«s^ Chapter-II Synthesis Of Selenol Esters Of Benzoic Acid...

«s^ Chapter-II Synthesis Of Selenol Esters Of

Benzoic Acid And Its Derivatives

SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 29

2.1 INTRODUCTION

It is evident that selenium plays a very important role in human as well as animal health.

The selenium supplements are needed for the consumers living in the areas that are

deficient of selenium. Though sodium selenite is widely used in feeds, several studies

have demonstrated that organic source of selenium is more bioavailable when compared

to inorganic source . Several efforts of synthesizing organoselenium compounds have

been made by many researchers^"'*.

Many methods have been followed to introduce selenium into organic compounds. As

discussed in chapter I, selenium exhibits both electrophilic and nucleophilic nature. Here

we have considered the introduction of selenium as a nucleophile. Many methods are in

practice to introduce selenide ion into the organic compounds. Phosphorous

pentaselenide is one of the important starting materials to prepare organoselenium

compounds and the existence of phosphorous pentaselenide was reported by Berzelius^

as early as year 1834. Phosphorous pentaselenide was used for converting the carbonyl

group to selenocarbonyl groups ' (Scheme-1).

PzSes

Scheme-1

Jensen et al. converted urea into selenourea by using phosphorous pentaselenide .

Phosphorous pentaselenide was also used to prepare selenophosphoric amides^. In

another publication the synthesis of Se-alkynyl selenocarboxylates was reported^''

(Scheme-2).

„ ! _ „ _ „ _ „ - RCOC1,0°C 1 K L - C 5>e ^ R _ C ^ C _ S e

Li Etp \ ^ C—R

// O

Scheme- 2


These were further used as precursors of o-alkyl selenocarboxylates (Scheme-3) and

selenamides.

R

R - C = C - S e ^ IT, dark

C-CH3 + 2 R 0 H 60-8(yc,2hours

Scheme-3 o" Se

Alkali metal borohydrides like sodium borohydrides react with chalcogen elements by

direct ftision^' and also in aprotoic solvents like ether'^, dioxane^^, tetrahydrofuran^''''^and

diglyme. But the selenium reacts with sodiumborohydride in aprotoic solvents to yield

the product which is difficult to isolate and has been found to be NaBH2Se3. Synthesis of

Se-alkyl selenoformates was reported by the reaction of aluminum selenolates with

formates'^ (Scheme-4).

Hexane, 20°C, 1h ^ ^

O K

Se H 20°C, 10min.

Scheme-4

Additional care needs to be taken while working with dibutylaluminium hydride due to

the flammability hazard involved with this potential reducing agent. Hydrogen selenide is

a good nucleophile and also a good reducing agent'^ and is used to synthesize various

organoselenium compounds. It is produced in situ by the reaction of elemental selenium

with reducing agents like sodium formaldehyde sulfaxylate (Na^HOCH2S02', Rongalite)

in aqueous sodium hydroxide solution, sodium in liquid ammonia, sodium borohydride in

water or ethanol and lithium trialkylborohydride in tetrahydrofuran.


Klayman'^has reported the formation of sodium hydrogen selenide by the reaction of

selenium metal with sodium borohydride in aqueous medium or in protoic solvent like

ethanol (Scheme-5). This is an instantaneous reaction which proceeds at atmospheric

pressure and at room temperature.

4NaBH4 + 2Se + VHjO *• 2NaHSe+ Na2B407 + HHj

Scheme-5

He converted the benzyl chloride to benzylselenol by using ethanolic solution of sodium

hydrogen selenide'*.

Sodium diselenides are also synthesized based on the mole ratios. Diselenides are

obtained easily by adding another one mole of selenium to sodium hydrogen selenide

(Scheme-6).

2NaHSe + Na2B407 + 2Se + SHjO *- ZNajSej + 4H3BO3

Scheme-6

Excess of sodium borohydride is required when methanol is adopted as solvent media

due to faster decomposition of sodium borohydride in methanol. EthanoUc solution of

sodium hydrogen selenide is more useful for nucleophilic displacement reactions, in

particular insoluble and hydrolysis sensitive organic compounds. Here removal of sodium

selenide gas formed during the reaction is very much necessary to take the reaction to

completion. Alcoholic solutions are not preferred for the preparation of sodium hydrogen

selenide when acid chloride is used in the reaction since formation of ester is more

favorable (Scheme-7) than the selenium product.

+ ROH

Scheme-7


Hence aqueous solution of sodium hydrogen selenide is a reagent of choice to prepare

some of the organoselenium compounds.

2.2 PRESENT WORK

Present work is based on the reaction of sodium hydrogen selenide in aqueous media with

benzoyl chloride followed by reaction with chloroacetic or chloropropionic acid. Selenol

esters obtained by this method are further converted to esters and amides via acid

chloride (Scheme-8).

2 NaHSe

O

Chloroacetic acid f l l [ ^ ^

kAySe , O

o

• I P J ^ " 25-30°C

Na, Se

water

SOCl, R-OH ^ ^ o j ,

SOCI2 Toluene

SOCI2 Toluene

RjNH

SOCl,, R-OH

0 ^ , 0 H

3-chloropropanoic acid^=^^^j^^^

O

4-11

NHR, Se

O 12 and 13

NR, Se

O 14 and IS

O^ ,0R

Se

16-23 O O^ ,NHR

SOClj Toluene

Se

24 abd 25

SOCl, Toluene

RjNH

O ^ N R ^

Se

O 26 and 27

Scheme-8


The present work has been divided into following subclasses.

