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One pot oxidative cleavage……… Chapter 1

37

One pot oxidative cleavage of 1,2-arylalkenes into arylketones under microwave in aqueous conditions

1.1 Introduction

The oxidative functionalization and cleavage of alkenes represents a fundamental

transformation [Lee and Chen (1991); Kuhn et al. (2004)] in organic synthesis

[Thottumkara and Vinod (2010)]. Depending upon the substitution pattern around the

double bond i.e. 1,2 or 1,1-disubstituted alkenes, the oxidative cleavage of respective

alkenes can lead to the formation of either aldehydes or ketones respectively (Scheme 1).

Scheme 1

1.2 Significance of oxidative cleavage

Oxidative cleavage has wide spread applications in synthesis of biologically important

compounds besides total synthesis of natural products [Green et al. (2008); Hirashima et al.

(2009)]. The major utility of such cleavage reactions is due to their unique ability to

truncate readily available hydrocarbon feedstocks with simultaneous introduction of

carbonyl functionality.

1.3 Reported methods for oxidative cleavage of alkenes

The oxidative cleavage of alkenes has been conventionally achieved mainly through two

principal approaches i.e. Ozonolysis [Bailey (1978); Larock (1999)] and Lemieux-Johnson

reaction [Shing et al. (1991)].

1.3.1 Conventional approaches

1.3.1.1 Ozonolysis

Ozonolysis has been used extensively in academic, research and industrial domains and it

involves the cleavage of an alkene or alkyne with O3 (ozone) to form organic compounds

R1

O

H

[O]R1

R2

R2

O

H

+

R1 R2

[O]

R1

O

R2

1,2-diarylalkene

1,1-diarylalkene

W here R 1 & R 2 = H, alkyl and Ar etc.

http://en.wikipedia.org/wiki/Alkene

http://en.wikipedia.org/wiki/Alkyne

http://en.wikipedia.org/wiki/Ozone


38

with carbonyl [Bailey and Erickson (1973); Claus and Schreiber (1990); Tietze and Bratz

(1998)] via the formation of ozonide intermediate through Criegee mechanism (Scheme 2).

The outcome of the reaction depends on the type of multiple bonds being oxidized and the

work up conditions. Oxidative workup results in the formation of acid along with ketone

while, reductive work up gives rise to aldehyde and ketone. Synthesis of (+) artemisinin via

Avery’s approach using ozone in the final step [Avery et al. (1992)] is a well known

example of ozonolysis. Inspite of immense applications, ozonolysis has generated grave

concerns due to the handling and health hazards related to ozone.

Scheme 2

1.3.1.2 Lemieux-Johnson reaction

In comparison to ozonolysis, the Lemieux-Johnson reaction involves two step methodology

(Scheme 3), i.e. dihydroxylation of the carbon-carbon double bond by the Lemieux-

Johnson reagent (sodium periodate-osmium tetraoxide) followed by cleavage into

Scheme 3

R'

RO

OsO

O

O

R'

R

R

R'

OH

OHNaIO4

O

IO

R'

R

O

OO

R H

O

R' H

O

2H2O

+

OsOO

OO

8+6+

IO

O

O_

_

OsOO

OHO_

5+

C C

R1

R2C C

R2 R3

HR1

O OO

OOO

H

R3

C C

R2 R3

HR1

O O

O

C

O

R2

C

O

R3

H

O

O O

O H

R3

R1

R2

O O

O H

R3

R1

R2

H2O2 C

R1

R2

OC

R1

R2

O CH

R3

O COH

R3

O

+

_+

R1

+

__

oxidative workupreductive workup

Zn(dust) in H2O+ +

ozonide

ozonide

molozonide

http://en.wikipedia.org/wiki/Oxygen

http://en.wikipedia.org/wiki/Dihydroxylation

http://en.wikipedia.org/wiki/Sodium_periodate


39

carbonyl compounds. However the strong oxidizing conditions associated with the above

protocol also enhances the probability of over oxidation into acids.

Lemieux-Johnson reaction has also been used in total synthesis of natural products like

isosteviol (Scheme 4) [Snider et al. (1998)] using sodium periodate-osmium tetraoxide.

Scheme 4

In spite of their immense utility, the ozonolysis and Lemieux-Johnson reaction are

considerable challenges in view of safety and over oxidation concerns. In particular, ozone

gas is highly toxic and its generation requires specialized equipment. Consequently, the

development of safer alternatives as well as conceptually newer olefinic cleavage

approaches has attracted increased attention.

1.3.2 Contemporary approaches for oxidative cleavage of alkenes

Travis et al. explored a mild, organometallic alternative to ozonolysis using OsO4 with

oxone as the co-oxidant in DMF, for oxidative cleavage of olefins to provide carboxylic

acids. Plausible mechanism involves the intermediacy of an osmate ester which undergoes

cleavage to provide the final oxidized product (Scheme 5) [Travis et al. (2002)].

Scheme 5

On the other hand, Yang et al. have successfully cleaved aryl olefins into aromatic

HO

O

OEt

HO

O

OEt

O

O

OH

O

OsO4, NaIO4

Isosteviol

R2R1

OsO4 (0.01 equiv.)

Oxone (4 equiv.)R1COOH + R2COOH

R2R1

OOOs

O OO O OSO3H

R1 and R2 = alkyl , aryl etc.

(DMF, 3h, RT)

intermediate

-

http://en.wikipedia.org/wiki/Sodium_periodate

http://en.wikipedia.org/wiki/Osmium_tetroxide


40

aldehydes rather than carboxylic acids, in excellent yields by using the system of RuCl3-

Oxone-NaHCO3 in CH3CN-H2O (1.5: 1) (Scheme 6) [Yang and Zhang (2001)].

Scheme 6

The current trend toward “clean and rapid” synthesis has lead to reagent immobilization to

enable easy recovery, reuse and disposal at an acceptable economic cost. In this context,

osmium tetraoxide microencapsulated in a polyurea matrix has been used as recyclable

catalyst in the dihydroxylation and the oxidative cleavage of olefins (Scheme 7) [Ley et al.

(2003)].

Scheme 7

Recently, Nicolaou et al. reported a one-pot combination of hydroxylation followed by the

addition of stoichiometric Ph(IOAc)2 to effect alkene cleavage in the presence of OsO4

(cat.) and 2,6-lutidine to yield the corresponding carbonyl compounds (Scheme 8). The

described synthetic method offers a convenient and economical alternative to the traditional

olefin cleavage methods for laboratory operations [Nicolaou et al. (2010)].

Scheme 8

R2 R3

R1

O

H R1 R2 R3

O

O

H R1 R2 R3

O

+

+

upto 90%

upto 98%

NMO (1.5 equiv), 2,6-lutidine (2.0equiv), acetone:H2O (10:1), then

PhI(OAc)2 (1.5 equiv), 25oC

PhI(OAc)2 (2.3 equiv), 2,6-lutidine(2.5 equiv), THF, 25oC

R1, R2, R3 = H, alkyl, aromatic etc.

R'

R R''

R R'

O2 mol% Os EnCat3eq. NaIO4

THF/H2O (2:1)rt, 1-8 h

Os EnCat = OsO4 microencapsulated in a polyurea matrix

(R, R', R'' = H, CH3, aryl etc.)

PhCHO

3.5 mol % RuCl31.5 eq. oxone, 4.7 eq. NaHCO3

CH3CN/H2O (1.5/1)

rt, pH 7-7.5, 0.5 h 85%Ph

Ph


41

Wang et. al. have reported a palladium catalyzed protocol with O2 as the sole oxidant for

efficient oxidation of a wide range of olefins into aldehydes or ketones (Scheme 9) [Wang

and Jiang (2010)].

Scheme 9

In another report, Ho et al. utilized heterogeneous recyclable catalyst comprising ruthenium

nanoparticles grafted onto hydroxyapatite for cis-dihydroxylation and oxidative cleavage of

alkenes (Scheme 10). The utility of protocol was demonstrated both on small and larger

scale [Ho et al. (2004)].

Scheme 10

Similarly, catalytic amounts of environmentally benign organo iodine reagent 4-IB Acid (4-

iodobenzoic acid) in the presence of oxone as a co-oxidant was employed for oxidative

cleavage of different alkenes (Scheme 11) [Thottumkara and Vinod (2010)].

Scheme 11

In the same vein, Xing et al. developed a unique gold catalysed homogeneous oxidation

process (Scheme 12) for cleavage of C=C bond to afford ketone or aldehyde products with

tertiary butyl hydrogen peroxide (TBHP) as the oxidant in water [Xing et. al. (2006)].

Pd(OAc)2, O2 (8 atm)

H2O, PTSACHO

24 h , 100oC

I

C OO H

I

C OO H

+OH

KHSO 4

_

R 2

R 3

H

R 1

Oxone

aq. Acetonitrile60oC aq. Acetonitrile

60oC

OxoneO

R 2

R 1

+ O

R 3

OH

R 1, R2, R 3 =H , aryl, alkyl etc.

