80

Chapter-III

Scandium(III) triflate catalyzed 1,4-addition of cyano group to

enones using tetraethylammonium cyanide as the cyanide source

3.1 Lewis acid Sc(OTf)3

The quest for better and efficient catalysts for various organic reactions, both

new and old is never ending. In particular, Lewis acid catalysis has been extensively

explored and continues to be, as evident by the plethora of books and publications in

this area.1

Among the requirements of a good Lewis acid catalyst, their ability to be

used in catalytic amounts, stability, reusability as well as specificity in promoting

just the desired reaction and none other are most important. Sc(OTf)3 is a new type

of Lewis acid that is different from other typical Lewis acids such as AlCl3, BF3,

SnCl4, etc. While most Lewis acids are decomposed or deactivated in the presence

of water, Sc(OTf)3 is more stable and works as a Lewis acid in water solutions.

While the element scandium (Sc) is in group 3 and lies above La and Y, its radius is

appreciably smaller than those of any other rare earth elements. The chemical

behavior of scandium is known to be intermediate between that of aluminium and

lanthanides.2

Scandium has been uncommon probably due to the lack of rich sources

and the difficulties in separation, and its use in organic synthesis is rather limited

although unique characteristics might be expected. In 1993, Kobayashi was the first

to introduce scandium trifuloromethanesulfonate [Sc(OTf)3] as a promising Lewis

acid in organic synthesis.3,4

Most of the studies have shown that Scandium(III) triflate is an effective

catalyst that is mild as well as nonhydrolysable in aqueous medium. It has been

shown that Scandium(III) triflate can be used as a catalyst for a variety of organic

81

transformations.5

Scandium(III) triflate can be used in catalytic amounts, is stable up

to 280 °C and can be easily recovered thus rendering itself as a reusable, safe and

environmentally benign catalyst.6

It is also easily accessible by reacting either

metallic scandium or its chloride with trifluoromethane sulfonic acid. Scandium(III)

triflate has been extensively used for various condensation-cyclization reactions to

afford the corresponding heterocycles, alkylation, Friedel-Crafts acylation, Fries

rearrangement, Diels-Alder reaction, etc. It has also proved to be a superior catalyst

for the Strecker reaction.7

Many nitrogen-containing compounds such as imines and hydrazones are

also successfully activated by using a small amount of Sc(OTf)3 in both organic and

aqueous solvents. In addition, Sc(OTf)3 can be recovered after reactions and can be

reused. While lanthanum triflate [Ln(OTf)3] has similar properties, the catalytic

efficiency of Sc(OTf)3 is higher than that of Ln(OTf)3 in several cases. In this

chapter, we have described a convenient method of cyanation of chalcones with

TEACN using Sc(OTf)3 as an efficient catalyst, where the 1,4- adducts were formed

selectively.

3.2 Review of a few reported methods for the applications of Sc(OTf)3 as

catalyst

Aldol reactions in organic solvents

Sc(OTf)3 was found to be an effective catalyst in aldol reactions of silyl enol

ethers with aldehydes.8

The activities of typical rare earth triflates [Sc, Y and

Yb(OTf)3] were evaluated with the reaction of 1-trimethylsiloxycyclohexane and

benzaldehyde in dichloromethane. While the reaction scarcely proceeded at -78 °C

in the presence of Y(OTf)3 and Yb(OTf)3,9

the aldol adduct was obtained in 81%

yield in the presence of Sc(OTf)3.

82

Scheme 3.1. Scandium triflate catalyzed synthesis of Aldol condensation in organic solvent

Aldol reactions in aqueous medium

The importance of aqueous reactions is now generally recognized,

and development of carbon-carbon bond forming reactions that can be carried

out in aqueous media emerges as one of the most challenging topics in

organic synthesis.10,11

It was found that Sc(OTf)3 was effective in the aldol

reactions of silyl enolates with aldehydes in aqueous media (water/THF).8

The

reactions of aromatic and aliphatic aldehydes such as benzaldehyde and

3-phenylpropanaldehyde with silyl enolates were successfully carried out in aqueous

solvents.

Scheme 3.2. Scandium triflate catalyzed synthesis of Aldol condensation in aqueous

medium

The Michael addition reactions of silyl enol ethers or ketene silyl

acetals with α, β-unsaturated carbonyl compounds are among the most common

carbon-carbon bond forming processes in organic synthesis. Sc(OTf)3 was found to

be an effective and reusable catalyst in these reactions.12

The reactions proceed

smoothly in the presence of catalytic amount of Sc(OTf)3 under extremely mild

conditions to give the corresponding 1,5-dicarbonyl compounds in high yields after

acid work-up.

83

Scheme 3.3. Sc(OTf)3 catalyzed Michael reactions of silyl enol ethers with α, β-unsaturated carbonyl compounds

Allylation reactions

Synthesis of homoallylic alcohols by the reaction of organometallic allyl

compounds is one of the most important processes in organic synthesis.12

The

allylation reactions of carbonyl compounds with tetrallyltin proceeded smoothly

under the influence of a catalytic amount of Sc(OTf)313

to afford the homoallylic

alcohols, in high yields under extremely mild conditions.14

Scheme 3.4. Sc(OTf)3 catalyzed allylation reactions of carbonyl compounds

Friedel-Crafts acylation and Fries rearrangement

While Friedel-Crafts acylation reactions are fundamental and important

processes in organic synthesis as well as in industrial chemistry,15

more than a

stoichiometric amount of a Lewis acids such as AlCl3 or BF3 is needed due to the

consumption of the Lewis acid by the coordination with the aromatic ketones

produced. But a small amount of Sc(OTf)3 was enough to catalyze the Friedel-Crafts

acylation reactions.16,17

The catalytic activity of Sc(OTf)3, was found to be much

higher than that of Ln(OTf)3 in this case too.

84

Scheme 3.5. Fries rearrangement and Friedel-Crafts acylation reactions in the presence of

Scandium triflate

Diels-Alder reaction

The Diels-Alder reaction is one of the most useful synthetic conversions

used to form cyclic structures. Diels- Alder reaction is reversible, and the lowest

quantity of catalysts allow the reaction to proceed at room temperature or below

with satisfactory yields.18

R H

N Ph

Me3SiO OMe

Cat Sc(OTf)3

R N O CH3CN, rt

Ph

Scheme 3.6. Diels-Alder reaction in presence Scandium triflate catalyst

Asymmetric Sc(OTf)3 catalysts

Recently, some efficient asymmetric Diels-Alder reactions catalyzed by chiral

Lewis acids have been reported.19

Although rare-earth compounds were expected to be

promising Lewis acid reagents, only a few asymmetric Diels-Alder reactions were

catalyzed by chiral rare-earth Lewis acid triflates especially, Yb(OTf)3 and Sc(OTf)3.

The chiral Scandium catalyst could be prepared from Sc(OTf)3, (R)-BINOL, and a

tertiary amine in dichloro methane.20

The catalyst was also found to be effective for the

Diels-Alder reactions of an acrylic acid derivative with dienes.

85

Fig. 3.1. Chiral scandium catalyst

Kobayashi et al., have reported a chiral scandium catalyst for

enantioselective Diels-Alder reactions. This catalyst prepared from scandium triflate

(Sc(OTf)3, (R)-(+)-1,1-bi-2-naphthol, and a tertiary amine in dichloromethane, was

quite effective in the enantioselective Diels-Alder reaction of acyl-1,3-oxazolidin-2-

ones with dienes, and the corresponding Diels-Alder adducts were obtained in high

yields with high diastereo- and enantioselectivities.20,21

Scheme 3.7. Chiral scandium catalyst in Diels-Alder reaction

3.3 Chalcones

Chalcones are the main precursors for the biosynthesis of flavonoids and

isoflavonoids.22

Chalcones comprise of a three carbon α, β-unsaturated carbonyl

system. These are the condensation products of aromatic aldehydes with

acetophenones in the presence of a catalyst.23

They undergo a variety of chemical

reactions and are found beneficial in the synthesis of pyrazoline, isoxazole and

pyrimidine, an assortment of heterocyclic compounds. Chalcones play pivotal role in

synthesizing a range of remedial compounds. Chalcones act as mediators in the

synthesis of beneficial therapeutic compounds. Special attention has been given to

86

chalcones due to their simple structures and diverse pharmacological activities.

