STUDIES ON SYNTHESIS OF -HYDROXY …shodhganga.inflibnet.ac.in/bitstream/10603/3442/10/10...STUDIES...

47

CHAPTER 2 (SECTION-A)

STUDIES ON SYNTHESIS OF -HYDROXY CARBOXYLIC ACIDS

2.1 INTRODUCTION:

The three most important classes of compounds in the pool of

chiral building blocks [1] are carbohydrates, amino acids and hydroxy

carboxylic acids. In contrast to the carbohydrates, many representatives

of the other two groups are now available in both the enantiomeric forms,

such as lactic acid [2, 3], mandelic acid, maleic acid [4], tartaric acid [5],

and phenyl lactic acid [6]. The variety is further increased by the fact that

some of the optically active amino acids can be converted to -

hydroxycarboxylic acids with retention of configuration [7]. Thus, it is not

surprising that compounds of this type are used frequently as starting

materials for the synthesis of other enantiomerically pure products.

Some of the -hydroxycarboxylic acids commonly encountered in natural

products and synthetic work are shown in Table-2.1.

Table 2.1 Some -hydroxycarboxylic acids

S. No Name of the compound Structure

1 2-Hydroxyethanoic acid

(Glycollic acid) H

OH

O

OHH

48

2 2-hydroxypropanoic acid

(Lactic acid) H3C

OH

O

OH

3 2-Methyl-2-hdroxypropanoic acid

(Methyl lactic acid) H3C

OH

O

OHH3C

4 2-Hydroxybutanoic acid H3C OH

O

OH

5 2-Hydroxypentanoic acid, OH

O

OH

H3C

6 2-Hydroxyhexanoic acid OH

O

H3C

OH

7 Maleic acid

COOH

COOH

HO

The synthesis of enantiomerically pure -hydroxy carboxylic acids

is of general interest and applicability to asymmetric organic synthesis as

it provides a direct route to the preparation of a large variety of

heterocyclic systems, as well as natural and pharmacologically

interesting products. In this regard, the preparation of -hydroxy

carboxylic acids is particularly important. Several different methods for

the synthesis of -hydroxycarboxylic acids have been reported. Some of

them are described below:

49

2.2 LITERATURE REPORTED METHODS:

Hulin et al., [8] have reported a racemic approach (Scheme-2.1) for

the synthesis of the title compound, where in trimethylsilyl cyanide was

added to phenyl acetaldehyde followed by acid hydrolysis of the silylated

cyanohydrin in alcoholic medium to afford racemic -hydroxy phenyl

propanoic ester, which was hydrolyzed to acid. The major disadvantage

of this method being the handling of raw materials, they are quite

unstable and difficult to store and use.

CO2R

OH

CHO CN

OSi(CH3)3

(CH3)3SiCNROH/HClHydrolysis

1 2 3

………Scheme-2.1

The approach adopted by Gerhard et al., (9) (Scheme-2.2) involves

substituted benzaldehyde, which is more stable, compared to aryl

acetaldehydes used in Hulin et al., method. The strategy involved in this

method is the condensation of aldehyde moiety with hydantoin to give

the corresponding hydantoin derivative. The later on hydrolysis under

basic conditions results in the formation of -ketoacid. Reduction of the

-ketoacid with sodium borohydride in alcoholic medium affords the

required racemic product in moderate yield. The disadvantages are being

the solubility of the intermediates and the instability of -keto acid.

50

CHO

HOHO

CO2H

O

HO

CO2H

OH

HO NH

HN

O

O

NH

HN

O

O

Piperidine Aq OH-

NaBH4 / IPA

45 6

7

………Scheme-2.2

The azalactone method developed by Herbest et al., (10) (Scheme-

2.3) for the synthesis racemic -hydroxycarboxylic acids is quite

interesting since the raw materials are quite easily available and

reactions are quite feasible. The major disadvantage is being the use of

mercury, for the reduction, which is quite poisonous and causes serious

effluent problem. The synthetic method consists of condensation of an

aromatic aldehyde with N-acetylglycine to furnish the corresponding

azalactones, which on further reductive hydrolysis using zinc amalgam &

conc. hydrochloric acid afforded the required racemic -hydroxy

carboxylic acid in moderate yield.

CHOCO2H

OHNO

O

CH2CO2H

NHCOCH3

AC2O/CH3CO2Na Zn-Hg/HCl

8 9 3

………Scheme-2.3

51

The method developed by Aston et al., (11) (Scheme-2.4), the title

compound was prepared by the oxidation of the methyl group and

subsequent reduction of the keto group of the acetophenone. The

oxidation of the methyl group was achieved by the halogenation of

acetophenone in acidic medium followed by base hydrolysis and

acidification to afford the -ketoacid, which was reduced to alcohol. The

major disadvantage is being the difficulty in controlling the halogenation

and the separation of the by- products. The yields are moderate and such

reactions are difficult to handle on the plant scale.

O O

Cl2 CO2H

OHNaOHHCl

2Cl2

10 11 12

………Scheme-2.4

The synthetic strategy adopted by Green et al., (12) (Scheme-2.5)

consists in the introduction of acetyl and the benzyl groups on to the

active methylene group of acetoacetic ester by acetyl chloride and the

benzyl bromide respectively in the presence of a strong base. The

resulting disubstituted acetoacetic ester was subjected to base hydrolysis

to obtain the required product in moderate yield. The drawbacks of this

method being the use of costly and sensitive reagents like LTA. The other

disadvantage is that the method has poor atom conservation and hence

it is not eco friendly.

52

H3COCO CO2C2H5

OH3COCO CO2C2H5

O

CH3COCH2COOC2H5

CO2H

OH

LTA

Benzene

350 C

NaHBnBrDioxane

NaethanolReflux

13 14 15

16

………Scheme-2.5

Kenji Koga et al., (13) have introduced a new method (Scheme-2.6)

for preparing chiral -hydroxycarboxylic acids by Chiron approach. In

this method the synthesis of required -hydroxy acid was achieved via

diazotizing the appropriate - amino acid with sodium nitrite and

mineral acid. The major disadvantage of the method is partial

racemisation.

CO2H

YOH

Y

HO

CO2H

YNH2

NaNO2

1NH2SO4

COOH

YOH

COOH

Y Y

COOH

/H2O+ +

+

16 17 18 19

20 21

………Scheme-2.6

Milton et al., (14) (Scheme-2.7) have modified the Kenji Koga

approach by introducing acetic acid in place of sulfuric acid. The author

53

has utilized acetic acid as one of the medium in the diazotization process

instead of aqueous sulfuric acid in the previous approach to obtain the

required product. The specific rotation data did not match with the

reported literature data, which is one of the drawbacks of the process.

CO2H

1N HCl

CH3CO2H

NaNO2CO2H

NH2 OH

22 23

………Scheme-2.7

Kenji Mori (15) (Scheme-2.8) approach is much more improvised in

obtaining relatively pure chiral form in spite of some racemisation. The

method is similar to the one demonstrated by Kenji Koga. The product

was recrystalized three times to attain the reported chiral purity. This

approach is similar to the earlier approach mentioned by Kenji Koga et

al., the difference being found in the workup procedure. The product

after three recrystallizations was found to be very close to the reported

value in terms of its optical rotation.

COOH COOH

NH2 OH

HNO2

24 25

………Scheme-2.8

54

Palomo et al., [16] used (Scheme 2.9) the different reaction

conditions were employed where in acid and nitrite solutions were added

simultaneously to the aqueous -amino acid solution to perform

diazotization for Valine. The product was isolated in 57% yield. The major

disadvantage of this method being the three recrystallizations required

for getting the pure product.

H2SO4/2N NaNO2

H2O,O0C-rtR COOH

NH2

R COOH

OHR= (26) CHMe2 (27)

(24) CH2CHMe2 (25)

(28) CH2Ph (3)

………Scheme- 2.9

The method developed by Junji Inanaga et al., (17) (Scheme-2.10)

is based on the regioselective ring opening of the,-epoxy esters. This

method consists of regioselective ring opening followed by methyl iodide

and subsequent reduction of the resulting iodohydrins to afford racemic

-hydroxycarboxylic acid. The disadvantage is being the possibility of the

by products and costly raw materials.

CO2H

OH

CO2H

OHY:77%

oCO2H

IMgI2 Bu3SnH

28 29 23

………Scheme-2.10

55

2.3. PRESENT WORK:

The literature review on the various methods of synthesis of -

hydroxycarboxylic acids revealed that the synthesis of this moiety was

achieved by using a racemic synthetic method followed by resolution to

its desired enantiomer. This method is traditional and no novelty is

involved. The other method followed is Chiron approach starting from

amino acids. This method is quite good in the sense that a single isomer

is expected to be the desired product. The mechanism involved in this

method is illustrated in the scheme-2.11.

Y

CH2

CH2N H

CO2H

Y

CH2

CH

OC

O

Y

CH2

CX H

CO2H

Y C

CH2X(30) (31)

(32)

(33)

CO2H

H


The amine group is subjected to diazotization and subsequently

eliminated. During the process,

the free hydroxy group of the carboxylic acid extends the anchimeric

assistance leading to the formation of oxirane derivative, which leads to

the inversion of the configuration. Subsequently hydroxyl group attacks

the ring from the rear side in SN2 type leading to the inversion of the

56

configuration for a second time. The two inversions amount to the

retention of the configuration. Hence the configuration of the amino acid

is retained in the -hydroxy carboxylic acid.

2.4. RESULTS AND DISCUSSION:

The reactions of nitrous acid on optically active -amino acids

having hydrogen and having an asymmetric -carbon atom are reported

to give exclusively -hydroxycarboxylic acids with retention of

configuration, due to the participation of the neighbouring carboxylate

group. From literature precedent it was known that the reaction is highly

dependent on the solvent.

In the present modified process, water miscible solvent namely

acetone was used along with water as a medium for diazotization

reaction and after completion of the reaction the pH of the solution was

increased by addition of conc. HCl followed by extraction. With these

modifications, the yields dramatically improved from 30% to 75%

subsequently this methodology was applied on different amino acid

substrates resulting in consistently higher yields.

The methods followed by various other authors have some

disadvantages like racemisation of the product, low yield, tedious work

ups and purification of the product by several recrystallisations. In view

57

of the present situation, a simple and efficient method has been

developed. The major advantages of this method are:

(i) The racemisation is arrested to a minimal level,

(ii) The work up has been simplified and

(iii) Yields and the purities have been improved.

