Arylidene Derivatives as Synthons in Heterocyclic Synthesis

doi:10.4236/oalib.1100367

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Published Online May 2014 in OALib. http://www.oalib.com/journal

http://dx.doi.org/10.4236/oalib.1100367

How to cite this paper: El-Gohary, N.S. (2014) Arylidene Derivatives as Synthons in Heterocyclic Synthesis. Open Access Li-

brary Journal, 1: e367. http://dx.doi.org/10.4236/oalib.1100367

Arylidene Derivatives as Synthons in

Heterocyclic Synthesis

N. S. El-Gohary

Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt

Email: dr.nadiaelgohary@yahoo.com

Received 18 March 2014; revised 25 April 2014; accepted 7 May 2014

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

Abstract

This review describes the synthetic procedures for the preparation of arylideneacetophenones,

arylidenecycloalkanones, 2-arylidene-1-indanones, 2-arylidene-1-tetralones, 2-arylidene-1-ben-

zosuberones, aurones, 1-thioaurones, 3-arylidene-4-chromanones, 3-arylidene-1-thio-4-chroma-

nones, 3-arylideneflavanones, 3-arylidene-1-thioflavanones, arylideneanilines, arylidenemalono-

nitriles, diethyl arylidenemalonates, ethyl arylidenecyanoacetates, arylidenecyanoacetamides, 5-

arylidene derivatives of barbituric and thiobarbituric acids, arylidene derivatives of Meldrum’s

acid and arylidene derivatives of dimedone. Also, it demonstrates the reactivity of these arylidene

derivatives in heterocyclic synthesis with emphasis on the most recent findings. Some of these are

the α,β-enones, víz. aurones and 3-arylidene-4-chromanones belong to the natural products. The

others are synthetic substances which are convenient and important intermediates for the syn-

thesis of a variety of useful and novel heterocyclic systems.

Keywords

Arylidenes, Synthesis, Reactions, Heterocycles

1. Introduction

The chemistry of different arylidene compounds has generated intensive scientific studies throughout the world.

Especial interest has been focused on the synthesis and pharmacological activities of different arylidene com-

pounds. They are versatile synthons so that a variety of novel heterocycles with good pharmaceutical profiles

can be designed. Those arylidenes are usually prepared through Knoevenagel condensations of aldehydes with

active methylene compounds, they are usually base [1], Lewis acid [2], or surfactant-catalyzed [3]; thus, create

much wastes. Recen tly, there was an interest in so-called solven t-free [4] [5] Knoevenagel condensations on solid

supports that were promoted by infrared [6] or microwave irradiation [7] [8]. Unfortunately, the latter tech niques

N. S. El-Gohary

require solvents for the extraction from the solid supports as well as for the preparation of the initial adsorbates,

and do not yield pure products. Thus, further solvents are required for purifying the workup. Even catalys t-free

Knoevenagel reactions in water could not reach quantitative yields [9]-[11]. This research deals with the various

methods of preparation of arylideneacetophenones, arylidenecycloalkanones, 2-arylidene-1-indanones, 2-aryli-

dene-1-tetralones, 2-arylidene-1-benzosuberones, aurones, 1-thioaurones, 3-arylidene-4-chromanones, 3-aryli-

dene-1-thio-4-chromanones, 3-arylideneflavanones, 3-arylidene-1-thioflavanones, arylideneanilines, arylidene-

malononitriles, diethyl arylidenemalonates, ethyl arylidenecyanoacetates, arylidenecyanoacetamides, 5-aryli-

dene derivatives of barbituric and thiobarbituric acids, arylidene derivatives of Meldrum’s acid and arylidene

derivatives of dimedone as well as their utilizatio n in heterocyclic synthesis.

2. Synthesis

2.1. Synthesis of Arylideneacetophenone Derivatives (Chalcones)

Different methods are available for the preparation of chalcones [12]-[14]. The most convenient method is the

Claisen-Schimdt condensation of equimolar quantities of arylmethylketones with aryl aldehydes in the presence

of aqueous alcoholic alkali [15]-[25]. Chalcones are used to synthesize several derivatives like cyanopyridines,

pyrazolines, isoxazoles, and pyrimidines having different heterocyclic ring systems [26]-[29].

2.1.1. Various Condensing Agents Have Been Used in the Synthesis of Chalcon es

1) Alkal i

Alkalis are the most widely used condensing agents for the synthesis of chalcones. They are used as an aque-

ous alcoholic solution of suitable concentration viz. 30%, 40%, 50% and 70% [15]-[25 ].

2) Acids

Methanolic solution of dry hydrochloric acid gas at 0˚C was us ed for the synthesis of chalcones from aromatic

ketones and aldehydes [26] [27]. In addition, concentrated sulfuric acid in acetic acid was used as a condensing

agent in the synthesis of chalcones [28].

3) Other Condensi n g Agents

Raval and Shah [29] used phosphorous oxychloride as a condensing agent to synthesize chalcones. In addition,

Szell and Sipos [30] condens e d 2-hydroxy-5-nitroacetophenone wit h benzalde hyde usin g a nhydrous A lCl3.

Besides the above, other condensing agents have been used in the synthesis of chalcones; namely, amino ac-

ids [31], an aqueous solution of borax [32], perchloric acid [33], piperidine [34], boron trifloride [35], alkali

metal alkoxides [36], magnesium tert-butoxide [37], and thionyl chloride [38].

In recent years, microwave assisted solid support solvent-free organic synthesis have attracted the attention as

they offer several advantages such as simple procedure, fast reaction rate, mild reaction conditions, eco-friendly

and improved yields as compared to conventional methods [39] [40].

2.1.2. Mechanism

The follo wi ng mechani s ms have been s ug ge sted for the synthesi s of chalco ne s:

1) Base catalyzed reaction (Scheme 1) [21] [41].

2) Acid catalyzed reaction (Scheme 2) [42].

2.1.3. Reactivity of Chalcone Derivatives

The chalcones 1 are useful intermediates for the synthesis of a variety of heterocyclic compounds. Isoxazoles 2

are prepared by the reaction of chalcones 1 with hydroxylamine hydrochloride and sodium acetate [43] (Scheme

3). Treatment of chalcones 1 with guanidine hydrochloride in the presence of alkali afforded 2-aminopyrimi -

dines 3 [44] (Scheme 3). Thiazines 4 and oxazines 5 can be synthesized by reaction of chalcones 1 with thiourea

and urea, respectively [45] (Scheme 3). Pyrazoles 6, 7 are obtained through the reaction of chalcones 1 with hy-

drazine hydrate and phenyl hydrazine derivatives, respectively [46]-[49] (Scheme 3). Furthermore, reaction of

hydrazine hydrate with 1 in the presence of different aliphatic acids resulted in the formation of pyrazole de-

rivatives containing N-acyl moiety 8a-c [49] [50] (Scheme 3). Condensation of chalcones 1 with malononitrile

and ammonium acetate yields 2-ami no-3-cyanopyridines 9 [49] [51] (Scheme 3). On the other hand, reaction of

1 with malononitrile in refluxing methanol or ethanol and in the presence of freshly prepared sodium alkoxide

solution yielded 3-cyanopyridines 10 [52] (Scheme 3). Reaction of cyanopyridines 10 with hydrazine hydrate

N. S. El-Gohary

(i)

(ii)

H-H

Scheme 1. Mechanism of base catalyzed condensation of aromatic ketones with aldehydes.

ArH

(i)

HAr

(ii)

OH OH

ArH

HAr

ArH

OH O

-H

Scheme 2. Mechanism of acid catalyzed condensation of aromatic ketones with al de hydes .