CHO

nano RuHAP (Ru. cat.)

NaIO4/H2SO4


42

Scheme 12

In an another strategy, Singh et al. utilized m-chloroperbenzoic acid (Scheme 13) for the

oxidative cleavage of 1,1-diarylalkenes into benzophenone via the formation of epoxide

intermediate [Singh et al. (2009)].

Scheme 13

However, only a limited number of papers in the field of microbial alkene cleavage have

been published. In one such report, an enzymatic oxidative cleavage of alkene using the cell

free extract of Trametes hirsuta has also been reported (Scheme 14) [Lara et al. (2009)] in

the presence of O2.

Scheme 14

Recently, Sharma et al. have used newly isolated Pseudomonas mandelii KJLPB5 and

[hmim]Br for direct conversion of aryl alkene into corresponding one or two carbon

shorter aryl aldehydes in H2O2 through oxidative cleavage pathway (Scheme 15). The ionic

liquid was proposed to either act as activator or help in stabilization of enzymes [Sharma et

al. (2011)].

CHO

O

H

Cell free extract

Trametus hirsuta

O 2

R1

R2

R3

O R1

R2

R3

m-CPBA (addition -78oC)

rt, 90-180 min

R1= H, CH3 R2= H, CF3 R3= H, CH3, OH, F, Cl, Br etc.

R1

R2

H

R3

O

R1

R2

O

H

R3

+

AuCl (5mol%)1 (5mol%)

TBHP, H2O, 90oC

N N1

R1= C6H5R2= H, CH3, C6H5, 4-CH3C6H4, 4-FC6H4 etc.R3= H, CH3


43

Scheme 15

On the other hand, Schiaffo et al. developed a method for ozonolysis of alkenes in a

mixture of water and a miscible organic solvent for a fast, convenient and efficient one-pot

synthesis of aldehydes and ketones without the need for a separate reductive step and

further avoiding the need to isolate or decompose ozonides (Scheme 16) [Schiaffo and

Dussault (2008)].

Scheme 16

Shaikh et al. have explored inexpensive iron (III) chloride hexahydrate (FeCl3·6H2O, 5

mol%) catalyst in combination with commercially available aqueous 70% TBHP as oxidant

for the cleavage of olefins into acids. The method was suitable for a wide range of aromatic

olefins and alkynes that contain electron-donating and electron withdrawing functional

groups (Scheme 17) [Shaikh and Honga (2011)].

Scheme 17

Hart et al. described the oxidative cleavage of olefins with osmium tetraoxide using

hydrogen peroxide (H2O2) as the terminal oxidant. The protocol offered the corresponding

aldehyde and ketone products in moderate to excellent yields (Scheme 18) [Hart et al.

(2011)].

R2R1

O3/O2

5% H2O in acetone

O

R2R1

O

+

HCOOH

H2OO

R2R10oC

R1, R2 = Ph, CH3, H etc.

-

R2

R1 R1

O

HP. mandelii KJLPB5

[hmim]Br , H2O2, 37oC

Where R1= 4-OCH3, 4-Cl, 4-NO2, 2-Cl etc.R2=CH3, H etc.

RR'

NaOH, H2O, 80oC, 10h R

O

OHR R'

FeCl3.6H2O, aqueous 70% TBHP

Acidic work up

FeCl3.6H2O, aqueous 70% TBHP

Acidic work up R= arylR'=H, alkyl, aryl, allyllic

NaOH, H2O, 80oC, 10h


44

Scheme 18

Similarly, Yu et al. reported an improved procedure for oxidative cleavage of olefins by

OsO4-NaIO4. The addition of 2,6-lutidine was found to suppress the side reactions and

dramatically improved the yield of the reaction (Scheme 19) [Yu et al. (2004)].

Scheme 19

Yusubov et al. disclosed the oxidative transformations of alkenes and alkynes under the

action of diacetoxyiodobenzene (DIB) and found that non terminal alkenes behave in a

different manner. For instance oxidation of E-stilbene with the DIB-H2SO4 system (Scheme

20) gave a mixture of different products with little amount of benzophenone [Yusubov et

al. (2004)].

Scheme 20

Kim et al. elaborated a new chemoentrapment strategy for recycling osmium in the

catalytic olefin cleavage reaction. This approach utilizes KOH/i-PrOH to generate water-

R2

PhR1

PhCHO PhCOOH+

OsO4 (0.01 equiv.)50% H2O2 (4 equiv.)

DMF (20 or 0 equiv.)CH3CN (0.1M), rt

R1= H, CHO, COOH, CH2OH, COOMeR2= H, CH3

traces

Ph

Ph DIB (diacetoxyiodobenzene)-H2SO4 system

Ph

OH

O

Ph Ph

O

O

Ph

O

PhPh

Ph

O

HPhO

Ph

+

+ +Ph

-20oC, 5h

R

OsO4 (0.02 eq.), NaIO4 (4 eq.)

2,6-lutidine (2eq.), dioxane/water (3:1)RCHO

Where R =

Me

OBn

OPMB

Meor

O

O

OTBSetc.


45

soluble Os (VI) species as a recyclable metal catalyst after the oxidative cleavage reaction

(Scheme 21) [Kim et al. (2011)].

Scheme 21

It is evident from foregoing discussion that the above contemporary approaches for

oxidative cleavage have resulted in a significant improvement over classical protocols. It

would also be apparent that the substitution pattern around an olefinic bond largely

determines the nature of cleavage products. Thus, all of the above approaches cleave 1,2-

disubstituted alkenes into aldehydes while ketone cleavage products are usually obtained

only from respective 1,1-disubstituted alkenes (Scheme 1). However, a general approach

for the counterintutive one step formal scission of abundantly available 1,2-arylalkene and

diarylalkenes into one carbon shorter arylketones

instead of arylaldehydes has not yet been

disclosed although in few cases such a

transformation has been noticed as a side reaction

during oxidation of stilbenes [Yusubov et al.

(2004)] (Scheme 20). Moreover the 1,1-

diarylketones formed by the oxidative cleavage of C=C bond of 1,2-arylalkenes constitute

an important core structure of several biologically active molecules e.g. hydroxyphenstatin

(Figure 1), an anticancer benzophenone.

In this context, it would be highly desirable if an approach complementary to classical

ozonolysis & Lemieux-Johnson reaction could be devised leading to selective oxidative

cleavage of aryl- & 1,2-diarylalkenes into one-carbon shorter arylketones. Such a

methodology would provide a useful complementary tool to the prevalent approaches as it

considerably enhances the flexibility for cleaving an olefinic bond into either aldehydes or

ketones irrespective of the substitution pattern around a double bond.

RR'

OsO4

NaIO4

H2O, rt, 14 h

R H

O

R' H

OOsO4

Org.

NaIO4

NaIO3

R H

O

R' H

O

Org.

NaIO3

Aq. Aq.

OsO42-

Reducing agent

R, R' = H, Phenyl, Alkyl etc.

t-BuOH

O OH

OH

OMe

MeO

MeO

OMe

Figure 1. Hydroxyphenstatin


46

1.4 Results and Discussion

In the course of our programme towards catalytic synthesis of biologically important

phenolics [Kumar et al. (2008); Sharma et al. (2008), (2009), (2010)], we initially desired

to achieve a one step conversion of abundantly available aryl alkenes such as anethole, β-

asarone etc. into corresponding α-arylpropionic acids, which are constituents of non

steroidal anti-inflammatory drugs (NSAID’s) [Marnett and Blobaum (2007)]. In this

context, we planned to utilize our recently developed approach [Sharma et al. (2009)]

comprising direct oxidation of aryl alkenes into α-aryl aldehydes for an in situ oxidation

[Dvorak (1983); Yan and Zhang (2006)] of such aldehydes into respective α- substituted

arylalkanoic acids. Consequently, PDC (pyridinium dichromate) was chosen as the in situ

oxidizing agent due to its known ability to convert such α-substituted aryl aldehydes into

arylalkanoic acids. However,

contrary to our expectations,

the reaction of 1a (Table 1)

with N-iodosuccinimide (NIS,

1.3 eq), CTAB followed by

treatment with PDC (6 eq) in

same pot under microwave

(MW) provided a product

whose detailed GC-MS and

NMR investigations revealed it

to be one carbon shorter

acetophenone (1b, C6-C2 unit)

instead of the expected α-

arylpropionic acid (C6-C3 unit).

So the direct

oxyfunctionalization and

cleavage of even 1,2-

arylalkenes into ketones

instead of aldehydes prompted

us to further explore its scope

Entry Oxidant Amount ofoxidant (eq.)

