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Chapter 2

Section A

“Oxidative Decarboxylation of

2-Aryl Carboxylic Acids Using

(Diacetoxyiodo) benzene for

Preparation of Aryl Aldehydes,

Ketones, and Nitriles”

Part A: Synthesis by using DIB and Sodium Azide Chapter 2

Novel Synthetic Methodologies for Bioactive Molecules Page 32

Part A: Using Reagent like DIB and NaN3:

Abstract

A facile and novel protocol for the oxidative decarboxylation of 2-aryl phenyl acetic

acid by active hypervalent Iodine (III) species generated in situ, from (diacetoxyiodo)

benzene and catalytic amount of sodium azide, as a highly active reaction system was

developed. The generated species exhibited remarkable activity and also used in

oxidative decarboxylation of α-substituted phenyl acetic acid to accessible product in

good yield. The protocol was applicable for a variety functionalized phenyl acetic acid

and afforded the desired benzaldehydes, ketones and Nitriles as products in good to

excellent yield. Advantages of this system are short reaction time, easy work-up and

good quality yield.

Further studies phenyl glycine with combination of hypervalent iodine (III)

reagent (DIB) and Catalytic amount of Sodium azide under goes formation of

Benzonitrile as a new, efficient and general method for the transformation (Telvekar

et al., 2010).

2A.1 Introduction:

Oxidative decarboxylation of carboxylic acids is a ‘‘classical” procedure in synthetic

organic chemistry which is well known in scope and mechanism. It is one of the most

significant protocols for synthesis of benzaldehydes, ketones and Nitriles rendering

their applications in organic synthesis, biological systems, natural products and

perfumery industry. With this convenience of α-amino acid degradation, wide

research has been approved out to know the mechanism and causes of the same. In

discovery of copying the nature pathways by synthetic pathways, there are many

pathways and their mechanism were proved by synthetic chemistry support and

OH

O

R

H

O

CH3

O

CN

Or Or

R = H, OH, CH3, NH2 R = H, OH R = CH3R = NH2

DIB, Cat. NaN3

MeCN, 0 oC to r.t.

20 min.

Scheme 2A.1


Novel Synthetic Methodologies for Bioactive Molecules 3

degradation of α-amino acid using chemical reagents. Reaction for the degradation of

α-amino acids is expected to precede stepwise manner as shown in (scheme 2A.12),

which was reported previously by other chemical reagents. The imine intermediate

may undergo hydrolysis giving aldehyde or undergo further oxidation to nitrile.

Hypervalent iodine reagents have become increasingly popular for affecting a variety

of synthetic transformations (Moriarty, 2008; Varvoglis, 1997; Zefirov et al., 2006;

2000; Fujiwara et al., 1997; Stang et al., 1999; 1998; Prakash et al., 1998; Grushin,

2000; Umemoto, 1996; Zhdankin et al., 1997; Okuyama, 2002; Wirth et al., 2004;

Ochiai, 2007; Deffieux et al., 2004; Chai et al., 2007) as well as have wide application

as versatile and environmentally benign oxidizing reagents in organic chemistry

(Fujioka et al., 2007; Wipf et al., 2004; Fujita et al., 2005; 2007; Kirmse, 2005;

Ghanem et al., 2006; Muller, 2004; Deffieux et al., 2008; Bardin et al., 2008). The

object of our present study is to investigate the possibility of oxidative

decarboxylation of 2-aryl phenyl acetic acid by using hypervalent (III) iodine reagent.

2A.2 Literature Survey

The chemistry of benzaldehydes, ketones and nitriles has received a more awareness

because benzaldehydes, ketones and nitriles have been broadly explored. There are

some methods are available for synthesis of benzaldehydes and ketones from phenyl

acetic acid using oxidative decarboxylation phenomenon but, Very few methods are

available for the synthesis of benzonitrile derivatives from phenyl glycine using as

starting materials in one pot.

1) Synthesis of benzaldehydes and ketones:

Oxidative decarboxylation of phenyl acetic acid and α-alkyl or aryl phenyl acetic acid

to formed benzaldehydes and ketones respectively can be achieved with various

oxidising agents.



a) Using Tetrabutylammonium periodate and imidazole, manganese meso

tetraarylporphyrins.

In organization with tetrabutylammonium periodate (n-Bu4NIO4) and

imidazole (ImH), manganese meso-tetraarylporphyrins have provided a useful

catalytic system for the oxidative decarboxylation of carboxylic acids (Karimiopouri

et al., 2007). Iron and Manganese Porphyrin Periodate Systems is another system use

in oxidative decarboxylation of α-aryl carboxylic acids to the resultant carbonyl

derivatives (Scheme 2A.2), α-hydroxy phenyl acetic acids also transformed in to

corresponding benzaldehyde derivatives (Tangestaninejad et al., 1998).

The oxidation of anti-inflammatory drugs such as Indomethacin and Ibuprofen

command corresponding carbonyl derivatives as the major products

b) Using manganese (III) Schiff base complexes:-

In this chemical scheme containing Mn (III)-salophen complex as catalyst, carboxylic

acids are changed efficiently to the corresponding carbonyl derivatives among sodium

periodate (Mirkhani et al., 2004).

