introduction to 1,8-naphthyridines -...

CHAPTER-I PART-C

Introduction

to

1,8-Naphthyridines

Introduction to 1,8-Naphthyridines

50

1. 1, 8-NAPHTHYRIDINES

Naphthyridine is the name commonly given to the fused-ring system

resulting from the fusion of two pyridine rings through two adjacent carbon

atoms, each ring thus containing only one nitrogen atom. The first

naphthyridine derivative was obtained and named by Arnold Reissert 18931 as

the pyridine like analogue to naphthalene. There are six different types of

naphthyridines which are defined through the position of the nitrogen atoms in

the bicyclic system (1-6).

N

N

N

N

N

N

N N

N

N

N N

1 2 3

4 5 6

1,5-Napthyridine 1,6-Napthyridine 1,7-Napthyridine

1,8-Napthyridine 2,6-Napthyridine 2,7-Napthyridine

The first unsubstituted naphthyridines synthesized, 1,5-naphthyridine2

and 1,8-naphthyridine3

were published in 1927 by Bobranski, Suchard and

Koller. 1,6-Naphthyridine, 1,7-naphthyridine and 2,7-naphthyridine were

reported by Ikekawa in 1958.4

2,6-Naphthyridine was independently reported

by Gicacomello et al and Tan et al in 1965.5

Among different types of naphthyridines, 1,8-naphthyridine derivatives

have received significant attention due to their exceptionally broad spectrum

of biological activity. The 1,8-naphthyridine skeleton is present in many


51

compounds that have been isolated from natural substances, with wide

spectrum of biological activities such as antibacterial,6-8

antimycobacterial,9

antitumor,10

anti-inflammatory,11

antiplatelet,12,13

gastric antisecretary,14

antiallergic,15

local anaesthetic,16

anti-HIV,17

anticancer,18

and benzodiazepine

receptor activity.19

Nalidixic acid (7), for example, possesses strong

antibacterial activity and used mainly for the treatment of urinary tract

infections with gram negative pathogens.20

In addition, Gemifloxacin (8) is an

oral broad-spectrum quinolone antibacterial agent used in the treatment of

acute bacterial exacerbation of chronic bronchitis and mild-to-

moderate pneumonia.21

One recent study showed that Gemifloxacin possess

anti-metastatic activities against breast cancer in vitro and in vivo (in mice).22

It is known that (E)- and (Z)-O-(diethylamino)ethyl oximes of 1,8-

naphthyridine series (9) are potential drugs for local anaesthesia23

and 1-(2-

fluorobenzyl)-3-(2-tolyl)-1,8-naphthyridin-2(1H)-one (10) is used for the

treatment of memory disorders, in particular, Alzheimer’s disease.24

2-Amino-

N-hydroxy-1,8-naphthyridine-3-carboxamidine (11) possesses herbicidal

properties and used for the selective control of weeds in barley, wheat, maize,

sorghum and rice crops.25

N N

C2H5

H3C

COOH

O

7

N N

COOH

O

F

H2N

H3CON

8

N NH

R2

R1

NOCH2CHEt2

9

10 11

N N

NH

NH

HO

H2N

N N

F

O

http://en.wikipedia.org/wiki/Broad-spectrum

http://en.wikipedia.org/wiki/Quinolone

http://en.wikipedia.org/wiki/Antibacterial

http://en.wikipedia.org/wiki/Bronchitis

http://en.wikipedia.org/wiki/Pneumonia

http://en.wikipedia.org/wiki/Breast_cancer


52

1,8-Naphthyridine derivatives also react with adenosine receptors of

subtypes A1 and A2A.26

The important biological properties just described

stimulated studies on the synthesis of various functionalized (particularly, at

positions 2, 4 and 7) 1,8-naphthyridine derivatives, with the goal of designing

new drugs for oral administration. In addition, 4-(N-

methylenecycloalkylamino)-1,8-naphthyridine derivatives substitution in

positions 2 and 7 are effective as antihypertensive agents.27

7-Amino-2-(4-carbethoxypiperazin-1-yl)-4-phenyl-1,8-naphthyridine

has recently been synthesized and reported to have marked activity against

mycobacterium tuberculosis.28

A survey of the literature shows that the major synthetic approach that

are used to prepare various types of 1,8-naphthyridine system involves

condensation of 2-aminopyridine derivatives with carbonyl compounds

containing active methylene group, aldehydes, acyclic and cyclic ketones or

diketones group in the presence of an acid or base catalyst.29-35

2. Synthesis of 1,8-naphthyridine nucleus:

Synthesis of 1,8-naphthyridines may be done by cyclisation of appropriate

aliphatic substrates, with or without auxiliary synthons, by cyclisation of

appropriate substituted pyridines with or without synthons or from other

heterocyclic substrates by several process.

a) 5-Methyl-3-(m-tolylethynyl)-2-pyridinamine (12) on treatment with sodium

ethoxide in the presence of ethanol on cyclisation produced 4-ethoxy-6-

methyl-2-m-tolyl-1,8-naphthyridine(13).36


53

a) 3-(2-Ethoxycarbonylvinyl)-2-pyridinamine (14) on treatment with sodium

ethoxide underwent cyclisation to form 1,8-naphthyridin-2(1H)-one (7) in

ethanol (15)37

.

