ant! JIntihyperoCycemic of PunctinaCizea (Benzenes,shodhganga.inflibnet.ac.in/bitstream/10603/18446/12/12_chapter 5.pdfCliapter 5 Syntliesis ant! JIntihyperoCycemic JIctivity of PunctinaCizea

Cliapter 5

Syntliesis ant! JIntihyperoCycemic JIctivity of PunctinaCizea (Benzenes, 1,2-'DiaryC-, 1,2,3-rrriaryC-, 1,2,3,4-

r:fetraary{6enzenes

5.1 Introduction

Polysubstituted benzenes are highly useful chemical entities, which are widely used

in industry as well as in the laboratory. The synthesis of polysubstituted benzenes in high

yields in a regioselective manner is one of the challenging problems in organic synthesis. I

Classical methods for the synthesis of polysubstituted benzenes are based on aromatic

substitution, which introduces a substituent to the given arene. A variety of synthetic

methodologies based on this route have been developed including the electrophilic or

nucleophilic substitutions, metal-catalyzed coupling reactions and metalation

functionalization reactions. However, these methods suffer from a long multi-step reaction

sequence, low yields of products and production of regiochemical ambiguities originating

from the activating or deactivating and orienting effects ofthe substituents.

Numerous approaches for the synthesis of aromatic compounds from acyclic

precursors have received growing interest due to their short synthetic steps and the avoidance

of regioisomeric problems. These general features are common in the most useful

benzannulation reactions such as [3+2+1] Dotz reaction of Fisher carbene complexes,2

Danheiser alkyne-cyclobutenone cyclization,3 [4+ 2]-cycloaddition of

metalacyclopentadienes and alkynes,4 transition-metal-catalyzed [2+2+2]- and [4+2]

cycloadditions,s [4+2]-Yamamoto benzannulation of o-alkynyl benzaldehyde and alkyne,6

[3+3]-cyclocondensation between bielectrophiles and binucleophiles/ and 1,6-

electrocyclization reaction.8 Recently, Kim and coworkers have developed a regioselective

synthesis of polysubstituted benzenes from Baylis-Hillman adducts via [4+2] annulation

protocol.9

In addition, the demand of functionally congested biaryl compounds for both

synthetic and medicinal purposes has increased dramatically during the past few decades.

Besides their large diversity in complex natural productslO and pharmaceutical agents, II

these compounds are fascinating and challenging research objects in material12 and polymer

sciences.13 Several of the biaryls, in which one of the aryl rings is substituted with one or

more isopropyl units have recently been reported as potent glucagon receptor antagonists for

the treatment of diabetes. 14 The biaryl Bay-27-9955 functionalized with two isopropyl units

has been reported to inhibit glucagon from the human glucagon receptor with an ICso value

of 110 nM.Is The compound was found to be orally active with a bioavailability of 40% and

half-life of 11-17h in male rats and was selected for advanced clinical trials. 16 Axially chiral

biaryls are useful as versatile auxiliaries for asymmetric synthesis,17 as chiral phases for

chromatographyl8 and as important substrates for chiral liquid crystalline materials.19

135

Recently, numerous natural products having terphenyl architecture have been reported with

interesting biological properties?O-23 Several synthetic terphenyl derivatives have been

designed as selective inhibitors for dihydroortate dehydrogenase24 and cyclooxygenase25

enzymes. Terphenyls containing acidic groups have recently been found to be potent insulin

sensitizers.26 Owing to their interesting optical27 and electrical28 properties, terphenyls find

several industrial applications as liquid crystals, conducting polymers, heat storage and heat

transfer agents, as textile dye carriers and as a laser dye. Recently a great deal of attention

has been focused to fabricate useful teraryl- or tetraaryl-benzene building blocks with

electron-withdrawing and releasing groups for preparing advanced electroluminescent

materials.29

Although numerous non-metal catalyzed approaches particularly, regio- and

stereoselective Diels-Alder cycloadditions30 of 2H-pyran-2-ones with electron deficient and

electron rich dienophiles do exist in the literature, they do not provide a general route for

preparing functionalized benzenes, di-, tri- or tetraarylbenzenes. The wide-ranging

applications and high demand of benzenes and arylatedbenzenes and paucity of non-metal

catalyzed synthetic methodologies prompted us to develop a simple, general and efficient

route that could offer flexibility of substituent variations on benzene scaffold.

In view of these findings a highly convenient synthesis of various functionalized

benzenes, bi-, tri- and tetraarylbenzenes of prototypes (I-VIII) have been developed through

ring transformation strategy. All the synthesized compounds have been evaluated for anti

hyperglycemic activity in in vitro model.

R2 1

SMe R3 y R SMe

R'X~C CN CN I~ R2

Rl h NH2 NH2 "=: NH2 NH2 CN CN R R3 h R4CN

II III IV

Rl R4 Rl Y

CN Rl

Rl

ft ~

Me R :;? 0 h R3 3 R2 R4

R "=: 0

R4 Rl 10 0

V VI R2

VIII

Figure 1. Structure of prototype (I-VIII).

136

5.2 Chemistry

2H-Pyran-2-ones prepared from a-oxo-ketene-S,S-acetae l (1) have promising

structural topology as useful substrates for ring transformation reactions, flexible substitution

pattern and the presence of a good leaving alkylsulfanyl group for generating molecular

diversity.32 It has been reported33 that a-pyranone ring can be converted to a benzene ring

under mild basic conditions. Such a new ring transformation34 (recently termed as 'Lactone

Methodology') prompted us to explore the route for preparing bent-cored 0ligo-pyridine35

and oligo-phenylene36 as useful building blocks for advanced materials. Recently, Goel et al

exploited the lactone methodology to synthesize biaryls using acetyltrimethylsilane as a

carbanion source.37 Our previous efforts were on preparing simple aromatic systems and now

we have systematically prepared functionalised benzenes, functionally congested 1,2-diaryl-,

1,2,3-triaryl- and 1,2,3,4-tetraarylbenzenes injust two steps, which are difficult to prepare by

conventional routes.

5.2.1 Synthesis of 4-alkyl-2-amino-6-methylsulfanyl-isophthalonitrile (3a-e): Our

approach to preparing benzene derivatives (3a-e) is based on the ring transformation of 6-

alkyl- or 5,6-dialkyl-3-cyano-6-methyl-4-methylsulfanyl-2H-pyran-2-ones (la-e) by using

malononitrile as a carbanion source. The 2H-pyran-2-ones (la-e) used as a parent precursors

were prepared by the reaction of ethyl 2-cyano-3,3-dimethylsulfanylacrylate35 with aliphatic

ketones under alkaline conditions in high yields. Lactones, (la-e) have three electrophilic

Entry RI

3a CH3

3b CH3CH2

3c CH3CH2

3d (CH3hCH 3e (CH3hCH2CH

Scheme 1.

11

Rl

H H CH3

H H

o

Yield (%) 87 94 92 88 93

137

centres; C-2, C-4 and C-6 in which the latter is highly reactive towards nucleophiles due to

the extended conjugation and the presence of the electron withdrawing substitutent at

position 3 of the pyran ring. The functionalized benzene derivatives (3a-e) were synthesized

by stirring an equimolar mixture of 2H-pyran-2-ones (la-e), malononitrile and powdered

KOH in DMF for 12-14 h at room temperature (Scheme 1). The reaction was monitored by

TLC and thereafter poured into ice water and neutralized with dilute HCI. The crude product

thus obtained was purified by neutral alumina chromatography using chloroform and hexane

(1 :4) as eluent.

The transformation of 6-alkyl- or 5,6-dialkyl-2H-pyran-2-ones into benzene

derivatives is possibly initiated by attack of the malononitrile carbanion at position C-6 of

lactone 1, followed by intra-molecular cyclization involving one of the nitrile functionalities

and C-3 of the pyranone ring and elimination of carbon dioxide to yield 3a-e. All the

synthesized compounds were characterized by their spectroscopic analysis. IR spectrum of

compound 3a showed a band at 2212 cm-I due CN group. The IH NMR spectrum of

compound 3a showed two singlets at 0 2.48 ppm and at & 2.54 ppm each for 3H were

assigned to Me and SMe groups, respectively. A broad singlet appeared at & 5.10 ppm for 2H

was assigned to NH2 group and a singlet appeared at 0.6.42 ppm for IH due to CH of

aromatic ring. Mass spectrum (FAB) at mlz 204 confirmed the structure as 2-amino-4-

methyl-6-methylsulfanyl-isophthalonitrile (3a).

L ! I

~CN MeJ..~NH2

CN

3a

5.2.2 Synthesis of 4-amino-2-methyl-6-methylsulfanyl-biphenyl-3,5-dicarbonitriles (Sa

t): Limited procedures are known for the synthesis of such biaryls in which one of the aryl

rings is functionalized with two or more aromatic rings in a juxtaposed manner. Palladium

catalyzed aryl-aryl cross-coupling between the electrophilic aromatic halides Ar(X)n (X

being generally Br, I, and OTf; n being mainly 0, 1 or 2) and organometallic species Ar-M

138

(M being Mg, Ni, Zn, Sn, and B) is a versatile synthetic method for the preparation of

diverse arylatedbenzene. Ofthe various coupling reactions, the Pd-catalyzed Suzuki-Miyaura

couplings of a diverse array of haloarenes with arylboronic acids has dominated in this area

due to the commercial availability and innocuous nature of the latter, easy workup and

tolerance of the reactions to aqueous media. Our approach to prepare congested biaryls (Sa

t) is very simple and concise, is based on the ring transformation of 2H-pyran-2-ones (4a-t)

by using malononitrile (2) as a carbanion source.38 The 2H-pyran-2-ones (4a-t) used as a

parent precursors were conveniently prepared by the reaction of methyl 2-cyano-3,3-

dimethylsulfanylacrylate9 with substituted phenyl acetones under alkaline conditions in high

yields. The synthesis of 4-amino-2-methyl-6-methylsulfanyl-biphenyl-3,5-dicarbonitriles

(5a-t) was acheived by stirring an equimolar mixture of 2H-pyran-2-ones (4a-t),

malononitrile (2) and powdered KOH in DMF for 10-12 h at room temperature (Scheme 2).

The mechanism for the formation of 4-amino-2-methyl-6-methylsulfanyl-biphenyl-3,5-

dicarbonitriles (5a-t) is similar to the formation of functionalized benzene derivatives (3a-e)

as shown in Scheme 1.

R3

KOH R2 + CH2(CNh -DMF

0 2 NH2 R4

4 CN 5

5 Ri R~ Rl R4 Yield (%)

a H H F H 89 b F H H H 92 c H H CF3 H 91 d OMe H OMe H 88 e H OMe OMe H 90 f H H H C6H5 92

Scheme 2.

All the synthesized compounds were characterized by their spectroscopic analysis. IR

spectrum of compound 5d showed bands at 2216, 3354 and 3426 cm-l due to eN and NH2

group, respectively. The lH NMR spectrum of compound 5d showed four singlets at & 2.24,

2.31, 3.86 and 3.94 ppm each for 3H assigned to Me, SMe, and two OMe group,

respectively. A broad singlet appeared at 8 5.17 ppm for 2H was assigned to NH2 groups. A

doublet appeared at & 6.93 ppm and a multiplet at 6.59-6.69 ppm were assigned to aromatic

protons. Mass spectrum (F AB) at mlz 340 confirmed the structure of 5d as 4-amino-3',4'

dimethoxy-2-methyl-6-methylsulfanyl-biphenyl-3,5-dicarbonitrile.