2.2.1 Synthesis of sodium benzoyl selenide (1)

2.2.2 Preparation of benzoylselenoglycolic acid (2)

2.2.3 Synthesis of 3-[(phenyl carbonyl)selenyl]propanoic acid (3)

2.2.4 Construction of esters of benzoylselenoglycoUc acids (4-11)

2.2.5 Construction of amides of benzoylselenoglycoUc acids (12-15)

2.2.6 Synthesis of ester and amide derivatives of 3-[(phenyl

carbonyl)selenyl]propanoic acid (16-27)

2.2.7 Experimental section

2.2.8 Physical properties of the newly synthesized compounds

2.2.1 Synthesis of sodium benzoyl selenide (1)

Athayde-Filho'^ et al have reported one pot synthesis of benzoylselenoglycoUc acid by

using sodium hydrogen selenide in water. This is a very useful method to synthesize

organoselenium compounds. This method is adopted here to prepare several

organoselenium compounds. In the reported method purification is done using

chloroform as solvent and the recoveries are low. Here purification was done via sodium

salt.

In the first step of synthesis, sodium borohydride is made to react with metallic selenium

in aqueous medium as per Scheme-5. In the second step freshly prepared benzoyl

chloride is reacted with sodium hydrogen selenide to give sodium benzoylselenides

(Scheme-9).

cuo o Water, 25-30°C^ f T ^ r ^ S e + NaCl + HjSe

2NaHSe + ,, , n , XT Na

1

Scheme-9

Sodium benzoylselenide obtained by this method was used in the next step without

isolation.


2.2.2 Preparation of benzoylselenoglycolic acid (2)

In the third step it is further made to react with chloroacetic acid to yield benzoylseleno

glycolic acid (Scheme-10).

H

J/ O

H-

Cl OH

Scheme-10

Benzoylselenoglycolic acid (2) was prepared by the above mentioned method. A non

polar impurity identified as dibenzoyldiselenide (Ila) was formed during the reaction.

This impurity formation is due to the formation of disodium diselenide during the

reaction (Scheme-11).

O

^ 0

Na2Se2

+ 2NaCl

Scheme-11 Dibenzoyl diselenide (Ila)

This impurity was not soluble in sodium bicarbonate solution wherein product is soluble

fi-eely and the impurity remains with organic layer during purification.

Formation of benzoylselenoglycolic aicd was confmned by IR spectrum. A peak at

1696cm' was corresponding to characteristic carbonyl stretching fi-equency of-COOH

group. Stretching vibration frequency at 1674cm"' was corresponding to the carbonyl

group of -CO-Se bond. A broad peak between 3000-3300cm"' was corresponding to the

vibration fi-equency of-OH group (Figure-1). Further proof to the structure was obtained

by NMR spectra of the molecule dissolved in CDCI3. A smglet peak at 8 3.88 was

corresponding to Se-CH2 protons. Peaks between 6 7.26-8.0 were corresponding to 5

protons in the aromatic ring, -OH proton of the carboxylic acid moiety appeared at 5

10.46 (Figure-2).

35

Kgl

5

u

CO

Z

I ce

O

CO

CQ

33 999 UE89 K90Z G£9fZ 99S9Z ZL908 ZfZ58 8Z6Z8 96 936 ezsee

f 8 9301 ezszoL I f lOLL eeofu 8SfZU 61Z8U L9P031 9L30£l 3f58£L 61 Z3n 3£0Sn f3 88t't ffL8Sl 5SS65L L8fZ9L L3969L

16 1983

ff 1953

fOS993

03 £363

8£ElOe

9f 6E£E

o o

o o o

o o

o o £ (N o

l _ <II

f -I

r <i)

> KW

o o

$ LO CNI

S

o o o CO

o o CO

1 1 1 1 T"

001- 06 08 OZ 09 OS

[o/o] 90ue]}iLusueji

Ot?

o o o

36

> H

a (Z3

H O Z < Q U

u S N Z

CP b

o

H

O z u .J !« o

K H Z >H

D;.J

r965

if L

9 9 .•

% L

r-

s

•J5=:5 c


2.2.3 Synthesis of 3-[(phenyIcarbonyl)selenyI]propanoic acid (3)

The intermediate sodium selenobenzoate was a very reactive species and was made to

react with chloropropionic acid (Scheme-12). Reaction with chloropropionic acid was

incomplete at 25-30*'C and proceeded smoothly at 60-70*'C. This is due to the reduced

nucleophilicity of the p carbon atom.

2NaHSe +

Na Se

At IS-^O^C in water

1

At 60 - 70°C water

O + NaCl + HjSe

O OH

NaCl

1 3 O

Scheme-12

Formation of the compoimd 3 was confirmed by IR spectrum.

A peak at 1697cm'' was corresponding to the carbonyl stretching frequency of -COOH

group. Carbonyl stretching frequency of-Se-CO bond appeared at 1665cm'' (Figure-3).

Further evidence to the structure was obtained by ' H N M R spectrum. Methylene groups a

and p to the carboxylic acid group appeared as triplets at 8 2.95 and 3.28 respectively.

Signal corresponding to aromatic protons appeared between 8 values of 7.42-7.9. The

signal due to -OH proton of-COOH group was not visible (Figure-4). However presence

of carboxylic acid group was confirmed by its reaction with sodiiun bicarbonate. Further

evidence was obtained by recording the mass spectrum of the molecule. Mass spectra

gave m/z peak at 257 (Figure-5). Esterification of compound 3 with various alcohols

confirmed the formation of the product.

