synthesis and biological evaluation of some nitrogen

Section A

Section A

Synthesis and Biological Evaluation of Some Nitrogen Containing Heterocycles

Chapter 1 Nitrogen Containing Heterocycles − A Brief Review Chapter 2 Synthesis and Biological Evaluation of Some Pyrazole Derivatives Chapter 3 Synthesis of Some Novel Imidazobenzothiazoles (IBTs) as Inhibitors of Apoptosis Chapter 4 Synthesis and Evaluation of Some Polyhydroquinolines as Antioxidants and Antimicrobial Agents Chapter 5 Synthesis and Biological Evaluation of Some Thiazolylhydrazinomethylideneferrocenes as Antimicrobial Agents

Chapter 1

Nitrogen Containing Heterocycles − A Brief Review

Brief review on nitrogen containing heterocycles

CHAPTER 1. Nitrogen Containing Heterocycles − A Brief Review

1.1. Spotlight on heterocyclic compounds The chemistry of heterocycles is one of the most complex but equally

important branch of organic chemistry, constituting one of the largest areas of

research for more than a century. It is equally interesting for its theoretical

implications, for the diversity of its synthetic procedures as well as continually

contributing to the development of society from a biological and industrial point of

view to understand the life processes and to improve the quality of life.1

Heterocyclic compounds are the cyclic organic substances which contain in

the ring system at least one atom other than carbon. Presumably, any atom which can

form two covalent bonds is capable of forming a heterocyclic compound. However,

with few exceptions like mercury or iodine, all the known heterocyclic compounds

involve an element from group IVB, VB or VIB of the periodic table. The most

important “heteroatoms” undoubtedly are nitrogen, oxygen and sulfur. It seems likely

that more than a third of the known organic compounds are heterocyclic. Many

alkaloids, vitamins, antibiotics as well as many synthetic medicines and dyestuffs are

heterocyclic, and so are many other substances such as nucleic acids which are

fundamental to any life process on planet earth. Simple fact that the heterocycles are

able to get involved in an extraordinarily wide range of reaction types which are, in

general, not feasible with carbocycles explains the reason as to why nature utilizes

heterocycles at such a scale.2 Depending on the pH of the medium, they may behave

as acids or bases, forming anions or cations. Some interact readily with electrophilic

reagents, others with nucleophiles, yet others with both. Some are easily oxidized, but

resist reduction, while others can readily be hydrogenated but are stable toward the

action of oxidizing agents. Certain amphoteric heterocyclic systems simultaneously

demonstrate all of the above-mentioned properties. The presence of different

heteroatoms makes tautomerism ubiquitous in the heterocyclic series. One of the

striking structural features inherent to heterocycles, which continues to be exploited to

great advantage by the drug industry, lies in their ability to manifest substituents

around a core scaffold in defined three dimensional representations.2 Moreover, these

1

Chapter 1

heterocycles are more flexible and better able to respond to many demands of

biochemical systems which could otherwise not be fulfilled by the carbocycles.

Just like carbocyclic derivatives, heterocycles may too be classified as

saturated, unsaturated, or aromatic. The constantly accelerating rate of research and

development in heterocyclic chemistry suggests that enormous number of heterocyclic

systems are well known and this number is still increasing rapidly.

1.2. Nitrogen containing heterocycles: A general introduction Nitrogen containing heterocycles are perhaps by far the most explored

heterocyclic compounds because of their occurrence in a myriad of natural products

and biologically active compounds. For this reason, synthetic chemists continue to be

interested in the construction and functionalization of these heterocycles. The most

common examples of naturally occurring N-heterocycles which otherwise too are of

fundamental importance to life are haemoglobin and chlorophyll (Figure 1.1).

Figure 1.1.

Human Blood Haemoglobin Plant Chlorophyll

Haemoglobin helps in oxygen transportation within body while chlorophyll

helps in light harvesting that is further used for making ATP and NADPH. A common

feature in haemoglobin and chlorophyll is that both contain porphyrin system in which

four pyrrole rings are interconnected through alternate single-double bonds on

periphery and connected with Fe2+ (haemoglobin) and Mg2+ (chlorophyll) in the

centre through nitrogen atoms. β-Lactam antibiotics such as penicillins (1) and

cephalosporins (2); nucleobases adenine (3), guanine (4), cytosine (5), thymine (6)

and uracil (7); alkaloids such as antimalarial quinine (8) and narcotic pain reliever

2


morphine (9) are some of the common examples of naturally occurring N-

heterocycles. Most of the commercially synthesized drugs belong to heterocyclic class

that can be anti-inflammatory indomethacin (10), antibacterial ciprofloxacin (11),

antifungal fluconazole (12), anti-HIV zidovudine (AZT) (13), calcium channel

blocker diltiazem (14), etc.

N

S

O

CH3

CH3

COOH

HNR

O NO

HNR2

O

S

R1

O OH

H

NH

N

N

N

H2N

NH

N

N

NH

O

NH2

NH

N

NH2

O NH

NH

O

O NH

NH

O

O

N

HON

O

N

F

N

HN

O

OH

O

O

HO

HH

HO

N CH3

N

O OH

O

O Cl

1 2 3 4

5 6 7 8

9 10

N

N N

11

OH

N

N

N

F

F

NH

O

ON

O

N3

HO

S

NO

O

O

CH3

O CH3

NH3C CH3

12 13 14

There can be one or more nitrogen atoms in the cyclic/aromatic systems or

ring may be consisting minimum of three atoms to maximum of supramolecular

3

Chapter 1

architecture. Rings may be connected through single/double bonds or may be fused.

There can be only nitrogen atoms in the rings along with carbons or may be in

combination with other heteroatoms such as sulfur, oxygen, etc. Thus, diversity and

multiplicity of ‘N’-Heterocycles are so vast and extraordinary that it will be

practically impossible to summarize in this brief review.

In this chapter, the focus is on nitrogen containing five membered pyrazoles

as well as pyrazolines; nitrogen and sulfur containing five membered thiazoles and

fused benzothiazoles; and six membered quinolines/polyhydroquinolines which have

been synthesized during the course of the Ph.D. work. For the sake of consistency,

brief introduction about each heterocycle is followed by a concise account of

biological applications and few important synthetic procedures as well as peculiar

spectral characteristics.