Yield [b]

2

5

6

7

1

34

CH3

O

MeO MeOMW ( 115oC, 250W)

Same pot ii) Oxidant, Additive

Oxone

6

1.5

1.21.5

1.5

1.5

8

1.5

1.5

6

6

12

13

64

61

23

62

46

41

41

42

42

1.59

38

_

_

_

_

1a 1b

71

i) NIS, CTAB,Dioxane/Water (3:1)

PDC

PDC

PDC

PDC

PCC

Ag2O

H5IO6

TBAF

K2Cr2O7

TBHP

H2O2

15

18

14

16

17

1.5

1.5

1.5

1.5

1.5

76

78

79 (71)[c]

76

61

PDC

PDC

PDCPDC

PDC

20

19

3530PDC/H2O2

PDC/TBHP

10

11

3

0.05/6

0.05/6

1.5

Additive

CH3COOH

CH3COOHCH3COOH

CF3COOH

NaOH

L-Proline

Pyridine-2,5-dicarboxylic acid

29

traces

_

_

_

_

_

_

_

_

_

CrO3

Table 1. Optimization of conditions for oxidative cleavage of 1,2-aryl-alkenes into aryl ketone under focused microwave irradiation.[a]

[a] CEM monomode microwave. General conditions: 1a (1.35 mmol), NIS(1.75 mmol), CTAB (0.08 mmol) in dioxane (11 ml), water (3.7 ml) wereirradiated under MW (115oC, 250 W) for 15 min followed by cooling andaddition of oxidant, additive (2.0 mmol) and further MW for 15 min.[b] Based on GC-MS analysis. [c] Isolated yield of pure product.

Published in Eur. J. Org. Chem. 2010, 6025-6032.


47

and mechanistic pathway.

Consequently, a detailed optimization study (Table 1) was conducted to evaluate the effect

of various oxidizing agents and additives. Interestingly, the use of other well known

oxidizing agents like oxone, TBHP, H2O2 etc. didn’t proved beneficial for oxidative

cleavage of arylalkenes (Table 1, entries 6, 12-13). However, addition of a reduced amount

of PDC (1.5 eq) led to a significantly increased yield of 1b (71%, Table 1, Entry 3).

Amongst the various acidic/basic additives, the use of acetic acid led to further

improvement in reaction performance besides helping in work up of the reaction mixture

(Table 1, Entry 14).

The apparently counterintuitive cleavage of even 1, 2-disubstituted arylalkenes into aryl

ketones instead of aryl aldehydes implied a oxygenation-rearrangement-oxidative cleavage

pathway. Thus, arylalkene (a) is initially converted to corresponding α-arylaldehyde in the

presence of NIS/H2O (Figure 2, a'). Subsequently, the oxidation of this α-arylaldehyde into

one carbon shorter ketone can proceed through a number of intermediates [Perlman et al.

(1994); Clennan and Pan (2003); Bryant et al. (2004); Velosa et al. (2007)] including α-

arylacid [Rozner et al. (2007); Das et al. (2008)] and enol [Heathcock et al. (1985);

Perlman et al. (1994)] etc. Thus, the incipient α-arylaldehyde (a′) can undergo oxidation

into corresponding α-arylacid which is further converted into respective ketone through

oxidative decarboxylation (Figure 2). In order to evaluate the above possibility, the standard

acids i.e. Flurbiprofen (2-(2-fluorobiphenyl-4-yl) propanoic acid) or Ibuprofen (2-(4-(2-

methyl propyl)phenyl)propionic acid) were treated with PDC under identical conditions,

however, the corresponding ketones were not detected. In another alternative pathway, the

incipient α-arylaldehyde undergoes acid catalyzed enolization [Heathcock et al. (1985);

Perlman et al. (1994)] followed by PDC assisted oxidative cleavage into corresponding

RR

O

I

O-H

a a' b

NIS/H2O

O

CO2

O

CHO

COOH

R

R

R

O

RHO

Figure 2. Plausible mechanistic pathways for one pot oxidative cleavage of 1, 2-disubstituted arylalkenesinto one carbon shorter ketones (Published in Eur. J. Org. Chem. 2010, 6025-6032).


48

ketone (b) (Figure 2) [Rozner et al. (2007); Das et al. (2008)].

In order to further confirm the above mechanistic rationale, arylalkene (1a) was treated with

PDC/acetic acid alone in dioxane/water (3:1) under MW. Interestingly, the above reaction

afforded only methoxybenzaldehyde, thereby, clearly highlighting the critical role of

cascade pathway (Figure 2) in providing an exclusive access to ketone cleavage products.

Further, the role of MW [Kappe (2004)] was also evaluated by reaction of 1a under thermal

heating at similar temp., however, 1b was obtained in comparatively lower yield (55%)

with longer reaction times (6 h). It is pertinent to mention here that such a cleavage of

incipient α-arylaldehyde into respective one carbon shorter ketones has earlier been

observed using reagents like O2 (in combination with polyoxometalates/zeolite), ruthenium-

oxo complexes, peroxidises and PhI(OAc)2 etc.

The utility of above optimized protocol for cleavage of C=C double bonds was

subsequently ascertained. As would be evident from Table 2, various aromatic and

polyaromatic arylalkenes bearing electron donating/withdrawing groups (EDG’s/EWG’s)

underwent facile oxidative cleavage into corresponding aryl ketones instead of the aryl

aldehydes. Further, the arylalkene with elongated side chain (C6-C5 unit) was also found

Entry Substrate(a)

Product(b)

H3COH3CO

O

i) NIS, CTAB,

MW (115oC, 250W)R

R'R'

O

H3CO

H3CO

O

O

1

H3CO

OCH3

OCH3

H3CO

OCH3

OCH3

H3CO H3CO

O

Yield[b] (%)

1-15a 1-15b

O

OO

H3CO

H3CO

O

3

4

O

5

71

78

51

86

45[c]

2

OCH3 OCH3

Same pot ii) PDC, CH3COOH R = H, OMe, OH, OCH2O, Cl,C6H5, OC4H9 , OC6H13 etc.R' = CH3, CH2CH2CH3 etc.

Dioxane /Water (3:1)

R

Table 2. Oxidative cleavage of 1,2-arylalkenes into arylketones instead of arylaldehydesunder focused microwave irradiation.[a]

H3CO H3CO

O

6

67


49

to be compatible (Table 2, Entry 3) with the developed methodology. On the other hand,

the olefin possessing free phenolic group (Table 2, Entry 11) provided lower yield of

respective aryl ketone owing to probable polymerization besides formation of some side

products. Similarly, the relatively unactivated substrates like 1,1-disubstituted (Table 2,

Entry 14) and aliphatic alkenes (Table 2, Entry 15) also led to low or no reaction

performance presumably due to the reduced formation of corresponding α-substituted aryl

aldehydes in the first step as shown in figure 2.

Having successfully realized the oxidative cleavage approach, it was envisaged to further

explore the one pot halogenation-oxidative cleavage sequence. However, the in situ

reaction of 2b (obtained from oxidative cleavage of 2a) with NIS [Yadav et al. (2004)]

C4H9O

OCH3

O

C4H9O

OCH3

HO

OCH3

O

HO

OCH3

11

12

14[c]

76

O

C6H13O

OCH3

C6H13O

OCH3

13

O

O

14

15

48

12[c]

nd[c-d]

O

[a] CEM monomode microwave. General conditions: Substrate (0.9 mmol), NIS (1.18 mmol),CTAB (0.08 mmol) in dioxane (11 ml), water (3.7 ml) were irradiated under MW (115oC, 250W)for 15 min followed by cooling and addition of PDC (1.36 mmol), CH3COOH (1.36 mmol) andfurther MW for 15 min. [b] Yield of pure isolated product (single run). The structure of all productswas confirmed by NMR (1H & 13C) and HRMS analysis. [c] Based on GC-MS. [d] Not detected.

O

O

O

8

9

23

37

Cl10

30[c]

O

Cl

O

7 54



50

didn’t afford the expected 2-iodoacetophenone (2b′) (Scheme 22). Surprisingly, an

alternative approach proved fruitful, wherein, initial treatment of 2a with excess NIS

[Sharma et al. (2009)] followed by oxidative cleavage with PDC provided the expected

iodo derivative 2b′,

thereby, demonst-

rating the success-

ful incorporation of

both oxygen and

iodo groups in a

single operational

step (Scheme 22). Scheme 22. One-pot halogenation-oxidative cleavage of arylalkene

The success with 1,2-arylalkenes (Table 2) motivated us to explore an analogous

oxidative cleavage of 1,2-diaryl alkenes into corresponding diarylketones (benzophenones).

However, the developed protocol didn’t provide expected result as stilbenes (16-18a) were

selectively cleaved into benzaldehydes (Scheme 23).