N. S. El-Gohary

Ar1Ar

NH2OH

Ar1

H2NNH2N N

Ar Ar1

NH2

Ar Ar1

NH2

H2NNH2

H2NNH2NO

Ar Ar1

NH2

NH2NH2.H2O

Ar1

NH2

NHNH2

Ar1

NH2NH2.H2O

RCOOH N

Ar1

Ar 8a: R= H

8b: R= CH3

8c: R= C3H7

COR

O12

COOC2H5

MeONa/MeOH

or EtONa/EtOHN

Ar1

OMe

NH4OAc

Ar1

(Et)

Urea-hydrogen peroxideAr

NNHNH

. HCl N

HN NH

NNH

HN NH

O O

Ar Ar

NAr

NNH

13a: R= H

13b: R= CH

Ar Ar

COCH

ArAr

CONH

COCH

HNOC

CONHNH

COOR

COCH

24a: R= CH

24b: R= C

O Ar

COOR

Scheme 3. Preparation of compounds 2-10 and 12-24.

using Lewis acid (1.0 equivalent of BF3∙Et2O) in refluxing ethanol under anhydrous conditions afforded 1H-py-

razolo[3,4-b]pyridines 11 in very good yields and short r eaction time [52] (Scheme 4). Similarly, treat ment of 1

with ethyl cyanoacetate in absolute ethanol and in the presence of ammonium acetate afforded cyanopyridine

derivatives 12 [49] (Scheme 3). Reaction of 1 with cyclohexane-1,3-diones produced 2,4-diaryl-5-oxo-5,6,7,8-

tetrahydro-2-chromenes 13a, b. [53] Similarly, acetoacetanilide and acetylacetone reacted with chalcones 1 to

afford cyclohexenone derivatives 14 and 15, respectively [49] (Scheme 3). Epoxidation of chalcones 1 with

urea-hydrogen peroxide (UHP) under ultrasound irradiation gave oxirane derivatives 16 [54] (Scheme 3). Reac-

tion of 1 with semicarbazide hydrochloride in glacial acetic acid/dioxane afforded pyrazoline-1-carboxamides

17 [55] (S cheme 3). The barbitones 18 are obtained upon condensation of chalcones 1 with barbituric acid [49]

[56] [57] (Scheme 3). Treating 1 with 4,5-diaminopyrimidine gave [1,4]diazepine derivatives 19 [58] (Scheme

3). Condensation of chalcones 1 with 2-aminothiophenol afforded [1,4]benzothiazepines 20 [59] (Scheme 3).

Tetrahydro-1H-azepines 21 were synthesized via reaction o f 1 with ethylen ediamine [60] (Scheme 3). Reaction

of chalcones 1 with cyclohexanone in benzene in the presence of sodium hydroxide and a catalytic amount of

N. S. El-Gohary

tributyl benzyl ammonium chloride (TBBAC) at room temperatue afforded 2-(1-oxo-1,3-diarylpropan-2-yl)

cyclohexanones 22 [61] [62] (Scheme 3). Furthermore, reaction of 1 with isonicotinoyl hydrazide in refluxing

ethanol gave N-isonicotinoyl-3,5-diarylpyrazolines 23 (Scheme 3) [49]. Reaction of 1 with methyl acetoacetate

or ethyl acetoacetate in refluxing ethanol and in the presence of catalytic amounts of piperidine and basic alu-

mina afforded 4,6-diaryl-2-oxocyclohex-3-enecarboxylates 24a, b [49] [63] (Scheme 3). Condensation of cy-

clohexenecarboxylates 24a, b with hydrazine hydrate produced 4,6-diaryl-3-oxo-2,3,4,5-tetrahydroindazoles 25

[49] (Scheme 5).

2.2. Synthesis of Arylidenecycloalkanone Derivatives

Arylidenecycloalkanones are frequently used α,β-unsaturated ketones. Their synthesis is based on the reaction of

the appropriate cyclic ketone with aldehydes, through aldol condensation reaction. Several reports exist for their

synthesis [64]-[69], involving the use of organic and inorganic bases, metal catalysts, different types of Friedel-

Crafts catalysts and trichloro-1,3,5-triazine (TCT). A more convenient method used solid potassium hydroxide

[70] [71] or sodium hydrox ide [72] as a catalyst for the condensation of different aldehydes with cycloalkanones

in ethanol and resulted in α,α'-bis(substituted benzylidene)cycloalkanones 26 and 27 in good yields. This me-

thod is economical and eco-friendly as neither any byproduct was formed nor any toxic material was used dur-

ing the synthesis, and the reactions were carried out at ambient temperature. In addition, the same condensation

was carried out in refluxing ethanol and in the presence of a catalytic amount of ammonium chloride to afford

α,α'-bis(arylidene)cycloalkanones [73]. Moreover, a simple and efficient procedure for the synthesis of α,α'-bis

(arylidene)cycloalkanones has been developed using N-bromosuccinimide (NBS) as a catalyst under mild reac-

tion conditions [74]. Recently, a simple, improved and solvent-free synthesis of 26 and 27 was perfo rmed using

activated barium hydroxide and grinding three to five minutes at room temperature [75].

Reaction of cyclopentanone with substituted benzaldehydes (1:2 molar ratio) in alcoholic alkali so lution pro-

duced α,α'-bis(substituted benzylidene)cyclopentanones 26 (Scheme 6) [76] [77].

Cyclohexanone was reacted with substituted benzaldehydes under alkaline reaction conditions (1:2 molar ra-

tio) to afford α,α'-bis(substituted benzylidene)cyclohexanones 27 which could be easily separated (Scheme 7)

[76]-[82]. The same condensation was carried out using amino-functionalized ionic liquid, 1-aminoethyl-3-me-

thyl tetrafluoroborate ([2-aemim][BF4]) as solvent and catalyst [83]. In addition, Brønsted acid-surfactant cat-

alyst was utilized for synthes is of α,ά-bis(substituted benzylidene)cyclohexanones in aqueous media [84].

In addition, α,α'-bis(substituted benzylidene)cycloalkanones 26 and 27 could be obtained by refluxing 1,1-

diacetates and cycloalkanones in tetrahydrofuran (THF) and in the presence of Samarium (III) Triiodide (SmI3)

as a catalyst (Scheme 8) [85].

Cyclohexylphenyl methanols 28 were prepared by D-glucosamine catalyzed aldol reaction of cyclohexanone

with substituted benzal de hydes (Scheme 9) [86].

3,5-Dibenzylidene-4H-pyran-4-ones (30, X = O) and 3,5-dibenzylidene-4H-1-thiopyran-4-ones (30, X = S)

were synthesized via reaction of tetrahydr o-4H-pyran -4-one (29, X = O) or tetrahydro-4H-1-thiopyran-4-one (29,

X = S) with substituted benzaldehydes either under alkaline [87]-[90] or acidic [91] [92] reaction conditions

(Scheme 10).

NH2NH2.H2O

BF3.Et2O/EtOH N

Ar1

OMe

(Et)

NH2

Scheme 4. Preparation of compounds 11.

Ar1

24a,b

Ar1

COOR

NH2NH2.H2O

Scheme 5. Preparation of compounds 25.

N. S. El-Gohary

OHC

EtOH

Scheme 6. Preparation of compounds 26 through reaction of cyclopenta-

none with substituted benzaldehydes under alkaline conditions.

HOHC

OH R

EtOH

Scheme 7. Preparation of compounds 27 through reaction of cyclohex-

anone with substituted benzaldehydes under alkaline conditions.

SmI

THF, reflux

26:

n=1

AcO

n=1; 2

27:

n=2

Scheme 8. Preparation of compounds 26 and 27 through reaction of 1,1-

diacetates and cycloalkanones.

OHC

D-glucosamine

O, 30

Scheme 9. Preparation of compounds 28.

OHC

29:

X = O; S

30:

X = O; S

Scheme 10. Preparation of compounds 30.

2.3. Synthesis of 2-Arylidene-1-Indanone Derivatives

2-Arylidene-1-indanones 32 are important intermediates for the synthesis of a wide variety of heterocyclic ring

systems. For this reason, it is useful to have simple and convenient procedures for their preparation. Most of the

utilized syntheses are based on the condensation of 1-indanones 31 with aldehydes in the presence of a catalyst

to afford 2-arylidene-1-indanones 32 (Scheme 11).

In most cases sodium or potassium hydroxide is used as a catalyst [93]-[99] and 2-arylidene-1-indanones 32

are obtained in good yields. In addition, various inorganic acids, viz. sulfuric, phosphoric or hydrochloric acids

were used as catalysts to prepare 32 [100]-[105]. It is worth mentioning that acetic anh ydride was used to facili-

tate the condensation of indanones with substituted benzaldehydes [106]. Basavaiah and Reddy [107] have in-

troduced a simple one-pot procedure for the preparation of 2-arylidene-1-indanones 32 starting from tert-butyl

3-aryl-3-hydroxy-2-methylenepropanoate 33, which was allowed to react with a catalytic amount of concen-

N. S. El-Gohary

trated sulfuric acid in benzene followed by reaction of the intermediates formed with trifluoroacetic anhydride

(TFAA) in methylene chloride to afford 32 (Scheme 12).

Reactivity of 2-Arylidene-1-Indanone Derivatives

The synthesis of indeno[1,2-c]pyrazoles 34 was accomplished via reaction of 2-aryliden e -1-indanones 32 with

phenylsulfonylhydrazide in an inert solvent such as aromatic hydrocarbon and in the presence of a catalytic

amount of acid [108] (Scheme 13). The [3 + 2] cycloaddition reactions of 2-arylideneindanones 32 with the

arylnitrile oxides generated in situ from arylhydroxyaminoyl chlorides 35 and triethylamine led to the formation

of the spiro derivatives 36 [109] (Scheme 14).