Worth mentioning activities of chalcones are in antiinflammatory,24

antifungal,

antibacterial,25

antimalarial,26

antitumor,27

antimicrobial,28

antiviral,29

antitubercular,30

antioxidant, antimitotic,31

antileishmanial,32

antiplatelet,33

anticancer34

and

antihypertensive activities.35

Owing to the above stated reasons, the synthesis of chalcones and chalcone

based functionalized derivatives had remained primary objective for a long time.

They have exhibited impressive curative efficacy for the treatment of numerous

diseases. Chalcone based derivatives have gained focus since they possess simple

structures and sundry pharmacological actions. A number of techniques and

schemes have been reported for the synthesis of these compounds. Chalcones and

their derivatives find application as

< Artificial sweeteners,36

scintillator37

< Polymerization catalyst,38,39

fluorescent whitening agent,40

organic

brightening agent,41

stabilizer against heat, visible light, ultraviolet light and

aging.42

< 3,2’,4’,6’-tetrahydroxy-4-propoxy-dihydrochalcone-4-β'-neohesperdoside

has been used as a synthetic sweetener and is 2200 times sweeter than

glucose.

< Chalcones are reactive towards several reagents e.g. (a) phenyl hydrazine,

(b) 2-amino thiophenol, etc.

< The chalcones have been found useful in elucidating structure of natural

products like hemlock tannin,43

cyanomaclurin,44

ploretin,45

eriodictyol,46

homo eriodictyol,47

naringenin, etc.

87

3.3.1 Chemistry of chalcones

The name “Chalcones” was given by Kostanecki and Tambor.48

The

chemistry of Chalcones has generated intensive scientific studies throughout the

world, especially, interest has been focused on the synthesis and biodynamic

activities of chalcones. These compounds are also known as benzalacetophenone or

benzylidene acetophenone. In chalcones, two aromatic rings are linked by an

aliphatic three carbon chain. Chalcone bears a very good synthon so that a variety of

novel heterocycles with good pharmaceutical profile can be designed. Chalcones are

unsaturated ketones containing the reactive ketoethylenic group –CO-CH=CH-.

These are coloured compounds because of the presence of the chromophore -CO-

CH=CH-, and the colour depends on the presence of other auxochromes. Different

methods are available for the preparation of chalcones.49

Chalcones are used to

synthesize several derivatives like cyanopyridines, pyrazolines isoxazoles and

pyrimidines having different heterocyclic ring systems.50

Fig. 3.2. Chemical structure of chalcone

3.3.2 Nomenclature of Chalcone

Different methods of nomenclatures for chalcone were suggested at different

times. The following pattern has been adopted by “Chemical Abstracts” published

by American chemical society.

Fig. 3.3. Nomenclature of chalcone

88

Scheme 3.8. Resonance stabilization of α, β-unsaturated ketones (enones)

3.3.3 General synthetic methods of chalcones

Claisen-Schmidt reaction

A variety of methods are available for the synthesis of chalcones and the most

convenient method is the one that involves the Claisen-Schmidt condensation of

equimolar quantities of a substituted acetophenone with substituted aldehydes in the

presence of aqueous alcoholic alkali.51

Amongst all the stated methods,

Aldol condensation and Claisen-Schmidt condensation still hold high position.52

Other renowned techniques include Suzuki reaction, Wittig reaction, Friedel-

Crafts acylation with cinnamoyl chloride, Photo-Fries rearrangement of phenyl

cinnamates, etc.

In the Claisen-Schmidt reaction, the concentration of alkali used

usually ranges between 10 and 60 %.53

The reaction is carried out at about 50 ºC

for 12-15h or at room temperature for one week. Under these conditions,

the Cannizaro Reaction54

also takes place and thereby decreases the yield

of the desired product. To avoid the disproportionation of aldehyde in the above

reaction, the use of benzylidene-diacetate in the place of aldehyde has been

recommended.55,56

Scheme 3.9. General method for synthesis of chalcone

89

3.4 1,4-Addition on α, β-unsaturated compounds

1,4-Conjugate addition of nucleophiles to the β-position of α, β-unsaturated

carbonyl compounds is one of the most frequently used reactions for bond

formation. Originally57

the Michael reaction was restricted to the conjugate addition

of an enolate to an α, β-unsaturated carbonyl group. Michael donors that contain

active methylene centers can be directly applied, whereas simple carbonyl

compounds had generally to be activated into more reactive species such as enolates

or enamines. Now “Michael reaction” is often referred to the 1,4-addition of every

nucleophile and a prefix indicating the nucleophilic species is generally added (e.g.,

oxa-, thia- or aza- for oxygen, sulfur and nitrogen nucleophiles, respectively).

However 1,4-conjugate addition reaction is the most correct name. Among the most

powerful methods in asymmetric synthesis is the enantioselective 1,4-addition of

carbon nucleophiles to α, β-unsaturated compounds in which a C-C bond and a new

stereogenic centre are formed.58

Conjugate addition has developed into one of the

most widely used methods for asymmetric carbon-carbon bond formation in organic

chemistry. This transformation involves the reaction of a nucleophile and

α, β-unsaturated system activated by an electron-withdrawing group (EWG). The

addition takes place at the β-carbon of the unsaturated system, resulting in the

formation of a stabilized carbanion. After protonation of the carbanion, the β-adduct

is formed with a single stereogenic centre, whereas quenching with an electrophile

(E+) results in the α, β-di-substituted product with two newly created stereocentres.

A typical problem associated with conjugate addition to α, β-unsaturated

carbonyl compounds is the regioselectivity of the nucleophilic addition. Addition of

a soft nucleophile occurs preferably at the β- or 4-position of the unsaturated system,

90

resulting in the 1,4-adduct, while 1,2-addition is favoured if hard nucleophiles are

used (Scheme 3.10).

Scheme 3.10. Addition of hard or soft nucleophiles to α, β-unsaturated carbonyl compounds

The first example of an un-catalyzed conjugate addition reaction was

reported in 1883 by Kommenos where he described the addition of diethyl

sodiomalonate to diethyl ethylidenemalonate.59

The tremendous versatility and scope

of the Michael addition using a variety of (soft) nucleophiles and the copper-

mediated conjugate addition of a range of (hard) organometallic reagents, as well as

various related methods, are testimony to the importance of these C-C bond

formations.

Scheme 3.11. 1,4-Conjugate addition of α, β-unsaturated carbonyl compounds

3.5 Importance of nitriles in organic chemistry

The cyano group serves as a stable and useful key functional group

for the synthesis of biologically important compounds. The reduction of the nitrile

group (RCN), depending on the nature of the reducing agent and experimental

conditions, can produce amines, aldehydes, primary alcohol, imines or alkanes

(RCH3 or RH).60

91

Hydrogen cyanide (HCN) was the most commonly used industrial reagent

for the introduction of cyano group.61

However, due to toxicity and to follow

abundant precautions in handling HCN, newer methods have been developed to

substitute it with other potentially less harmful and easily manageable reagents.