38

i9ra ZOS/9 8969/ 80Z08

26Z88 (M£?6

8ZEZU 92£(Zl Qinzi

£S19Zi

zimi

60 999 L ISZ691

—I 1 1 1 T"

96 06 98 08 9Z

[%] 90UB}}!UJSUBJ1

O o in

o o o

o o ID

o _ o

o CO

o o

CO

o ~ o n E (N o

o F m n V c s > DC

o o

CO bn

lo CN

o o o

39

>

< > MM

Q 'Ji H Q Z < Q U -< u O S5 Z OQ b O

»3

.J

o z u yi b. O

X H Z >-

I

3


l U U -

O OH

0Ase-Ao

189 53 63 81 91 "" 115 128 147 165 171 203 221 233 245 ji

-;-TT-r,-r''Tr'nii;;!' ;••; T—r-vr tTr rcM' ; ' i ' t't:.ii i—; i;:nT!MMT-ir?i:rri—s T ' in i ' ; : M'II H'!—i iiii; : i . ' ; i ' ! r i i ' i Hiil.]! i')T-n]!rri-n'';-i-rrrr'-;-rrTrTn'-*^rn—rrk-H-rrTTi;-

50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 27(

MS Peak Table Pealrf R.Time [Time F.Time Area Height A/H Mark %Total Name Base m/z Base Int.

1 0.708 0.527 0.9431214463250 93360795 13.00 100.00 257.0010682599 1214463250 93360795 100.00

Figure-5

2.2.4 Construction of esters of benzoylselenoglycolic acid (4-11)

Several esters were prepared from compound 2 to study the effect of substitution on the

biological activity and also to enhance the stability of the molecule. Esterification can be

brought about in many ways. In one of the common methods followed, acid is made to

react with alcohol in presence of H2SO4 or PTSA as catalyst. In this method it is

necessary to remove the byproduct water either through azeotropic distillation or by using

a dehydrating agent like molecular sieve. On the other hand HCl gas can also be used as

catalyst to bring about the esterification. Alternatively, acid anhydrides are made to react,

with alcohols to yield esters. This method does not hold good for those acids which are

likely to undergo degradation during anhydride preparation. When the esterification

reactions were carried out using sulfuric acid as catalyst at high temperature, impurity

formation was observed. Hence esters were synthesized via acid chloride (Scheme-13,

Table-1). Esters 4-7 were more stable. Few esters (8-11) were unstable and underwent

degradation very quickly.


R-OH, SOCL

Comp. No

50-60°C

Scheme-13

Table-1

R

-CH3

-C2H5

-C3H7

-C4H9

Comp. No

10

11

R

H . C ^ ^ C H

As an example compound 5 was prepared by adding thionyl chloride to the ethanolic

solution of compound 2 at 50-60°C. The Formation of ethyl ester was preliminarily

confirmed by recording the IR spectrum. The carbonyl frequency of -COOH group of

compound 2 was shifted to 1731cm"' from 1696cm"\ Vibrational frequency of-Se-CO

group remained unaltered. Broad peak at 3000cm'' disappeared (Figure-6). Further proof

to the product was obtained by ' H N M R spectra. A triplet at 6 1.28 was corresponding to

the methyl proton and protons of-O-CH2 group gave a quartet at 5 4.19. A singlet at 5

3.84 was corresponding to -Se-CH2- protons. Aromatic protons appeared at 8 7.27-7.92

accounting for 5 protons (Figure-7). Mass spectrum gave m+2 peak at m/z:273 (Figure-

8). Complete spectral data of the remaining ester molecules along with compounds 2 and

3 are depicted in Table-2.


Table-2: Spectral analysis data of compounds (2-11)

Comp. No ' H N M R values in 5 ppm. IRYmax in cm"' Mass :m/z 2 3.88(s, 2H,Se-CH2),

7.26-8.02(5,m, Ar-H). 1700(-COOH), 1674(-Se-CO-).

243

3 2.92 (t, 2H, -CH2-CO), 3.28 (t,2H, -Se-CH2), 7.42 -7.9 (m, 5H, Ar-H). •

1697 (-COOH)' 1665 (-Se-CO-).

257

4 3.74 (s,3H,-OCH3), 3.85 (s, 2H,Se-CH2), 7.4-7.9 (m, 5H).

1722 (-C00-), 1672 (-Se-CO-).

259

5 1.28(t,3H,-CH3), 3.84 (s, 2H, Se-CH2), 4.19(q,2H,-OCH2), 7.26 -7.92 (m, 5H, Ar-H).

1731 (-C00-), 1678 (-Se-CO-).

273

6 1.12(d,6H,-C(CH3)2), 3.83(s,2H,Se-CH2), 5.078 (m, IH, -OCH), 7.39-8.06 (m, 5H, Ar-H).

1725 (-C00-), 1677 (-Se-CO-).

287

7 0.92 (t, 3H, -CH3), 1.4(m,2H, -CH2), 1.56(p,2H,-CH2), 3.84 (s, 2H, Se-CHz), 4.14(t,2H,-OCH2), 7.43-7.91 (m,5H, Ar-H).

1730(-COO-), 1677 (-Se-CO-).

301

8 1.2(d,6H,-C(CH3)2 2.34 (s, 3H, Ph-CHj) 3.1(m, 1H,-CH) 3.88 (s, 2H, Se-CH2), 7.06 -7.9 (8H, Ar-H).

1730(-COO-), 1677 (-Se-CO-).

377

9 3.88 (s,2H,Se-CH2), 7.26-8.72 ( l l , m , Ar-H).

1757(-COO-), 1667(-Se-CO-).

372

10 3.72(s, 2H, Se-CH2), 7.26-9.02 (10, m, Ar-H)

1748(-COO-), 1672(-Se-CO-).

406

11 3.78(s,2H, Se-CH2), 7.26-8.82(9 m, Ar-H).

1745(-COO-), 1672(-Se-CO-).

441

43

o h o to

ITL

<

Q VI H Q

< Q U

u O N Z OQ

o

H t »

hJ o z u >J

173

h O yj

H

09 529 Z0ZZ9

f289Z

zezza

fr8 520l

ooetzi £3f92l

t?9Zffl

raszgi eOLEZl

o _ o

o

o o in

o • ^ ~

o o E CN o

a>

E 3 VO C

> s O O 5 U) CN

o o o CO

00 L 06

—I 1 1—

08 OZ 09 [o/o] eoUBHILUSUBJl

o

eo

09 017

o o o

44

5S C SS 0 cC 0 ?fi 0 ;6 0 g: I 6: i 5? i 3c i ?e I

9e5e E

'1695 :

C9 •

9,: ; ;3 J ?g £

IE" SI 61

9J

_ ccco e "93;D 2

9c-

IV

15 55

39 38 9 6 •

8 i £ r c J ISO I i035 I

I

S Ml

•mm

it*

m 6 —-, fi 6 - • "

SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERTVATIVES 45

MS Siicclruili

mm

1 iiK« 1 R rime 0-^lll Scan* i l l PUMIHC MassPcaks 1W RMcPcak J T : O-U'IH I K I | KawMtHJc Single 0 M j i 311 UG MmJcPcikSianiJ 1II>I:M

HMi

o^'-r^

: ' • '

;, ;,, -1 - ~ L-., ' '•< "> "> . , , , , , - ; , , j "! , . . ->- : • ' • «

5u fru ~n 8(1 '111 100 110 i:o 130 uo i?i) iso po ign IQO 200 210 220 230 240 250 260 270 280 200 niz

MM'cal, lab!.: Peaks K lime

1 HMI 1 liinc h hmc Area Hciyhl A.M M.uk "oliilal Name 0 410 OT43 <)4.W86'' ^IJl"?: 10 : : hXllXl

<»}Qii}i 'J. ' j i?: i w w

Hasc ni7 liasc Inl 2"2'J5 201130

Figure-8

2.2.5 Construction of amides of benzoylselenoglycolic acid (12-15)

Several amide derivatives were prepared to study the effect of substitution on the

biological activity. Compound 2 was converted to acid chloride and further it was made

to react with different amines to get corresponding amides (Scheme-14, Table-3).

O

, ^ OH Se

O

i) Toluene /SOCl^ at 55-60"C ii)Ri-NH2at5-10"C *"

i) Toluene /SOCI2 at SS-eO^C

ii)R,-NHat5-10T

O

NHR, ,Se

O

12 and 13

O

NRn ,Se

O

14 and 15

Scheme-14


Table-3

Comp. No. NHRi NR2

12 ^ N H , ^ ^ ^ ^ - ^

~

13 HN''

V CH3

14

•^0 15 -0

Formation of the amide was confirmed by spectral analysis of the newly synthesized

compounds. IR spectrum of the compound 12 gave a peak at 1654cm" corresponding to the

amide peak (Figure-9). Disappearance of broad peak corresponding to -OH group provided

further evidence to the amide formation. A sharp peak was observed at 3293cm'

corresponding to -NH stretching vibration of the amide bond. Further proof to the structure was

obtained by ' H N M R spectrum (Figure-10). Mass spectrum of the product confirmed the

formation of the product. M+ 2 peak was observed at m/z value of 320 (Figure-11). Spectral

analysis data of the amides (12-15) has been tabulated in Table-4.

47

IZK9 622Z9 9100/ 0Z99Z

111.93 93 696 S6 666

CM 8201 6Z9Z0t Z6 9601 ^SZSU Cgt'ZU OS COS L

zaz/zi 6LS0ei zcsiei . Eszaei 8S96fL S8 62SI £6 969t 06>99l 0eSZ9L

gesiK

OSEKE

—1 1 1 1 1—

06 08 01 09 09 [%] eouemaisueJi

8 to

o o o

o o

o t : CN O

3

> (a

o •> CN

0^ I

S 60

o _ o

o CO

o o CO

o o o

48

OCO 0

OiO C -

1

l » n ' D - o OCO 0

OiO C -- * - ^ J , l » n ' D - o

I

i 1

--

ej8 i f.it i

ej8 i \ f.it i

- V

1 1 1

r40 i \

>«

l ie .• i 8n i .

»K I -

b<f9 i •

?!6 i

f

• • — — ^ / :

- MlC I ' 91E9 E

aw./ r

-«

8n i .

»K I -

b<f9 i •

?!6 i

f

- MlC I ' 91E9 E

aw./ r

-«

8n i .

»K I -

b<f9 i •

?!6 i

f

- MlC I ' 91E9 E

aw./ r

-«

8n i .

»K I -

b<f9 i •

?!6 i

f • -

- MlC I ' 91E9 E

aw./ r

-«

8n i .

»K I -

b<f9 i •

?!6 i

f !

- MlC I ' 91E9 E

aw./ r

-«

e ^ B

O-

5

01

o

i i

1

i

»C3 I f f »w;

01


Table-4: Spectral analysis data of compounds 12-15

Comp ' H N M R values in 6 ppm. IR Ymax in cm"' Mass :m/z

12 3.78 (s, 2H, Se-CH2 ), 1672 (-Se-CO-), 320

7.054 -8.322 (m, 1IH, 10 ArH+ 1654(-CO-NH-)

1 -NHCO). 3293 (Ph-NH-

CO).