139

5.2.3 Synthesis of 3-amino-6-methyl-5-methylsulfanyl-biphenyl-2,4-dicarbonit riles (7a

c) and 3-amino-6-methyl-5-secondaryamino-l-yl-biphenyl-2,4-dicarbon it riles (9a-c):

The reaction was further exploited to prepare 3-amino-6-methyl-5-methylsulfanyl-biphenyl-

2,4-dicarbonitriles (7a-c) by using 2H-pyran-2-ones (6a-c) as a starting material and

malononitrile as carbanion source. The synthesis of 3-amino-6-methyl-5-methylsulfanyl

biphenyl-2,4-dicarbonitriles (7a-c) was achieved by stirring an equimolar mixture of 2H-

pyran-2-ones (6a-c), malononitrile (2) and powdered KOH in DMF for 10-12 h at room

temperature (Scheme 3)38.

Scheme 3.

SMe

~e I~ CN

I ~ 0 0 R ~ 6

MeOH !sec.amine

Q Me:(xCN

Ar 0 0 8

Entry R

7a H 7b Cl 7c OMe 9a H 9b H 9c OMe

CH2(CNh • DMF/KOH

R

Q Me*CN

I~ Ar NH2

CN 9

SMe CN

7

Q Yield (%)

I 94 91 89

piperidine 92 4-Me-piperidine 89

piperidine 90

The reaction was further exploited to prepare 3-amino-6-methyl-5-secondaryamino

biphenyl-2,4-dicarbonitriles (9a-c) by using 6-aryl-5-methyl-2-oxo-4-secondaryamino-l-yl-

2H-pyran-3-carbonitriles (8a-c) as a starting material and malononitrile as carbanion source.

The synthesis of 6-aryl-5-methyl-2-oxo-4-secondryamine-l-yl-2H-pyran-3-carbonitriles (Sa

c) has been discussed in chapter 2. The synthesis of 3-amino-6-methyl-5-secondaryamine-l

yl-biphenyl-2,4-dicarbonitriles (9a-c) was achieved by stirring an equimolar mixture of 2H-

pyran-2-ones (8a-c), malononitrile (2) and powdered KOH in DMF for 8-10 h at room

temperature as shown in Scheme 3. The mechanism for the formation of 3-amino-6-methyl-

5-secondaryamine-l-yl-biphenyl-2,4-dicarbonitriles (9a-c) was similar to the formation of

substituted benzene derivatives (3a-e).

140

• • i T

n In V~


spectrum of compound 9a showed a band at 2218 cm-1 due to eN group, 3346 and 3409 cm-I

due to NH2 group. The IH NMR spectrum 9a showed a singlet at Q 1.88 ppm was assigned to

Me group. A broad singlet appeared at Q 5.l2 ppm for 2H was assigned to NH2 group. Two

set of multiplets appeared at 0 1.62-1.72 ppm for 6H and 3.25-3.34 ppm for 4H were

assigned to piperidine. Two set ofmultiplets appeared at 07.20-7.24 ppm for 2H and at 7.44-

7.50 ppm for 3H were assigned to aromatic protons. The molecular ion peak at m/z 316 in

mass spectrum together with HRMS confirmed the structure 9a as 3-amino-6-methyl-5-

piperidin-l-yl-biphenyl-2,4-dicarbonitrile.

5.2.4 Synthesis of 4'-amino-6'-methylsulfanyl-[1,1 ';2',1 "]terphenyl-3' ,5'-dicarbonitriles

(1la-f): Diarylbenzenes have been synthesized either by the coupling of biaryltriflate

compounds with Grignard reagents in presence of a palladium catalyst in moderate to good

yields,39 or by the iterative coupling of aryl boronic acid with aromatic halides40 separately.

Our aim was to synthesize functional group containing 1,2-diarylbenzenes by using 4-

methylsulfanyl-2-oxo-5,6-diaryl-2H-pyran-3-carbonitrile (lOa-f) as a starting material and

malononitrile as carbanion source. In order to prepare 1,2-diarylbenzenes, we attempted the

reaction of a-cyano-ketene-S,S-acetal (1) with various functionalized deoxybenzoins under

alkaline conditions, which afforded 5,6-diaryl-2H-pyran-2-ones (lOa-f) in excellent yields.

Various functionalized deoxybenzoins were prepared by heating a mixture of functionalized

phenyl acetic acid and substituted benzenes in polyphosphoric acid as described previously.

The synthesis of 4'-amino-6'-methylsulfanyl-[I,1 ';2',1 "]terphenyl-3',5'-dicarbonitriles (1la-f)

was achieved by stirring an equimolar mixture of 4-methylsulfanyl-2-oxo-5,6-diaryl-2H

pyran-3-carbonitriles (lOa-f), malononitrile (2) and powdered KOH in DMF for 10-12 h at

room temperature in 89-94% yield (Scheme 4).41

141

11 Rl Rl RJ R4 Yield (Ofo) a H H H H 90 b H H H OMe 91 c H F OMe OMe 94 d H OMe H OMe 89 e OMe OMe H OMe 92 f H F H OMe 90

Scheme 4.


spectrum of compound lIe showed bands at 2216,3350 and 3466 cm-I due to CN and NH2

groups, respectively. The IH NMR spectrum of compound lIa showed a singlets at () 2.30

ppm for 3H was assigned to SMe group. Three singlets were appeared at () 3.65 ppm, 3.76

ppm and 3.84 ppm due to three OMe groups. A broad singlet appeared at ~ 5.27 ppm for 2H

was assigned to NH2 group. A singlet at () 6.38 ppm for IH and a doublet at ~ 6.54 ppm for

IH were assigned to aromatic ring protons. Two sets of multiplets appeared at ~ 6.69-6.76

ppm for 3H and 6.92-6.96 ppm for 2H were assigned to aromatic protons. Mass spectrum

(FAB) at m/z 432 was in agreement with the proposed structure as 4'-amino-3,4,4"

trimethoxy-6'-methylsulfanyl-[I, 1';2', 1 "]terphenyl-3',5'-dicarbonitrile. Finally the structure of

compound lIc was unambiguously confirmed by single crystal X-ray analysis as shown in

Figure 2.

X-ray analysis of compound lIe: The structural analysis42 of compound lIe revealed that

the average mean plane angle for the twist of the phenyl rings from the plane of the central

benzene was 59.34°. The crystal packing of lIe showed a soft C-H ... n interaction involving

atom C21-H21B and the centroid of the central benzene ring of another molecule (Symmetry

code: x, -l+y, z) with parameters [H21B ... Cg (ring C): 2.88 A, C2l. .. Cg (ring C): 3.836(4)

A, C21-H21B ... Cg (ring C): 170°]. The X-ray structure further revealed the presence of a

network of strong intermolecular H-bonding NI-HIB ... 02 with hydrogen bonding

parameters [NI-HIB. . .o2 (x, y, -l+z), HIB ... 02: 2.39 A, Nl. .. 02: 3.020 (3) A, and Nl

HIB-02: l31°] and C21-H21C .... N3 with H-bonding parameters [C21-H21C ... N3 (I-x,

-y l-z), H 21C ... N3: 2.57 A, C2l. .. N3: 3.495 (6) A, C21-H21C-N3: 161°].

142

N2

Figure 2. ORTEP diagrams of 1,2-diarylbenzene (He) with arbitrary numbering. Thermal ellipsoids

are drawn at the 50% probability level.

5,2,5 Synthesis of substituted 4'-methyl-6'-methylsulfanyl-

[1,1 ';2',1 ";3',1 "']quaterphenyl-5'-carbonitriles (13a-g): In order to explore this reaction

further to prepare 1,2,3-triarylbenzenes, we carried out the reaction of 5,6-diphenyl-4-

methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (10a-f, X=CN) with substituted

phenylacetones (12) under alkaline conditions as shown in Scheme 5. The reaction was

monitored by TLC and pure compound was isolated as 4'-methyl-6'-methylsulfanyl

[1,1 ';2', 1 ";3', 1111]quaterphenyl-5'-carbonitriles (13a-g) in good yield.

R1 R1

R3~COMe DMF 1'-':: •

+ KOH 0 R4 .0 Me

R5 R3

10 12 R4

13 RI R2 R3 R4 R~ X Yield {%} a H H OMe H OMe CN 62 b H H H OMe OMe CN 59 c H OMe H H OMe CN 64 d H OMe OMe H OMe CN 62 e H OMe H OMe OMe CN 60 f OMe OMe H OMe OMe CN 61 g OMe OMe OMe H OMe COOMe 46

Scheme 5,

The transformation of 5,6-diaryl-2H-pyran-2-ones into substituted 4'-methyl-6'-

methylsulfanyl-[l,1 ';2', 1 ";3', llll]quaterphenyl-5'-carbonitriles (13a-t) is possibly initiated by

attack of the carbanion generated from substituted phenyl acetone (12) at position C-6 of

143

lactone (10a-t), followed by intramolecular cyclization involving the carbonyl functionality

of 12 and C-3 of the pyranone ring and elimination of carbon dioxide, followed by

protonation and dehydration to yield substituted 4'-methyl-6'-methylsulfanyl-[I, 1 ';2', 1 ";3',

1 "']quaterphenyl-5'-carbonitriles (13a-t) in good yields.

In order to check the compatibility of reaction with other substituents, an independent

reaction of 5,6-bis-(4-methoxyphenyl)-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylic acid

methyl ester (10, X = COOMe) with 2',4'-dimethoxyphenylacetone under the similar reaction

condition was carried out, which afforded 4'-methyl-6'-methylsulfanyl-[I, 1 ';2', 1 ";3',

1 "']quaterphenyl-5'-carboxylic acid methyl ester (13g) in good yield. All the synthesized

compounds were characterized by their spectroscopic analysis. IR spectrum of compound

13a showed a band at 2221 cm-I due to CN group. The IH NMR spectrum of compound 13a

showed four singlets at 8. 2.27, 2.35, 3.63 and 3.72 ppm each for 3H assigned to SMe, Me

and two OMe groups, respectively. Two sets of multiplets were appeared at & 6.26-6.31 ppm

for 2H and at 6.66-7.12 ppm for IIH due to aromatic protons. Mass spectrum (FAB) at m/z

452 confirmed the structure as 2"',4"'-dimethoxy-4'-methyl-6'-methylsulfanyl-[I, 1 ';2', 1 ";3',

1 "']quaterphenyl-5'-carbonitrile.