Cyanide sources like, trimethylsilyl cyanide (TMSCN), tetraethyl ammonium

cyanide (TEACN), tetrabutyl ammonium cyanide, etc., along with or without

catalysts have been reported for the introduction of cyano group.62

Depending on the

reaction conditions, the hydrocyanation of unsaturated carbonyl compounds lead to

β-cyanoketones, β-cyano-cyanohydrins, or vinyl cyanohydrins as a result of 1,2- or

1,4-additions.63

The conjugate addition of cyano group to α, β-unsaturated carbonyl

compounds is one of the most important carbon-carbon bond formation reactions

because, the resulting β-cyano adducts can be converted into biologically important

γ-aminobutyric acids under reducing conditions (GABA analogues).64

The conjugate

hydrocyanation reaction of enones is recently employed for the total synthesis of

natural products like terpenes, alkaloids, steroids etc.65

The reactions of enones with TMSCN in the presence of base catalysts

provided selectively the 1,2-adducts which also serve as a method of protection of

the carbonyl groups.66

In contrast, employing Lewis acid catalysts such as

Et2AlCN,67

Et3Al,68

AlCl3, SnCl2,69

Pd(OAc)2,70

ionic liquids71

and microwave

irradiation,72

resulted in the selective 1,4-additions. Recently, Shibasaki and

co-workers employed Ni(0) and Gd(OTf)3 as the co-catalysts in the 1,4-addition of

cyanide using TMSCN, and the catalytic enantioselective conjugate addition of

cyanide to enones was also disclosed.73

Asymmetric catalytic hydrocyanation of α,

β-unsaturated ketones by using Me3SiCN and [Ru(phgly)2(binap)]/Li salt has been

92

very recently reported.74

Yanagisawa and co-workers described that, un-activated

arylalkenes could be effectively converted to benzylic nitriles in the presence of

triflic acid and TMSCN.75

Very recently, Fu-Xue Chen and co-workers reported the

1,4-addition of TMSCN to enones in presence of Cs2CO3 and CsF catalysts.76

Despite these achievements, practical regioselective 1,4-hydrocyanation of enones

using newer cyanide sources is still demanding. Scandium(III) triflate has been

extensively used as an efficient Lewis acid catalyst for various organic reactions.77

3.5.1 Review of literature for the 1,4-conjugative addition of cyano group to α,

β-unsaturated carbonyl compounds

Yasutaka Ishil et al., reported a new method using acetone cyanohydrin and

isopropenyl acetate for the hydrocyanation of carbonyl compounds catalyzed by

Cp*

Sm(thf) under ambient conditions.

78 2 2

Scheme 3.12. Hydrocyanation of carbonyl compounds with acetone cyanohydrins

The Michael addition of hydrogen cyanide to α, β-unsaturated carbonyl

compounds was promoted by Cp

* Sm(thf) . Several α, β-unsaturated carbonyl

2 2

compounds were reacted with acetone cyanohydrin in the presence of Cp*2Sm(thf)2

at room temperature for 15h.78

Scheme 3.13. Hydrocyanation of enones with acetone cyanohydrin

93

Fu-Xue Chen et al., have described the facile enantioselective 1,4-addition of

TMSCN to aromatic enones using chiral sodium phosphate. Thus, in presence of

20mol% of sodium salt generated in-situ from (R)-3,3’-di(1-diadamandyl)-1,1’-

binapthyl-2-2'-diylphosphoric acid and NaOH, β-cyano ketones were obtained at 80

°C in toluene.79

Scheme 3.14. Asymmetric 1,4-addition of cyanide to chalcones

Cyanotrimethylsilane added to α, β-unsaturated ketones in conjugative

manner under the catalytic action of Lewis acid as triethylaluminium, aluminium

chloride and SnCl2. Hydrolysis of the products yielded β-cyano ketones which were

identical to the hydrocyanated products of the starting enones.80

Scheme 3.15. Lewis acid catalyzed synthesis of β-cyano ketones

Eric Jacobsen et al., have reported highly enantioselective conjugative

cyanation of unsaturated imides using co-operative dual catalysis. Reactions were

carried out for 24h at room temperature in presence of dual catalyst and

trimethylsilylcyanide as cyanide source.81

Scheme 3.16. Asymmetric hydrocyanation of unsaturated imides using co-operative dual catalyst

94

3.6 Results and Discussion

Earlier methods for 1,4-addition of cyano group to α, β-unsaturated

compounds used cyanide sources like trimethylsilylcyanide, KCN, NaCN, with

various metal and Lewis acid catalysts. Further, most of these methods will liberate

free HCN making them not environmentally friendly and require more safety

protocols. Herein, we report a simple, convenient and milder method for the 1,4-

addition of cyanide to α, β-unsaturated enones using tetraethylammonium cyanide as

the cyanide source using Sc(OTf)3 as the Lewis acid catalyst without the liberation

of any HCN. This method selectively leads to 1,4-addition of cyanide to enones

resulting in moderate to high yield of the products. The reaction procedures were

easy and in most of the cases the products were obtained in high purity that needed

no further purification processes.

Scheme 3.17. Sc(OTf)3-catalyzed 1,4-addition of TEACN with chalcones

In order to determine the most appropriate reaction conditions and to

evaluate the efficiency of scandium(III) triflate as catalyst for the

hydrocyanation, synthesis of 4-oxo-2,4-diphenylbutanenitrile was taken as a

model reaction (Entry 8, Table 3.3). Among the tested solvents, DMF (Table 3.1,

Entry 5) gave the best results for the hydrocyanation of (E)-chalcone (1.0 equiv)

using TEACN (1.0 equiv) and Sc(III) triflate (30% weight of chalcone taken).

95

The use of chlorinated solvents like DCM, EDC, CHCl3, etc., or hydrocarbons as

solvent did not provide good yields of the expected product.

Table 3.1. Effect of solvent in the 1,4-addition of cyano group to enones with

TEACN/Sc(III) triflate

Entrya

Solvent

Catalyst

Time (h)

Yield (%)

1 CH3CN Sc(III)OTf 6 75

2 THF Sc(III)OTf 12 56

3 EDC Sc(III)OTf 8 32

4 Toluene Sc(III)OTf 24 -

5 DMF Sc(III)OTf 2-3 72-92

6 DMSO Sc(III)OTf 3-6 43

7 Dioxane Sc(III)OTf 12 52

8 DCM Sc(III)OTf 8 27

aAll reactions were conducted with 30% of catalyst, 1 mmol of chalcone (benzylidene

acetophenone) and 1 mmol of TEACN in 30 vol. of solvent.

This may be attributed to the poor solubility of TEACN in these solvents

which has resulted in a heterogeneous reaction mixture (TEACN is not freely

soluble in non-polar solvents) leading to the reduction in its reactivity. It is

noteworthy that the order of addition of reagents was also very important for the

success of the reaction. Initially, a mixture of TEACN and chalcones should be

prepared in DMF at -5 °C to 0 °C by stirring for 10min followed by the addition

of scandium(III) triflate. If scandium(III) triflate has been added at the

beginning, no reaction was observed. The catalytic activities of various triflates

and other catalysts were also investigated using a loading of 30% of the

respective catalyst (Table 3.2) wherein, almost all of the catalysts (except

Scandium(III) triflate) studied were found to be ineffective for the cyano

addition to chalcones with TEACN as cyanide source. Though the TMS(OTf)

gave modest yield of the desired product (Entry 3), it is having difficulty in

96

handling due to its ready hydrolysis. Zn(OTf)2 afforded only a trace of the

product whereas, the other lanthanide triflate, namely, the ytterbium triflate also

resulted in moderate yields leading to the conclusion that Sc(III) triflate is the

promising catalyst for this reaction.

Table 3.2. Effect of different catalysts on 1,4-addition of cyano group to

enones with TEACN/ Sc(III) triflate

Entrya

Catalyst

Time (h)

Yield (%)

1 Sc(III) OTf 2-3 72-92

2 Yb(III) OTf 2-3 30-40

3 TMS (OTf) 3-6 56-70

4 Zn(OTf)2 12 27

5 Iodine 1 --

6 TFA 1 43

7 HBr 2 37

8 TBABr 12 --

9 TBAF 12 -- aAll reactions were conducted with 30% of catalyst, 1 mmol of chalcone

(benzylideneacetophenone) and 1 mmol of TEACN in 30 vol. of solvent.

In order to extend the scope of the scandium(III) triflate catalyzed

hydrocyanation reaction, various chalcones were subjected to the reaction (Table

3.3). Interestingly, no substituent effects on the yields were noted. Thus, the

chalcones with either electron withdrawing or electron donating groups at any

positions, gave the 1,4-adducts in good to moderate yields (Table 3.3, Entries 1-

14). It was observed that no 1,2-adduct was obtained in any of the reactions. In

order to clarify the scope and limitation of the present method, some reactions of

the enones other than chalcones were performed under same reaction conditions.

Unfortunately, cyclohexenone and α, β-unsaturated esters such as methyl

cinnamate did not undergo 1,4-addition at all, and the starting materials were

recovered.

97

Scheme 3.18. Plausible mechanism for the Sc(III) OTf-catalyzed 1,4-addition of

TEACN with chalcones

The mechanism of the reaction is not completely understood at this stage.

However, since the order of the addition of reagents is crucial for the success of

the reaction, we can give a reasonable explanation as shown in the Scheme 3.18.

It has been observed that if scandium(III) triflate is added at the beginning no

reaction takes place. Besides, there should be an induction period of 10min after

addition of TEACN to chalcones and before addition of the triflate salt. These

two facts indicate that a weak interaction is needed between chalcone and

TEACN at the beginning of the reaction to initiate the transfer of cyano group.

Once scandium(III) triflate is added it coordinates with the carbonyl oxygen and

helps the delocalization of electron through a six member cyclic transition state

(Scheme 3.18) and in this course the cyanide is added in 1,4-fashion rather than

the 1,2-fashion. Finally, during quenching the neutral product is generated. This

model thus takes into account the importance of the order of addition of reagents

and selectivity of the reaction. If scandium(III) triflate is added at the beginning

it gives rise to a strong interaction with the carbonyl oxygen and does not allow

the TEACN salt to interact with the chalcone. Hence no reaction takes place.

98

Table 3.3. Synthesis of 4-oxo-2,4-diphenylbutanenitrile derivatives

Entrya

Chalcones Time (h) Product Yieldc

(%)

3 74ψ

1

3 72 ψ

2

O

3 Br F

1c

3 75 ψ

2 80

4

5 2 90

2 92 6

2 87 7

8 2 92

9 3 73

99

10 3 80

11 2 72

12 3 72 ψ

13 2 92

14 2 90

aAll reactions were conducted with 30% of catalyst, 1 mmol of chalcone and 1 mmol of TEACN in

30 volume of dry DMF, ψNew compounds, cIsolated yield.

3.7 Conclusion

The present investigation has demonstrated that the use of

TEACN/scandium(III) triflate offers a novel, simple, and convenient method for

the conversion of wide varieties of chalcones to their corresponding

β-cyanoketones, without the liberation of HCN gas. This method shows excellent

selectivity giving the 1,4-adduct in good yields. The ready availability of the

reagents, easy handling of them, the absence of generation of HCN during the

reaction, mild reaction conditions and high yield of the product make this method

attractive for direct synthesis of cyano substituted 1,4-adducts from enones.

100

3.8 Experimental Section

All the melting points of the products were measured on an Buchi melting

point (B-545) apparatus. 1H and

13C NMR spectra were recorded on a Bruker

400MHz instrument using CDCl3 as the solvent with tetramethylsilane (TMS) as the

internal standard. Mass spectra were recorded on an Agilent 6330 ion trap

instrument. Elemental analysis for C, H and N were obtained using a Vario-micro-

cube CHN-O-Rapid analyzer. TEACN from Alfa Aesar (purity > 97%), and

Scandium(III) triflate from Aldrich (purity>98%) were used as procured.

3.8.1 General synthetic procedure

The chalcones used in the present study have been prepared as per literature

procedures. TEACN (0.075gm, 0.48 mmol) was dissolved in DMF (3 mL, 30 vol) at

room temperature, then cooled to -5 °C to 0 °C. To that, chalcone (0.1gm, 0.48

mmol) was added and stirred maintaining the temperature between -5 °C to 0 °C for

10min and then, Sc(III) triflate (0.03gm, 30% weight of chalcones taken) was added

at 0 °C, and the reaction mixture was slowly warmed to 25 °C. It was stirred for

appropriate time at 25 °C under N2 atmosphere. The reaction was monitored by thin

layer chromatography. After completion (about 3h), the reaction mixture was

quenched with 5 mL water and extracted with diethyl ether (3×5 mL). The combined

organic layer was dried (over anhydrous MgSO4), filtered, concentrated and purified

by column chromatography with silica gel 230-400 mesh (hexane/ethyl acetate 8:2)

to give the desired product.

3.8.2 Spectral data

4-Oxo-4-phenyl-2-(2-(trifluoromethyl)phenyl)butanenitrile (Entry 1, Table 3.3):

Yellow Colour Oil. 1H NMR (400 MHz, CDCl3): δ = 3.42 (dd, J = 3.6, 18.0 Hz,1H),

101

3.72 (dd, J = 10.4, 18.0 Hz, 1H), 4.89 (dd, J =3.6, 10.4 Hz, 1H), 7.48 –7.54 (m, 3H,

ArH), 7.62–7.65 (t, 1H, ArH), 7.67–7.71 (t, 1H, ArH), 7.74–7.76 (d, 1H, ArH),7.84–

7.86 (d, 1H, ArH), 7.95–7.97 (d, 1H, ArH) ppm.13

C NMR(100 MHz, CDCl3) δ =

28.81, 44.70, 120.01, 123.79 (q, J = 273.82Hz, CF3), 126.84 (q, J = 6.03 Hz, ortho

carbon to CF3), 127.61, 127.92, 128.12, 128.75, 128.87, 129.88, 132.95, 133.96,

135.43, 193.91 ppm. 19

F NMR (376 MHz, CDCl3) δ = –59.22 ppm.MS: m/z =

303.29 (M)+. Anal. Calcd. for C17H12F3NO: C: 67.33; H: 3.99; N: 4.62%; Found: C:

67.30; H: 3.93, N: 4.64%.

2-(5-Chloro-2-(trifluoromethyl)phenyl)-4-oxo-4-phenylbutanenitrile (Entry 2,

Table 3.3): Yellow pasty mass. 1H NMR (400 MHz, CDCl3): δ = 3.43 (dd, J = 4,

18 Hz,1H), 3.77 (dd, J = 10.4, 18 Hz, 1H), 4.89 (dd, J = 3.6, 10.4 Hz, 1H), 7.46–

7.49 (t, 3H, ArH), 7.61–7.64 (m, 1H, ArH) 7.68–7.73 (d,1H, ArH), 7.83(s, 1H,

ArH), 7.95–7.99 (d, 2H, ArH) ppm.13

C NMR (100.66 MHz, CDCl3) δ = 28.74,

44.41, 119.46, 123.51 (q, J = 273.79Hz, CF3), 126.24 (q, J = 31.2 Hz, C-CF3),

128.28 (q, J = 5Hz, Ortho carbon to CF3) 128.62, 128.91, 129.07, 130.18, 134.15,

135.25,135.90, 136.53, 139.40, 193.50 ppm. MS: m/z = 337.04 (M) +. Anal. Calcd.

for C17H11ClF3NO: C: 60.46; H: 3.28; N: 4.15%; Found: C: 60.43; H: 3.26, N:

4.18%.

2-(4-Bromo-2-fluorophenyl)-4-oxo-4-phenylbutanenitrile (Entry 3, Table 3.3):

White solid; mp = 118.2–119.7 °C, 1H NMR (300 MHz, CDCl3): δ = 3.56 (dd, J =

5.73, 18 Hz,1H), 3.72 (dd, J = 8, 18 Hz, 1H), 4.70 (dd, J = 5.7, 7.8 Hz, 1H), 7.26–

7.34 (m, 2H, ArH ), 7.43–7.51 (m, 3H, ArH), 7.59–7.64 (m, 1H, ArH), 7.91–7.94

(d, 2H, ArH) ppm. 13

C NMR (75 MHz, CDCl3) δ = 26.35, 42.05, 118.92,

119.59,119.91, 121.32,123.04, 128.02, 128.82, 130.73, 134.00, 135.32, 159.64

102

(broad d, J = 251.25Hz, F attached Carbon), 194.07 ppm. 19

F NMR (376 MHz,

CDCl3) δ = –114.04ppm. MS: m/z = 332.17 (M)+. Anal Calcd. for C16H11 BrFNO:

C: 57.85; H: 3.34; N: 4.22%. Found: C: 57.82; H: 3.31, N: 4.25%.