This method has been utilized for conducting experiments on both

aromatic and aliphatic amino acids. The detailed experimental procedure

and the spectral data are given in the experimental section.

2.4.1. GENERAL PROCEDURE:

The reactions were carried out as follows: To a solution of optically

pure L-amino acids in 6% H2SO4 and acetone (1:1 ratio), were added 3

molar equivalents of sodium nitrite in water solution at 00c for 15 min.

After complete addition, the reaction was maintained at same temp for

additional 120 min and the whole was allowed to stand at room

temperature overnight. Reaction mass was poured in water (25ml) and

hydrochloric acid (5ml) was added. The product was extracted into ethyl

acetate (3x25ml), combined organic layers were washed with water

(1x25ml) and concentrated to a syrupy residue. Optical rotation of the

work up compound was checked and matched with reported values.

58

ROH

NH2

O

R'OH

OH

O

34 (a-f) 35 (a-f)

………Eqn-2.1

Reaction conditions: H2SO4/NaNO2/ H2O/Acetone/ (-) 50C-RT

2.5. EXPERIMENTAL SECTION

Preparation of 35 a-f: (General procedure)

A mixture of optically pure L-amino acids 34 a-f (1.0 g) in acetone

(5.0 ml) and dilute sulfuric acid (6%, w/v 5.0ml) was placed in a three-

necked round bottomed flask, equipped with a magnetic stirrer and

cooled to (-) 50C.To this was added a solution of sodium nitrite (2.32 g,

0.033 mole) in water (5.0 ml) slowly below 00c for 15min. After complete

addition, the reaction was maintained at same temp for additional 120

min and brought to room temperature while stirring overnight.

Reaction mass was poured in water (25 ml) and hydrochloric acid

(5 ml) was added. The product was extracted into ethyl acetate (3X25 ml)

combined organic layers were washed with water (1X25 ml) and

concentrated to a syrupy residue. This was purified by column

chromatography, eluting the product with mixtures of pet-ether and ethyl

acetate to yield pale yellow syrup.

59

Representative Spectral data

35a: IR (Neat): 3448 (OH, broad), 2923 (m), 1731 (s), cm-1; 1HNMR

(DMSO-d6) δ 3.0-3.2 (dd, 2H, CH2), 4.5 (dd, 1H, CH), 5.0 (OH), 7.3 (m,

5H, Ar-H). Mass (CI method): (M++1) 167.

35b: IR (Neat): 3449 (s), 2928 (br), 1723 (s) cm-1; 1HNMR (in DMSO) δ 3.5

(brs, 1H, OH), 5.0 (s, 1H, CH), δ 7.4 (m, 5H, Ar-H). Mass (CI method):

(M++1) 153.

35c: IR (Neat): 3448 (OH), 2923 (m), 1731 (s), cm-1; 1HNMR (in CDCl3) δ

0.95 (d, 3H, CH3), 1.1 (d, 3H, CH3), 2.1 (M, 1H, CH), 4.15 (d, 1H, CH), 5.9

(OH). Mass (CI method): (M++1) 119.

35d: IR (CHCl3):3414 (br), 3018 (w), 2967 (s), 2928 (w), 2875 (w), 1719

(br) cm-1; 1HNMR (in CDCl3) δ 0.9 (t, 3H, CH3), 1.1 (d, 3H, CH3), 1.4 (m,

2H, CH2), 1.9 (m, 1H, CH), 4.1 (d, 1H, CH) 4.6 (OH). Mass (CI method):

(M++1) 133.

35e: IR (Neat): 3448 (OH), 2923 (m), 1731 (s), cm-1; 1HNMR (in CDCl3) δ

1.0 (d, 6H, 2XCH3), 1.66 (q, 2H, CH2), 2.0 (m, 1H, CH), 4.9 (s, 2H, ) 5.2

(dd, 2H). Mass (CI method): (M++1) 133.

35f: IR (Neat): 3398 (OH, br), 2007 (br), 1730 (br) cm-1; 1HNMR: (in

DMSO) δ1.1 (d, 3H, CH3), 3.5 (s, OH), 4.0 (q, 1H, CH). Mass (CI method):

(M++1) 91.

60

CHAPTER 2 (SECTION-B)

SYNTHESIS OF 3-ARYL-2-QUINAZOLINYL-PHENYLACETIC ACID

ESTER DERIVATIVES

2.6. INTRODUCTION TO QUINAZOLINONES:

Quinazolinones (fig-1) are a building block for several naturally

occurring compounds isolated till date from different families of the plant

kingdom, animals and microorganisms. The primary quinazolinone was

synthesized [18] in the late 1860s from anthranilic acid and cyanogens to

give 2-cyanoquinazolinone. Awareness in the medicinal chemistry of

quinazolinone derivatives was inspired in the early 1950s with the

clarification of a quinazolinones alkaloid named as Febrifugine from an

Asian plant Dichroa febrifuga, which is an element of a conventional

Chinese herbal solution useful against malaria.

N

N

O

R1

R2

Figure-1. Quinazolinone basic structure

In view of the significance of the above quinazolinone derivatives

are possible for several activities, it has been considered of interest to

intend and synthesize new quinazolinone moieties for linking them to

derivatives of α-hydroxy carboxylic acids through piperazine moiety.

61

2.7. LITERATURE REPORTED METHODS

Bhatta et al., [19] has introduced a new method for preparing

substituted quinazol-4(3H)-ones by condensation in presence of pyridine

& cyclization in presence of potassium carbonate. In this method the

synthesis from anthranilic acid with chloroacetyl chloride in pyridine

followed by cyclization with appropriate amine in presence of potassium

carbonate at reflux. The disadvantage of this method is usage of highly

carcinogenic solvent like benzene and lesser yields (Scheme 2.12)

NH2

R1

R2

CO2H

NH

R1

R2

CO2H

COCH2Cl

N

N

Cl

O

RR2

R1

RNH2/K2CO3

ethanolClCOCH2Cl

Pyridine/reflux

36 37 38

………Scheme 2.12

Pandey et al., [20] utilized the substituted anthranilic acids to

condense with benzoyl chloride in pyridine giving benzoxazinone addition

product, which on reaction with a substituted amine in pyridine resulted

in the substituted quinazolines. The disadvantage of this method is use

of a large excess of pyridine and removal of pyridine as solvent by

addition of excess of water leading to the loss of yields (Scheme 2.12)

NH2

R1

CO2H

N

O

O

R1

Ph N

N

O

R1

R

Ph

PHCOClRNH2

pyridine

Pyridine/reflux

39 40 41 ………Scheme 2.13

62

Ichizo Inoue et al., [21] have attempted the alternate reaction of

anthranilic acid with thionylchloride in boiling benzene, followed by

treatment with the amines afforded the anthranilamines in moderate

yields and cyclization of anthranilamines with excess chloroacetyl

chloride in acetic acid at 110°C gives substituted quinazolines. The

disadvantage of this method is using highly carcinogenic benzene and

fewer yields (Scheme 2.14)

NH2

R2

CO2H

R1

NH2

NH

O

R2

R

R1

N

N

O

R2

R

Cl

R1

42 43 44

SOCl2

R-NH2

ClCOCH2Cl


Substituted quinazolinones Ahmad et al., [22] have been

synthesized in high to excellent yields through the one-pot condensation

of anthranilic acid, trimethyl othoformate and primary amines in the

presence of 5 mol% of Bismuth (III) trifluoroacetate immobilized on n-

butyl pyridinium tetrachloro ferrate ionic liquid at room temperature.

The major disadvantage in this approach is using of costly reagents like

bismuth (III) and n-butyl pyridinium tetrachloro ferrate (Scheme 2.15)

NH2

CO2H

N

N

O

R

45 46

R-NH2+ + HC(OR)3

Bi(TFA)3-[nbp]FeCl4


63

Venkateswarlu et al., [23] have developed a quick one-pot

synthesis of substituted quinazolinones from reaction of anthranilic acid,

trialkyl orthoformate and amines in the presence of lanthanum (III)

nitrate hexahydrate under solvent free conditions. The disadvantage of

this method is that the author did not mention the isolated yield and

usage of rare reagents like lanthanum complex (Scheme 2.16)

NH2

CO2H

N

N

O

R1

1R-NH

2

45 47

+ + HC(OR)3

La(NO3)3.6H2O


S R Pattan et al., [24] have prepared pirazine derivative by

condensing 3-substituted quinazolinones with pirazine amines in excess

pyridine and acetic anhydride. The main disadvantage of this approach is

the usage of excess pyridine and costly reagent like acetic anhydride and

getting lower yields (Scheme 2.17)

N

N

O

Cl

S

N

R1

N

NNH2

N

N

O

S

N

R1

NH

N

N

+

Py/Ac2O

48 49 50


64

Shanthan Rao et al., [25] have developed one-pot synthesis of

substituted quinazolinones has been carried out by the three-component

coupling of anthranilic acid and amines in presence of Nafion-H (a

perfluorinated resin-supported sulfonic acid) as a heterogeneous catalyst

under solvent free microwave irradiation condition. The major

disadvantage of this method is that the reactions cannot be handled on

larger scales (>50-100 g) & industrially not feasible method (Scheme

2.18)

NH2

OH

O

NH2

N

N

O

+

Nafion-HMW

45 51 52


Kurosh Rad et al., [26] have developed a convenient method for the

synthesis of 3-substituted quinazolin-4(3H)-ones using the convergent

reactions of formic acid a primary amine and isotoic anhydride under

solvent free conditions and with microwave irradiation (Scheme 2.19)

NH2

NH

O

R

N

N

O

R

53 54

HCO2H,MW


65

Besson et al., [27] have reported 3H-quinazolin- 4-one by using

microwave irradiation and improved the yields and reduced the reaction

time (Scheme 2.20)

NH2

OH

O

N

NH

O

N

OH

O

NH2

+ H2N-CHO

45 55 56

reflux130-150°C


2.8 PRESENT WORK:

The present work describes the design and synthesis of novel

quinazolinone derivatives of 2-(2-(4-((3,4-dihydro-4-oxo-3-arylquina

zolin-2-yl)methyl)piperazin-1-yl)acetoyloxy)-2-phenyl acetic acid esters

(57) incorporating three biologically active moieties such as

quinazolinones, piperazine and L-mandelic acid derivatives in a single

molecule. (Scheme 2.21)

OR

O

O

N

O

N

N

N

O

R1

57

66

The present work also describes the synthesis of several novel

derivatives of quinazolinones by incorporating different substituted aryl

amines at 3rd position and cyclic rings containing nitrogen nucleophiles

such as ethyl 4-piperidinecarboxylate, morpholine and piperidone at 2nd

position of quinazolinone nucleus in solution phase and also under

solvent-free conditions using Poly ethylene glycol (PEG-400) by simple

physical grinding with mortar and pestle.

