 (3), 301 (10), 299 (13),
265 (20).
5.4. Macrocycle 15c
14c (1.03 g, 2 mmol), 13c (0.81 g, 3 mmol) and CsF
(0.45 g, 15 mmol) in monoglyme (500 ml), after recrystal-
lisation from n-hexane, gave macrocycle 15c (0.3 g, 25%) as
white crystals; mp 299–300 8C. (Found: C, 52.2; H, 3.1; N,
4.4. C52H36Cl8N4O12 requires: C, 52.4; H, 3.0; N, 4.6%); dH
2.2 (3H, s, CH3), 4.0 (3H, s, OCH3), 6.3–6.6 (3H, m, ArH);
dC 21.1 (s, CH3), 61.0 (s, OCH3), 105.3 (s, CCl), 113.2 (s,
Ar), 119.7 (s, Ar), 140.1 (s, C-CH3), 153.3 (s, Ar-O), 156.3
(s, C-2), 162.8 (s, C-4); m/z (EI+) 596 (100).
5. Synthesis of macrocycles 15
5.1. General procedure
A mixture consisting of the bridged bi-pyridine 14, bis-
silyl derivative 13 and CsF in monoglyme (50 ml) was
heated at reflux temperature for 3 days. The resulting
mixture was poured into cold water and extracted into
dichloromethane. The organic layer was separated, dried
(MgSO4), and solvent was removed under reduced pressure
to give a crude product which was purified by column
chromatography on silica gel.
5.4.1. Crystal data
C52H36Cl8N4O1215c2, M = 1192.45, T = 110 K, tetra-
gonal, space group P42/n (No. 86), a = 13.470(1),
3
˚
˚
c = 13.986(1) A, V = 2537.5(7) A , Z = 2, Dc = 1.552 g
cmꢀ3, m = 0.51 mmꢀ1, 27,785 reflections with 2u ꢁ 558,
2926 unique, Rint = 0.056, final R = 0.040 [2242 data with
F2 ꢂ s( F2)], wR( F2) = 0.116 (all data). CCDC 255962.
5.2. 19,20-Diaza-7,9,16,18-tetrachloro-8,17-dimethyl-
2,5,11,14-tetraoxatricyclo[13.3.1.1<6,10>]icosa-
1(18),6,8,10,(20),15 (19),16-hexane 15a
References
14a (4.5 g, 0.01 mol), 13a (2.28 g, 0.015 mol) and CsF
(2.28 g, 0.015 mol) in monoglyme (50 ml), after recrystal-
lisation from light petroleum, gave 19,20-diaza-7,9,16,18-
tetrachloro-8,17-dimethyl-2,5,11,14-tetraoxatricyclo[13.3.
1.1<6,10>]icosa-1(18),6,8,10,(20), 15(19),16-hexane 15a
(1.5 g, 32%) as a white solid; 204–206 8C, dH 3.9 (6H, m,
OCH3), 4.6 (8H, s, CH2); dC 60.8 (s, CH3), 65.0 (s, C-8),
103.9 (s, C-1), 155.8 (s, C-2), 162.3 (s, C-6); m/z (EI+) 476
(4%, M++2), 474 (15%, M++2), 472 (27%, M+), 470 (21),
264(32), 262(50), 239 (15), 238 (36), 237 (69), 236 (59),
235 (100), 210 (11), 102 (13), 87 (12), 77 (19), 73(22),
70 (19).
[1] R.D. Chambers, A. Khalil, P. Richmond, G. Sandford, D.S. Yufit,
J.A.K. Howard, J. Fluorine Chem. 125 (2004) 715–720.
[2] R.D. Chambers, C.R. Sargent, Adv. Heterocycl. Chem. 28 (1981) 1–
71.
[3] G.M. Brooke, J. Fluorine Chem. 86 (1997) 1–76.
[4] R.D. Chambers, Fluorine in Organic Chemistry, Blackwell, Oxford,
2004.
[5] R.D. Chambers, P.R. Hoskin, A. Khalil, P. Richmond, G.
Sandford, D.S. Yufit, J.A.K. Howard, J. Fluorine Chem. 116 (2002)
19–22.
[6] R.D. Chambers, P.R. Hoskin, A.R. Kenwright, A. Khalil, P. Richmond,
G. Sandford, D.S. Yufit, J.A.K. Howard, Org. Biomol. Chem. 1 (2003)
2137–2147.
[7] R.D. Chambers, J. Hutchinson, W.K. Musgrave, J. Chem. Soc. (1964)
3573–3576.
5.3. 25,26-Diaza-10,12,22,24-tetrachloro-11,23-
dimethoxy-2,5,8,14,17,20-hexaoxatricyclo[19.3.
1.1<9,13>]hexacosa-1(24),9,11,13(26),21(25),
22-hexaene 15b
[8] R.D. Chambers, J. Hutchinson, W.K. Musgrave, J. Chem. Soc. (1964)
5634–5640.
[9] X. Xu, X. Qian, Z. Li, G. Song, J. Fluorine Chem. 88 (1998) 9–14.
[10] C. Kaneko, K. Uchiyama, M. Sato, N. Katagiri, Chem. Pharm. Bull. 9
(1986) 3658–3671.
14b (4.96 g, 0.01 mol), 13b (3.75 g, 0.015 mole) and CsF
(2.28 g, 0.015 mole) in monoglyme (50 cm3), after recrys-
tallisation from light petroleum ether, gave 25,26-diaza-
10,12,22,24-tetrachloro-11,23-dimethoxy-2,5,8,14,17,20-
2
CCDC 255962 contains the supplementary crystallographic data for this
paper. These data can be viewed free of charge via http://www.ccdc.ca-
m.ac.uk/cont/retrieving.html or from the CCDC, 12 Union Road, Cam-
bridge, CB21EZ; fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk.