Utility of 2,4-Dioxoesters in the Synthesis of New Heterocycles

HETEROCYCLES, Vol. 81, No. 1, 2010, pp. 1 - 55. © The Japan Institute of Heterocyclic Chemistry Received, 10th September, 2009, Accepted, 23rd October, 2009, Published online, 5th November, 2009 DOI: 10.3987/REV-09-659

UTILITY OF 2,4-DIOXOESTERS IN THE SYNTHESIS OF NEW

HETEROCYCLES

Kamal M. Dawood,1 Hassan Abdel-Gawad,2 Hanan A. Mohamed,2 and

Bakr F. Abdel-Wahab2*

1 Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt 2 Applied Organic Chemistry Department, National Research Centre, Dokki, Giza,

Egypt

*Corresponding author. Tel: 202 3371635; Fax: 202 7601877.

E-mail: [email protected]

Abstract – This review deals with synthesis and reactions of 2,4-dioxoesters.

Some of these reactions have been applied successfully to the synthesis of

biologically important compounds. The data published over the last years on the

methods of synthesis and chemical properties of 2,4-dioxoesters are reviewed here

for the first time.

INTRODUCTION

2,4-Dioxoesters, the acylation products of methyl ketones with dialkyl oxalate, are valuable multi-purpose

intermediates in organic synthesis and their preparation is well documented. 2,4-Dioxoesters are used in

production e.g. pyrazole-3(5)-ethyl esters and their derivatives which are known to be important

intermediates in the preparation of agrochemicals, microbicides, herbicides,1 plant growth regulators and

protectants,2 and also production of 3(2H)-furanone ring system which is the key skeletal element of

many natural product antitumor agents.3 Recently a review on utility of regio- and chemoselective

features of benzoylpyuravtes in heterocyclic synthesis has been appeared.4 The main purpose of this

review is to present a survey of the literature on the synthesis of 2,4-dioxoesters and its reactions and

provides useful and up-to-date data for medicinal chemists.

METHODS OF SYNTHESIS

2,4-Dioxoesters 1 were prepared by Claisen condensation of the appropriate methylketone with oxalic

acid dialkyl esters in the presence of sodium alkoxides (Scheme 1) then acidified with dilute acid to give

an excellent yields of the precursors 1.5-21

HETEROCYCLES, Vol. 81, No. 1, 2010 1

O

R Me+

CO2R1

CO2R1

1.R1ONaO

R

O

CO2R1

2. H+1

Scheme 1 R= alkyl, aryl, heterocycle ; R1 = Et, Me

Cyclic ketones 2 were condensed with dimethyl or diethyl oxalate to give the diketoester 3 which present

in two tautomeric structures (Scheme 2).22-26

XR1

O(CO2R)2

NaHXR1

OO

CO2R XR1

OOH

CO2R

2 3 3

Scheme 2 X = (CH2)1-3, O ; R1=R= Me, Et

CHEMICAL PROPERTIES OF 2,4-DIOXOESTERS

2,4-Diketoalkanoates have both the structural features of α-keto esters and β-diketones (Figure 1). In the

case of α-keto esters 4, the adjacent carboxyl moiety imparts the ketone with an enhanced electrophilic

character due to its inductive withdrawal. However, this may be moderated by the presence of active

protons due to keto/enol tautomerisation between 5 and 6. In the case of β-diketones 4, sharing an active

methylene group enables both carbonyl functionalities to undergo keto/enol tautomery forming a Michael

acceptor.4

Ar

O O

CO2R Ar

O O

O

OR

H

Ar

O O

O

OR

H

Ar

O O

CO2R

H

Figure 1: Expected tautomeric contributions in aroylpyruvates.

4 5

67

1. HYDROLYSIS The β-diketo esters are converted to the corresponding pyruvic acids 8 (Scheme 3).8, 27

2 HETEROCYCLES, Vol. 81, No. 1, 2010

O

R2

R3

O

CO2EtH2SO4

NaOHO

R2

R3

O

CO2H

8Scheme 3 R2, R3 = H, OMe, CF3

2. REDUCTION

The hydrogenation of 2,4-dioxovalerates 9, in the presence of chiral rhodium or ruthenium catalysts

provides direct access to 3-hydroxy-5-subs.tetrahydrofuran-2-one with syn:anti ratios of up to 84:16 and

with up to 98% and 94% ee in the syn and anti form 10 and 11 respectively (Scheme 4).28, 29

O

R

O

CO2Et

H2 [cat.]

"one pot" OO+

OHOH

R

RO

O

antisyn

H2 [cat.]

O

R

OH

CO2Et

H2 [cat.]OH

R

OH

CO2Et

OH

R

OH

CO2Et+

anti syn

1110

Scheme 4 R= Me, i-Bu, 2-thienyl

9

The derivatives of 4-substituted 2-hydroxybutyric acids are valuable synthons for the production of

antihypertensive substances, homoamino acids, hydroxamic acids, and other compounds.30,31 Thus

hydrogenation of ethyl 4-substituted 2,4-dioxobutyrate 12 at palladium black and Pt/Al2O3 were studied.

During the hydrogenation of compounds 12 at palladium black at room temperature with a hydrogen

pressure of 1 atm in ethanol solution, the first reaction products are ethyl

2-hydroxy-4-oxo-4-subs.-butyrate 13, which then reduced with Pd/C to give ethyl

2-hydroxy-4-phenylbutanoate 14 (Scheme 5).32

CO2Et

O O

RPt / Al2O3 CO2Et

O OH

RR = Ph

Pd/CCO2Et

OH12 13 14

R = Ph

Scheme 5 R= Ph, 2-furyl


Ethyl 2,4-dioxo-4-phenylbutyrate was converted to 3-oxo-3-phenyl-1-propanol 15 in 90% yield by

reaction with baker's yeast. Reductive amination with sodium cyanoborohydride in the presence of

ammonium acetate gave the racemic 3-amino-3-phenyl-1-propanol 16 in 65% yield. Enzymic resolution

of the corresponding N-phenylacetyl derivative with penicillin G acylase, immobilized on an epoxy resin

gave (S)-amide 18 and (R)-amino 19 alcohols in high enantiomeric purity (ee >99%) and >45% yields for

each enantiomer in addition to phenylacetic acid as side product, while reduction of 15 with sodium

borohydride gave 1,3-diols 20 (Scheme 6).33

O O

CO2Et baker's yeast

diisopropyl ether/phosphate bufferpH 4.5

O OH

(90%)

NaBH3CN

NH4OAc

NH2 OH

NaBH4

OH OH

NaOH

PhCH2COCl

HN

HO

O

Ph

PenG acylasephosphate bufferpH 7.5

NH2

HO

+

HN

HO

O

Ph

+ PhCH2CO2H

45%, ee 99% 47.5%, ee 99%

1516

17 18 19

20

Scheme 6

Ethyl 2,4-dioxo-4-phenylbutyrate, was reduced enantio- and regiospecifically by baker's yeast in a

diisopropyl ether/water two-phase system to give (-)-ethyl (R)-2-hydroxy-4-oxo-4-phenylbutyrate 21 with

an 98% ee in 80% isolated yield. This (hydroxy)keto ester 21 was hydrogenated over Pd-C to obtain (-)-

ethyl (R)-2-hydroxy-4-phenylbutyrate (HPB ester) 22, an important intermediate for the synthesis of ACE

inhibitors. Prolonged contact of the reduction product with baker's yeast produced 3-phenyl-3-

oxopropanol 23 in 90% yield (Scheme 7).8


CO2Et

O OH

CO2Et

O O

[H]baker's yeast

diisopropyl ether/water Pd-C

[H]

CO2Et

OH

[H]

baker's yeast O

OH 21 22

23

Scheme 7

2,4-Dioxoalkanoates 24 and the parent compound γ-keto-α-enamino esters 25 are regioselectively

reduced by baker’s yeast to α-hydroxy-γ-keto esters 26, in moderate to good yields (Scheme 8).34

O

R1

O

CO2R2

AcONH4

AcOH

benzene

O

R1

NH2

CO2R2

O

R1

OH

CO2R2

baker's yeast

25

26

Scheme 8 R1 =Et, Me; R2 = Et, Me

24

baker's yeast

Ethyl 2,4-dioxo-4-phenylbutanoate was hydrogenated in the presence of (+)-dihydrocinchonidine and the

O-acetylated product underwent hydrolysis in the presence of lipase PS to give (R)-ethyl 2-acetoxy-4-

oxo-4-phenylbutanoate of 99.6% ee 27 and (S)-2-hydroxy-4-oxo-4-phenylbutanoic acid of 99.4% ee 28

(Scheme 9).35

O

Ph

O

CO2Et

1. [H](+)-dihydrocinchonidine

2. O-acetylion3.Lipase PS

O

Ph

O

CO2Et

O

Me O

Ph

OH

CO2H+

27 28

Scheme 9

Ethyl 2,4-dioxoalkanoates 29 react chemoselectively with pyrrolidine acetate at the more electrophilic C-

2 carbonyl, producing enaminone esters 31. Reduction of 31 with sodium cyanoborohydride followed by

pyrrolidine elimination gave β-oxo-acrylates 3236 (Scheme 10).