OH

O

R

H

O

or

O

R = H, OH, Ph R = H, OH R = Ph

Mn III (tpp) Cl

Bu4NaIO 4, r.t.

Scheme 2A.3

OH

O

H

O

Mn (T PP) CN /

immidazole,r.t.

n - Bu 4NIO4

Scheme 2A.2



The capacity of various Schiff base complexes in the oxidative decarboxylation of

carboxylic acids was also investigated. Montazerozohori et al. shows Bis (2-

hydroxybenzene) phthaldiimine (BHBPDI) as a new quadridentate Schiff base ligand

and its Mn (III) and Fe (III) complexes were synthesized and characterized by

analytical and spectral data. The Mn (III) and Fe (III) complexes were working as

catalysts in the oxidative decarboxylation of a variety of arylacetic acids using

tetrabutylamonium periodate as oxidant (Scheme 2A.4) (Montazerozohori et al.,

2008).

The Fe (III) analog system showed less catalytic activity at the same conditions.

c) Polystyrene-bound Mn (T4PyP):

In the presence of manganese (III) tetra (4-pyridyl) porphyrin supported on cross-

linked chloromethylated polystyrene [Mn (T4PyP)-CMP] as a catalyst (Moghadam, M

et al, 2009) carboxylic acids were transformed to their matching carbonyl compounds

via oxidative decarboxylation with sodium periodate using imidazole as axial ligand

(Scheme 2A.6)

O

OH

Ph O

[M(III)(BHBPDI)Cl] / (n-Bu)4NaIO4

Imidazole, CH2

Cl2

, RT

Scheme 2A.5

OH

O

R

H

O

orCH3

O

R = H, alkyl, aryl gr. R = H R = CH3

Mn(III)-Salophen/NaIO 4

immidazole/aq.acetonitrile,r.t.

Scheme 2A.4



d) HgF2 under a dioxygen atmosphere:

Mercuric fluoride (HgF2) as a light-sensitive inorganic compound, in the presence of

dioxygen is capable to transfer various aryl and α-substituted phenyl acetic acid acids

into the corresponding aldehydes and ketones selectively under photoirradiation via

trapping of the benzylic radical by O2 (Scheme 2A.7) (Farhadi et al., 2006)

This reagent is not a decarboxylating agent in the absence of light, can

probably be activated photochemically affording selectively decarboxylated product.

e) Using Mesoporous Silicas:

FSM-16, mesoporous silica was originate to catalyze oxidative photo-decarboxylation

of phenyl acetic acid derivatives and N-acyl-protected α-amino acids to afford the

corresponding carbonyl compounds (Scheme 2A.8) (Akichika ITOHet al., 2006)

X

O

OH

Y

H

O

orCH3

O

X = H, CH3, C2H5, Ph

Y=H,OH

X = H and Y = H X = CH3 and Y = H

HgF2 / O2 / hv

CH3CN / r.t.

Scheme 2A.7

O

OH

R O

[Mn(T4PyP)-CMP], NaIO4

CH3

CN / H2

O, RT

orH

O

R = Ph,H R = PhR=H

Scheme 2A.6



f) 2-Nitrobenzenesuifonyl Chloride and Superoxide:

The oxidative decarboxylation of aryl, diaryl or arylalkylacetic acids has been

achieved by a 2-nitrobenzenesulfonyl peroxy radical intermediate generated by the

reaction of 2-nilrobenzenesulfonyl chloride with potassium superoxide at -20 oC in

dry acetonitrile (Scheme 2A.9) (Yong Hae Kim et al., 1998)

Decarboxylation does not take place with superoxide in the absence of 2-

nilrobenzenesulfonyl chloride at 25 oC for 24 h.

2) Synthesis of benzaldehyde from mandelic acid:

There are very few examples of oxidative decarboxylation of mandelic acid to

benzaldehyde as product.

a) N-Iodosuccinamide reagent:

This method showing conversion of α-hydroxy carboxylic acids under goes bond-

cleavage products when treated with NIS. Thus, NIS is another reagent to consider in

addition to lead tetraacetate and sodium periodate preparing aldehydes and ketones

CH3

O

OH

+

SO2Cl

NO2

+ KO2

CH3CN

- 20 oC

CH3

O

Scheme 2A.9

Ph

Ph

O

OH

OH

Ph Ph

OFNS - 16, hv (400w)

hexane, r.t.

Scheme 2A.8



via decarboxylation of α-hydroxy carboxylic acids (Scheme 2A.10) (Beebe et al.,

1982)

b) Bi (0) - Catalyzed Oxidation:

Mandelic acid derivatives were oxidized with a bismuth-catalyzed oxidation system

based on Bi0/DMSO/O2. Benzaldehyde and/or benzoic acid derivatives could be

obtained chemoselectively depending on the catalytic system and the substitution on

the aromatic ring (Scheme 2A.11) (Elisabet, D et al, 2002)

In case of unsustituted phenyl acetic acid there are formation of benzoic acid is a

major product and benzaldehyde is minor product.

