Polyhalogenated heterocyclic compounds. Part 47. Syntheses of multi-substituted pyridine derivatives from pentafluoropyridine

Article abstract of DOI:10.1039/b105950p

A sequence of nucleophilic aromatic substitution and palladium catalysed coupling processes were used to transform pentafluoropyridine into various pyridine derivatives that bear five different functional groups.

Full text of DOI:10.1039/b105950p

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Polyhalogenated heterocyclic compounds. Part 47.1 Syntheses of
multi-substituted pyridine derivatives from pentafluoropyridine
Richard D. Chambers,*a Philip R. Hoskin,a Graham Sandford,*a Dmitrii S. Yufitb and
Judith A. K. Howardb
1
a Department of Chemistry, University of Durham, South Road, Durham, UK DH1 3LE.
E-mail: r.d.chambers@durham.ac.uk. E-mail: graham.sandford@durham.ac.uk
b Chemical Crystallography Unit, Department of Chemistry, University of Durham,
South Road, Durham, UK DH1 3LE
Received (in Cambridge, UK) 4th July 2001, Accepted 12th September 2001
First published as an Advance Article on the web 10th October 2001
A sequence of nucleophilic aromatic substitution and palladium catalysed coupling processes were used to transform
pentafluoropyridine into various pyridine derivatives that bear five different functional groups.
heteroaromatic derivatives utilises perfluorinated heterocyclic
systems as starting materials (Scheme 1). Highly fluorinated
Introduction
Heteroaromatic systems have, of course, a vast chemistry2 and
heteroaromatic systems are very susceptible towards nucleo-
a great number of materials, pharmaceuticals and other life-
philic attack and an extensive chemistry principally involving
science products are heterocyclic derivatives. In the ongoing
search for novel biologically active “lead” compounds, the
life-science industries have extensive discovery programmes
focussed upon the synthesis of a wide range of structurally
diverse, multi-functional systems, including those based upon
heterocyclic “scaffolds” that, ideally, can be accessed by parallel
substitution of fluorine by a variety of nucleophiles continues
to emerge.5,6 Indeed, a number of commercially significant
fibre-reactive dyes are prepared on a large scale by such
processes.7
Pentafluoropyridine 1 is a very versatile “building block”
because, in principle, all five fluorine substituents in penta-
synthesis. Consequently, development of effective methodology
fluoropyridine could be substituted by nucleophiles. Therefore,
for the synthesis of heterocyclic derivatives bearing several dif-
potentially, a range of polysubstituted systems could be derived
ferent functional groups has become a topic of great interest
from this core molecule by nucleophilic aromatic substitution
particularly in the drug discovery arena where the search for
processes. Furthermore, it is well established5,6 that, in general,
novel pharmacophores is a primary goal. Application of, for
the order of activation towards nucleophilic attack follows the
example, sequential electrophilic substitution and palladium
catalysed coupling reactions to the synthesis of many hetero-
sequence 4-fluorine > 2-fluorine > 3-fluorine. Consequently, for
a succession of five nucleophilic substitution steps, where Nuc1
is the first nucleophile, Nuc2 is the second, etc., the order of
substitution is predicted to be selective as outlined in Scheme 2,
cyclic analogues (rapid analogue synthesis, RAS) has been
reviewed recently in this journal3 and the requirement for short,
high yielding, regioselective and flexible routes to multiply func-
although a few exceptions to these general rules have been
tionalised heteroaromatic derivatives has been emphasised.4 A
reported.8
sequence of substitution processes involving the functionalis-
ation of a heteroaromatic “core scaffold” is a strategy fre-
quently employed. This idea is illustrated in Scheme 1 in which
Scheme 2
A very limited number of relatively highly reactive poly-
chloroheterocyclic derivatives such as trichloro-s-triazine have
been used recently as substrates for parallel synthesis.9 How-
ever, the vastly increased reactivity of carbon–fluorine bonds in
heterocyclic systems towards nucleophiles compared with
corresponding carbon–chlorine bonds, the enhanced selectiv-
ity of perfluorinated heterocycles towards nucleophilic attack
as compared to corresponding perchlorinated derivatives
(for example, pentachloropyridine gives a mixture of 2- and
4-substituted products on reaction with sodium ethoxide,10,11
whereas pentafluoropyridine gives 4-substitution exclusively12)
and the opportunity for using 19F NMR as a structural probe
Scheme 1 Penta-functional pyridine derivatives.
pyridine is the parent of heterocyclic systems bearing up to five
different substituents R1–R5.
Our approach towards the synthesis of highly functionalised
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This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b105950p

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Fig. 1 Conformers 4a and 4b.
make perfluorinated heterocyclic systems much more prefer-
able substrates for analogue synthesis than the corresponding
chlorinated derivatives.
In this paper, we describe an approach to the synthesis of a
range of penta-substituted pyridine derivatives in which the
heteroaromatic ring bears up to five different substituents by a
sequence of substitution processes using pentafluoropyridine as
the starting material.13
Fig. 2 X-Ray structure of 4.
Results and discussion
Perfluoroalkylation of pentafluoropyridine 1 was achieved by
reaction with hexafluoropropene and a catalytic amount of a
tertiary amine to afford perfluoroisopropylpyridine 2, as
described previously.14 This methodology, which is suitable for
scale-up, allows ready isolation of the perfluoroisopropyl
derivative 2 by simple distillation from the crude reaction
mixture. Bromination of 2 by a superacidic hydrogen bromide–
aluminium tribromide mixture15 gave the dibromopyridine
derivative 3 in high yield (Scheme 3).
Scheme 3 Reagents and conditions: i, CF2᎐᎐CF–CF3, tetrakis(dimethyl-
amino)ethylene, 60 ЊC; ii, AlBr3 (2.2 equiv.), HBr (2.2 equiv.), 160 ЊC,
48 h.