2.4. Synthesis of 2-Arylidene-1-Tetralone Derivatives

2-Arylidene-1-tetralones 38 are useful intermediates for the synthesis of polycyclic ring systems. Several syn-

thetic methods have been developed for their preparation. The majority of compounds 38 have been synthesized

by the condensation of 1-tetralones 37 with aromatic aldehydes in aqueous alcoholic solution of sodium or po-

tassium hydroxide [94] [110]-[122]. Piperidine is another alkaline catalyst which has also been used to obtain

2-arylidene-1-tetralones 38 [108] [123]-[126]. In addition, acidic catalysts such as sulfuric, phosphoric and hy-

drochloric acids were utilized for this condensation [127]-[129] (Scheme 15).

Reactivity of 2-Arylidene-1-Tetralone Derivatives

The naphtho[1,2-c]pyrazole derivatives 39 were prepared via reaction of 2-arylidene-1-tetralones 38 with phe-

nylsulfonylhydrazide in an inert solvent such as aromatic hydrocarbon and in the presence of a catalytic amount

of acid [108] (Scheme 16).

The reaction of 38 with the bicyclic carbonyl ylide 41 generated from the α-diazo ketone 40 in the presence of

Rh2(OAc)4, afforded the spirodioxa ring systems 42 [130] (Scheme 17).

OHC

31 32

Scheme 11. Preparation of compounds 32 through condensa-

tion of 1-indanones 31 with aldehydes.

HO COOtBu

Benzene Ar

H COOtBu

HCOOH TFAA

33 32

Scheme 12. Preparation of compounds 32 starting from tert-butyl 3-a ry l-3-hydroxy-2-methyle ne -

propanoate 33.

NHNO

NNH

Scheme 13. Preparation of compounds 34.

Ar1C

NOH

Ar1

Et3N

Scheme 14. Preparation of compounds 36.

N. S. El-Gohary

ArOHC

37 38

Scheme 15. Preparation of compounds 38.

NHNO

NNH

Scheme 16. Preparation of compounds 39.

(OAc)

Scheme 17. Preparation of compounds 42.

Moreover, the preparation of benzo[g]pyrazolo[3,4-b]quinolines 43 was accomplished via cyclocondensation

reaction of 38 with ami nopyrazoles under solvent-free conditions [131] (Scheme 18).

Treatment of 38 with potassium isothiocyanate gave 2-[aryl(isothiocyanato)methyl]-3,4-dihydronaphthalen-

1(2H)-ones 44. Reaction of 44 with primary aromatic amines gave 4-aryl-1-(substitu ted phenyl)-1,4,5,6-terahy-

drobenzo[h]quinazoline-2-thiols 45 [129] (Scheme 19).

Dispiropyrrolidinyl derivatives, 1',2',3',4'-tetrahydronaphthalen-1'-one-spiro[3'.3]-4-aryl-N-methylpyrro lid in e-

2-spiro -2''-acenaph th en-1''-ones 48 were obtained through reaction of 2-arylidene-1-tetralones 38, acenaphthy-

lenequinone 46 and sarcosine 47 in aqueous met ha nol [132] (Scheme 20).

Furthermore, 1',2',3',4'-tetrahydronaphthalen-1'-one-spiro[2'.3]-(4-aryl)pyrrolidine-spiro-[2.2'']oxindoles 50

were synthesized via reaction of 2-arylidene-1-tetralones 38, isatin (49) and benzylamine in dry acetonitrile [132]

(Scheme 21).

A new method to prepare benzo[c]xanthones 51 was reported by the ultraviolet radiation-mediated tandem

reaction through irradiating a solution of 2-benzylidene-1-tetralones 38 in acetonitrile with ultravio let light (500

W middle-pressure Hg) [133] (Scheme 22).

2.5. Synthesis of 2-Arylidene-1-Benzosuberone Derivatives

2-Arylidene-1-benzosuberones 53 were synthesized by the condensation of 1-benzosuberone 52 with aromatic

aldehydes using alka l i ne [96] [121] [134] [135] or acidic [136] catalysts (Scheme 23).

2.6. Synthesis of Aurone Derivatives

Aurones 55 are the oxa analogues of the 2-arylidene-1-indanones 32, different procedures were adopted for their

N. S. El-Gohary

NNNH

Fusion

NNN

Ar 43

Scheme 18. Preparation of compounds 43.

KNCS

N C S

NH2

44 45

Scheme 19. Preparation of compounds 45.

CH3

CH2COOH

OCH3

CH2

OCH3

CH2

MeOH/H2O

CH3

4647

Scheme 20. Preparation of compounds 48.

49 50

MeCN

Scheme 21. Preparation of compounds 50.

hv, O2

rose BengalO

OOH

R1O

MeCN

Scheme 22. Preparation of compounds 51.

N. S. El-Gohary

preparation. First, the Algar-Flynn-Oyamada reaction based on the oxidative cyclization of 2'-hydroxychalcones,

where aurone is one of the products formed during preparation of 2'-hydroxychalcone [137]-[139]. Another

procedure described by Donnelly and co-workers [140] [141] is based on bromomethylation of chalcones and

2'-acetoxychalcones followed by ring closure of the bromodihydro analogues providing aurones 55. However,

none of these procedures can be considered as a rational method for the synthesis of aurones.

The most common synthetic procedures for aurones 55 are based on the condensation of coumaran-3-ones 54

with substituted benzaldehydes in the presence of a catalyst. As catalyst, sodium hydroxide [142] [143], potassium

hydroxide [144], anhydrous sodium acetate [145], sulfuric [145], hydrochloric [146], and phosphor ic acids [ 147]

were used for this condensation (Scheme 24). Farkas et al. [148]-[150] performed the condensation of the ap-

propriate coumaran-3-one 54 with substituted benzaldehydes in refluxing acetic anhydride to obtain aurones 55.

Another synthetic procedure was developed for the prepa ration of aurones 55 through cyclization of 1-(2-hy-

droxyphen yl)-3-(substituted phenyl)prop-2-en-1-ones 56 in methanol and in the presence of a catalytic amount

of silver nitrate [151] (Scheme 25).

In addition, other synthetic procedures were adopted for the preparation of aurones 55 through cyclization of

56 using mercuric acetate in pyridine [152] [153], mercuric acetate in polyethylene glycol (PEG-400) [154],

mercuric acetate in dimethyl sulfoxide (DMSO) [155], and cupric bromide in DMSO [152] (Scheme 25).

ArOHC

OAr

52 53

Scheme 23. Preparation of compounds 53.

OHC

54 55

Scheme 24. Preparation of compounds 55 through condensation of coumaran-3-

ones 54 with substituted benzaldehydes.

Hg(OAc)

PEG-400 O

Hg(OAc)

Pyridine

Hg(OAc)

DMSO

CuBr

MeOH

AgNO

Scheme 25. Preparation of compounds 55 through cyclization of 1-(2-hydroxy-

phenyl)-3-(substituted phenyl)prop-2-en-1-ones 56.

N. S. El-Gohary

Mechanism of Cyclization Using Mercuric Acetate in Pyridine [152]

The mechanism of cyclization of 56 into aurone deri va tives 55 is illustrated in Scheme 26.

Furtherm ore, gold-catalyzed cyclization of alkynol derivatives 57 has become an efficient tool in the synthesis

of aurones 55 and provided the best results under mild reaction conditions and excellent selectivities, avoiding

the formation of flavones as byproducts [156] [157] (Scheme 27).

2.7. Synthesis of 1-Thioaurone Derivatives

1-Thioaurones 59 are synthetic thio analogues of the naturally-occurring aurones, their synthesis has already

been published [158]-[162]. Condensation of 1-thiocoumaran-3-ones 58 with aromatic aldehydes in the presence

of phospho ric acid [147] or piperidine [159] afforded 59. In addition, the same reaction was carried out in THF

and in the presence of 1.5 equivalents of lithium diisopropylamide (LDA) at −10˚C [163] (Scheme 28).

Moreover, a convenient one-step synthesis has been published [161], whereas, equimolar amounts of (2-me-

thylthio)benzoic acid derivatives 60 and aromatic aldehydes were allowed to react with 2.0 equivalents of LDA

in THF at 0˚C to yield 1-thioaurones 59 (Scheme 29).

In 2010, Boughaleb et al. [162] described new synthetic pathway for the preparation of 1-thioaurones 59

(Scheme 30).

Reactivity of Aurone and 1-Thioaurone Derivatives

Reaction of 55 or 59 with 2-aminoth iophenol in ethanol and in the presence of sodium ethoxide gave the spiro

compounds 61a, b. By the way of contrast, the 6,12-dihydrobenzofuro[2,3-c][1,5]benzothiazepines 62a and the

HgOAc

Hg(OAc)

Pyridine

Scheme 26. Mechanism of cyclization of compounds 56 into aurone

derivatives 55 using mercuric acetate in pyridine.