Scheme 23. Selective oxidative cleavage of symmetrical and unsymmetrical 1,2- diarylalkenes into arylaldehydes

In the view of above result as well as the well known tendency of such diarylalkenes

towards cleavage into arylaldehydes, a reduced amount of PDC (0.8 eq.) was also tried but

to no avail. On the other hand, the use of other oxidizing agents like H2O2, TBHP, K2Cr2O7

etc. did provide desired benzophenone (19b, Table 3) but in low yields. Further, some

unreacted starting 1,2-diaryl alkene was also obtained using above reaction conditions.

Thereafter, detailed studies were conducted for identifying an oxidation system compatible

with such 1,2-diaryl alkenes. Interestingly, a combination of catalytic PDC (0.05 eq.),

i) NIS, CTAB,

MW (115oC, 250W)

Dioxane/ Water (3:1)

16-18c

Same pot ii) PDC, CH3COOH16-18a

CHOR2

R1

R3

R2

i) 16c, 69 % yieldii) 17c, 78 % yieldiii) 18c, 45 % yield + 5-Iodovanillin; (41% yield)

R1i) 16a , R1, R2, R3 = Hii) 17a, R1 = H, R2 = R3 = OMeiii) 18a, R1

, R3 = OMe, R2 = OH

R2

R1

O

R3

16-18b

NIS (1.3 eq.)PDC (1.5 eq.)

(i)

(ii)

NIS (4 eq.)

MeO

MeO

MeO

MeO

CHO

I

MeO

MeO

O

MeO

MeO

O

PDC (2.5 eq.)

I

XNIS (2.0 eq.)

2a

2b

2b' (24% overall yieldfrom two steps)

Same pot

Same pot


51

TBHP (6 eq.) along with an increased amount of NIS (2 eq. in place of 1.3 eq., Table 2)

and acetic acid (at the start) was required to overcome the initial sluggish conversion of

such diaryl substituted alkenes into corresponding iodohydrins (Figure 2) which finally

afforded the desired 19b (Table 3, Entry 19) in enhanced 49% yield. Subsequently, above

optimum reaction conditions were also found to be applicable on various unsubstituted,

electron rich and electron deficient 1,2-diaryl alkenes (Table 3, Entries 19-22 & 25-26)

Entry Substrate(a)

Product(b)

i) NIS, CTAB, CH3COOH

MW (115oC, 250W)

H3CO

H3CO

19-26b

21

20

OCH3

Same pot ii) Catal. PDC/TBHP

OCH3

OCH3

49

60

R1

R2

19

O

O

H3CO OCH3

O

H3CO

OCH3

OCH3

63

Yield[b] (%)

O

Dioxane/Water (3:1), MW

R1, R2 = H, OMe, OH , Cl etc.

R2R1

Table 3. Oxidative cleavage of 1,2-diarylalkenes into benzophenones instead ofbenzaldehydes under focused microwave irradiation[a]

O

O

OCH3

22

O

O

OCH3

67

H3CO

OCH3

H3CO

O

2329

OCH3

24

O

OCH3

H3CO

ClO

H3CO Cl

HO

OCH3

OCH3

HO

OCH3

O

OCH3

31

65

15[c]

25

O

26

OCH3

[a] CEM monomode microwave. General conditions: Substrate (0.79 mmol), NIS (1.5 mmol),CH3COOH (1.16 mmol), CTAB (0.08 mmol) in dioxane (11 ml), water (3.7 ml) were irradiatedunder MW (115oC, 250W) for 15 min followed by cooling and addition of PDC (0.04mmol)/TBHP (4.7 mmol), and further MW for 15 min. [b] Yield of pure isolated product (singlerun). The structure of all products was confirmed by NMR (1H & 13C) and HRMS analysis. [c]Based on GC-MS.(Published in Eur. J. Org. Chem. 2010, 6025-6032).


52

along with the substrates having aromatic or polyaromatic cores (Table 3, Entry 23 & 24).

It is pertinent to mention that the oxidative cleavage of olefins into benzophenones has

been earlier reported using only 1,1-diaryl substituted C=C double bonds. In this context,

the developed methodology affords the first direct scission of even 1,2-diaryl olefins into

corresponding benzophenones.

Having developed a new approach for oxidative cleavage of diverse arylalkenes, we were

intrigued to evaluate further applications of the developed methodology. In this context, we

were attracted by several reports of total synthesis of natural products, wherein, a two step

sequence of oxidative cleavage followed by condensation [Gwaltney II et al. (1996); Hayes

et al. (2006); Somu and Johnson (2006)] has comprised an important strategy. Consequently,

the realization of a one pot protocol for tandem oxidative cleavage-condensation would be

beneficial as it would eliminate isolation of intermediates [Somu and Johnson (2006)]. As a

proof of concept, 1a was subjected to developed oxidation protocol (Table 2) till formation of

1b (Table 2), and thereafter a base such as NaOH (10 %) and 2,4,5-trimethoxybenzaldehyde

Entry Substrate(a)

Benzaldehyde

i) NIS, CTAB, Dioxane/Water (3:1)

MW (115oC, 250W)

H3CO

29

27

28

O

O

30

Yield[b] (%)

H3CO

OCH3

OCH3

OCH3

31

Product(b)

O

H3CO Cl

O

H3CO Cl

Cl

O

H3CO Cl

OCH3

O

H3CO OCH3

OCH3

OCH3

O

O

O

Cl

R1 = R2 = H, OMe, Cl etc.

O

R1 Same pot iii) Benzaldehyde, NaOH, MeOH

ii) PDC, CH3COOH

27-37b R2R1

60

56

34

52

68

1a

(1a)

(2a)

(4a)

ClCl

CHO

H3CO

CHO

Cl

CHO

CHO

Cl

CHO

Cl

Table 4. One pot oxidative cleavage-condensation of arylalkenes with benzaldehydesunder focused microwave irradiation[a]

1a

(a)


53

(1.3 eq) was added to the same pot and stirred for 2 h (Table 4). Gratifyingly, this one pot

approach proved useful to directly obtain the condensation product (27b) from corresponding

arylalkene (1a) in 56% overall yield (Table 4, Entry 27). Later on, the above one pot strategy

was also successfully applied for hitherto unknown route to one pot oxidation-condensation

of arylalkenes (Table 4). Further various condensation products (Table 4, 28-37) along with

some heteroaromatic moieties (Entries 32-37) have also been synthesized.

1.5 Conclusion

In conclusion, a new oxidative cleavage approach has been developed which affords for the

first time a selective scission of 1,2-disubstituted alkenes into one carbon shorter ketones

using NIS and PDC/TBHP as co-oxidants. The methodology considerably enhances the

flexibility for cleaving a 1,2-disubstituted olefinic bond into either ketones or aldehydes.

Moreover, the reaction showed wide substrate scope as diverse 1,2-arylalkenes as well as

O

H3CO

OCH3

N33 14

H

2a

O

O

O

N BrNBr

CHO

[a] CEM monomode microwave. General conditions: Substrate (1.35 mmol), NIS (1.75mmol), CTAB (0.08 mmol), dioxane (11 ml), water (3.7 ml) were irradiated under MW(250W, 115oC) for 15 min followed by cooling and additon of PDC (2.0 mmol). CH3COOH(2.0 mmol) and further MW for 15 min thereafter added 10% NaOH (5-8 ml) andmethanolic solution (2-3 ml) of benzaldehyde (1.48 mmol) and stirred for 2 h.[b] Overall yield of pure isolated product from arylalkene (single run).

35 51

37

36

O

H3COS CHO

S

49

50

O

H3CO

O

O CHO

4a

1a

1a

O

CHO

34 524a

O

O

O

O

HN

CHO

32

O

H3CO

OCH3

48S CHO

S2a



54

1,2-diaryl alkenes bearing electron donating or withdrawing groups underwent facile

cleavage into corresponding arylketones. Significantly, the protocol also paved way for the

synthesis of chalcones and some hetroaromatic chalcones through valuable one pot

oxidative cleavage-condensation reaction which has widespread utility in total synthesis of

natural products.

1.6 Experimental Section

1.6.1 General

β-asarone was obtained from natural Acorus calamus oil following our earlier reported

procedure [Sinha et al. (2002)]. The naphthyl and stilbene derivatives were prepared

through a previously reported Grignard–dehydration [Kumar et al. (2008)] or Heck

approach [Plevyak and Heck (1978)] respectively. The rest of the arylalkenes and NIS (N-

iodosuccinimide) were reagent grade (purchased from Merck and Aldrich). Glacial acetic

acid (99-100 % for synthesis), PDC (pyridinium dichromate) and other oxidants were

purchased from either Merck or Aldrich and used as supplied. The solvents used for

isolation/purification of compounds were obtained from commercial sources (Merck) and

used without further purification. Column chromatography was performed using silica gel

(Merck, 60-120 mesh size). 1H (300 MHz) and 13C (75.4 MHz) NMR spectra were

recorded on a Bruker Avance-300 spectrometer. The following abbreviations were used to

designate chemical shift multiplicities: s = singlet, d = doublet, dd = double doublet, t =

triplet, m = multiplet, q = quartet. HRMS-ESI spectra were determined using micromass Q-

TOF ultima spectrometer. GC-MS analysis was carried out on Shimadzu MS-QP-2010

system equipped with a stationary phase DB-5MS column (Agilent Technologies, U.S.A.).