5.2.6 Synthesis of 3,4,5,6-tetraaryl-pyrano[3,4-c]pyran-1,8-diones (15a-e): Transition

metal-catalyzed aryl-aryl cross coupling reactions are commonly employed for the

construction of biaryl compounds. These coupling procedures sometimes place constraints

on the choice of catalyst or reaction conditions when sterically hindered patness are

involved. Since our approach to prepare 1,2,3-triarylbenzenes (13) is highly convenient and

require easily accessible precursors, we attempted the synthesis of functionally congested

1,2,3,4-tetraarylbenzenes, which are difficult to prepare by classical approaches known

today. In order to prepare 1,2,3,4-tetraarylbenzenes, we attempted the reaction of 5,6-bis-(4-

methoxyphenyl)-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylic acid methyl ester (10) with

functionalized deoxybenzoins (14) in dry DMF in presence ofKOH at room temperature for

14-15h, which afforded 3,4,5,6-tetraaryl-pyrano[3,4-c ]pyran-l ,8-dione derivatives (15a-e) to

gether with unreacted lactone 10. Surprisingly no formation of corresponding 1,2,3,4-

tetraarylbenzenes (16) was observed. The transformation of 5,6-bis-(4-methoxyphenyl)-4-

methylsulfanyl-2-oxo-2H-pyran-3-carboxylic acid methyl ester (10) into 3,4,5,6-tetraaryl

pyrano[3,4-c]pyran-l,8-dione derivatives (15a-e) is possibly initiated by attack of the

deoxybenzoin carbanion at position C-4 of lactone (10), followed by intra-molecular

cyclization involving carbonyl functionality of deoxybenzoin and COOMe ofthe 2-pyranone

and elimination of MeOH to yield pyrano[3,4-c ]pyran-l ,8-diones (15a-e).

144

SMe

R2+COOMe +

R1)lo~o 10

16

15 Ri

a 4-0Me-C6H4 b 4-0Me-C6H4 c 4-Me-C6H4 d 4-0Me-C6H4 e 4-0Me-C6H4

Scheme 6.

R2

4-0Me-C6~ 4-0Me-C6H4 H 4-0Me-C6H4 4-0Me-C6H4

Rl

C6HS

H 4-0Me-C6H4 H 4-0Me-C6H4

R4

C6Hs

j-MeOH

ft3 7'R40

R2 ":: 0

R1 10 0

15

Yield {%} 56

3,4-02CH2Me-C6H3 55 4-0Me-C6~ 64 4-0Me-C6~ 58 4-0Me-C6~ 54

Literature on pyrano[3,4-c]pyran-l,8-diones ring system shows paucity of synthetic

approaches. Molecular orbital calculations, correlation of delocalization energies, It-bond

order and It-charge density of different theoretical pyranopyrandiones have been reported.43

Some interesting photochemical44 and luminescence properties45 have been reported for

compounds with similar molecular architecture. Various natural and synthetic products

having the basic scaffold of pyranopyrandiones have demonstrated anticancer46 and

antibacterial47 activities.

All the synthesized compounds were characterized by their spectroscopic analysis.

The IH NMR spectrum of compound 15a showed two singlets at 0 3.68 ppm for 3H and 3.73

ppm for 3H assigned to two OMe groups. Two doublets appeared at 0 6.33 ppm for 2H and

6.53 ppm for 2H were assigned to aromatic protons. Three sets of multiplets appeared at 0

6.57-6.66 ppm for 4H, at 6.80-6.94 ppm for 3H and 6.97-7.22 ppm for 7H were assigned to

aromatic protons. Molecular ion peak at 529 in mass spectrum and presence of two bands at

1710 and 1782 cm-I in IR for two carbonyl groups spectrum confirmed the structure of

compound 15a as 3,4-bis-( 4-methoxyphenyl)-5,6-diphenyl-pyrano[3,4-c ]pyran-l ,8-dione.

The structure of one of the compounds 15c was unambiguously confirmed by single crystal

X-ray analysis as shown in Figure 3.

145

035

Figure 3. ORTEP diagrams ofpyrano[3,4-c]pyran-I,8-diones (15c) with arbitrary numbering.

5.2.7 Synthesis of substituted 6'-methylsulfanyl-[1,1 ';2',1 ";3',1 "';4',1 ""]quinquephenyl-

5'-earbonitriles (17a-f) and 4-(2-oxo-1,2-diarylethyl)-5,6-diaryl-pyran-2-ones (lSa-f): In

order to exploit the reaction for the preparation of 1,2,3,4-tetraarylbenzenes or pyrano[3,4-

c ]pyran-l ,8-diones, reaction of 5,6-diaryl-2-oxo-2H-pyran-3-carbonitriles (10) with

substituted deoxybenzoins were carried out in the presence of KOH in dry DMF at room

temperature for 8-10h (Scheme 7). The reaction was monitored by TLC, which showed an

intense blue spot when exposed to short-wave UV radiation at 254 nm. After completion, the

reaction mixture was poured into ice water and neutralized with dilute HCl. The precipitate

was filtered, dried over CaCh and the crude product thus obtained was purified by neutral

alumina column chromatography using CHCh:hexane (1 :4) as eluent. The purified

compound (17e) and (lSe) obtained in 29% and 62% yield respectively, were characterized

by spectroscopic analysis as 4"',4""-dimethoxy-6'-methylsulfanyl-[I, 1 ';2', 1 ";3', 1 "';4', 1 1111]

quinquephenyl-5'-carbonitrile (17e) and 4-[1 ,2-bis-( 4-methoxyphenyl)-2-oxo-ethyl]-2-oxo-

5,6-diphenyl-2H-pyran-3-carbonitrile (lSe).

The plausible reaction mechanisms for the formation of 1,2,3,4-tetraarylbenzenes

(17a-f) and 4-(2-oxo-l ,2-diarylethyl)-5,6-diaryl-pyran-2-ones (lSa-f) are depicted in Scheme

7. The transformation of 5,6-diaryl-2-oxo-2H-pyran-3-carbonitriles (10) into 1,2,3,4-

tetraarylbenzenes (17) is possibly initiated by attack of the carbanion generated from

deoxybenzoins (14) at position C6 of lactone 10, followed by intramolecular cyclization

involving the carbonyl functionality of 14 and C3 of the pyranone ring and elimination of

carbon dioxide and water to yield 17a-f.

146

R4

17 ~-C02 - NH3

R4

R4

R1

R1 H2O NH2 --=--

-CO2 NH2 -NH3

R2 R2

Entry RI Rl R3 R4 Yield (%) Yield (%) 17 18

a H H H H 31 56 b H H H Cl 30 60 c H H OMe OMe 29 62 d OMe OMe H Cl 40 57 e OMe OMe H H 38 58 f OMe OMe OMe OMe 32 59

Scheme 7.

147

Similarly, the formation of 4-(2-oxo-l ,2-diarylethyl)-5,6-diaryl-pyran-2-ones (18a-f)

could proceed through the attack of the carbanion at the less electrophilic position 4 with

elimination of methyl mercaptan followed by intramolecular cyclization involving the

carbonyl group and the nitrile functionality of the 2H-pyran-2-one (10) to form an

intermediate A. This intermediate A on alkaline hydrolysis furnishes 4-(2-oxo-l,2-

diarylethyl)-5,6-diaryl-pyran-2-ones (18a-O instead of corresponding pyrano[3,4-c ]pyran-

1,8-dione (15).

IR spectrum of compound 17c showed a band at 2215 cm-1 due to CN group. The IH

NMR spectrum of compound 17c showed three singlets at 9 2.33 ppm, 3.61 and 3.77 ppm

assigned to SMe, and two OMe groups, respectively. Three sets of multiplets appeared at 9

6.42-6.46 ppm for 2H, at 6.58-6.86 ppm for 10H and 7.05-7.16 ppm for 6H were assigned to

four aromatic ring protons. A peak in mass spectrum at mlz 514 was in agreement with the

proposed structure as 4"',4""-dimethoxy-6'-methylsulfanyl-[I,I';2', 1 ";3',1"';4', 1 ""]

quinquephenyl-5'-carbonittile. Finally the compound 17c was unambiguously confirmed by

the single crystal X-ray analysis as shown in Figure 4.

The IH NMR spectrum of compound 18e showed two singlets at q 3.48 and 3.66 ppm

were assigned to two OMe groups. Two singlets were appeared at 95.71 and 5.97 ppm were

assigned to CH pyran ring and CH of benzylic proton. Two doublets were appeared at B 6.72

ppm for 2H and 7.08 ppm for 2H which were assigned to aromatic ring protons. Two sets of

multiplets were appeared at 6.36-6.66 ppm for 2H and 7.18-7.52 ppm for 12H, assigned to

aromatic ring protons. Absence of bands around 2200-2300 cm-1 for CN in IR spectrum and

molecular ion peak at m/z 502 in mass spectrum revealed the possibility of compound 18e as

4-[1 ,2-bis-( 4-methoxyphenyl)-2-oxo-ethyl]-5,6-diphenyl-pyran-2-one. The structure of 18e

was unambiguously confirmed by the single crystal X-ray analysis shown in Figure 4.

02

Figure 4. ORTEP diagrams 1,2,3,4-tetraarylbenzene (17c) and pyran-2-one (ISe) with arbitrary numbering.

148

To achieve higher yields of 1,2,3,4-tetraphenylbenzenes, a series of optimization

studies for compound 17c was carried out by varying reaction conditions and by changing

inorganic bases such as NaH, KOH, K2C03, LDA, I-BuOK. Only the potassium hydroxide

and I-BuOK in various solvents were resulted in the formation of 1,2,3,4-

tetraphenylbenzenes, rest of the bases was found to be unsuitable. The optimization results

are summarized in Table 1.

Table 1.

Entry Base" Solvent Temp Duration Yield (%) 1 KOH DMF RT 5h 29 2 KOH DMSO RT 6h 20 3 KOH pyridine reflux 40h 66b

4 KOH toluene reflux 20h 17 5 t-BuOK THF reflux 30h 19

"1.2 Equivalents of bases was used in all the reactions. bIsolated Yield IS reported considering the total consumption oflactone 10.

It is interesting to note that the KOH-pyridine combination was found to be the best

condition observed (Entry 3: yield: 66%) for the preparation of a 1,2,3,4-tetraphenylbenzene.

Except pyridine, other solvents were resulted in a mixture of side products. In the case of

pyridine, no side products were observed and the 1,2,3,4-tetraphenylbenzene was the sole

product. The yield of 17c was reported considering the total consumption of starting lactone

10 (R1 = R2 = OMe). A series of 1,2,3,4-tetraarylbenzenes (17a-t) was prepared in 58-69%

yields by the refluxing of a mixture of substituted 5,6-diaryl-2H-pyran-2-ones (10) with

functionalized deoxybenzoins (14) in the presence of KOH in pyridine as shown in Scheme

8.

Pyridine •

+ KOH

SchemeS.

5.2.S Synthesis of substituted 6'-dimethylamino-[I,1 ';2',1 II ;3',1 111;4',1""]_

quinquephenyl-5'-carbonitriles (20a-g): A recent report by Luo and coworkers48

demonstrated the potential applications of aryl benzenes containing cyano groups in organic

light emitting diode (OLED) fabrication. It has been well documented that the introduction

of alkoxy substituents in 7t-conjugated materials enhances the solubility of the polymer and

149

the presence of the cyano group influences photophysical and electroluminescent properties

by lowering the energy of the LUMO, thus exhibiting a relatively low threshold voltage and

high quantum efficiency in LED devices.49 The paucity of synthetic methodology for the

preparation of 1,2,3,4-tetraarylbenzenes containing electron donar and acceptor groups

prompted us to exploit our methodology for preparing 6-amino-5-cyano-I,2,3,4-

tetraarylbenzenes (20a-g).

+

20 a b c d e f g

Scheme 9.