The bromofluoroheterocyclic derivative 3 was expected to be
a very versatile “building block” because we have recently estab-
lished15 that in reactions involving polybromo-fluorohetero-
cyclic systems fluorine is preferentially substituted by “hard”
nucleophiles whereas bromine is substituted by “soft” nucleo-
philes. With this type of reactivity profile in mind, we explored
reactions between 3 and representative oxygen and nitrogen
nucleophiles.
Scheme 4 Reagents and conditions: i, NaOMe (1.5 equiv.), MeOH,
reflux, 24 h; ii, NaOMe (3 equiv.); iii, NaOMe (6 equiv.).
Reaction of 3 with methoxide gave products that depended
upon reaction conditions. Fluorine is substituted by methoxide
to give 4 and 5 upon reaction of 3 with one or two equivalents
of sodium methoxide respectively (Scheme 4) and these results
are consistent with the HSAB rationale established previously.15
Reaction of 3 with an excess of sodium methoxide under more
forcing conditions does, however, lead to bromine substitution
and 6 was isolated (Scheme 4).
Rotation of the perfluoroisopropyl group in 4 is restricted
by the 5-methoxy substituent to such an extent that two
conformers, 4a and 4b (Fig. 1), can be observed by 19F NMR
Scheme 5 Reagents and conditions: i, piperidine (2 equiv.), MeCN,
80 ЊC, 24 h.
at room temperature.16 Large through space coupling (4JFF
=
96 Hz) is recorded when two fluorine atoms are in close prox-
imity such as in conformer 4a. The two conformers 4a and 4b
were also characterised by X-ray analysis (Fig. 2).
On the other hand, reaction of 3 with a “softer” nucleophile,
such as piperidine, gave 7 arising from bromine substitution
(Scheme 5). Thus, these reactions demonstrate that the regio-
selectivity of nucleophilic substitution depends critically on the
choice of nucleophile.
beyond nucleophilic aromatic substitution processes, we turned
our attention to the use of the bromine substituents as func-
tional groups in various metallation and palladium catalysed
processes.
Other functional groups may be attached to the heterocyclic
ring by lithiation of 3 using n-butyllithium followed by trapping
of the intermediate carbanionic species 8 by an electrophile
(Scheme 6). Lithiation of 3 gave 8 and reaction of a solution of
8 in THF with ethanol and trimethylsilyl chloride gave 9 and 10
respectively.
In order to widen the range of selective functionalisation
reactions possible for bromofluoroheterocycles, such as 3,
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Palladium catalysed reactions,17 involving coupling between
3 and pent-1-yne (Sonogashira reactions) were carried out and
gave 11 and 12 after reaction of 3 with one or two equivalents
of pent-1-yne, a palladium catalyst and triethylamine respect-
ively (Scheme 7). By a similar procedure, bis-phenylalkynylation
of 3 was carried out by stirring an excess of phenylacetylene
with 3 and a Pd catalyst. Mono- and bis-phenylalkynylated
products 13 and 14 were separated by column chromatography.
A consideration of the mechanism17 for palladium catalysed
coupling reactions (Scheme 8), allows the effect of perfluoro-
alkyl substituents on such processes to be assessed. Insertion of
the palladium catalyst into the carbon–bromine bond can be
envisaged as a nucleophilic attack by the palladium centre
and this will be aided by the presence of the highly electron
withdrawing perfluoroalkyl group located on the pyridine ring.
The coordination of the nucleophilic alkynyl group with the
palladium atom, however, is the more likely rate determining
step and, again, this will be aided by the perfluoroalkyl group
which renders the metal site more electrophilic in nature.
In the final stage of synthesis, reaction of heterocycles, 4, 7,
11 and 13, each bearing four different substituents, yielded
penta-substituted systems upon reaction with a further nucleo-
phile (Scheme 9 and Scheme 10). Reaction of 4 with piperidine
gave a mixture of isomers 15 and 16 in approximately equal
amounts, as estimated by 19F NMR and GC–MS analysis
(Scheme 9). However, in contrast, reaction of the piperidyl
system 7 with methoxide gave predominantly isomer 15, arising
from substitution of the fluorine atom located ortho to the
piperidyl group, and only a trace quantity of 16 by GC–MS
analysis. The structure of 15 was confirmed by X-ray crystal-
lography (Fig. 3).
Methoxylation of the phenylethynylpyridine derivative 13
gave predominantly 17, resulting from the substitution of the
fluorine atom para to the phenylethynyl group (Scheme 10). A
small amount (5%) of isomer 18 was formed but was not
isolated. Purification and isolation of the major product 17 was
achieved by column chromatography.
Since 17 did not give crystals suitable for X-ray analysis, its
structure was assigned by a consideration of less reliable 19F
NMR calculations, using substituent chemical shift data. The
Scheme 6 Reagents and conditions: i, n-BuLi (1.2 equiv.), THF,
Ϫ78 ЊC; ii, excess EtOH, Ϫ78 ЊC–rt; iii, Me3SiCl (4 equiv.), Ϫ78 ЊC–rt.
Fig. 3 X-Ray structure of 15.
Scheme 7 Reagents and conditions: i, pent-1-yne (2 equiv.), CuI, Pd(OAc)2, PPh3, Et3N, rt, 3 days; ii, phenylacetylene (2 equiv.), CuI, (Ph3P)2PdCl2,
Et3N, rt, 16 h.
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Scheme 8
Scheme 10 Reagents and conditions: i, NaOMe (1.7 equiv.), MeOH,
reflux, 24 h.
major product δF = Ϫ109.6/Ϫ112.0 ppm and minor product
δF = Ϫ100.0/Ϫ102.4 ppm, confirms the structures of the
products 17 and 18.
Similarly, reaction of 11 with sodium methoxide gives 19,
arising from substitution of the fluorine located para to the
alkynyl group and a trace amount of isomer 20 (Scheme 10).
The regiochemistry of each nucleophilic substitution reac-
tion in Schemes 9 and 10 can be explained by the following
mechanistic rationale. In principle, reaction of 21 with meth-
oxide could give two transition states resembling 22 and 23
depending on the site of nucleophilic attack (Scheme 11).