CEM Discover© focused microwave (2450 MHz, 300W) was used wherever mentioned.

The temperature of reactions in microwave heating experiments was measured by an inbuilt

infrared temperature probe that determined the temperature on the surface of reaction flask.

The sensor is attached in a feedback loop with an on-board microprocessor to control the

temperature rise rate. In the case of conventional heating in oil bath, the temperature of

reaction mixture was monitored by an inner thermometer.


55

1.6.2 Optimization of reaction conditions

1.6.2.1 One pot cascade oxidative cleavage of p-methoxyphenylpropene (1a) into one

carbon shorter 4′-methoxyacetophenone using NIS/PDC as an oxidizing agent (Table

1, Entry 1)

The p-methoxyphenylpropene (1a, 1.35 mmol) was treated with NIS (1.75 mmol), CTAB

(0.08 mmol) in dioxane (11ml), water (3.7 ml) was conducted under focused microwave

system (250W, 115oC) for 15 min followed by treatment with PDC (6 eq) in same pot

under microwave (250W, 115oC) for 15 min. The above mixture was cooled, washed with

saturated aq. Na2S2O3 solution (1x10 ml) and extracted with ethyl acetate (3x20 ml). The

combined organic layer was washed with brine (1x10 ml), dried over Na2SO4 and vacuum

evaporated. The obtained residue was subsequently purified by column chromatography on

silica gel (60-120 mesh size) using hexane:ethylacetate (9.3:0.7) to give a product (light

yellow solid, 41% yield) whose detailed GC-MS and NMR investigations revealed it to be

4′-methoxyacetophenone (1b) instead of the expected α-arylpropionic acid.

4′-methoxyacetophenone (1b, Table 1)

Light yellow solid, m.p. 35-39°C (lit. m.p. 36-38°C) [Ohno et al. (2004)], 1H NMR (300

MHz, CDCl3); (ppm) 7.93 (2H, d, J = 7.8 Hz), 6.93 (2H, d, J = 8.2 Hz), 3.84 (3H, s),

2.53 (3H, s); 13C NMR (75.4 MHz, CDCl3); (ppm) 195.6, 162.7, 130.6, 130.3, 113.7, 56.4

and 28.1.

1.6.2.2 One pot cascade oxidative cleavage of p-methoxyphenylpropene (1a) into one

carbon shorter 4′-methoxyacetophenone using varying amounts of PDC (Table 1,

Entries 2-4) as an oxidizing agent

To a stirred mixture of p-methoxyphenylpropene (1a, 0.2 g, 0.9 mmol) and dioxane (11ml),

water (3.7 ml), CTAB (0.03g, 0.08 mmol) and NIS (0.26 g, 1.18 mmol) were added and the

mixture was allowed to stir for 5 min at room temperature. Subsequently, the flask was

irradiated under focused microwave system (250W, 115oC) for 15 min. Thereafter, the

above reaction flask was cooled and varying amounts of PDC (3 or 1.5 or 1.2 equiv.

H3CO

O


56

respectively) were added and further irradiated under microwave (250W, 115oC) for 15

min. The above mixture was cooled, washed with saturated aq. Na2S2O3 solution (1x10 ml)

and extracted with ethyl acetate (3x20 ml). The combined organic layer was washed with

brine (1x10 ml), dried over Na2SO4 and vacuum evaporated and obtained residue subjected

to GCMS analysis. The above experiments provided 1b in 64, 71 and 61% yields in the

case of 3, 1.5 and 1.2 eq of PDC respectively. Thus, 1.5 equiv. of PDC was found to be the

appropriate.

1.6.2.3 One pot cascade oxidative cleavage of 1a into 1b using different oxidizing agent

(Table 1, Entries 5-13)

The reactions were performed in the same manner as given in section 1.6.2.2 with PCC,

oxone, Ag2O, H5IO6, TBAF, CrO3 and K2Cr2O7 replacing PDC in equal molar amounts in

each case, while in case of TBHP and H2O2, 6 equivalents of each were utilized. The above

reactions upon completion followed by work up as given in section 1.6.2.2 and followed by

GCMS analysis provided 1b in 42, 38, 42, 29, traces, 23, 62, 46 and 41% yields in the each

case respectively.

Thus, PDC (Table 1, Entry 3) was found to be the optimum oxidizing agent and used in all

the subsequent experiments.

1.6.2.4 One pot cascade oxidative cleavage of 1a to 1b using PDC and different acidic

and basic additives (Table 1, Entries 14-18)

The reactions were performed in the same manner as given in section 1.6.2.2 except that

(2.0 mmol) of CH3COOH, CF3COOH, NaOH, L-Proline or pyridine-2,5-dicarboxylic acid

were added in the second step of each case. The above reactions upon completion followed

by work up and GCMS analysis as given in section 1.6.2.2 provided 1b in 79 (71% after

column purification), 76, 61, 78 and 76% yields in each case respectively. Thus,

CH3COOH was found to be the effective additive and used in all the subsequent

experiments.

1.6.2.5 One pot cascade oxidative cleavage of 1a to 1b using H2O2 and TBHP as co-

oxidant with PDC using CH3COOH as additive (Table 1, Entries 19 & 20)

The reactions were performed in the same manner as given in section 1.6.2.2 except that

PDC (0.05 equiv.) was used along with H2O2 and TBHP (6 equiv. of each) as co-oxidants


57

and acetic acid (2.0 mmol) as additive. The above reactions upon completion followed by

work up and GCMS analysis as given in section 1.6.2.2 provided 1b in 30 and 35% yields

respectively.

1.6.2.6 Optimized procedure for one pot cascade oxidative cleavage of 1a to 1b using

PDC as oxidising agent with CH3COOH as additive (Table 2)

To a stirred mixture of p-methoxyphenylpropene (Table 2, Entry 1, 0.2 g, 0.9 mmol) and

dioxane (11ml), water (3.7 ml), CTAB (0.03g, 0.08 mmol) and NIS (0.26 g, 1.18 mmol)

were added and the mixture was allowed to stir for 5 min at room temperature.

Subsequently, the flask was irradiated under focused microwave system (250W, 115oC) for

15 min. Thereafter, the above reaction flask was cooled then acetic acid (0.08 ml, 1.36

mmol), PDC (0.51 g, 1.36 mmol) were added and further irradiated under microwave

(250W, 115oC) for 15 min. The above mixture was cooled, washed with saturated aq.

Na2S2O3 solution (1x10 ml) and extracted with ethyl acetate (3x20 ml). The combined

organic layer was washed with brine (1x10 ml), dried over Na2SO4 and vacuum evaporated.

The obtained residue was subsequently purified by column chromatography on silica gel

(60-120 mesh size) using hexane: ethylacetate (9.3:0.7) to give 1-(4-

methoxyphenyl)ethanone (1b) as light yellow solid in 71% yield, m. p. 35-39°C.

The above procedure was also followed for oxidative cleavage of all the other

arylalkenes (Table 2, 2-14a) into corresponding product (Table 2, 2-14b)

3', 4'- Dimethoxyacetophenone (2b, Table 2)

White solid, m.p. 48-50°C (lit. m.p. 49-51°C) [Jiang and Ragauskas (2007)], 1H NMR (300

MHz, CDCl3); (ppm) 7.56 (1H, d, J = 8.6 Hz), 7.49 (1H, s), 6.87 (1H, d, J = 8.6 Hz),

3.92 (6H, s), 2.54 (3H, s); 13C NMR (75.4 MHz, CDCl3); (ppm) 197.2, 153.8, 149.6,

131.1, 123.7, 110.7, 56.5 and 26.6.

H3CO

H3CO

O


58

1-(3, 4-Dimethoxyphenyl)- 1-butanone (3b, Table 2)

White solid, m.p. 65-68°C, 1H NMR (300 MHz, CDCl3); (ppm) 7.60 (2H, t, J = 9.2 Hz),

6.90 (1H, s), 3.94 (6H, s), 2.92 (2H, t, J = 7.1 Hz), 1.80-1.72 (2H, m), 1.03 (3H, t, J = 7.9

Hz); 13C NMR (75.4 MHz, CDCl3); (ppm) 199.4, 153.5, 149.4, 130.8, 123.0, 110.6,

56.4, 40.4, 18.5 and 14.6.

