Highly Functionalized Heterocycles and Macrocycles from

Chapter 13

Highly Functionalized Heterocycles and Macrocycles from Pentafluoropyridine

Downloaded by UNIV OF AUCKLAND on May 3, 2015 | http://pubs.acs.org Publication Date: July 21, 2005 | doi: 10.1021/bk-2005-0911.ch013

Graham Sandford Department of Chemistry, University of Durham, South Road, Durham, DH1 3LE, United Kingdom

Pentafluoropyridine is a synthetically versatile, pluripotent 'building block' which reacts sequentially with a variety of nucleophiles to provide a range of poly substituted pyridine and macrocyclic derivatives, with potential applications to the life science andsupramolecularfields.

248

© 2005 American Chemical Society

In Fluorine-Containing Synthons; Soloshonok, V.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005.


249 Highlyfluorinatedheteroaromatic systems are very susceptible towards nucleophilic attack and chemistry involving substitution offluorineby a variety of nucleophiles continues to emerge (i,2). In particular, the chemistry of pentafluoropyridine 1 has been widely studied (3) and many reactions involving the regioselective replacement of thefluorineatom located at the 4-position by a range of nucleophiles has been established (2,3). Reactions proceed by the familiar two-step nucleophilic aromatic substitution pathway involving Meisenheimer complexes as intermediates (4) (Scheme 1). Mono-substituted pyridines 2 are, of course, highly activated systems towards nucleophilic attack but the utility of such derivatives as substrates for the synthesis of more synthetically elaborate multi-substituted pyridine systems has not been developed to any great extent, despite the almost limitless range of new polyfunctional systems that could be accessed if several or allfluorineatoms present in 2 are replaced regioselectively. Reports describing the formation of a pentasubstituted system 3 from the reaction between pentafluoropyridine and sodium thiophenolate (5) gives an indication (Scheme 1) of the reactivity of the parent heterocycle and all intermediate fluoropyridines towards nucleophilic attack.

Polyfunctions! Pyridine Derivatives 1

3, quant

Scheme I. Nucleophilic aromatic substitution ofpentafluoropyridine Here, we discuss the use of pentafluoropyridine as a building-block for the synthesis of a variety of polyfunctional pyridines and macrocycles that may be obtained for applications in the life science industries and supramolecular chemistry by a sequence of nucleophilic aromatic substitution processes. A variety of highly halogenated heterocyclic derivatives are commercially available and, indeed, some are prepared on the industrial scale for use in the fibre reactive dye industry and as intermediates, e.g. 3,5-dichloro-2,4,6trifluoropyridine is a herbicide precursor manufactured by the Dow company (6). No special handling procedures are required for syntheses involving perfluoroheterocyclic derivatives and, consequently, the chemistry of perfluorinated heterocycles could readily be used by the general organic chemistry community and scaled up by industry.

Highly Substituted Pyridine Derivatives In the ongoing search for novel biologically active "lead" compounds, In Fluorine-Containing Synthons; Soloshonok, V.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005.


