Multi-substituted heterocycles

Article abstract of DOI:10.1016/S0022-1139(01)00480-8

Pentafluoropyridine was used as the starting material for the preparation of a range of pyridine derivatives that bear five different substituents. In this context, syntheses of penta-functional pyridine systems by sequences of nucleophilic aromatic substitution, palladium catalysed coupling and bromo-lithiation processes are described.

Full text of DOI:10.1016/S0022-1139(01)00480-8

Journal of Fluorine Chemistry 112 ?2001) 133±137
Multi-substituted heterocycles
Hadjar Benmansour, Richard D. Chambers*, Philip R. Hoskin, Graham Sandford*
Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK
Abstract
Penta¯uoropyridine was used as the starting material for the preparation of a range of pyridine derivatives that bear ®ve different
substituents. In this context, syntheses of penta-functional pyridine systems by sequences of nucleophilic aromatic substitution, palladium
catalysed coupling and bromo-lithiation processes are described. # 2001 Elsevier Science B.V. All rights reserved.
Keywords: Heterocycles; Heteroaromatic systems; Penta¯uoropyridine
1. Introduction
paration of many analogue derivatives of poly-functional
heterocyclic systems.
Heteroaromatic systems have, of course, a vast chemistry
[1] and a great number of pharmaceuticals, materials and
life-science products are heterocyclic derivatives. In the
ongoing search for novel biologically active ``lead'' com-
pounds, the life-science industries have extensive discovery
programmes focused upon the synthesis of a wide range of
structurally diverse, multi-functional systems that, ideally,
can be accessed by parallel synthesis methodologies. A
particular target is the development of procedures for the
synthesis of a variety of poly-substituted heteroaromatic
derivatives that bear several different functionalities and,
therefore, methodologies for the transformation of unsub-
stituted heterocyclic systems to poly-substituted derivatives
is under constant development. This idea is illustrated in
Scheme 1 in which pyridine is the parent of heterocyclic
systems bearing up to ®ve different substituents R1±R5.
The challenges involved in the synthesis of analogues of
multi-substituted heteroaromatic systems have been
reviewed by Collins [2] and Snieckus [3] recently and the
problems associated with the use of established synthetic
procedures such as low reactivity of heteroaromatics
towards electrophiles and nucleophiles and low selectivity,
have been discussed. Furthermore, effective synthetic stra-
tegies for the drug discovery arena should ideally be short
synthetic sequences that are high yielding, selective and
amenable to parallel synthesis which allow the rapid pre-
Our approach towards the synthesis of highly functiona-
lised heteroaromatic derivatives utilises per¯uorinated het-
erocyclic systems as starting materials.
We chose penta¯uoropyridine as a suitable `building
block' for the construction of multi-functional pyridine
derivatives because this system is very susceptible towards
nucleophilic attack and so, in principle, all ®ve ¯uorine
atoms may be substituted by an appropriate nucleophile.
Furthermore, it is well established [4,5] that, in general, the
order of activation towards nucleophilic attack follows the
sequence 4-fluorine > 2-fluorine > 3-¯uorine. Therefore,
for a succession of ®ve nucleophilic substitution processes,
where Nuc1 is the ®rst nucleophile, Nuc2 the second, etc.,
the order of substitution is predicted to be selective as
outlined in Scheme 2.
However,reactionsofper¯uoroheterocyclesareprincipally
those of nucleophilic substitution processes. Therefore, we
sought to identify related perhalo-heterocyclic systems that
could be suitable, more synthetically versatile start materials
and we envisaged that related bromo¯uoro-heterocyclic deri-
vatives such as 1 and 2, would be effective starting materials
for poly-functionalisation. The Durham group has previously
established[6]thatinreactionsof1, ``hard''nucleophilessuch
as oxyanions selectively replace ¯uorine whereas ``soft''
nucleophiles replace bromine ?Scheme 3). Furthermore, the
presence ofbrominesubstituentsshould allow variousbromo-
metallation and palladium catalysed processes to be per-
formed,thusextendingtherangeofselectivefunctionalisation
reactions possible on these systems.
* Corresponding authors. Tel.: ‡44-191-374-4639;
fax: ‡44-191-384-4737.
In this presentation, we describe our results which outline
syntheses of penta-substituted pyridine systems derived
originally from penta¯uoropyridine.
E-mailaddresses : graham.sandford@durham.ac.uk,
r.d.chambers@durham.ac.uk ?R.D. Chambers).
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ? 0 1 ) 0 0 4 8 0 - 8