1.3. Pyrazoles Pyrazoles are the nitrogen containing aromatic heterocycles characterized by a

five-membered ring structure composed of three carbon atoms and two nitrogen atoms

at adjacent positions. They basically belong to azole family and seem to be derived

from pyrrole through substitution of a carbon at position-2 by nitrogen atom.

1.3.1. Biological properties of pyrazoles Owing to their prevalence in various biologically active molecules, pyrazoles

have occupied an important position in medicinal and pesticide chemistry having a

wide range of bioactivities such as antimicrobial,3- 5 anticancer,6 anti-inflammatory,7,8

antidepressant,9 anticonvulsant,9,10 antiviral,11 etc. It has been shown in vivo that

some of the pyrazole derivatives have appreciable antihypertensive activity.12 These

compounds are also known to exhibit properties such as cannabinoid type-1 (CB1)

receptor antagonists,13,14 inhibitors of CDK2 with good activity against a range of

human tumour cell lines,15 and inhibitors of tissue-nonspecific alkaline phosphatase

(TNAP).16 They are promising to show antiplatelet activity.17 In pesticide chemistry,

they emerged as broad spectrum insecticides, fungicides and herbicides.18- 21 Pyrazole

motif makes up the core structure of numerous biologically active compounds,

including blockbuster drugs such as Sildenafil (Viagra)22 (15) and Celecoxib23 (16).

Sildenafil (Viagra) (15) is an FDA approved drug used to treat erectile dysfunction

4


whereas celecoxib (16) is a powerful COX-2 inhibitor and exhibits analgesic and

antiarthritic effects. Difenamizole24,25 (17) is used as a drug with analgesic, anti-

inflammatory and antipyretic activities.

O

N

NH

O

NN

S NO

O

N

NN

Ph

NH

O

Me2N

N N

H3C

H2NO2S

1716

CF3

15

Ph

Difenzoquat26 (18) is used for post-emergence control of wild oat in small

grain crops. Ethiprole (19) and Fipronil (20), both27 are significant agricultural

insecticides with extensive use for the control of the insects on corn and soyabean, as

well as stored grain insect pests. Fomepizole (21) is indicated for use as an antidote in

confirmed or suspected methanol28 or ethylene glycol29 poisoning, used either alone

or in combination with haemodialysis. Eltrombopag30 (22) is a medication that has

been developed for conditions that lead to thrombocytopenia (abnormally low platelet

counts). NESS-032731 (23) is a drug used in scientific research which acts as an

extremely potent and selective antagonist of the cannabinoid receptor CB1.

NN

Me

Ph

Ph Me

18

MeOSO3

NN

ON

NH

OH

OH

22

NN

FF

F

Cl

Cl

N

H2N

SH3CO

NN

FF

F

Cl

Cl

N

H2N

S

OF

FF

19 20

N N O

HN N

ClCl

Cl

NH

N

21

23

Pyrazole analogues like 2432 were identified as potent and selective inhibitors

of CARM1 (coactivator-associated arginine methyltransferase1) enzyme. Pyrazole

5

Chapter 1

acid 25 has recently been identified as EP1 receptor antagonist33 whereas

pyrazolo[1,5-a]pyrazin-4(5H)-one (26) has been found to act as an effective molecule

in inhibiting A549 cell growth.34 Recently, Ding et al.35 discovered pyrazole

derivatives 27 as modulators for apoptosis or autophagy in A549 lung cancer cells.

Sanchez-Maréno et al.36 reported pyrazole based Benzo[g]phthalazine 28 which were

found to be more effective and less toxic than reference drug, benznidazole in the two

stages against chagas disease (trypanosomiasis). Fused pyrazolo[4,3-c]quinoline 29

synthesized by Christodoulou et al.37 emerged as a promising lead compound, with

inhibitory activity against endothelial and tumour cell proliferation in vitro and

angiogenesis in vivo. Thaher et al.38 recently synthesized tetra-substituted pyrazole

derivatives 30 which showed activity against cancer kinases.

NN

NH2

N

F

R

30

NN

F3CHN

O

HN

ONH2

24

NN

O

COOH

25

27

NN

ONH

R

Br

26

N NN

OCl

NN

HN NNH

HN

NNN

OH

HO

O

29

NHN

28

Bekhit et al.39- 44 synthesized pyrazole derivatives 31-36 showing pronounced

dual anti-inflammatory and antimicrobial activities.

6


N N

H3C NN N

S

NH2

O

NH2

N

NN N

S

Br

NN

H2NO2S

NN

N

O

N N

OH

CH3

HN

OF3C

NN

CN

H2NO2S

31 32

33 34

35 36

N

NHN

S

S

Br

CONH2

1.3.2. Synthetic procedures As there are a large number of methods available for the synthesis of a

pyrazole nucleus, the emphasis here is given on more recent methods while including

the classical method from β-diketones:

1.3.2.1. Condensation of hydrazines with 1,3-dicarbonyl compounds

Condensation of 1,3-diketones or their derivatives with appropriate hydrazines

provides an excellent route to synthesize pyrazoles. A single pyrazole derivative (39)

is obtained when a symmetrical 1,3-diketone (38) reacts with hydrazine (37) as shown

in Scheme 1.1. On the other hand, reaction of substituted hydrazine (37) with

unsymmetrical 1,3-diketone (40) affords mixture of two isomeric pyrazoles (41 & 42)

(Scheme 1.1).

Various alternative strategies have been used by the chemists to

regioselectively synthesize only one pyrazole isomer.45- 48 Gosselin et al.49 reported

7

Chapter 1

that regioselectivity of cyclocondensation of arylhydrazine hydrochlorides with 1,3-

diketones is solvent dependent. Aprotic solvents with strong dipole moments such as

R1 R1

O O

R NHNH2 +N N

R1

R1

R

R1 R2

O O

N NR2

R1

RN N

R1

R2

R

+

393837

41 42

40

Scheme 1.1.

N,N-dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), N-methylpyrrolidinone

(NMP), 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPU) and N,N-

tetramethylurea (TMU) provided highest and consistent regioselectivity than the polar

protic solvents such as ethanol and acetic acid (Scheme 1.2).

