Ojima I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology

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Perﬂ uorinated Heteroaromatic Systems as Scaffolds for Drug Discovery 297

(e.g. O - , N - , C - , S - centred) makes the theoretical number of highly functionalized pyridine

ring systems that could be accessed by this methodology very large indeed if the sequence

of nucleophilic aromatic substitution processes can be achieved in a controllable manner.

Surprisingly, however, the number of sequential nucleophilic substitution processes using

pentaﬂ uoropyridine as the starting material is very small despite the potential reactivity

of these systems, but the few examples reported so far demonstrate the viability of the

potential use of this substrate as a scaffold in the manner indicated in Figure 11.4 . For

example, as shown in Figure 11.5 , heating 4 - methoxytetraﬂ uoropyridine 5 with an excess

of sodium methoxide in methanol gave the 2,4,6 - trimethoxypyridine derivative 6 [30] . In

a controlled stepwise process, perﬂ uoro - 4 - isopropylpyridine 7 , prepared by nucleophilic

substitution of the 4 - ﬂ uorine atom of pentaﬂ uoropyridine by perﬂ uoroisopropyl anion

(i.e. Nuc

= (CF

)

−

, Figure 11.4 ), generated in situ from hexaﬂ uoropropene and

TDAE [31] , subsequently gave trisubstituted products 8 (Nuc

and Nuc

, Figure 11.4 ) by

reaction with a range of oxygen - , nitrogen - and carbon - centred nucleophiles (see Figure

11.5 ) [32] .

The reactivity proﬁ le established for pentaﬂ uoropyridine, where the 4, 2 - and 6 -

positions are sequentially, regiospeciﬁ cally substituted by a succession of oxygen - centred

nucleophiles, has allowed medicinal chemists to use pentaﬂ uoropyridine as a core scaffold

for the synthesis of small arrays of biologically active pyridine systems that fall within

the Lipinski parameters (see Table 11.3 ).

The factor VIIa/TF (tissue factor) complex and Xa are proteins known to be involved

in the blood coagulation cascade [33] and, as such, are validated targets in the search

for novel antithrombotic drugs [34, 35] . Having established that a series of 2,6 -

diphenoxypyridines, including several 3,5 - diﬂ uoro - 4 - methyldiaryloxypyridines derived

from 4 - methyltetraﬂ uoropyridine, to be modest inhibitors of factor Xa, medicinal chemists

synthesized a small library of 3,5 - diﬂ uorotriaryloxypyridines 9 from pentaﬂ uoropyridine

[36] . The 2,4,6 - substitution pattern was obtained through sequential nucleophilic aromatic

substitution by substituted phenols in typically high yields and polysubstitution could

often be accomplished in a single reaction vessel. Systems derived from this series of

2,6 - diphenoxypyridines served as a basis for creating a more potent system, leading to the

potent FVIIa/TF inhibitor 10 , formed by reaction of a sequence of nitrogen, oxygen and

oxygen - centred nucleophiles.

Figure 11.5 Polysubstituted products from pentaﬂ uoropyridine [30, 32] .

CF(CF

)

CF(CF

)

O O

=CF-CF

TDAE, MeCN

OCH

THF, reflux, 24 h

NMeO

OMe

OMeNF

OMe

MeONa, MeOH

6, 74%

7, 76%

8, 76%

298 Fluorine in Medicinal Chemistry and Chemical Biology

It is thought that inhibition of the p38 kinase protein could treat the underlying cause

of chronic inﬂ ammatory diseases, and it is in this context that chemists in Switzerland

prepared a diverse set of aryl - substituted pyridinylimidazoles 11 to achieve potentially

high - afﬁ nity binding to the active site [37] . Deprotonation of the SEM (2 - [trimethylsilyl]

ethoxymethyl) - protected imidazole gave a carbanion that reacted as a nucleophile with

pentaﬂ uoropyridine to give the expected 4 - substituted pyridine. Bromination at the 4 -

and 5 - positions of the imidazole was followed by regioselective Stille reaction to yield a

pyridinylimidazole derivative, while subsequent Suzuki or Stille coupling at the remaining

carbon – bromine bond was followed by deprotection of the imidazole. Finally, diamination

Table 11.3 Biologically active polysubstituted systems synthesized from

pentaﬂ uoropyridine

Perﬂ uorinated Heteroaromatic Systems as Scaffolds for Drug Discovery 299

at the 2 - and 6 - positions of the tetraﬂ uoropyridine gave the desired biologically active

3,5 - diﬂ uoropyridine system 11 .