3', 4'- (Dioxymethylene) acetophenone (4b, Table 2)

White solid, m.p. 84-87°C (lit. m.p. 86–89°C) [Giddens et al.(2005)] ; IR (KBr): 1663 cm-1

(C=O); 1H NMR (300 MHz, CDCl3); (ppm) 7.57 (1H, d, J = 8.2 Hz), 7.43 (1H, s), 6.86

(1H, d, J = 8.2 Hz), 6.05 (2H, s), 2.54 (3H, s); 13C NMR (75.4 MHz, CDCl3); (ppm)

197.1, 152.7, 149.1, 133.1, 125.7, 108.9, 108.8, 102.8, and 27.4.

1-(6'-Methoxy-2'-naphthyl)ethanone (6b, Table 2)

White solid, m.p. 63-66°C, 1H NMR (300 MHz, CDCl3); (ppm) 8.37 (1H, s), 8.01 (1H,

d, J = 8.4), 7.84 (1H, d, J = 8.7), 7.76 (1H, d, J = 8.7), 7.21 (1H, d, J = 8.7), 7.14 (1H, s),

3.92 (3H, s), 2.69 (3H, s) ; 13C NMR (75.4 MHz, CDCl3); (ppm) 198.2, 160.2, 137.7,

133.0, 131.5, 130.1, 128.2, 127.5, 125.0, 120.3, 106.5, 55.8 and 26.9. HRMS-ESI: m/z

[M+H]+ for C13H12O2, calculated 201.0894; observed 201.0882.

1-Naphthyl methyl ketone (7b Table 2)

H3CO

O

OCH3

O

H3CO

O

O

O

O


59

Light yellow liquid, [Yao et al. (2003)], 1H NMR (300 MHz, CDCl3); (ppm) 8.78 (1H, d,

J = 8.7), 8.00-7.83 (3H, m), 7.63-7.46 (3H, m), 2.74 (3H, s); 13C NMR (75.4 MHz, CDCl3);

(ppm) 202.2, 135.8, 134.4, 133.4, 130.6, 129.1, 128.8, 128.4, 126.8, 126.4, 124.7 and

30.3.

4-Acetylbiphenyl (8b Table 2)

Creamish solid, m.p. 116-119°C (lit. m.p. 117-120°C), [Balasankar et al. (2005)], 1H NMR

(300 MHz, CDCl3); (ppm) 8.26 (2H, t, J = 8.8 Hz), 7.96-7.92 (4H, m), 7.74 (3H, t, J =

8.8 Hz), 2.90 (3H, s) ; 13C NMR (75.4 MHz, CDCl3); (ppm) 197.8, 145.8, 139.9, 135.9,

129.0, 128.3, 127.3 and 14.2.

Acetophenone (9b, Table 2)

Colourless liquid, 1H NMR (300 MHz, CDCl3); (ppm) 8.14 (2H, d, J = 8.0 Hz), 7.74

(1H, dd, J = 6.0, 8.0), 7.64 (2H, dd, J = 7.8, 6.7), 2.75 (3H, s) ; 13C NMR (75.4 MHz,

CDCl3); (ppm) 197.5, 137.1, 132.7, 128.2, 127.9 and 26.1.

4'-Butoxy-3'-methoxyacetophenone (12b, Table 2)

Creamish solid, m.p. 35-37°C; IR (KBr): 1674 cm-1 (C=O), 1H NMR (300 MHz, CDCl3);

(ppm) 7.66 (2H, t, J = 6.5 Hz), 7.08 (1H, s), 4.30 (2H, t, J = 7.1 Hz), 4.07 (3H, s), 2.78

(3H, s), 2.12-2.04 (2H, m), 1.79-1.67 (2H, m), 1.23 (3H, t, J = 6.7Hz); 13C NMR (75.4

MHz, CDCl3); (ppm) 197.0, 153.1, 149.4, 130.4, 123.4, 111.2, 110.6, 68.9, 56.2, 31.1,

26.3, 19.3 and 14.0. HRMS-ESI: m/z [M+H]+ for C13H18O3, calculated 223.1302; observed

O

O

O

OCH 3

O


60

223.1315.

4'-Hexoxy-3'-methoxyacetophenone (13b, Table 2 )

Transparent viscous liquid, 1H NMR (300 MHz, CDCl3); (ppm) 7.62 (2H, d, J = 7.6 Hz),

6.98 (1H, t, J = 9.5 Hz), 4.17 (2H, d, J = 6.9 Hz), 4.01 (3H, s), 2.65 (3H, s), 1.94 (2H, s),

1.54-1.35 (6H, m), 0.97 (3H, s); 13C NMR (75.4 MHz, CDCl3); (ppm) 197.5, 153.7,

150.0, 130.9, 123.9, 111.8, 111.2, 69.8, 56.7, 32.2, 29.6, 26.0, 25.4, 23.2 and 14.7. HRMS-

ESI: m/z [M+H]+ for C15H22O3, calculated 251.1614; observed 251.1628.

1.6.2.7 Representative procedure for one pot halogenation-oxidative cleavage of 3,4-

dimethoxyphenylpropene into 1-(2-Iodo-4,5-dimethoxyphenyl) ethanone (2b', Scheme

22) :

To a stirred mixture of 3,4-dimethoxyphenylpropene (2a, 0.2 g, 1.1 mmol) in dioxane

(11ml), water (3.7 ml) added CTAB (0.03 g, 0.08 mmol) and NIS (1.0 g, 4.44 mmol) and

the reaction mixture was allowed to stir for 5 min at room temperature. Subsequently the

flask was irradiated under focused microwave system (250W, 115oC) for 15 min.

Thereafter, reaction flask was cooled, acetic acid (0.096 ml, 1.66 mmol), PDC (1.05g, 2.79

mmol) were added and further irradiated under microwave (250W, 115oC) for 15 min. The

above mixture was cooled, washed with saturated aq. Na2S2O3 solution (1x10 ml) and

extracted with ethyl acetate (3x20 ml). The combined organic layer was washed with brine

(1x10 ml), dried over Na2SO4 and vacuum evaporated. The residue was purified by column

chromatography on silica gel (60-120 mesh size) using hexane: ethylacetate (9.3:0.7) to

give 1-(2-Iodo-4, 5-dimethoxyphenyl) ethanone (2b', 0.082 g, 24 % yield).

1-(2-Iodo-4, 5-dimethoxyphenyl) ethanone (2b', Scheme 22)

O

H3CO

OCH3

I

O

O

OCH 3


61

Yellow viscous liquid, 1H NMR (300 MHz, CDCl3); (ppm) 7.34 (1H, s), 7.12 (1H, s),


135.9, 123.9, 112.9, 81.9, 56.7 and 55.8. HRMS-ESI: m/z [M+H]+ for C10H11O3I,

calculated 306.9879; observed 306.9826.

1.6.2.8 Representative procedure for selective oxidative cleavage of 1,2-diaryl alkenes

(16a, Scheme 23) into corresponding benzaldehydes

To a stirred mixture of trans- stilbene (16a, 0.2 g, 1.1 mmol) and dioxane (11 ml), water

(3.7 ml), CTAB (0.03 g, 0.08 mmol ), NIS (0.5g, 2.2 mmol) and acetic acid (0.095 ml, 1.66

mmol) were added and the reaction mixture was allowed to stir for 3-4 hr at room

temperature. Subsequently the flask was irradiated under focused microwave system

(250W, 115oC) for 15 min. Thereafter, reaction flask was cooled, PDC (0.63g, 1.67 mmol)

was added and further irradiated under microwave (250W, 115oC) for 15 min. The above

mixture was cooled, washed with saturated aq. Na2S2O3 solution (1x10 ml) and extracted

with ethyl acetate (3x20 ml). The combined organic layer was washed with brine (1x10

ml), dried over Na2SO4 and vacuum evaporated. The GCMS analysis of residue revealed in

it 69% benzaldehyde (16c, Scheme 23).

The above procedure was also applied on other symmetrical and unsymmetrical 1, 2

diaryl alkenes (Scheme 23, 17a –18a) and products (17c-18c) confirmed through

GCMS analysis.

1.6.2.9 Representative procedure for cascade oxidative cleavage of trans-stilbene into

corresponding benzophenones

To a stirred mixture of trans-stilbene (19a, 0.2 g, 0.79 mmol) and dioxane (11 ml), water

(3.7 ml), CTAB (0.03 g, 0.08 mmol), NIS (0. 35 g, 1.5 mmol) and acetic acid (0.07 ml,

1.16 mmol) were added and the reaction mixture was allowed to stir for 3-4 hr at room

temperature. Subsequently, the flask was irradiated under focused microwave system

(250W, 115oC) for 15 min. Thereafter, the reaction flask was cooled, PDC (0.015g, 0.04

mmol), TBHP (0.45ml, 4.7 mmol) were added and further irradiated under microwave

(250W, 115oC) for 15 min. The above mixture was cooled, washed with saturated aq.