R1

OO

+ DMAc, rt, 24 hN N

R1

RR

NHNH2 HCl

R = SO2NH2, Br, H; R1 = Me, CF3, CF2H; R2 = H, Br, OCH3, NO2

R2R2

43 44 45

0.5 eq. HCl

Scheme 1.2.

1.3.2.2. Synthesis from propargyl-N-sulfonylhydrazones An efficient and regioselective synthesis of 1,3- and 1,5-disubstituted,

and1,3,5-trisubstituted pyrazoles (47) has been reported by Lee & Chung50 from

R3 R2

Scheme 1.3.

NN

R1

R2

NN

R1

R3

5 mol% AgSbF6

CH2Cl215 0C ~ 20 0C, 3h

R1 = H, Me; R2 = H, Me, Ph; R3 = Ph, alkyl, styrenyl46 47

sulfonyl sulfonyl

8


propargyl-N-sulfonylhydrazones (46) under mild conditions (Scheme 1.3). The

reaction proceeds with the migration of sulfonyl group (Ts, Ms).

1.3.2.3. Synthesis from unsymmetrical enaminodiketones A regiospecific synthesis of 4-substituted 1H-pyrazole-5-carboxylates (49)

from the cyclocondensation reaction of unsymmetrical enaminodiketones (48) with

tert-butylhydrazine hydrochloride or carboxymethylhydrazine was reported by Rosa

et al.51 (Scheme 1.3).

R

O O

Me2NO

OEt EtOHReflux

O

N

N

Scheme 1.4.

1.3.2.4. Synthesis from acid chlorides One-pot synthesis of pyrazoles (52) by Sonogashira-type reaction of acyl

chlorides (50) with substituted acetylenes (51), followed by cyclocondensation in the

presence of various hydrazines has been disclosed by Liu et al.52 (Scheme 1.5).

Scheme 1.5.

1.3.2.5. One pot solvent free synthesis from aldehydes A three component, one pot synthesis of fully substituted pyrazoles (56) using

ytterbium perfluorooctanoate [Yb(PFO)3] as catalyst under solvent free conditions has

been described by Shen et al.53 (Scheme 1.6).

Scheme 1.6.

EtOOCR

Me3CNHNH2 HCl+

R = Ar, HetAr, CCl3, CF3

48 49

R1

R1

Cl

O

+ R22. R3NHNH2, MeCN, rt, 16h

1. PdCl2(PPh3)2/CuI Et3N, THF, rt, 2h

R1 = Ar, HetAr; R2 = Ar; R3 = H, Ph

NN

R2

R350 51

52

R1CHO +

O

R2 + NHNH2N

N

R2

R1

Yb(PFO)3 (10 mol%)neat, 120 0C

53 54 55 56

R1 = Ar; R2 = COOMe, COOEt

9

Chapter 1

1.3.2.6. Triphenylphosphine mediated synthesis of pyrazoles Reaction of triphenylphosphine and dialkyl azodicarboxylate (57) with allenic

esters (58) is reported to provide highly functionalized pyrazoles54 (59) as shown in

Scheme 1.7.

N

NROOC

COOR+ PPh3 + C

COOEt

R1N

N

OEtROOC

COOR

R1DMF, rt

R1 = CH3, Ph, 4-ClPh, 4-MeOPh; R = isopropyl, ethyl

57 58 59

Scheme 1.7.

1.3.2.7. Synthesis from terminal alkynes Ahmad et al.55 reported a palladium-catalyzed four component coupling of a

terminal alkyne (60), hydrazine (61), carbon monoxide, and an aryl iodide (62) to

furnish pyrazole derivatives (63). The reaction proceeds at room temperature and at

ambient pressure of carbon monoxide in an aqueous solvent system (Scheme 1.8).

5 mol% PdCl2(PPh3)22 mol% CuICO (ambient pressure)

THF/H2O (1:1)rt, 24-36 h

N NI R1

Scheme 1.8.

1.3.3. Spectral characteristics 1H NMR spectroscopy has indeed shown promise as an elegant tool for the

characterization of pyrazoles.56,57 In N-unsubstituted pyrazoles, position-3 and -5

become equivalent due to existence of tautomeric equilibria. In N-substituted

pyrazoles having different substituents at position-3 and -5, it is challenging to

unambiguously distinguish the isomers and 1H NMR is found to be very helpful in

assignments of these isomers. For example, in case of 1-alkyl-3- or 5-methylpyrazole

pairs, a paramagnetic displacement of the C-3(5) ring proton peak and a diamagnetic

shift of the methyl peak on going from the 3-methyl to 5-methyl isomer was observed

by Habraken and Moore.58 The following tools are generally employed for assigning

the structure of pyrazoles on the basis of 1H NMR spectra.

+

R1NHNH2 +R2R

R2

6360

R R = H, Me; R1 = H, Me, Ph; R2 = H, Me, OMe

61 62

10


1. The J4,5 is always larger than J3,4 and this difference generally goes on

increasing with the electron-withdrawing ability of the N-substituent due to the

location of electrons of the π-system. This fact has been helpful for the spectral

assignment of compounds having two adjacent protons like 3- or 5-amino- or

hydroxyl-pyrazoles.59 However, this method is not applicable to 1H-19F or 19F-19F coupling constants in pyrazoles.60,61

2. Nuclear quadrupole relaxation effect of N-2 broadens the signal of the proton

in position-3. If the C3-H signal is a singlet (R4 ≠ H), the broadening effect is

smaller for C3-H than that of the signal for C5-H and if it is a doublet (R4 = H),