The present work illustrate the synthesis of various sulfones of 2-

(4-methanesulfonylpiperazin-1-yl-methyl)-3-phenyl-quinazolin-4(3H)-one

& 2-(4-benzenesulfonyl-piperazin-1-yl-methyl)-3-phenyl-quinazolin-4(3H)

-one from anthranilic acid.

2.10. RESULTS AND DISCUSSION:

The retro synthetic analysis of present route (Scheme-2.21)

revealed that the molecule could be dissected into two intermediates

namely 2-chloroacetoxyphenyl acetic acid esters (58) and 3-aryl-2-

(piperazin-1-yl)quinazolin-4(3H)-one (59), which can be condensed

conveniently to afford the final product. Accordingly, the present work

describes here a more efficient method wherein the two key intermediates

58 & 59 are made simultaneously and upon condensation produce 2-(2-

(4-((3,4-dihydro-4-oxo-3-arylquinazolin-2-yl) methyl)piperazin-1-yl)

acetoyloxy)-2-phenyl acetic acid esters (57).

67

O

O

OR

O

N

N

N

N

O

Ar

O

O

OR

O

Cl

NH

N

N

N

O

Ar+

57 58 59


The synthetic strategy described above was implemented by

making the two key intermediates 58 & 59 simultaneously. The crucial

α-hydroxy compound process was developed by same group & prepared

by a stereo selective diazotization of L-phenyl glycine (34b) in aqueous

acetone, using sodium nitrite in presence of dil. H2SO4, to afford (L)-2-

hydroxy-2-phenyl acetic acid (35b) in 70% yield with more than 99%ee.

These results are further supported by comparison with known

compound of L-Mandelic acid by optical rotation and chiral HPLC. When

compare the previous literature reports, this method is very

advantageous because product is obtained in good yields and no side

products are formed. 35b on treatment with isopropyl alcohol in

presence of catalytic amount of Conc. H2SO4 under refluxing conditions,

gave, the previously reported [28] isopropyl (2S)-2-hydroxy-2-

phenylethanoate (60). The latter on treatment with chloroacetyl chloride

in dichloromethane using triethylamine as a base at room temperature to

obtain desired isopropyl (2S)-2-[(2-chloroacetyl) oxy)-2-phenylethanoate

(58) and further it was characterized by IR, 1H NMR & Mass. (Scheme-

68

2.22) In IR spectra showed two strong absorptions at 1768.4 & 1747.19

cm-1 for carbonyl group. The main resonances in 1HNMR spectra in

CDCl3 are, i) two resonances at 1.05-1.1 and 1.15-1.20 ppm, usually

two three proton doublets which corresponds to two methyl groups on

isopropyl, ii) a doublet of doublet at 4.2-4.3 ppm, usually two proton

adjacent to chlorine group iii) a multiplet single proton at 5.1 ppm of

isopropyl group iv) a sharp singlet at 5.9 ppm of chiral proton and v)

five proton multiplet at 7.4-7.5ppm for aromatic protons. The (M++1)

peak 217.9 showed in mass spectra.

O

O

OR

O

ClOH

O

OH

OH

O

OR

35b 60 58

i ii

R = Me, Et, Isopropyl


Reagents and Conditions: i) R-OH, Conc.H2SO4 (R= Me, Et, Isopropyl)/

Δ; ii) Chloro acetyl chloride, TEA, DCM, RT.

In another sequence of reactions anthranilic acid (45) was treated

with chloroacetyl chloride in presence of triethylamine in

dichloromethane at room temperature to obtain previously reported [20]

2-chloromethyl benzo [d][1,3]oxazin-4-one (61). The latter on treatment

with aniline in refluxing pyridine for 5-6 h, followed by simple processing

69

resulted in the formation of 2-(chloromethyl)-3-phenyl-3,4-dihydro-4-

quinazolinone (62) [21]. 62 reacted with N-Boc-piperazine in acetonitrile

and K2CO3 as a base in presence of catalytic amount of KI under

refluxing conditions for 1-2 h, yielded a neat product which has been

characterized as tert-butyl-4-[(4-oxo-3-phenyl-3,4-dihydro-2-quinazolin

yl)methyl]-1-piperazinecarboxylate (63), on the basis of IR, 1H NMR &

Mass spectral data (Scheme-2.23). In IR spectra a strong absorption

showed at 1687.4 cm-1 for carbonyl group. The major resonances in

1HNMR spectra of the 63 in CDCl3 are i) a sharp singlet at 1.4 ppm

usually nine proton of tert-butyl group, ii) a broad singlet at 2.25 ppm

usually four protons of piperazine, iii) a sharp singlet corresponds to CH2

protons between quinazolinone and piperazine and four piperazine

protons together appeared at 3.2-3.25 ppm, iv) nine aromatic proton

multiplet appeared at 7.3-8.3. The mass peak showed at 421.1 (M+1

peak) with 100% abundance, a 40% abundance showed at 365 with loss

of tert-butyl group. Treatment of 63 with methanolic HCl (10% w/w)

solution at room temperature for Boc deprotection gave 3-phenyl-2-

(piperazinomethyl)-3,4-dihydro-4-quinazolinone hydrochloride salt (59).

The compound 59 further characterized by IR, 1H, 13C NMR & Mass

spectral data. In IR spectra a strong absorption showed at 1676.8 cm-1

for quinazolinone carbonyl group. The major resonances in the 1HNMR

spectra in CDCl3 are i) a two broad singlets at 2.2 and 2.8 ppm for

piperazine CH2 protons, ii) a sharp singlet at 3.25 usually a CH2

70

protons between quinazolinone and piperazine and iii) a multiplet at

7.35-8.35 for nine aromatic protons. The mass peak showed at 321.4

(M++1) with 100% abundance.

NH2

CO2H

N

O

O

Cl N

N

O

Cl

Ar

N

N

O

N

ArN

O

O

N

N

O

N

ArNH. HCl

45 61 62 63

59

i ii iii

iv


Reagents and Conditions: i) chloroacetyl chloride, TEA, DCM; ii) Ar-

NH2, (Ar = a=-C6H4-2-CF3; b = -C6H4-3-OCH3; c=-C6H4-2-CH3; d=-C6H5),

pyridine, Δ; iii) N-BOC-piperazine, K2CO3, KI, CH3CN, Δ; iv) 10%

methanolic HCl.

Having made two key intermediate 58 & 59 simultaneously, the

two units were condensed (Scheme-2.24) in presence of potassium

carbonate and catalytic amount of KI in refluxing acetonitrile to afford

desired compound isopropyl (2S)-2-[(2-{4-[(4-oxo-3-phenyl-3,4-dihydro-2-

quinazolinyl)methyl]piperazine} oxy]-2-phenylethanoate (57) in good

yields. The obtained product was characterized by IR, 1H, 13C NMR, &

Mass spectral analysis. The major IR absorptions showed at 1747, 1695,

1602 and 1585 cm-1. The main resonances in the 1HNMR in CDCl3 are i)

a two three proton doublets at 1.3 & 1.5 ppm corresponds to methyl

71

groups on isopropyl, ii) a two broad singlet’s at 2.55-2.8 corresponds to

CH2 piperazine protons, iii) a singlet at 3.45 ppm corresponds to CH2 in

between quinazolinone & piperazine ring, iv) a doublet of doublet at

3.5-3.65 ppm which corresponds for CH2 protons in between piperazine

and carbonyl group, v) a multiplet showed at 5.2 ppm for CH proton on

isopropyl group, vi) a sharp singlet showed at 6.1 ppm usually

corresponds to chiral proton of mandalate and vii) a 14 proton multiplet

at 7.5-8.5 ppm correspond to aromatic protons. The major resonances

in the 13CNMR in CDCl3 are 21.28, 21.55 (two CH3), 52.48 (four

piperazine CH2), 58.7 (one CH2 between quinazolinone & piperazine),

61.0 (one CH2 between piperazine and carbonyl), 69.4 (CH of isopropyl),

74.6 (CH of Chiral carbon on mandalate), 121.1 (quaternary Carbon on

quinazolinone ring attached to keto), 146.9 (quaternary Carbon on

quinazolinone adjacent to N), 162 (carbonyl of quinazolinone), 167.9 &

169.5 ( two carbonyls of adjacent to chiral carbon). The mass spectra

showed a major 100% abundance at 555 (M++1 peak), this is strongly

supports the M++1 ion peak (compound mol weight is 554), another

molecular ion showed with 10% abundance at 379 which corresponds to

cleavage of mandalate ester. During this, reaction racemisation takes

place which is confirmed by checking of isolated compounds for optical

purity by Polarimeter and value showed is 0°. The explanation for the

racemisation is α- hydrogen is labile and thus causing racemisation

under the given conditions.

72

O

O

OR

O

N

N

N

N

O

Ar

O

O

OR

O

Cl

NH

N

N

N

O

Ar+

58 59 57

i


Reagents and Conditions: i) K2CO3, KI, CH3CN, Δ.

2.10.1 NITROGEN NUCLEOPHILES

The reaction of 2-(chloromethyl)-3-(2-methylphenyl)-3,4-dihydro-4-

quinazolinone 62 (Ar = C6H4-3-OCH3) with 4-Piperidone, K2CO3 and KI,

under refluxing acetonitrile for 90-120 min. resulted in the formation of

3-(2-methylphenyl)-2-[(4-oxopiperidino)methyl]-3,4-dihydro-4-quinazolin-

one (64). Structure of the latter compound was established by spectral

and analytical data. (Scheme-2.25) This reaction found general one and

has been extended to other nitrogen nucleophilic substrates such as

ethyl-4-Piperidinecarboxylate, morpholine and products thus obtained

were assigned structures 65 and 66 respectively on the basis of their

spectral data.