250 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. It is now widely accepted that molecules that are most likely to possess drug-like physiochemical properties that may be administered orally, fall within the empirical "rules of 5" described by Lipinski (7). Consequently, there is a continuing great need for the development of methodology that allows the ready synthesis of libraries of small molecules that may be screened against new and existing biological targets for the purpose of lead generation. The synthesis of libraries of Lipinski-type molecules is based upon the rapidly developing *privileged structures' strategy (#). Privileged structures are typically rigid polycyclic systems possessing a range of functionalities in a well defined structural system that can, potentially, interact with a variety of unrelated receptor sites and libraries of molecules that bear such privileged structures as sub-units have been targeted for drug discovery. Examples of privileged structures (9) that have been used for library generation (10) include benzamidines, indoles, sp/ro-piperidines, benzyl piperidines, benzopyrans (8) and various carbohydrates (11). An ideal privileged structure for lead generation must be easily synthetically manipulated to provide great structural diversity (8). Heteroaromatic systems have, of course, a vast chemistry (12) and are excellent candidates for privileged structures given the criteria stated above. A very significant number of pharmaceuticals and other life-science products are heteroaromatic derivatives and the existence of many natural products and drugs that contain heteroaromatic cores bearing several pendant substituents exemplify these facts. Furthermore, the low molecular weight of heteroaromatic units provide suitable platforms for the synthesis of molecules that fall within the Lipinski rules. Heteroaromatic derivatives may form the basis of polyfunctional core scaffolds but, in order to be valuable synthetic scaffolds, such systems must be easily synthesized in high yield and selectivity. However, the problems associated with the use of established synthetic procedures, such as low reactivity of heteroaromatics towards electrophiles and nucleophiles and low selectivity, are well known and, of course, restrict the variety of heteroaromatic derivatives that can berapidlysynthesized using this strategy. Methodology for the synthesis of ranges of structurally diverse heteroaromatic derivatives is, therefore, under continuing development and application of, for example, sequential electrophilic substitution and palladium catalyzed coupling reactions to the synthesis of many heterocyclic analogues (rapid analogue synthesis, RAS) has been reviewed recently (13,14). In order to synthesize large numbers of structurally diverse systems, the principles of the newly emerging field of Diversity Oriented Synthesis (15-17) may be considered. DOS is aimed at the synthesis of collections of many molecules having structural complexity and diversity rather than the synthesis of specific target molecules. Successful DOS takes a starting material buildingblock' that may undergo several complexity generating reactions in which the product of the first reaction acts as a substrate of the second (the so-called


251

'Librariesfromlibraries' approach). Further diversity may be introduced into a system by varying stereochemistry and the presence of'branch points' whereby a common substrate may be transformed into several products bearing different polyfunctional molecular skeletons. For both RAS and DOS strategies, however, the requirement for short, high yielding, regioselective and flexible routes to multiply functionalised heteroaromatic derivatives must be emphasized. A sequence of substitution processes involving the functionalisation of a heteroaromatic "core scaffold" is a strategy frequently employed and this idea is illustrated below (Scheme 2) in which pyridine is the parent of heterocyclic systems bearing up to five different substituents R\ - R . Our complimentary approach utilises pentafluoropyridine 1 as the starting material (Scheme 2).


5

Reactions R

Reactions - metallation/halogenation - electmphilic substitution - nucleophilic substitution - palladium catalysed coupling

2

- A :

Ν""

F

F

Rf

Applications - Rapid Analogue Synthesis - Parallel Synthesis - Lead Generation and Discovery

Ν

Ri - Rs * H, F, CI, Br, R, OR, NR , Ph, etc. 2

Scheme 2. Approaches to the synthesis ofpolysubstitutedpyridine deriva Consequently, we envisaged that a range of polyfunctional pyridine derivatives could be derivedfrompentafluoropyridine by a series of nucleophilic aromatic substitution processes. Furthermore, it is well established (1,2) that, in general, the order of activation towards nucleophilic attack follows the sequence 4-fluorine > 2-fluorine > 3-fluorine and so, for a succession of five nucleophilic substitution steps, where Nuci is the first nucleophile, Nuc2 is the second, etc., the order of substitution is potentially selective as outlined below (Scheme 3). However, a few exceptions to these general rules have been reported (18) and this general scheme for regioselectivity may be effected by the growing number of non-fluorine substituents present on the pyridine ring.

Nuc

Nuc

3

Nuc

4

5

Nuc

2

Scheme 3. Potential orientation of polysubstitution in pentafluoropyridine


252

At Durham, the viability of this idea was explored by first preparing perfluoro-4-isopropylpyridine 4 by nucleophilic substitution of the 4-fluorine atom by perfluoroisopropyl anion (i.e. Nuci = (CF ) CF", Scheme 3), generated in situfromhexafluoropropene and trimethylamine (19). A range of oxygen, nitrogen and carbon centred nucleophiles reacted with 4 (Scheme 4) to give diand tri-substituted products (Nuc and Nuc , Scheme 3) depending on the reaction stoichiometry and following the regiochemistry predicted earlier (20). 3 2