C3-H is less well resolved than that of the signal for C5-H.62

3. The signal due to the proton at position-5 is more sensitive to solvent polarity

than that of the substituent at position-3 when the solvent is gradually changed

from C6D6 to the more polar CDCl3, DMSO-d6 and [(CH3)2N]3P(HMPT).63,64

4. It has been established by theoretical studies that the π-electron density at

position-4 of the pyrazole is maximum as compared to position-3 and -5.65

The observation is supported by the fact that C4-H appears relatively upfield at

about δ 5.8 in 1H NMR spectrum.66

5. The C- or N-phenyl signal appears as a singlet when a substituent, generally a

methyl group, is located at the vicinal position. In case, there is no substituent,

the phenyl protons appear as two multiplets (ortho protons at low fields, meta

and para protons at high fileds).67 The difference between chemical shifts of

ortho and meta-para protons is characteristic of the position of a phenyl group

in the azole ring.68

6. The methyl protons at position-3 and -5 in N-alkyl or N-arylpyrazoles resonate

without any appreciable difference in the chemical shift at about δ 2.35. On the

contrary, replacement of N-alkyl or N-aryl group by a heterocyclic moiety

causes a dramatic change in the chemical shift of the methyl protons

particularly at position-5 of the pyrazole moiety.69 This deshielding of the C5-

CH3 protons may arise due to a variety of reasons, for example weak hydrogen

bonding, lone pair effect, ring current effect,70 etc. The methyl protons at

position-3 and -5 in 1-heterocyclylpyrazoles resonate at around δ 2.3 and δ 2.7

respectively.

11

Chapter 1

1.4. Pyrazolines Pyrazolines are well known and important nitrogen containing 5-membered

heterocycles having two adjacent nitrogen atoms and three carbons within the ring,

bearing only one endocyclic double (C=N) bond and are basic in nature. Most of the

studies have been centered around the isomer 2-pyrazoline which is considered as a

cyclic hydrazine. They are extensively used as useful synthons in organic synthesis.71

1.4.1. Biological properties of pyrazolines Diversely substituted pyrazolines and their derivatives are important biological

agents and possess a wide variety of medicinal as well as agrochemical applications

such as anti-inflammatory,72- 74 analgesic,72,73 antimicrobial,75,76 antiamoebic,77,78

anticancer,79 insecticidal,80 etc. Their derivatives are also found to exhibit potent

receptor selective biological activities81 like nitric oxide synthase (NOS) inhibitor and

cannabinoid CB1-receptor modulators. Phenazone (64) and methampyrone (65)

(analgesic as well as antipyretic); phenylbutazone (66) and oxyphenbutazone (67)

(anti-inflammatory); sulfinpyrazone (68) (uricosuric agent) are some of the

therapeutic market drugs bearing pyrazoline nucleus being used.

NN

H3CCH3

ON

NH3C

O

H3C N

CH3

H3CSO

O ONa

NN

O

O

NN

O

OOH N

N

S

O

O O

65 66

67 68

64

Abid and Azam82 synthesized a series of 1-N-substituted cyclized pyrazoline

analogues (69a-69e) of thiosemicarbazones that were found to possess excellent anti-

amoebic activity against HM1:1MSS strain of Entamoeba histolytica. Some novel

12


3,5-diarylpyrazolines like 70 synthesized by Jeong et al.83 were identified as potent

low-density lipoprotein (LDL) oxidation inhibitors.

t-Bu t-Bu

Pyrazoline bisphosphonate esters 71 synthesized by Nugent et al.84 have

proved to be better anti-inflammatory agents which are capable of inhibiting both

chronic arthritis and inflammation in animals. Kaplancıklı et al.85 synthesized some

novel triazolo-pyrazoline derivatives (72) exhibiting different levels of activities as

compared to reference drug fluoxetine and none changed motor coordination of

animals when assayed in the Rota-Rod test. A series of 1,3,5-trisubstituted pyrazolines

(73) synthesized by Acharya et.al.86 exhibited strong antimalarial activity against

chloroquine resistant strain of Plasmodium falciparum. Some novel pyrazoline

derivatives (74) mimicing bacterial siderophores were synthesized by Stirrett et al.87

NNR

R1

S

69a R = Cl;

69b R = Br; 69c R = Cl;

69d R = Br; 69e R = Cl;

N(CH2)3CH3

CH3

NCH2CH3

CH2CH3

N(CH2)2CH3

(CH2)2CH3

R1 =

R1 =

R1 =

HNN

OHt-Bu

HOt-Bu

t-Bu

70

HN N

O

RP

PO

O

(C2H5O)2

(C2H5O)2

a R = Hb R = 3-F

71

NN

OSN

NN

NH2

HO

R1

R2

S

72

NNHO

O

N

R5

R4

R2

R3

R1

73

N N

R1 R

SNH

H

R2

R3

R4

O

S

R5

R6

H

74

13

Chapter 1

which showed promising antibacterial activity against iron-scarcity adapted

Mycobacterium tuberculosis and Yersinia pestis.

1.4.2. Synthetic procedures A few recent methods used for the synthesis of pyrazoline derivatives are

summarized below:

1.4.2.1. Zinc-catalyzed regioselective synthesis of aryl-substituted pyrazolines

Alex et al.88 demonstrated an elegant zinc-catalyzed novel regioselective

synthesis of aryl-substituted pyrazolines 77. Substituted phenylhydrazines 75 have

been shown to react with 3-butynol in the presence of a catalytic amount of zinc

triflate to give pyrazoline derivatives 77 in excellent yields (Scheme 1.9). A plausible

mechanism for this reaction is believed to involve two steps as shown in Scheme 1.9,

first hydrohydrazination of 3-butynol forming corresponding intermediate

arylhydrazone 76 followed by an unusual nucleophilic substitution of the hydroxy

group yielding pyrazoline 77.

NHH2N

R

OH+

5 mol% Zn(OTf)2,

THF, 24 h, 1000C

N

R

N

+ H2O

NH

R

N

OH

75 77

76

Zn catalyst

Scheme 1.9.

1.4.2.2. Synthesis of 1,3,5-triaryl-2-pyrazolines in aqueous medium under ultrasound irradiation Li et al.89 reported an efficient and green practical procedure for the synthesis

of 1,3,5-triaryl-2-pyrazolines 78 by ultrasound irradiation of an aqueous solution of

14


chalcones and phenylhydrazine hydrochloride containing sodium acetate and acetic

acid as depicted in Scheme 1.10.

))))

N

N

Ar1

Ar2NHNH2. HCl

Ar2Ar1

O

+CH3COONaCH3COOH/H2O/

78

Scheme 1.10.