O

R

O

CO2Et +NH

AcOHO

R

N

CO2Et

[H]O

R

N

CO2Et

O

R CO2Et

60-70%

31

32

29 30

Scheme 10 R = Ph, furyl, Me, Et, H2C:CHCH2CH2, Me2CHCH2, pentyl, hexyl

3. DECARBONYLATION

The α,γ-diketoesters 33 are subjected to decarbonylation conditions with excess methanol in a sealed

reactor at a lower temperature (105-120 °C) to give carbon monoxide and ketenes 34 (Scheme 11).37

O

R1

O

O

O R3

H

R2

O

R1

R2

CO

+ R3OH + CO

3433

Scheme 11

4. ALKYLATION

Methylation of ethyl acetylpyruvate with diazomethane gave a mixture of two enol ethers, ethyl 2-

methoxy-4-oxopent-2-enoate 35 and ethyl 4-methyl-2,5-dioxohex-3-enoate 36 in 68:77 to 23:32 ratios

depending on the temperature (Scheme 12).38,39

O

Me CO2Et

OMeO

Me

Me O

CO2Et+

O

Me CO2Et

O

35 36Scheme 12

CH2N2

REACTIONS OF 2,4-DIOXO-ESTERS

1. FORMATION OF BENZENE DERIVATIVES

3-Hydroxy-5-methylbenzoic acid 37, which used in the synthesis of thrombin inhibitor, was prepared in

high yield from ethyl 2,4-dioxopentanoate in two reaction steps by the reaction with acetic acid followed

by treatment with magnesium oxide (Scheme 13).40


O

Me

O

CO2Et1. AcOH, H2O, NaOH, 100%;

2.MgO, H2O, 100 °C, 74%;

Me

OH

O

HO

37Scheme 13

The pyridones 38 reacted with sodium salt of ethyl acetopyruvate in pyridine at 70 °C to give 45.0-98.1%

phenols 39 and 10.9-84.2% nitroacetamide 4041 (Scheme 14).

N

O2N NO2

O

R

O

Me

O

CO2Et+

Na

pyridine

70 °C

OH

CO2Et

NO2

+

O

NH

R NO2

3839

40

Scheme 14 R = Me, 3-O2NC6H4CH2, 2-pyridylmethyl, 2-pyridyl, 2,4-(O2N)2C6H3, MeO, 4-O2NC6H4CH2O

2. FORMATION OF HETEROCYCLES

2.1. FIVE MEMBERED SYSTEMS

2.1.1. 2,4-PYRROLIDINEDIONES

The condensation of α,γ-diketoesters 41 with aromatic amine and aromatic aldehydes was a convenient

method for the synthesis of 4-acyl-2,3-pyrrolidinediones 42 (Scheme 15).14,42-47

R

O O

CO2EtArCHO

Ar1NH2N

O

O

OR

Ar1

Ar

4241

Scheme 15 R= alkyl, Aryl, heterocyles

The condensation of α,γ-diketoesters 43 with aldimines 44 derived from o-hydroxybenzaldehydes

provides a route to the pyrrolo[3,2-c]benzopyran ring system 46, via cyclization of the intermediate

pyrrolidinedione 45 which was not isolated (Scheme 16).45


R

O O

CO2Et

OH

N

Me

+AcOH

N

O

O

Ar

O

R

HO

N

O

O

Ar

O

R

45 4643 44

Scheme 16 R= Et, Ph, 4-tolyl

Some substitution products of 2,3-pyrrolidinones 47 and 48 are obtained by condensing an easily

saponifiable derivative of a hydroxybenzaldehyde or a hydroxybenzaldehyde alkylcarbonic ester with

primary amines and α,γ-diketoesters.48 The products 47 may be treated then to remove the saponifiable

group (Scheme 17). It has been found that these products are useful as drugs or intermediates for drugs.

CHO

OCO2Me

+ RNH2 +

O

R

O

CO2Et N

O

O Ph

O

R

OCO2Me

OH-

N

O

O Ph

O

R

OH

47 48Scheme 17 R= Me, Ph

The condensation of α,γ-diketoesters with Schiff bases, was further extended to the use of ketimines,

in such case, the spirocyclic system 49 was obtained via the formation of 50 (Scheme 18).45

O

R

O

CO2Et+

NH

N Ph

O

NH

HN

PhO

OO

CO2Et

R

NH

N

O

OO

R

O

Ph

49 50

Scheme 18 R= Me, Ph

Reaction of 2-oxocycloalkylglyoxylate esters 50-52 with N-phenylmethyleneaniline yields 2-aza-3,4,6-

trioxo-1,2-diphenylspiroalkanes 53-55 (Scheme 19).49


NPh

Ph

X

O

CO2Et

O

+X

O

N

O O

Ph

Ph

O O

CO2Et + NPh

Ph

O

N

O O

Ph

Ph

O O

CO2Et + NPh

Ph

ON

OO

Ph

Ph

50

51

52

53

54

55

Scheme 19 X= CH2, CH2CH2

- EtOH

- EtOH

- EtOH

2.1.2. PYRROLES

3-Acetylpyrrole-2-carboxylic acid 56 was prepared by treatment of ethyl 2,4-dioxovalerate with

aminoacetaldehyde in presence of 20% aqueous sodium hydroxide, followed by acidification (Scheme

20).50

Me

O

OEt

O O

+

O

NH2H 1. 20% NaOH

2. dil. H2SO4 NH

O

OH

OMe

56Scheme 20

Ethyl 2-(hydroxyimino)acetate and ethyl 2,4-dioxopentanoate were reacted with at 45 °C diethyl 5-

methyl-2,3-pyrroledicarboxylate 57 and ethyl 5-ethoxycarbonyl-2,4-dimethyl-3-pyrroleglyoxylate 58

(Scheme 21).51

CH

N CO2EtHO O

Me CO2Et

O

+45 °C

NHEtO2C

EtO2C

MeNH

EtO2CO

Me

Me CO2Et+

57 58Scheme 21

Low-valent rhodium complexes are efficient catalysts for the activation of α-C-H bond of isonitriles.

Catalytic synthesis of pyrrole 59, in 76% yield, can be performed by cyclocondensation of ethyl 2-

cyanoacetate with ethyl 2,4-dioxopentanoate (Scheme 22).52


Me

O O

CO2Et + NC CO2EtRh4(CO)12

- CO, -H2O NH

Me

CO2Et

CO2Et

59Scheme 22

Pyrrole chalcone 61 was prepared in by piperidineacetate-catalyzed condensation of 2,5-dimethyl-1-

phenyl-1H-pyrrole-3,4-dicarbaldehyde 60 with ethyl acetylpyruvate (Scheme 23).53

N

OO

Me Me

Ph

HH

O

Me

O

CO2Et +piperidinium acetate

N

O

Me

Me

Ph H

O

CO2EtMeOC

60 61Scheme 23

2.1.3. PYRAZOLES

Hydrazine and its monosubstituted derivatives react smoothly with 2,4-dioxoesters in a highly

chemoselective manner to afford 3,5-difunctionalized pyrazoles as only one product.54–59 Thus, 1-alkyl-5-

pyrazolecarboxylic acid esters 64, which are intermediates for pyrazolecarboxamide derivatives useful as

drugs and agrochemicals, are in high yields prepared by mixing alkylhydrazine 63 with acylpyruvic acid

62 (Scheme 24).60-65

NN

R2

CO2R4

R1

R1NHNH2

O O

CO2R4R2

R3

+

R3

646362

Scheme 24 R1, R2 = alkyl, cycloalkyl; heteocycles, R3 = H, alkyl, cycloalkyl; R4 = alkyl