Since the electronegativity of bromine is not significantly
different to that of nitrogen, there is no real difference in the
electrophilicity of the 3 and 5 ring carbon atoms in the initial
state for 21 (X = piperidyl) and therefore the relative stabilities
of the anionic transition states determine the regiochemistry of
the reaction. If the negative charge density in the transition
states 22 (X = piperidyl) and 23 (X = piperidyl) is considered to
be greater at the carbon atoms para to the sites of nucleophilic
attack, then the transition state 23 (X = piperidyl), in which the
carbon bearing the highest negative charge density is attached
to the bromine substituent, will be more stable than the
transition state 22 (X = piperidyl), in which the carbon bearing
negative charge is bonded to the piperidyl group (destabilising
24a). It seems reasonable, therefore, to conclude that nucleo-
philic substitution occurs at the site that leads to greater charge
density adjacent to bromine, rather than nitrogen, in the transi-
tion state and, of course, this leads to the product 15.
Scheme 9 Reagents and conditions: i, piperidine, THF, reflux, 16 h;
ii, NaOMe (1.7 equiv.), MeOH, reflux, 24 h.
19F NMR shift of the ring fluorine substituent in 4, where the
structure was proved unambiguously by X-ray crystallography
(Fig. 1), is Ϫ104.3/Ϫ106.5 ppm (two conformers). A com-
parison of the published 19F NMR data of bromopentafluoro-
benzene18 (F-ortho Ϫ132.6; F-meta Ϫ161.2; F-para, Ϫ155.2
ppm) with 1-phenylethynylpentafluorobenzene19 (F-ortho
Ϫ136.7; F-meta Ϫ162.7; F-para, Ϫ153.7 ppm) reveals that
replacement of a bromine substituent by a phenylethynyl group
in an aromatic ring causes chemical shifts of Ϫ4.1 for ortho-
fluorine, Ϫ1.5 for meta-fluorine and ϩ1.5 ppm for para-
fluorine. Thus, we can predict that the ring fluorine in 17 should
have a shift of Ϫ108.4/Ϫ110.6 ppm whereas in 18 the chemical
shift is calculated to be Ϫ102.8/Ϫ105.0. A comparison of these
predicted chemical shift values with the observed resonances,
Similarly, we can conclude that methoxylation of 21
᎐
(X = C᎐C–Ph) leads to the more stable transition state 22
᎐
᎐
᎐
(X = C᎐C–R) because, in this case, the C᎐C–R group is
᎐
᎐
more stabilising than a bromine substituent, due to further
delocalisation of charge 24c, giving product 17. Finally,
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Scheme 11
substitution of bromine in 4 by piperidine gives a mixture of
products 15 and 16 because there is not a large difference in the
ability of fluorine and methoxy to stabilise carbanion centres
where, in each case, stabilising inductive electron withdrawal is
offset by electron pair repulsions. The latter are known to be
more important when the attached carbanion centre is planar.
In summary, we have outlined an approach for the synthesis
of a range of pyridine derivatives that bear four or five different
substituents by carrying out a short, efficient sequence of sub-
stitution (nucleophilic, palladium catalysed, lithiation, etc.)
processes on pentafluoropyridine starting material. Clearly,
pentafluoropyridine and, by analogy, other highly fluorinated
heterocyclic systems, can be utilised as core units for the syn-
thesis of a range of highly substituted heterocyclic derivatives.
(1,2,2,2-tetrafluoro-1-trifluoromethylethyl)pyridine 3 (21.6 g,
80%) as a colourless liquid; bp 56 ЊC (4 mmHg) (Found: C,
21.8; N, 3.1. C8Br2F9N requires C, 21.8; N, 3.2%); δF Ϫ75.8 (6F,
m, CF3), Ϫ103.7 and Ϫ105.8 (2F, br s, F-3), Ϫ180.0 (1F, m,
CFCF3); δC 91.5 (dsept, 1JCF 216, 2JCF 36.0, CFCF3), 114.1 (dt,
2
1
2
2JCF 22.5, JCF 13.3, C-4), 119.7 (qd, JCF 289, JCF 27.1, CF3),
124.0–126.2 (br m, C-2), 148.0–155.0 (br m, C-3); m/z (EIϩ) 443
(Mϩ, 33%), 441 (Mϩ, 41), 439 (Mϩ, 48), 343 (11), 341 (11), 324
(24), 322 (48), 320 (27), 212 (15), 193 (18), 162 (32), 124 (20), 69
(100).
Reactions of 2,6-dibromo-3,5-difluoro-4-(1,2,2,2-tetrafluoro-1-
trifluoromethylethyl)pyridine 3 with methoxide
General procedure. Under an atmosphere of dry nitrogen,
sodium metal was added to methanol (20 ml) and stirred until
hydrogen evolution was complete. Compound 3 was added to
the solution which was stirred at reflux temperature for 24 h
before water (25 ml) was added. The mixture was extracted with
dichloromethane, dried (MgSO4) and evaporated to yield crude
material which was purified by column chromatography on sil-
ica gel, using dichloromethane and hexane (2 : 1) as the eluent.
Experimental
All starting materials were obtained commercially (Aldrich,
Lancaster or Fluorochem). Compound 2 was prepared accord-
ing to literature procedures.14 All solvents were dried using
literature procedures. NMR spectra were recorded in deuterio-
chloroform, 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 tetramethyl-
silane and trichlorofluoromethane as internal standards. Mass
spectra were recorded on a Fisons VG-Trio 1000 Spectrometer
coupled with a Hewlett Packard 5890 series II gas chromato-
graph using a 25 m HP1 (methylsilicone) column. Elemental
analyses were obtained on a Exeter Analytical CE-440 ele-
mental 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 per-
formed using a Fischer Spaltrohr MS220 microdistillation
apparatus. Column chromatography was carried out on silica
gel (Merck no. 109385, particle size 0.040–0.063 nm) and TLC
analysis was performed on silica gel TLC plates (Merck).