1.4.2.3. Synthesis of 5-hydroxy N-acylpyrazolines from 2-alkyn-1-ones

Waldo et al.90 recently synthesized a number of novel 5-hydroxy N-

acylpyrazolines 80 in moderate to excellent yield by reacting corresponding 2-alkyn-

1-ones 79 with acetylhydrazine in toluene at 80 °C (Scheme 1.11).

Ar

O

R

NN

R

Ar

HO

Me O

2 eq. H2N NHAc

toluene, 80 0C, 6h

79 80

R = Ar, alkyl, vinyl

Scheme 1.11.

1.4.2.4. 2-Pyrazolines formation by domino reaction of 2-acylaziridines with the Huisgen zwitterions

Huisgen zwitterions 82 generated in situ by the redox coupling of

triphenylphosphine and dialkyl azodicarboxylates 81 on domino reaction91 with 2-

acylaziridines 83 have been reported to yield 2-pyrazolines 84 quantitatively by

refluxing in toluene (Scheme 1.12).

RO2CN

NCO2R

+

HN

ArAr'

O

toluene, N2reflux, 2h N N

Ar'

NHCO2R

Ar

RO2C

+PPh3

RO2CN

NCO2R

PPh3

82

81

83 84

Scheme 1.12.

15

Chapter 1

1.4.2.5. Gold(I)-catalyzed formation of 3-pyrazolines through cycloaddition of diaziridine to alkynes

Capretto et al.92 reported the first gold(I)-catalyzed cycloaddition of diaziridine

86 on to alkynes 85 giving high yields of 3-pyrazolines 87 (Scheme 1.13).

H

R

+

NNPhCbz

NN

R

Cbz

Ph

10 mol% Ph3PAuNTf2Touene, 18h, 70

0C

R = alkyl, aryl85 86 87

Scheme 1.13.

)

A A,B A,X

chemical shift values of carbon atoms C-3 (154-156 ppm), C-4 (42-44 ppm) and C-5

1.4.3. Spectral characteristics Although a large number of pyrazolines have been synthesized and

characterized, general trends or guidelines for 1H NMR spectral assignments for the

pyrazoline class have still not emerged contrary to the pyrazole class. It has been

undoubtedly reported that 1,3,5-trisubstituted-2-pyrazolines display three doublets of

doublets, a typical pattern of ABX type system due to three protons, two at position-4

and one at postion-5, and the coupling constants (

were found to be quite sensitive to the

nature of the substituent on the

nitrogen atom.

Jgem, Jcis and Jtrans ) of these protons

93 1H NMR spectra of

1,3,5-trisubstituted-2-pyrazolines (88

synthesized by Andotra et al.94

displayed first doublet of doublet,

centred at δ ≅3.26 which was assigned to H (J ≅18.0 Hz and J ≅5.0 Hz trans);

signal due to HB appeared as doublet of doublet at around δ ≅3.86 while the third

doublet of doublet due to third proton of pyrazoline appeared centred at δ ≅5.4

attributed to HX (JX,A 5.0 Hz trans, JX,B 11.0 Hz cis). The non-equivalence of C4-HA

and C4-HB might be due to the chiral centre at C5, which makes the protons

diastereotopic. Presumably, the appearance of HA at a higher field than the

diastereotopic proton HB might be attributed to the fact that HA being cis to C5-Ar may

be lying in the shielding zone of the benzene ring. In the 13C NMR spectra of 88, the

N N

Ac

HX

ORROHB HA

Ar

12

3

4 5

R = CH3, CH2CH3

Ar = Ph, p-anisyl, etc.

88

16


(56-58 ppm) supports the 2-pyrazoline structure determined by 1H NMR

spectroscopic measurements.95

1.5. Thiazoles Thiazole or 1,3-thiazole is a member of azole heterocycle class featuring both

a nitrogen and sulfur atom at 1,3-positions within five-membered aromatic ring.

Thiazole is not as reactive as thiophene toward electrophilic substitution reaction and

its reactivity would parallel the deactivated benzenoid compound, m-dinitrobenzene.

This is because of the presence of the “pyridine-like” electronegative nitrogen which

not only withdraws electron density from the ring but under the acidic conditions of

many electrophilic reactions, the nitrogen is protonated becoming less prone to further

attack by a positively charged electrophile.

1.5.1. Biological properties of thiazoles Thiazole ring system is a useful structural motif that has found extensive

applications in drug development, e.g. for the treatment of inflammation,96- 98

microbial infections,99- 101 hypertension,102,103 diabetes,104,105 neurodegenerative

disorders such as schizophrenia,106 Alzheimer’s disease,107 and Parkinson’s

disease,108 leishmaniasis and typanosomiasis,109 etc. and also found to be novel

inhibitors of kinases,110 cholinesterase,111 etc. Tiazofurin (89) (antineoplastic

agent),112 ritanovir (90) (anti-HIV drug),113 fanetizole (91) (immunoregulatory

agent),114 meloxicam (92) (anti-inflammatory agent),115 nizatidine (93) (antiulcer

OHO

OH OH

NS

O

NH2

HNN

S

HO

NH

O

O

N

S

HN

ONH

N

S

NO

NS

OH

O O

NH

ON

S

S

N

SNH

N

NH NO O

89

90

91

92

93

S

H2N

NH

S

NO O

94

OS

NNH

N

NH

95

17

Chapter 1

agent),116 sulfathiazole (94) (antimicrobial drug)117 and abafungin (95) (antifungal

drug) are some of the prominent examples of thiazole bearing marketed drugs.

Thifluzamide118,119 (96), tricyclazole120 (97) and thiabendazole121 (98) are

marketed drugs for the control of various agricultural pests. Busravich et al.122

reported 2-anilino-4-aryl-1,3-thiazole 99 scaffold as a potent inhibitor of vasolin-

containing protein (VCP or p97) whose overexpression may lead to gastric, colon,

pancreatic and hepatocellular cancers. Thiazole carboxamide derivatives 100

synthesized by van Tilburg et al.123 were found to be potent antagonists for the

adenosine A1 receptor. Xi et al.124 identified another novel thiazole carboxamide

derivative 101 as a vallinoid receptor 1 antagonist.