Ethyl 3-ethyl-5-pyrazolecarboxylate 65, which is an intermediate for the acaricide tebufenpyrad, was

synthesized at a yield of more than 87% with ethyl propionylpyruvate and hydrazine hydrate or

dihydrazine sulfate (Scheme 25).66-69

CO2Et

OO

H2N NH2+ NH

N CO2Et

65Scheme 25


Ethyl propionylpyruvate was reacted with methylhydrazine with the molar ratio above 1: 1.2 to give 95%

of ethyl 3-ethyl-1-methyl-1H-pyrazole-5-carboxylate 66 (Scheme 26).70-72

O

CO2Et

O+

NN CO2Et

Me

66Scheme 26

MeNHNH2

Ethyl 2,4-dioxopentanoate was cyclocondensed with methylhydrazine and the product 67 was saponified

to give 1,5-dimethylpyrazole-3-carboxylic acid 68 which were amidated by 2,6-dimethylbenzenamine to

give title compound 69 (Scheme 27). The latter compound gave complete protection against electroshock-

induced convulsions to mice at 15 mg/kg i.v.73,74

Me

O O

CO2Et + MeNHNH2

NN

EtO2C

Me

Me

OH-

NN

EtO2C

Me

MeNH2

MeMe

NN

O

Me

Me

NH

Me

Me

67 68

69Scheme 27

4-Bromo-2-(hydrazinylmethyl)phenol treated with ethyl 2,4-dioxopentanoate to yield predominantly the

desired regioisomer 70 which was conveniently purified by preferential crystallization from the reaction

mixture upon cooling (Scheme 28).75

Br

OH

NH

NH2

O

Me

O

CO2Et+AcOH, reflux N

MeN

EtO2C

OHBr

70Scheme 28

The synthesis of 1,5-diarylpyrazoles 72 was done (Scheme 29) by regioselective cyclization of

arylhydrazines 71 with ethyl 2,4-dioxo-4-phenylbutanoate in refluxing ethanol. Esters 72 were reduced


with LiBH4 (anhydrous THF, argon), yielding the primary alcohols 73. Bromination of the crude products

with (C6H5)3P-NBS gave the pyrazoles 74. The alkyl bromides 74 were reacted with diverse phenols in

basic medium to give 3-Phenoxymethylpyrazoles 75 which are useful in prostate cancer chemotherapy.76

NH

NH2

RPh

O O

CO2Et+ EtOH, reflux

Ph

N N

CO2Et

R

LiBH4, THF

Ph

N N

CH2OH

R

(C6H5)3P, NBS, CH2Cl2, rt

Ph

N N

R

Br

ArOH

basePh

N N

R

OAr

72 73

74 75

71

Scheme 29 R= 4-CH3SO2, H, 4-F, 4-Cl, 4-Me, 4-OMe, 4-NH2SO2, 4-CF3O, 3,4-Cl2, 3,4-(Me)2

The diarylpyrazole backbone 76 was prepared from ethyl 2,4-dioxo-4-phenylbutanoate and the

corresponding 4-methylsulfonylphenylhydrazine and acetic acid in refluxing ethanol. Compound 76 was

reduced in the presence of LiAlH4 in anhydrous THF yielding the 1-(4-methylsulfonylphenyl)-5-phenyl-

1H-pyrazole-3-methanol 77. The alcohol 77 was then mesylated in the presence of triethylamine in

dichloromethane and reacted with 3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenol and Cs2CO3 in

DMF at 80 °C to yield 3-{[(3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy)methoxy]methyl}-

1-(4-(methylsulfonyl)phenyl)-5-phenyl-1H-pyrazole 78 (Scheme 30) which used as dual cyclooxygenase-

2/5-lipoxygenase inhibitor.77

OMeO

F

O

O O

CO2Et +

MeO2S

NHNH2.HCl

AcOH

EtOH, refluxN

N CO2Et

Ph

MeO2S

Cs2CO3 / DMF80 °C

LiAlH4 / THF

NN

Ph

MeO2S

OH

NN

Ph

MeO2S

F

HO

O

OMe

76

77

78

Scheme 30


Synthesis of ethyl 1-(2`-hydroxy-3`-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate 81 is outlined in

Scheme 31. Starting compounds, ethyl 3-aryl-1H-pyrazole-5-carboxylate and hydrazine. The reaction of

ethyl 3-aryl-1H-pyrazole-5-carboxylate 79 with 2-aryloxymethylepoxide 80 in the presence of potassium

carbonate at refluxing in acetonitrile afforded ethyl 1-(2`-hydroxy-3`-aroxypropyl)-3-aryl-1H-pyrazole-5-

carboxylate 81 in moderate yields and completely regioselectivity.7

O

R1

O

CO2Et NH2NH2

AcOH/rt

HN

NCO2Et

R1

OO

R2

K2CO3/MeCN81°C, 15-18h54-93%

NN

CO2Et

R1

OH

O

R2

79

80

81

Scheme 31 R1= H, Me, OMe; R2= H, 2-OMe, 2-NO2, 4-NO2, 4-Cl

1-(3-Methoxyphenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester 82 was prepared in 36% yield

by the reaction of ethyl 4-phenyl-2,4-dioxobutanoate with 3-methoxyphenylhydrazine hydrochloride in

dry ethanol under a nitrogen atmosphere and in the presence of equivalent of triethylamine at refluxing

temperature (Scheme 32).78

O

Ph CO2Et

OH

+

OMe

NHNH2

EtOH / Et3N

reflux

NN

Ph

CO2EtMeO

82Scheme 32

HCl

Cyclocondensation of 1-(phthalazin-1-yl)hydrazine-HCl and substituted ethyl cinnamoylpyruvates 83

gave 1-(1-phthalazinyl)-3-carbethoxy-5-(3- or 4-substituted styryl)pyrazoles 8479 (Scheme 33).

N

N

HN NH2

+ EtO2C

O O

R

N

N

NN

EtO2C

HC CH

R

83 84

Scheme 33 R2 = H, 4-MeO, 4-Cl, 3-MeO, 4-NO2

HCl


Ethyl (2-furoyl)pyruvate condensed with hydrazine to give bis(furylpyrazole)hydrazide 85. While

condensing with formaldehyde and phenols and hydrazine gave 86 (R = CH2R1)80 (Scheme 34).

O

O O

CO2EtNH2NH2

O N NH

O

NH

HN

O

ONHN

1.CH2O / R1OH2. NH2NH2

O N NH

O

NH

HN

O

ONHNR1

R1

85

86

Scheme 34 R1 = 2-naphthyl, 2,4-(HO)2MeC6H3

Cyclization of ethyl 2-thenoylpyruvate with hydrazines in acetic acid gave pyrazole derivative 87 which

reacted with hydrazine in refluxing EtOH/AcOH to give hydrazides 88 in high yields. Reaction of 88 with

aldehydes and formic acid gave 89 and pyrazolotriazinone 90, respectively in good yields (Scheme

35).17,81

S

O O

CO2EtRNHNH2 / AcOH

S

N N

CO2EtN2H4 / EtOH-AcOH

S

N N

O

NH

NH2 S

N N

O

NH

N R1

R1CHO

HCO2H

NNN

NH

O

S

R= H

R

R R

87

88

90

89

Scheme 35 R= H, Ph; R1 = Ar

While reaction of ethyl 2-thienoylpyruvate with hydrazine hydrate in neutral or basic medium led to the

decomposition to 2-acetylthiophene and oxalohydrazide 92 (Scheme 36).17


S

O O

CO2Et excess hydrazine

baseS

O N

CO2Et

NH2

hydrazine

S

O

Me+

O

OHN

NH

NH2

NH2

91

92

Scheme 36

Recently, Abdel-Wahab et al. reported the reaction of ethyl 2-benzofuroylpyruvate with phenylhydrazine

in glacial acetic acid to give the pyrazole-3-carboxylate 93 which then reacted with hydrazine hydrate to

give the corresponding carbohydrazide 94, Reactivity of the latter hydrazide towards aromatic aldehydes

and phathalic anhydride were studied to give the corresponding hydrazones 95 and imides 96 (Scheme

37).15,82,83

CO2Et

O

O

O

PhNHNH2

AcOHCO2Et

N

O

NPh

NH2NH2

EtOH

N

O

NPh

O

NH

NH2 ArCHO

EtOH / AcOHN

O

NPh

O

NH

NAr

O

O

O

N

O

NPh

O

NH

N

O

O

93

94

95

96Scheme 37

AcOH

When 5-hydrazinylmethyl-3-methyl-1-(3-methyl-1H-pyrazol-5-yl)methyl)-1H-pyrazole 97 was treated

with ethyl 2,4-dioxopentanoate in ethanol gave a mixture of two tris-pyrazoles 98 and 99 in 10% and