2-(4-Fluorophenyl)-4-oxo-4-phenylbutanenitrile (Entry 4, Table 3.3): White

Solid; mp = 100.7–101.6 °C (lit. 82,83,

mp 101.9-102.5 °C); 1H NMR (300 MHz,

CDCl3): δ = 3.51 (dd, J = 6.3, 18 Hz,1H), 3.71 (dd, J = 7.5, 18 Hz, 1H), 4.55–4.59

(t, 1H), 7.05–7.10 (m, 2H, ArH), 7.38–7.58 (m, 5H, ArH), 7.60–7.61 (dd, 2H, ArH),

ppm.13

C NMR (75 MHz, CDCl3) δ = 31.19, 44.44, 116.26, 120.46, 128.08, 128.87,

129.28, 131.05, 133.99, 135.62, 162.53 (broad d, J = 246.75Hz, F attached Carbon),

194.41 ppm. 19

F NMR (376 MHz, CDCl3) δ = –112.04 ppm. MS:m/z = 253.27 (M)+.

Anal. Calcd. for C16H12F NO: C: 75.88; H: 4.78; N: 5.53%; Found: C: 75.86; H:

4.76, N: 5.51%.

2-(3-Chlorophenyl)-4-oxo-4-phenylbutanenitrile (Entry 5, Table 3.3): Yellow

Solid; mp = 101–102.8 °C, 1H NMR (400 MHz, CDCl3): δ = 3.50 (dd, J = 6.4, 18

Hz,1H), 3.71 (dd, J =7.2, 18 Hz, 1H), 4.58 (dd, J= 7.2, 14 Hz, 1H), 7.35–7.44 (m,

3H, ArH), 7.45–7.49 (m, 1H, ArH), 7.56–7.67 (m, 2H, ArH), 7.90–7.92 (m, 1H,

ArH ), 7.99–8.04 (m, 1H, ArH), 8.01–8.10 (m, 1H, ArH) ppm. 13

C NMR (100 MHz,

CDCl3) δ = 31.32, 44.31, 119.7, 127.75, 128.23, 128.84, 129.43, 129.90, 130.04,

132.41, 133.8, 135.61, 194.42 ppm. MS: m/z = 269.32 (M)+. Anal. Calcd. for

C16H12ClNO: C: 71.25; H: 4.48; N: 5.19%; Found: C: 71.28; H: 4.45, N: 5.16%.

2-(4-Chlorophenyl)-4-oxo-4-phenylbutanenitrile (Entry 6, Table 3.3): White

Solid; mp = 111.2–111.9 °C, (lit. 82,84

mp 112-113 °C);1H NMR (400 MHz, CDCl3):

δ = 3.50 (dd, J = 6.4 19.6 Hz,1H), 3.71 (dd, J = 7.2, 14.4 Hz, 1H), 4.57 (dd, J = 6.58,

13.6 Hz,1H), 7.35–7.44 (m, 3H, ArH), 7.59–7.62 (m, 1H, ArH), 7.90–7.93 (m, 2H,

103

ArH), 7.99–8.01 (m, 2H, ArH), 8.01–8.10(dd,1H, ArH) ppm. 13

CNMR (100MHz,

CDCl3) δ = 31.32, 44.33, 120.96, 126.82, 128.50, 128.56, 128.61, 128.67, 128.97,

133.77, 134.06, 134.48, 135.55, 194.43 ppm. MS: m/z = 269.32 (M)+. Anal. Calcd.

for C16H12Cl NO: C: 71.25; H: 4.48; N: 5.19%; Found: C: 71.28; H: 4.45, N: 5.16%.

4-Oxo-4-phenyl-2-p-tolylbutanenitrile (Entry 7, Table 3.3): White Solid; mp =

129.3–131.7 °C, (lit.82,83,80b

mp 129-131 °C); 1H NMR (400 MHz, CDCl3): δ = 2.42

(s, 3H), 3.41 (dd, J = 5.2, 17.2 Hz, 1H), 3.74 (dd, J = 9.2 18 Hz, 1H), 4.71 (dd, J =

5, 8.8 Hz,1H), 7.20–7.27 (m, 2H, ArH),7.28–7.29(m, 1H, ArH), 7.46–7.51(m, 3H,

ArH),7.61–7.93 (m, 1H, ArH),7.94–7.96 (m, 2H, ArH) ppm.13

C NMR (100 MHz,

CDCl3) δ = 19.27, 28.75, 43.10, 120.72, 127.04, 127.50, 128.13, 128.48, 128.87,

131.27, 133.40, 133.94, 135.68, 194.77 ppm. MS: m/z = 249.32 (M)+. Anal Calcd.

for C17H15NO: C: 81.90; H: 6.06; N: 5.62%; Found: C: 81.87; H: 6.00, N: 5.59%.

4-Oxo-2,4-diphenylbutanenitrile (Entry 8, Table 3.3): White Solid; mp = 121–

123.4 οC, (lit.

82,83 mp 122-125 °C);

1H NMR (400 MHz, CDCl3): δ = 3.49 (dd, J = 6,

18.0 Hz,1H), 3.70 (dd, J = 8, 18.0 Hz,1H), 4.56 (dd, J = 6.0, 8.0 Hz,1H), 7.34–7.49

(m, 7H, ArH), 7.57–7.60 (m, 1H, ArH), 7.89–7.92 (m, 2H, ArH)ppm. 13

C NMR

(100 MHz, CDCl3) δ = 31.38, 44.31,120.9, 127.5, 128.09, 128.88, 128.95, 129.45,

134.03, 135.3, 135.8, 194.6 ppm. MS: m/z = 235.29 (M)+. Anal. Calcd. for

C16H13NO: C: 81.68; H: 5.57; N: 5.95%; Found: C: 81.64; H: 5.53, N: 5.98%.

4-(1-Cyano-3-oxo-3-phenylpropyl)benzonitrile (Entry 9, Table 3.3): Yellow

Solid; mp = 134.7–135.2 °C, (lit.83

mp 136.8-137.3 °C); 1H NMR(400 MHz,

CDCl3): δ = 3.55 (dd, J = 6.8, 18 Hz ,1H), 3.75 (dd, J = 6.8, 18 Hz, 1H) , 4.67 (dd, J

= 6.8, 13.8 Hz, 1H), 7.46–7.50 (m, 2H, ArH), 7.58–7.61 (m, 3H, ArH), 7.69–7.71

(m, 2H, ArH), 7.90–7.92 (m, 2H, ArH) ppm. 13

C NMR (100 MHz, CDCl3) δ =

104

28.97, 43.82, 113. 34, 128.11, 128.44, 129.61, 129.85, 129.50, 131.27, 133.03,

133.96, 194.96ppm. MS: m/z = 260.30(M)+. Anal. Calcd. for C17H12N2O: C: 78.44;

H: 4.65; N: 10.76 %; Found: C: 78.40; H: 4.63, N: 10.64%.

2-(2,4-Dichlorophenyl)-4-oxo-4-phenylbutanenitrile (Entry 10, Table 3.3):

White Solid; mp = 89.2–90.1 °C, (lit.80b,85

mp 90-91 °C); 1H NMR (400 MHz,

CDCl3): δ = 3.53 (dd, J = 4.6, 18 Hz, 1H), 3.69 (dd, J = 9.2, 18.0 Hz, 1H), 4.88 (dd,

J = 5.2, 12.0 Hz, 1H), 7.34–7.37 (m, 1H, ArH), 7.40–7.48 (m, 3H, ArH), 7.65–7.69

(m, 2H, ArH), 7.72–7.74 (m, 1H, ArH), 7.93–7.95 (m, 1H, ArH) ppm.13

C NMR

(100 MHz, CDCl3) δ = 28.91, 44.68, 118.9, 126.86, 128.10, 128.72, 128.85, 129.87,

131.30, 132.92, 133.96, 135.2,135.5, 193.86, ppm. MS: m/z = 303.39 (M)+. Anal.