2

3

Reagents and Conditions: i, cyclohexanol (1 equiv.), NaH, THF, reflux, 2 MeO-C6H ONa (4 equiv.), THF, reflux, 24 h; Hi, CH OCH CH aNa"', THF, reflux, 24 h; iv, PhCH NHMe (1 equiv.), THF, reflux, 30 min; v, Et NH, THF reflux, 24 h; vi, BuLi (1 equiv.), Et O -78°C, 45 min ; vii, CH C=C-MgBr (1 equiv.), THF, reflux, 24 h. +

4

3

2

2

2

2

2

t

3

Scheme 4. Reactions ofperfluoro-4~isopropylpyridine 4 As we can see, 4 is a useful building block but, since reactions are limited to nucleophilic substitution processes, we sought to develop chemistry of other related core scaffolds that possessed more versatile functionality. Therefore, we synthesized 2,4,6-tribromo-3,5-difluoro-pyridine 5 and 2,6-dibromo-perfluoro4-isopropyl pyridine 6 in high yield by heating 1 and 4 with a mixture of hydrogen bromide and aluminium tribromide at 140°C respectively (21).


253

CF(CF )2 F HBr, AIBr h

ÇF(CF )2 .F 3

3

HBr, AIBr

F 3

CF =CF-CF3 2

Br

Ν

Br

140°C

140°C

Μθ Ν 3

5, 91%

4, 64%

3

Br^

Br 6,80%


Scheme 5. Synthesis of key bromo-fluoropyridine building blocks. We envisaged that not only would nucleophilic substitution of C-F and C-Br bonds be possible, but also the C-Br bonds could potentially be used for metallation, followed by trapping of the carbanion generated by an appropriate electrophile, and palladium catalysed coupling processes. Indeed, model polybromo-fluoro-heterocyclic derivative 5 reacts with a variety of nucleophiles and it was established (21) that Tiard' nucleophiles (e.g. oxygen centred nucleophiles) selectively replace fluorine whereas 'soft' nucleophiles (e.g., sulfur, nitrogen, etc.) selectively replace bromine (Scheme 6). Furthermore, debromo-lithiation of 5 occurs selectively at the 4-position and the resulting lithiated pyridine species was trapped by a variety of electrophiles (22) while palladium catalysed Sonogashira-type coupling reactions allowed the synthesis (23) of various alkynyl derivatives (Scheme 6).

Prf (72%)

7S°C-r.t.; ii, 78TC; Reagents and Conditions: i,(a) n-BuLi, Et 0,(b) EtOH, MeONa (1 equiv.) MeOH, r.t.; Hi, PhSNa, MeCN, reflux, 24 h; rv, Et NH, 5 3 d; v, Ph-C=C-H, Cul, Pd(Ph P) Cl , EtsN, r.t.; vi, (a) n-BuLi, Et 0, -78°C MesSiCl, -78°C - r.t; vii, ,(a)n-BuLi, Et 0, -78°C; (b) PhCOCl, -78°C - r.t.; viii, (a) n-BuLi, Et 0, -78°C; (b) C0 -78°C-r.t. 2

2

3

2

2

2

2

2

2f

Scheme 6. Reactions of2,4,6'tribromo-3,5-difluoropyridine 5


254

Of note is the palladium catalysed Sonagashira coupling reaction (reaction v, Scheme 6) which, upon addition of an excess of acetylene derivative provides 2,6-disubstituted pyridine systems (21). When 2-chlorophenylacetylene is used as the substrate, two different polymorphic, crystalline forms of product 7 may be engineered depending upon the solvent that is used as the crystal growth medium (Scheme 7).


Br

Scheme 7. Synthesis of 7 and crystal lattices of two polymorphs of 7. Carbanions may also be prepared in situfromthe perfluoroisopropyl pyridine derivative 6 and subsequent addition of the electrophilic heterocycle 4 furnishes (24) polyfiinctional bipyridine system 8. Bipyridine 8 reacts selectively with sodium methoxide to give product 9 arising from substitution of fluorine located ortho to ring nitrogen, rather than bromine (Scheme 8).