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H. Benmansour et al. / Journal of Fluorine Chemistry 112 '2001) 133±137
Scheme 1. Penta-functional pyridine derivatives.
Scheme 4. Reagents and conditions: ?i) HBr, AlBr3, 1408C, 24 h; ?ii)
CF2=CF±CF3, NMe3, 608C.
bromine can also occur to give the trimethoxylated product 5
on prolonged heating in methanol. In contrast, bromine is
selectively replaced by `softer' nitrogen nucleophiles
because 6 was obtained from reaction between 2 and
piperidine. Therefore, the selectivity of the nucleophilic
substitution processes involving perbromo¯uoro-hetero-
cycles is controlled, quite simply, by the nature ?`hard' or
`soft') of the nucleophile.
In order to widen the range of selective functionalisation
reactions possible for bromo¯uoro-heterocycles 1 or 2
beyond nucleophilic aromatic substitution processes, we
next focussed our attention on the use of the bromine
substituents as functional groups in various metallation
and palladium catalysed processes.
Pyridyl lithium derivative 7, which was prepared in situ by
adding n-butyl lithium solution to 2 in THF at low tem-
perature, was trapped by a variety of electrophiles such as
protons ?from ethanol) and trimethylsilyl ?from trimethylsi-
lyl chloride) to give 8 and 9, respectively ?Scheme 6).
However, reaction of lithio derivative 11 with acetyl
chloride was not as straightforward because, in this case,
the di-pyridyl system 10 was isolated as the major product
?Scheme 7). Initial reaction of lithio derivative 11 with
acetyl chloride gives the expected ketone 12 as an inter-
mediate ?Scheme 7) but, here, the carbonyl group is very
activated towards nucleophilic attack due to the presence of
the highly electron withdrawing pyridine ring and further
reaction involving nucleophilic attack by 11 at the carbonyl
Scheme 2.
2. Results and discussion
Bromo¯uoro-heterocycles 1 and 2 were prepared as
shown in Scheme 4. Per¯uoroalkylation of penta¯uoropyr-
idine was achieved by reaction with hexa¯uoropropene and
a tertiary amine, following methodology previously estab-
lished by the Durham group [7]. Brominations of penta-
¯uoro- and per¯uoro-4-isopropyl-pyridine were carried out
[6] by heating each substrate with an excess of hydrogen
bromide gas and aluminium tribromide in an autoclave at
1408C giving 1 and 2, respectively.
We investigated reactions of bromo¯uoropyridine deriva-
tive 2 with both `hard' and `soft' nucleophiles ?Scheme 5).
Substitution of ¯uorine by the relatively hard methoxide
nucleophile occurs in 2 selectively to give the mono- and di-
methoxylated derivatives 3 and 4 upon reaction with 1.5 and
3.0 equivalents of sodium methoxide, respectively. How-
ever, if an excess of methoxide is used, replacement of
Scheme 3.