Phenyl glycine when subjected to oxidative decarboxylation, generally there is

formation of benzaldehyde is product but in our reaction system we observed that

when phenyl glycine undergoes oxidative decarboxylation with our reaction system it

twisted Benzonitrile product in good yield. There is very little report that shows

formation of Benzonitrile product starting from phenyl glycine.

OH

O

OH

HO

OMe

Bi (0) , O2

DMSO

H

O

HO

OMe

+

OH

OMe

OH

O

87 % 13 %

Scheme 2A.11

OH

O

OHNIS

benzene , THF, r.t

H

O

Scheme 2A.10



3) Synthesis of Benzonitrile.

Oxidative decarboxylation of α-amino acid to resultant one carbon less nitrile is

precious transformation. The present conversion is the reaction course of oxidation of

amino group to nitrile with decarboxylation. There are only few methods are existing

for the direct conversion of α-amino acids to corresponding one carbon less nitriles. In

previous literature there are many methods, but these gives mixture of aldehyde and

nitrile. Oxidative decarboxylation of α-amino acids is a significant metabolic

transformation in variety of organisms having large application in biochemistry and

peptide cleavages (Gassman et al., 1989). Reaction for the degradation of α-amino

acid is expected to precede stepwise manner as shown in (Scheme 2A.12) which was

reported earlier by other chemical reagents. The imine intermediate may undergo

hydrolysis giving aldehyde or undergo further oxidation to nitrile.

a) N-bromo succinamide:

NBS react with aqueous solution of some α-amino phenyl acetic acid at room

temperature to formation of benzonitrile as product but in this case there is also

benzaldehyde formed as side product. Mostly aliphatic amino acids under goes this

transformation to obtained Nitrile as product (Scheme 2A.13) (Stevenson et al., 1961)

H3C

NH2

O

OHH3C NH

CH3 Noxidising agents

CO2H2O

Oxidation

CH3 H

O

Scheme 2A.12



b) Using Sodium hypobromide (NaOBr)

Friedman et al. reported reaction of sodium hypobromide with α-amino acids

producing mixture of nitrile and aldehyde (Scheme 2A.14) (Friedman et al., 1936). It

was reported that the amount of formation of aldehyde and nitrile depends upon

alkalinity of the reaction media.

Also they have observed that if the longer the carbon chain in α-amino acids

yield of obtained nitrile is additional.

R

NH2

O

OHR N +

R H

ONaOBr

r.t

R = aliphatic, aromatic etc.

Scheme 2A.14

ROH

NH2

O

R N

NBS

Where R = aliphatic, aromatic etc.

acid or base

Scheme 2A.13



c) Gowda et al. reported that t-butyl hypochlorite is also used as oxidation reagent for

the conversion of α-amino acids to resulting mixture of aldehydes and nitriles

(Scheme 2A.15) the role of hypochlorite species was confirmed by studding

mechanistic and kinetic exploration.

e) Sodium-N-chloro-4-toluenesulfonylamide (Chloramine-T)

The preparation of nitrile or aldehyde by oxidation of amino acid sodium-N-chloro-4-

toluensufonylamide (Chloramine-T) used (Dakin et al., 1996; Sharma et al., 1980).

Chloramine-T used under acidic as well as basic conditions in 24h (Scheme 2A.16).

Depending upon the reaction condition ratio of formation of nitrile and aldehyde was

shown to be varied. Kinetics and mechanistic studies has been done.

R

NH2

O

OHR CH +

R H

O


Chloramine-T

acid or base

Scheme 2A.16

R

NH2

O

OHR N +

R H

O


t-Butyl hypochloride

NaOAc/aq.AcOH

Scheme 2A.15



f) 1-Chlorobenzotriazole (1-CBT)

Hiremath et al. reported 1-Chlorobenzotriazole (1-CBT) is fine source of electrophilic

chlorine (Hiremath et al., 1987). This reagent in combination with perchloric acid and

sodium chloride used for oxidation of α-amino acids (Scheme 2A.17) electrophilic

chlorine of 1-CBT helpful for oxidation process and formation of nitrile was studied

through mechanistic and kinetic investigation.

g) Copper (II) bromide/Lithium tert-butoxide (CuBr2/t-BuOLi):

Takeda et al. urbanized Copper (II) bromide/Lithium tert-butoxide (CuBr2/t-BuOLi)

system is also used for the conversion of α-amino acids to resultant nitriles (Scheme

2a.18) (Takeda et al., 1996). In this report yields are lower and long reaction time

required for completion of reaction.

h) Trichloroisocynuric acid (TCCA):

Trichloroisocynuric acid (TCCA) in presence of sodium hydroxide oxidise α-amino

acid to nitrile at 50 oC in water while Hiegel et al. Reported the same reaction with

R

NH2

O

OHR N


CuBr2 / t-BuOLi

THF

Scheme 2A.18

R

NH2

O

OHR CH


1- CBT

HClO4, NaCl

Scheme 2A.17



pyridine as base in methanol water mixture but obtained yield of product is very low

(De Luca et al., 2004; Hiegel et al., 2004).