73

N

N

O

Cl

Ar

N

N

O

Ar

N

O

N

N

O

Ar

N

O

N

N

O

Ar

N

CO2Et

i ii iii

62c

64 65 66

(Ar = a = -C6H4-3-OCH3; b=-C6H5; c=-C6H4-2-CH3; d=-C6H4-2-CF3)


Reagents and Conditions: i) 4-Piperidone, K2CO3, KI, CH3CN, Δ; ii)

morpholine, K2CO3, KI, CH3CN, Δ; iii) 4-ethyl piperdinecarboxylate,

K2CO3, KI, CH3CN, Δ; Under Solvent-Free conditions: i/ii/iii) 4-

Piperidone / morpholine/ ethyl 4-Piperdinecarboxylate, K2CO3, KI, PEG-

400, mortar and pestle.

The IR spectrum of 64 showed the main absorption showed at

region 1712.48 & 1684.52 cm-1 corresponds to carbonyl groups present

in quinazolinone and piperidine. The main resonances in the 1HNMR in

CDCl3 are at 2.15 a sharp singlet corresponds to CH3 group on

74

benzene, ii) a two four proton multiplet at 2.3-2.4 & 2.5-2.66 ppm

usually corresponds to piperidone iii) a two proton doublet of doublet at

3.25-3.44 corresponds to CH2 protons between quinazolinone and

piperidone iv) a series of multiplet at 7.2-8.3 corresponds to eight

aromatic protons. The mass spectrum showed the major peak at 348.3

(M++1) with 100% abundance and

Conversion of 62 to corresponding 64, 65, and 66 derivatives is

favoured in presence of KI. This is probably due to the fact that in

presence of KI, the chlorine of 62 is initially replaced by iodine and

subsequent reaction of iodo derivative of 62 with the nitrogen

nucleophile is facile.

R-Cl + KI R-I+ KCl


In recent years considerable attention has been paid to reactions

done under solvent-free conditions [29]. One of the areas of central

attention in this field includes reactions between solids. These reactions

are not only of interest from an economical point of view in many cases

they also offer considerable synthetic advantages in terms of yield,

selectivity and simplicity of the reaction procedure.

PEG-400 [30] has been applied here as an efficient reaction

medium for the preparation of quinazolinone derivatives containing

75

nitrogen cyclic ring systems. It is a biologically acceptable inexpensive

polymer and an eco-friendly reagent. The PEG-400 is widely used in

many organic reactions for several conversions

Alternatively, reaction of 62 with 4-Piperidone in presence of PEG-

400 is carried out in solid phase by physical grinding in a mortar and

pestle for ~8 min. and subsequent work-up yielded product identical with

64 obtained in solution phase in all respects by comparison with mp, IR

data.

It was found that above reactions between 62 and 4-Piperidone did

not occur in the absence of PEG-400 even after grinding mixture of solids

for 3-4 hrs (scheme 2.27). Thus it appears that PEG-400 acts like a

Crown ether and that is why the addition of KI makes the reaction much

faster because PEG-400 enhances the nucleophilicity of the iodide ion

and facilitating reaction between 62 and 4-Piperidone.

N

N

O

Cl

Ar

N

N

O

R

ArR, K2CO3, KI, Solvent-free

Ar= -C6H5-2-CH3; R= 4-Piperidone


Above reactions are of significant in nature when compare to the

solution phase method in terms of time, yield and eco-friendly nature of

the reaction.

76

Reaction between 62 and 4-Piperidone in solution phase and also

under solvent-free conditions using PEG-400 as catalyst has been found

to be a general one and has been extended to other nitrogen nucleophilic

substrates such as ethyl-4-Piperidinecarboxylate, morpholine and

products thus obtained were assigned structures 65 and 66 respectively

on the basis of their spectral data. Furthermore, reactions of ethyl

piperdine-4-carboxylate, morpholine and 4-Pieridone are very general

and have been found to occur with other quinazolinone derivatives

resulting in the formation of 64, 65, 66 (whose structures were assigned

based on spectral data

2.10.2 SULFONES:

The compound 59 was treated with methanesulfonyl chloride

(MsCl) in dichloromethane containing TEA as base to obtain 2-(4-

methanesulfonyl-piperazin-1-yl-methyl)-3-phenyl-quinazolin-4(3H)-one

(67, R=-CH3). The structure of 67 has been established on the basis of

their spectral data. The above reaction of 59 to 67 has been found to be

general and has been extended to other aryl groups. The conversion of

59 with benzenesulfonyl chloride give 2-(4-benzenesulfonyl-piperazin-1-

yl-methyl)-3-phenyl-quinazolin-4(3H)-one (67, i.e. R=-C6H5) (Scheme-

2.28). All the products obtained in the above work have been

characterized by spectral data.

77

N

N

O

N

ArNH

N

N

O

N

ArN

SR

O

O

59 67

R-SO2-Cl

TEA, DCM

(R= Me, Ph)


Alternatively the title compounds 67 could also be prepared by the

following sequence of reactions. N-BOC Piperazine was treated with

methanesulfonyl chloride in acetone containing pyridine at ambient

temperature to yield 4-methanesulfonyl piperazine-1-carboxylic acid tert-

butyl ester 68, which was treated with isopropyl alcohol-hydrochloric

acid (IPA-HCl, 5-10%) at rt gave the hydrochloride salt of 1-

methanesulfonyl-Piperazine 69, (i.e. R=-CH3) by the de protection of the

BOC group. Reaction of 62 with 69 in presence of K2CO3 as a base and

catalytic amount of KI in refluxing acetonitrile for 2h followed by simple

processing resulted in the formation of 67 which was found to be

identical with the product obtained from 59 in all respects i.e. TLC, mp,

NMR and IR (Scheme-2.29)

N

N

O

N

ArN

SR

O

O

N NH

O

O

N N

O

O

S

O

O

R HN N S

O

O

R

67

68 69

i ii

62, iii


78

Reagents and conditions: i) methanesulfonyl chloride/benzenesulfonyl

chloride, pyridine, acetone, RT; ii) IPA-HCl (5-10%), rt; iii) 62, K2CO3, KI,

CH3CN, Δ

2.11. CONCLUSION:

In conclusion, we have achieved the synthesis of {2-(2-(4-((3,4-

dihydro-4-oxo-3-arylquinazolin-2-yl)methyl)piperazin-1-yl)acetoyloxy)-2-

phenyl acetic acid esters, through the preparation of two key

intermediates, by incorporating three moieties such as quinazolinones,

piperazine and L-mandelic acid in a single molecule. We have developed

a simple and efficient method for preparation of new 4(3H)-Quinazolinone

derivatives in solution phase and also under solvent-free conditions

using PEG-400 by simple physical grinding in mortar and pestle at room

temperature. A simple, efficient, novel method for synthesis of various

sulfones has been developed by incorporating three biologically active

moieties such as quinazolinone, piperazine and a sulfones group in a

single molecule.

79

2.12. EXPERIMENTAL SECTION

Preparation of 60:

To a solution of 35 (1.52 g, 10 mmol) in isopropanol (20 mL) were

added few drops of conc. H2SO4 and the mixture refluxed on a water bath

for 3 h. At the end of this period, the excess solvent was removed by

distillation. The residue was dissolved in water, cooled to 0oC and

gradually neutralized with solid NaHCO3. Reaction mass was extracted

into dichloromethane (3x20 mL). Combined organic layers were washed

with water (25 mL) and dried over anhyd.Na2SO4. Finally the solvent was

distilled off under reduced pressure to dryness to give a desired product

60 as light yellow liquid (1.66g, 100% yield). (Scheme-2.22)

Preparation of 58:

A mixture of 60 (10 mmol), triethylamine (4.17 ml, 30 mmol) in

dichloromethane (20 ml) was cooled to 0-5°C. Chloro acetyl chloride

(0.956 ml, 12 mmol) was added slowly at 0-5°C during the period of 15-

20 min. After complete addition reaction mass was brought to rt and

maintained for 5-6 h. The progress of the reaction was monitored by TLC

for disappearance of 60. After completion of reaction, water (20 ml) was

added and the layers separated. Aq. layer further extracted in to

dichloromethane (2x10 ml). Combined organic layers were washed with

water (20 ml) and dried over anhyd.Na2SO4. The organic layer was

evaporated to dryness to give a pure product 58. (Scheme-2.22)

80

Representative Spectral Data

58a: R= -CH3; Yield= 82%; Mp. Colourless liquid; IR (KBr): 1754.9 (COO)

cm-1; 1H NMR (CDCl3, 200 MHz): δ 3.8 (s, 3H, -OCH3), 4.18-4.22 (d, 2H, -

CH2), 6.20 (S, 1H, -CH), 7.40-7.50 (m, 5H, Ar-H); m/z (M++1): 243. Anal.

Calcd. For (C11H11ClO4); require: C, 54.45, H, 4.57; Found: C, 54.41, H,

4.51%.

58b: R= -C2H5; Yield= 76%; Mp Colourless liquid; IR (KBr): 1747.19

(COO) cm-1; 1H NMR (CDCl3, 200 MHz): δ 1.09-1.30 (t, 3H, -CH3), 4.05-

4.25 (q, 2H, -CH2), 5.90-6.0 (s, 1H, -CH), 7.30-7.50 (m, 5H, Ar-H); m/z

(M++1): 257. Anal. Calcd. For (C12H13ClO4); require: C, 56.15, H, 5.10;

Found: C, 56.09, H, 5.02%.

58c: R= CH(CH3)2; Yield= 82%; Mp Colourless liquid; IR (KBr): 1768.5

(COO) cm-1; 1H NMR (CDCl3, 200 MHz): δ 1.10-1.15 (d, 3H, -CH3), 1.22-

1.30 (dd, 3H, -CH3), 4.07-4.25 (q, 2H, -CH2), 5.00-5.10 (m, 1H, -CH),

5.90-5.95 (s, 1H, -CH), 7.38-7.50 (m, 5H, Ar-H); m/z (M++1): 271. Anal.

Calcd. For (C13H15ClO4); require: C, 57.68, H, 5.59; Found: 57.62, H,

5.54%.