In order to prepare

Ri Rl Rl

H H H H H H H OMe H H H OMe H OMe H H OMe OMe OMe OMe OMe

DMF. KOH

R4

H CI H OMe OMe OMe OMe

Yield (%) 92 89 87 88 90 92 89

1,2,3,4-tetraarylbenzenes (20a-g) exclusively, we attempted to

reduce the electrophilicity at position 4 of 2H-pyran-2-one (10) by replacing the methyl

sulfanyl group with a secondary amine. The synthesis of 4-dimethylamino-2-oxo-5,6-diaryl-

2H-pyran-3-carbonitrile (19) have been discussed in chapter 2. The synthesis of substituted

6'-dimethylamino-[I,1 ';2', 1 ";3', 1 "';4',1 IIII]quinquephenyl-5'-carbonitriles (20a-g) was

achieved by stirring an equimolar mixture of 2H-pyran-2-one (19a-g) and functionalized

deoxybenzoins (14) in presence of KOH in dry DMF for 2-4h at room temperature in 87-

92% yield (Scheme 9). All the compounds were characterized by the spectroscopic analysis.

IR spectrum of compound 20a showed a band at 2216 cm-I due to eN group. The IH

NMR spectrum of 20a showed a singlet at 2.67 ppm for 6H due to two NMe groups. Four

sets ofmultiplets appeared at 6.67-6.76 ppm for 4H, 6.80-6.87 ppm for 6H, 6.97-7.04 ppm

for 2H and 7.14-7.22 ppm for 8H were assigned to aromatic protons. Molecular ion peak at

m/z 451 confirmed the structure of compound 20a as 6'-dimethyl amino

[1,1 ';2', 1 ";3', 1 "';4', 1 IIII]quinquephenyl-5'-carbonitrile.

150

5.3 X-ray Crystal Structure Analysis of compound 17c

In order to study the confonnational arrangements of peripheral rings of the

polyarylbenzenes, which has been a matter of several studies, a compound from the series of

1,2,3,4-tetraarylbenzene was crystallized for X-ray structural studies. Diffraction-quality

crystals of compound 17c were obtained by slow evaporation at room temperature. The

conformations of compound 17c together with arbitrary numbering are shown as ORTEP

diagrams in Fig. 4, which indicates propeller like confonnation for peripheral aryl rings with

respect to a central benzene ring. The selected torsion angles and mean-plane angles between

the central benzene ring and peripheral aryl rings of the compounds 17c are shown in Table

2.

The X-ray structure analysis41 of compound 17c showed that the dihedral angles

between peripheral and the central benzene ring ranges from 75° to 83°. The average mean

plane angle of the phenyl rings (rings B, C, D, E) from the plane of the central benzene was

found to be 79.7°, which showed that the peripheral rings are arranged nearly orthogonal to

the central benzene ring, which was found to be ~ ] 5° higher compare to hexaarylbenzene. As

a consequence, the four n-frameworks are arranged in propeller-like fashion. The crystal

packing of 17c showed C-H ... n interaction involving atom C 17-H 17 and the centroid of

another benzene molecule (symmetry code: 1/2-x, I-y, -1!2+z) with parameters [H 17 ... Cg

(ring B): 2.99 A, CI7 ... Cg (ring B): 3.602(6) A, C17- H17 ... Cg (ring B): 125°]. It is highly

interesting to note that the crystal structure analysis of compound 17c showed "N ... tt

interaction" (face lone pair-n interaction) as shown in Figure 5.

Figure 5. The crystal packing ellipsoid diagram of 17c showing "N ... n" interaction with neighbouring molecule. The sp-hybidized nitrogen of a cyano group (N I) is interacting directly with the face of the central benzene ring of another molecule with C-N .. . benzene centroid distance of 3.668 A with parameters [C31-NI. .. Cg (ring A): 3.6675 A, CNI-Cg (ring A): 147°] and with symmetry code: [-1 /2+x, 1/2-y, 2-z]. Atoms are colored as carbon-off-white; oxygen-red, nitrogen-blue and sulfur-yellow.

151

Table 2: Selected Torsion and Twist angles for the compound 17c

Compound Atoms Torsion Mean plane angle (twist angle)

angles

12c C6-C l -C7-C8 -80.8 (6) Ring A - Ring B 79.6 (2)

CI-C2-C13-CI4 -79.7(7) Ring A - Ring C 79.7(1)

C2-C3-C 19-C20 -74.9(6) Ring A - Ring D 78.9 (2)

C3-C4-C25-C26 -83.2 (7) Ring A - Ring E 80.4(1)

C 50 H 51 S 52 d 0 (I . )53 There are several reports on -H ... n, N- ... n, ... n; an ... n one palr-n

interactions, but little attention has been focused on describing N ... n interactions. 54 A critical

Cambridge Structural Database (CSD) search (ConQuest 1.8) on such N ... n interactions

(Fig. 6) revealed that in most of the cases, the nonbonded distances were greater than the van

der Waals summation of Nand n-contact (3 .3 A). In approximately 150 hits, the observed

range for N ... it interactions was found to be 2.9 to 4.1 A with no selectivity in directionality

and most of the interactions were angled close to 125 0• The crystal packing of 17 c (Fig. 6)

revealed that lone pair of sp-hybridized nitrogen of a cyano group is interacting with the face

of the central benzene ring at a distance of 3.667 A with an angle of 147° showing N ... n

interaction between molecules related by a two-fold screw axis running in a direction.

"I ~ . .... • 39 .~ . • •

II ~ ~. • • E 37 • • rJI • ~ .J.. . .. , • • ;;; . ... •• '" c: .. .... , • ~ 3.5 • -. 1: :. ... 4.:-c: ". . .. ~ 3.3 • •

• • 3.1 1 ..

• • 29 .1-- -~

115 125 135 145 155 165 175 165

An91e (Degree)

Figure 6. Scatter plot showing N ... n interactions. Each black square represents a hit obtained by CSD search on N .. . n interactions.

The mean plane angle between a central benzene ring and the below neighbouring

central benzene ring was found to be 70°. The cyano-group containing central benzene rings

are colored (carbon-orange, nitrogen-blue and centroid-green) for clarity. It is interesting that

the repeat of the N ... n interaction around the axis of the 1,2,3,4-tetraarylbenzene 17c

152

17c, these helices are connected with each other through H ... H intermolecular short

contacts.

:- :- :;: ,I .1 .-- -r- ,- ;-.: ,: .r

:- t- t-,I ,: .r

t- :- r-,: .r ,:

Figure 7. The crystal packing diagram of I7c showing N ... n interaction between molecules related by a two-fold screw axis running in a direction. The dihedral angle between a central benzene ring and the neighbouring central benzene ring is 70°. Central benzene rings are colored (carbon-orange, nitrogen-blue and centroid-green) for clarity. Hydrogens are omitted for clarity.

5.4 Summary

We have demonstrated a new synthetic approach for preparing functionalized

benzene derivatives, functionally crowded biaryls, 1,2-diaryl-, 1,2,3-triaryl- and 1,2,3,4-

tetraarylbenzenes from ketene-S,S-acetals using readily available substrates in just two steps

in good to excellent yields. This methodology have several advantages over classical metal

assisted aryl-aryl coupling reactions such as: i) highly simple reaction process; ii) flexibility

of introducing electron-donor or acceptor groups even at sterically demanding ortho-

positions, iii) does not require expensive organometallic reagent or catalyst, iv) versatile

approach for generating molecular diversity, and v) high yield of aromatic compounds. xray structural analysis of a 1,2,3,4-tetraarylbenzene 17c revealed a 'N ... 7t interaction ', in

which lone pair of a sp-hybridized nitrogen atom is interacting to the face of a central

benzene ring of neighbouring molecule with a distance of3.668 A.

5.5 Results and Discussion

5.5.1 Evaluation of Antihyperglycemic Activity

The in vitro glucose-6-phosphatase, glycogen phosphorylase, protein tyros ine

phosphatase-l B and a-glycosidase activity of most of the compounds at 100 f!M

concentration were examined as described in experimental section of chapter 2.

Table 3. In vitro anti hyperglycemic activity of compounds 3a-e, 5a-c, 7a-c, 9a-c, 11 a-f, 17a-f and 18a-f.

153

Table 3. In vitro antihyperglycemic activity of compounds 3a-e, 5a-c, 7a-e, 9a-e, 11a-f, 17a-f and 18a-f.

Entry % Inhibition G-6-Pase GP a-G Iyeosidase PTPase

3a 11.4 50.0 ND 8.40

3b 19.6 61.9 ND 13.4

3e 54.7 20.0 ND 9.20

3d 5.30 16.5 ND +5.8

3e 18.9 NI ND 4.20

Sa 8.20 20.0 NI 40.2

5b 41.8 5.0 17.3 3.60

5e 14.4 55.0 22.1 58.5

5d 0.08 50.0 10.5 25.6

5e 6.10 10.0 6.70 0.00

Sf 24.5 11.6 ND ND

7a 0.96 45.0 6.70 NI

7b 19.3 12.5 6.70 7.30

7e 12.3 37.5 17.3 0.00

9a 38.2 4.70 ND 31.1

9b 10.9 2.30 ND NI

ge 33.3 15.7 ND NI

11a 7.40 NI 10.5 81.6

11b 6.80 37.9 5.70 61.5

11e 1.90 74.3 11.5 28.2

11d 5.50 6.90 14.4 76.9

11e 0.30 13.8 25.9 30.7

11f 5.50 NI 13.4 48.8

17a 2.60 47.5 ND 7.00

17b 0.90 38.3 ND 43.8

17e 40.9 43.2 ND 12.3

17d 1.50 35.2 ND 21.9

17e 4.20 39.2 ND 11.4

17f 6.90 29.7 ND 12.3

18a 44.3 15.8 ND 28.5

18b 0.95 5.40 ND 28.5

18e 8.10 5.40 ND 34.3

18d 7.20 37.8 ND ND

18e 2.10 18.0 ND 34.3

18f 28.8 37.8 ND NI

a Compounds were evaluated at 100 J.lMconcentration; ND means: not determined; NI means no inhibition.

Compound 3c showed 54.7% inhibition against glucose-6-phosphatase enzyme while

154

compounds 3a, 3b, Sc, Sd and llc showed 50.0, 61.9, 55.0, 50.0 and 74.3% inhibition

against glycogen phosphorylase enzyme, respectively. 1,2-Diarylbenzene derivatives lla,

llb and lld showed 81.6, 61.5 and 76.9% inhibition against protein tyrosine phosphatase

enzyme. Compound Sc was only compound which showed 55.0 and 58.5% inhibition against

two enzymes glucose-6-phosphatase and protein tyrosine phosphatase, respectively.

S.S.2 Evaluation of Antileishmanial activity

In the sandfly vector, Leishmania parasites exist as extracellular promastigotes, while

in the mammalian hosts they exist primarily as intracellular amastigotes within

phagolysosomes of macrophages. Various in vitro models have been developed to access in

vitro antileishmanial activity of drug candidates. Our biological test system involves

microscopic counting of live promastigotes in control and treated culture. Taking

pentamidine as a control, we have evaluated antileishmanial activity of functionalized biaryls

against extracellular promastigotes of L. donovani and intracellular amastigotes residing

murine macrophages at various concentrations. The activity profile of the compounds is

summarized in Table 4.