13 2.23 &2.3 ( s, 6H Ar-(CH3)2), 1669 (-Se-CO-), 348

3.75 (s, 2H, Se-CH2), 1652 (-CO-NH-),

7.02 -8.4 (m, 9H, 8ArH +1 3287 (Ph-NH-

NHCO). CO).

14 1.4 (m,6H, Ring-(CH2)3), 1674 (-Se-CO-), 312

3.55 (b,4H, Ring-N-CH2-),

4.0 (s, 2H, Se-CH2),

7.39 -7.922 (m, 5H, Ar-H).

1632 (-CO-N-).

15 1.95 (m, 4H, Ring -CH2 -CH2), 1673 (-Se-CO-), 298

3.55 (b, 4H, Ring -N-CH2),

3.933 (s, 2H, Se-CHz),

7.4 -7.9 (m, 5H, Ar-H).

1625 (-CO-N-).

Many impurities were formed during the reaction. One such impurity formed during the

reaction with aniline was N- phenylbenzamide (lib).

^ NH " ^

lib (N-phenylbenzamide)


2.2.5.1 Structural elucidation of N-phenylbenzamide

This type of reaction is generally observed when amines are made to react with esters and are

known as aminolysis of esters. Aminolysis of esters has been intensively investigated and their

mechanisms are well understood^"'^'. Koh et al ^ studied the aminolysis reaction of

cyclopropanecarboxylate with benzylamines in acetonitrile (Scheme-15).

OC6H4Z + 2 XC6H4CH2NH2

O MeCN

NHCH2C6H4X + 2 XC6H4CH2NH3^ "OC6H4Z

O

X= P-CH3O, P-CH3, m-Cl or p-Cl

X=m-CN, m-NOj, P-CH3CO, p-CN or P-NO2

Scheme-15

Aminolysis of thiol ester has been studied to a lesser extent than its oxygen analogue

(Scheme-16) 33-36


O

X .NH Ph

ArS O

,NH

R

NH = r z / HN.

R=H or CH3

^2

O

Ph" N H

ArS

R= CHj NH, NCH2CH2OH, O, NCHO, NHj

Scheme-16

Aniline makes nucleophilic attack at the carbonyl group of acid chloride moiety leading

to the formation of the desired product. Simultaneously the selenol ester carbonyl group

competes with the carbonyl group within the molecule leading to the formation of

A^-phenylbenzamide, which can be explained by the following mechanism (Scheme-17).

Toluene at 5-10''C O

NH O

12-desired product

Toluene at S-IO^C \ /

NH O

nb- impurity

Scheme-17


Formation of N-phenylbenzamide was confirmed by reacting benzoyl chloride and

aniline in toluene (Scheme-18).

CI HoN

+ O

Toluene at 25-30 "C

^ V N H o

Scheme-18 lib

Product was compared with the impurity obtained during desired amide preparation by

TLC and by recording the IR spectrum. It confirmed that, the product formed was N-

phenylbenzamide. Similarly impurity formation was also observed when piperidine and

pyrrolidine were used as sources of amine.

Further to confirm the aminolysis reaction, benzoylselenoglycolic acid was made to react

with various amines at room temperature (Scheme-19, Table-5).

^ 2 Toluene, 25-30°C

R3

NH R2

R3

Scheme-19

Table-5

Il(b-d)

Compound Ri R2 R3

lib H H H

lie CH3 H CH3

lid H CF3 H

The melting point of the products was matching with that of the standards obtained by

reacting respective amines with benzoyl chloride. Further formation of the aminolysis

product as impurity was confirmed by spectroscopic methods. For example IR spectrum


of lib gave a peak at 1650cm" corresponding to the -CO vibration frequency of the

amide group. A new peak at 3293.2cm"^ was observed due to aromatic -N-H stretching

frequency. ' H N M R spectrum showed the presence of 11 protons in the aromatic region

corresponding to 10 aromatic protons and a proton of -NH-CO group. A singlet due to

Se-CH2 protons which was present in compound 2 was disappeared in the NMR spectra

of l ib confirming the nucleophilic attack at carbonyl group of -CO-Se moiety as shown

in Scheme-19.

2.2.6 Synthesis of ester and amide

carbonyl)selenyl] propanoic acid (16-27)

derivatives of 3-[(phenyl

Similarly several ester derivatives of compound 3 were prepared (16-23, Scheme-20).

Impiirity formation was minimized may be due to the increased stability of 3-[(phenyl

carbonyl)selenyl]propanoic acid. Esters were purified using column chromatography.

Various amide (24-27, Scheme-20) derivatives of compound 3 were also synthesized

(Table-6). Aminolysis of selenol esters was observed in these reactions also.

O^^OH

0-^OR

SQCl , R-QH

Se

O

i. SOCI2, Toluene

ii. R1NH2

16-23 O^NHRj

Se

O 24 abd 25

i. SOCI2, Toluene

ii. R^NH

OyNRj

Se

O 26 and 27

Scheme-20

SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DEMVATIVES 54

Table-6

Comp. No. R NHRi NR2 Comp. No. R NHRi NR2

16 -CHj 22 60 CI

17 -C2H5 23

CI

18 -C3H7 24 '•0

19 -C4H9 25 jbf'^

20 26 ^0 21 l ^ ^ ^ N 27 -0

Esters 20 -23 were highly unstable and decomposed to acid and alcohol within a week.