2,6-Dibromo-3-fluoro-5-methoxy-4-(1,2,2,2-tetrafluoro-1-tri-
fluoromethylethyl)pyridine 4. Sodium methoxide (0.38 g, 6.9
mmol) gave 2,6-dibromo-3-fluoro-5-methoxy-4-(1,2,2,2-tetra-
fluoro-1-trifluoromethylethyl)pyridine 4 (1.26 g, 62%) as a
colourless liquid; bp 254–255.6 ЊC (Found: C, 23.8; H, 0.6; N,
3.1. C9H3Br2F8NO requires C, 23.8; H, 0.7; N, 3.1%); con-
former A: δH 3.99 (s, CH3); δF Ϫ74.6 (6F, m, CF3), Ϫ106.5 (d,
4JFF 96, F-3), Ϫ176.3 (d, 4JFF 96, CFCF3); δC 62.3 (s, CH3), 92.2
1
2
1
2
(dsept, JCF 216, JCF 34.7, CFCF3), 119.9 (qd, JCF 289, JCF
2
27.4, CF3), 121.1 (m, C-4), 124.6 (d, JCF 27.7, C-2), 129.6 (s,
1
3
C-6), 151.6 (d, JCF 268, JCF 21, C-3), 151.9 (br s, C-5); con-
former B: δH 3.88 (s, CH3); δF Ϫ74.6 (6F, m, CF3), Ϫ104.3 (s,
F-3), Ϫ181.5 (s, CFCF3); δC 63.2 (s, CH3), 92.2 (dsept, 1JCF 216,
2JCF 34.7, CFCF3), 119.9 (qd, JCF 289, JCF 27.4, CF3), 120.1
(m, C-4), 124.1 (d, 2JCF 28.9, C-2), 134.1 (s, C-6), 153.6 (d, 1JCF
278, C-3), 153.5 (br s, C-5); m/z (EIϩ) 455 (Mϩ, 14%), 453 (Mϩ,
31), 451 (Mϩ, 20), 305 (31), 303 (34), 290 (13), 288 (13), 69
(100).
1
2
2,6-Dibromo-3,5-difluoro-4-(1,2,2,2-tetrafluoro-1-trifluoro-
methylethyl)pyridine 3
A Hastalloy autoclave was charged with aluminium bromide
(34.1 g, 0.13 mol), 2,3,5,6-tetrafluoro-4-(1,2,2,2-tetrafluoro-1-
trifluoromethylethyl)pyridine 2 (19.2 g, 0.06 mol) and hydrogen
bromide gas (10.2 g, 0.13 mol). The autoclave was heated at 160
ЊC for 48 h. After cooling, excess hydrogen bromide was neu-
tralised by release into a sodium hydrogen carbonate solution.
The autoclave was opened and ice–water was cautiously added
to the solid contents. This mixture was then extracted with
dichloromethane and the extracts were dried (MgSO4) and dis-
tilled under reduced pressure to give 2,6-dibromo-3,5-difluoro-4-
2,6-Dibromo-3,5-dimethoxy-4-(1,2,2,2-tetrafluoro-1-trifluoro-
methylethyl)pyridine 5. Sodium methoxide (0.76 g, 13.9 mmol)
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gave
2,6-dibromo-3,5-dimethoxy-4-(1,2,2,2-tetrafluoro-1-tri-
150.0–158.0 (br m, C-3,5); m/z (EIϩ) 363 (Mϩ, 18%), 361 (Mϩ,
fluoromethylethyl)pyridine 5 (1.75 g, 83%) as a white solid; mp
72.7–74.0 ЊC (Found: C, 26.1; H, 1.3; N, 2.9. C10H6Br2F7NO2
requires C, 25.8; H, 1.3; N, 3.0%); δH 3.90 (3H, s, OCH3), 4.00
(3H, s, OCH3); δF Ϫ73.9 (6F, m, CF3), Ϫ177.2 (m, CFCF3);
δC 62.0 (s, CH3), 63.0 (s, CH3), 93.3 (dsept, 1JCF 213, 2JCF 35.1,
CFCF3), 119.9 (qd, JCF 292, JCF 27.9, CF3), 126.4 (d, JCF
19.8, C-4), 129.4 (s, C-2), 133.1 (s, C-6), 152.0 (s, C-3), 153.8 (m,
C-5); m/z (EIϩ) 467 (Mϩ, 29%), 465 (Mϩ, 70), 463 (Mϩ, 52), 317
(61), 315 (66), 260 (36), 221 (24), 205 (28), 93 (22), 69 (100).
18), 244 (23), 242 (22), 69 (100).
2-[6-Bromo-3,5-difluoro-4-(1,2,2,2-tetrafluoro-1-trifluoro-
methylethyl)-2-pyridyl]-2-methyl-2-silapropane 10. Trimethyl-
silyl chloride (2.4 g, 22.2 mmol), after column chromatography,
using hexane and dichloromethane (6 : 1) as the eluent, gave
2-[6-bromo-3,5-difluoro-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-
ethyl)-2-pyridyl]-2-methyl-2-silapropane 10 (0.9 g, 48%) as a
colourless liquid; bp 211.0–212.1 ЊC (Found: C, 30.3; H, 2.0;
N, 3.2. C11H9BrF9NSi requires C, 30.4; H, 2.1; N, 3.2%);
δH 0.38 (s); δF Ϫ73.4 (6F, m, CF3), Ϫ100.4 and Ϫ103.0 (1F, br s,
F-3), Ϫ108.6 and Ϫ110.6 (1F, s, F-5), Ϫ177.3 (1F, m, CFCF3);
δC Ϫ1.8 (s, CH3), 91.8 (dsept, 1JCF 214, 2JCF 36.3, CFCF3), 111.9
(m, C-4), 120.1 (qd, 1JCF 289, 2JCF 27.1, CF3), 128.2 (br m, C-6),
152.0–160.0 (br m, C-2,3,5); m/z (EIϩ) 420 (Mϩ Ϫ CH3, 14%),
418 (Mϩ Ϫ CH3, 14), 270 (11), 232 (16), 170 (16), 77 (100).
