synthesis and biological evaluation of some nitrogen
TRANSCRIPT
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
Brief review on nitrogen containing heterocycles
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
Brief review on nitrogen containing heterocycles
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
Brief review on nitrogen containing heterocycles
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
Brief review on nitrogen containing heterocycles
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
Brief review on nitrogen containing heterocycles
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
Brief review on nitrogen containing heterocycles
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
Brief review on nitrogen containing heterocycles
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
Brief review on nitrogen containing heterocycles
(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
Brief review on nitrogen containing heterocycles
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
Brief review on nitrogen containing heterocycles
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
Brief review on nitrogen containing heterocycles
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
Brief review on nitrogen containing heterocycles
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
Brief review on nitrogen containing heterocycles
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
Brief review on nitrogen containing heterocycles
29
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