As seen from the above Literature many reagents have been investigated towards

oxidative decarboxylation of α-amino acid which give nitrile or mixture of nitrile and

aldehyde as the products. Only some oxidizing agents such as TCCA, 1-CBT,

CuBr2/t-BuOLi give only nitrile where as other oxidizing agents such as NaOBr,

NBS, BTI/Pyridine, Chloramine-T, enzyme bromoperoxidase, t-BuOCl, and

electrolysis using silver electrode give mixture of aldehydes and nitriles. A number of

reagents are a smaller amount studied and produce a mixture of products.

2A.3 Objectives and Scope

Develop the first reaction in which benzaldehydes, ketones and nitriles are

synthesized from phenyl acetic acid and α- substituted phenyl acetic acid using single

reaction system.

OH

O

R

H

O

orR

O

Whrer R = H, OH, aliphatic, aromatic etc R = H, OH R = aliphatic, aromatic

DIB, Cat. NaN3

CH3CN, 0 - rt, 20 min

Scheme 2A.20

R

NH2

O

OHR N


+ R H

OTCCA

base

Scheme 2A.19



In view the importance of oxidative decarboxylation of phenyl acetic acid and α-

substituted phenyl acetic acid in to corresponding aldehydes, ketones and nitriles as

products, our aim is to build up is single reaction system useful for the transformation

of phenyl acetic acid and α-substituted phenyl acetic acid in to corresponding products

in good yields. In previous case of oxidative degradation of α-amino acid (phenyl

glycine) there is invariably formation of mixture of nitriles and aldehydes reported so,

we report formation of nitrile as main product with excellent to good yield in very

short time, also application of trivalent iodine reagents with combination of Catalytic

NaN3 in current conversion will be discussed. Our research group is dynamically

working on (diacetoxyiodo) benzene i.e. DIB and IBX mediated reactions (Telvekar

et al., 2010). DIB is readily soluble in Acetonitrile. We thought that hypervalent

iodine reagent can be useful this transformation.

2A.4 Work done on each objective

To develop a suitable protocol for oxidative decarboxylation reactions, initially the

reaction of phenyl acetic acid with (diacetoxyiodo) benzene and catalytic sodium

azide in the acetonitrile solvent was chosen as a model reaction (Scheme 2A.21) and

influence of presence of Sodium azide was examined in the case.

It was interesting to observe that, only in presence of catalytic amount of

sodium azide reaction proceed very well (Scheme 2A.21).

OH

O

DIB, CH3CN, 0 - rt

DIB, CH3CN, 0 - rt

Cat. NaN3

H

O

No Reaction

Scheme 2A.21



a) Study for Temperature and Reaction Time:

Optimization of reaction condition in case of synthesis of benzaldehydes and ketones

from phenyl acetic acid and 2-aryl or alkyl phenyl acetic acid respectively in terms of

time and temperature is also carried out. Reactions were carried out at different

temperatures from room temperature to reflux condition and it was observed that

reactions are smooth, clean and gives better yields when we carried out reaction at 0

to room temperature. In case of phenylglycine reaction was carried out at room

temperature and reaction required 45 min for completion, gives only benzonitrile as

product with excellent to good yields.

b) Solvent study:

Furthermore reaction subjected to different solvent like acetone, water,

dichloromethane and acetonitrile; found that acetonitrile is suitable solvent for this

transformation.

c) Reagent Mole Ration:

Experiments were performed using varied equivalents of (diacetoxyiodo) benzene and

NaN3 when less than 1.5 eq of DIB used then reactions remained incomplete. Finally

1.5 equiv. of DIB and Catalytic amount of NaN3 was optimized quantity for the

reaction. Only catalytic amount of sodium azide (0.12 eq) required for transformation

However, a further increase in concentration did not show any significant

enhancement in the yield.

d) Comparison with other hypervalent iodine Reagents:

Other hypervalent iodine reagents were also examined for this transformation as

Reaction was not proceed when HIO3, DMP, KIO3 reagent was used. From these

studies, we had done that reactions performed at r.t. proceeds smoothly and fast with

better yields. Among these trivalent iodine reagents, DIB with catalytic NaN3 was

better reagent for the conversion.



2A.4.1 Optimise reaction conditions:

With above studies, it is renowned that finest results were obtained with 1.5 equiv of

DIB and NaN3 (0.12 eq) in acetonitrile solvent at room temperature and all further

reactions were carried out using these optimized parameters.

We also imagine observing reactivity of α-substituted phenyl acetic acid

towards this optimise reaction conditions and effect is summarised in results and

discussion.