1
2
2
2-Bromo-3,5,6-trimethoxy-4-(1,2,2,2-tetrafluoro-1-trifluoro-
methylethyl)pyridine 6. Sodium methoxide (1.5 g, 27.5 mmol)
gave
2-bromo-3,5,6-trimethoxy-4-(1,2,2,2-tetrafluoro-1-tri-
fluoromethylethyl)pyridine 6 (1.2 g, 64%) as a colourless liquid;
bp 260.5–262 ЊC (Found: C, 31.6; H, 2.0; N, 3.3. C11H9BrF7NO3
requires C, 31.7; H, 2.2; N, 3.4%); δH 3.8, 3.9 and 4.0 (all 3H,
all s, CH3); δF (major conformer) Ϫ74.2 (6F, m, CF3), Ϫ179.3
(1F, m, CFCF3); δF (minor conformer) Ϫ74.2 (6F, m, CF3),
Ϫ176.7 (1F, m, CFCF3); δC (major conformer) 54.4 (s, CH3),
Palladium catalysed coupling reactions of 3
1
2
General procedure. A mixture consisting of 3, the alkyne
derivative, copper() iodide, palladium() acetate, triphenyl-
phosphine and triethylamine was stirred at rt, under an atmos-
phere of dry nitrogen, for 3 d. Water (30 ml) was added and the
mixture was filtered and extracted into dichloromethane. The
organic extracts were dried (MgSO4) and evaporated to give a
crude product which was purified by column chromatography.
60.4 (s, CH3), 62.5 (s, CH3), 93.5 (dsept, JCF 210, JCF 35.1,
1
2
2
CFCF3), 120.5 (qd, JCF 287, JCF 28.3, CF3), 123.5 (d, JCF
20.2, C-4), 127.8 (m, C-2), 141.1 (s, C-3), 146.9 (s, C-5), 152.6 (s,
C-6).
Reaction of 3 with piperidine
6-Bromo-3,5-difluoro-2-piperidyl-4-(1,2,2,2-tetrafluoro-1-tri-
fluoromethylethyl)pyridine 7. A solution of 3 (1.0 g, 2.3 mmol)
and piperidine (0.4 g, 4.5 mmol) in acetonitrile (15 ml) was
stirred at reflux temperature for 24 h. Water (30 ml) was added
and the mixture was filtered and extracted into dichloro-
methane. The organic extracts were dried (MgSO4) and evapor-
ated affording a liquid (1.9 g). Flash-column chromatography,
using dichloromethane as the eluent, yielded 6-bromo-
3,5-difluoro-2-piperidyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-
ethyl)pyridine 7 (1.62 g, 80.2%) as a yellow liquid; bp 284.5–
286.6 ЊC (Found: C, 35.2; H, 2.0; N, 6.3. C13H10BrF9N2 requires
C, 35.1; H, 2.2; N, 6.3%); δH 1.6 (3H, m, CH2), 3.3 (2H, m,
CH2N); δF Ϫ73.3 (6F, m, CF3), Ϫ117.6 and Ϫ120.2 (1F, br m,
F-3), Ϫ120.3 and Ϫ122.8 (1F, br m, F-5), Ϫ177.3 (m, CFCF3);
δC 24.4 (s, CH2), 25.6 (s, CH2CH2N), 49.2 (s, CH2N), 91.8
(dsept, 1JCF 214, 2JCF 38.2, CFCF3), 113.9 (br s, C-4), 120.2 (qd,
1JCF 287, 2JCF 27.5, CF3), 120–122 (br m, C-6), 142.0–149.0 (br
m, C-2,3,5); m/z (EIϩ) 446 (Mϩ, 28%), 444 (Mϩ, 33), 417 (20),
415 (21), 361 (20), 84 (46), 69 (100).
Reaction with pent-1-yne. Pent-1-yne (0.31 g, 4.5 mmol),
3 (1.0 g, 2.3 mmol), copper() iodide (0.01 g, 0.05 mmol),
palladium() acetate (0.04 g), triphenylphosphine (0.08 g) and
triethylamine (15 ml), after column chromatography using
hexane–DCM (1 : 2) as the eluent, gave 6-bromo-3,5-difluoro-
2-pent-1-ynyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethylethyl)-
pyridine 11 (0.6 g, 63%) as white crystals; mp 55.2–56.5 ЊC
(Found: C, 36.5; H, 1.6; N, 3.2. C13H7BrF9N requires C, 36.5;
H, 1.6; N, 3.3%); δH 1.05 (3H, t, 3JHH 7.2, CH3), 1.67 (2H, sex,
3JHH 7.2, CH2CH3), 2.48 (2H, t, 3JHH 7.2, CH2); δF Ϫ75.4 (6F, m,
CF3), Ϫ101.2 and Ϫ104.2 (1F, m, F-5), Ϫ111.9 and Ϫ114.2 (1F,
m, F-3), Ϫ179.8 (1F, m, CFCF3); δC 13.4 (s, CH3), 21.4 (s,
1
2
CH2CH3), 72.3 (s, C-CH2), 91.5 (dsept, JCF 215, JCF 36.2,
1
CFCF3), 101.4 (s, Ar-C), 113.5 (m, C-4), 119.8 (qd, JCF 276,
2JCF 25.6, CF3), 124–135 (br m, C-2,6), 150–158 (br m, C-3,5);
m/z (EIϩ) 429 (Mϩ, 38%), 427 (Mϩ, 50), 414 (24), 412 (100), 345
(49), 343 (52), 200 (33); and, 3,5-difluoro-2,6-dipent-1-ynyl-4-
(1,2,2,2-tetrafluoro-1-trifluoromethylethyl)pyridine 12 (0.15 g,
16.4%) as a yellow oil (bp >300 ЊC) (Found: C, 52.2; H, 3.4; N,
3.3. C18H14F9N requires C, 52.0; H, 3.4; N, 3.4%); δH 0.95 (3H,
t, 3JHH 7.2, CH3), 1.57 (2H, sex, 3JHH 7.2, CH2CH3), 2.38 (2H, t,
3JHH 7.2, CH2); δF Ϫ76.1 (6F, m, CF3), Ϫ111.2 and Ϫ113.7 (2F,
m, F-3), Ϫ180.5 (1F, m, CFCF3); δC 12.9 (s, CH3), 21.2 (s,
CH2CH3), 21.3 (s, CH2), 72.7 (s, C-CH2), 91.6 (dsept, 1JCF 214,
2JCF 35.8, CFCF3), 99.1 (s, Ar-C), 112.1 (m, C-4), 119.8 (qd,
1JCF 289, 2JCF 27.5, CF3), 128–132 (br m, C-2), 150–159 (br m,
C-3); m/z (EIϩ) 415 (Mϩ, 100%), 400 (72), 387 (72), 358 (34),
331 (31), 302 (27), 252 (27).