Na2S2O3 solution (1x10 ml) and extracted with ethyl acetate (3x20 ml). The combined


62

organic layer was washed with brine (1x10 ml), dried over Na2SO4 and vacuum evaporated.

The obtained residue was subsequently purified by column chromatography on silica gel

(60-120 mesh size) using hexane: ethylacetate (9.3:0.7) to give benzophenone (19b, Table

3) (49% yield).

Benzophenone (19b, Table 3)

White solid, m.p. 46-48°C (lit. m.p. 47-48°C) [Rao et al. (2009)]; IR (KBr): 1651 cm-1

(C=O), 1H NMR (300 MHz, CDCl3); (ppm) 8.02 (4H, d, J = 6.2 Hz), 7.80-7.68 (6H, m); 13C NMR (75.4 MHz, CDCl3); (ppm) 197.5, 138.4, 133.2, 130.8 and 129.0.

The above procedure was also used for oxidative cleavage of all the other 1,2-diaryl

alkenes (Table 3, Entries 20-26)

4, 4'-Dimethoxybenzophenone (20b, Table 3)

White solid, m.p. 135-137°C, [Rao et al. (2009)], IR (KBr): 1636 cm-1 (C=O); 1H NMR

(300 MHz, CDCl3); (ppm) 7.80 (4H, d, J = 9.5 Hz), 6.98 (4H, d, J = 7.5 Hz), 3.89 (6H,

s); 13C NMR (75.4 MHz, CDCl3); (ppm) 194.8, 163.2, 132.6, 131.3, 113.9 and 55.8.

HRMS-ESI: m/z [M+H]+ for C15H14O3, calculated 243.1016; observed 243.1026.

3, 4, 4'-Trimethoxybenzophenone (21b, Table 3)

White solid, m.p. 57-60°C, 1H NMR (300 MHz, CDCl3); (ppm) 7.81 (2H, d, J = 8.7

Hz), 7.44 (1H, s), 7.38 (1H, d, J = 9.1 Hz), 6.98 (3H, m), 3.96 (3H, s), 3.94 (3H, s), 3.89

(3H, s); 13C NMR (75.4 MHz, CDCl3); (ppm) 194.5, 162.9, 152.7, 149.0, 132.3, 130.2,

124.9, 114.3, 112.4, 109.9, 56.1 and 55.4. HRMS-ESI: m/z [M+H]+ for C16H16O4,


O

OCH3H3CO

H3CO

O

OCH3H3CO

O


63

3-4-Dioxymethylene-4'-methoxybenzophenone (22b, Table 3)

White solid, m.p. 96-98°C, 1H NMR (300 MHz, CDCl3); (ppm) 7.80 (2H, d, J = 9.7 Hz),

7.33 (2H, d, J = 9.3 Hz), 7.00 (2H, d, J = 9.7 Hz), 6.95 (1H, d, J = 8.0 Hz), 6.07 (2H, s),

3.89 (3H, s); 13C NMR (75.4 MHz, CDCl3); (ppm) 194.4, 163.3, 151.5, 148.2, 132.9,

132.6, 131.0, 126.6, 113.9, 110.3, 108.0, 102.1 and 55.9. HRMS-ESI: m/z [M+H]+ for

C15H12O4, calculated 257.0808 observed 257.0816.

(6- Methoxy-2-naphthalen-2yl) (4′-methoxyphenyl) methanone (23b, Table 3)

White solid, m.p. 128-131°C; IR (KBr): 1645cm-1 (C=O), 1H NMR (300 MHz, CDCl3);

(ppm) 8.20 (1H, s), 7.89-7.81 (5H, m), 7.23 (2H, d, J = 8.4 Hz), 7.01 (2H, d, J = 7.6 Hz),


137.1, 133.7, 132.8, 131.6, 131.2, 128.0, 127.3, 127.0, 120.0, 113.9, 106.1, 60.8 and

55.8. HRMS-ESI: m/z [M+H]+ for C19H16O3, calculated 293.1310; observed 293.1382.

1-(2-Naphthyl )-4′-methoxyphenylmethanone (24b, Table 3 )

Yellow viscous liquid, 1H NMR (300 MHz, CDCl3); (ppm) 8.30 (1H, d, J = 9.7 Hz),

8.00-7.80 (5H, m), 7.61-7.52 (2H, m), 7.26-7.19 (3H, m), 3.96 (3H, s); 13C NMR (75.4

MHz, CDCl3); (ppm) 198.5, 160.3, 139.1, 138.9, 132.8, 131.7, 130.6, 128.9, 127.6,

127.2, 120.4, 106.4 and 56.1. HRMS-ESI: m/z [M+H]+ for C18H14O2, calculated

263.1066; observed 263.1065.

O

OCH3

O

O

O

OCH3H3CO

O

OCH3


64

4-Chloro- 4'- methoxybenzophenone (25b Table 3 )

White solid, m.p. 111-115°C, [Rao et al. (2009)], IR (KBr): 1637 cm-1 (C=O), 1H NMR

(300 MHz, CDCl3); (ppm) 7.80 (2H, d, J = 8.9 Hz), 7.71 (2H, d, J = 8.6 Hz), 7.45 (2H,

d, J = 8.9 Hz), 6.97 (2H, d, J = 9.1 Hz), 3.89 (3H, s); 13C NMR (75.4 MHz, CDCl3);

(ppm) 194.2, 163.5, 138.3, 136.7, 132.5, 131.2, 130.0, 128.6, 113.8 and 55.6. HRMS-ESI:

m/z [M+H]+ for C14H11ClO2,calculated 247.0520 observed 247.0519.

1.6.2.10 Representative procedure for one pot oxidative cleavage-condensation of 4-

(methoxyphenyl)propene with 2,4,5-trimethoxybenzaldehyde (Table 4, 27b)

To a stirred mixture of 1a (0.2 g, 1.35 mmol) and dioxane (11ml), water (3.7 ml), CTAB

(0.03 g, 0.08 mmol), NIS (0.395 g, 1.75 mmol) were added and the reaction mixture was

allowed to stir for 5 min at room temperature. Subsequently, the flask was irradiated under

MW (250W, 115oC) for 15 min followed by addition of acetic acid (0.12 ml, 2.0 mmol),

PDC (2.0 mmol) and further MW (250W, 115oC) for 15 min. Thereafter, the reaction

mixture was filtered and 5-8 ml of 10% sodium hydroxide (till basic conditions) along with

a methanolic solution (2-3 ml) of 2,4,5-trimethoxybenzaldehyde (0.29 g, 1.48 mmol) were

added. The reaction mixture was allowed to stir for 2 hr after which it was washed with

saturated aq. Na2S2O3 solution (1x10 ml) and extracted with ethyl acetate (3x20 ml). The

combined organic layer was washed with brine (1x10 ml), dried over Na2SO4 and vacuum

evaporated to obtain a crude mixture which upon addition of methanol, led to precipitation

of condensation product (27b, 0.24 g, 56% yield).

1-(4′-Methoxyphenyl)-3-(2,4,5-trimethoxyphenyl)- 2-propen-1-ones (Table 4, 27b)

O

OCH3Cl

O

H3CO

OCH3

OCH3

OCH3


65

Light yellow solid, m.p. 107-110°C, 1H NMR (300 MHz, CDCl3); (ppm) 8.10-8.00 (3H,

m), 7.50 (1H, d, J = 16.6 Hz), 7.12 (1H, s), 6.96 (1H, d, J = 8.0 Hz), 6.50 (1H, s), 3.87 (3H,

s), 3.85 (6H, s), 3.84 (3H, s); 13C NMR (75.4 MHz, CDCl3); (ppm) 189.6, 163.5, 154.9,

151.8, 143.1, 139.6, 132.0, 130.8, 120.5, 116.5, 114.1, 112.0, 97.1, 57.3, 57.0, 56.3 and


The above procedure was also used for the one pot oxidative cleavage-condensation of

all the other arylalkenes (Table 4, 28-31b)

3-(4-Chlorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one, [Dong et al. (2008)] (Table

4, 28b)

Creamish solid, m.p. 128-131°C, 1H NMR (300 MHz, CDCl3); (ppm) 7.97 (2H, d, J = 9.3

Hz), 7.69 (1H, d, J = 16.2 Hz), 7.50 (2H, d, J = 8.1 Hz), 7.46 (1H, d, J = 16.2 Hz), 7.31

(2H, d, J = 8.1 Hz), 6.92 (2H, d, J = 8.7 Hz), 3.81 (3H, s); 13C NMR (75.4 MHz, CDCl3);

(ppm) 188.4, 163.5, 142.4, 136.1, 133.6, 130.8, 129.5, 129.2, 122.3, 113.9 and 55.5.