AuCl/

, MeCN

MnO

, CHCl

Scheme 27. Preparation of compounds 55 through cyclization of al-

kynol derivatives 57.

N. S. El-Gohary

OHC

Scheme 28. Preparation of compounds 59 through condensation of 1-thiocoumaran-3-ones

58 with aromatic aldehydes .

OHC

60 59

THF

LDA

Scheme 29. Preparation of compounds 59 through reaction of (2-methylthio)benzoic acid

derivatives 60 with aromatic aldehydes.

OHClCH

COOH NaOH SCH

COOH

AcOH

OCOCH

OHC

NaOH / N

RRR

Scheme 30. Preparation of compounds 59 starting from 2-mercaptobenzoic acid derivatives.

6,12-dihydrobenzothieno[2,3-c][1,5]benzothiazepines 62b were obtained in good yields v ia heating 55 or 59,

respectively with 2-aminothiophenol in polyphosphoric acid (PPA) under nitrogen. Treatment of 62a, b with

2-chloroethyl-N,N-dimethylammonium chloride and potassium carbonate in ethyl acetate produced the annu-

lated benzofuran and benzothiophene derivatives 63a, b. The tetracyclic derivatives 62a, b were deprotonated

with sodium hydride in DMF to afford compounds 64a, b [164] (Scheme 31).

Reaction of aurones 55 with hydrazine hydrate in ethanol gave the benzofuro[3,2-c]pyrazole derivatives 65.

Refluxing aurones 55 with phenyl hydrazine in glacial acetic acid gave the benzofuro[3,2-c]pyrazole derivatives

66. In addition, benzofuro[3,2-c]isoxazole derivatives 67 were synthesized by the reaction of aurones 55 with

hydroxylamine hydrochloride in alcoholic solution of potassium hydroxide. Furthermore, benzofuro[2,3-c]pyri -

dine derivatives 68 were obtained through reaction of aurones 55 with a cetamide in alcoholic solution of potas-

sium hydroxide. Finally, benzofuro[3,2-d]pyrimidine derivatives 69 were synthesized via reaction of aurones 55

with urea or thiourea in alcoholic solution of potassium hydroxide [165] (Scheme 32).

2.8. Synthesis of 3-Arylidene-4-Chromanone Derivatives

The synthesis and chemical transformation of 3-arylidene-4-chromanones and related compounds received much

attention due to the abundance of this moiety in many natural products and biologically active substances

[166]-[169]. Thiochromones are synthetic compounds and some of their derivatives are reported to have medi-

cinal uses [170] [171]. Current literature showed th at there has been an increasing trend towards the synthesis of

heterocycles containing these two ring systems [172].

The synthesis of 3-arylidene-4-chromanones 71 is based on the condensation of 4-chromanones 70 with aro-

matic aldehydes in the presence of a catalyst (Scheme 33). Acid-catalyzed condensation (H2SO4, H3PO4 or HCl)

of the two components was accomplished [173]-[180]. In addition, Farkas et al. [181]-[183] performed the same

reaction in hot acetic anhydride, which is a very simple and convenient method, but sometimes it requires a pro-

longed time. Another procedure used for the synthesis of 71 is the base catalyzed condensation of 4-chroma-

nones 70 with aromatic aldehydes using sodium hydroxide [184], sodium methoxide [185], anhydrous potas-

sium acetate [186], piperidine [187]-[189], or pyrrolidine [190]. A new synthetic method for 71 was through

N. S. El-Gohary

NH2

SH X

NaOEt

NH2

PPA / N

NaH / DMF

55: X=O 59: X=S

61a,b

62a,b 63a,b

64a,b

/ EtOAc

Scheme 31. Preparation of compounds 61-64.

NHph

OH.HCl

CONH

CNH

NNH

X = O; S

Scheme 32. Preparation of compounds 65-69.

N. S. El-Gohary

condensation of different aromatic aldehydes with 4-chromanones 70 using amberlyst-15 as a catalyst under mi-

crowave irradiation in solvent-free conditions [191]. However, it should be mentioned that in case of using pipe-

ridine as a catalyst, an exo-endo double bond migration takes place if the aldehyde has strong electron-with-

drawing substituents [188] [192]. In such a case, 3-arylmethyl-4-chromenone (homoisoflavone) 72 is the prod-

uct instead of the expected 3-arylidene-4-chromanone 71 (Scheme 34). Basavaiah et al. [107] [193] synthesized

3-arylidene-4-chromanones 71 by ring closure of the acrylic acid derivatives 73 with TFAA in methylene chlo-

ride (Scheme 35).

Reactivity of 3-Arylidene-4-Chromanone Derivatives

Refluxing a solution of 3-arylidene-4-chromanone 71, isatin (49) and sarcosine (74) afforded 4-ar yl -N-me -

thyl-spiro[2.3'](2-oxoindoline)-spiro[3.3'' ](substituted 4-chromanone)pyrrolidines 75 [194] (Scheme 36). Whe-

reas, refluxing a solution of 71, isatin (49) and L-proline (76) in aqueous methanol gave 4-aryl-spiro[2.3'](2-

oxoindoline)-spiro[3.3'']-(substituted 4-chromanone)hexahydropyrrolizines 77. The reaction proceeded via for-

mation of an azomethine ylide which readily undergoes 1,3-dipolar cycloaddition reaction with 3-arylidene-4-

chromanones to give a single cycloadduct [194] (Scheme 36).

2.9. Synthesis of 3-Arylidene-1-Thio-4-Chromanone Derivatives

The synthesis of 3-arylidene-1-thio-4-chromanones 79 is based on the condensation of 1-thio-4-chromanones 78

with aromatic aldehydes under acidic conditions [195]-[199]. The same condensation was accomplished using

piperidine as a catalyst [187]-[189], or amberlyst-15 under microwave irradiation [191] (Scheme 37). As de-

scribed for the condensation of 4-chromanone 70 with aromatic aldehydes [187] [188], in case of aromatic al-

dehydes bearing strongly electron-withdrawing substituents, an exo-endo double bond transposition also takes

place, resulting in the formation of 3-arylmethyl-1-thio-4-chromenones 80 instead of 3-arylidene-1-thio-4-

chromanones 79 [188] (Scheme 38).

2.10. Synthesis of 3-Arylideneflavanone Derivatives

3-Arylideneflavanones (flavindognides) 82 are well known flavanone derivatives. They were first synthesized by

Katschalowsky and von Kostanecki in 1904 [200]. They wer e also synthes ized by the acid -catalyzed cond ensation

OHC

70 71

Scheme 33. Preparation of compounds 71 through condensa-

tion of 4-chromanones 70 with aromatic aldehydes.

OHC

7072

ArCHO = Aromatic aldehydes substituted with electron-withdrawing groups

Piperidine

Scheme 34. Preparation of compounds 72.

TFAA

HOOC

Scheme 35. Preparation of compounds 71 through cyclization

of acrylic acid derivatives 73 with TFAA.

N. S. El-Gohary

MeOH / H

HO O

MeOH / H

71 49

Scheme 36. Preparation of compounds 75 and 77.

ArOHC

78 79

ArCHO = Aromatic aldehydes substituted with electron-donating groups

Scheme 37. Preparation of compounds 79.

ArCHO = Aromatic aldehydes substituted with electron-withdrawing groups

OHC

78 80

Scheme 38. Preparation of compounds 80.

of flavanones 81 with aromatic aldehydes [200]-[204] (Scheme 39). In addition, glycine was described as a ca-

talyst for this condens ation [205]. It was reported that in some cases the base catalyzed condensation of hydrox-

yacetophenone with benzaldehyde gave 3-benzylideneflavanone as a coproduct of the corresponding hydroxy-

chalcone [206]-[208]. Furthermore, the synthesis of 82 via base-catalyzed condensation of flavanone 81 with

aromatic aldehydes was reported [189] [209]. It is worth mentioning that if aldehydes with strong electron-with-

drawing substituents are used, 3-arylmethylflavones 83 are obtained instead of 3-arylideneflavanones 82 [210]

(Scheme 40). 3-Arylmethylflavones 83 w ere also obtained via treatment of 82 with pyridinium chlorochromate

(PCC) (5.0 equivalent) in DMF [211] (Scheme 41).

2.11. Synthesis of 3-Arylidene-1-Thioflavanone Derivatives

3-Arylidene-1-thioflavanones 85 were synthesized by the acid-catalyzed condensation of 1-thioflavanones 84

with aromatic aldehyd es [212] [213] (Scheme 42). Also, b ase catalyzed condensation of thioflavanones 84 with

aromatic aldehydes using piperidine was reported [214]. However, this procedure can be used only for the syn-

thesis of 3-aryliden e -1-thioflavanones substituted with electron-donating or slightly electron-withdrawing sub-

stituents in the aryliden e moiety. When aromatic aldeh ydes substituted with strongly electron-with drawing sub-

stituents were used, 3-arylmethyl-1-thioflavones 86 were obtained [214] [215] (Scheme 43).