Preparation of 63:

A mixture of 62 (10 mmol), N-BOC-piperazine (2.66 g, 15 mmol),

K2CO3 (2.76 g, 20 mmol), KI (0.016 g, 0.01 mmol) and CH3CN (20 mL)

was heated at 80 oC for 90-120 min. The progress of reaction was

81

monitored by TLC for complete disappearance of 62. On completion of

reaction, mixture was diluted with water and extracted with ethyl acetate

(2x 25 mL). The combined organic layer was washed with water,

saturated solution of NH4Cl (25 mL) (to remove un reacted BOC-

piperazine), brine and then dried with anhydrous Na2SO4. The organic

layer was distilled under reduced pressure, gave 63 (Scheme-2.23)


63a: R1= -C6H4-2-CF3; Yield= 86%; Mp 166-68; IR (KBr): 1684 (C=O),

1695 (COO) cm-1; 1H NMR (CDCl3, 200 MHz): δ 1.4 (t, 9H, BOC -CH3),

2.1-2.4 (m, 4H, Piperazine), 3.1-3.2 (dd, 2H, -CH2), 3.2-3.4 (m, 4H,

Piperazine), 7.45 -7.85 (m, 7H, Ar-H), 8.30 (m, 1H, Ar-H); m/z (M++1):

489. Anal. Calcd. For (C25H27 F3N4O3); require: C, 61.47, H, 5.57; N,

11.47; Found: 61.38, H, 5.49, N, 11.41%.

63b: R1= -C6H4-3-OCH3; Yield= 78%; Mp 152-54 °C; IR (KBr): 1680

(C=O), 1697 (COO) cm-1; 1H NMR (CDCl3, 200 MHz): δ 1.4 (s, 9H, BOC -

CH3), 2.0-2.4 (m, 4H, Piperazine), 3.1-3.2 (dd, 2H, -CH2), 3.3-3.4 (m, 4H,

Piperazine), 3.7 (s, 3H, Ar-OCH3), 7.1-8.3 (m, 7H, Ar-H); m/z (M+.+1):

451.5. Anal. Calcd. For (C25H30N4O4); require: C, 66.65, H, 6.71; N,

12.44; Found: 66.58, H, 6.65, N, 12.38 %.

63c: R1= -C6H4-2-CH3; Yield= 74%; Mp 132-34 °C ; IR (KBr): 1680 (C=O),

1694 (COO) cm-1; 1H NMR (CDCl3, 200 MHz): δ 1.4 (s, 9H, BOC CH3),

2.10-2.35 (m, 4H, Piperazine), 2.2 (s, 3H, Ar-CH3), 3.1-3.2 (dd, 2H, -CH2),

82

3.2-3.4 (m, 4H, Piperazine), 7.18-7.20 (d, 1H, Ar-H),7.3-7.4 (m, 3H, Ar-

H), 7.45-7.70 (t, 1H, Ar-H), 7.75-7.81 (m, 2H, Ar-H), 8.3 (d, 1H, Ar-H);

m/z (M+.+1): 435. Anal. Calcd. For (C25H30N4O3); require: C, 69.10, H,

6.96; N, 12.89; Found: C, 69.00, H, 6.92, N, 12.83 %.

63d: R1= -C6H5; Yield= 84%; Mp. 126-30 °C; IR (KBr): 1687 (C=O), 1696

(COO) cm-1; 1H NMR (CDCl3, 200 MHz): δ 1.4 (s, 9H, BOC CH3), 2.2-2.3

(m, 4H, Piperazine), 3.2 (d, 2H, -CH2), 3.2-3.3 (m, 4H, Piperazine), 7.30-

7.35 (d, 2H, Ar-H), 7.42-7.55 (m, 4H, Ar-H), 7.75-7.80 (m, 2H, Ar-H),

8.28 (d, 1H, Ar-H); M/Z (M+.+1): 421. Anal. Calcd. For (C24H28N4O3);

require: C, 68.55, H, 6.71; N, 13.32; Found: C, 68.48, H, 6.65, N,

13.28%.

Preparation of 59: (deprotection of-BOC)

Compound 63 (10 mmol) was suspended in methanolic HCl (15

mL, 10-12% w/v) at ambient temperature. The mixture was stirred at

same temp for 1-2 h. After completion of reaction, MtBE (15 mL) was

added and stirred the mixture for another 30 min at RT. The separated

solid was filtered and washed with MtBE (5 mL) (to remove excess of

HCl). The solid was dissolved in water (5 mL) and pH was adjusted to ~

8-9 by adding sufficient amount of saturated aqueous Na2CO3 solution.

The aq. layer was extracted in to DCM (3x20 mL). The organic layers were

combined, washed successively with water (2x 10 mL, until aq layer pH

is neutral), brine and then dried with anhydrous. Na2SO4. The organic

83

layer was distilled under reduced pressure, to obtain a residue of 59

(Scheme-2.23)


59a: R1= -C6H4-2-CF3; Yield= 80%; Mp 142-145°C; IR (KBr): 1754.9

(COO) cm-1; 1H NMR (CDCl3, 200 MHz): δ 2.2-2.4 (m, 4H, Piperazine), 2.7-

2.8 (m, 4H, Piperazine), 3.15-3.25 (dd, 2H, -CH2), 7.5-7.9 (m, 7H, Ar-H),

8.3 (m, 1H, Ar-H); M/Z (M+.+1): 389. Anal. Calcd. For (C20H19F3N4O);

require: C, 61.85, H, 4.93; N, 14.43; Found: 61.81, H, 4.89, N, 14.38%

59b: R1= -C6H4-3-OCH3; Yield= 78%; Mp 112-114°C; IR (KBr): 1674

(C=O) cm-1; 1H NMR (CDCl3, 200 MHz): δ 2.0-2.4 (m, 4H, Piperazine), 2.6-

2.8 (m, 4H, Piperazine), 3.1-3.4 (dd, 2H, -CH2), 3.7 (s, 3H, Ar-OCH3), 7.1-

7.85 (m, 7H, Ar-H), 8.3 (m, 1H, Ar-H); M/Z (M+.+1): 351.5. Anal. Calcd.

For (C20H22N4O2); require: C, 68.55, H, 6.33; N, 15.99; Found: C, 68.51,

H, 6.28, N, 15.93%.

59c: R1= -C6H4-2-CH3; Yield= 72%; Mp 170-74°C; IR (KBr): 1684 (C=O)

cm-1; 1H NMR (CDCl3, 200 MHz): δ 2.1 (s, 3H, Ar-CH3), 2.2-2.4 (m, 4H,

Piperazine), 2.7-2.9 (m, 4H, Piperazine), 3.05-3.4 (dd, 2H, -CH2), 7.1-7.4

(m, 4H, Ar-H), 7.4-7.6 (m, 1H, Ar-H), 7.7-7.8 (m, 2H, Ar-H), 8.3 (d, 1H,

Ar-H); M/Z (M+.+1): 335.5. Anal. Calcd. For (C20H22N4O); require: C,

71.83, H, 6.63; N, 16.75; Found: C, 71.78, H, 6.58, N, 16. 68%.

84

59d: R1= -C6H5; Yield= 76%; Mp 152-54°C ; IR (KBr): 1676 (C=O) cm-1;

1H NMR (CDCl3, 200 MHz): δ 2.2-2.45 (m, 4H, Piperazine), 2.7-2.8 (m, 4H,

Piperazine), 3.2 (s, 2H, -CH2), 7.3-7.4 (d, 2H, Ar-H),7.42-7.60 (m, 4H, Ar-

H), 7.7-7.80 (m, 2H, Ar-H), 8.3 (d, 1H, Ar-H); M/Z (M+.+1): 321.5. Anal.

Calcd. For (C19H20N4O); require: C, 71.23, H, 6.29; N, 17.49; Found: C,

71.18, H, 6.25, N, 17.45 %.

Preparation of 57:

A mixture of 58 (10 mmol, 1.0 equiv.), 59 (10 mmol, 1.0 equiv)

were dissolved in CH3CN (20 mL), K2CO3 (2.76 g, 20 mmol) and KI (0.016

g, 0.1 mmol) were added in respective order. The mixture (a suspension)

was heated at 80 °C for 90-120 min. The progress of the reaction was

monitored by TLC. On completion of reaction, the mixture was diluted

with water and extracted with ethyl acetate (2x 25 mL). The combined

organic layer was washed with water, brine and then dried with

anhydrous Na2SO4. The organic layer was distilled under reduced

pressure, to obtain the final compound 57 (Scheme-2.24).


57a: R= -CH3; R1= -C6H4-2-CF3; Yield= 78%; Mp liquid; IR (KBr): 1670

(C=O), 1754.9 (COO) cm-1; 1H NMR (CDCl3, 200 MHz): δ 2.2-2.4 (m, 4H,

Piperazine), 2.4-2.6 (m, 4H, Piperazine), 3.10-3.20 (d, 2H, N-CH2), 3.30-

3.50 (d, 2H, N-CH2-CO), 3.75 (s, 3H, -OCH3), 5.95-6.00 (s, 1H, -CH),

7.40-7.9 (m, 12H, Ar-H), 8.3 (m, 1H, Ar-H); M/Z (M+.+1): 595.4. Anal.

85

Calcd. For (C31H29F3N4O5); require: C, 62.62, H, 4.92; N, 9.42; Found: C,

62.58, H, 4.89, N, 9.36 %.

57b: R= -CH3; R1= -C6H4-3-OCH3; Yield= 80%; Mp liquid; IR (KBr):

1688.4 (C=O), 1749.1 (COO) cm-1; 1H NMR (CDCl3, 200 MHz): δ 2.4-2.5

(m, 4H, Piperazine), 2.5-2.6 (m, 4H, Piperazine), 3.20-3.30 (d, 2H, N-

CH2), 3.30-3.40 (d, 2H, N-CH2-CO), 3.75 (s, 3H, -OCH3), 3.82 (s, 3H, -

OCH3), 5.95-6.00 (s, 1H, -CH), 6.8-7.0 (m, 3H, Ar-H),7.4-7.5 (m, 7H, Ar-

H), 7.75-7.80 (m, 2H, Ar-H), 8.3 (m, 1H, Ar-H); M/Z (M+.+1): 557.4. Anal.

Calcd. For (C31H32N4O6); require: C, 66.89, H, 5.79; N, 10.07; Found: C,

66.85, H, 5.74, H, 10.01 %.