Calcd. for C16H11Cl2 NO: C: 63.18; H: 3.65; N: 4.60 %. Found: C: 63.12; H: 3.71,

N: 4.64%.

2-(2-Chlorophenyl)-4-oxo-4-phenylbutanenitrile (Entry 11, Table 3.3): White

Solid; mp = 107.1–108.4 °C, (lit.86

mp 106-108 °C); 1H NMR (400 MHz, CDCl3): δ

= 3.50 (dd, J = 6.4, 18 Hz,1H), 3.71 (dd, J = 7.2, 18 Hz,1H), 4.57 (dd, J = 8, 12

Hz,1H), 7.35–7.39 (m, 4H, ArH), 7.40–7.49 (m, 2H, ArH), 7.59–7.62 (m, 1H, ArH),

7.91 (dd, J = 1, 8.4 Hz, 2H, ArH) ppm.13

C NMR (100 MHz, CDCl3) δ = 31.38,

44.31, 119.7, 127.4, 128.09, 128.88, 128.95, 129.45, 130.7, 132.6, 134.03,135.9,

194.3 ppm. MS: m/z = 269.014(M)+. Anal. Calcd. for C16H12ClNO: C: 71.25; H:

4.48; N: 5.19 %; Found: C: 71.21; H: 4.43, N: 5.16%.

2-(4-Methylnaphthalen-1-yl)-4-oxo-4-phenylbutanenitrile (Entry 12, Table 3.3):

Yellow Solid Mp = 132.4–134.7 °C, 1H NMR (400 MHz, CDCl3): δ = 2.71 (s, 3H),

3.56 (dd, J = 4, 18 Hz, 1H), 3.86 (dd, J = 9.6, 18 Hz, 1H), 5.31 (dd, J = 3.8, 10 Hz,

1H), 7.35–7.37 (m, 1H, ArH), 7.44–7.46 (m, 2H, ArH), 7.48–7.61 (m, 3H, ArH),

105

7.67–7.69 (m, 1H, ArH), 7.93–7.96 (m, 3H, ArH), 7.97–8.07 (m, 1H, ArH)ppm.

13CNMR (100MHz, CDCl3) δ = 19.517, 28.971, 43.836, 12.79, 122.51, 125.54,

125.61, 126.13, 126.86, 128.15, 128.83, 129.73, 133.29, 133.90, 135.70,

194.98ppm; MS: m/z = 299.38 (M)+. Anal. Calcd. for C21H17NO: C: 84.25; H: 5.72;

N: 4.68; O: 5.34%; Found: C: 84.28; H: 5.69, N: 4.68%.

4-(4-Bromophenyl)-4-oxo-2-phenylbutanenitrile (Entry 13, Table 3.3): Yellow

Solid; mp = 119.4–121.5 °C, (lit.82

mp 122-124 °C); 1H NMR (400 MHz, CDCl3): δ

= 3.45 (dd, J = 6, 18 Hz,1H), 3.68 (dd, J = 8, 19.6 Hz,1H), 4.54 (dd, J = 7.2, 8 Hz,

1H), 7.34–7.43 (m, 5H, ArH), 7.60–7.62 (m, 2H, ArH), 7.77–7.79 (m, 2H, ArH)

ppm.13

C NMR (100 MHz, CDCl3) δ = 31.28, 44.50, 120.30, 127.48, 128.0, 128.49,

129.04, 129.35, 129.56, 132.22, 134.20, 135.05, 194.28 ppm. MS: m/z = 314.18

(M)+. Anal Calcd. for C16 H12BrNO: C: 61.17; H: 3.85; N: 4.46 %; Found: C: 61.15;

H: 3.88, N: 4.49%.

4-(3-Bromophenyl)-4-oxo-2-phenylbutanenitrile (Entry 14, Table 3.3): Yellow

Solid; mp = 85.7–86.4 °C (lit.82

mp 86–87 °C); 1H NMR (400 MHz, CDCl3): δ =

3.45 (dd, J = 6, 18 Hz, 1H), 3.69 (dd, J = 8, 19.6 Hz,1H), 4.52 (dd, J = 5.97, 18 Hz,

1H), 7.36–7.45 (m, 5H, ArH), 7.70–7.72 (m, 2H, ArH), 7.80–7.84 (m, 2H, ArH)

ppm.13

C NMR (100 MHz, CDCl3) δ = 31.28, 44.50, 120.30, 127.45, 128.0, 128.46,

129.01, 129.35, 129.56, 132.22, 134.23, 135.05, 194.28 ppm. MS: m/z = 314.18

(M)+.

106

3.8.3 Spectra for novel compounds

Fig. 3.4. 1H and 13C-NMR spectra of 2-(4-fluorophenyl)-4-oxo-4-phenyl butanenitrile

(Entry 4, Table 3.3)

107

Fig. 3.5. 19F-NMR spectrum of 2-(4-fluorophenyl)-4-oxo-4-phenylbutanenitrile (Entry 4, Table 3.3)

108

CN O

CF3

Fig. 3.6. 1H and 13C-NMR spectra of 4-oxo-4-phenyl-2-(2 (trifluoromethyl)phenyl)butanenitrile.

(Entry 1, Table 3.3)

109

CN O

CF3

Fig. 3.7. 13C-NMR spectrum (expansion) of 4-oxo-4-phenyl-2-(2-(trifluoromethyl)phenyl)

butanenitrile (Entry 1, Table 3.3)

110

CN O

Cl

CF3

Fig. 3.8. 1H and 13C NMR spectra of 2-(5-chloro-2-(trifluoromethyl)phenyl)-4-oxo-4-

phenylbutanenitrile (Entry 2, Table 3.3)

111

Fig. 3.9. 13C-NMR spectrum (expansion) of-2-(5-chloro-2-(trifluoromethyl) phenyl)-4-oxo-4-

phenylbutanenitrile (Entry 2, Table 3.3)

112

CN O

Br F

Fig. 3.10. 1H and 13C-NMR spectra of 2-(4-bromo-2-fluorophenyl)-4-oxo-4-phenylbutanenitrile

(Entry 3, Table 3.3)

113

Fig. 3.11.

13C-NMR spectrum (expansion) of 2-(4-bromo-2-fluorophenyl)-4-oxo-4-

phenylbutanenitrile (Entry 3, Table 3.3)

114

Fig. 3.12. 19F-NMR spectrum (expansion) of 2-(4-bromo-2-fluorophenyl)-4-oxo-4-

phenylbutanenitrile (Entry 3, Table 3.3)

115

3.9 References

1. Yamamoto, H. Ed., Lewis Acids in Organic Synthesis; Wiley-VCH:

Weinheim, 2000; Vols. 1 & 2.

2. Cotton, F. A.; Wilkinson, G. Advanced Inorganic Chemistry, 5th

ed., Wiley,

New York, 1988, p. 973.

3. Kobayashi, S.; Hachiya, I.; Araki, M.; Ishitani, H. Tetrahedron Lett. 1993,

34, 3755.

4. Lubi-neau, A.; Ange, A.; Queneau, Y. Synthesis 1994, 741.

5. Prakash, G. K. S.; Mathew T.; Panja, C.; Alconcel, S.; Vaghoo, H.; Do, C.

Proc. Natl. Acad. Sci. USA, 2007, 104, 3703.

6. Kobayashi, S.; Nagayama, S.; Busujima, T. J. Am. Chem. Soc. 1998, 120,

8287.

7. Kobayashi, S.; Busujima, T.; Nagayama, S. Chem. Commun. 1998, 981.

8. Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki, M. Synlett 1993, 472.

9. Kobayashi, S. Synlett 1994, 689.

10. Li, C. J. Chem. Rev. 1993, 93, 2023.

11. Kobayashi, S.; Busujima, T.; Nagayama, S. Synlett 1999, 545.

12. Bellucci, C.; Cozzi, P. G.; Umani-Ronchi, A. Tetrahedron Lett. 1995, 36,

7289.