N NH2

O

C2H5ONa

12 13

N N

OC2H5

N NH2

OC2H5

O

C2H5ONa

14 15

N NH

O

b) 2,5-Bis-(3-aminopropyl)pyridine (16) on treatment with NaNH2 in toluene

after cyclisation gave 2-(3-aminopropyl)-1,2,3,4-tetrahydro-1,8-

naphthyridine (17)38

. 6-(2-acetyl-1-methylethylidene) amino-2-

pyridinamine (18) gives 5,7-dimethyl-1,8-naphthyridin-2-amine (19) after

cyclisation on treatment with NaNH2 in presence of phosphoric acid at

100oC.

39

16 17

NH

NNH2

N N

18 19

N N

NNH2

H2N NaNH2

NaNH2

COCH3

H2NH2N


54

c. 3-(2-Nitrovinyl)-2-pyridinamine (20) underwent condensation with

benzaldehyde in xylene and gave 3-nitro-2-phenyl-1,8-naphthyridine (21)40

.

2-Pyridinamine (22) on treatment with benzaldehyde and subsequently with

acetic acid produced 2-phenyl-1,8-naphthyridine-4-carboxylic acid (23) in

ethanol41

.

20 21

N N C6H5

N NH2

22 23

N N Ph

N NH2

C6H5CHO

COOH

NO2 NO2

C6H5CHO

CH3COOH

2-Amino-3-pyridinecarbonitrile (24) on treatment with m-chlorobenzyl

cyanide, KOH/H2O on microwave irradiation produced 3-m-chlorophenyl-1,8-

naphthyridin-2-amine (25).42

The same substrate (24) with ethyl cyanoacetate

in ethanol and trace amounts of piperidine gave 2-oxo-1,2-dihydro-1,8-

naphthyridine-3-carbonitrile (26)43

.

25

N N NH2

N NH2

24

N NH

O

CNCH2COOC2H5CHO CN

26

m-chlorobenzyl cyanide

Cl


55

e) Niementowski synthesis:

In the first route Hitherto44

described was an extension of the

Niementowski synthesis to the preparation of 1,8-napthyridine-2,4-diols.

7-phenyl-1,8-napthyridine-2,4-diols (28) by the condensation of ethyl-2-

amino-6-phenyl nicotinate (27) with simple esters in the presence of sodium.

N NH2

27

N N OH

COOC2H5R

28

R-CH2-COOC2H5

OH

C6H5C6H5

Na

f) Friedlander synthesis:

In the second route Friedlander was described the synthesis of 1,8-

naphthyridine derivatives containing phosphorus.45

The first 2, 3 substituted

1,8-naphthyridine (31) bearing a phosphorus moiety have been synthesized by

the Friedlander annulations of 2-aminonicotinaldehyde (29) with diphenyl

phosphoryl cyclopentanones (30).

N NH2

29

N N

CHO

30O

P

R Ph

Ph

X

P

Ph

PhX31

The Friedlander condensation of 2-amino nicotinaldehyde with active

methylene compounds in the presence of catalyst lithium chloride under the

two non-conventional methods like microwave irradiation and by grinding in a

mortar afforded the corresponding 1,8–naphthyridines (32).46

Both these


56

methodologies are attractive as they are relatively nontoxic, economical and

highly effective. The results shows that microwave procedure as slightly

superior to the solid-state methods in terms of reduced time period and better

yields.

N NH2

N N

CHO

32

CH3COCH2COC6H5

LiCl

MW

C6H5

O

g) Reductive cyclisation:

The third route was investigated for synthesis of 1,2-dihydro-2-oxo-1,8-

naphthyridine-3-carboxylic acid (34) by reductive cyclization of diethyl 2-((2-

nitropyridin-3-yl)methylene)malonate (33).47

N NO2N N

H

O

34

OH

OCOOC2H5

COOC2H5

33

h) Recent Literature:

TABO (1,3,3-trimethyl-6-azabicyclo[3.2.1]octane) is a highly reactive

and regioselective catalyst for the preparation of 2-substituted-1,8-

naphthyridines (35) from unmodified methyl ketones and o-aminoaromatic

aldehydes. Regioselectivity increased with slow addition of the methyl ketone

substrate to the reaction mixture.48


57

Y NH2 Y N

CHOR

1.1 eq. (TABO)