57c: R= -CH3; R1= -C6H4-2-CH3; Yield= 82%; Mp liquid; IR (KBr): 1698

(C=O), 1750 (COO) cm-1; 1H NMR (CDCl3, 200 MHz): δ 2.2 (s, 3H, -CH3),

2.4-2.5 (m, 4H, Piperazine), 2.5-2.6 (m, 4H, Piperazine), 3.10-3.20 (dd,

2H, N-CH2), 3.30-3.40 (d, 2H, N-CH2-CO), 3.75 (s, 3H, -OCH3), 5.95 (s,

1H, -CH), 7.1-7.2 (m, 1H, Ar-H),7.3-7.4 (m, 8H, Ar-H), 7.4-7.5 (m, 1H,

Ar-H),7.7-7.8 (m, 2H, Ar-H), 8.3 (m, 1H, Ar-H); M/Z (M+.+1): 541. Anal.

Calcd. For (C31H32N4O5); require: C, 68.87, H, 5.97; N, 10.36; Found: C,

68.81, H, 5.95, N, 10.32%.

57d: R= -CH3; R1= -C6H5; Yield= 89%; Mp liquid; IR (KBr): 1683 (C=O),

1753 (COO) cm-1; 1H NMR (CDCl3, 200 MHz): δ 2.3-2.4 (m, 4H,

Piperazine), 2.4-2.5 (m, 4H, Piperazine), 3.20-3.25 (d, 2H, N-CH2), 3.30-

3.40 (d, 2H, N-CH2-CO), 3.75 (s, 3H, OCH3), 5.95 (s, 1H, -CH), 7.3-7.6

86

(m, 11H, Ar-H), 7.75-7.8 (m, 2H, Ar-H), 8.35 (m, 1H, Ar-H); M/Z

(M+.+1): 527.5. Anal. Calcd. For (C30H30N4O5); require: C, 68.43, H, 5.74;

N, 10.64; Found: C, 68.39, H, 5.70, N, 10.58 %.

57e: R= -C2H5; R1= -C6H4-2-CF3; Yield= 80%; Mp liquid; IR (KBr): 1692.2

(C=O), 1747.2 (COO) cm-1; 1H NMR (CDCl3, 200 MHz): δ 1.19-1.20 (t, 3H,

-CH3), 2.2-2.3 (m, 4H, Piperazine), 2.4-2.6 (m, 4H, Piperazine), 3.05-3.20

(dd, 2H, -CH2), 3.2-3.4 (dd, 2H, N-CH2-CO), 4.10 (q, 2H, -CH2), 5.95 (s,

1H, -CH), 7.2-7.8 (m, 12H, Ar-H), 8.3 (m, 1H, Ar-H); M/Z (M+.+1): 609.0.

Anal. Calcd. For (C32H31F3 N4O5); require: C, 63.15, H, 5.13; N, 9.21;

Found: C, 63.15, H, 5.08, N, 9.17%.

57f: R= -C2H5; R1= -C6H4-3-OCH3; Yield= 84%; Mp liquid; IR (KBr):


(t, 3H, -CH3), 2.4-2.5 (m, 4H, Piperazine), 2.5-2.6 (m, 4H, Piperazine),

3.25-3.30 (dd, 2H, -CH2), 3.3-3.4 (dd, 2H, N-CH2-CO), 3.85 (s, 3H, -

OCH3), 4.15 (q, 2H, -CH2), 5.95 (s, 1H, -CH), 6.8-7.0 (m, 3H, Ar-H), 7.3-

7.5 (m, 7H, Ar-H), 7.75-7.80 (m, 2H, Ar-H), 8.3 (m, 1H, Ar-H); M/Z

(M+.+1): 571.5. Anal. Calcd. For (C32H34N4O6); require: C, 67.35, H, 6.01;

N, 9.82; Found: C, 67.29, H, 5.98, N, 9.78%.

57g: R= -C2H5; R1= -C6H5; Yield= 86%; Mp liquid; IR (KBr): 1686.4 (C=O),

1748.2 (COO) cm-1; 1H NMR (CDCl3, 200 MHz): δ 1.19-1.20 (t, 3H, -CH3),

2.4-2.5 (m, 4H, Piperazine), 2.5-2.6 (m, 4H, Piperazine), 3.25-3.30 (dd,

2H, -CH2), 3.3-3.4 (dd, 2H, N-CH2-CO), 4.15 (q, 2H, -CH2), 5.95 (s, 1H, -

87

CH), 7.2-7.5 (m, 11H, Ar-H), 7.75-7.8 (m, 2H, Ar-H), 8.3 (m, 1H, Ar-H);

M/Z (M+.+1): 541.5. Anal. Calcd. For (C31H32N4O5); require: C, 68.87, H,

5.97; N, 10.36; Found: C, 68.82, H, 5.92, 10.30%.

57h: R= -CH(CH3)2; R1= -C6H4-2-CF3; Yield= 76%; Mp liquid; IR (KBr):


(d, 3H, -CH3), 1.22-1.30 (d, 3H, CH3), 2.2-2.4 (m, 4H, Piperazine), 2.4-2.6

(m, 4H, Piperazine), 3.1-3.2 (d, 2H, N-CH2), 3.3-3.4 (d, 2H, N-CH2-CO),

4.90-5.1 (m, 1H, -CH), 5.9 (s, 1H, -CH), 7.35-7.8 (m, 10H, Ar-H), 7.75-

7.80 (m, 2H, Ar-H), 8.3 (m, 1H, Ar-H); M/Z (M+.+1): 623.5. Anal. Calcd.

For (C33H33 F3N4O5); require: C, 63.66, H, 5.34; N, 9.00; Found: C, 63.63,

H, 5.29, N, 8.95%.

57i: R= -CH(CH3)2; R1= -C6H4-3-OCH3; Yield= 80%; Mp liquid; IR (KBr):


(d, 3H, -CH3), 1.22-1.30 (d, 3H, -CH3), 2.4-2.5 (m, 4H, Piperazine), 2.5-

2.6 (m, 4H, Piperazine), 3.2-3.3 (d, 2H, N-CH2), 3.3-3.4 (d, 2H, N-CH2-

CO), 3.85 (s, 3H, -OCH3), 5.00-5.10 (m, 1H, -CH), 5.9 (s, 1H, -CH), 6.8-

7.0 (m, 3H, Ar-H), 7.35-7.45 (m, 7H, Ar-H), 7.75-7.80 (m, 2H, Ar-H),

8.35 (m, 1H, Ar-H); M/Z (M+.+1): 585.0. Anal. Calcd. For (C33H36N4O6);

require: C, 67.79, H, 6.21; N, 9.58; Found: C, 67.75, H, 6.15, 9.54%.

57j: R= -CH(CH3)2; R1= -C6H4-2-CH3; Yield= 80%; Mp liquid; IR (KBr):

1698 (C=O), 1750 (COO) cm-1; 1H NMR (CDCl3, 200 MHz): δ 1.10-1.15 (d,

3H, -CH3), 1.22-1.30 (d, 3H, -CH3), 2.15 (s, 3H, -CH3), 2.2-2.3 (m, 4H,

88

Piperazine), 2.4-2.6 (m, 4H, Piperazine), 3.15-3.2 (d, 2H, N-CH2), 3.25-3.4

(dd, 2H, N-CH2-CO), 5.0-5.10 (m, 1H, -CH), 5.9 (s, 1H, -CH), 7.15-7.2

(m, 2H, Ar-H), 7.3-7.55 (m, 8H, Ar-H), 7.75-7.80 (m, 2H, Ar-H), 8.35

(m, 1H, Ar-H); M/Z (M+.+1): 569.0. Anal. Calcd. For (C33H36N4O5); require:

C, 69.70, H, 6.38; N, 9.85; Found: C, 69.66, H, 6.34, N, 9.82%.

57k: R= -CH(CH3)2; R1= -C6H5; Yield= 88%; Mp liquid; IR (KBr): 1695.1

(C=O), 1747.2 (COO) cm-1; 1H NMR (CDCl3, 200 MHz): δ 1.25-1.20 (d, 3H,

-CH3), 1.4-1.50 (d, 3H, -CH3), 2.15 (s, 3H, -CH3), 2.5-2.6 (m, 4H,

Piperazine), 2.6-2.8 (m, 4H, Piperazine), 3.40-3.50 (d, 2H, N-CH2), 3.5-3.6

(d, 2H, N -CH2-CO), 5.15-5.25 (m, 1H, -CH), 6.05 (s, 1H, CH), 7.5-7.75

(m, 11H, Ar-H), 7.9-8.0 (m, 2H, Ar-H), 8.4 (m, 1H, Ar-H); M/Z (M+.+1):

555.0. Anal. Calcd. For (C32H34N4O5); require: C, 69.30, H, 6.18; N,

10.10; Found: C, 69.26, H, 6.14, N, 10.04%.

Preparation of compounds 64-66 (General procedure in solution)

A mixture of 62 (10 mmol, 1.0 equiv), ethyl piperdine-4-

carboxylate/morpholine/ piperidine -4-one (10 mmol, 1.0 equiv), K2CO3

(2.76 g, 20 mmol, 2.0 equiv.), KI (0.57 g, 3 mmol, 0.3 equiv.) and CH3CN

(20 mL) was heated at 80 oC for 90-120 min. The progress of reaction

was monitored by TLC for complete disappearance of 62. On completion

of reaction, mixture was diluted with water and extracted with ethyl

acetate (2x 25 mL). The combined organic layer was washed with water,

brine and then dried with anhydrous Na2SO4. The organic layer was

89

distilled under reduced pressure, gave respectively 64/65/66. (Scheme-

2.25)

Preparation of compounds 64-66 (General procedure under solvent-

free)

A mixture of powdered anhydrous K2CO3 (4.14 g, 30 mmol, 3.0 eq),

PEG-400 (10mol%), KI (0. 57 g, 3 mmol, 0.3 equiv) and ethyl piperdine-4-

carboxylate/morpholine/piperidine (10 mmol, 1.0equiv) were taken in a

mortar and ground with a pestle for few minutes. To this mixture,

starting material 62 (10mmol) was added and the whole mixture was

ground with pestle in the same mortar at room temperature for 7-15 min.

The progress of reaction was monitored by TLC. After complete

disappearance of starting material, mixture was treated with ice-cold

water (50ml). Product separated was filtered, washed with water, and

dried to obtain 65/66 (Table-1). Product 64 separated out as oil, which

was extracted in to DCM, washed with water, and organic layer on

evaporation gave pure 64 as residue.