β

8, 20%

9, 79%

Scheme 8. Synthesis and reactions of bipyridine 8. With the reactivity profile of 5 in mind we were able to synthesize (23) representative examples of pyridine derivatives bearing five different substituents from key intermediate 6 (Scheme 9). The structures of the


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pentasubstituted products obtained were governed by the order of nucleophilic substitution. For example, reaction of 6 with methoxide followed by piperidine gave a 1:1 mixture of pentasubstituted products 9 and 10 rendering this particular route inappropriate for efficient analogue synthesis whereas 9 was obtained as the major product (structure of 9 confirmed by X-ray crystallography) by simply changing the order of nucleophilic substitution (piperidine followed by methoxide). Palladium catalysed Sonagashira coupling of 6 with phenylacetylene gives intermediate 11 which furnishes pentasubstituted pyridine derivative 12 upon reaction with methoxide. CF(CF )

3 2

F(CF ) F

3 2

Br

Ν

>^

MeOH

11,63%

Ph 12, 55%

Ph-C=C-H Pd (0) catalyst Cut, Et N 3

ÇF(CF ) 3

ÇF(CF ) F^ / k X 3

ΒΓ

Ν

Br

2

CF(CF )

2

3 2

+ 9

MeONa MeOH

β

Ν Br ^

Ν

Br

M e C N

62%

»

reflux

N^Br 10

Ratio 1:1,64% combinée!

piperidine MeCN reflux CF(CF ) /F

ÇF(CF )

3 2

F\ Br

Ν 83%

Ν

3

MeONa

2

F^L.ONte

MeOH 9,80%

Scheme 9. Synthesis ofpyridine derivatives that bearfivedifferent functionalities In summary, the sequential replacement of the fluorine atoms of pentafluoropyridine may be utilised for the synthesis of many multifunctional pyridine derivatives by reaction with the great number of nucleophilic species that are available. The application of the parallel synthesis techniques widely practised in the pharmaceutical industry would enable rapid access to a considerable number of pyridine analogues.


256


Macrocycles Polyfunctional building blocks are, of course, used for many applications such as the synthesis of polymers, dendrimers and biopolymers as well as for various applications in supramolecular chemistry. The synthesis and properties of macrocyclic derivatives has become a major research field (25-27) since the pioneering work of Pedersen (28) and Lehn (29), whose syntheses of crown ethers and cryptands respectively, and their observations of intermolecular complexation phenomena, has rapidly developed into the more general field of supramolecular and biomimetic chemistry. Furthermore, macrocyclic compounds are now used as sensors, imaging agents for MRI treatment, catalysts and for ion analysis (26), providing further stimuli for the development of this field. In particular, the incorporation of heteroaromatic subunits into a macrocyclic ring has been the focus of much attention due to the often unusual chemical, physical and biological properties of such systems. By a consideration of the reactivity of pentafluoropyridine 1 towards nucleophiles (Scheme 3), a versatile two step macrocyclic ring forming process may be envisaged, in which the ring is constructed by processes involving reactions with a variety of a difunctional nucleophiles (Scheme 10). This strategy offers, in principle, a general route to many structurally diverse macrocycles with specific function that is dependent upon, for example, structural variation and functionality of exocyclicringsubstituents.

Scheme 10. General strategy for the synthesis of macrocyclic derivatives pentafluoropyridine Syntheses of macrocycles that involve a nucleophilic aromatic substitution process as the ring forming step have not been widely adopted (30). However, macrocycles may be prepared upon reaction of 2,6-dihalopyridine building blocks with various polyethylene glycol derivatives (31J2), although yields could be low. Recently, in related processes, trichloro-s-triazine provided access to arangeof macrocyclic and cage derivatives (33-35). By adapting the chemistry described above (Scheme 4), perfluoro-4isopropylpyridine 4 was found to be an excellent building block for macrocycle


257


synthesis (36,37). Nucleophilic substitution reaction of 4 with di-oxyanions, prepared in situ from bis-trimethylsilyl derivatives of diols and catalytic quantities of fluoride ion, firstly gives a bridged system 13, in which two pyridine sub-units are connected by a polyether chain. Ring closure to macrocycle 14, which was characterized by X-ray crystallography, is readily achieved by addition of a further equivalent of dinucleophile (Scheme 11).