11.2.2 Tetraﬂ uoropyrimidine as a Core Scaffold

Perﬂ uorinated diazines (pyrimidine, pyrazine and pyridazine) are typically 1000 times

more reactive towards nucleophiles than is pentaﬂ uoropyridine and application of the

sequential nucleophilic substitution methodology to reactions involving various diazine

systems with a range of nucleophiles would, in principle, lead to the synthesis of many

novel polyfunctional diazine derivatives. However, only a very limited number of reports

concerning reactions of perﬂ uorinated diazines with nucleophiles have been published [25,

26] and the use of tetraﬂ uorodiazines as scaffolds has not been developed to any great

extent. Several instances of reactions of tetraﬂ uoropyrimidine 12 (Table 11.4 ) with a small

range of nucleophiles have been reported [38] and, in all cases, nucleophilic substitution

occurs selectively at the 4 - position. A recent systematic study of reactions of the 4 -

aminopyrimidine systems (see Table 11.4 ) found that second and third substitution

processes occurred selectively at the 6 - and 2 - positions, respectively, giving ready access

to a small array of 5 - ﬂ uoro trisubstituted pyrimidine derivatives 13 [39] .

11.2.3 Perbromoﬂ uoropyridine Scaffolds

Clearly, the range of nucleophiles that is available, the functionality that could be installed

(for example upon a pyridine or pyrimidine ring) and, of course, the functional groups on

pendant substituents may, in principle, allow access to a great variety of polyfunctional

pyridine analogues. However, despite this, the reactions outlined above are restricted to a

sequence of nucleophilic substitution processes, thereby limiting the variety of structural

arrays that can be synthesized from such perﬂ uorinated core scaffolds. Consequently,

related perhalogenated scaffolds that have more ﬂ exible functionality may be advanta-

geous and, in this context, 2,4,6 - tribromo - 3,5 - diﬂ uoropyridine 14 , synthesized by reaction

of pentaﬂ uoropyridine with a mixture of hydrogen bromide and aluminium tribromide in

an autoclave at 140 ° C [40] was assessed as a potential polyfunctional scaffold system (see

Figure 11.6 ). In a series of model reactions it was established that the bromoﬂ uoropyridine

system reacts with “ hard ” nucleophiles (e.g. oxygen - centred nucleophiles) to give products

15 arising from selective replacement of ﬂ uorine, whereas “ soft ” nucleophiles (sulfur,

nitrogen, etc.) selectively replace bromine to give product 16 [40] . The presence of

carbon – bromine bonds on this scaffold allows Pd - catalysed Sonogashira [41] and Suzuki

[42] coupling reactions to occur giving, for example, 17 , and selective debromo - lithiation

at the 4 - position followed by trapping of the lithiated pyridine species [43] by a variety

of electrophiles, giving access to a wide range of polyfunctional pyridine systems 18 that

could be utilised as scaffolds in their own right. Subsequently, a combination of nucleo-

philic aromatic substitution and Pd - catalysed Sonogashira reactions involving pentaﬂ uo-

ropyridine as the core scaffold has enabled the synthesis of several pentasubstituted

pyridine systems such as 19 and 20 [44] (see Figure 11.6 ).

300 Fluorine in Medicinal Chemistry and Chemical Biology

11.2.4 Polyfunctional Fluorinated [5,6] - and [6,6] - Bicyclic

Heteroaromatic Scaffolds

Bicyclic nitrogen heterocyclic systems can have a range of very valuable biological

activity and there are several examples of [5,6] - and [6,6] - ring - fused systems in which a

ring - fused pyridine motif is a constituent part (see Figure 11.2 ). However, many bicyclic

nitrogen - containing heterocycles remain surprisingly inaccessible [23] despite the relative

simplicity of their molecular structures, and the chemistry of even the least complex

heterocycles of this class remains largely unexploited. Inevitably, this provides great

opportunities for the discovery of new small - molecule chemical entities that fall within

Table 11.4 Tetraﬂ uoropyrimidine as a core scaffold [39]

Perﬂ uorinated Heteroaromatic Systems as Scaffolds for Drug Discovery 301

the RO5, if suitable polyfunctional, bicyclic, nitrogenated heterocyclic scaffolds can be

reliably accessed.

In this context, a polyﬂ uorinated imidazopyridine system 21 has been prepared by a

multistep synthetic route (see Figure 11.7 ) beginning from 3 - chlorotetraﬂ uoropyridine 22 ,

via the formation and subsequent condensation of 3,4 - diamino - 2,5,6 - triﬂ uoropyridine with

diethoxymethyl acetate [45] . Subsequent reaction of the ring - fused system with ammonia

demonstrated the potential of such systems as polyfunctional scaffolds, if much shorter

Figure 11.6 Perﬂ uorobromopyridine derivatives as core scaffolds [40 – 44] .

NBr

14, 91%

HBr, AlBr

140

MeONa

MeOH, r.t.

NBr

OMe

15, 70%

SPh

NBr

16, 85%

PhPh

17, 72%

18, E = H, SiMe

H, PhCO

PhSNa, MeCN,

reflux, 24 h

(a) BuLi, Et

O, -78

(b) E

, -78

C - r.t.