25% yields respectively (Scheme 38).84


NNH

Me

N

N

Me

NHNH2

O

Me

O

CO2Et

EtOH, reflux NNH

Me

N

N

Me

NN

Me

CO2Et

NNH

Me

N

N

Me

NN

EtO2C

Me

10%

25%

+

9798

99

Scheme 38

When ethyl 2,4-dioxo-4-(pyridin-3-yl)butanoate was treated with methoxyamine hydrochloride gave

ethyl 2-methoxyimino-4-oxo-4-(pyridin-3-yl)butanoate 100, which then reacted with 3-

hydrazinylbenzonitrile to give a mixture of two isomers 101 and 102 in a percentage 1:9 respectively

(Scheme 39).65

N

O O

CO2Et

MeONH2 HCl

EtOH, rt 87%

N

O N

CO2Et

OMeHN

NH2NC

AcOH, 68%

NN CO2Et

N

NCNN

CO2Et

N

NC

+

1 : 9

100

101 102

Scheme 39

Treatment of pyruvate 103 with dinitrogen trioxide (generated from sodium nitrite and HCl) in ethanol

gave the oxime 104. Cyclization of 104 with methyl hydrazine gave a mixture of the nitroso pyrazoles

105 and 106, which were separated by flash chromatography. Reduction of the nitroso group with sodium

dithionite in aqueous THF gave the respective aminopyrazoles 107 and 108 (Scheme 40).85


O

Ar

O

CO2EtN2O3, EtOH

85-94%

O

Ar

O

CO2Et

NOH

MeNHNH2

69-78%

NN

Ar

EtO2C

ON

Me

+ NN

Ar

EtO2C

ON

Me

Na2S2O4,THF-H2O,59-68%

Na2S2O4,THF-H2O,59-68%

NN

Ar

EtO2C

H2N

Me

NN

Ar

EtO2C

H2N

Me

103

104

105106

107

108

Scheme 40

HCl

MeOH-H2O

Ethyl 3-methyl-1-phenyl-1H-5-carboxypyrazoles 109 were prepared regioselectively from a condensation

of the appropriate phenylhydrazine and ethyl 2-(N-methoxyimino)-4-oxopentanoate.86,87 Coupling of ester

109 with the known amines 110 gave good yields of the amides 111. Deprotection of the tert-

butylsulfonamide moiety, by treatment with trifluoroacetic acid, afforded compounds 112. Treatment of

the methoxy-substituted precursor compounds 112 with excess boron tribromide afforded the phenolic

analogues 113 (Scheme 41), which is useful as non-amidine factor Xa inhibitors.88,89

HNNH2

R

+ Me

O NOCH3

CO2Et

AcOH, refluxN

N

Me

CO2Et

R

+

X SO2NH-i-BuH2N

Al(Me)3/CH2Cl2 NN

Me

O

HN X SO2NH-i-Bu

R

TFA, refluxN

N

Me

O

HN X SO2NH2

R

BBr3/CH2Cl2N

N

Me

O

HN X SO2NH2

HO

109

110

111 112

113

Scheme 41 R = H, 2-OMe, 3-OMe, 4-OMe; X = CH, N, C-F


The pyrazole derivatives were synthesized from para or meta nitrobenzaldehydes which was refluxed

with triethyl orthoformate to give the enol ether 114. Cyclization of 114 with hydrazine afforded 115 that

were then linked to trityl resin through one of the pyrazole nitrogens. The hydrolysis of the ester 116 to

117 by alkali (Scheme 42).90

O O

CO2EtO2N

HC(OEt)3

Ac2O, reflux

O O

CO2EtO2N

OEt

NH2NH2

reflux NNH

NO2

EtO2C

trityl chloride

NN

NO2

EtO2C

PhPh

Ph

OH-

NN

NO2

HO2C

PhPh

Ph

114 115

116 117

Scheme 42

C-Alkylation of α,γ,-diketoesters with 6-chloropiperonyl chloride were performed in the presence of

EtONa and NaI in DMF. The crude compounds 118 were allowed to react directly with hydrazine

monohydrate in ethanol to afford the desired pyrazole esters 119. Regioselective alkylation of 119 with

the requisite alkyl halide or alkyl tosylate in the presence of NaH in DMF at room temperature gave

compounds 120. Finally, the pyrazole acids 121 (Scheme 43) were obtained after saponification in good

yields which useful as potent nonpeptide endothelin antagonists.6

O

Ar

O

CO2Et

O

O Cl

Cl

NaOEt/DMF,NaI, rt, 16 h

O

Ar

O

CO2Et

O

OCl

H2NNH2

EtOH, reflux, 4 h

N

Ar

NH

CO2Et

O

OCl

R`X, NaH

DMF, rt, 20 h50 - 87%

N

Ar

N

CO2H

O

OCl

R`

NaOH (2 N), EtOH

reflux, 2 h 75- 100%

N

Ar

N

CO2H

O

OCl

R`118

119 120121

Scheme 43


The target compounds 123, 124 starts from 2,4-dioxopentanoic acid ethyl ester 122 (R1 = Me) or the 2,4-

dioxo-4-phenyl-butyric acid ethyl ester 122 (R1 = Ph). These β-diketo compounds undergo reactions with

methyl and phenyl hydrazine, yielding a 2:1 to 1:2 mixture of the two isomeric disubstituted pyrazole-3-

carboxylic acid ethyl esters 123 and 124, respectively (Scheme 44).91,92

R1OH

OCO2Et

+ MeNHNH2

N

N

R1

Me

CO2Et+

N

N

R1

CO2EtMeEtOH

reflux, 3 h 80%

122 123 124

Scheme 44 R1 = Me, Ph

The reaction of the ethyl 4-(furan-2-yl)-2,4-dioxobutanoate with methylhydrazine in ethanol at room

temperature afforded an almost 1:1 mixture of the two 5-furyl 125 and 3-furyl 126 regioisomers in high

yield; these were then easily separated with the aid of flash chromatography. In contrast to the lack of

regioselectivity observed in EtOH, when the condensation reaction was carried out with the fluorinated

solvents TFE and HFPI, the ratio increased to 93:7 in favor of the desired regioisomer 125, which was

obtained in almost quantitative yield. 3-(Ethoxycarbonyl)-5-(2-furyl)-N-methylpyrazole 125 was then

converted into the aldehyde 128, obtained in 75% combined yield through a two-step sequence involving

LiAlH4 reduction to the corresponding alcohol 128 and subsequent oxidization with MnO2, Compound

127 was then used as the key intermediate for the preparation of the rest of the fluorinated analogs of

tebufenpyrad (Scheme 45). Reaction of 128 with MeMgBr afforded the 1-hydroxyethyl derivative 129 in

94% yield. Subsequent treatment of 129 with deoxofluor provided the monofluorinated derivative 130 in

61% yield.93,94


O

O O

CO2Et MeNHNH2

solvent, rtN

N

EtO2C

Me O

+N

N

EtO2C

OMe

LiAlH4 / THF, 98%

NN

HOH2C

Me O

MnO2

MeCN / 75%

NN

OHC

Me O

MeMgBr

NN

Me O

MeOH

94%

NN

Me O

MeF

61%

Deoxofluor/ CH2Cl2

125 126

127128

129 130

Scheme 45

GSK183390A 134 has recently emerged as a potent dual agonist of PPARα/γ and a candidate for

treatment of dyslipidemia, the synthesis of 2-{4-[(5-(4-tert-butylphenyl)-1-methyl-1H-pyrazole-3-

carboxamido]methyl]-2-methylphenoxy}-2-methylpropanoic acid 134 is depicted in Scheme 46 via

coupling of benzylamine and pyrazole. The condensation between methylhydrazine and diketoester

produced a mixture of 1,3,5-trisubstituted pyrazole 131 and its isomer 132. Coupling of 131 with

benzylamine derivatives in the presence gave the target drug 134 in 73% yield.16


O O

CO2EtMeNHNH2

EtOH, reflux

NNMe

CO2Et +

NN

CO2Et

Me

NaOH , rt, 99%

NNMe

CO2HNH2

OEtO2C

1. SOCl2, toluene

2.