13. Akiyama, T.; Iwai, J. Tetrahedron Lett. 1997, 38, 853.

14. Hachiya, I.; Kobayashi, S. J. Org. Chem. 1993, 58, 25.

15. Olah, G, A.; Friedel-Crafts and related reactions; Wilely-Interscience: New

York, 1964, Vol II, part 1.

116

16. Kobayashi, S.; Moriwaki, M.; Hachiya, I. J. Chem. Soc. Chem. Commun.

1995, 1527.

17. Kobayashi, S.; Ishitani, H.; Nagayamma, S. Chem. Lett. 1995, 423.

18. Matsuo, J.; Tsuchiya, T.; Odashima, K.; Kobayashi, S. Chem. Lett. 2000,

178.

19. Hasimoto, S.; Komeshima, N.; Koga, K. J. Chem. Soc. Chem. Comm. 1979,

437.

20. Kobayashi, S.; Araki, M.; Hachiya, I. J. Org. Chem. 1994, 59, 3758.

21. Review: Hart, F. A. Comprehensive Coordination Chemistry (Ed.; G.

Wilkinson), vol, 3, Pergamon, Yew York, 1987, 1059.

22. Avila, H.; Smania, E.; Monache, F.; Junior, A. Bioorg. Med. Chem. 2008, 16,

9790.

23. Nowakowska, Z. Eur. J. Med. Chem. 2007, 42, 125.

24. (a) Nowakowska, Z. Eur. J. Med. Chem. 2007, 42, 125. (b) Yang, H. M.;

Shin, H. R.; Cho, S. H.; Bang, S. C.; Song, G.Y.; Ju, J. H.; Kim, M. K.; Lee,

S. H.; Ryu, J. C.; Kim, Y.; Jung, S. H. Bioorg. Med. Chem. 2007, 15, 104. (c)

Lee, S. H.; Seo, G. S.; Kim, J. Y.; Jin, X. Y.; Kim, H. D.; Sohn, D. H. Eur. J.

Pharmacol. 2006, 532, 178. (d) Rajendra, P.; Srinivasa, R. A.; Rambabu, R.

Asian. J. Chem. 2009, 21, 907.

25. Siddiqui, Z. N.; Praveen, S.; Musthafa, T. N. M.; Ahmad, A.; Khan, A. U. J.

Enz. Inhib. Med. Chem. 2012, 27, 84.

26. (a) Valla, A.; Valla, B.; Cartier, D.; Guillou, R.; Labia, R.; Florent, L. Eur. J.

Med. Chem. 2006, 41, 142. (b) Dominguez, J.; León, C.; Rodrigues, J.;

Domínguez, N.; Gut, J.; Rosenthal, P. Farmacology 2005, 60, 307. (c) Motta,

117

L. F.; Gaudio, A. C.; Takahata, Y. Inter. Elect. J. Mol. Design. 2006, 5, 555.

(d) Dominguez, J.; Charris, J.; Lobo, G.; Gamboan, N.; Dominguez, N.;

Moreno, M.; Riggione, F.; Sanchez, E.; Olson, J.; Rosenthal, P. Eur. J. Med.

Chem. 2001, 36, 555. (e) Liu, M.; Wilairat, P.; Go, M. L. J. Med. Chem.

2002, 45, 1734.

27. Seo, W.; Ryu, Y.; Curtis-Long, M.; Lee, C.; Ryu, H.; Jang, K. Eur. J. Med.

Chem. 2010, 45, 2010.

28. Tomar, V.; Bhattacharjee, G.; Kamaluddina, Kumar, A. Bioorg. Med. Chem.

Lett. 2007, 17, 5321.

29. Trivedi, J. C.; Bariwal, J. B.; Upadhyay, K. D.; Naliapara, E. D.; Joshi, S. K.;

Pannecouque, C. C.; Clercq, E. D.; Shah, A. K. Tetrahedron Lett. 2007, 48,

8472.

30. Lin, Y.; Zhou, Y.; Flavin, M. T.; Zhou, L.; Nie, W.; Chen, F. Bioorg. Med.

Chem. 2002, 10, 2795.

31. Gacche, R.; Dhole, N.; Kamble, S.; Bandgar, B. J. Enz. Inhib. Med. Chem.

2008, 23, 28.

32. Ducki, S.; Forrest, R.; Hadfield Kendall, A.; Lawrence, R.; McGown, A.;

Rennison, D. Bioorg. Med. Chem. Lett. 1998, 8, 1051.

33. Boeck, P.; Falco, C.; Leal, P.; Yunes, R.; Filho, V.; Torres-Santos, E.; Rossi-

Bergmann, B. Bioorg. Med. Chem. Lett. 2006, 14, 1538.

34. Zhao, L.; Jin, H.; Sun, L.; Piaoa, H.; Quana, Z. Bioorg. Med. Chem. Lett.

2005, 15, 5027.

35. Bonesi, M.; Loizzo, M.; Statti, G.; Michel, S.; Tillequin, F.; Menichini, F.

Bioorg. Med. Chem. Lett. 2010, 20, 1990.

118

36. Horowitz, R. M.; Gentili, B. U. S. Patent. 1975, 3, 890, 298, Chem. Abstr.

1975, 83, 147706.

37. Delcarmen, M.; Barrio, G. Barrio, J. R.; Walker, G.; Noveli, A.; Leonard, N.

J. J. Am. Chem. Soc. 1973, 95, 489.

38. Mitsubishi Petrochemical Co. Ltd., British Patent 1968, 1,128, 90.

39. Hercules Powder Co., British Patent 1959, 873, 021.

40. Hayakawa, G.; Inoue, T. Japanese Patent. 1971, 7, 386.

41. Phillip's, N. V. Gloeilampenfabrieken. Netherland Patent. 1966, 6, 841.

42. Adams, J. H. British Patent, 1971, 1, 250, 388.

43. Russell, A. J. Chem. Soc.1934, 1506.

44. Mitter, P.; Saha, S. J. Indian Chem. Soc. 1934, 11, 257.

45. Shinoda, J.; Sato, S.; Kawagoe, M. J. Pharm. Soc. Jpn. 1904, 24, 1459.

46. Shinoda, J.; Sato, S. J. Pharm. Soc Jpn. 1929, 49, 64.

47. Schraufstater, E.; Deutch, S. Chem. Abstr. 1950, 44, 3563.

48. Kostanecki, S. V.; Tambor. J. Chem. Ber. 1899, 32, 1921.

49. (a) Rupe, H.; Wasserzug, D. J. Chem Ber. 1901, 34, 3527. (b) Hermes, S. A.

Chem. Ber. 1969, 70, 96422. (c) Breslow, D. S.; Houser, C. R. Chem. Ber.

1940, 62, 2385.

50. (a) El. M. A.; Hashah, M.; El-Kady, Saiyed, M. A.; Elaswy, A. A. Egypt. J.

Chem. 1985, 27, 715. (b) Crawley, L. S.; Fanshawe, W. J. J. Heterocyclic

Chem. 1977, 14, 531. (c) Taylor, E. C.; Morrison, R. W. J. Org. Chem.

1967, 32, 2379. (d) Utale, P. S.; Raghuvanshi, P. B.; Doshi, A. G. Asian J.

Chem. 1998, 10, 597.

51. Kohler, E. P.; Chandwell, H. M. Org. Synth. Coll. 1922, 2, 1.

119

52. (a) Schraufstalter, E.; Deutsch, S. Chem. Ber. 1948, 81, 489. (b) Smith, H.

E.; Paulson, M. C. J. Am. Chem. Soc. 1954, 76, 4486. (c) Obara, H.;

Onodera, J.; Kurihara, Y. Bull. Chem. Soc. Jpn. 1971, 44, 289. (d) Shinoda,

J.; Sato, S. J. Pharm. Soc. Japan 1928, 48, 791. (e) Kurth, E. F. J. Am.

Chem. Soc. 1946, 68, 697. (f) Gaissman, T. A.; Clinton, R. O. J. Am.

Chem. Soc. 1946, 68, 697. (g) Martin, G. J.; Beler, J. M.; Avakian, S. U. S.

Patent 1956, 2, 769.