All the compounds were characterized by mass, IR and proton NMR spectroscopic

methods and the data has been tabulated in Table-7.


Table-7: Characterization data of the compounds 16-27

Comp. No. ^H NMR values in 6 ppm. IR Ymax in cm'' Mass :in/z 16 2.86 (t, 2H, -CH2-C0),

3.29 (t, 2H, -Se-CH2), 3.71(s,3H,OCH3), 7.4 -7.9 (m, 5H, Ar-H).

1722 (-C00-), 1672 (-Se-CO-).

273

17 1.3(t,3H,-CH3), 2.84 (t, 2H, -CH2-CO), 3.29 (t, 2H, -Se-CH2), 4.15(q,2H,-OCH2), 7.4 -7.9 (m, 5H, Ar-H).

1731 (-C00-), 1669 (-Se-CO-).

287

18 1.26(d,6H,-C(CH3)2, 2.84 (t, 2H, -CH2-C0), 3.29 (t, 2H, -Se-CH2), 5 (m, IH, -OCH ), 7.4 -7.9 (m, 5H, Ar-H).

1727(-COO-), 1670 (-Se-CO-).

301

19 0.92 (t, 3H, -CH3), 1.393 (m,2H,CH2), 1.62 (p,2H,CH2), 2.84 (t, 2H, - CH2-CO), 3.29 (t, 2H, -Se-CH2), 4.03 (t, 2H, -OCH2)), 7.4 -7.9 (m 5H, Ar-H).

1735 (-C00-), 1673 (-Se-CO-).

315

20 1.2(d,6H,-C(CH3)2, 2.34 (s, 3H, Ph-CH3), 2.82 (t, 2H, -CH2-CO), 3.1(m, 1H,-CH), 3.31(t,2H, Se-CH2), 7.06 -7.9 (8H, Ar-H).

1727 (-C00-), 1659 (-Se-CO-)

389

21 2.9 (t-3H, -CH2-CO), 3.38 (t, 2H, Se-CHz), 7.26-8.22 ( l l , m , Ar-H).

1730(-COO-), 1677 (-Se-CO-).

384

22 2.9 (t-3H, -CH2-CO), 3.41(t,2H,Se-CH2), 7.26-8.22 (10, m, Ar-H).

1730(-COO-), 1677 (-Se-CO-).

418

23 2.9 (t-3H, -CH2-CO), 3.29 (t, 2H,Se-CH2), 7.26-8.22 (9, m, Ar-H).

1730(-COO-), 1677 (-Se-CO-).

453

24 2.85 (t, 2H, -CH2-CO), 3.28 (t, 2H, Se-CHz), 6.98-7.8(m, 1IH, Ar-H + Ar-NH).

1673 (-Se-CO-), 1653 (-CO-NH-).

334


25 2.8 (t, 2H, CH2-CO), 2.23 & 2.3 (m, 6H Ar-(CH3)2), 3.38 (s,2H,Se-CH2), 7.054-8.322 (m, lOH).

1613 (-Se-CO-), 1659 (-CO-NH-).

360

26 1.59(b,6H,Ring(CH2)3), 2.855 (t, 2H, CH2-CO), 3 .2-3.4 (b, 4H, Ring N(CH2)2, 3.54 (t, 2H, -Se-CH2), 7.39-7.911 (m, 5H, Ar-H).

1668 (-Se-CO-),

1635 (-CO-N-).

326

27 1.89 (m,4H, Ring (CH2)2), 2.8 (t, 2H, CH2-CO), 3.3-3.65 (m, 6p, Se-CH2and ring N(CH2)2), 7.28 -7.9 (m, 5H, Ar-H).

1664 (-Se-CO-), 1634 (-CO-N-).

310

2.2.7 Experimental section

i. Syntliesis of benzoyl chloride

Benzoic acid (20 mmol) was dissolved in 100 ml of toluene in a 4 necked round bottom

flask and heated to SO C. Thionyl chloride (30mmol) was added to it slowly at 80-85V.

Reaction mass was refluxed for 3 hours at 100-110*^0 to complete the conversion. Solvent

was distilled at below 120°C. Benzoyl chloride was collected as a second fraction at 180-

190V. Product was transferred to an air tight container and stored under inert atmosphere

till it is used.

ii. Synthesis of Benzoylselenoglycolic acid (2)

Selenium metal (12.66 mmol) was suspended in 12 ml of water. Sodium borohydride

(26.5 mmole) was dissolved in 12 ml of water and added slowly to selenium metal.

Exothermic reaction with vigorous evolution of hydrogen gas was observed. Benzoyl

chloride (12.8 mmol) was added slowly at 30*'C. Sodium salt of selenobenzoate (1) was

obtained as a yellow colored solution and used without isolation to the next step.

Chloroacetic acid (12.8mmol) was added slowly at 25- 30^0, solid was precipitated at the

end of addition. Product was filtered and the residue was dissolved in 20 ml of

dichloromethane. Product was extracted with 5% sodium bicarbonate solution. pH of the


sodium bicarbonate layer was adjusted to 4-5 using 5% HCl. Product was extracted into

dichloromethane and concentrated under vacuum to get pure solid.

iii. Synthesis of 3-[(phenyl carbonyl)selenyI]propanoic acid (3)

Selenium metal (12.66 mmol) was suspended in 12 ml of water. Sodium borohydride

(26.5 mmoles) was dissolved in 12 ml of water and added slowly to selenium metal.

Exothermic reaction with vigorous evolution of hydrogen gas was observed. Benzoyl

chloride (12.8 mmol) was added slowly at SO^C. A yellow colored solution was obtained.