, Et3N

NNMe

O

NH

OHO2C

3. NaOH

131 132

133

134

Scheme 46

Solventless condensation of ethyl 2,4-dioxopentanoate and a hydrazine in the presence of a catalytic

amount of sulfuric acid at room temperature afforded pyrazole derivatives 135 in high yield, while its

reaction with phenylhydrazine under the same conditions gave the equal percentage of two pyrazole

isomers 136 and 137 (Scheme 47).95

O

Me

O

CO2EtRNHNH2+

R = H

H+N

NH

Me

EtO2C

90%

NN

Me

EtO2C

R = Ph

H+NN

Me

EtO2C

PhPh

+

91%

1 : 1135136137

Scheme 47

Compound 136 was prepared from commercially available 5-methyl-1H-pyrazol-3-amine by diazotation

in HCl followed by reduction with tin chloride and the intermidiate diamine is not isolated but has

immediately undergone a condensation with the β-diketones to give the ester 136 in a 36% yield. The

methylation of this product in the presence of t-BuOK as base led to one isolated α-isomer 137 in a 29%,

Finally, the compound 137 was convert to the target product 138 using LiAlH4 as agent of reduction

(Scheme 48).96


HNN NH2

Me1) NaNO2 / HCl2) SnCl2

3)

O

Ph

O

CO2Et NH

NMe

N NCO2Et

Ph

1) t-BuOK / THF

2) MeI

N NMe

N NCO2Et

Ph

Me

LiAlH4

THF N NMe

N N

Ph

Me

OH

136

137 138

Scheme 48

2H2O

Reaction of methyl 5,5-dimethyl-3-dimethylaminomethylene-2,4-dioxohexanoate 139 with

phenylhydrazine afforded methyl 1-phenyl-4-pivaloyl-1H-pyrazole-5-carboxylate 140 which was

converted to 1-phenyl-4-pivaloyl-1H-pyrazole 141 by basic hydrolysis followed by loss of carbon dioxide

(Scheme 49).97

CO2Me

Me O

ONMe

Me

Me Me

+ PhNHNH2 N

N

CO2Me

Me

MeMe

O Ph N

NMe

MeMe

O Ph1. NaOH

2. - CO2

Scheme 49

139 140 141

Reaction of ethyl 4-(1H-indol-3-yl)-2,4-dioxobutanoate98,99 with phenylhydrazine in refluxing acetic acid

gave the pyrazole 142 (Scheme 50).99

NH

O

OCO2Et

PhNHNH2

NH

NN CO2Et

Ph

142Scheme 50

Condensed pyrazoles 146 which exhibit antiproliferative activity were prepared by treating 143 with

arylhydrazines, followed by ester hydrolysis and amination of 145 to give the target molecules (Scheme

51).21-25


XR1

OOH

CO2R

R2

HNNH2

XR1

N N

CO2R

R2

XR1

N N

CO2H

R2

OH- QNH2

XR1

N N

R2

O

HN

Q

143 144 145

146

Scheme 51 X = (CH2)1-3, CH:CH, O; R = CO2Me, CO2Et, R1 = H, Cl, OMe, NMe2, OH; R2 = H, 4-Cl, 4-F, 2-Cl, 3-Me, 4-CO2H, 2-Me, 4-OMe, 2-CO2H

The 1H-pyrazolo-[3,4-d]-pyridazin-7(6H)-one core analog 149 was prepared. Therefore, 1-(1-bromo-

2,2,2-trifluoroethylidene)-2-(4-methoxyphenyl)hydrazine was treated with ethyl 2,4-dioxovalerate in the

presence of ethanolic sodium ethoxide to afford a good yield of a separable 1:1 mixture of pyrazole

regioisomers 147 and 148. The desired 148 was smoothly condensed with 4-bromophenylhydrazine in

refluxing ethanol to give the 1H-pyrazolo[3,4-d]pyridazin-7(6H)-one core 149 (Scheme 52), which

crystallized out of solution upon cooling.100

F3C Br

NNH

OMe

+ Me

O O

CO2EtNaOEt, EtOH

(75%)

NN

F3C

Me

CO2Et

OMe

NN

F3C

CO2Et

OMe

+

1 : 1

O

Me

4-bromophenylhydrazine, EtOH, reflux (80%)N

N

F3C

OMe

N

Me

N

OBr

147

148

149Scheme 52


Aminoguanidine was treated with ethyl acetopyruvate at 100 °C and pH 1 to give pyrazole 150, whereas

the reaction at pH 4 gave triazine 151. While at room temperature and at pH 6-7 gave the dimer 152 that

was hydrolyzed by dil. HCl to give 151 (Scheme 53).101

NH

NH2NH

H2N

O

Me CO2Et

O+

pH 1

100 °C

NN

Me

NH2HN

HO2CpH 4

N

NN

NH2

HO

O

Me 100 °C

pH 6-7 rt

O

Me

O

O

HN

NH

HN N

H

OHEtO2C

OMe

dil. HCl

150151

152Scheme 53

Nitroaminoguanidine was treated with ethyl acetopyruvate at pH 1-7 to give 153 and pyrazole-5-ester 154

(Scheme 54).101

NH

NH

NH

H2NO

Me CO2Et

O+

pH 1-7NO2

HN

NHO2NNH

NCO2Et

H2CO

Me NN

Me

EtO2C

NH2HN

+

153 154Scheme 54

Dihydralazine 155 reacted with ethyl 2,4-dioxoalkanoates to give dipyrazolylphthalazines 156 (Scheme

55).102

R

O O

CO2Et+

N

NN

R

CO2Et

NR

CO2Et

HN

HNNH2

NH2

155156

Scheme 55 R = Ph, anisyl, tolyl


2.1.4. ISOXAZOLES

Diketoester 157 was converted to isoxazole ester 158 upon reaction with hydroxylamine hydrochloride in

refluxing ethanol. Isoxazole ester 158 was reduced to the corresponding alcohol 159 using lithium

aluminum hydride in THF at -78 °C. Alcohol 159 was treated with triphenylphosphine dibromide to

furnish bromide 160, which was converted to isoxazole azide 161 by reaction with sodium azide in

acetone, azide 161 can be converted to the corresponding amine 162 by using 1,3-propanedithiol reduced

organic azides selectively to amines, itself being oxidized to the cyclic disulfide (Scheme 56).10

R

O O

CO2EtEtOH, reflux, 2 h

R

O N

CO2Et

74-100%

LiAH4 (0.60 eq,)

THF. -78 °C, 30 min R

O N

OH

60-95%

Ph3PBr2 (1.1 eq.)

CH2CH2, rt , 1 h R

O N

BrNaN3 (3.0 eq.)

acetone, rt, 24 hR

O N

N3

SH SH S S

NaBH4

R

O N

NH2

84-91%

157 158 159

160 161 162

Scheme 56 R= Ph, Me, i-Pr

NH2OH HCl(3.0 eq.)

The reaction of 2,4-diketo esters 163 with hydroxylamine hydrochloride gave 3-isoxazole esters 164, in

excellent yield, these ester were reduced with lithium aluminum hydride and the resulting alcohols 165

were oxidized with pyridinium chlorochromate (PPC) to yield substituted 3-isoxazolecarbaldehydes 166.

These aldehydes were then treated with various activated alkenes in the presence of DABCO in the

absence of any solvent to furnish the Baylis-Hillman adducts 167 in excellent yields, also, the

isoxazolecarboaldehydes undergo fast reaction with cyclohexenone in the presence of DMAP to give 168

(Scheme 57).103


O

R

O

CO2Et

NH2OH

EtOH, reflux, 1 h

NO

CO2Et

R LiAlH4 , Et2O

reflux, 30 min

NO

CH2OH

R

PCC

CH2Cl2, rt, 5 h

NO

CHO

REWG

DABCO,15-30 min

NOR

OHEWG

O

DMAP, dioxane:H2O (2:1), rt, 1 h

NOR

OH O

163 164 165

166167

168

Scheme 57 R= Ph, 4-MeC6H4, 4-Br-C6H4, 4-F-C6H4; EWG = CN, CONH2, CO2R

HCl

Ethyl 2-furoylpyruvate was reacted with hydroxylamine hydrochloride in the presence of sodium

carbonate to afford ethyl 5-(2-furyl)-3-isoxazolecarboxylate 169 which then hydrolyzed with HCl-H2O to

give 5-(2-furyl)-3-isoxazolecarboxylic acid 170 (Scheme 58).14

ON

EtO2C

OO

O O

CO2EtNH2OH

Na2CO3

HCl-H2O

ON

HO2C

O

169 170

Scheme 58

HCl

Ethyl 2-benzofuroylpyruvate on treatment with hydroxylamine hydrochloride in water give the dioxime

171, while in acetic acid afforded ethyl 5-(2-benzofuryl)-3-isoxazolecarboxylate 172 (Scheme 59).15

CO2Et

O

O

ONH2OH CO2Et

N

O

NOHHO

H2OAcOH

ON

EtO2C O+

172 171

Scheme 59

HCl

Reaction of with hydroxylamine hydrochloride in the presence of anhydrous potassium carbonate to give

the corresponding oxime 173 while in pyridine gave ethyl isoxazole-3-carboxylate 174 in good yields