Lithiation of 3 and trapping by electrophiles
General procedure. A solution of n-butyllithium (3.5 ml of
1.6 M solution in hexanes, 5.5 mmol) was added, under an
atmosphere of dry nitrogen, to a cooled (Ϫ78 ЊC), stirred solu-
tion of 3 (2.0 g, 4.5 mmol) in tetrahydrofuran (25 ml). The
electrophile was added and the mixture was stirred for a further
30 min at Ϫ78 ЊC, before being allowed to warm to rt. Water
(30 ml) was added and the organic components were extracted
into dichloromethane. The organic extracts were dried (MgSO4)
and evaporated to give a residue which was purified by column
chromatography on silica gel.
Reaction with phenylacetylene. Phenylacetylene (0.5 g, 4.5
mmol), 3 (1.0 g, 2.3 mmol), copper() iodide (0.01 g, 0.05
mmol), bis(triphenylphosphine)palladium dichloride (0.04 g,
0.06 mmol) and triethylamine (10 ml), after column chrom-
atography using hexane–DCM (1 : 2) as the eluent, gave
6-bromo-3,5-difluoro-2-phenylethynyl-4-(1,2,2,2-tetrafluoro-1-
trifluoromethylethyl)pyridine 13 (0.23 g, 21%) as white crystals;
mp 84.7–86.2 ЊC (Found: C, 41.9; H, 1.1; N, 3.1. C16H5BrF9N
requires C, 41.6; H, 1.1; N, 3.0%); δH 7.3–7.6 (5H, m, ArH);
δF Ϫ75.2 (6F, m, CF3), Ϫ100.2 and Ϫ103.0 (1F, m, F-5), Ϫ110.7
and Ϫ113.0 (1F, m, F-3), Ϫ179.7 (1F, m, CFCF3); δC 80.1 (s,
2-Bromo-3,5-difluoro-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-
ethyl)pyridine 9. Ethanol (30 ml), after column chromato-
graphy, using hexane and dichloromethane (4 : 1) as the eluent,
gave
2-bromo-3,5-difluoro-4-(1,2,2,2-tetrafluoro-1-trifluoro-
methylethyl)pyridine 9 (1.2 g, 73%) as a colourless liquid; bp
180.6–182.2 ЊC (Found: C, 26.4; H, 0.2; N, 3.8. C8HBrF9N
requires C, 26.5; H, 0.3; N, 3.9%); δH 8.27 (s); δF Ϫ71.2 (6F, m,
CF3), Ϫ97.0 and Ϫ100.0 (1F, br s, F-3), Ϫ116.0 and Ϫ119.0
1
2
(1F, s, F-5), Ϫ175.6 (m, CFCF3); δC 91.5 (dsept, JCF 214, JCF
2
2
1
2
36.2, CFCF3), 113.8 (dt, JCF 22.4, JCF 12.3, C-4), 119.8 (qd,
1JCF 291, 2JCF 27.5, CF3), 127.0 (br m, C-2), 135.4 (br m, C-6),
C-C6H5), 91.6 (dsept, JCF 215, JCF 35.8, CFCF3), 98.6 (m,
Ar-C), 114.2 (dt, 2JCF 22.1, 2JCF 13.3, C-4), 119.9 (qd, 1JCF 290,
J. Chem. Soc., Perkin Trans. 1, 2001, 2788–2795
2793

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2JCF 27.1, CF3), 121.0 (s, Aripso), 128.8 (s, Armeta), 130.4 (s,
Arpara), 132.5 (s, Arortho), 126–132 (br m, C-2,6), 150–160 (br m,
C-3,5); m/z (EIϩ) 463 (Mϩ, 94%), 461 (Mϩ, 100), 313 (26), 293
(30), 244 (66), 69 (68); and 2,6-bis(2-phenylethynyl)-3,5-
difluoro-4-(1,2,2,2-tetrafluoro-1-trifluoromethylethyl)pyridine
14 (0.86 g, 78%) as white crystals; mp 172.8–173.2 ЊC (Found:
C, 59.5; H, 2.0; N, 2.8. C24H10F9N requires C, 59.6; H, 2.1; N,
2.9%); δH 7.33 (3H, m, ArH), 7.55 (2H, m, ArH); δF Ϫ75.3 (6F,
m, CF3), Ϫ108.5 and Ϫ110.9 (2F, m, F-3), Ϫ179.9 (1F, m,
product mixture; δF (two conformers) Ϫ72.6 (6F, m, CF3),
Ϫ100.0 and Ϫ102.4 (1F, m, F-5), Ϫ179.6 (1F, m, CFCF3); m/z
(EIϩ) 475 (Mϩ, 32%), 473 (Mϩ, 32), 305 (38), 303 (36), 182 (45),
155 (54).