2A.5 Results and Discussion

As discussed in design part DIB/NaN3 combination is superior oxidizing combination

for conversion of phenyl acetic acid compounds, catalytic amount of sodium azide

increase the reactivity of reagent and formed new active species (1) which is mention

in mechanism part, which is responsible for the conversion (Scheme 2A.26). We also

increase amount of sodium azide in reaction up to 1 to 2 mmol but we found that

catalytic amount of sodium azide is sufficient for the conversion. It was determined to

subject phenyl acetic acid to reaction with DIB/NaN3 complex. As expected the

reaction proceeds smoothly in 20-45 min with the formation of aldehydes as product

with good yield achievement of reaction was monitored by TLC with complete

consumption of starting material. Isolated product was analyzed by IR and GC. IR

Spectra shows peak at 1707, 2845, 2740 cm-1

frequency due to benzaldehyde was the

product. This was further supported by single peak obtained in GC analysis at

retention time of authentic benzaldehyde for the confirmation, GC-MS of the product

was recorded and only benzaldehyde was observed. These results indicate that phenyl

acetic acid with DIB/NaN3 acetonitrile system gives only benzaldehyde as the

product.

O

OHDIB/ Cat.NaN3

CH3CN /r.t,

H

O

Scheme 2A.22



It was fascinating to examine that, under similar reaction conditions mandelic

acid under goes this transformation to obtained same i.e. benzaldehyde as product

with good yield (Scheme 2A.23)

As usual, the reaction proceeds smoothly in 20-45 min, with the formation of

benzaldehyde as product with good yield. Achievement of reaction was monitored by

TLC with complete consumption of starting material and isolated product was

analyzed by IR and GC. IR shows peak at 1704 cm-1

frequency due to benzaldehyde

was the product (Scheme 2A.23), further to cheque the efficiency of reaction system

we decided to subject α-alkyl or aryl phenyl acetic acid for this transformation, it was

interesting to observe that under same reaction conditions, we got required ketones as

product with good yield (Scheme 2A.24)

As discussed in design part DIB/NaN3 mixture is good oxidizing combination

for amino compounds, it was decided to focus on oxidation of α-phenylglycine with

DIB/NaN3 complex. As ordinary the reaction proceeds smoothly in 45 minute, the

expected product as shown in (Scheme 2A.25) were identified with IR of the crude

reaction mass which shows both benzaldehyde (1702 cm-1

) as well as benzonitrile

O

OH

R

DIB / Cat. NaN3

CH3CN / 0 - r.t,

R

O

Where R = alkyl, aryl group etc.

Scheme 2A.24

O

OH

OH

DIB / Cat. NaN 3

CH3CN / r.t,

H

O

Scheme 2A.23



(2228 cm-1

) peaks. GC analysis of the crude reaction mass was carried out and found

85% of benzonitrile (Scheme 2A.25)

a) Generality of the Substrates:

With these results in hand, to observe the range and simplification of the method, a

wide variety of substrates were studied as shown in (Table 2a.1). To expand the scope

of our reaction system phenyl acetic acid and α-hydroxyl phenyl acetic acid are

subjected to oxidative decarboxylation, in both cases we were found to respond

smoothly providing highest yield of benzaldehyde as preferred product. We also

checked the role of NaN3 (Catalytic amount) in our reaction system and it was

observed that superior reaction proceeds only in the presence of NaN3.

Further To explore the simplification and applicability of the protocol we

turned our attention towards the oxidative decarboxylation of α-alkyl phenyl acetic

and α-aryl phenyl acetic acid with DIB (1.5 eq) and NaN3 (0.12 eq) in acetonitrile at 0

to r.t. (Table 2a.1, entry 10, 11) The reaction gave 85% yield of ketones under the

optimized reaction conditions; further increase in NaN3 concentration up to 2 eq had

no profound effect on the yield of the desired product. The developed protocol proved

to be general for the oxidative decarboxylation of α-alkyl or α-phenyl acetic acid with

DIB (1.5 mmol) and NaN3 (0.12 eq) providing good to excellent yields of the desired

product. We think that the presence of NaN3 plays the role of catalyst; the effects of

various solvents on oxidative decarboxylation was studied and find out that

acetonitrile solvent system provides good yields. During optimization of the reaction

parameters, we observed that in case of phenyl acetic acid, mendalic acid and α-alkyl

or aryl phenyl acetic acid if the DIB (1.5 eq) , Catalytic amount of NaN3 is (0.12 eq)

and acetonitrile solvent system at 0 to room temperature then product formed with

good yield. To investigate the generalization and applicability of the protocol we

NH2

O

OH CNDIB / Cat. NaN3

CH3CN / r.t,

Scheme 2A.25



turned our attention towards the oxidative decarboxylation of α-amino acid (phenyl

glycine). Found that DIB (1.5 eq), Cat.NaN3 (0.12 eq) in acetonitrile solvent at r.t.

(Table 2a.1, entry 13, 14, 15) reaction gave 85-90% yield of benzonitrile. In order to

study the promising and general applicability of the developed methodology, various

phenyl acetic acids containing different functional groups were subjected to this

transformation. We observed that electron donating as well as electron withdrawing

groups provided significant yield of products. A variety of functional groups

including methoxy, methyl, chloro, nitro group were well tolerated and gave good

yield (Table 2a.1, entry 2-7). In order to study the α-alkyl or aryl phenyl acetic acid

under these reaction conditions, we treated α-methyl phenyl acetic acid with DIB and

NaN3 which was resulted in the formation of good yield of Acetophenone is achieved