Ph-C=C-H, CuI,

Pd(Ph

N, r.t.

NBr

CF(CF

)

MeONa

MeOH

CF(CF

)

OMe

Piperidine

MeCN, reflux

CF(CF

)

OMe

62%

19a : 19b, 1:1, 64% combined

Ph-C=

C-H

Pd (0) catalyst

CuI, Et

NBr

CF(CF

)

63%

MeONa

MeOH

MeO

CF(CF

)

20, 55%

NBr

CF(CF

)

OMe

Piperidine

MeCN

reflux

NBr

CF(CF

)

83%

MeONa

MeOH

19b, 80%

+ 19b

1) CF

=CF-CF, TDAE

2) HBr, AlBr

, 140

19a

302 Fluorine in Medicinal Chemistry and Chemical Biology

synthetic sequences for the preparation of a range of these structural core scaffolds could

be developed.

A convenient synthetic strategy for the synthesis of polyﬂ uorinated polycyclic ring

scaffolds involving reaction of pentaﬂ uoropyridine with bifunctional nucleophiles could,

in principle, provide access to a wide range of polyfunctional systems (see Figure 11.8 ).

Here, for example, substitution of the 4 - position of the pentaﬂ uoropyridine scaffold would,

in principle, be followed by attack at the adjacent 3 - position owing to the geometric con-

straints of the system to give appropriate ring - fused systems 23 . The bicyclic scaffold

possesses further sites that are activated towards nucleophilic attack and could, therefore,

provide approaches to the synthesis of a wide variety of functional fused ring systems 24 ,

if the orientation of subsequent nucleophilic substitution processes could be controlled.

However, initial attempts to use this strategy to prepare azapurine derivatives, by

reaction of pentaﬂ uoropyridine and either guanidine or thiourea, led to 4 - aminopyridine

25 and bispyridyl derivatives 26 respectively via base - induced elimination processes [46]

(see Figure 11.9 ).

In these cases, while nucleophilic substitution at the 4 - position of pentaﬂ uoropyridine

by guanidine could be achieved readily [46] , attack at the less activated 3 - position by the

weak NH

nucleophile present on the guanidine moiety made cyclization a less favoured

process than elimination. Consequently, in order to achieve cyclization by nucleophilic

substitution in the second step, a more reactive second nucleophile is necessary.

Figure 11.7 Synthesis of imidazopyridine systems 21 from 3 - chlorotetraﬂ uoropyridine 22 .

ClF

F F

ClF

F F

10 % Pd / C

NEt

, H

NHNO

F F

KNO

Raney Ni

, EtOH

Figure 11.8 Strategy for the synthesis of ring - fused heterocycles from pentaﬂ uoropyridine.

1) Nuc

2) Nuc

Nuc

4232

Nuc

Nuc Nuc

Perﬂ uorinated Heteroaromatic Systems as Scaffolds for Drug Discovery 303

Pentaﬂ uoropyridine and several nucleophilic model difunctional secondary diamines,

such as N,N ′ - dimethylethylene diamine 27a , gave pyrido[3,4 - b ]pyrazine systems 28 in a

two - step one - pot annelation reaction, upon reﬂ ux or microwave heating [47] (see Table

11.5 ). The chemistry of tetrahydropyrido[3,4 - b ]pyrazine systems is relatively undeveloped

because of the difﬁ cult, low - yielding multistep syntheses, either from diaminopyridine

[48] or chloroaminopyridine [49] precursors or by reduction of pyrido[3,4 - b ]pyrazine

derivatives by metal hydrides [50 – 55] , which are required to prepare even the simplest

member of this heterocyclic class. Indeed, for the synthesis of appropriate multisubstituted

scaffold systems based upon the tetrahydropyrido[3,4 - b ]pyrazine subunit, this difﬁ cult

situation is magniﬁ ed further. Less - nucleophilic primary diamine nucleophiles such as

27b gave only noncyclized products 30 arising from substitution of the 4 - position of

pentaﬂ uoropyridine.

The pyrido[3,4 - b ]pyrazine scaffold reacted with a series of nucleophiles to give major

products arising from substitution at the 7 - position [47] . Although this process was not

regiospeciﬁ c, the alkoxylated scaffold could be isolated and puriﬁ ed by column chroma-

tography from the minor isomer that was formed by substitution of the ﬂ uorine atom

located at the 5 - position.

The triﬂ uorinated scaffold reacts preferentially at the 7 - position with some product

arising from competing substitution at the 5 - position and this selectivity is due to the

activating inﬂ uence of ring nitrogen and maximizing of the number of activating ﬂ uorine

atoms that are ortho to the site of attack (see Figure 11.10 ). The diﬂ uorinated scaffolds

are still activated towards nucleophilic attack and a short series of ﬂ uoropyrido[3,4 -

b ]pyrazines 29 has been synthesized in which the remaining ﬂ uorine atoms that are located

ortho to pyridine nitrogen were displaced [47] .