1
2
CFCF3); δC 80.3 (m, C-C6H5), 91.8 (dsept, JCF 215, JCF 35.9,
2
2
CFCF3), 97.4 (m, Ar-C), 112.9 (dt, JCF 22.1, JCF 13.1, C-4),
1
2
120.2 (qd, JCF 306, JCF 27.5, CF3), 121.3 (s, Aripso), 128.8 (s,
Armeta), 130.2 (s, Arpara), 132.5 (s, Arortho), 126–132 (br m, C-2,6),
150–160 (br m, C-3,5); m/z (EIϩ) 483 (Mϩ, 100%), 344 (13), 242
(75), 182 (30).
4-(1,2,2,2-Tetrafluoro-1-trifluoromethylethyl)-2-bromo-3-
methoxy-5-fluoro-6-pent-1-ynylpyridine 19. Sodium methoxide
(0.3 g, 5.9 mmol) in methanol (35 cm3) and 11 (1.7 g, 4.0 mmol)
gave 4-(1,2,2,2-tetrafluoro-1-trifluoromethylethyl)-2-bromo-3-
methoxy-5-fluoro-6-pent-1-ynylpyridine 19 (1.5 g, 88%) as a
yellow oil; bp >300 ЊC (Found: C, 38.5; H, 2.2; N, 3.2. C14H10-
BrF8NO requires C, 38.2; H, 2.3; N, 3.2%); δH 0.99 (3H, t, 3JHH
Penta-substituted derivatives—reactions with methoxide
General procedure. Under an atmosphere of dry nitrogen,
sodium methoxide (0.3 g, 5.9 mmol) was added to methanol
(35 ml) and stirred. The heterocyclic derivative was added to the
solution and then stirred at reflux temperature for 24 h before
water (25 ml) was added. The mixture was extracted with
dichloromethane, dried (MgSO4) and evaporated to yield crude
material which was purified by column chromatography, using
dichloromethane and hexane (1 : 1) as the eluent.
3
3
7.2, CH3), 1.61 (2H, sex, JHH 7.2, CH2CH3), 2.41 (2H, t, JHH
7.2, Ar-CH2), 3.86–3.96 (3H, br m, OCH3); δF (major con-
former B) Ϫ74.9 (6F, m, CF3), Ϫ112.6 (1F, m, F-5), Ϫ181.5 (1F,
m, CFCF3); δF (minor conformer A) Ϫ74.9 (6F, m, CF3),
Ϫ115.1 (1F, d, 4JFF 96.0, F-5), Ϫ176.6 (1F, d, 4JFF 96.0, CFCF3);
m/z (EIϩ) 441 (Mϩ, 81%), 439 (Mϩ, 100).
4-(1,2,2,2-Tetrafluoro-1-trifluoromethylethyl)-2-bromo-3-
fluoro-5-methoxy-6-piperidinopyridine 15. Sodium methoxide
(0.3 g, 5.9 mmol) in methanol (35 ml) and 7 (1.5 g, 3.4 mmol),
gave 4-(1,2,2,2-tetrafluoro-1-trifluoromethylethyl)-2-bromo-3-
fluoro-5-methoxy-6-piperidinopyridine 15 (1.2 g, 80%) as a white
solid; mp 81.1–83.0 ЊC (Found: C, 36.6; H, 2.8; N, 6.0.
C14H13BrF8N2O requires C, 36.8; H, 2.8; N, 6.1%); δH 1.5–1.65
(6H, m, CH2), 3.2 (4H, m, CH2N), 3.7 (3H, s, CH3O); δF (minor
conformer B) Ϫ73.6 (6F, m, CF3), Ϫ116.0 (1F, m, F-3), Ϫ179.3
(1F, m, CFCF3); δF (major conformer A) Ϫ73.4 (6F, m, CF3),
Ϫ118.4 (1F, d, 4JFF 95.9, F-3), Ϫ174.9 (1F, d, 4JFF 95.9, CFCF3);
δC (major conformer A) 24.3 (s, CH2), 25.8 (s, CH2), 49.2 (m,
Reaction of 4 with piperidine
1
2
CH2N), 57.7 (br s, CH3O), 92.8 (dsept, JCF 211, JCF 35.1,
A mixture consisting of 4 (0.80 g, 1.7 mmol), piperidine (0.17 g,
2.0 mmol) and THF (20 ml) was heated at reflux temperature
for 16 h. The reaction mixture was cooled before water (25 ml)
was added. The mixture was extracted with dichloromethane,
dried (MgSO4) and evaporated to yield crude material which
consisted of 15 and 16 (0.51 g, 64%) in a 1 : 1 ratio by GC–MS
analysis; no further purification was attempted and spectral
data for 15 were as described above.
1
2
CFCF3), 120.4 (qd, JCF 287, JCF 28.2, CF3), 120.8 (m, C-4),
2
1
121.5 (d, JCF 28.2, C-2), 143.3 (m, C-6), 148.1 (d, JCF 267,
C-3), 151.5 (m, C-5); m/z (EIϩ) 458 (Mϩ, 36%), 456 (Mϩ, 36),
443 (23), 441 (23), 69 (83), 41 (100).
X-Ray crystal structures.† All single crystal data were col-
lected on a Bruker SMART-CCD diffractometer (ω-scan, 0.3Њ/
frame) at 120.0(2) K using graphite monochromated Mo-Kα
radiation (λ = 0.71073 Å). The data were corrected for absorp-
tion and systematic errors using the SADABS procedure. The
structures were solved by direct method and refined by full-
matrix least squares on F 2 for all data using SHELXL
software.20
Crystal data for 4. C9H3Br2F8NO, M = 452.94, monoclinic,
space group P21/c, a = 10.446(2), b = 7.122(1), c = 17.251(4) Å,
β = 93.71(3)Њ, U = 1280.8(4) Å3, F(000) = 856, Z = 4, Dc = 2.349
mg mϪ3, µ = 6.424 mmϪ1. 12605 reflections (1.95 ≤ θ ≤ 27.5 Њ)
were collected yielding 2941 unique data (Rmerg = 0.032).
CF(CF3)2 group of the molecule is disordered over two posi-
tions which were refined with equal occupancy. Final wR2(F 2) =
0.1435 for all data (176 refined parameters), conventional
R(F) = 0.0528 for 2346 reflections with I ≥ 2σ, GOF = 1.008.