Chloropropanoic acid (13 mmol) was added slowly at 65-70*'C. Solid was precipitated at

the end of addition. Product was filtered and dissolved in 20 ml of dichloromethane and

extracted with 5% sodium bicarbonate solution. To the collected sodium bicarbonate

layer, pH was adjusted to 4-5 using 5% HCl. Product was extracted back into

dichloromethane, dried over anhydrous sodium sulfate and concentrated under vacuum to

get white solid.

iv. Methyl 2-(benzoyIselenyl)acetate (4)

Benzoyl selenoglycolic acid (4.1 mmol) was dissolved in 20 ml of methanol, 6 mmol of

thionyl chloride was added slowly at 50-55''C. Reaction mass was stirred for one hour.

Reaction mass was concentrated under vacuum at 35-40°C. The residue was dissolved in

10 ml of dichloromethane and washed with 5% sodium bicarbonate solution followed by

water wash. Organic layer was collected and dried over anhydrous sodium sulfate.

Product was obtained as yellow colored liquid which was purified using column

containing silica gel as stationary phase and using hexane and ethyl acetate as mobile

phase.

Esters 5-7 and 16-19 were also synthesized by the same method.

V. 2-Isopropyl-5-methylphenyl 2-(benzoylselenyI)acetate (8)

Benzoylselenoglycolic acid (4.1 mmol) was dissolved in 20 ml of toluene, thionyl

chloride (6 mmol) was added at 60-65^0. Reaction mass was stirred for one hour.

Excess of thionyl chloride was removed under vacuum at 40-45°C. Thymol (4mmol) was

dissolved in 10 ml of toluene and added to the acid chloride slowly at 50-60''C. After the

completion of the reaction, the reaction mass was poured into water and washed with

sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate


and concentrated to get oily residue. The product obtained after the reaction had many

impurities including starting materials. Crude material was loaded on to the column and

product was isolated with 20% ethyl acetate in hexane. Column fractions were

concentrated to get product as pale yellow colored oil.

Esters 9-11 and 20-23 were also synthesized by the same methodology.

vi. Se-[2-oxo-2-(phenylaniino)ethyl]benzenecarboselenate(12)

Benzoylselenoglycolic acid (4.1 mmol) was dissolved in 20 ml toluene, 6 mmols of

thionyl chloride was added slowly at 50-55°C. Reaction mass was stirred for one hour.

Excess thionyl chloride was removed under vacuum at SO-SS^C. Fresh toluene was added

and the reaction mass was chilled to O-S C, 4 ramoles of aniline was dissolved in 5 ml of

toluene and added slowly at S-IO^C. Reaction mass was stirred for two hours at 5-10 C.

The reaction mass was washed using 10% HCl solution followed by 5% sodium

bicarbonate solution. Organic layer was collected and dried over anhydrous sodium

sulfate. Solvent was removed under reduced pressure at 45-50''C. Product obtained was

solid and recrystallized from isopropyl alcohol to get pure material.

Amides 13-15 and 24-27 were also synthesized by the same methodology.


2.2.8 Table-8: Physical properties of the newly synthesized compounds

Compd. No.

M.P. in "C Yield in %

Solubility Mol. Formula Se. content in% Found(calculated)

2 82-84 80 MeOH, CHCI3 CgHsOsSe 31.8(32.48)

3 84-86 80 MeOH, CHCI3 CioHioOaSe 29.9 (30.71)

4 Liquid 60 MeOH, CHCI3 CioHio03Se 29.32 (30.71)

5 Liquid 70 MeOH, CHCI3 CiiHi203Se 28.42 (29.1)

6 Liquid 70 MeOH, CHCI3 Ci2Hi403Se 27.9 (27.69)

7 Liquid 75 MeOH, CHCI3 Ci3Hi603Se 26.10(26.39)

8 Liquid 29 MeOH, CHCI3 Ci9H2o03Se 20.08(21.04)

9 Liquid 25 MeOH, CHCI3 C,8Hi3N03Se 21.78(21.33)

10 Liquid 15 MeOH, CHCI3 CigHisClNOsSe 18.6(19.51)

11 Liquid 15 MeOH, CHCI3 Ci8H,iCl2N03Se 16.92(17.98)

12 124 - 126 40 CHCI3 CisHnNOzSe 24.1 (24.8)

13 144 - 146 35 CHCI3 C,7H,7N02Se 22.54 (22.8)

14 Liquid 50 CHCI3 C,4Hi7N02Se 24.76(25.45)

15 Liquid 45 CHCI3 Ci3Hi5N02Se 25.75(26.66)

16 Liquid 75 MeOH, CHCI3 CiiHi203Se 28.9(29.1)




20 Liquid 30 MeOH, CHCI3 C2oH2203Se 18.05(20.2)

21 Semisolid 25 MeOH, CHCI3 CsHisNOsSe 17.95 (20.5)

22 Semisolid 20 MeOH, CHCI3 Ci9Hi4ClN03Se 15.68 (18.86)

23 Semisolid 20 MeOH, CHCI3 Ci9Hi3Cl2N03Se 16.23 (17.4)

SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERFVATIVES 60

24 120-122 (Crude)

40 CHCI3 Ci6Hi5N02Se 21.84(23.76)

25 133-135 (Crude)

40 CHCI3 CigHigNOaSe 21.54(21.91)

26 Liquid 50 CHCI3 CisHigNOiSe 24.12(24.35)

27 Liquid 45 CHCI3 Ci4Hi7N02Se 24.1(25.45)

Among the compounds synthesized, the esters of compound 2 and 3 with 8-hydroxy

quinoline, 5-chIoro-8-hydroxy quinoline and 5,7-dichloro-8-hydroxy quinoline were

unstable and underwent quick degradation within a week. Hence the activity of these

compounds was not tested. Remaining newly synthesized compounds were screened for

their antimicrobial efficacy in vitro. Also they were screened for antioxidant efficacy by

DPPH fi-ee radical scavenging method and the details of the same is discussed in the

Chapter-VI.