Reactivity of 3-Arylidene-1-Thioflavanone Derivatives

Reaction of 3-arylid ene-1-thioflavanones 85 with sodium oxychloride and hydrogen peroxide gave 3-arylidene-

N. S. El-Gohary

ArCHO = Aromatic aldehydes substituted with electron-donating groups

OHC

81 82

Scheme 39. Preparation of compounds 82 through condensation

of flavanones 81 with aromatic aldehydes substituted with elec-

tron-donating groups.

ArCHO = Aromatic aldehydes substituted with electron-withdrawing groups

81 83

OHC

Scheme 40. Preparation of compounds 83 through condensation

of flavanones 81 with aromatic aldehydes substituted with strong

electron-withdrawing groups.

82 83

PCC (5 equiv.)

DMF, 40

Scheme 41. Preparation of compounds 83 through treatment of

3-arylideneflavanones 82 with pyridinium chlorochromate (PCC).

OHC

84 85

ArCHO = Aromatic aldehydes substituted with electron-donating groups

Scheme 42. Preparation of compounds 85 through condensation

of 1-thioflavanones 84 with aromatic aldehydes substituted with

electron-donating groups.

84 86

OHC

ArCHO = Aromatic aldehydes substituted with electron-withdrawing groups

Scheme 43. Preparation of compounds 86 through condensation

of 1-thioflavanones 84 with aromatic aldehydes substituted with

strong electron-withdrawing groups.

N. S. El-Gohary

1-thioflavanone epoxides 87 [216]. Reaction of epoxide derivatives 87 with dimethyldioxirane (DMD) yielded

the sulfoxide and sulfone derivatives 88 and 89 [216] (Scheme 44).

2.12. Synthesis of Arylideneaniline Derivatives (Schiff Bases)

Schiff bases are typically formed by the condensation of primary amines with aldehydes. Schiff b as es a r e i mpo r-

tant intermediates for the synthesis of various bioactive compounds. Literature survey revealed that these com-

pounds have been associated with diverse chemotherapeutic activities, including antimalarial [217], anticancer

[218], antibacterial [219], antifungal [220], antitubercular [221], ant i -inflammatory [222], antimicrobial [222]

and antiviral [223] activities. On the other hand, they are fundamental materials for the synthesis of various

Schiff base ligands which are used as chiral auxiliaries in asymmetric synthesis [224]. Metal complex Schiff

bases have also been used in oxidation reactions [225].

2.12.1. Various Reaction Conditions Have Been Used in the Synthesis of Schiff Bases

Schiff bases are compounds containing an azomethine group (-C=N-). They are usually formed by condensation

of primary amines with carbonyl compounds according to the following equation [226]; R-NH2 + R1-CHO →

R-N = CH-R1 + H2O, where R, R1 may be an aliphatic or aromatic group. Schiff bases of aromatic aldehydes

have an effective conjugated system and are more stable [227]. They are prepared under various reaction condi-

tions, the use of organic solvents such as THF and 1,2-dichloroethane (DCE) was reported [228]. The reaction

was also carried out in ethanol at room temper ature [229] [230], in refluxing ethanol [231], in refluxing ethanol

and in the presence of a catalytic amount of glacial acetic acid [222] [232], in refluxing methanol and in the

presence of a catalytic amount of glacial acetic acid [233], in methanol at room temperature and in the presence

of a catalytic amount of concentrated hydrochloric acid [234], in refluxing ethanol and in the presence of a cata-

lytic amount of concentrated sulfuric acid [235], in refluxing mixture of ethanol/dioxane and in the presence of a

catalytic amount of glacial acetic acid [236], in refluxing ethanol and in the presence of a catalytic amount of

anhydrous zinc chloride [237], in refluxing benzene [238], in dichloromethane (DCM) at room temperature and

in the presence of anhydrous magnesium sulfate [238], using DCM and a catalytic amount of neutral alumina

under microwave irradiation [238], under solvent-free conditions in the presence of lemon juice as natural acid

catalyst [239], in refluxing methanol and in the presence of a catalytic amount of nickel nitrate [240], and using

phosphorus pentoxide/silica gel (P2O5/SiO2) [241]. In addition, a green and efficient method for the synthesis of

Schiff bases in aqueous media was described [242].

2.12.2. Mechanism

Concerning the mechanism of the transformation of aldehydes and amines into Schiff bases 90, two possible

pathways are illustrated (Scheme 45 an d S cheme 46) [239]. In S cheme 45, th ere is nucleophilic attack of a p ri-

mary amine on carbonyl carbon that affords hydroxyl compound which on dehydration gives Schiff bases. The

i. NaOCl

ii. H

/NaOH

DMD

89 O

88 O

OOO

Scheme 44. Preparation of compounds 87-89.

N. S. El-Gohary

Aryl or heteroaryl

RNAryl or heteroaryl

-H

NAryl or heteroaryl

Scheme 45. Mechanism of condensation of benzaldehyde derivatives with primary amines

without using Lewis acid as a catalyst.

NAryl or heteroaryl

H Lewis acid

Aryl or heteroaryl

NAryl or heteroaryl

Lewis acid

-H

Scheme 46. Mechanism of condensation of benzaldehyde derivatives with primary amines

using Lewis acid as a catalyst.

formation of Schiff bases 90 in this method largely depends on the rate of removal of water from the reaction

mixture. Originally, the classical synthetic route for preparation of Schiff bases was reported by Schiff [243]

which involves the condensation of primary amines with carbonyl compounds under azeotropic distillation [244]

with the simultaneous removal of water. The removal of water during this condensation was conventionally fa-

cilitated by using molecular sieves [245] or a Dean-Stark apparatus [246]. In literature, the removal of water in

situ has been accomplished by using dehydrating solvents such as tetramethyl orthosilicate [247] and trimethyl

orthoformate [248] [249].

To overcome the difficulties in the removal of water, an alternative method has been employed in which

Lewis acid is used as a catalyst that accelerates nucleophilic attack of amines on carbonyl carbon as well as serv-

ing as a dehydrating agent for removal of water in the second step (Scheme 46). Several modified methods for

synthesis of Schiff bases have been reported in literature in which Lewis acids were used as catalysts such as

ZnCl2 [250], TiCl4 [251], alumina [252], P2O5 [253] and also by us i ng hydrotalcite [254].

2.12.3. Reactivity of Schiff Bases

Schiff bases are important intermediates for the synthesis of many heterocyclic compounds. Condensation of 90

with indole in basic medium afforded N-substituted indoles 91 [255]-[258]. The thiazolidin-4-one derivatives

92a,b were obtained via reaction of 90 with thioglycolic [259]-[268] and thiolactic acids [269], respectively.

Reaction of Schiff bases 90 with chloroacetyl chloride in dioxane and in the presence of triethylamine gave

chloroacetamido derivatives 93 [266] or the azetidin-2-ones 94 [265] [270]. Similarly, reaction of 91 with phe-

nylacetyl chloride in dioxane and in the presence of triethylamine produced the azetidinones 95 [271]. The pyr-

rol-2-one derivatives 96 can be synthesized by reaction of 90 with maleic anhydride [272]-[275] (Scheme 47).

2.13. Synthesis of Arylidenemalononitrile Derivatives

The Knoevenagel reaction is the most simple and straightforward method used to produce the substituted al-

kenes [276]. Classically, the process consists of condensation of aldehydes or ketones with active methylene

N. S. El-Gohary

NAryl or heteroaryl

OCl

ClCOCH

NAryl or heteroaryl

92a:

= H

92b:

= CH

HS COOH

NAryl or heteroaryl

OCl

ClCOCH

OONAryl or heteroaryl

COCl

NAryl or heteroaryl

Scheme 47. Preparation of compounds 91-96.

compounds in the presence of a variety of reagents. Several bases [276]-[279], Lewis acids [280] [281] or hete-

rogeneous media [282]-[289] were used as catalysts in Knoevenagel condensation reaction for the synthesis of

arylidenemalononitriles 97. In addition, a simple and more efficient procedure was developed for the condensa-

tion of malononitrile with aromatic, heteroaromatic and aliphatic aldehydes in water [290] (Scheme 48).