3-(2,4-Dichlorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one, [Liu et al. (2001)] (Table

4, 29b)

White solid, m.p. 134-137°C, 1H NMR (300 MHz, CDCl3); (ppm) 8.09-8.00 (3H, m),

7.67 (1H, d, J = 8.0 Hz), 7.49 (1H, d, J = 15.8 Hz), 7.43 (1H, s), 7.28 (1H, d, J = 8.4 Hz),

6.98 (2H, d, J = 8.2 Hz), 3.88 (3H, s); 13C NMR (75.4 MHz, CDCl3); (ppm) 188.4, 164.0,

138.6, 136.5, 136.2, 132.4, 131.3, 131.0, 130.4, 128.8, 127.8, 125.2, 114.3 and 55.8.

3-(4-dichlorophenyl)-1-(3, 4-dimethoxyphenyl)prop-2-en-1-one (Table 4, 30b)

O

H3CO Cl

OCH3

O

H3CO Cl

O

H3CO ClCl


66


Hz), 7.71 (1H, d, J = 8.9 Hz), 7.64-7.51 (4H, m), 7.42 (1H, d, J = 8.0Hz), 6.96 (1H, d, J =

8.2 Hz), 3.99 (6H, s); 13C NMR (75.4 MHz, CDCl3); (ppm) 188.6, 153.8, 149.8, 142.8,

136.6, 134.0, 131.6, 129.9, 129.6, 123.4, 122.5, 111.2, 110.4 and 56.5.

1-(4′-Chlorophenyl)-3-(3,4-dioxymethylenephenyl)- 2-propen-1-ones (Table 4, 31b)


Hz), 7.57 (1H, d, J = 8.0 Hz), 7.49-7.44 (3H, m), 7.40 (1H, d, J = 15.7 Hz), 7.31 (2H, d, J

= 8.4 Hz), 6.82 (1H, d, J = 8.0 Hz), 5.98 (2H, s); 13C NMR (75.4 MHz, CDCl3); (ppm)

187.9, 151.8, 148.3, 142.7, 136.2, 133.5, 132.8, 129.5, 129.2, 124.7, 122.1, 108.4, 107.9

and 101.9. HRMS-ESI: m/z [M+H]+ for C16H11ClO3, calculated 287.0469; observed

287.0467.

The above procedure was also successfully followed for the synthesis of

heteroaromatic based chalcones (32b-37b) (Table 4).

1-(3,4-dimethoxyphenyl)-3-(thiophen-2-yl)prop-2-en-1-one (Table 4, 32b)

Light yellow solid, m.p. 97-98 °C, 1H NMR (300 MHz, CDCl3); (ppm) 7.97 (1H, d, J=

15.3 Hz), 7.68 (1H, d, J= 8.4 Hz), 7.62 (1H, s) 7.41-7.33 (3H, m), 7.01 (1H, t, J= 4.2 Hz),

6.94 (1H, d, J= 8.3 Hz), 3.97 (6H, s); 13C NMR (75.4 MHz, CDCl3); (ppm) 188.3, 153.7,

149.7, 141.0, 136.7, 132.1, 131.7, 128.8, 128.7, 123.3, 120.9, 111.2, 110.4 and 56.4.

HRMS-ESI: m/z [M+H]+ for C15H14SO3, calculated 275.0736; observed 275.0719.

1-(3,4-dimethoxyphenyl)-3-(1H-indol-3-yl)prop-2-en-1-one (Table 4, 33b)

O

O

O

Cl

O

S

MeO

OMe

O

H3CO

OCH3

NH


67

Dark orange solid, m.p. 73-75 °C, 1H NMR (300 MHz, CDCl3); (ppm) 8.85 (1H, s), 8.35

(1H, s), 8.16 (1H, d, J= 15.5 Hz), 7.87 (1H, s), 7.78-7.62 (2H, m) 7.36-7.28 (4H, m), 7.00

(1H, d, J= 8.3 Hz), 3.99 (6H, s); 13C NMR (75.4 MHz, CDCl3); (ppm) 185.6, 153.3,

149.6, 138.6, 135.9, 132.4, 130.5, 125.8, 124.8, 123.9, 122.1, 121.0, 117.9, 114.9, 112.4,

111.3, 110.5 and 56.5. HRMS-ESI: m/z [M+H]+ for C19H17NO3, calculated 308.1281;

observed 308.1267.

1-(2H-1,3-benzodioxol-5-yl)-3-(furan-3-yl)prop-2-en-1-one (Table 4, 34b)

Brown solid, m.p. 95-97 °C, 1H NMR (300 MHz, CDCl3); (ppm) 7.67 (1H, d, J= 8.1 Hz),

7.60 (1H, d, J= 15.3Hz), 7.53-7.52 (2H, m), 7.43 (1H, d, J= 15.3 Hz), 6.89 (1H, d, J= 8.1

Hz), 6.70 (1H, s), 6.50 (1H, s), 6.05 (2H, s); 13C NMR (75.4 MHz, CDCl3); (ppm) 187.9,

152.2, 152.1, 148.7, 145.2, 133.4, 130.5, 125.0, 119.5, 116.2, 113.0, 108.7, 108.3 and


1-(2H-1,3-benzodioxol-5-yl)-3-(6-bromopyridin-3-yl)prop-2-en-1-one (Table 4, 35b)

White solid, m.p. 146-148 °C, 1H NMR (300 MHz, CDCl3); (ppm) 8.56 (1H, s), 7.89

(1H, s), 7.64-7.51 (5H, m), 6.90 (1H, s), 6.07 (2H, s); 13C NMR (75.4 MHz, CDCl3);

(ppm) 180.3, 159.8, 149.7, 148.2, 138.2, 136.7, 133.1, 131.7, 128.8, 124.7, 123.3, 107.9,

107.6 and 101.7. HRMS-ESI: m/z [M+H]+ for C15H10BrNO3, calculated 331.9916;

observed 331.9959.

1-(4-methoxyphenyl)-3-(thiophen-2-yl)prop-2-en-1-one (Table 4, 36b)

Brown solid, m.p. 93-94 °C, 1H NMR (300 MHz, CDCl3); (ppm) 8.06 (2H, d, J= 4.5 Hz),

7.97 (1H, d, J= 15.3 Hz), 7.42-7.33 (3H, m), 7.10-7.07 (1H, m), 7.01 (2H, d, J= 4.5 Hz),

O

O

O

O

O

O

O

N Br

O

H3CO

S


68

3.89 (3H, s); 13C NMR (75.4 MHz, CDCl3); (ppm) 188.4, 163.8, 140.9, 136.8, 132.1,

131.4, 131.1, 128.8, 128.7, 121.1, 114.2 and 55.9. HRMS-ESI: m/z [M+H]+ for C14H12 SO2,


3-(Furan-2-yl)-1-(4-methoxyphenyl)prop-2-en-1-one (Table 4, 37b)

Brown solid, m.p. 68-70°C, 1H NMR (300 MHz, CDCl3); (ppm) 8.05 (2H, d, J= 8.8 Hz),

7.60-7.43 (3H, m), 6.97 (2H, d, J= 8.8 Hz), 6.69 (1H, s), 6.50 (1H, s), 3.85 (3H, s); 13C

NMR (75.4 MHz, CDCl3); (ppm) 188.4, 163.8, 152.2, 145.1, 131.4, 131.1, 130.3, 119.6,

116.1, 114.2, 113.0 and 55.8. HRMS-ESI: m/z [M+H]+ for C14H12O3, calculated 229.0859;

observed 229.0831.

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74

Spectral figures of some representative compounds

1H NMR (in CDCl3) spectrum of 3',4'-Dimethoxyacetophenone (2b, Table 2)

13C NMR (in CDCl3) spectrum of 3',4'-Dimethoxyacetophenone (2b, Table 2)

H3CO

H3CO

O


75

1H NMR (in CDCl3) spectrum of 4-Chloro-4'-methoxybenzophenone (25b, Table 3)

13C NMR (in CDCl3) spectrum of 4-Chloro-4'-methoxybenzophenone (25b, Table 3)

O

OCH3Cl


76

9 8 7 6 5 4 3 2 1 ppm

Prep ByNPP DIVISIONIHBT (CSIR)SHIV

m/z100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 290

%

0

100

AKB6H 11 (0.194) Cm (7:13) TOF MS ES+ 1.36e4247.0519

102.1694

212.0410153.0847

174.1484 195.1440

249.0606

HRMS spectrum of 4-Chloro-4'-methoxybenzophenone (25b, Table 3)

1H NMR (in CDCl3) spectrum of (2E)-3-(furan-2-yl)-1-(4-methoxyphenyl)prop-2-en-1- one (37b, Table 4)

O

H3CO

O


77

220 200 180 160 140 120 100 80 60 40 20 ppm

13C NMR (in CDCl3) spectrum of (2E)-3-(furan-2-yl)-1-(4-methoxyphenyl)prop-2-en-1- one (37b, Table 4)

O

MeO

MeO

OMe

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