(Table 2a.1, entry 10, 11, 12). 2-phenyl butanoic acid and diphenyl acetic acid were

readily converted in to corresponding products (Table 2a.1, entry 11, 12). It was found

that phenyl glycine, amino (4-chlorophenyl) acetic acid and amino (naphthalen-2-yl)

acetic acid were successfully converted into the corresponding nitriles in good yields

(Table 2a.1, entries 13, 14, 15). In case of phenyl acetic acids and α-substituted

phenyl acetic acids reaction proceed. In mechanism part of the reaction when aromatic

substrates submitted to reaction intermediate like (phenylmethylium radical) may be

formed this is well stabilised by aromatic ring and further under goes oxidation to

form final product. In case of aliphatic acids intermediate ion is not stable. All

benzaldehydes, ketones and nitriles were characterized by comparing spectral

properties and comparing their physical properties with that of reported compounds in

the literature. Detailed data is present in the experimental section.

Table 2a.1 Decarboxylation of 2-aryl carboxylation acids using (Diacetoxyiodo)

benzenea

Sr.No Substrate Product Time(Min) Yield%b

1

OH

O

H

O

20 88

2

OH

OCH3

H

O

CH3

15 85



3 O

OHH3CO

OCH3

H

O

H3CO

OCH3

15 89

4 OH

O

Cl

H

OCl

20 85

5 O

OH

Cl

H

O

Cl

20 85

6

OH

OEtOOC

H

O

EtOOC

25 85

7

OH

OO2N

H

O

O2N

25 90

8

OH

O

H

O

20 87

9

OH

O

OH

H

O

30 90

10

CH3

O

OH

CH3

O

20 85

11

O

OH

CH3

O

CH3

20 85

12

COOH

O

15 90



13 OH

O

NH2

CN

60 90

14 OH

O

NH2

Cl

CN

Cl

60 86

15

NH2

O

OH

CN

55 85

16

CH3

OH

O

-- 120 NR

c

17

CH3

OH

O

CH3

-- 120 NRc

18

CH3

OH

O

H2N

-- 120 NRc

Reaction conditions: Substrate (1 equiv), (diacetoxyiodo) benzene (1.5 equiv), and catalytic

NaN3 (0.12 equiv) in MeCN (10 ml).bisoleted yields after column of IR and

1HNMR with

authentic materials. cNo reaction



1H NMR of 4-Methyl benzaldehyde (Table 1, entry 2)

H

O

CH3



IR Spectra of 4- Methyl benzaldehyde (Table 1, entry 2)

H

O

CH3



1H NMR Spectra of 4- Chloro benzaldehyde (Table 1, entry 5)

H

O

Cl



IR Spectra of 4- Chloro benzaldehyde (Table 1, entry 5)

H

O

Cl



1H NMR Spectra of 3, 5 dimethoxy benzaldehyde (Table 1, entry 3)

H

O

MeO

OCH3



IR Spectra of 3, 5 dimethoxy benzaldehyde (Table 1, entry 3)

H

O

MeO

OCH3



1H NMR Spectra of Naphthaldehyde (Table 1, entry 8)

H

O



IR Spectra of Naphthaldehyde (Table 1, entry 8)

H

O



1H NMR Spectra of 4- Chloro benzonitrile (Table 1, entry 14)

CN

Cl



IR Spectra of 4- Chloro benzonitrile (Table 1, entry 14)

CN

Cl



2A.5.1 plausible mechanism for the transformation:

(Diacetoxyiodo) benzene reacted with sodium azide and formed active species (1)

which react with phenyl acetic acid in acetonitrile to form primary alcohol as

intermediate with elimination of CO2, PhI and acids. Further oxidation of primary

alcohol with active hypervalent iodine species to formed benzaldehyde as product

with good yields.

Plausible mechanism for formation of benzaldehyde from phenyl acetic acid

2A.6 Possible Potential Applications

It is one of the most significant protocols for synthesis of benzaldehydes, ketones and

Nitriles rendering their applications in organic synthesis, biological systems, natural

products and perfumery industry.

I

OAc

OAc CH3CN, O oC

I.

OAc

(1)

OH

O

(1)

- PhI- CO2

OH (1)

Oxidation

H

O

CH3CN

NaN3

N3

.

-NaOAc

-HOAc

-HN3

Scheme 2A.26



2A.6.1 Applications of benzaldehydes in synthesis of drugs molecules

a) Anisindione

Benzaldehyde use intermediate for synthesis of Anisindione, which is Synthetic

anticoagulant.

b) Synthesis of Monasterol

It was synthesized in 1967 and was subsequently used as an Antidepressant in

Europe. Benzaldehyde derivatives use as intermediate for synthesis of Monasterol

c) Synthesis of Amphetamine

Amphetamines a psychostimulant drug

NHCH3

Amphetamine

Monasterol

NH

NH

O

H5C2O

CH3 S

OH

OMe

O

O

Anisindione



2A.6.2 Application of Synthesized Ketones Molecule

a) Amfepramone

Ketones are used as intermediate in a Synthesis of Amfepramone. Amfepramone

(diethylpropion) is a stimulant drug of the phenethylamine, amphetamine, which is

used as an appetite suppressant.

b) Amfebutamone

Amfebutamone is an effective antidepressant.

c) Banmoxin

It was synthesized in 1967 and was subsequently used as an antidepressasant.

