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Chapter-III Scandium(III) triflate catalyzed 1,4-addition...
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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
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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.
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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.
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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.
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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.
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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
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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.
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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
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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
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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,
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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
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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
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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.
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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
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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
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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).
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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
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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.
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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.
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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.
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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
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