CF(CF ) 3

CF(CF )

2

3

13, 90%

2

14, 43%

Scheme 11. Synthesis and X-ray crystallographic structure of macrocycle 14 This stepwise methodology allows the synthesis of many structurally diverse macrocycles (Scheme 12)frompentafluoropyridine, depending upon the choice of nucleophile and di-nucleophile (37). By analogy to the synthesis outlined in Scheme 11,20-membered ring system 15 may be synthesized in two steps from 4 and a longer chain polyether linking unit. Variation of substituents that are present on the pyridine ring section of the macrocycle is very simple. For example, 16 is prepared from 1, an appropriate polyfluoroalcohol (Nuci = C6F13CH2CH2O", Scheme 10) and Ν,Ν'-dimethyethylene-diamine (Nuc , Nuc = MeNHCH CH NHMe, Scheme 10) in three stages while 17 is synthesized from 1, sodium methoxide and ethylene glycol by a similar procedure (38). Variation of the structural unit linking the two pyridine moieties is also readily achieved. For example, 18, in which the two pyridine rings are connected by different linking groups, is synthesized from 4, di-ethylene glycol (NucrNuc = 2

2

3

2

2


258

HOCH2CH2OCH2CH2OH, Scheme 10) and Ν,Ν'-dimethylethylene-diamine (Nuc -Nuc = MeNHCH CH NHMe, Scheme 10).


3

3

2

17

2

18

19

Scheme 12. Structurally diverse macrocycles derivedfrompentafluoropyr

Analysis by X-ray crystallography reveals that macrocycles 15 and 16 have some unusual structural features (Scheme 13). For 15, we would expect the two very bulky perfluoroisopropyl groups to occupy positions within the crystal lattice that are distant from each other. However, we observe that this is not the case and the macrocyclic ring buckles so that these two perfluorinated groups may occupy positions that are as close to each other as possible (Scheme 13). Inspection of the crystal lattice reveals that the individual molecules adopt headto-head positions which results in the presence offluorine-and hydrocarbon-rich 'domains' within the crystal, reflecting the solubility characteristics of fluorocarbon systems that has been used so effectively in fluorous phase chemistry (39,40). The segregation of perfluorinated 'domains' within the crystal lattice is also seen in the structure of macrocycle 16 in which the long perfluoroalkyl substituent groups overlap to formfluorine-richenvironments.



259

Scheme 13. Single crystal X-ray molecular structures of macrocycle IS (left crystal lattice showing head-to-head arrangement fright;fluorineatoms hav been removedfor clarity).

Mixing a solution of macrocycle 19 with a mixture of aqueous sodium chloride, bromide and iodide led to the observation of macrocycle/anion complexes by negative ion electrospray mass spectrometry. Whilst the number of macrocyclic derivatives that bind cations is now quite extensive, the number of macrocycles capable of anion recognition is considerably smaller. Systems that form complexes with anionic guests, such as polyammonium, guanidinium and pyrrole based systems (41) usually contain sites that are capable of directed hydrogen bonding, a situation that is not present in 19. However, recent theoretical studies have indicated that interactions between the centre of electron deficient heterocyclic rings, such as trifluoro-s-triazine, and anions are possible and this may provide a clue to the type of complexation occurring in these cases. In summary, pentafluoropyridine may be used for the construction of a variety of structurally diverse macrocycles by a sequence of nucleophilic aromatic substitution processes. The availability of perfluoroaromatic systems and a great many suitable difunctional nucleophiles makes the number of supramolecular systems that are available using this approach virtually limitless. The structural and complexation phenomena exhibited by just the relatively few systems that have been reported so far, indicate the fascinating opportunities that are provided by these multi-functional systems.


260


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Highly Functionalized Heterocycles and Macrocycles from

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