Reactivity of Arylidenemalononitrile Derivatives

The arylidenemalononitr iles 97 are useful intermediates for the synthesis of a variety o f hetero cyclic co mpounds,

2-aminobenzo[h]chromene-3-carbonitrile derivatives 98 were synthesized via condensation of 97 with α-n aph -

thol in the presence of Mg/Al hydrotalcite under single-mode microwave irradiation [291] (Sch eme 49). On the

other hand, 3-aminobenzo[f]chromene-2-carbonitrile derivatives 99 were obtained through condensation of 97

with β-naphthol [292] (Scheme 49). Pyrano[3,2 -c]chromenes 100 were prepared by heating 4-hydroxycoumarin

with 97 in pyridine [293], in ethanol and in the presence of triethylamine as a catalyst [294] or in water [295]

(Scheme 49). Acid hydrolysis of pyrano[3,2-c]chromenes 100 produced compound 101, which is subsequently

transformed into warfarin 102 (Ar = phenyl) [293] [296]-[298] (Scheme 50). Several pyrano[3,2-c]quinolines

103 were prepared via reaction of 4-hydroxyquinolin-2(1H)-ones with arylidenemalononitriles 97 [299] [300]

(Scheme 49). Three component reaction between arylidenemalononitriles 97, 1,3 -indanedione and thioglycolic ac-

id under microwave irradiation afforded indeno[1,2-b]pyridine derivatives 104 [301] (Scheme 49). The analogous

three-component reaction of 97 with 1,3-indanedione and 4-methylbenzenethiol, or aromatic amine under micro-

wave irradiation afforded indeno[1,2-b]pyridines 105 [301] (Scheme 49). A series of dihydropyrrolo[1,2-f]phe-

nanthridines 106 was prepared via reaction between 97, isocyanides and phenanthridine in dry diethyl ether [302]

N. S. El-Gohary

(Scheme 49). Condensation of 97 with 5-methylresorcinol monohydrate in ethanol afforded the chromene deri-

vatives 107 [303] (Scheme 49). Hexahydroquinolin-5-ones 108 were synthesized through reaction of 3-ami no-

cyclohex-2-en-1-ones with 97 [304] (Scheme 49). The thiazolopyridine derivatives 109 were obtained using 2:1

molar ratio of 97 and 2-(4,5-dihydro-4-oxothiazol-2-yl)acetonitrile or ethyl 2-(4,5-dihydro-4-oxothiazol-2-

yl)acetate [305] [306] (Scheme 49). Reaction of 2-isoxazolin-5-ones with 97 was reported to yield pyrazo-

lo[2,3-c]isoxazole derivatives 110 [307] (Scheme 49). Condensation of 97 with 3-methylpyrazo l-5-ones gave the

pyranopyrazole derivatives 111 [292] (Scheme 49). Whereas, pyrano[2,3-d]thiazole derivatives 112 were pre-

pared through reaction of 97 with α-(4 -oxothiazolin-2-yl)-α-phenylhydrazonoacetamide [308] (Scheme 49).

Condensation of 97 with barbituric or thiobarbituric acid afforded the corresponding pyrano[2,3-d]pyrimidine

derivatives 113 [308] (Scheme 49). In addition, the pyrido[1,2-a]quinazoline derivatives 114 were synthesized

via condensation of 97 with 2-(2-cyanoacetamido)benzoic acid [309] (Scheme 49). It was found that 3-phenyl-

2-thiohydantoin rea c t s wi th 97 to give the corresponding pyrrolo[1,2-c]imidazole derivatives 115 [310] (Scheme

49). Reaction of 3-oxo-3-phenyl-N-(pyridin-3-yl)propanamide with 97 in ethanol gave tetrahydropyridines 116

[311] (Scheme 49). In addition, 6-acetyl-3-amino-2,5-diphenyl-2,3,4,5-tetrahydropyridazine-4-carbonitrile de-

rivatives 117 were obtained through reaction of 97 with 1-(phenylhydrazono)propan-2-one in pyridine [312]

Ar CHO CN

Ar CN

Scheme 48. Preparation of compounds 97.

Ar CN

OH O

100

104

OHSCH

COOH

HOOCH

105

X=S; NH, R=alkyl; aryl

OHXR

NN C

106

NCN

103

107

OHHO

108

NHR

109

R = H; C

CNH

ONH

112

NNH

Ar R

110

R = H; C

Ar CH

111

ONH

X = O; S

XO113

X = CN; COOEt

Ar CN

N. S. El-Gohary

Ar CN

COOH

NCN

114

SNH

115

116

OON

NNCH

ONN

117

118

COC

O O

119

NC N

NaN

RNH2

.HCl N

NH2

R120

NC CONH NAr1

N O

NCH Ar1

H2N121

122

HSCH2COOH

COOC

OOC

H2N

COOC2H5

H2N

123

124

NH2CSNH2

NH2

125

Ar CN

Scheme 49. Preparation of compounds 98-100 and 103-125.

(Scheme 49). Reaction of 97, ethyl acetoacetate and aqueous solution of ammonium hydroxide afforded 4H-

pyran derivatives 118 [313] (Scheme 49). Tetrazoles 119 have been prepared through reaction of 97 with so-

dium azide in water [314] (Scheme 49). Micheal additions of arylidenemalononitriles 97 with amidines in re-

fluxing acetonitrile and in the presence of a catalytic amount of magnesium oxide produced the pyrimidine de-

rivatives 120 [289] (Scheme 49). Reaction of 97 with hydrazide-hydrazone derivatives in dioxane and in the

presence of triethylamine as a catalyst gave 6-amino-2-oxopyridine-3,5-dicarbonitriles 121 [315] (Scheme 49).

The synthesis of thiophene derivatives 122 was accomplished through the condensation of 97 with thioglycolic

acid [316] [317] (Scheme 49). 2-Ami no-1,1,3-tricyanoprop-2-ene reacts with 97 to yield the pyridine deriva-

tives 123 [318] [319] (Scheme 49). Similary, diethyl 3-amino-2-cyanopent-2-ene-1,5-dicarboxylate was reacted

with 97 to yield the pyridine derivatives 124 [319] [320] (Scheme 49). Treatment of 97 with thiourea in DMF

and in the presence of a catalytic amount of piperidine resulted in the formation of the thioxopyrimidine deriva-

tives 125 [321] (Scheme 49).

Reaction of arylidenemalononitriles 97 with 2-cyanothioacetamide in ethanol and in the presence of piperi-

dine as a basic catalyst afforded 1,6-dihydro-6-thioxopyridine-2,3,5-tricarbonitriles 126. Reaction of thioxopy-

ridines 126 with (2-acetoxyethoxy)methyl bromide in DMF and in the presence of sodium hydride afforded

6-[(2-acetoxyethoxy)methylthio]pyridine-2,3,5-tricarbonitriles 127 that is further reacted with ammonia in me-

thanol to produce 6-[(2-hydroxyethoxy)methylthio]pyridine-2,3,5-tricarbonitriles 128. Reaction of 126 with

ethoxymethyl chloride in DMF and in the presence of sodium hydride gave 6-(ethoxymethylthio)pyridine-2,3,5-

tricarbonitriles 129 [322] (Scheme 51).

It was reported that thermal Michael addition reaction takes place when 6,7-dimethoxyisochromanone 130

was treated with arylidenemalononitriles 97 at 190˚C to afford 131 which underwent elimination of malononi-

trile producing 132 [323] (Scheme 52).

2.14. Synthesis of Diethyl Arylidenemalonate Derivatives

Diethyl arylidenemalonates 133 are easily accessible by Knoevenagel condensation [324] [325] (Scheme 53).

N. S. El-Gohary

100

ArOH

OCOOH

ArOH

101

102

Scheme 50. Preparation of compounds 101 and 102.

Ar CN

CNNC

NC SN

CNNC

NC S

AcO

CNNC

NC S

Piperidine O

AcO

NaH/DMF

NaH/DMF NH

/MeOH

CNNC

NC S

126 127

128

129

EtOH

Scheme 51. Preparation of compounds 126-129.

Ar CN

130

MeO

MeO O

131

MeO

Ar CN

190

132

MeO

Scheme 52. Preparation of compounds 132.

Ar CHO COOEt

COOEt

Ar COOEt

COOEt

133

Scheme 53. Preparation of compounds 133.

Various reaction conditions were reported for the preparation of diethyl arylidenemalonates 133. The reaction

was performed in water or ethanol without catalyst [326], in refluxing dry xylene and in the presence of a cata-

lytic amount of piperidine/glacial acetic acid (3:1) [327], in refluxing ethanol and in the presence of a catalytic

amount of piperidine/glacial acetic acid (2:1) [328] or in refluxing pyridine [329]. In addition, Knoevenagel

condensations of benzaldehyde or substituted benzaldehydes with diethyl malonate was carried out in Lewis

acidic 1-butyl-3-methylimidazolium chloroaluminate, [bmim]Cl∙xAlCl3 and 1-butylpyridinium chloroaluminate,

N. S. El-Gohary

[bpy]Cl∙xAlCl3 ionic liquids [330].