(Scheme 60).18

NH

O

OCO2Et

K2CO3

NH

O

NCO2Et

OH

NH2OHpyridine

NH

N CO2Et

O

+

173174

Scheme 60

HCl

2.1.5. TRIAZOLES

The reactivity of benzolpyruvates as β-diketo moiety towards 1,3-dipoles was studied. Thus, when treated

with an organic azide 175, benzoylpyruvates may react to form cycloadducts, like 1,2,3-triazole 176

(Scheme 61).104 O ONa

CO2Et +

N3

NO2

THF

40-60 °C

O

N NN

O2N

CO2Et

175 176

Scheme 61

2.1.6. FURANONES

Ethyl 2,4-dioxoalkanoates, are used in the synthesis of 3(2H)-furanone ring system, the key skeletal

element of many natural product antitumor agents. The first method consisted in the reaction of the 2,4-

dioxoalkanoates with hydroxylamine hydrochloride in ethanol to form in good yield the corresponding

3,5-disubstituted isoxazoles 177.105 Isoxazoles have long been regarded as a protected form of l,3-

diketones, from which are commonly prepared, by virtue of its catalytic or chemical reduction to β-

enamino-ketones.106 Primary alcohols 178 were obtained in essentially quantitative yield by action of

sodium borohydride on 177 in methanol, while secondary alcohols 182 were derived in a two-step

sequence, namely reaction with methyl magnesium iodide in the presence of triethylamine to give the

ketone 181 followed by reduction with sodium borohydride. Tertiary alcohols 185 were directly obtained

by treatment of 177 with an excess of Grignard reagent in more than 80% yield. On exposure of all the

isoxazole alcohols to hydrogen and PtO2/Ni-Raney mixture of catalysts in methanol a rapid reaction

ensued to give the corresponding β-enaminoketones having a primary 179, 183 or tertiary 186 γ-hydroxy

group. All these vinylogous amides were cleanly transformed to 3(2H)-furanones 180, 184 and 187


respectively by treatment at room temperature in AcOH:H2O 2:l mixture in good yields (Scheme 62).3

OO

EtO2C R

NH2OH.HCl

EtOH NO

EtO2C

R

NaBH4

MeOH NO

HOH2C

R

[H]

PtO2/Ni H2N

HO

O

R

MeMgI / Et3N

NO R

OMe

NaBH4

NO R

OHMe [H]

H2N

Me

O

R

OH

excessMeMgI

NO R

Me OH

Me[H]

NH2Me O

ROHMe

179

183

186

O

RO

O

RO

Me

AcOH. H2O

O

RO

Me

Me

AcOH. H2O

AcOH. H2O

177178

181

182

184

180185

187

Scheme 62 R = Et, pentyl, Me2CHCH2, Ph, 2-MeOC6H4

2.2. SIX-MEMBERED SYSTEMS

2.2.1. PYRIDINE DERIVATIVES

Ethyl 2,4-dioxopentanoate was condensed with 2-cyanoacetamide in the presence of diethyl amine to give

ethyl 3-cyano-2-hydroxy-6-methylpyridine-4-carboxylate 188 which on nitration with nitric acid in acetic

anhydride give the corresponding 5-nitro derivatives 189, halogenation followed with reduction of the

latter compound gave ethyl 3-amino-6-chloro-5-cyano-2-methylpyridine-4-carboxylate 191 (Scheme


63).107

Me

O O

CO2Et + NC

O

NH2Et2NH

N

CN

OHMe

CO2Et

HNO3

Ac2ON

CN

OHMe

CO2Et

O2N

PCl5

chlorobenzene N

CN

ClMe

CO2Et

O2N [H]

SnCl2 / HClN

CN

ClMe

CO2Et

H2N

188 189

190 191

Scheme 63

Ethyl 2-hydroxy-4-oxopent-2-enoate was condensed with 2-cyanoacetamide in H2O/ EtOH in piperdine

to give ethyl 2-methyl-5-cyano-6(1H)-pyridone-4-carboxylate the tautomeric form of 192 which then

treated with a mixture of PCl5 and POCl3 to give ethyl 2-methyl-5-cyano-6-chloro-4-pyridinecarboxylate

193, Reduction of the latter compound followed by cyclization afforded 2-methyl-5-aminomethyl-4-

pyridinecarboxylic acid lactam 194 in 41.7% (Scheme 64).108

NH

O

CO2Et

CN

Me

O

Me

OH

CO2Et + NC

O

NH2 H2O / EtOH

piperidine

POCl3 / PCl5

N Cl

CO2Et

CN

Me

N

OMe

HNEtOH / HCl

Pd / C

192193

194Scheme 64

Oka et al. reported the synthesis of diethyl 2-methyl-6-(naphthalen-2-yl)pyridine-3,4-dicarboxylate 196

by reaction of ethyl 4-(naphthalen-2-yl)-2,4-dioxobutanoate 195 with ethyl 3-aminobut-2-enoate (Scheme

65).109 O O

CO2Et +

NH2Me O

OEt

NMe

CO2Et

CO2Et

Scheme 65

195 196


For the Hantzsch pyridine synthesis, methyl acetopyruvate was reacted with methyl 3-aminocrotonate and

3-nitrobenzaldehyde in isopropanol to give a mixture of two isomers 197 and 198 in 26.7 % and 9.2%

yields, which separeted by column chromatogrphy. Reduction of 197 with sodium borohydride in alcohol

led to lactone 199 (Scheme 66).110

O

Me

O

CO2Et+

Me

NH2CO2Me +

CHO

O2N

i-PrOH

NO2

NH

MeO2C

Me

O

Me

CO2Me

NO2

NH

MeO2C

Me

O

CO2Me

Me

+

NO2

NH

MeO2C

Me

Me

O

O

NaBH4

197 198

199Scheme 66

2.2.2. PYRIMIDIMES

Benzoylpyruvates can be reacted as β-diketones111–114 with N,N`-dinucleophiles such as amidines 200a,

isoureas 200b, guanidines 200c (R =NH2, NH-alkyl, NH-aryl etc.) and ureas 201 (R = O or S), Resulting

in the formation of an aromatic or latent aromatic system, the reaction should accordingly be highly

favored, yielding 2,4,6-trifunctionalized pyrimidines 202 or derivatives thereof (Scheme 67).

O

Ar

O

CO2R

R or X

HN NH2

or

Y

NH2H2N

N

Ar

N

CO2R

R; X or YH

200

Scheme 67201

202

The synthesis of pyrimidin-2-ones like 204 has been reported. Thus, the presence of base has been used to

promote condensation between a benzoylpyruvate 203 and urea (Scheme 68).115


HN

Ph

Ph

OMe

O O

CO2Et

O

H2N NH2

EtOH / NaOAc 70%

HN

Ph

Ph

OMe

HN N

CO2Et

O

203 204

Scheme 68

In a similar fashion, condensation between a benzoylpyruvate 205 and guanidine gives an entry to the

imprinted 2-aminopyrimidine 206 (Scheme 69).116

OF

Me

O O

CO2Et

OBn

NH.HCl

NH2H2N

K2CO3 / DMF, 39% OF

Me

N

CO2Et

OBn

N

NH2

Scheme 69

205 206

2.2.3. PIPERAZINES

Benzoylpyruvate can react across α-keto ester moiety with N,N`-dinucleophiles. Reactions involving

ethylene diamines 207 or α-amino acrylamides 209 lead to piperazine-2-one derivatives like 208 and 210

(Scheme 70).117–120

Ph

O O

CO2R

NH2NH

R N

NH

O

OPh

R

OH2N

H2N

Ar

N

NH

O

OPh

R

O

Ar

208

207209

210

Scheme 70

2.2.4. 1,2,4-TRIAZINES

Condensation of ethyl 2,4-dioxobutyrates with imidio-hydrazides 211 or S-methylisothiosemicarbazide

hydroiodide in pyridine gave the corresponding 1,2,4-triazin-5(2H)-ones 212 and 213 in 50-80%

(Scheme 71).20,120-122


R1

O O

CO2Et + NH

CHN

R

NH2

1. NaOEt / EtOH2. NH2NH2

R1 N

NN

O211 212

Cl

R

Scheme 71 R = Me, Ph, R1 = CH2COR2; R2 = Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4

NH2N=C(SMe)NH2

pyridineNH

N

N SMeOO

Ar

213

HI

Similarly, reaction with semicarbazides 214 and aminoamidine 215 lead to 1,2,4-triazine-5-one

derivatives like 216 and 217 (Scheme 72).117-120

N

HN

NH

PhO

OPh

NH

HNPh

H2N

Ph

O O

CO2R

X

H2N

NH

H2N

X = O, S

NH

HN

NH

XO

OPh

214215

216217

Scheme 72

2.2.5. PYRONE DERIVATIVES

2-Pyrone derivatives 219 were prepared in a one step procedure from (chlorocarbonyl)phenylketene 218

and ethyl 2,4-dioxopentanoate (Scheme 73).123

C OCPh

OCl +

O

Me

O

CO2Et

dry Et2O

OMe

O

EtO2C

OH

Ph

O

218 219

Scheme 73

Thus the cycloaddition mechanism represented in Scheme 74 accomplished by mixing the equimolar

quantities of (chlorocarbonyl)phenyl ketene 218 and 1,3-diketones at ambient temperature in dry ether.