Representative Spectral data for 64-66 compounds:

64a: IR (KBr) cm-1:1670, 1711. 1H NMR (200MHz, CDCl3): δ 2.3. (m, 4H,

piperidone), 2.6-2.8 (m, 4H, piperidone), 3.4 (s, 2H, -CH2), 3.8 (s, 3H, -

OCH3), 6.9-8.3 (m, 8H, Ar-H). M/z (M +. +1): 364. Anal. Calcd. for

(C21H21N3O3) requires: C, 69.41, H, 5.82; N, 11.56; Found: C, 69.38; H,

5.80; N, 11.54%.

90

64b: IR (KBr) cm-1: 1675, 1714. 1H NMR (200MHz, CDCl3): δ 2.3 (t, 4H,

piperidone), 2.6 (t, 4H, piperidone), 3.4 (s, 2H, -CH2), 7.2-8.3 (m, 9H, Ar-

H). M/z (M +. +1): 334. Anal. Calcd. for (C20H19N3 O2) requires: C, 72.05; H,

5.74; N, 12.60; Found: C, 72.01; H, 5.78; N, 12.58%.

64c: IR (KBr) cm-1: 1678, 1714: 1H NMR (200MHz, CDCl3): δ 2.2 (s, 3H, -

CH3), 2.3 (dd, 4H, piperidone), 2.6 (dd, 4H, piperidone), 3.2-3.4 (dd, 2H, -

CH2), 7.2-8.3 (m, 8H, Ar-H). M/z (M +. +1): 348. Anal. Calcd. for

(C21H21N3O2) requires: C, 72.60, H, 6.09, N, 12.10; Found: C, 72.62; H,

6.01; N, 12.04%.

64d: IR (KBr) cm-1: 1686, 1717. 1H NMR (200MHz, CDCl3): δ 2.3 (m, 4H,

piperidone), 2.7-2.9 (m, 4H, piperidone) 3.3 (dd, 2H, CH2), 7.5-8.3 (m,

8H, Ar-H). M/z (M++1): 402. Anal. Calcd. for (C21H18F3N3O2) requires: C,

62.84; H, 4.52, N, 10.47; Found: C, 62.80; H, 4.46; N, 10.42%.

65a: IR (KBr) cm-1: 1672. 1H NMR (200MHz, CDCl3): δ 2.3-2.4 (m, 4H,

morpholine), 3.2 (s, 2H,-CH2), 3.6 (m, 4H, morpholine), 3.9 (s, 3H, OCH3),

6.9-8.3 (m, 8H, Ar-H). M/z (M +. +1): 352. Anal. Calcd. for (C20H21N3O3)

requires: C, 68.36; H, 6.02, N, 11.96; Found: C, 68.32; H, 6.08; N,

11.98%.

65b: IR (KBr) cm-1: 1676. 1H NMR (200MHz, CDCl3): δ 2.4 (m, 4H,

morpholine), 3.3 (s, 2H, -CH2), 3.5-3.6 (m, 4H, morpholine), 7.3-8.3 (m,

91

9H, Ar-H). M/z (M +. +1): 322. Anal. Calcd. for (C19H19N3O2) requires: C,

71.01; H, 5.96; N, 13.08; Found: C, 71.05; H, 5.92; N, 13.02%.

65c: IR (KBr) cm-1: 1684. 1H NMR (200MHz, CDCl3): δ 2.15 (s, 3H, -

CH3), 2.2-2.4 (m, 4H, morpholine), 3.1-3.3 (dd, 2H, -CH2), 3.5-3.6 (m,

4H, morpholine), 7.2-8.3 (m, 8H, Ar-H). M/z (M +. +1): 336. Anal. Calcd.

for (C20H21N3O2) requires: C, 71.62; H, 6.31; N, 12.53; Found: C, 71.58;

H, 6.26; N, 12.55%.

65d: IR (KBr) cm-1: 1678. 1H NMR (200MHz, CDCl3): δ 2.2-2.4 (dd, 4H,

morpholine), 3.1-3.2 (dd, 2H, -CH2), 3.6 (q, 4H, morpholine), 7.5-8.3 (m,

8H, Ar-H). M/z (M +. +1): 390. Anal. Calcd. for (C20H18F3N3O2) requires: C,

61.69; H, 4.66; N, 10.79 ; Found: C, 61.65; H, 4.62; N, 10.72%.

66a: IR (KBr) cm-1:1670, 1730. 1H NMR (200MHz, CDCl3): δ 1.2 (t, 3H, -

OCH2-CH3), 1.5-2.6 (m, 9H, -piperidine), 3.1-3.3 (dd, 2H, -CH2), 3.8 (s,

3H, -OCH3), 4.1 (q, 2H, -OCH2-CH3), 6.85-8.3 (8H, Ar-H). M/z (M+. +1):

422. Anal. Calcd. for (C24H27N3O4) requires: C, 68.39; H, 6.46; N, 9.97;

Found: C, 68.34; H, 6.40; N, 9.92%.

66b: IR (KBr) cm-1:1685, 1728. 1H NMR (200MHz, CDCl3): δ 1.2 (t, 3H, -

OCH2-CH3), 1.6-2.7 (m, 9H, piperidine), 3.2 (dd, 2H, -CH2), 4.1 (q, 2H, -

OCH2-CH3), 7.3-8.3 (m, 9H, Ar-H). M/z (M +. +1): 392. Anal. Calcd. for

(C23H25N3O3) requires: C, 70.57; H, 6.44; N, 10.73; Found: C, 70.51; H,

6.38; N, 10.75%.

92

66c: IR (KBr) cm-1:1678, 1730. 1H NMR (200MHz, CDCl3): δ 1.2 (t, 3H, -

OCH2-CH3), 1.6-2.6 (m, 9H, piperidine), 2.2 (s, 3H, -CH3), 3.1-3.3 (dd,

2H, -CH2), 4.1 (q, 2H, -OCH2-CH3), 7.2-8.3 (m, 8H, Ar-H). M/z (M +. +1):

406. Anal. Calcd. for (C24H27N3O3) requires: C, 71.09; H, 6.71; N, 10.36;

Found: C, 71.00; H, 6.65; N, 10.28%.

66d: IR (KBr) cm-1: 1680, 1730. 1H NMR (200MHz, CDCl3): δ 1.2 (t, 3H, -

OCH2-CH3), 1.6-2.6 (m, 9H, piperidine), 3.15 (dd, 2H, -CH2), 4.1 (q, 2H, -

OCH2-CH3), 7.5-8.3 (m, 8H, Ar-H). M/z (M +. +1): 460. Anal. Calcd. for

(C24H24F3N3O3) requires: C, 62.74; H, 5.26; N, 9.15; Found: C, 62.68; H,

5.20; N, 9.11%.

Preparation of 67:

A mixture of 59 (10 mmol), TEA (4.17 ml, 30 mmol) and DCM (20

ml), was cooled to 0-5°C. Methanesulfonyl chloride (11 mmol) was added

slowly at the same temp during a period of 5-10 min. After complete

addition, reaction mass was brought to rt and maintained at RT with

stirring for 5-6 hours. The progress of reaction was monitored by TLC till

disappearance of 59. After completion of reaction, water (20 ml) was

added and the layers separated. Aq. layer was further extracted in to

DCM (2x10 ml). Combined organic layers were washed with water (20ml)

and dried over anhydrous Na2SO4. The organic layer was evaporated to

dryness to yield a crude product 67. This was purified by column

93

chromatography, eluting the product with a mixture of hexane and ethyl

acetate to obtain pure as off-white crystalline solids (Scheme-2.28).

67a: 7a: Ar =-C6H5; R=-CH3; Yield 76%; m.p. 80-84°C; IR (KBr): 1682

(C=O), 1325 cm-1 (S=O); 1H NMR (CDCl3, 200 MHz): δ 2.4-2.5 (m, 4H,

piperazine), 2.7 (s, 3H, SO2-CH3), 3.1-3.2 (m, 4H, piperazine), 3.3 (s, 2H,

-CH2), 7.3-8.3 (m, 9H, Ar-H); 13C NMR (CDCl3, 50 MHz): δ 162.30,

152.37, 146.76, 136.61, 134.50, 129.17, 129.13, 128.76, 127.41,

127.25, 126.92, 121.10, 60.61, 52.00, 45.56, 34.41; MS: m/z (M+.+1)

399. Anal. Calcd for (C20H22N4O3S) requires: C, 60.28; H, 5.56; N, 14.06.

Found: C, 60.22; H, 5.53; N, 14.02%.

67b: Ar =-C6H4-3-OCH3; R=-CH3; Yield 80%; m.p. 76-78°C; IR (KBr):

1684 (C=O), 1327 cm-1 (S=O); 1H NMR (CDCl3, 200 MHz): δ 2.2-2.5 (m,

4H, piperazine), 2.2 (s, 3H, Ar-CH3), 2.7 (s, 3H, SO2-CH3), 3.1-3.2 (m, 4H,

piperazine), 3.2-3.4 (dd, 2H, -CH2), 7.1-8.3 (m, 8H, Ar-H); 13C NMR

(CDCl3, 50 MHz): δ 161.44, 151.99, 146.81, 137.28, 135.5, 135.35,

134.74, 130.13, 127.53, 127.41, 127.07, 127.05, 126.78, 120.88, 60.9,

52.15, 45.42, 34.10, 15.83; MS: m/z (M+.+1) 429.5. Anal. Calcd for

(C21H24N4O4S) requires: C, 58.86; H, 5.65; N, 13.07. Found: C, 58.84; H,

5.61; N, 13.02%.

67c: Ar =-C6H4-2-CH3; R=-CH3; Yield 78%; m.p. 73-75°C; IR (KBr): 1682

(C=O), 1325 cm-1 (S=O); 1H NMR (CDCl3, 200 MHz): δ 2.2 (s, 3H, Ar-CH3),

2.3-2.5 (m, 4H, piperazine), 2.7 (s, 3H, SO2-CH3), 3.1-3.2 (m, 4H,

94

piperazine), 3.2-3.4 (dd, 2H, -CH2), 7.2-8.3 (m, 8H, Ar-H); 13C NMR

(CDCl3, 50 MHz): δ 161.43, 152.36, 146.78, 136.02, 135.68, 134.39,

130.75, 129.30, 128.33, 127.28, 127.08, 126.82, 126.68, 120.88, 60.51,

52.02, 45.30, 34.22, 17.82; MS: m/z (M+.+1) 413. Anal. Calcd for

(C21H24N4O3S) requires: C, 61.14; H, 5.86; N, 13.58. Found: C, 61.10; H,

5.82; N, 13.56%.