The data suggests that several arylanthranilodinitriles represent interesting leads as

antileishmanial agents.55 The structure-activity relationship of the screened biaryls revealed

that antileishmanial activities are significantly dependent on the point of attachment of aryl

ring (R1 or R2 = aryl) on the basic anthranilodinitrile ring. In general, aryl ring para to amino

group (Sa-e, RI = aryl, R2 = Me) of anthranilodinitrile ring possessed good inhibitory activity

against extracellular promastigotes (59-83% at 8 llg/mL concentration) and intracellular

amastigotes (53-70% at 20 llg/mL concentration) of Leishmania donovani, while aryl ring

meta to amino functionality (7a-c) showed moderate inhibition. It is evident from the activity

profile of Sa-c and 7a-c that the compounds have weak inhibitory effect on the L. donovani

promastigotes, comparing with standard drug pentamidine, whereas they exhibited better

inhibition against intracellular amastigotes of the L. donovani.

Among various screened compounds, 4-amino-2-methyl-6-methylsulfanyl-4'

trifluoromethyl-biphenyl-3,5-dicarbonitrile (Sc) was found to be the most active, which

showed 83% inhibition against promastigotes and 70% inhibition against amastigotes of L.

donovani at 8 llg/mL and 20 llg/mL concentrations, respectively. Rest of the compounds

possessed slightly better inhibition against amastigotes comparing with standard drug.

155

Table 4. In vitro antileishmanial activity for the compounds 5a-e and 7a-c.

Rt Rl Concentration Promastigo Concentrat A mastigote (~glmL) tes* (% ion s*(%

Inhibition) (~glmL) Inhibition)

5a 2-FC6H4 CH3 4 37 20 61 8 60

5b 4-FC6H4 CH3 4 43 20 62 8 65

5c 4-CF3C6~ CH3 4 67 20 70 8 83

5d 2,4-( OCH3)zC6H3 CH3 4 36 20 56 8 59

5e 3,4-(OCH3)2C6H3 CH3 4 60 20 53 8 69

7a CH3 C6Hs 4 25 20 23 8 48

7b CH3 4-C1C6H4 4 46 20 10 8 50

7c CH3 4-CH30C6H4 4 31 20 25 8 53

Pentamidine 2 71 20 48 ·Values are the average of percentage inhibition after day 1, 2, 3, and 4.

5.5 Experimental Section

General procedure for the synthesis of compounds 3a-e: A mixture of 6-alkyl or 5,6-

dialkyl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitrilel (1 mmol), malononitrile (1 mmol)

and powdered KOH (1.2 mmol) in dry DMF (5 mL) was stirred at room temperature for 12-

14 h. At the end the reaction mixture was poured into ice water with vigorous stirring and

finally neutralized with dilute HCl. The solid thus obtained was filtered and purified on a

neutral alumina column using chloroform-hexane (1 :5) as eluent.

2-Amino-4-methyl-6-methylsulfanyl-isophthalonitrile (3a)

White solid; mp 236-238 °C; IH NMR (200 MHz, CDC h) 0 2.48 (s, 3H, Me), 2.54(s, 3H,

SMe), 5.10 (brs, 2H, NH2), 6.42 (s, IH, ArH); IR (KBr) 2213(CN), 3353, 3442 cm-I (NH2);

MS (FAB) 204 (M++l); HRMS calcd. for CIOH9N3S 203.0532, found: 203.0517.

2-Amino-4-ethyl-6-methylsulfanyl-isophthalonitrile (3b)

White solid; mp 146-148 °C; IH NMR (200 MHz, CDC h) 0 1.29 (t, J = 7.6 Hz, 3H, Me),

2.56 (s, 3H, SMe), 2.73 (q, J= 7.6 Hz, 2H, CH2), 5.13 (brs, 2H, NH2), 6.44 (s, IH, ArH); IR

(KBr) 2211(CN), 3328, 3422 cm-I (NH2); MS (FAB) 218 (M++l).

2-Amino-4-ethyl-5-methyl-6-methylsulfanyl-isophthalonitrile (3c)

White solid; mp 202-204 °C; IH NMR (200 MHz, CDC h) 0 1.23 (t, J = 7.6 Hz, 3H, Me),

2.43 (s, 3H, Me), 2.51 (s, 3H, SMe), 2.86 (q, J= 7.6 Hz, 2H, CH2), 5.04 (brs, 2H, NH2); IR

(KBr) 2220 (CN), 3349, 3417 em-I (NH2); MS (FAB) 231 (M++l).

2-Amino-4-isopropyl-6-methylsulfanyl-isophthalonitrile (3d)

156

White solid; mp 138-140 DC; IH NMR (200 MHz, CDCh) 8 1.29 (d, J = 6.8 Hz, 6H, 2Me),

2.57 (s, 3H, SMe), 2.75-2.86 (m, IH, CH), 5.14 (brs, 2H, NH2), 6.48 (s, IH, ArH); IR (KBr)

2220 (CN), 3343, 3405 cm-I (NH2); MS (FAB) 231 (M++l).

2-Amino-4-isobutyl-6-methylsulfanyl-isophthalonitrile (3e)

White solid; mp 164-166 DC; IH NMR (200 MHz, CDC h) 8 0.97 (d, J = 6.6 Hz, 6H, 2Me),

1.95-2.03 (m, IH, CH), 2.55 (s, 3H, SMe), 2.62 (d, J = 7.2 Hz, 2H, CH2), 5.13 (brs, 2H,

NH2), 6.37 (s, IH, ArH); IR (KBr) 2222 (CN), 3348, 3408 cm-I (NH2); MS (FAB) 246

(~+1).

General procedure for the synthesis of compounds 5a-f: A mixture of 5-aryl-3-cyano-6-

methyl-4-methylsulfanyl-2H-pyran-2-ones 4 (1 mmol), malononitrile (1 mmol) and

powdered KOH (1.2 mmol) in dry DMF (5 mL) was stirred at room temperature for 12-15 h.

At the end the reaction mixture was poured into ice water with vigorous stirring and finally

neutralized with dilute HCI. The solid thus obtained was filtered and purified on a neutral

alumina column using chloroform-hexane (1 :3) as eluent.

4-Amino-2'-fluoro-2-methyl-6-methylsulfanyl-biphenyl-3,5-dicarbonitrile (5a)

White solid; mp 192-194 DC; IH NMR (200 MHz, CDCh) 8 2.20 (s, 3H, CH3), 2.30 (s, 3H,

SCH3), 5.22 (brs, 2H, NH2), 7.04-7.19 (m, 4H, ArH); IR (KBr) 2220 (CN), 3352 (NH), 3413

cm-1 (NH); MS (FAB) 298 (M++l); Anal. Calcd. for CI6H12FN3S: C, 64.63; H, 4.07;

N,14.13. Found: C, 64.69; H, 4.10, N, 14.19.

4-Amino-4' -fluoro-2-methyl-6-methylsulfanyl-biphenyl-3,5-dicarbonit rile (5b)


SCH3), 5.22 (brs, 2H, NH2), 7.06-7.22 (m, 4H, ArH); IR (KBr) 2219 (CN) 3334 (NH), 3452

cm-I (NH); MS (FAB) 298 (~+1).

4-Amino-2' ,4' -dimethoxy-2-methyl-6-methylsulfanyl-biphenyl-3,5-dicarbonitrile (5c)

White solid; mp 206-208oC; IH NMR (200 MHz, CDC h) 8 2.18 (s, 3H, CH3), 2.28 (s, 3H,

SCH3), 3.73 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 5.15 (brs, 2H, NH2), 6.52-6.61 (m, 2H,

ArH), 6.88 (d, J= 8.4 Hz, IH, ArH); IR (KBr) 2218 (CN) 3348 (NH), 3424 cm-I (NH); MS

(FAB) 340 (M++l); HRMS calcd. for CI8H17N302S 339.1029, found: 339.1041.

4-Amino-3' ,4'-dimethoxy-2-methyl-6-methylsulfanyl-biphenyl-3,5-dicarbonitrile (5d)

White solid; mp 212-214 DC; IH NMR (200 MHz, CDCh) 8 2.24 (s, 3H, CH3), 2.31 (s,3H,

SCH3), 3.86 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 5.17 (brs, 2H, NH2), 6.59-6.69 (m, 2H,

ArH), 6.93 (d, J= 8.0 Hz, IH, ArH); IR (KBr) 2216 (CN) 3354 (NH), 3426 cm-I (NH); MS

(FAB) 340 (M++1); HRMS calcd. for CI8H17N302S 339.1028, found: 339.1041.

4-Amino-2-methyl-6-methylsulfanyl-4'-trifluoromethyl-biphenyl-3,5-dicarbonitrile (5e)

157

White solid; mp 122-124 DC; IH NMR (200 MHz, CDCh) 0 2.20 (s, 3H, CH3), 2.31 (s,3H,

SCH3), 5.25 (brs, 2H, NH2), 7.24-7.41 (m, 2H, ArH), 7.53-7.73 (m, 2H, ArH); IR (KBr)

2221 (CN) 3351 (NH), 3416 cm-I (NH); MS (FAB) 348 (~+1); HRMS calcd. for

C17HI2F3N3S 347.0708, found: 347.0704.

4-Amino-2-benzyl-6-methylsulfanyl-biphenyl-3,5-dicarbonitrile (5f)

White solid; mp 138-140 DC; IH NMR (200 MHz, CDCh) 8 2.28 (s, 3H, SCH3), 3.95 (s, 2H,

CH2), 5.26 (brs, 2H, NH2), 6.72-6.81 (m, 2H, ArH), 6.90-6.99 (m, 2H, ArH), 7.11-7.19 (m,

3H, ArH), 7.29-7.37 (m, 3H, ArH); IR (KBr) 2214 (CN), 3343, 3424 cm-I (NH2); MS (FAB)

355 (~+1).

General procedure for the synthesis of compounds 7a-c: A mixture of 5-methyl-4-

methylsulfanyl-2-oxo-6-aryl-2H-pyran-3-carbonitrile 6 (1 mmol), malononitrile (1 mmol)

and powdered KOH (1.2 mmol) in dry DMF (5 mL) was stirred at room temperature for 12-

15 h. At the end the reaction mixture was poured into ice water with vigorous stirring and

finally neutralized with dilute HCI. The solid thus obtained was filtered and purified on a


3-Amino-6-methyl-5-methylsulfanyl-biphenyl-2,4-dicarbonitrile (7a)


SCH3), 5.12 (brs, 2H, NH2), 7.20-7.25 (m, 2H, ArH), 7.47-7.50 (m, 3H, ArH); IR (KBr)

2221 (CN), 3348 (NH), 3407 cm-I (NH); MS (FAB) 280 (M++l); Anal. Calcd. for

CI6H\3N3S: C, 68.79; H, 4.69; N,15.04. Found: C, 68.88; H, 4.78, N, 15.16.

3-Amino-4' -chloro-6-methyl-5-methylsulfanyl-biphenyl-2,4-dicarbonitrile(7b)


SCH3), 5.15 (brs, 2H, NH2), 7.18 (d, J= 8.2 Hz, 2H, ArH), 7.48 (d, J= 8.2 Hz, 2H, ArH); IR

(KBr) 2221 (CN) 3350 (NH), 3413 cm-I (NH); MS (FAB) 314 (~+1), HRMS calcd. for

CI6H12CIN3S 313.0450, found: 313.0440.