1,3-Diketones exist mainly in the enol forms, therefore, the OH group of the enol form will attack the acyl

chloride of the ketene followed by ring closure of 220 to produce the product 219.123


CO

CPh

O

O

Me

O

CO2Et

dry Et2O

OMe

O

EtO2C

OH

Ph

O

O

Me

OH

CO2Et

+ O

Me

OEtO2C

O+ O

Ph

O-O

Me

EtO2C

H

C OCPh

OCl

218 220

221 219

Scheme 74

The reaction between malononitrile and benzoylpyruvate 222 gave 3,4,6-functionalized pyran-2-one 223

(Scheme 75).115 The incipient enolate, formed by initial conjugate addition, attacks in turn one of the

electrophilic nitriles to render a 3,4,6-functionalized pyran-2-one 223.

HN

Ph

Ph

OMe

O O

CO2Et

+ NC CNAcOH, NaOAc

74%

HN

Ph

Ph

OMe

O

O O

CN

CO2Et

222 223

Scheme 75

Benzoylpyruvates may themselves serve as cyclic precursors in the absence of external nucleophiles.

With heteroatoms located at the 2-position of the aryl moiety, as in the case of 224, it is possible to obtain

fusion by intramolecular cyclodehydration across the a-keto group. This approach has been used to

prepare chromone esters like 225 (Scheme 76).4

O O

CO2EtMeO

MeO OH

AcOH / NaOAc

94%

O

O

CO2Et

MeO

MeO

224 225

Scheme 76

2.2.6. THIADIAZINE DERIVATIVES The synthesis of 2-substituted 1,2,6-thiadiazine-5-carboxylates were carried out with ethyl 2,4-


dioxovalerate 228. Thus, the reaction of 227 with sulfamides 226 in ethanol or diglyme afforded the

corresponding 3-methyl-1,2,6-thiadiazine-3-carboxylates 228.The preparation of the amides 229 was

carried by reaction of 228 with amines124 (Scheme 77).

O R2

O

CO2EtH2N

SOO

HN R1

+HCl N

O2SN

CO2Et

R1

R2

1) R3NH2, AlMe3

2) HCl

N

O2SN

R1

R2

OHN

R3

226 227228 229

Scheme 77 R1= Ph, 4-ClPh, benzyl, 2,4-diClBn, cyclohexyl, hexyl; R2= phenyl, 4-chlorophenyl, benzyl, cyclohexyl, hexyl; R3 = cyclohexyl, morpholinyl, piperidinyl, Ph

2.3. FUSED HETEROCYCLIC SYSTEMS

2.3.1. BENZIMIDAZOLE DERIVATIVES The synthetic pathway to 1-aryl-3-(1H-benzimidazol-2-yl)-3-hydroxypropenone 232 are depicted in

Scheme 1. The pyruvates 230 were converted by basic hydrolysis into the corresponding acids 231 which

were subsequently condensed with 1,2-phenylenediamine hydrochloride to give the target compounds in

microwave oven and conventional heating (Scheme 78).19

O

R

OH

CO2Et NaOH

dioxane

O

R

OH

CO2H

NH2

NH2

a) H2O , 120 °C, 2 horb) H2O, MW 250 W, 3 min

O

R

OH

HN

N

85-100%

12-96%

230 231 232

Scheme 78 R=H, 2-OH, 3-OH

Condensation of ethyl 2-thionyl pyruvate with o-phenylenediamine in glacial acetic acid under reflux,

gave the corresponding 1-(1H-benzimidazole-2-yl)-3-thiophen-2-yl)-propane-1,3-dione 233.

Pyrrolo[1,2-a]benzimidazole derivatives 234 and 235 were prepared via cyclocondensation of compound

233 with acetic anhydride in presence of sodium acetate and phosphorus oxychloride respectively

(Scheme 79).125


S

O O

CO2Et +

NH2

NH2

AcOH

S

O O

NH

N

N

N

O

H3C

O

S

Ac2O / AcONaPOCl3

N

N

O

S

233

234235Scheme 79

2.3.2. PYRROLO[2,3-c]PYRIDINE

Ethyl 6,7-dihydro-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylate 236 was obtained similarly by

treatment of ethyl 2,4-dioxopentanoate with 3-ethoxycarbonyl-1-methyl-4-piperidone (Scheme 80).51

N

O

Me

EtO2C O O

CO2Et+

N NH

Me

CO2Et

Me

236

Scheme 80

2.3.3. PYRAZOLO[3,4-c]PYRIDINES

Pyrazolo[3,4-c]pyridines 241 were prepared by catalytic hydrogenation of 240 followed by cyclization.

240 were obtained (Scheme 81) by treating ω-bromoacetophenone oxime with sodium salt of

acylpyruvate 237 and then hydrazine (yield 70-75%).126

H2C Br

PhN

OH

+

O CO2R1

O

R EtONa

or MeONa O CO2R1

O

R

H2CPh

NHO

NH2NH2

H2CPh

NHO NH

N

R

R1O2C

H2

Pd / C

H2CPh

NH2 NHN

R

R1O2C

OH-

HN NH

N

R

O

Ph

237 238 239

240 241

Scheme 81 R= Me, Ph; R1 = Me, Et


2.3.4. PYRAZOLOPYRIMIDINES

Reaction between benzoylpyruvates and five-membered aza-heterocyclic amines may offer an entry to a

variety of [a]-fused pyrimidines, in consonance with the regiochemical supposition. An illustration of this

strategy is cyclodehydration involving 3-aminopyrazole 242, which affords only pyrazolo[1,5-

a]pyrimidine 243 (Scheme 82).127,128

NHNPh

NH2

+

O

R CO2Et

O

NNN

Ph

CO2EtR

EtOH / HCl,

80-90%

242243

Scheme 82 R= Me, Ph

Cyclocondensation of 3-amino-3-pyrazolin-5-one with ethyl acylpyruvate gave chiefly pyrazolo[3,4-

b]pyridinones 244 (Scheme 83) and smaller amount of pyrazolo[2,3-a]pyrimidin-2-(1H)-one 245 up to

30%.129

O

R

O

CO2Et

HN NH

O

NH2

+N

NHNH

O

HO

R

+ N

N

NH

R

OH

O

244 245

Scheme 83 R = Me, pyridyl, Ar

2.3.5. PYRAZOLO[1,5-d]TRIAZINES

Diaminoguanidine was treated with ethyl 2,4-dioxopentanoate in either acid of neutral aqueous solution

to give pyrazolo[1,5-d]triazine 246 (Scheme 84).101

NH

NH

NH

H2NO

Me CO2Et

O

+NH2

NN

HN

HN

Me

O

NH2

246

Scheme 84

2.3.6. IMIDAZO[1,5-b]PYRIDAZINES

Ethyl or methyl acylpyruvates 247 were condensed with ω-bromo-acetophenonesemicarbazone in sodium

ethoxide to give semicarbazone derivatives 248, which underwent acid catalyzed intramolecular

cyclization to afford the corresponding imidazo[1,5-b]pyridazinediones 249, methylation of the latter with

diazomethane afforded the N-methyl derivatives 250 (Scheme 85).130


H2CC

NNH

O NH2

PhBr

+ O

CO2R`

O

R NaOEtH2C

C

NNH

O NH2

Ph CH

OR

O

CO2R`

HCl / EtOH

NN

NH

Ph

O

R

O

O

CH2N2N

N

N

Ph

O

R

O

O Me

247

248

249

250

Scheme 85 R= Me, Ph; R`= Me, Et

2.3.7. ISOXAZOLO[3,4-d]PYRIDAZINE DERIVATIVES

Ethyl 4-ethyloxoacetate-5-methylisoxazole-3-carboxylate 251, was prepared by reaction of ethyl 2,4-

dioxopentanoate with ethyl chloro(hydroximino)acetate in ethoxide solution. Reaction of 251 with

hydrazine hydrate in ethanol gave ethyl {(6,7-dihydro-3-methyl-7-oxoisoxazole[3,4-d]pyridazinyl}-4-

carboxylate 252. Treatment of the latter with 1-(3-bromopropyl)-4-(3-chlorophenyl)piperazine in

anhydrous DMF containing anhydrous K2CO3 give Ethyl 6-{[4-(3-chlorophenyl)piperazin-1-yl]propyl}-