S

N

NH

R2

R1

99

S

NF

F F

HN

O

Br

BrO

F

FF

N

S

N

N

CH3

N

HN

N

S

96 97 98

N

S NHO

NHF3C

Cl Cl

NS

HN

O R1

R2

R3

100 101

Benzothiazole is a fused thiazole variant in which 1,3-thiazole is fused to a

benzene ring forming a bicyclic aromatic system, and has also been reported to

possess considerable biological activities such as antibacterial,125 antifungal,126 anti-

inflammatory,127 antidiabetic,128 antiproliferative,129 anthelmintic,130 antiviral,131 anti-

HIV,132 etc. Riluzole133 (102) is the only FDA approved drug bearing benzothiazole

moiety for symptomatic amyotrophic lateral sclerosis (ALS) treatment which prevents

further degeneration of motor neurons by targeting glutamate tranporters. A novel

N

S

N

R6R5

R1

R2

R3

R4

104

N

SNH2

O

F

F

F

102S

NS N N

N

R

103

18


scaffold (103) consisting of 2-mercaptobenzthiazole and 1,2,3-triazole was recently

synthesized by Shafi et al.134 following click chemistry approach possessing

significant anti-inflammatory activity. Imidazobenzothiazoles (IBTs) 104 are well

known inhibitors of apoptosis and exhaustive work135- 138 has been done on these

compounds. These aromatic IBTs (104) have shown better anti-apoptotic activity

compared to well known standard drug piffithrin-α (PFT-α) following p-53

independent pathway.

1.5.2. Synthetic procedures Some latest methods as well as the most celebrated classic Hantzsch method

used for the synthesis of thiazole and benzothiazole derivatives are summarized

below:

1.5.2.1. Hantzsch thiazole synthesis It is the chemical reaction139 between α-haloketones (105) and thiamides (106)

to form substituted thiazoles (107) as shown in Scheme 1.14.

OR1

R2X

HNH

R3S+

N S

R3

R1 R2

105 106

X = Cl, Br

107

Scheme 1.14.

1.5.2.2. Synthesis from N,N-diformylaminomethyl aryl ketones N,N-Diformylaminomethyl aryl ketones (108)140 on treatment with phosphorus

pentasulfide and triethylamine in chloroform have been reported to yield 5-

arylthiazoles (109) in good yield as shown in Scheme 1.15.

Scheme 1.15.

1.5.2.3. Synthesis from 1H-1-(1′-alkynyl)-5-methyl-1,2,3-benziodoxathiole 3,3-dioxides

ArS

NNCHOAr

CHOO

2 eq. P2S5, 2 eq. NEt3CHCl3, 60 0C, 45-60 min.

108 109

19

Chapter 1

Ishiwata and Togo141 synthesized 2,4-disubstituted thiazoles 112 by reacting

1H-1-(1′-alkynyl)-5-methyl-1,2,3-benziodoxathiole 3,3-dioxides (111) with

thioamides 110 in the presence of potassium carbonate (Scheme 1.16). The advantage

claimed for this reaction is that the coproduct, potassium 2-iodo-5-

methylbenzenesulfonate (113) formed in this reaction can be separated just by

filtration and is used to regenerate reactant 111.

IOS

OO

R'R

S

NH2+

N

S

R'

R2.3 eq. K2CO3

THF, r.t. or 45 0C5h - o.n

+I

SO3 K

112110 111 113

1.2 eq.R = Ar, Me, NH2R' = Ph, Bu, C6H13

IOS

OO

OH Ac-O-OH, conc. H2SO4

AcOH, 10 -> 25 0C, [17h]TsOH.H2O, MeCN,

reflux, [20h]

C CHR'

114

115

Scheme 1.16.

1.5.2.4. Aqueous phase synthesis under supramolecular catalysis Narender et al.142 reported one pot synthesis of 2-amino-4-alkyl/arylthiazole-

5-carboxylates (117) by α-halogenation of β-ketoesters (116) with N-

bromosuccinimide (NBS), followed by cyclization with thiourea in the presence of β-

cyclodextrin in water at 50 °C (Scheme 1.18).

R OR'

O O

H2N NH2

S

+

S

NR

H2NOR'

O1.2 eq. NBS

1eq. β-cyclodextrinH2O/acetone (20:1)

50 0C, 1.2-1.5 h116 117

1.2 eq.R = alkyl or arylR' = alkyl

Scheme 1.17.

1.5.2.5. Synthesis from α-amido-β-ketoesters α-Amido-β-ketoesters143 118 formed by the double acylation of protected

glycine on reaction with Lawesson’s reagent (119) provide 2,5-disubstituted thiazoles

120 as depicted in Scheme 1.18.

20


O

Scheme 1.18.

1.5.2.6. Synthesis by domino alkylation-cyclization Castagnolo et al.144 recently reported a fast, high yielding synthesis of 2-

aminothiazoles 123 by domino alkylation-cyclization reaction of propargyl bromides

(121) with thioureas (122) under microwave irradiation as shown in Scheme 1.19.

a fast, high yielding synthesis of 2-

aminothiazoles 123 by domino alkylation-cyclization reaction of propargyl bromides

(121) with thioureas (122) under microwave irradiation as shown in Scheme 1.19.

S

N

S

NRNHR'Br

R S NHR'

NH2

+1 eq. K2CO3

DMF, MW (300W)130 0C, 2-5 min. R = Ar, H, COPh

R' = H, alkyl, allyl121 122 123

Scheme 1.19.

1.5.2.7. Benzothiazole synthesis by cyclization of thioformanilides Bose at al.145 reported the high yielding synthesis of various benzothiazoles

(125) by the intramolecular cyclization of thioformanilides (124) using DDQ (Scheme

1.20).

Scheme 1.20.

1.5.2.8. Solvent-free microwave-assisted synthesis of 2-substituted benzothiazoles Seizas et al.146 found Lawesson’s reagent as an efficient promoter in the

solvent-free microwave-assisted synthesis of 2-substituted benzothiazoles (127) from

carboxylic acids (126) and 2-aminothiophenol as depicted in Scheme 1.21.

Scheme 1.21.