Reactivity of Diethyl Arylidenemalonate Derivatives

Reaction of diethyl arylidenemalonates 133 with indole 134 in isobutanol at room temperature, employing

Cu(OTf)2-bis(oxazoline) complexes under nitrogen afforded ethyl 3-aryl-2-etho xycarbon yl-3-(3-indolyl)

propanoates 135 [331] (Scheme 54). Reaction of diethyl 4-methoxybenzylidenemalonate 136 with but-2-yne-

1,4-diol 137 in the presence of sodium hydride (NaH) in THF at room temperature for five minutes afforded

ethyl 3-(4-methoxyphenyl)-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-carboxylate 138 [332]-[335]

(Scheme 55).

2.15. Synthesis of Ethyl Arylidenecyanoacetate Derivatives

Ethyl arylidenecyanoacetates 139 are prepared via Knoevenagel condensation of aldehydes with ethyl cyano-

acetate (Scheme 56). Several publications were reported for the synthesis of ethyl arylidenecyanoacetates. The

reaction was carried out in aqueous medium at room temperature [336], in refluxing ethanol and in the presence

of piperidine/glacial acetic acid (2:1) [328], in refluxing ethanol and in the presence of Trizma [337]. Also , this

condensation was performed in ethanol/water mixture and in the presence of sodium or potassium hydroxide at

50˚C - 60˚C [279]. The same reaction was carried out using magnesium bromide diethyl etherate (MgBr2∙OEt2)

as Lewis acid in the presence of triethylamine [338]. In addition, poly(4-methyl vinylpyridinium hydroxide)/

SBA-15, a novel basic polymeric composite was applied as a recyclable catalyst for the Knoevenagel condensa-

tion reaction of aromatic alde hydes with ethyl cyanoacetate in water at 95˚C [339]. Furthermore, they were pre-

pared via heating a mixture of aldehyde and ethyl cyanoacetate at 80˚C - 85˚C in an oil bath and in the presence

of rare earth triflates as Yb(OTf)3 [340]. The same reaction was performed in distilled water and in the presence

of hydroxyapatite supported caesium carbonate as a recyclable solid base catalyst (HAP-Cs2CO3) [278] or under

microwave irradiation [341].

Reactivity of Ethyl Arylidenecyanoacetate Derivatives

The thiazolopyridine derivatives 109 were also obtained using 2:1 molar ratio of ethyl arylidenecyanoacetates

139 and 2-(4,5-dihydro-4-oxothiazol-2-yl)acetonitrile or ethyl 2-(4,5-dihydro-4-oxothiazol-2-yl)acetate [305]

[306] (Scheme 57). Reaction of ethyl arylidenecyanoacetates 139 with hydrazide-hydrazone derivatives in dio-

xane and in the presence of a catalytic amount of triethylamine produ ced ethyl 2-amino-5-cyano-6-oxopyridine-

3-carboxylates 140 [298 ] (Scheme 57). The synthesis of thiophene derivatives 141 was accomplished through

the condensation of 139 with thioglycolic acid [316] [317] (Scheme 57). Reaction of 139 with 2-cyanoacetic

Ar COOEt

COOEt

133

Ligand-Cu (II)

COOEt

134 135

Isobutanol

Scheme 54. Preparation of compounds 135.

COOEt

NaH/CuI

THF

COOEt

OCH

137

136138

Scheme 55. Preparation of compounds 138.

Ar CHOCOOEt

Ar COOEt

139

Scheme 56. Preparation of compounds 139.

N. S. El-Gohary

NC CONH NAr

ArCOOEt

N O

NCH Ar

EtOOC

139

140

(C2H5)3N/dioxane

HSCH2COOH

COOEt

NHNH

141

N NH

COOEt

142

COOH

NCN

COOEt

144

OOH

145

ONH

COOEt

146

CNH

ONH

COOEt

147

NNH

N SCH

HN N

SCH

143

X = O; S

R = H; C

109

X = CN; COOEt

Scheme 57. Preparation of compounds 109 and 140-147.

N. S. El-Gohary

acid hydrazide gave the pyridine derivatives 142 [342] (Scheme 57). The reaction of 139 with S-methylthiourea

in pyridine produced the pyrimidine derivatives 143 [343]. In addition, the pyrido[1,2-a]quinazoline derivatives

144 were synthesized via condensation of 139 with 2-(2-cyanoacetamido)benzoic acid [309] (Scheme 57).

Moreover, the pyrano[2,3-c]pyrazole derivatives 145 were obtained through condensation of 139 with 3-me-

thylpyrazolone derivatives [344] [345] (Scheme 57). Condensation of 139 with barbituric or thiobarbituric acids

afforded the corresponding pyrano[3,2-d]pyrimidine derivatives 146 [308] (Scheme 57). Whereas, pyrano[2,3-d]

thiazole derivatives 147 were prepared through reaction of 139 with α-(4-oxothiazolin-2-yl)-α-phenylhydrazo-

noacetamide [308] (Scheme 57).

Reaction of 139 with 2-cyanothioacetamide in ethanol and in the presence of a catalytic amount of piperidine

afforded ethyl 3,5-dicyano-1,6-dihydro-6-thioxopyridine-2-carboxylates 148. Reaction o f 6-thioxopyridines 148

with (2-acetoxyethoxy)methyl bromide in DMF and in the presence of sodium hydride afforded ethyl 3,5-di-

cyano-6-[(2-acetoxyethoxy)methylthio]pyridine-2-carboxylates 149 that is further reacted with ammonia in me-

thanol to produce ethyl 3,5-dicyano-6-[(2-hydroxyethoxy)methylthio]pyridine-2-carboxylates 150. Reaction of

148 with ethoxymethyl chloride in DMF and in the presence of sodium hydride gave ethyl 3,5-dicyano-6-

(ethoxymethylthio)pyridine-2-carboxylates 151 [322] (Scheme 58).

2.16. Synthesis of Arylidenecyanoacetamide Derivatives

Arylidenecyanoacetamides 152 are prepared v ia Knoevenagel condensation of aldehydes with cyanoacetamide

derivatives (Scheme 59). The reaction was carried out under solvent-free conditions [346], in water and in the

presence of triethylbenzylammonium chloride (TEBA) [347], in aqueous medium at room temperature [326], or

via grinding of aldehydes w ith cyanoacetamide derivatives at room temperature and in the presence of a cataly-

tic amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) [348].

Reactivity of Arylidenecyanoacetamides

The benzylidenecyanoacetamide derivative 153 has been extensively utilized in heterocyclic synthesis. Reaction

of 153 with hydrazine hydrate or phenylhydrazine in refluxing ethanol and in the presence of a catalytic amount

of piperidine produced the pyrazole derivatives 154 (Scheme 60) [349]. The 2-oxopyrimidine derivative 155

was prepared through condensation of 153 with urea in refluxing ethanol and in the presence of a catalytic

amount of pi peridine (Scheme 60) [349]. In addition, the 2-thi oxopyrim i dine deri vative 156 was obtained through

Ar CN

COOEt

NH2

EtOOC SN

EtOOC S

AcO

EtOOC S

Piperidine O

AcO

NaH/DMF

NaH/DMF NH3/MeOH

EtOOC S

139

148 149

150

151

EtOH

Scheme 58. Preparation of compounds 148-151.

Ar CHO CONHR

Ar CONHR

152

Scheme 59. Preparation of compounds 152.

N. S. El-Gohary

NHR

Piperidine/EtOH

CONH

Piperidine/EtOH

NHRX

Piperidine/EtOH

NHCSNH

HN O

CH3

R = H; C

HCN

H3C

NH2

H3C

N NH2

OCH3

153

154

156

155

157

X = O, R = H

X = S, R = H

X = O, R = NH

Scheme 60. Preparation of compounds 154-157.

condensation of 153 with thiosemicarbazide in refluxing ethanol and in the presence of a catalytic amount of

piperidine (Scheme 60) [349]. Moreover, reaction of 153 with cyanoacetamide, cyanothioacetamide or cyano-

acetic acid hydrazide afforded the cyanopyridine derivatives 157 (Scheme 60) [349].