3-Amino-4'-methoxy-6-methyl-5-methylsulfanyl-biphenyl-2,4-dicarbonitrile(7c)


SCH3), 3.87 (s, 3H, OCH3), 5.13 (brs, 2H, NH2), 7.00 (d, J= 8.0 Hz, 2H, ArH), 7.17 (d, J=

8.0 Hz, 2H, ArH); IR (KBr) 2228 (CN) 3364 (NH), 3432 cm-I (NH); MS (FAB) 310 (M++l);

HRMS calcd. for C17H1SN30S 309.0936, found: 309.0940.

General procedure for the synthesis of compounds 9a-c: A mixture of 5-methyl-2-oxo-6-

aryl-4-sec.amino-l-yl-2H-pyran-3-carbonitrile 8 (1 mmol), malononitrile (1 mmol) and

powdered KOH (1.2 mmol) in dry DMF (5 mL) was stirred at room temperature for 12-15 h.

At the end the "reaction mixture was poured into ice water with vigorous stirring and finally

158

neutralized with dilute HCl. The solid thus obtained was filtered and purified on a neutral


3-Amino-6-methyl-5-pi peridin-l-yl-biphenyl-2,4-dicarbonitrile (9a)

White solid; mp 210-212 °C; IH NMR (200 MHz, CDCh) 8 1.62-1.72 (m, 6H, 3CH2), 1.88

(s, 3H, CH3), 3.25-3.34 (m, 4H, 2CH2), 5.02 (brs, 2H, NH2), 7.20-7.24 (m, 2H, ArH), 7.44-

7.50 (m, 3H, ArH); IR (KBr) 2218 (CN), 3346 (NH), 3409 cm-1 (NH); MS (FAB) 316 (Ml.

HRMS calcd. for C20H20N4 316.1689, found: 316.1688.

3-Amino-6-methyl-5-( 4-methyl-piperidin-l-yl)-biphenyl-2,4-dicarbonitrile (9b)

White solid; mp 192-194 °C; IH NMR (200 MHz, CDCh) 8 1.02 (d, J= 6.2 Hz, 3H, CH3),

1.30-1.43 (m, 2H, CH2), 1.52-1.64 (m, IH, CH), 1.70-1.79 (m, 2H, CH2), 1.86 (s, 3H, CH3),

3.26-3.34 (m, 4H, 2CH2), 5.04 (brs, 2H, NH2), 7.17-7.22 (m, 2H, ArH), 7.42-7.50 (m, 3H,

ArH); IR (KBr) 2219 (CN), 3341 (NH), 3411 cm-1 (NH); MS (FAB) 330 (Ml.

3-Amino-4' -chloro-6-methyl-5-piperidin-l-yl-biphenyl-2,4-dicarbonitrile (9c)

White solid; mp 210-212 °C; IH NMR (200 MHz, CDCh) 8 1.62-1.68 (m, 6H, 3CH2), 1.87

(s, 3H, CH3), 3.26-3.32 (m, 4H, 2CH2), 5.04 (brs, 2H, NH2), 7.18 (d, J= 8.0 Hz, 2H, ArH),

7.46 (d, J= 8.0 Hz, 2H, ArH); IR (KBr) 2213 (CN), 3351 (NH), 3414 cm-1 (NH); MS (FAB)

350 (M++l). HRMS calcd. for C2oH1 9CIN4 350.1297, found: 350.1298.

General procedure for the synthesis of compounds lla-f: A mixture of 4-methylsulfanyl-

2-oxo-5,6-diphenyl-2H-pyran-3-carbonitrile 10a-f (1 mmol), malononitrile (1 mmol) and

powdered KOH (1.2 mmol) in dry DMF (5 mL) was stirred at room temperature for 6-8h. At

the end reaction mixture was poured into ice water with vigorous stirring and finally

neutralized with dilute HCl. The solid thus obtained was filtered and purified on a neutral


4'-Amino-6'-methylsulfanyl-[I,1 ';2',1 "]terphenyl-3' ,5'-dicarbonitrile (lla):

White solid; mp 198-200 °C; IH NMR (200 MHz, CDCh) 8 2.27 (s, 3H, SCH3), 5.31 (brs,

2H, NH2), 6.93-6.96 (m, 2H, ArH), 7.00-7.04 (m, 2H, ArH), 7.15-7.22 (m, 6H, ArH); !3C

(200 MHz, CDCh) 8 19.67 (SCH3), 97.92, 100.83, 115.77 (CN), 115.9 (CN), 127.85,

128.21, 128.41, 128.87, 129.57, 131.31, 135.19, 137.18, 147.73, 150.03, 152.03; IR (KBr)

2219 (CN), 3353, 3468 cm-1 (NH2); MS (FAB) 342 (M++l).

4' -Amino-4" -methoxy-6' -methylsulfanyl-[I,1 ';2' ,1' ']terphenyl-3' ,5' -dicarbonitrile

(llb):

White solid; mp 240-242 °C; IH NMR (200 MHz, CDCh) 8 2.26 (s, 3H, SCH3), 3.74 (s,3H,

OCH3), 5.29 (brs, 2H, NH2), 6.71 (d, J= 8.6 Hz, 2H, ArH), 6.94 (d, J= 8.2 Hz, 4H, ArH),

7.17-7.20 (m, 3H, ArH); !3C (200 MHz, CDCh) 8 19.63 (SCH3), 55.54 (OCH3), 98.16,

159

100.60, 113.87, 115.79 (CN), 116.10 (CN), 127.79, 128.26, 129.34, 131.04, 131.33, 135.49,

137.35, 149.85, 151.97, 159.95; IR (KBr) 2214 (CN), 3348, 3464 cm-1 (NH2); MS (FAB)

372 (M++l).

4'-Amino-4-fluoro-2" ,4"-dimethoxy-6'-methylsulfanyl-[I,1 ';2',1 "]terphenyl-3' ,5'

dicarbonitrile (Hc):


OCH3), 3.75 (s, 3H, OCH3), 5.22 (brs, 2H, NH2), 6.31 (d, J= 8.0 Hz, IH, ArH), 6.71 (d, J= 8.0 Hz, IH, ArH), 6.84-6.90 (m, 4H, ArH), 7.17 (d, J = 8.0 Hz, IH, ArH); IR (KBr) 2214

(CN), 3348, 3464 cm-1 (NH2); MS (FAB) 420 (M++l).

4'-Amino-4,4 "-dimethoxy-6'-methylsulfanyl-[I,1 ';2',1 "]terphenyl-3' ,5'-dicarbonitrile

(Hd):


20CH3), 5.25 (brs, 2H, NH2), 6.69-6.76 (m, 4H, ArH), 6.85 (d, J= 8.8 Hz, 2H, ArH), 6.95

(d, J = 8.8 Hz, 2H, ArH); IR (KBr) 2209 (CN), 3347, 3423 cm-1 (NH2); MS (FAB) 402

(~+1).

4' -Amino-3,4,4" -trimethoxy-6' -methylsulfanyl-[I,1 ';2' ,1 "]terphenyl-3' ,5' -dicarbonitrile

(He):


OCH3), 3.76 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 5.27 (brs, 2H, NH2), 6.38 (s, IH, ArH),

6.54 (d, J = 8.0 Hz, IH, ArH), 6.69-6.76 (m, 3H, ArH), 6.92-6.96 (m, 2H, ArH); IR (KBr)

2216 (CN), 3350, 3466 cm-1 (NH2); MS (FAB) 432 (M++l).

4'-Amino-4-fluoro-4"-methoxy-6'-methylsulfanyl-[I,1 ';2',1 "]-terphenyl-3' ,5'

dicarbonitrile (Hi):


OCH3), 5.29 (brs, 2H, NH2), 6.74 (d, J = 8.6 Hz, 2H, ArH), 6.88-6.92 (m, 6H, ArH); IR

(KBr) 2219 (CN), 3349, 3470 cm-1 (NH2); MS (FAB) 390 (M++l).

General procedure for the synthesis of compounds 13a-g: A mixture of 4-methylsulfanyl-

2-oxo-5,6-diphenyl-2H-pyran-3-carbonitrile 10a-f (1 mmol), substituted phenylacetone 12

(1.2 mmol) and powdered KOH (1.2 mmol) in dry DMF (5 mL) was stirred at room

temperature for 6-8h. At the end reaction mixture was poured into ice water with vigorous

stirring and finally neutralized with dilute HCl. The solid thus obtained was filtered and

purified on a neutral alumina column using chloroform-hexane (1 :4) as eluent.

2"',4'" -Dimethoxy-4' -methyl-6' -methylsulfanyl-[1,1';2' ,1 ";3', 1 "']q uaterphenyl-5'

carb~nitrile (13a)

160

White solid; mp 204-206 °C; IH NMR (200 MHz, CDC h) 8 2.27 (s, 3H, SCH3), 2.35 (s, 3H,

CH3), 3.63 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 6.26-6.31 (m, 2H, ArH), 6.66-7.12 (m, IIH,

ArH); IR (KBr) 2221 em-I (CN); MS (FAB) 452 (M++l).

3111 ,4111-Dimethoxy-4'-methyl-6'-methylsulfanyl-[I,1 ';2',1 ";3', 1 "']quaterphenyl-5'

earbonitrile (13b)

White solid; mp 154-156 °C; IH NMR (200 MHz, CDCh) 8 2.27 (s, 3H, Me), 2.44 (s, 3H,

SCH3), 3.62 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 6.36 (d, J= 1.6 Hz, IH, ArH), 6.52-6.74 (m,

4H, ArH), 6.82-6.93 (m, 4H, ArH), 7.04-7.25 (m, 4H, ArH); IR (KBr) 2217 (CN) em-I; MS

(FAB) 452 (M++l).

4" ,4111-Dimethoxy-4'-methyl-6'-methylsulfanyl-[I,1 ';2',1 ";3',1 "']quaterphenyl-5'

earbonitrile (13e)


SCH3), 3.60 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 6.38 (d, J= 8.6 Hz, 2H, ArH), 6.55 (d, J=

8.6 Hz, 2H, ArH), 6.71 (d, J = 8.6 Hz, 2H, ArH), 6.83 (d, J = 8.6 Hz, 2H, ArH), 6.94-7.01

(m, 2H, ArH), 7.11-7.19 (m, 3H, ArH); IR (KBr) 2220 (CN) em-I; MS (FAB) 452 (~+1).

4'-Methyl-6'-methylsulfanyl-2111 ,4" ,4"'-trimethoxy-[I,1 ';2',1 ";3',1 "']quaterphenyl-5'

earbonitrile (13d)

White solid; mp 194-196 °C; IH NMR (200 MHz, CDCh) 8 2.26 (s, 3H, SCH3), 2.33 (s,3H,

CH3), 3.60 (s, 3H, OCH3), 3.63 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 6.29 (s, IH, ArH), 6.32-

6.41 (m, 3H, ArH), 6.50-6.74 (m, 3H, ArH), 6.92-7.29 (m, 5H, ArH); IR (KBr) 2220 em-I

(CN); MS (FAB) 482 (M++l).

4'-Methyl-6'-methylsulfanyl-3'" ,4" ,4"'-trimethoxy-[I,1 ';2',1 ";3',1 III]quaterphenyl-5'

earbonitrile (13e)


SCH3), 3.60 (s, 3H, OCH3), 3.64 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.34-6.42 (m, 3H,

ArH), 6.52-6.62 (m, 3H, ArH), 6.72 (d, J= 8.2 Hz, IH, ArH), 6.87-6.93 (m, IH, ArH), 7.03-

7.25 (m, 4H, ArH); IR (KBr) 2215 (CN) em-I; MS (ESI) 482 (~+1).