5 mol % H2SO4

Y = N, CH, CBr

RO

1.1 eqEtOH, 65oC, 150 min

HN

Y N

R

9 : 1 35

A novel copper-catalyzed [5+1] annulation of 2-ethynylanilines with

an N,O-acetal gives quinoline derivatives with an ester substituent on the 2-

position (36). A combination of CuBr2 and trifluoroacetic acid (TFA) promotes

a [5+1] annulation of 2-ethynylaniline with ethyl glyoxylate in the presence of

piperidine.49

Y NH2

1 eq. piperidine, 0.1 eq. CuBr2

Y = N, CH

H

4 eq. Na2SO4, 0.1 eq. TFA, EDC,Reflux, 1 h.Y N

OEtRR

O

O

OEt

O

36

Mogilaiah et al.50

have been reported an efficient and convenient method for

synthesis of 1-(5-aryl-[1,3,4]oxadiazol-2-ylmethyl)-3-(3-trifluromethyl-phenyl-

1H-[1,8]naphthyridin-2-ones (37), by the oxidation of [2-oxo-3-(3-

trifluoromethyl-phenyl)-2H-[1,8]naphthyridin-1-yl] acetic acid

arylildenehydrazides with iodobenzene diacetate under microwave irradiation in

solvent free condition.

N N O

O

NN

Ar

CF3

37

Ar = C6H5, 4-CH3C6H4


58

Mogilaiah et al.51

have been synthesized of 1,3,4-oxadiazolyl-1,8-

naphthyridines using iodobenzene diacetate in solid state. A simple and highly

efficient procedure has been described for the synthesis of 1-((5-phenyl-1,3,4-

oxadiazol-2-yl)methyl)-3-m-tolyl-1,8-naphthyridin-2(1H)-one (38) by the

oxidation of the corresponding [2-oxo-3-(3-methylphenyl)-2H-

[1,8]naphthyridin-1-yl]acetic acid arylidene hydrazides with iodobenzene

diacetate [ph(OAc)2] in solid state.

N N O

O

NN

C6H5

38

3. PHYSICOCHEMICAL PROPERTIES:

The physical properties and X-ray crystallographic analysis recorded

that all naphthyridines are planar with the exception of 1,8-naphthyridine is

non-planar due to repulsion of the nitrogen lone pairs of electrons, but becomes

planar when chelation with metal atom.52

The weaker bases of parent

naphthyridines than quinoline (pka 4.94) and isoquinoline (pka 5.40) are

attributed to the electron-withdrawing inductive effect of one doubly bonded

nitrogen atom to the other.53

In the fact that 1,6-naphthyridine (pka 3.78) and

1,7-naphthyridine (pka 3.63) are stronger bases as compared to the 1,5-

naphthyridine (pka 2.91) and 1,8-naphthyridine (pka 3.39) and also both of the

new derivatives are stronger bases as compared with the pka value of quinoline

and isoquinoline which they are consistent protonation occurring on N-6 and


59

N-7 of the 1,6- and 1,7-isomer respectively.54

A new series of fluorophore

derivatives from 1,8-naphthyridine were developed and shown the first

naphthyridine PET sensor that can signal Cd selectively with fluorescent

enhancement and red-shift. Other 1,8–naphthyridines were found to be

fluorescent in solution and they were studied in the presence of Cu+ and Cu

2+

ions and it was verified that the metal causes the quenching of their

fluorescence emission, due to the formation of complexes between the

naphthyridine and the metal.55, 56

Many 1,8-naphthyridine derivatives were characterized by single crystal

X-ray diffraction analysis, and a comprehensive study of their spectroscopic

properties involving experimental and theoretical studies. They found an

intramolecular 1,3-hydrogen transfer and photo-induced isomerization for some

derivatives while flexible structures was observed under 365 nm light

irradiation. Quantum chemical calculations revealed that the dinuclear

complexes with structural asymmetry exhibit different metal-to-ligand charge-

transfer transitions.57

4. REACTIVITY:

The naphthyridines possess ten delocalized π– electrons which are

located in five molecular orbitals and they are distorted by the presence of the

nitrogen atoms that causing an electron drift in that direction. This perturbation

causes the position ortho and para to the nitrogen atoms to have π–electron

densities than the meta-positions and this led to electrophilies react

preferentially at a position meta to a ring nitrogen and nucleophiles at ortho and