H. Benmansour et al. / Journal of Fluorine Chemistry 112 '2001) 133±137
135
Scheme 5. Reagents and conditions: ?i) NaOMe ?1.5 eq.), MeOH, reflux,
24 h; ?ii) NaOMe ?3 eq.), MeOH, reflux, 24 h; ?iii) NaOMe ?6 eq.), MeOH,
reflux, 24 h; ?iv) piperidine ?2 eq.), MeCN, 808C, 24 h.
Scheme 7. Reagents and conditions: ?i) n-BuLi ?1.2 eq.), THF, À788C; ?ii)
CH3COCl, À788C to RT.
site occurs to give oxyanion 13 which, in turn, is acetylated
to give product 10.
By an analogous bromo-metallation process, difunctio-
nalisation can also be achieved by addition of excess n-BuLi
to 2 which may generate a dianion equivalent 14 that can be
trapped by, for example, trimethylsilyl chloride giving 15
?Scheme 8).
Palladium catalysed coupling processes involving halo-
heterocyclic derivatives have found many applications in
organic synthesis [8] and we are interested in developing the
use of such methodology for use in organo¯uorine chem-
istry. Bromo-heteroycles 1 and 2 were used as model
compounds in the development of various palladium cata-
lysed processes and in Scheme 9, our initial results in this
area are outlined. Sonogashira-type coupling processes gave
mono- or bis-alkylethynyl products depending on reaction
conditions. For example, reaction of 2 with one equivalent of
pentyne and a Pd?0) catalyst gave predominantly the mono-
alkylethynyl derivative 16 whereas reaction of 2 with two
equivalents of phenylacetylene and a Pd?0) catalyst gave the
bis-phenylethynyl system 19 as the major product. In related
processes, Suzuki coupling of 4-methylboronic acid with 2
gave the di- and tri-phenylated systems 20 and 21.
A combination, therefore, of nucleophilic substitution and
palladium catalysed processes leads readily to a variety of
pyridine derivatives such as 6 and 18 which bear four
different ring substituents. Synthesis of penta-derivatised
pyridine systems was achieved by reaction of, for example, 6
and 18 with sodium methoxide ?Scheme 10). Although these
reactions were not entirely regioselective, the major pro-
ducts 22 and 23 were isolated in good yield by column
Scheme 6. Reagents and conditions: ?i) n-BuLi ?1.2 eq.), THF, À788C; ?ii)
excess EtOH, À788C to RT; ?iii) Me3SiCl ?4 eq.), À788C to RT.
Scheme 8. Reagents and conditions: ?i) n-BuLi ?2.4 eq.), THF, À788C; ?ii)
Me3SiCl, À788C to RT.

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H. Benmansour et al. / Journal of Fluorine Chemistry 112 '2001) 133±137
Scheme 9. Reagents and conditions: ?i) pent-1-yne ?2 eq.), CuI, Pd?OAc)2, PPh3, Et3N, RT, 3 days; ?ii) phenylacetylene ?2 eq.), CuI, ?Ph3P)2PdCl2, Et3N, RT,
16 h; ?iii) p-CH3±C6H4±B?OH)2, Ba?OH)2 ?2 eq.), Pd?PPh3)4, monoglyme, reflux; ?iv) p-CH3±C6H4±B?OH)2, Ba?OH)2 ?3.5 eq.), Pd?PPh3)4, monoglyme,
reflux.
Scheme 10. Reagents and conditions: ?i) NaOMe ?1.7 eq.), MeOH, reflux, 24 h.
chromatography and identi®ed by a combination of NMR
spectroscopy and single crystal X-ray analysis.
used to access a great range of multi-functional heterocyclic
systems all originally derived from highly ¯uorinated het-
erocyclic starting materials.
In summary, in this presentation we have shown that
penta¯uoropyridine may be used as a starting material for
short, ef®cient and potentially ¯exible syntheses of pyridine
derivatives that bear ®ve different substituents. A sequence
of nucleophilic substitution, novel palladium catalysed cou-
pling and bromo-metallation processes could, therefore, be
Acknowledgements
We thank the University of Durham ?studentship to PH),
the European Union TMR Scheme ?studentship to HB) and

H. Benmansour et al. / Journal of Fluorine Chemistry 112 '2001) 133±137
137
[3] V. Snieckus, Med. Res. Rev. 19 ?1999) 342.
the Royal Society ?University Research Fellowship to GS)
for ®nancial support.
[4] R.D. Chambers, C.R. Sargent, Adv. Heterocycl. Chem. 28 ?1981) 1.
[5] G.M. Brooke, J. Fluorine Chem. 86 ?1997) 1.
[6] R.D. Chambers, C.W. Hall, J. Hutchinson, R.W. Millar, J. Chem. Soc.,
Perkin Trans. 1 ?1998) 1705.
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