Banmoxin

NH

O

NH Ph

CH3

O

CH3

NHtBu

Cl

Amfebutamone

Amfepramone

N

O

CH3

CH3

CH3



2A.6.3 Application of benzonitrile in drugs Synthesis

a) Nitriles are found wide application in drugs and intermediate synthesis, so this

method will help to introduce respective nitrile containing intermediates.

b) There is need to appreciate biochemical processes in living organisms, because

mechanism of these processes help to understand the abnormalities and diseases in

living organisms. This method will be applicable in amino acid degradation studies in

biochemistry, especially in peptide chemistry.

C) Bunitrolol:

CN

OH

+ ClO

NaOH

CN

O

CH3

NH2

CH3

CH3

CN

O

OHNH

CH3

CH3 CH3

2-methylpropan-2-amine

Scheme 2A.27



2A.6.3.1 Few Applications of Benzonitrile:

Fig 2A.1



2A.6.3.2. pharmaceutically important benzonitrile derivatives:

Fig 2A.2

2A.7 Summary & Conclusion

In summary, we developed a new protocol for oxidative decarboxylation of phenyl

acetic acid, mandelic acid and α-alkyl or aryl phenyl acetic acid to obtained

benzaldehydes and ketones as products. Where phenyl glycine under goes oxidative

decarboxylation to achieve an excellent yield of desired benzonitrile product, this is

an efficient and novel method has been developed for oxidative decarboxylation of α-

amino acids to one carbon less nitriles using the mixture of DIB and NaN3 in

acetonitrile solvent. This method possesses immense functional group tolerance i.e.

chemoselective under the reaction conditions. Using this combination, a series of α-

amino acids could be dehomologated to nitriles. This method exhibits a broad range,

affords spotless product in high yields and will be of immense efficacy in organic

synthesis. Lower reaction time adds an additional credit to the present study In

general; all kinds of functional groups were very well tolerated giving higher yields.

The reaction was optimized with respect to various reaction parameters and

enabled oxidative decarboxylation of various electron-rich, electron-deficient phenyl

acetic acid and α-substituted phenyl acetic acid, affording excellent yields of the

N

S

CN

N

OCH3

NN

N

NC CN

N

NNC

Arensin (Ciba-Geigy)

Femara (Novarties Pharma)

Aolept (Bayer)



desired products, thus illustrating the broad applicability of the methodology. The

developed protocol might prove a hopeful alternative for oxidative decarboxylation

for benzaldehydes and ketones and nitriles synthesis.

2A.8 Experimental Section:

2A.8.1 General experimental procedure for oxidative decarboxylation of phenyl

acetic acids and mandelic acids:

(Diacetoxyiodo) benzene (1.5 equiv) and NaN3 (0.12 equiv) in acetonitrile (10 ML)

were stirred at 0 oC for 2 to 5 min, then phenyl acetic acid (1 equiv) was added to the

stirred solution , reaction kept at room temperature .The reaction mixture was allowed

to stirring continued until completion of reaction (TLC), then it was quenched with

H2O (25 ml) and extracted with CHCl3 (3x10 mL) .The combined organic layers were

washed with dilute NaHCO3 (20 ml), followed by H2O (3x20 ml), dried over Na2SO4

and Concentrated in vacuum. The residue was purified by column chromatography

(SiO2, mesh size 60–120 eluent and ethyl acetate–hexane, 9:1) to yield desired

product.

2A.8.2 General experimental procedure for oxidative decarboxylation of α-alkyl

or aryl phenyl acetic acids:

General experimental procedure for oxidative decarboxylation of α-alkyl or aryl

phenyl acetic acids is same like above procedure.

2A.8.3 General experimental procedure for oxidative decarboxylation of α-amino

(phenyl) acetic acids:

(Diacetoxyiodo) benzene (1.5 equiv) and NaN3 (0.12 equiv) in acetonitrile (10 ML)

were stirred at room temperature for 2 to 5 min, then α-amino (phenyl) acetic acid (1

equiv) was added to the stirred solution. The reaction mixture was allowed to stirring

continued until completion of reaction (TLC), then it was quenched with H2O (25 ml)

and extracted with CHCl3 (3x10 mL) .The combined organic layers were washed with

dilute NaHCO3 (20 ml), followed by H2O (3x20 ml), dried over Na2SO4, and

Concentrated in vacuum. The residue was purified by column chromatography (SiO2,



mesh size 60–120, eluent, and ethyl acetate–hexane, 9:1) to yield desired benzonitrile

product.

2A.9 Characterization Data of benzaldehydes

Benzaldehyde (Table 1, Entry 1): Liquid, BP 177 oC. IR (KBr): 2821, 2734,

1704,1597,1430,1361 cm-1

. 1H NMR (300 MHz, CDCl3): δ = 10.00 (1H, s), 7.87 (2H,

d, J = 7.0,), 7.62 (1H, t, J = 7.3,), 7.52(2H, t, J = 7.2).