53. Fujise, S.; Tatsuta, H. J. Chem. Soc. Jpn. 1942, 63, 932.

54. Dhar, D. N.; Lal, J. B. J. Org. Chem. 1958, 23, 1159.

55. Davey, W.; Gwilt, J. R. J. Chem. Soc. 1957, 1008.

56. (a) Lyle, R. E.; Paradis, L. P. J. Am. Chem. Soc. 1955, 77, 6667. (b)

Marathey, M. G. J. Uni. Poona. 1952, 1.

57. Michael, A.; Ueber die. J. Prakt. Chem. 1887, 35, 349.

58. Tomioka, K.; Nagaoka, Y. In Comprehensive Asymmetric Catalysis, ed.

Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.; Springer-Verlag, Berlin,

Heidelberg, vol 3, ch. 31.1; for a comprehensive discussion on preparation,

handling and safety issue of organometallic reagents, see: L. Brandsma and

H. Verkruijsse, Preparative Polar Organometallic Chemistry 1, Springer-

Verlag Berlin, Germany, 1987; Organometallics in Synthesis, a Manual, ed.

M. Schlosser, Wiley VHC, Weinheim, Germany, 2002, 2nd edn.

59. Kommenos, T. Justus Liebigs Ann. Chem. 1883, 218, 145.

60. Till, O. Synthesis 2009, 12, 1941.

61. (a) Lapworth, A. J. Chem. Soc. Trans. 1903, 83, 995. (b) Kurtz, P. Ann.

Chem. 1951, 572, 23. (c) Allen, C. F. H.; Johnsons, H. B. Organic Synthesis

120

Wiley, New York, 1963, Collect Vol. IV, pp. 804. (d) Groutas, W. C.;

Felker, D. Synthesis 1980, 861. (e) Nazarov, I. N.; Zavyalov, J. Gen. Chem.,

USSR Engl. Transl. 1954, 24, 475. (F) House, H. O. Modern Synthetic

Reactions, 2nd

ed.; Benjamin, Inc.; New York, 1972, 623. (g) Kawasaki, Y.;

Fujii, A.; Nakano, Y.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 1999, 64, 4214.

(h) Iranpoor, N.; Firouzabadi, H.; Akhlaghinia, B.; Nowrouzi, N. J. Org.

Chem. 2004, 69, 2562.

62. Seokan, P.; Hae-Jo, K. Chem. Commun. 2010, 46, 9197.

63. (a) Wang, J.; Liu, L. W.; Chu, V.; Lin, Y.; Liu, L. X.; Feng, X. Org. Lett.

2010, 12, 1280. (b) Mazet, C.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2008,

47, 1762. (c) Madhavan, N.; Weck, M. Adv. Synth. Catal. 2008, 350, 419. (d)

Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato, A.; Furusho, S.; Kanai, M.;

Shibasaki, M. Tetrahedron 2007, 63, 5820. (e) Mowry, D. T. Chem. Rev.

1948, 42, 189. (d) Nagata, W. Okumura, T. Yoshioka, M. J. Chem. Soc.

1970, 2347. (e) Baeza, A.; Najera, C.; Retamosa, M.; Sansano, G.; De, J. M.

Synthesis 2005, 2787.

64. Siwicka, A.; Cuperly, D.; Tedeschi, R.; Vezouet, L.; White, A. J. P.;

Barrett, A. G. M. Tetrahedron 2007, 63, 5903.

65. (a) Muratake, H.; Natsume, M. Tetrahedron 2006, 62, 7071. (b) Mander, L.

N.; Thomson, R. J. J. Org. Chem. 2005, 70, 1654. (c) Rahman, S. M. A.;

Ohno, H.; Yoshino, H.; Satoh, N.; Sukaguchi, M. T.; Murakami, K.; Iwata,

C.; Maezaki, N.; Tanaka, T. Tetrahedron 2001, 57, 127. (d) Rahman, S. M.

A.; Ohno, H.; Maezaki, N.; Iwata, C.; Tanaka, T. Org. Lett. 2000, 2, 2893.

(e) He, B.; Li, Y.; Feng, X. Synlett 2004, 1776.

121

66. (a) Higuchi, K.; Onaka, M.; Izumi, Y. Bull. Chem. Soc. Jpn. 1993, 66, 2016.

(b) Nagata, W.; Yoshioka, M. Org. React. 1977, 25, 255.

67. Utimoto, K.; Obayashi, M.; Shishiyama, Y.; Inoue, M.; Nozaki, H.

Tetrahedron Lett. 1980, 21, 3389.

68. Utimoto, K.; Wakabayashi, Y.; Horiie, T.; Inoue, M.; Shishiyama, Y.;

Obayashi, M.; Nozaki, H. Tetrahedron 1983, 39, 967.

69. Hayashi, M.; Kawabata, H.; Shimono, S.; Kakehi, A. Tetrahedron Lett.

2000, 41, 2591.

70. Yadav, L. D. S.; Aswathi, C.; Rai, A. Tetrahedron Lett. 2008, 49, 6360.

71. Iida, H.; Moromizato, T.; Hamana, H.; Matsumoto, K. Tetrahedron Lett.

2007, 48, 2037.

72. Tanaka, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 6072.

73. (a) Yamatsugu, K.; Kamijo, S.; Suto, Y.; Kanai, M.; Shibasaki, M.

Tetrahedron Lett. 2007, 48, 1403. (b) Mita, T.; Sasaki, K.; Kanai, M.;

Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 514. (c) Tanaka, Y.; Kanai, M.;

Shibasaki, M. Synlett 2008, 2295.

74. Nobuhito, K.; Noriyuki, N.; Yusuke, S.; Masato, U.; Takeshi, O. Angew.

Chem. Int. Ed. 2011, 50, 5541.

75. Yanagisawa, A.; Nezu, T.; Mohri, S. Org. Lett. 2009, 11, 5286.

76. (a) Yang, V.; Shen, V.; Chen, F. X. Synthesis 2010, 1325. (b) Yang, J.; Wu,

S.; Chen, F. X. Synlett 2010, 18, 2725. (c) Yang, J.; Wang, Y.; Wu, S.; Chen,

F. X. Synlett 2009, 20, 3365. (d) Aki, M.; Sami, J. K.; Ari, M. P. J. Org.

Chem. 2007, 72, 5411.

122

77. (a) Surya, K.; Richard, A. Tetrahedron Lett. 2005, 46, 1811. (b) Kobayashi,

S.; Siguira, M.; Kitagawa, H.; Lam, W. W. Chem. Rev. 2002, 102, 2227. (c)

Kobayashi, S. Eur. J. Org. Chem. 1999, 15. (d) Kobayashi, S. Chem. Soc.

Rev. 1999, 28, 1. (e) Yadav, J. S.; Reddy, B. V. S.; Parisse, C.; Carvalho,

P.; Rao, T. P. Tetrahedron Lett. 2002, 43, 2999.

78. Kawasaki, Y.; Fujii, A.; Nakano, Y.; Sakaguchi, S.; Ishil, Y. J. Org. Chem.

1999, 64, 4214.

79. Yang, J.; Wu, S.; Chen. F. X. Synlett 2010, 18, 2725.

80. Utimoto, K.; Wakabayashi, Y.; Horiie, T.; Inoue, M.; Shishiyama, Y.;

Obayashi, M.; Nozaki, H. Tetrahedron 1983, 39, 967.

81. Glenn, M.; Sammis, Hiroshi, D.; Jacobsen, E. J. Am. Chem. Soc. 2004, 126,

9928.

82. Iida, H.; Moromizato, T.; Hamana, H.; Matsumoto, K. Tetrahedron Lett.

2007, 48, 2037.

83. Ellis, J. E.; Davis, M.; Brower, P. L. Organic Process Research &

Development. 1997, 1, 250.

84. Ciller, J. A.; Seoane, C.; Soto, J. L. Liebigs Ann. Chem. 1985, 51.

85. Jingya, Y.; Fuxue, C. Chin. J. Chem. 2010, 28, 981.

86. Davis, R. J. Org. Chem. 1959, 24, 879.