60

para-positions. However, because naphthyridines are π–electrons deficient,

they are highly susceptible to nucleophilic attack and strongly deactivated for

electrophilic attack.58

4.1. ELECTROPHILIC SUBSTITUTION:

In the bromination of 1,8-naphthyridine hydrobromide with 1:1

equivalent ratio of bromine in nitrobenzene, the 3-bromo-1,8-naphthyridine

(39) and 3,6- dibromo-1,8-naphthyridine (40) were obtained in equivalent ratio

(1:1), but compound (40) is obtained in 73% yield when equivalent ratio of

bromine is ((2:5). 59

N N

H Br

Br2

Nitrobenzene N N N N

Br Br Br

39 40

However, presence of electron-donating substituents facilitates

electrophilic substitution and hence bromination was proceed under much

milder conditions as shown in conversion of naphthyridin-2-one derivatives

(41) into 3-bromo-naphthyridin-2-one derivatives (42).60

N NH

Br2 in AcOH

N NH

Br

41 42

O KBrO3 in HBr O

Oxidation reaction61

with KClO3 in HCl and the nitration occurs only

when electron-donating groups are present in the 2-or 4-position. Thus,


61

1,7-naphthyridone (11) can be mononitrated to 3-nitro-1,7-naphthyridone

(12).63

NNH

NNH

43 44

Fumming HNO3

O O

NO2

4.2: NUCLEOPHILIC SUBSTITUTION

Naphthyridines are very easily undergoing nucleophilic substitution

reactions because of the presence of nitrogen atoms in their ring system thus

they easily undergo nucleophilic attack. There are numerous investigations

using nitrogen nucleophilies.64, 65

The replacement of halogen by an amino

group provides potential application in synthetic chemistry and is therefore a

topic of great interest. It is apparent that nucleophilic substitution of halo

pyridine can proceed in three pathways namely ipso, cine and tele substitutions

Figure-1.66

N

N

N

N

N

N

Nu

NuNu

Nu

Nu

X

tele cine

ipso

Figure1: Ipso, cine and tele nucleohilic substitution of naphthyridines

The mechanism for the formation of both cine and ipso products can be


62

explained via a didehydronaphthyridine intermediate (45), so, the reactions of

4- bromonaphthyridine (46) and 3-bromonaphthyridine (47) with potassium

amide in liquid ammonia afford 4- aminonaphthyridine (48) and 3-

aminonaphthyridine (49) figure-2.67

N

N

N

N

N

NH2

Figure-2: Mechanism of formation of ipso and cine products

N

N

Br

Br

N

NH2

45

47

4648

49

Aminodehalogenations involving tele and ipso substitution have been

reviewed. The replacement of a halogen by a hydrogen atom is conveniently

achieved by initial reaction with hydrazine followed by oxidation with copper

(II) sulphate.68

4.3. REDUCTION:

The hydrogenation over PtO2 or Pd gives preferentially tetrahydro

products.69

But sodium and alcohol afford the fully reduced trans isomers only.

However, both cis and trans isomers were obtained when reduction is done

over PtO2 in acetic acid. The hydrogenation of naphthyridines has been

reviewed.70

Lithium aluminum hydride changes the 8-oxo-1,7-naphthyridine

(50) and the 4,6-dioxo-1,5-naphthyridine (51) into tetrahydro-1,7-

naphthyridine (52) and tetrahydro-1,5- naphthyridine (53) respectively

Scheme-4. 71, 72


63

NN

NN

HN

N

HN

N

R

OR

LiAlH4

LiAlH4

O

O

50

51

52

53

4.4. ADDITION REACTION:

The Reissert reaction of naphthyridine with acyl halides and potassium

cyanide has been studied including conversion of 1,7-naphthyridine into 7-

acyl-8-cyano- 1,7-naphthyridine (54).73

NN

NN

RCOCl

54

KCNH

CNR

O

In the addition reaction of 1,6-naphthyridine with acetic anhydride, 6-

acetyl-1,6-naphthyridine-5-acetic acid (55) was obtained, while the reaction of

1,6-naphthyridine with diethylmalonate and acetic anhydride gave 6-acetyl-5-

diethyl malonate-1,6-naphthyridine (56).74, 75

N

N

56 55

Ac2O

N

N

2

CH2(CO2Et)2 Ac2O

CH(CO2Et)2

O N

N

CH2CO2H

O

N-alkylation preferentially takes place on the isoquinoline nitrogen as

shown in the reaction of 1, 6-naphthyridine to give 6-methyl-1, 6-

naphthyridone (57).76


64

57

N

N

i) CH3IN

N

O

ii) [O]

In view of the hitherto importance of 1,8-naphthyridines with various

structural features exhibiting a range of biologically useful properties, the

present investigation involves the synthesis of 1,8-naphthyridine derivatives

and are presented in the forth coming chapters.


65

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