4-Methyl benzaldehyde (Table 1, Entry 2): Liquid, 203 oC BP .IR (KBr): 2920,

2823, 2734, 1704, 1607, 1450, 847, 769, 640 cm-1

. 1H NMR (300 MHz, CDCl3): δ =

7.22 (2H, d, J =7.8Hz), 7.68(2H, d, J =8.1Hz), 9.86(1H, s).

2, 5 dimethoxybezaldehyde (Table 1, Entry 3): Solid .IR (KBr): 2940, 2829, 2728,

1690, 1586, 1460,866,783, cm-1

. 1HNMR (300 MHz, CDCl3): δ=7.43-7.37(2H, m),

6.95(1H, d, J=8.1Hz), 9.82(1H, s)

4-Chlorobenzaldehyde (Table 1, Entry 4): Solid, Mp 46 oC .IR (KBr):2833, 2730,

1699, 1573, 1431, 1194, 896,785,676 cm-1

. 1H NMR (300 MHz, CDCl3): δ=7.81(2H,

d, J=8.1Hz), 7.50(2H, d, J=10Hz), 9.96(1H, s)

2-Naphthaldehyde (Table 1, Entry 5): Liquid, BP 154 oC. IR (KBr): 2952, 2921,

2865, 2724,1699,1573,1461, 786 cm-1

. 1H NMR (300 MHz, CDCl3) δ= 9.26(1H, d,

J=8.7 Hz), 7.98-7.46(6H, m) 10.3(1H, s)

4-nitro-benzaldehyde (Table 1, Entry 7): Yellow solid, M.P. 105-107 oC. IR (KBr,

cm-1

): 3107, 2926, 2956, 1705, 1608, 1454, 1420, 1346, 862, 740. 1H NMR (300

MHz, CDCl3, ppm): δ = 10.17 (s, 1H) 8.42 (d, J= 8.48 Hz, 2H), 8.02 (d, J= 8.48 Hz,

2H)

4-acetylbenzoic acid ethyl ester (Table 1, Entry 6): IR (KBr, cm-1

): 3065, 2738,

2696, 1698, 1643, 1424, 1388, 1377, 1270, 695, 746, 663. 1H-NMR (300 MHz,

CDCl3): δ 1.41 (t, 3H, J=7.0Hz), 2.62 (s, 3H), 4.42 (q, 2H, J=7.0Hz), 8.02 (m, 2H),

8.13 (m, 2H).



2A.9.1 Characterization Data of ketones:

Benzophenone (Table 1, Entry 12): Solid, MP 306 oC. IR (KBr): 2925, 2867,

2854,1668,1401,1365, 700 cm-1

1H NMR (300 MHz, CDCl3) δ=7.8(2H, d, J=6.9Hz)

7.79-7.44(8H, m)

Acetophenone (Table 1, Entry 10): Colourless liquid, IR (KBr): 1692, 1601, 1368,

1265, 690, 588 cm-1

1H NMR (300 MHz, CDCl3, ppm): δ = 7.71 (d, J = 8.0 Hz, 2H),

6.75-6.41 (m, 3H), 2.73 (s, 3H)

Propiophenone (Table 5, Entry 9): Colorless liquid, (bp 225 oC),

1H NMR (300

MHz, CDCl3): ƒÂ 7.94- 7.91(d, J = 7.5Hz, 2H), 7.52-7.48(t, J = 7.05Hz, 1H), 7.44-

7.40(t, J = 7.35Hz, 2H), 2.94-2. 88(t, J = 7.2Hz, 2H), 1.00-0.95(t, J = 7.35Hz, 3H)

ppm. IR (neat) 1685, 1589, 1581, 1492, 761 and 691 cm-1

2A.9.2 Characterization of Nitriles:

Benzonitrile (Table 1, Entry 13): Colorless liquid, (bp 193 oC).

1H NMR (60 MHz,

CCl4): δ 7.72-7.35 (m, 5H) ppm; IR; 2227cm-1

.

4- Chloro benzonitrile (Table, 1, Entry 14): IR (KBr, cm-1

); 3000, 2223, 1555,

1464, 1215, 1093, 757, 459; 1H NMR (300 MHz, CDCl3); δ 7.61-7.58 (m, 2H, ArH),

7.47-7.44 (m, 2H, ArH)

Naphthalene-1-carbonitrile (Table 1, Entry 15): pale yellow solid, Mp 35-37 oC.

IR (KBr): 2223, 1592, 1613, 1602, 1375, 802, 771, 500. 1H NMR (300 MHz, CDCl3,

J values are reported in Hz): δ 8.22 (d, J = 8.2, 1H), 8.10 (d, J = 8.3, 1H), 7.92 (d, J =

8.1, 1H), 7.95 (dd, J = 7.2, J = 1.1, 1H), 7.71 (ddd, J = 8.3, J = 6.9, J = 1.34, 1H), 7.61

(ddd, J = 8.3, J = 7.1, J = 1.2, 1H), 7.57 (dd, J = 8.3, J = 7.1, 1H); IR (neat, cm-1

):

2224, 1602, 1515, 1378, 853, 802, 772, 684, 451.

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