R NH

O

CO2Bn

O R'

PO

S

S PO THF, reflux, 14h+

S

N

R R'

CO2BnO R, R' = alkyl, aryl120118 119

N

S

NH

Ar

SR

1.1 eq. DDQCH2Cl2, r.t. 20 min.

ArR

124 125

H2N

HSR COOH

N

S+

0.35 eq. Lawesson's reagentMW (300 W), 190 0C, open vessel

neat, 0.5-4 min.

R

R = alkyl, aryl or hetaryl

127126

21

Chapter 1

1.5.3. Spectral characteristics 1,3-Thiazole possesses three protons, HA, HB, HC at 2, 4 and

5-position respectively where HA appears at δ 8.68, HB at δ 7.83 and

HC at δ 7.19 having coupling constants 0.0 Hz (JAB), 1.9 Hz (JAC)

and 3.2 Hz (JBC) indicating that the electron density is maximum at position-5 of

thiazole. It has been revealed100 that 2,4-disubstituted-1,3-thiazoles display a

downfield shift for C5-H which appears at about δ 7.7 in 1H-NMR spectra in this case. 13C-NMR spectra of thiazoles display C-2, C-4 and C-5 signals in the region δ 165-

170, δ 145-150 and δ 100-105, respectively when recorded in DMSO-d6

S

N

HA

HB

HC

12

34

5

/CDCl3

mixture

MR

while the corresponding carbon signal (C-2) in 13C NMR is displayed at δ 166.4 when

-

azanaphthalene, 1-benzazine and benzo[b]pyridine. Quinoline and its derivatives,

.

Benzothiazole possesses a characteristic C2-H proton which

appears at δ 8.97 in 1H NMR spectrum and carbon signal (C-2) in 13C NMR is displayed at δ 153.8. NH2 group of 2-

aminobenzothiazole appears as a broad exchangeable singlet at δ 5.85 in 1H N

2

34

5

1S

NH

67

recorded in CDCl . 3

1.6. Quinolines Quinoline is a bicyclic heteroaromatic compound in which a pyridine ring is

fused with a benzene ring. It is also known by several other names such as 1

whether natural or synthetic ones, are classified and placed under the alkaloids class.

1.6.1. Biological properties of quinolines Quinolines are considered to be valuable building blocks in pharmaceuticals

and are known for exhibiting various pharmacological activities such as

antimicrobial,147,148 anti-inflammatory,149,150 anti-asthmatic,151,152 anti-oxidants,153

anticancer,154 anti-HIV,155,156 antileishmanial,157,158 antituberculosis,159,160 etc.

Natural quinine (8) as well as synthetic chloroquine (128) and its analogues are some

of the quinoline-based antimalarials161 used for the treatment of malaria which are

supposed to act by interfering haemoglobin digestion in the blood stages of the

malaria parasite’s life cycle. Norfloxacin (129), ciprofloxacin (11) and levofloxacin

(130) are some of the important antibiotics classified under the class

22


fluoroquinolones.162 Oxamniquine (131), a tetrahydroquinoline drug has been found

to be effective anthelmintic with schistosomicidal activity against Schistosoma

mansoni. Martinelline (132) and martinellic acid (133) alkaloids163 containing fused

tetrahydroquinoline nucleus are isolated from the roots of Martinella iquitosensis used

as an eye medication in South America. L-689560 (134) has been reported as a very

potent N-methyl-D-aspartate (NDMA) antagonist.164 Ethoxyquin (135)165 is a

quinoline based antioxidant used as a food preservative (E324) as well as pesticide

and is sold under commercial name “Stop-Scald” in many cosmetics. It is commonly

used as a preservative in pet foods to prevent the rancidification of fats. It is also used

as a rubber stabilizer.

N

HON

O

8

N

HNN

Cl

128

N

F

N

HN

O

OH

O

N

F

N

HN

O

OH

O

N

F

N

N

O

OH

O

O

129

130

NH

HN

HO

N

O

O

NH

O

OR

HN

NH

HN

HN

NHHN

NH

H2N

R = H

R =

131

132

133

NH

O

135

NH

Cl

Cl

COOH

HN

O

NH

134

11

23

Chapter 1

Some substituted quinolines (136) synthesized by Shi et al.166 have been

shown to exhibit potent anti-breast cancer activity. 4-Carboxyl quinoline derivative

137 synthesized by Zarghi et al.167 has been identified as a selective cyclooxygenase 2

(COX 2) inhibitor with potency greater than reference drug celecoxib. Eswaran et

al.168 synthesized a novel series of quinoline based hydrazones 138 which

demonstrated excellent antibacterial and antituberculosis activities. Many of the

sulfonamido-substituted polyhydroquinoline derivatives (139) synthesized by the

research group of Ghorab169- 177 have been shown to be potentially better

antitumor/anticancer agents as compared to the standard drug doxorubicin that act by

es.

few recent methods used for the synthesis of quinoline derivatives are

summarized below:

t and convenient route for the

by nickel-catalyzed

in

Scheme 1.22.

inhibiting carbonic anhydrase isozymR1

1.6.2. Synthetic procedures A

1.6.2.1. Synthesis from 2-iodoanilines Korivi and Cheng178 have developed an efficien

synthesis of 2,4-disubstituted quinoline ood yields

Schem

s (142) in g

cyclization of 2-iodoanilines (140) with alkynyl aryl ketones (141) as shown

e 1.22. The purpose of addition of zinc powder along with nickel catalyst

(NiBr2(dppe)) is to regenerate the catalyst in situ during catalytic cycle.

NH2

IR1

R3

R2

O

+R1

N

R3

R2NiBr2(dppe)

acetonitrile, Zn,80 0C

140 141 142R1 = H, alkyl R2, R3 = alkyl, aryl

N

OF3CH3CO

CH3

NHR

136

N

COOH

SO2Me

137

N CF3

HNN

CF3

R

R = alkyl, aryl, heteroaryl

138

N

OCN

R3

R2

SO2NH2

139

24


1.6.2.2. Synthesis from o-aminophenylboronic acid derivatives Horn et al.179 designed a direct convergent two-component synthesis of

quinolines 146 from o-aminophenylboronic acid derivatives 143 and α,β-unsaturated

ketones (144) through the intermediacy of 3,4-dihydroquinolines (145) as shown in

Scheme 1.23. Such a synthesis is reg tary to the traditional Skraup-

Dobner-Von Miller synthesis and proceeds under basic rather than strongly acidic

Scheme 1.23.

l propargyl alcohol

Reduction of secondary and tertiary o-nitrophenyl propargyl alcohols (147)

followed by acid-catalyzed Meyer-Schuster rearrangement is reported to give 2,4-

disusbtituted quinolines (148) in good yields (Scheme 1.24).180

Scheme 1.24.