4'-Methyl-6'-methylsulfanyl-31114,4" ,4"'-tetramethoxy-[I,1 ';2',1 ";3',1 "']quaterphenyl-

5'-earbonitrile (13t)

White solid; mp 154-156 °C; IH NMR (200 MHz, CDC h) 8 2.26 (s, 3H, Me), 2.41 (s,3H,

SCH3), 3.62 (5, 3H, OCH3), 3.64 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.82 (5, 3H, OCH3),

6.35 (d, J= 1.2 Hz, IH, ArH), 6.40 (d, J= 8.4 Hz, 2H, ArH), 6.50-6.86 (m, 7H, ArH), 6.97

(dd, J= 8.4 Hz, 1.4 Hz, IH, ArH); IR (KBr) 2221 (CN) em-I; MS (FAB) 512 (~+1).

161

4'-Methyl-6'-methylsulfanyl-2"'4,4" ,4"'-tetramethoxy-[I,1 ';2',1 ";3',1 "']quaterphenyl

S'-carboxylic acid methyl ester (13g)

White solid; mp 214-216°C; IH NMR (200 MHz, CDCh) 0 2.01 (5, 3H, Me), 2.02 (5, 3H,

SCH3), 3.60 (5, 6H, 20CH3), 3.72 (5, 3H, OCH3), 3.73 (5, 3H, OCH3), 3.98 (5, 3H, OCH3),

6.23-6.32 (m, 2H, ArH), 6.33-6.42 (m, 2H, ArH), 6.50-6.58 (m, IH, ArH), 6.60-6.74 (m, 4H,

ArH), 6.93 (d, J = 8.4 Hz, 2H, ArH), 6.99 (d, J = 8.4 Hz, 2H, ArH); IR (KBr) 1709 (CO) cm

I; MS (FAB) 545 (M++1).

General procedure for the synthesis of compounds ISa-e: A mixture of 5,6-Bis-(4-

methoxy-phenyl)-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitrile 14b (1 mmol),

functionalised deoxybenzoins 14 (1.2 mmol) and powdered KOH (1.2 mmol) in dry DMF (5

mL) was stirred at room temperature for 14-15h. At the end reaction mixture was poured into

ice water with vigorous stirring and finally neutralized with dilute HCl. The solid thus

obtained was filtered and purified on a neutral alumina column using chloroform-hexane

(1 :4) as eluent.

3,4-Bis-(4-methoxyphenyl)-S,6-diphenylpyrano[3,4-c]pyran-l,8-dione (ISa)

Yellow solid; mp 178-180 °C; IH NMR (200 MHz, CDCh) 0 3.68 (5, 3H, OCH3), 3.73 (5,

3H, OCH3), 6.33 (d, J= 8.6 Hz, 2H, ArH), 6.53 (d, J= 8.6 Hz, 2H, ArH), 6.57-6.66 (m, 4H,

ArH), 6.80-6.94 (m, 3H, ArH), 6.97-7.22 (m, 7H, ArH); IR (KBr) 1710 (CO), 1782 em-I

(CO); MS (F AB) 529 (M+ + l).

6-Benzo[I,3] dioxol-S-yl-3,4-bis-( 4-methoxyphenyl)pyrano[3,4-c ]pyran-l ,8-dione (ISb)


3H, OCH3), 6.04 (5, 2H, CH2), 6.28 (5, IH, CH), 6.73 (d, J= 8.8 Hz, 2H, ArH), 6.84 (d, J= 8.8 Hz, 2H, ArH), 7.01 (d, J = 8.8 Hz, 2H, ArH), 7.15 (d, J = 8.8 Hz, 2H, ArH), 7.28-7.37

(m, 3H, ArH); IR (KBr) 1706 (CO), 1773 (CO) em-I; MS (FAB) 497 (M++l).

3,4-Bis-( 4-methoxyphenyl)-6-p-tolyl-pyrano[3,4-c ]pyran-l ,8-dione (ISc)

Yellow solid; mp 166-168 °C; IH NMR (200 MHz, CDCh) 0 2.40 (5, 3H, CH3) 3.80 (5, 3H,

OCH3), 3.91 (5, 3H, OCH3), 6.40 (5, lH, CH), 6.74 (d, J= 8.8 Hz, 2H, ArH), 7.02 (d, J= 8.8

Hz, 2H, ArH), 7.15 (d, J= 8.8 Hz, 2H, ArH), 7.23 (d, J= 8.8 Hz, 2H, ArH), 7.34 (d, J= 8.8

Hz, 2H, ArH), 7.64 (d, J = 8.8 Hz, 2H, ArH); IR (KBr) 1708 (CO), 1775 (CO) em-I; MS

(FAB) 467 (M++l).

3,4,6-Tris-( 4-methoxyphenyl)pyrano[3,4-c] pyran-l,8-dione (ISd)


3H, OCH3), 3.90 (5, 3H, OCH3), 6.32 (5, IH, CH), 6.73 (d, J= 8.8 Hz, 2H, ArH), 6.92 (d, J=

8.8 Hz, 2H, ArH), 7.01 (d, J= 8.8 Hz, 2H, ArH), 7.15 (d, J= 8.8 Hz, 2H, ArH), 7.34 (d, J=

162

8.8 Hz, 2H, ArH), 7.70 (d, J= 8.8 Hz, 2H, ArH); IR (KBr) 1712 (CO), 1775 (CO) cm-!; MS

(FAB) 483 (M++l).

3,4,S,6-Tetrakis-( 4-methoxyphenyl)pyrano[3,4-c ]pyran-l ,8-dione (ISe)

Yellow solid; mp 234-236 °C; !H NMR (200 MHz, CDCh) 0 3.69 (s, 6H, 20CH3), 3.73 (s,

6H, 20CH3), 6.37 (d, J= 8.8Hz, 4H, ArH), 6.52 (d, J= 8.8 Hz, 4H, ArH), 6.61 (d, J= 8.8

Hz, 4H, ArH), 7.03 (d, J = 8.8 Hz, 4H, ArH); IR (KBr) 1708 (CO), 1775 (CO) cm-!; MS

(FAB) 589 (~+1).

General procedure for the synthesis of compounds 17a-f and 18a-f: A mixture of 4-

methylsulfanyl-2-oxo-5,6-diphenyl-2H-pyran-3-carbonitrile (10) (1 mmol), functionalised

deoxybenzoins (14) (1.2 mmol) and powdered KOH (1.2 mmol) in dry DMF (5 mL) was

stirred at room temperature for 2-5h. At the end reaction mixture was poured into ice water

with vigorous stirring and finally neutralized with dilute HCI. The solid thus obtained was

filtered and purified on a neutral alumina column using chloroform-hexane (l :2) as eluent.

Selective synthesis of compounds 17a-f: A mixture of 4-methylsulfanyl-2-oxo-5,6-

diphenyl-2H-pyran-3-carbonitrile 10 (1 mmol), and functionalised deoxybenzoins 14 (1.2

mmol) in pyridine (5 mL) was heated at reflux temperature for 45-48h. After completion, the

solvent was evaporated under reduced pressure and was added water (15 mL) to give the

crude compound. The pure compounds were isolated on neutral alumina, using chloroform

hexane (1:4) as eluent.

6' -Methylsulfanyl-[I,1 ';2' ,1 ";3',1"';4' ,1 'III]q uinquephenyl-S' -carbonitrile (17 a): White

solid; mp 216-218 °C; !H NMR (200 MHz, CDCh) 8 2.34 (s, 3H, SCH3), 6.64-6.67 (m, 5H,

ArH), 6.81-6.90 (m, 6H, ArH), 7.01-7.25 (m, 9H, ArH); IR (KBr) 2224 cm-! (CN); MS

(FAB) 454 (~+1).

4""-Chloro-6'-methylsulfanyl-[I,1 ';2',1 ";3',1 "';4',1 ""]-quinquephenyl-S'-carbonitrile

(17b):

White solid; mp 248-250 DC; !H NMR (200 MHz, CDCh) 8 2.33 (s, 3H, SCH3), 6.62-6.80

(m, 3H, ArH), 6.83-6.93 (m, 6H, ArH), 7.00-7.09 (m, 2H, ArH), 7.12-7.35 (m, 8H, ArH); IR

(KBr) 2215 cm-! (CN); MS (FAB) 488 (M++l).

4111,4""-Dimethoxy-6'-methylsulfanyl-[I,1 ';2',1 ";3',1 "';4',1 ""]-quinquephenyl-S'

carbonitrile (17 c):

White solid; mp 210-212 °C; !H NMR (200 MHz, CDCh) 8 2.33 (s, 3H, SCH3), 3.61 (s,3H,

OCH3), 3.77 (s, 3H, OCH3), 6.42-6.46 (m, 2H, ArH), 6.58-6.86 (m, lOH, ArH), 7.05-7.16

(m, 6H, ArH); IR (KBr) 2215 cm-! (CN); MS (FAB) 514 (M++l).

163

4""-Chloro-4,4"-dimethoxy-6'-methylsulfanyl-[I,1 ';2',1 ";3',1 "';4',1 ""]-quinquephenyl-

5'-carbonitrile (17d):

White solid; mp 222-224 °C; 'H NMR (200 MHz, CDCh) 0 2.32 (s, 3H, SCH3), 3.61 (s,3H,

OCH3), 3.77 (s, 3H, OCH3), 6.41 (d, J = 8.4 Hz, 2H, ArH), 6.58 (d, J = 8.4 Hz, 2H, ArH),

6.68-6.76 (m, 4H, ArH), 6.90-7.98 (m, 5H, ArH), 7.09 (d, J= 8.4 Hz, 2H, ArH), 7.20 (d, J=

8.4 Hz, 2H, ArH); IR (KBr) 2214 cm-' (CN); MS (FAB) 548 (M++l).

4,4"-Dimethoxy-6·-methylsulfanyl-[I,1 ';2',1 ";3',1 "';4',1 ""]-quinquephenyl-5'

carbonitrile (17e):

White solid; mp 202-204 °C; 'H NMR (200 MHz, CDCh) 0 2.33 (s, 3H, SCH3), 3.61 (5,3H,

OCH3), 3.77 (5, 3H, OCH3), 6.42 (d, J= 8.6 Hz, 2H, ArH), 6.62 (d, J= 8.6 Hz, 2H, ArH),

6.69-6.87 (m, 8H, ArH), 7.02-7.18 (m, 6H, ArH); IR (KBr) 2215 cm-' (CN); MS (FAB) 514

(M++l).

6' -Methylsulfanyl-4,4" ,4'" ,4 "" -tetramethoxy-[ 1,1 ';2' ,1 ";3' ,1 "';4' ,1 ""]-q uinq uephenyl-

5'-carbonitrile (17f):

White solid; mp 213-220 °C; 'H NMR (200 MHz, CDCh) 0 2.32 (s, 3H, SCH3), 3.63 (s, 6H,

20CH3), 3.76 (s, 6H, 20CH3), 6.39-6.45 (m, 4H, ArH), 6.56-6.62 (m, 4H, ArH), 6.70-6.78

(m, 4H, ArH), 6.95 (d, J= 8.6 Hz, 2H, ArH) 7.07 (d, J= 8.6 Hz, 2H, ArH); \3C (200 MHz,

CDCh) 20.16 (SCH3), 55.32 (OCH3), 55.48 (OCH3), 112.88, 113.02, 113.27, 113.76, 118.11

(CN), 118.81,130.82,131.26,131.63,131.86,132.01,132.31,139.80, 142.42, 146.21,

146.48, 146.75, 157.87, 158.64, 159.31; IR (KBr) 2219 cm-' (CN); MS (FAB) 574 (M++l).