By a similar strategy, an imidazopyridine scaffold 32 was synthesized by reaction of

pentaﬂ uoropyridine and benzamidine 31 [56] and, in this case, subsequent nucleophilic

substitution occurs at the 5 position to give 33 , presumably because of interaction of the

nucleophile and the imidazo ring NH bond which directs the incoming nucleophile to the

less activated site adjacent to pyridine ring nitrogen.

This overall synthetic strategy (see Figure 11.8 ) was adapted to give a range of

isomeric pyrido[2,3 - b ]pyrazines structures 34 by simply varying the order of reaction

with appropriate mono - and difunctional nucleophiles [57, 58] (see Table 11.6 ).

For example, reaction of sodium phenylsulﬁ nate with pentaﬂ uoropyridine gives the

Figure 11.9 Reactions of pentaﬂ uoropyridine with urea and guanidine systems [46] .

F F

NaH

64 %

NaH

Sulpholane

NEt

, 80 - 200

N S N

F F

FF F F

25, 38%

26, 71%

Table 11.5 Synthesis of pyrido[3,4 - b ]pyrazine and imidazopyridine scaffolds [47, 56]

Figure 11.10 Regioselectivity of nucleophilic substitution of pyrido[3,4 - b ]pyrazine and

imidazopyridine scaffolds [56] .

F F

ctivated by

ortho ring N

ortho F

meta F

Activated by:

ortho ring N

meta F

Deactivated by:

para F

F F

Activated by:

ortho ring N

Directed by NH

Perﬂ uorinated Heteroaromatic Systems as Scaffolds for Drug Discovery 305

Table 11.6 Synthesis of pyrido[2,3 - b ]pyrazine scaffolds [57, 58]

306 Fluorine in Medicinal Chemistry and Chemical Biology

Figure 11.11 Reaction of 4 - cyanotetraﬂ uoropyridine with amidines [56] .

NaHCO

MeCN

N NH

N Ph

F F

.HCl

36, 20% 37, 5%

N Ph

F F

F N

··

F F

H H

reflux, 4 d

NaHCO

MeCN

N Ph

N F

.HCl

38, 58%

reflux, 4 d

4 - phenylsulfonylpyridine derivative and, since the phenylsulfonyl group is strongly

electron withdrawing, annelation by reaction with appropriate diamines proceeded

readily to give pyrido[2,3 - b ]pyrazine scaffolds [57, 58] . In addition, 4 - bromo - and 4 -

cyanotetraﬂ uoropyridine systems gave the corresponding pyrido[2,3 - b ]pyrazines, 34f and

34g respectively, upon reaction with N,N ′ - dimethylethylene diamine [58] .

However, not all tetraﬂ uoropyridine derivatives were suitable substrates for the

synthesis of pyrido[2,3 - b ]pyrazine scaffolds by analogous annelation reactions [58] . The

4 - ethoxy and 4 - dimethylaminotetraﬂ uoropyridine systems gave only noncyclized products

34h and 34i , respectively, arising from substitution of the 2 - position. However, the 4 - nitro

derivative led to the formation of a mixture of products 34j, k arising from substitution

of both the 2 - ﬂ uorine and 4 - nitro group, which is itself a very labile leaving group in

nucleophilic aromatic substitution processes [58] .

Additionally, 4 - cyanotetraﬂ uoropyridine 35 reacts with amidines [56] to give a

mixture of products 36 and 37 arising from substitution of ﬂ uorine at both the 2 - and

3 - positions in a 1 : 1 ratio (see Figure 11.11 ). The product derived from 3 - substitution and

subsequent cyclization onto the cyano group, reﬂ ects the activating inﬂ uence of the

strongly electron - withdrawing cyano group on adjacent heteroaromatic carbon sites and

the electrophilicity of the cyano group itself. An excess of the amidine leads to high yields

of 38 [56] .

Preliminary reactions involving scaffold 39 derived from 1,2 - diaminoethane with

nitrogen and sulfur nucleophiles led to products 40 arising from substitution of the phe-

nylsulfonyl group, a very good leaving group that is located at an activated site para

to pyridine nitrogen, and reaction of acetic anhydride gave selective acylation yielding

41 (see Figure 11.12 ), indicating some of the possibilities for functionalization of these

bicyclic scaffolds [57] .

In an application of this annelation strategy to a medicinal chemistry project, tricyclic

2 - pyridone 42 was synthesized using pentaﬂ uoropyridine as the core scaffold and all but

one of the ﬂ uorine atoms were displaced in a multistep process in which a carbon – oxygen

centred difunctional nucleophile is used as the annelating reagent (see Figure 11.13 ).