2.17. Synthesis of 5-Arylidene Derivatives of Barbituric and Thiobarbituric Acids

Barbituric and thiobarbitur ic acids have attracted the attention of medicinal chemists for over hundred years due

to their therapeutic valu e s [350] [351]. 5-Arylidenebarbiturate/thiobarbiturate derivatives are important members

of the pyrimidine family. The major importance of these compounds has been centered on their application as

useful precursors in the preparation of new heterocyclic compounds [293] and as selective oxidizing agents

[352]-[354]. Barbituric acid and its derivatives exhibited different biolog ical activities such as antibacterial, hy -

potensive and tranquilizing activities [355]. The clinical use of barbiturates in neurological disorders has also

been investigated [356]. 5-Arylidenebarbiturates/thiobarbiturates 158 (Scheme 61) have been synthesized by

Knoevenagel reaction of barbituric acid with different aldehydes under various conditions. The reaction was car-

ried out under aqueous reflux using acetic acid as a catalyst [357]. Villemin and Labiad [358] synthesized 5-ary-

lidenebarbiturates under microwave irradiation and in the presence of montmorillonite KSF clay. Dewan and

Singh [359] reported various catalysts like NH4OAc/AcOH, montmorillonite K-10, silica gel, basic alumina,

NaCl, montmorillonite KSF, and KSF/NaCl for the synthesis of 5-arylidene barbiturates/thiobarbitura tes 158. A

grinding method has also been employed for the synthesis of 158 [360]. The same reaction was promoted by

N. S. El-Gohary

infrared irradiation in absence of solvent [361]. Also, it was carried out on basic alumina in a conventional mi-

crowave oven in the absence of solvent [362]. In addition, the same reaction has been achieved by employing

bismuth chloride under solvent-free conditions [363]. Reddy et al. [364] reported the same reaction under mi-

crowave irradiation in absence of solvent and catalyst. In addition, Khan et al. [365] reported an improved, rapid

and convenient met hod un de r e c o-benign conditions i.e. , using water as a solvent and bismuth chloride as a cata-

lyst at room temperature. Recently, 5-arylidenebarbiturate/thiobarbiturate derivatives 158 were obtained in ex-

cellent yields and high purity through condensation of barbituric or thiobarbituric acid with aromatic aldehydes

in distilled water at room temperature and in the presence of a catalytic amount of ethanolamine [366] or L-ty-

rosine [367].

Reactivity of Arylidenebarbiturates and Thiobarbiturates

Reaction of 158 with malononitrile in ethanol and in the presence of a catalytic amount of piperidine afforded

7-amino-5-aryl-2-oxo(thioxo)-4-oxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitriles 159 [366]

(Scheme 62). Cycloaddition reactions of 5-aryliden eba rbiturate derivatives 158 with a tenfold excess of ethyl

vinyl ether in methylene chloride at room temperature afforded 2H-pyrano[2,3-d]pyrimidine-2,4-(3H)-diones

160 [368] (Scheme 63).

2.18. Synthesis of Arylidene Derivatives of Meldrum’s Acid

2,2-Dimethyl-1,3-dioxane-4,6-dione (Meldrum’s acid) undergoes standard Knoevenagel condensation with

aromatic and heteroaromatic aldehydes furnishing the corresponding arylidene derivatives 161 (Scheme 64),

which are versatile substrates for different kinds of reactions [369]. In addition , they are useful intermediates for

cycloaddition reaction and for the synthesis of heterocyclic compounds with potential pharmacological activity

[370]. The Knoevenagel condensation of aldehydes with Meldrum’s acid is generally catalyzed by bases, such

as pyridine [371] or by piperidine/glacial acetic acid in benzene [372]. Uncatalyzed reaction was reported in li-

terature us ing DMF or DMSO as solvent [373]. In addition, anhydrous zinc chloride was reported to promote the

reaction in absence of any solvent [374]. The same reaction was also carried out in water [375]. In additio n, the

Knoevenagel condensation of aromatic aldehydes with Meldrum’s acid proceeded efficiently in the recyclable

Ar CHO

X = O; S158

Scheme 61. Preparation of compounds 158.

158

159

X = O; S

Scheme 62. Preparation of compounds 159.

OC2H5

158

160

R = H; CH3; C2H5; i-Bu

H2CCH OC2H5

CH2Cl2 / r.t.

Scheme 63. Preparation of compounds 160.

N. S. El-Gohary

ionic liquid [bmim]BF4 at room temperature and in the presence of a catalytic amount of piperidine [376]. Also,

the same condensation was carried out in methanol at room temperature [377].

Reactivity of Arylidene Derivatives of Meldrum’s Aci d

The epoxide analogues of arylidene Meldrum’s acid 162 were prepared through reaction of 161 with hydrogen

peroxide in acetonitrile at room temperatu re [378] [379] (Scheme 65).

Rhodium-catalyzed additions of arylboron reagents to 161 in dioxane at room temperature gave compounds

163 [380] (Scheme 66). The condensation of 161 with 3-amin o-1,2,4-triazole in nitrobenzene afforded 4,5,6,7-

tetrahydro-1,2,4-triazolo[1,5-a]pyrimidin-5-ones 164. In DMF, the reaction proceeds with the formation of

arylsubstituted N-(2H-1,2,4-triazol-3-yl)-3-(2H-1,2,4-triazol-3-ylamino)propionamides 165, in addition, the

amide 166 and the aldehydes were present in the reaction mixture [381] (Scheme 67).

ArCHO

161

Scheme 64. Preparation of compounds 161.

Ar H2O2/MeCNO

161 162

Scheme 65. Preparation of compounds 162.

161

Bxn

[Rh(cod)Cl]

(1.5 mol %)

KOH (1 equiv), dioxane, r.t.

(2 equiv)

163

Bxn

B(OH)

OSiMe

Scheme 66. Preparation of compounds 163.

161

Ar-CHO

NCH

Nitrobenzene

-Me

-CO

DMF

-Me

-CO

164

165 166

Scheme 67. Preparation of compounds 164 and 165.

N. S. El-Gohary

2.19. Synthesis of 2-Arylidene Dimedone and Bisdimedone Derivatives

5,5-Dimethylcyclohexane-1,3-dione (dimedone) was condensed with aromatic aldehydes in equimolar ratio and

in presence of bases such as potassium hydroxide [382] [383] or piperidine [383] to give 2-arylidene-5,5-di me-

thylcyclohexane-1,3-dione derivatives 167 (Scheme 68). The same products were obtained through fusion of

equimolar amounts of the aromatic aldehydes and dimedone in an oil bath at 150˚C [384]. On the other hand,

reaction of dimedone with aromatic aldehydes in 2:1 molar ratio afforded the bisdimedone derivatives 168

(Scheme 68), several reaction conditions were reported for this reaction. The reaction was performed in reflux-

ing aqueous ethanol and in the presence of a catalytic amount of piperidine [385], under solvent-free conditions

[346], in aqueous ethanol at room temperature and in the presence of a catalytic amount of piperidine [386], in

water at 100˚C and in the presence of a catalytic amount of iodine [387], HClO4-SiO2 or PPA -SiO2 [388], in re-

fluxing aqueous methanol [389], in aqueous media at room temperature [390] or in refluxing acetonitrile and in

the presence of of zinc oxide as a catalyst [391], also it was carried out in dry methylene chlorid e and in the pre -

sence of silica chloride nano particle (nano SiO2-Cl) [392] to afford the corresponding 2,2'-(arylmethy-

lene)bis(3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one) (bisdimedone derivatives) 168. The same reaction was

performed using ytterbium triflate [Yb(OTf) 3-SiO2] and amine as a catalytic system under solvent-free conditions

Ar CHO

167

OH HO

1:1

1:2

168

Scheme 68. Preparation of compounds 167 and 168.

167

169

Scheme 69. Preparation of compounds 169.

OH HO

Ar O

/EtOH

NHCSNH

AcOH

Ar O

HN CNH

Ar OO

N N

AcOH

168

170

171

172

Scheme 70. Preparation of compounds 170-172.

N. S. El-Gohary

[393]. This method is advantageous as being eco-friendly, non-corrosive, and allow s reutilization of the catalytic

system. Recently, bisdimedone derivatives 168 were obtained through reaction of dimedone with aromatic al-

dehydes in 2:1 molar ratio in ethylene glycol and in presence of nickel nanoparticles [394].

Reactivity of 2-Arylidene Dimedone and Bisdimedone Derivatives

Reaction of arylidenedimedone derivatives 167 with N-benzyl-N-phenylhydrazine in 50% acetic acid produced

compounds 169 [384] (Sch eme 69).

When bisdimedone derivatives 168 were reacted with different amines in ethanol and in the presence of a ca-

talytic amount of P2O5, 10-(substituted phenyl)-3,4,6,7,9,10-hexahydro-1,8(2H, 5H)-acridinedione derivatives

170 were obtained. The condensation of N-(2-aminoethyl)piperazine with bisdimedones 168 in acetic acid af-

forded the acridinediones 171 in which the N-acetylation of the piperazine ring has also occurred. The reaction

of bisdimedones 168 with thiosemicarbazide gave N-(3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydro-1,8-dioxo-(2H,

5H)-acrid in-10-yl)thiourea derivatives 172 [395] (Scheme 70).

3. Conclusion

Literature data have been summarized to help chemists to find information appropriate for the high synthetic

potential of different arylidene derivatives. Syntheses of many biologically active heterocyclic compounds be-

longing to these compounds have also been reported.

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