4-(2-0xo-l, 2-diphenylethyl)-5,6-diphenyl-pyran-2-one (18a):

White solid; mp >250 °C; 'H NMR (200 MHz, DMSO-d6) 0 5.83 (s, IH, CH), 5.99 (s, IH,

CH), 6.70-7.55 (m, 20H, ArH); \3CNMR (50.0 MHz, CDC h) 56.66, 109.49, 118.45, 119.91,

126.61, 127.31, 128.01, 128.34, 128.77, 129.40, 129.82,131.74, 132.10, 132.49, 133.51,

134.92, 135.89, 136.33, 146.20, 153.47, 162.36, 197.07; IR (KBr) 1635 cm-' (CO); MS

(F AB) 442 (M+).

4-[1-( 4-Chlorophenyl)-2-oxo-2-phenylethyl]-5,6-diphenyl-pyran-2-one (18b):

White solid; mp >250 °C; 'H NMR (200 MHz, DMSO-d6) 0 5.75 (5, IH, CH), 5.95 (s, IH,

CH), 6.62-7.52 (m, 19H, ArH); \3CNMR (50.0 MHz, CDC h) 56.68, 118.44, 119.78, 127.29,

128.02, 128.34, 128.78, 128.89, 129.45, 129.81, 130.22, 131.73, 132.15, 132.41, 132.66,

133.52, 134.43, 134.85, 135.84, 136.28, 138.46, 146.16, 153.48, 162.34, 197.04; IR (KBr)

1641 cm-' (CO); MS (FAB) 476 (M+).

5,6-Bis-( 4-methoxy-phenyl)-4-(2-oxo-l ,2-diphenyl-ethyl)-pyran-2-one (18c):

164

White solid; mp >250 °C; IH NMR (200 MHz, DMSO-d6) 0 3.47 (s, 3H, OMe), 3.66 (s, 3H,

OMe), 5.71 (s, IH, CH), 5.96 (s, IH, CH), 6.40-6.68 (m, 2H, ArH), 6.72 (d, J= 8.6 Hz, 2H,

ArH), 7.08 (d, J = 8.6 Hz, 2H, ArH), 7.19-7.52 (m, 12H, ArH); IR (KBr) 1645 cm-I (CO);

MS (F AB) 502 (~).

4-[2-( 4-Chloro-phenyl)-2-oxo-1-phenyl-ethyl]-5,6-bis-( 4-methoxy-phenyl)-pyran-2-one

(lSd)


OMe), 5.71 (s, IH, CH), 5.97 (s, IH, CH), 6.25-6.65 (m, 2H, ArH), 6.72 (d, J= 8.8 Hz, 2H,

ArH), 6.94 (d, J= 8.8 Hz, 2H, ArH), 7.03-7.52 (m, IIH, ArH); IR (KBr) 1644 cm-I (CO);

MS (FAB) 536 (M"').

4-[1,2-Bis-( 4-methoxyphenyl)-2-oxo-ethyl]-5,6-diphenyl-pyran-2-one (lSe):

White solid; mp >250 °C; IH NMR (200 MHz, DMSO-d6) & 3.48 (s, 3H, OMe), 3.66 (s, 3H,

OMe), 5.71 (s, IH, CH), 5.97 (s, IH, CH), 6.36-6.6.66 (m, 2H, ArH), 6.72 (d, J = 8.8 Hz,

2H, ArH), 7.08 (d, J = 8.8 Hz, 2H, ArH), 7.18-7.52 (m, 12H, ArH); IR (KBr) 1643 cm-I

(CO); MS (F AB) 502 (M+).

4-[1,2-Bis-( 4-methoxy-phenyl)-2-oxo-ethyl]-5,6-bis-( 4-methoxy-phenyl)-pyran-2-one

(lSf):


OMe), 3.82 (s, 3H, OMe), 3.84 (s, 3H, OMe), 5.77 (s, IH, CH), 5.87 (s, IH, CH), 6.38-6.68

(m, 2H, ArH), 6.66-6.80 (m, 3H, ArH), 6.84 (d, J= 8.8 Hz, 2H, Ar), 6.95 (d, J= 8.8 Hz, 2H,

ArH), 7.07-7.28 (m, 5H, ArH) 7.50 (d, J= 8.6 Hz, 2H, ArH); 13CNMR (50.0 MHz, DMSO

~) 55.10, 55.41, 55.81, 113.44, 113.76, 114.72, 118.10, 118.98, 127.13, 133.21, 133.83,

155.11, 158.22, 158.95, 159.36, 162.42, 163.19, 195.65; IR (KBr) 1636 cm-I (CO); MS

(F AB) 562 (M+).

General procedure for the synthesis of compounds 20a-g: A mixture of 4-dimethylamino-

2-oxo-5,6-diaryl-2H-pyran-3-carbonitrile 19 (I mmol), functionalised deoxybenzoins 14 (1.2

mmol) and powdered KOH (1.2 mmol) in dry DMF (5 mL) was stirred at room temperature

for 2-5h. At the end reaction mixture was poured into ice water with vigorous stirring and

finally neutralized with dilute HC!. The solid thus obtained was filtered and purified on a


6'-Dimethylamino-[1,1 ';2',1 ";3',1 "';4',1 ""]quinquephenyl-5'-carbonitrile (20a)

White solid; mp 174-176 °C; IH NMR (300 MHz, CDCh) 0 2.67 (s, 6H, 2NMe), 6.67-6.76


(KBr) 2215 cm-I (CN); MS (ESI) 451 (M++l).

165

4"" -Chloro-6' -dimethylamino-[I,1 ';2' ,1 ";3' ,1 "';4',1 ""]q uinq uephenyl-5' -carbonitrile

(20b)

White solid; mp 188-190 °C; 'H NMR (200 MHz, CDC h) 0 2.66 (s, 6H, 2NMe), 6.64-6.77


(KBr) 2218 cm-' (CN); MS (ESI) 485 (M++l).

4" -Methoxy-6' -dimethylamino-[I,1 ';2' ,1 ";3' ,1 "';4' ,1 ""]q uinq uephenyl-5' -carbonitrile

(20c)

White solid; mp 224-226 °C; 'H NMR (200 MHz, CDCh) 0 2.66 (s, 6H, 2NMe), 3.59 (s, 3H,

OMe), 6.38 (d, J= 8.6 Hz, 2H, ArH), 6.59 (d, J= 8.6 Hz, 2H, ArH), 6.67-6.74 (m, 2H, ArH),

6.81-6.88 (m, 3H, ArH), 7.00 (d, J=8.6 Hz, 2H, ArH), 7.07-7.18 (m, 8H, ArH); IR (KBr)

2214 cm-' (CN); MS (ESI) 481 (M++l).

4'" ,4""-Dimethoxy-6'-dimethylamino-[I,1 ';2',1 ";3',1 "';4',1 ""]quinquephenyl-5'

carbonitrile (20d)


OMe), 3.76 (s, 3H, OMe), 6.39 (d, J = 8.6 Hz, 2H, ArH), 6.61 (d, J = 8.6 Hz, 2H, ArH),

6.64-6.80 (m, 4H, ArH), 6.81-6.91 (m, 3H, ArH), 6.93-7.02 (m, 2H, ArH), 7.05-7.20 (m, 5H,

ArH); IR (KBr) 2214 cm-' (CN); MS (ESI) 511 (~+1).

4" ,4""-Dimethoxy-6'-dimethylamino-[I,1 ';2',1 ";3',1 "';4',1 ""]quinquephenyl-5'

carbonitrile (20e)


OMe), 3.74 (s, 3H, OMe), 6.38 (d, J = 8.8 Hz, 2H, ArH), 6.58 (d, J = 8.8 Hz, 2H, ArH),

6.67-6.76 (m, 4H, ArH), 6.82-6.93 (m, 3H, ArH), 6.95-7.02 (m, 2H, ArH), 7.04-7.22 (m, 5H,

ArH); IR (KBr) 2216 cm-' (CN); MS (ESI) 511 (M++l).

6'-Dimethylamino-4" ,4'" ,4""-trimethoxy-[I,1 ';2',1 ";3',1 "';4',1 ""]quinquephenyl-5'-

carbonitrile (20t):


OMe), 3.57 (s, 3H, OMe), 3.72 (s, 3H, OMe), 6.32-6.44 (m, 4H, ArH), 6.50-6.62 (m, 4H,

ArH), 6.70 (d, J= 8.6 Hz, 2H, ArH), 6.90-6.98 (m, 2H, ArH), 7.00-7.19 (m, 5H, ArH); IR

(KBr) 2217 cm-' (CN); MS (ESI) 541 (M++l).

6'-Dimethylamino-4,4" ,4'" ,4""-tetramethoxy-[I,1 ';2',1 ";3',1 "';4',1 ""]quinquephenyl-

5'-carbonitrile (20g):


20Me), 3.76 (s, 6H, 20Me), 6.41 (d, J= 8.6 Hz, 4H, ArH), 6.54-6.64 (m, 4H, ArH), 6.66-

166

6.78 (m, 4H, ArH), 6.88 (d, J= 8.6 Hz, 2H, ArH), 7.07 (d, J= 8.6 Hz, 2H, ArH); IR (KBr)

2213 cm- I (CN); MS (ESI) 571 (M++l).

5.5.1 In vitro extracellular promastigote Assay

To assess the inhibition of promastigote growth, 1 x 106 promastigotes/mL were

allowed to multiply for 4 days in medium alone or in presence of serial dilution of drug

ranging from 4 Ilg to 8 Ilg ImL.The protozoan counts were taken using haemocytometer.

Pentamidine was used as positive control.

5.5.2 Drug susceptibility assay for amastigotes in macrophages

For assessing activity of compound against amastigote stage of the parasite, mouse

macrophage cell line J-774A was used. Cells were seeded in 96 well plate 5xl04

cells/lOOIlLlwell and the plates were incubated at 37° in CO2 (5%) incubator. After 24h the

medium was replaced with fresh medium containing stationary phase promastigotes (2.5

X 105 promastigotes!l OOIlLl well). Promastigotes invade the macrophages and transformed

into amastigotes. The test compounds in appropriate concentration (20Ilg/mL in complete

medium) were added after replacing the previous medium. Plate was incubated at 37° in C02

(5%) incubator for 48h more. Pentamidine was used as positive control. After incubation the

drug containing medium were decanted and the cell mono layers were stained with Giemsa

for 45min and at least 100 infected macrophages per sample were counted under optical

microscope. Efficacy was expressed as the percent inhibition of amastigote multiplication

using the following formula:

PI= 100- {(AT X 100)/AC}

Where PI is percent inhibition of amastigote multiplication, AT is actual number of

amastigotes cells in treated groups and AC is actual number of amastigotes per 100

macrophage cells in untreated control group.

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