67d: Ar =-C6H4-3-Cl; R=-CH3; Yield 82%; m.p. 168-72°C; IR (KBr): 1671

(C=O), 1327 cm-1 (S=O); 1H NMR (CDCl3, 200 MHz): δ 2.3 (m, 2H,

piperazine), 2.5 (m, 2H, piperazine), 2.8 (s, 3H, SO2 -CH3), 3.2 (m, 4H,

piperazine), 3.4 (q, 2H, -CH2), 7.3-8.3 (m, 8H, Ar-H); 13C NMR (CDCl3, 50

MHz): δ 162.10, 151.77, 146.62, 137.72, 134.72, 134.28, 130.15,

130.11, 129.28, 127.51, 126.92, 126.70, 120.97, 60.79, 51.85, 45.62,

34.02; MS: m/z (M+.+1) 434. Anal. Calcd for (C20H21ClN4O3S) requires: C,

55.49; H, 4.89; N, 12.94. Found: C, 55.46; H, 4.82; N, 12.92%.

67e: Ar =-C6H4-3-F; R=-CH3; Yield 75%; m.p. 140-44°C; IR (KBr): 1685


piperazine), 2.5-2.6 (m, 2H, piperazine), 2.8 (s, 3H, SO2-CH3), 3.1 (m, 4H,

piperazine), 3.4 (q, 2H, -CH2), 7.1-8.3 (m, 8H, Ar-H); 13C NMR (CDCl3, 50

MHz): δ 162.10, 151.8, 146.63, 134.71, 130.37, 130.30, 127.51, 127.47,

126.93, 124.49, 120.97, 117.15, 116.96, 116.23, 60.68, 51.99, 45.58,

34.26; MS: m/z (M+.+1) 417. Anal. Calcd for (C20H21FN4O3S) requires: C,

57.68; H, 5.08; N, 13.45. Found: C, 57.64; H, 5.07; N, 13.41%.

95

67f: Ar =-C6H3-3-F-4-F; R=-CH3; Yield 73%; m.p. 156-58°C; IR (KBr): 1685


piperazine), 2.5-2.6 (m, 2H, piperazine), 2.8 (s, 3H, SO2 -CH3), 3.1 (m, 4H,

piperazine), 3.3 (s, 2H, -CH2), 7.1-8.3 (m, 7H, Ar-H); 13C NMR (CDCl3, 50

MHz): δ 162.15, 151.58, 146.54, 134.82, 127.57, 126.91, 125.25, 120.84,

119.22, 119.07, 117.65, 117.50, 60.77, 52.05, 45.56, 34.34; MS: m/z

(M+.+1) 435. Anal. Calcd for (C20H20F2N4O3S) requires: C, 55.29; H, 4.64;

N, 12.90. Found: C, 55.28; H, 4.62; N, 12.88%.

67g: Ar =-C6H3-2-F-3-Cl; R=-CH3; Yield 74%; m.p. 186-90°C; IR (KBr):


2H, piperazine), 2.5-2.6 (m, 2H, piperazine), 2.7 (s, 3H, SO2 -CH3), 2.9-

3.1 (m, 4H, piperazine), 3.3-3.5 (dd, 2H, -CH2), 7.2-8.3 (m, 7H, Ar-H); 13C

NMR (CDCl3, 50 MHz): δ 161.31, 151.66, 146.56, 134.91, 131.33,

127.65, 127.48, 127.24, 126.98, 124.52, 124.48, 121.45, 120.70, 61.23,

51.59, 45.36, 33.47; MS: m/z (M+.+1) 452. Anal. Calcd for

(C20H20ClFN4O3S) requires: C, 53.27; H, 4.47; N, 12.43. Found: C, 53. 21;

H, 4.45; N, 12.40%.

67h: Ar =-C6H4-3-OCH3; R=-C6H5; Yield 72%; m.p. 168-70°C; IR (KBr):


4H, piperazine), 2.2 (s, 3H, Ar-CH3), 3.1-3.2 (m, 4H, piperazine), 3.2-3.4

(dd, 2H, -CH2), 7.1-8.3 (m, 13H, Ar-H); 13C NMR (CDCl3, 50 MHz): δ

161.26, 151.55, 147.65, 140.89, 137.23, 135.61, 134.82, 133.78,

132.26, 129.65, 128.97, 127.45, 127.33, 127.16, 124.87, 122.54,

96

120.88, 119.50, 61.55, 51.68, 45.88, 17.36; MS: m/z (M+.+1) 495.5.

Anal. Calcd for (C26H26N4O4S) requires: C, 63.66; H, 5.34; N, 11.42.

Found: C, 63.62; H, 5.30; N, 11.40%.

67i: Ar =-C6H4-2-CH3; R=-C6H5; Yield 77%; m.p. 174-76°C; IR (KBr):


4H, piperazine), 3.1 (m, 4H, piperazine), 3.3 (s, 2H, -CH2), 7.2-8.3 (m,

13H, Ar-H); 13C NMR (CDCl3, 50 MHz): δ 162.16, 152.11, 146.35, 141.19,

136.83, 136.21, 135.12, 134.18, 133.06, 129.45, 128.27, 127.54,

127.13, 127.10, 124.27, 122.14, 120.48, 119.22, 61.35, 51.68, 44.65;

MS: m/z (M+.+1) 475.5. Anal. Calcd for (C26H26N4O3S): requires: C, 65.80;

H, 5.52; N, 11.81. Found: C, 65.82; H, 5.54; N, 11.79%.

Preparation of 68:

A mixture of N-Boc Piperazine (10 mmol), pyridine (2.42 ml, 30

mmol) and acetone (20 ml) was cooled to 0-5°C. Methanesulfonyl chloride

(11 mmol) was added slowly at same temp during a period of 5-10 min.

After the completion of addition, reaction was maintained at the same

temp for 1h and then brought to rt and maintained for 2h. TLC was used

to monitor the progress of the reaction till the disappearance of N-Boc

Piperazine. After completion of reaction, the excess solvent was removed

by distillation, and the residue treated with chloroform (25 ml). The

chloroform layer was washed with water (3x25 ml) and dried (anhyd.

Na2SO4). The organic layer was evaporated to dryness to obtain crude 68

97

which was used as such without further purification in the next step

(Scheme-2.29).

68a: R =-CH3; Yield 85%; m.p. 86-88°C; IR (KBr): 1720 (COO), 1315 cm-1

(S=O); 1H NMR (CDCl3, 200 MHz): δ 1.4 (s, 9H, BOC -CH3), 2.8 (s, 3H, -

SO2-CH3), 3.2 (m, 4H, piperazine), 3.5 (m, 4H, piperazine); MS: m/z

(M+.+1) 265. Anal. Calcd for (C10H20N2O4S) requires: C, 45.44; H, 7.63; N,

10.60. Found: C, 45.40; H, 7.61; N, 10.56%.

68b: R =-C6H5; Yield 87%; m.p. 124-26°C; IR (KBr): 1710 (COO), 1325

cm-1 (S=O); 1H NMR (CDCl3, 200 MHz): δ 1.4 (s, 9H, BOC CH3), 3.2 (m,

4H, piperazine), 3.5 (m, 4H, piperazine), 7.3-7.9 (m, 5H, Ar-H); MS: m/z

(M+.+1) 326. Anal. Calcd for (C15H22N2O4S) requires: C, 55.19; H, 6.79; N,

8.58. Found: C, 55.17; H, 6.77; N, 8.56%.

Preparation of 69: (deprotection of BOC)

Compound 68 (10 mmole) in IPA-HCl (10-12% w/v, 30 mmole) was

mixed at ambient temperature. The reaction mixture was stirred for 1-2

hr at the same temperature. The progress of the reaction was monitored

by TLC till the disappearance of 68. After the disappearance of starting

material, MTBE (15 mL) was added and the mixture stirred for another

30 min at RT. The separated solid was filtered and washed with MTBE (5

mL) (to remove excess of HCl), yielding hydrochloride salt of 69 (Scheme

2.29)

98

69a: R =-CH3; Yield 90%; m.p. 142-46°C; IR (KBr): 1320 cm-1 (S=O); 1H

NMR (CDCl3, 200 MHz): δ 3.0 (s, 3H, -SO2-CH3), 3.4 (m, 4H, piperazine),

3.6 (m, 4H, piperazine); MS: m/z (M+.+1) 164. Anal. =-C6H5; Yield 88%;

m.p. 108-10°C; IR (KBr): 1330 cm-1 (S=O); 1H NMR (CDCl3, 200 MHz): δ

3.2 (m, 4H, piperazine), 3.5 (m, 4H, piperazine), 7.3-7.9 (m, 5H, Ar-H);

MS: m/z (M+.+1) 226. Anal. Calcd for (C11H15NO2S) requires: C, 58.64; H,

6.71; N, 6.22. Found: C, 58.60; H, 6.75; N, 6.18%.Found: C, 44.12; H,

8.01; N, 8.56%.

Preparation of 67 (from 69):

A mixture of 69 (10 mmole), 62 (10 mmole), solid K2CO3 (2.76 g, 20

mmole) and KI (0.016 g, 0.1 mmole) in CH3CN (20 mL) was refluxed for 2

hr. The progress of the reaction was monitored on TLC, till the

disappearance of 62. On completion of reaction (~2 hr), the reaction

mixture was filtered and the insoluble material washed with CH3CN (2 ×

5 mL); the combined filtrate was distilled to dryness under reduced

pressure and the residue treated with chloroform (25 mL). The organic

layer was washed with water, brine and dried (anhyd. Na2SO4). The

chloroform layer was distilled under reduced pressure to obtain a residue

of 67. This was purified by column chromatography, eluting the product

with a mixture of hexane and ethyl acetate to yield pure 67 as off-white

crystalline solids (Scheme 2.29).

Yield (%): a= 75, b= 76, c= 78, d= 75, e= 72, f=75, g= 69, h= 70, i = 75.

99

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