1.6.2.4. Synthesis from 2-aminoarylketones Mohammadpoor-Baltork et al.181 synthesized 2,4-disubtituted quinolines (152)

through a one pot reaction of structurally diverse 2-aminoaryl ketones (149) with

various arylacetylenes (150) in the presence of K5CoW12O40 • 3H2O as a reusable and

environmentally benign catalyst under microwave irradiation and solvent-free

conditions. Sarma and Prajapati182 used zinc trifluoromethanesulfonate (in catalytic

iocomplemen

conditions.

1.6.2.3. Reductive cyclization of o-nitrophenyderivatives

B(OR)2

NH2

R4R3

R2

R1

O+N R1

R2

R3

R4

3 mol% [RhCl(cod)]22 eq. KOH (3.8 M)toluene, rt, 24h

N R1

R2

R3

R4

0.2 eq. Pd/C (5%)air

reflux, 4h

143 144 145

146

2 eq.

H/R2H/R2

R3R1

NO2

R1N

1) 4.8 eq. Fe EtOH, conc. HCl (cat.), 80 0C, >2h

2) EtOH/ 10% HCl (pH < 4), 80 0C, 25 h

147R3

148

25

Chapter 1

amoun

e-component reaction of 2-

alkynylbromobenzenes (153), 2-alkynylanilines (154), and electrophiles (155) such as

allyl bromide, NBS or NCS as shown in 6. This conversion is claimed to

rns on the 11H-

t) in the ionic liquid medium [hmim+]PF6-, while indium(III)

trifluoromethanesulfonate under microwave irradiation and solvent free conditions

was used by Lekhok et al.183 for obtaining the desired quinolines 152 by reacting the

same starting materials (Scheme 1.25).

Scheme 1.25.

1.6.2.5. Palladium-catalyzed quinoline synthesis A recent report184 described the synthesis of diverse 11H-indeno[1,2-

c]quinolines (156) via palladium-catalyzed thre

O

R1

NH2

RAr

+0.1 eq. K5CoW12O40 . 3H2O

neat, MW (1000 W)110 0C, 5-20 min. N Ar/Ph

R1

R

Ph

149 150 152

1 mol-% Zn(OTf)2

[hmim+][PF6-]

85 0C, 2-2.5 h

NNMe C6H13where hmim+:

151

1 mol-% In(OTf)3

neat, MW110 0C, 3.5-5 min.

Ph

151

Scheme 1.2

tolerate a wide variety of functionality and substitution patte

indeno[1,2-c]quinoline ring.

Br

R2

R1+

NH2

R4

R3

Br

NR2

R4X

R1 R3

or NBS / NCS

Pd(OAc)2 (5 mol%)PCy3 (10 mol%)

t-BuONa, 1,4-dioxane100 0C

153 154

155(a) (b) (c)

(a) X = allyl(b) X = Br156(c) X = Cl

Scheme 1.26.

26


1.6.2.6. Synthesis of N-arylquinoline derivatives Wang et al.185 reported the three component green synthesis of N-

Ghorab et al.169,170 synthesized benzenesulfonamide bearing polyhydro-

quinolines x-

Scheme 1.28.

arylquinoline derivatives in ionic liquid. Various arylaldehydes 157, 3-arylamino-5,5-

dimethylcyclohexen-2-enone (158), and active methylene compounds including

malonolitrile, meldrum’s acid or 1,3-indanedione were reacted together in ionic liquid

[Bmim+][BF4-] at 90 °C affording N-arylquinoline derivative (159-161), respectively

as depicted in Scheme 1.27. Gao et al.186 disclosed the fluoride ion catalyzed synthesis

of 159 in aqueous medium by reacting 157, 158 and malononitrile together in TBAF

as shown in Scheme 1.27.

Scheme 1.27.

(163) by reacting appropriate aromatic aldehydes 157, 4-(3-oxo-cyclohe

ArCHO

O

NHCH2(CN)2

157

SO2NH2

+ Et3N (cat.)EtOH, reflux

O

N

SO2NH2

ArCN

NH2

+

163162

ArCHO +

O

NH

Ar' N

CN

NH2

Ar

Ar'

O

CH2(CN)2

O O

O O

NAr'

O

ArO

O

O

N

O Ar O

Ar'

TBAF (10 mol%)5 mL H2O

reflux

159160

161

157 158

[Bmim+][BF4-]

[Bmim+][BF4-] [Bmim+][BF4

-]

27

Chapter 1

1-enylamino)-benzenesulfonamide (162) and malononitrile together in refluxing

ethanol in the presence of catalytic amount of triethylamine (Scheme 1.28).

1.6.3. Spectral characteristics Quinoline shows close similarities with naphthalene and

pyridine in spectral characteristics. 1H NMR spectrum of quinoline

displays seven NMR peaks: H-2 at δ 8.81, H-3 at δ 7.26, H-4 at δ 8.00, 13

6

2

345

6

7 N18

4a

8a

H-5 at δ 7.68, H-6 at δ 7.43, H-7 at δ 7.61 and H-8 at δ 8.05 while C NMR spectrum

shows nine signals: C-2 at δ 150.3, C-3 at δ 120.8, C-4 at δ 135.7, C-5 at δ 127.6, C-

at δ 126.3, C-7 at δ 129.2, C-8 at δ 129.3, C-4a at δ 128.0 and C-8a at δ 148.1 when

recorded in CDCl3.187 ArO

N-substituted-4-aryl-polyhydroquinolines185-188 (164)

display a characteristic singlet near at δ 4.5 corresponding to C4-

H.

1NR4

R4

R1

R2R3

2

345

8

164

6

7

28


29

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