2.3 REFERENCES

1. M. M. Abdel-monem and M. D. Anderson., US 20040254239 A., 2004.

2. E. Wincent, H. Shirani, J. Bergman, U. Rannug and T. Janosik., Bioorganic and

Med. Chem., 2009, 17, 1648.

3. J. Roy, W. Gordon, I. L. Schwartz and R. Walter., J. Org. Chem., 1970, 35, 510.

4. W. Frank, Z Physiol.Chem., 1964, 339, 214.

5. J. J. Berzelius., Gmelins Handbuch der anorthermic ganischen Chemie. SYS. no.

9-12. Verlag Chemie, Weinheim/Bergstr, 1942, 244.

6. J. H. Van den hende and E. Klingsberg., J. Am. Chem. Soc, 1966, 88, 5045.

7. M. V. Kudchadker, R. A. Zingaro and K. J. Irgolic., Can. J. Chem., 1968, 46,

1415.

8. K. A. Jensen, G. Selbert and B. Kagi., Acta Chem. Scand., 1965, 20, 281.

9. R. G. Melton and R. A. Zingaro., Can. J. Chem., 1968, 46, 1425.

10. H. Ishihara, M. Yoshimi, N. Hara, H. Ando and S. Kato., Bull. Chem. Soc. Jpn.,

1990, 63, 835.

11. E. Chopin and P. HagenmuUer., Bull. Soc. Chim. Fr., 1965, 3031. - [ - 1 4 8 5

12. H. Noth and G. Mikulaschek., Z. Anorg. Allg Chem.. 1961, 311, 241.

13. A. R. Shah, D. K. Padma and A. R. Vasudeva Murthy., Indian. J. Chem., 1971, 9,

885.

14. J. M. Lalancette and M. Amac, Can. J. Chem, 1969, 47, 3695

15. J. M. Lalancette, A. Freche and R. Monteux., Can. J. Chem., 1968, 46, 2754.

16. H. Maeda, T. Tanabe, K. Hotta and K. Mizuno., Tetrahedron Lett., 2005, 46,

2015.

17. F. Asinger and M. K. Schmitz., Monatsh. Chem., 1982, 113, 1191.

18. D. L. Klayman and T. S. Griffin., J. Amer. Chem. Soc, 1973, 95, 197.

19. P. F. Athayde-Filho, A. G. Souza, S. A. Morals, J. R. Botelho, J. M. Barbosa-

Filho, J. Miller and B. F. Lira, ARKIVOC, 2004, 22. Kuvemou University Library

20. W. P. Jencks., J. Chem. Soc. Rev., 1981, 10, 345. Jnana Sahyadri, Shankaraghatta

21. W. P. Jencks and M. Gilchrist., J. Am. Chem. Soc, 1968, 90, 2622.

22. M. J. Gresser and W. P. Jencks., J. Am. Chem. Soc, 1977, 99, 6963.

(o60


23. E. A. Castro, M. Acuna, C. Soto, C. Trujillo, B. Vasquez and J. G. Santos., J.

Phys. Org. Chem., 2008, 21,816.

24. E. A. Castro, M. Gazitua and J. G. Santos., J. Org. Chem., 2005, 70, 8088.

25. E. A. Castro, M. Aliaga and J. G. Santos., J. Org. Chem., 2005, 70, 2679.

26. E. A. Castro, G. R. Echevarria, A. Opazo, P. Robert and J. G. Santos., J. Phys.

Org Chem., 2006, 19, 129.

27. I. H. Urn, S. E. Jeon and J. A. Seok., Chem. Eur. J., 2006, 12, 1237.

28. I. H. Urn, K. H. Kim, H. R. Park, M. Fujio and Y. Tsuno., J. Org. Chem., 2004,

69, 3937.

29. I. H. Urn, J. Y. Lee, M. Fujio and Y. Tsuno., Org. Biomol. Chem., 2006, 4, 2979.

30. I. H. Urn, J. Y. Lee, H. W. Lee, Y. Nagano, M. Fujio and Y. Tsuno., J. Org

Chem., 2005,70,4980.

31. I. H. Um, H. R. Park, Y. M. Fujio, M. Mishima and Y. Tsuno., J. Org. Chem.,

2007,72,4816.

32. H. J. Koh, C. H. Shin, H. W. Lee and I. Lee., J. Chem. Soc, Perkin Trans., 1998,

2, 1329.

33. H. K. Oh, S. Y. Woo, C. H. Shin and L Lee., Bull. Korean Chem. Soc, 1995, 16,

657.

34. E. A. Castro, R. Aguayo, J. Bessolo and J. G. Santos., J. Org. Chem., 2005, 70,

7788.

35. E. A. Castro, R. Aguayo, J. Bessolo and J. G Santos., J. Org. Chem., 2005, 70,

3530.

36. E. A. Castro, R. Aguayo and J. G. Santos., J. Org. Chem., 2003, 68, 8157.

«s^ Chapter-II Synthesis Of Selenol Esters Of Benzoic Acid...

Documents

Transcript of «s^ Chapter-II Synthesis Of Selenol Esters Of Benzoic Acid...