The largest peak on the residual map (1.341 e ÅϪ3) is located in
4-(1,2,2,2-Tetrafluoro-1-trifluoromethylethyl)-2-bromo-3-
methoxy-5-fluoro-6-(2-phenylethynyl)pyridine
17.
Sodium
methoxide (0.3 g, 5.9 mmol) in methanol (35 ml) and 13 (1.8 g,
4.0 mmol) gave 4-(1,2,2,2-tetrafluoro-1-trifluoromethylethyl)-2-
bromo-3-methoxy-5-fluoro-6-(2-phenylethynyl)pyridine 17 (1.0
g, 55%) as a yellow oil; bp >300 ЊC (Found: C, 42.6; H, 1.6; N,
2.8. C17H8BrF8NO requires C, 43.0; H, 1.7; N, 2.9%); δH 3.91
and 3.99 (3H, br s, CH3O), 7.3–7.5 (5H, m, ArH); δF (major
conformer B) Ϫ72.9 (6F, m, CF3), Ϫ109.6 (1F, m, F-5), Ϫ179.6
(1F, m, CFCF3); δF (minor conformer A) Ϫ72.9 (6F, m, CF3),
Ϫ112.0 (1F, d, 4JFF 89.9, F-5), Ϫ174.6 (1F, d, 4JFF 89.9, CFCF3);
m/z (EIϩ) 475 (Mϩ, 34%), 473 (Mϩ, 40), 325 (100), 262 (11), 256
(25), 237 (13).
A minor product, 4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-
ethyl)-2-bromo-3-fluoro-5-methoxy-6-(2-phenylethynyl)pyridine
18 (5% by 19F NMR integration) was observed in the crude
† CCDC reference numbers 167082 and 167083. See http://www.rsc.org/
suppdata/p1/b1/b105950p/ for crystallographic files in .cif or other
electronic format.
2794
J. Chem. Soc., Perkin Trans. 1, 2001, 2788–2795

View Article Online
5 R. D. Chambers and C. R. Sargent, Adv. Heterocycl. Chem., 1981,
28, 1 and references cited therein.
6 G. M. Brooke, J. Fluorine Chem., 1997, 86, 1 and references cited
therein.
7 K. J. Herd, in Organofluorine Chemistry. Principles and Commercial
Applications, eds. R. E. Banks, B. E. Smart and J. C. Tatlow, Plenum
Press, New York, 1994, p. 287.
8 R. E. Banks, W. Jondi and A. E. Tipping, J. Chem. Soc.,
Chem. Commun., 1989, 1268.
9 C. R. Johnson, B. Zhang, P. Fantauzzi, M. Hocker and K. M. Yager,
Tetrahedron, 1998, 54, 4097.
10 W. T. Flowers, R. N. Haszeldine and S. A. Majid, Tetrahedron Lett.,
1967, 2503.
11 H. Suschitzky and B. Iddon, in Polychloroaromatic Compounds,
ed. H. Suschitzky, Plenum, London, 1974, p. 197.
12 R. D. Chambers, J. Hutchinson and W. K. R. Musgrave, J. Chem.
Soc., 1964, 3736.
the vicinity of one of the bromine atoms and caused by termin-
ation errors.
Crystal data for 15. C14H13BrF8N2O, M = 457.17, monoclinic,
space group P21/c, a = 10.530(2), b = 13.802(3), c = 11.485(2) Å,
β = 90.86(3)Њ, U = 1669.1(4) Å3, F(000) = 904, Z = 4, Dc = 1.819
mg mϪ3, µ = 2.553 mmϪ1. 17323 reflections (1.93 ≤ θ ≤ 27.5Њ)
were collected yielding 3834 unique data (Rmerg = 0.028). The
CF(CF3)2 group of the molecule is severely disordered. Final
2
wR2(F ) = 0.1802 for all data (238 refined parameters), con-
ventional R(F) = 0.0692 for 3118 reflections with I ≥ 2σ, GOF =
1.118. The largest peak on the residual map is located in the
vicinity of the bromine atom and caused by termination errors.
Acknowledgements
13 Presented by the authors at the ACS 15th Winter Fluorine
Conference, St. Petersburg, Florida, USA, 2001.
14 R. D. Chambers, W. K. Gray and S. R. Korn, Tetrahedron, 1995, 51,
13167.
We thank the University of Durham (Studentship to PH) and
the Royal Society (University Research Fellowship to GS) for
financial support.
15 R. D. Chambers, C. W. Hall, J. Hutchinson and R. W. Millar,
J. Chem. Soc., Perkin Trans. 1, 1998, 1705.
16 R. D. Chambers, J. A. Jackson, W. K. R. Musgrave, L. H. Sutcliffe
and G. J. T. Tiddy, Tetrahedron, 1970, 26, 71.
17 J. Tsuji, Palladium Reagents and Catalysts. Innovations in Organic
Synthesis, Wiley-Interscience, New York, 1995.
18 M. I. Bruce, J. Chem. Soc. A., 1968, 1459.
19 M. R. Wiles and A. G. Massey, Tetrahedron Lett., 1967, 51, 5137.
20 G. M. Sheldrick, SHELXTL, Version 5/VMS, Bruker Analytical
X-Ray Instruments, 1995.
References
1 Part 46, see H. Benmansour, R. D. Chambers, G. Sandford,
G. McGowan, S. Dahaoui, D. S. Yufit and J. A. K. Howard,
J. Fluorine Chem., 2001, in press.
2 Comprehensive Heterocyclic Chemistry, Pergamon, eds. A. R.
Katritzky and C. W. Rees, Oxford, 1984, vols. 1–8.
3 I. Collins, J. Chem. Soc., Perkin Trans. 1, 2000, 2845.
4 V. Snieckus, Med. Res. Rev., 1999, 19, 342.
J. Chem. Soc., Perkin Trans. 1, 2001, 2788–2795
2795