3-methylisoxazolo[3,4-d]pyridazin-7-(6H)-one-4-carboxylate 253 which is useful as potent

antinociceptive agent.131

O

CO2Et

O

Me +

Cl CO2Et

NOH

EtOH, EtONa

NO

Me

EtO2C

OCO2Et NH2NH2

EtOH, rt

NO Me

NCO2EtO

HN

DMF, anhydrous K2CO3, 60-70 °C

N

NClBr

NO

Me

N

CO2Et

O

N

N

NCl

251

252 253

Scheme 86

H2O

2.3.8. QUINOLINE Treatment of cyclohexane-1,3-dione with ethyl 4-(4-chlorophenyl)-2,4-dioxobutanoate led to 5,6,7,8-


tetrahydro-5-oxoquinoline-4-carboxylate derivative 254 (Scheme 87).132

Cl

O O

CO2EtOO+

AcOH

AcONH4

N

CO2EtO

Cl

254Scheme 87

2.3.9. QUINOXALINE DERIVATIVES

2-Chloro-3-(2'-thenoylmethyl)quinoxaline 256 was prepared by the reaction of 1,2-benzenediamine and

2-thienoyl pyruvate, followed by treatment with phosphorus oxychloride (Scheme 88).133

S

O O

CO2Et +

NH2

NH2 NH

N

OO

S

POCl3

N

N

OCl

S

255 256

Scheme 88

3-Functionalized 1H-quinoxaline-2-ones 257 can be made by reacting benzoylpyruvates with N-

phenylbenzene-1,2-diamine (Scheme 89).79,134–137

R

O O

CO2Me +NH2

NH

Ph

i-PrOH,

44-86%R

O

N

HN

O

Ph

257Scheme 89 R= Me, OMe, OEt, Br, Cl, F, NO2

Reaction of 3-hydrazino-2(1H)-quinoxalinone 258 with ethyl aroyl pyruvates 259 afforded the

corresponding hydrazones 260 which upon thermolysis at 230 °C eliminated a molecule of ethanol to

give triazinoquinoxaline 261 (Scheme 90).138


N

HN O

NH

NH2Ar

O O

CO2Et+

N

HN O

NH

N

Ar

O

CO2EtEtOH

reflux

pyrolysisN

HN O

N

N

O

O

Ar

258 259 260

261

Scheme 90 Ar = Ph, 4-MeOC6H4

3-(2-Oxo-2-phenylethylidene)-3,4-dihydro-1H-quinoxalin-2-one 262 was prepared in 38% yield by solid

state synthesis. Thus, when ethyl benzoylpyruvate and o-phenylenediamine were mixed and stirred at

room temperature gave the title compound 262. In the case of the condensation of ethyl benzoylpyruvate

with o-aminophenol at room temperature, the solution-phase reaction afforded just product 3-(2-oxo-2-

arylethylidene)-3,4-dihydro-benzo[1,4]oxazin-2-ones 262 in 31% yield. When sulfamic acid (SA) was

used as catalyst in concentration 10% the yield of 262 raised 81% while 262 to 73% without using any

solvent Also, the yield of other derivatives increased (Scheme 91).139

O O

CO2Et +

X

NH2NH

X O

O

SA(10%mol)

no solvent70 °C, 5-20 minR

R

262

Scheme 91 R = H,4-Cl, 4-OH, 4-OMe, 4-NH2, 4-NO2; X=NH, O

Cyclic N,O-dinucleophiles appended by a two-unit linker are restricted to 2-aminophenols. Thus, when a

benzoylpyruvate reacts with 2-aminophenol 263 itself, the result is formation of the corresponding 1,4-

benzoxazine-2-one 264 (Scheme 92).140-142

R

O O

CO2Me +NH2

OHR

O

O

HN

O

EtO2SAcOH,

54-92%

SO2Et

263 264

Scheme 92 R= H, Me, vinyl, OMe, OEt, Cl, Br, NO2


The Beirut reaction of benzoyl pyruvate with 1,3-benzoxadiazole 1-oxide and ethyl 2,4-dioxo-4-

phenylbutyrate in ethanol or acetonitrile, catalyzed by triethylamine, gave first ethyl 3-

benzoylquinoxaline-2-carboxylate 1,4-dioxide 266 and then, in a slower reaction, 2-benzoylquinoxaline

1,4-dioxide 269.143

Pathways for the formation of the dioxides 266 and 269 are suggested in Scheme 93. The intermediate

265 is of the type proposed previously for the Beirut reaction of 1,3-benzoxadiazole 1-oxide with

carbonyl compound cyclization and dehydration, path a, leads to the ester dioxide 266. Nucleophilic

attack on compound 265 with concomitant loss of carbon dioxide, path b, yields, after protonation of

intermediate 267 the aldehyde 268, Subsequent cyclodehydration produces the dioxide 269.143

NO

N

O

+

O

Ph CO2Et

OEtOH or MeCN, Et3N

NO

O

PhO

OOMe

NHOH

Nu

- CO2

- EtNupath b

NO

O

PhC

O

NHOH

H+

NO

O

PhC

O

NHOH

H

N

N

O

Ph

O

O

N

NHOH

O O

Ph

CHO

N

N

O

Me

CO2Et

O

O

- H2O

path a

266

269

268

267

265

Scheme 93


2.3.10. PYRIDO[2,3-d]PYRIMIDINE Condensation of ethyl benzoylpyurvate and 4-aminouracil in refluxing acetic acid afforded ethyl 2,4-

dioxo-7-phenyl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylate 270 as shown in Scheme 94.

Basic hydrolysis and coupling with (R,S)-1-phenylpropylamine provided compound 271.144

HN

NH

O

O NH2

+

CO2Et

O

O

AcOH reflux, 20 h

N

HN

NH

O

O

CO2Et

1. KOH, 95% EtOH, 3 h

2. (9)-Ph(Et)CHNH2, Et3N, HBTU, CH2Cl2:MeCN (1:1), 4 h

N

HN

NH

O

O

O NH

95% yield

70%

270

271

Scheme 94

2.3.11. PYRIDO[2,3-b]PYRAZINES Compound 276 was prepared as shown in Scheme 95. Thus, Guareschi condensation of nitroacetamidine

with ethyl 2,4-dioxo-4-phenylbutanoate in refluxing ethanol resulted in high yields of ethyl 2-amino-3-

O O

CO2Et+

O2N

NH

NH2 95% EtOH,

reflux, 20 h NH2N

O2N

CO2Et

H2, 10% Pd:C, 95%

EtOH:THF, (1:1), 22 h

N

CO2Et

H2N

H2N

2,3-dihydroxy-1,4-dioxane,

95% EtOH, 30 h N

CO2Et

N

N

1. KOH, EtOH:H2O (1:1), reflux, 3 h

2. 1 N HCl;

N

CO2H

N

N

DCC, HOBT, (S)-(-)-Ph(Et)CHNH2,

THF:MeCN (1:1), rt, 15 h.

N

N

N

O NH

272

273 274

275 276

Scheme 95


nitro-6-phenylpyridine-4-carboxylate 272, which was transformed into the diamine 273 by catalytic

hydrogenation of the nitro function. The six-membered fused pyrazine ring was incorporated by

condensation of 274 with a masked dialdehyde, the 2,3-dihydroxy-1,4-dioxane, producing ethyl

6-phenylpyrido[2,3-b]pyrazine-8-carboxylate 275.145 Subsequent hydrolysis of the ester functions under

basic conditions and coupling reaction with (S)-(-)-1-phenylpropylamine afforded the desired secondary

amide 276.144

2.3.12. PTERIDINE

In some cases, the ethene bridged diamines need not an aromatic framework as support. For instance,

benzoylpyruvates 277 react with 5,6-diaminopyrimidine-2,4-dione derivatives 278 yielding

dihydropteridine-2,4,6-trione 279 and 280 (Scheme 96).146 It has been demonstrated that, depending on

whether the reaction media is basic or acidic, it is possible to influence the regioselectivity residing on the

non-symmetrical nature of the N,N`-dinucleophile.

O

CO2Et

ONa

R

+ N

N

O

R`

O

R`

H2N

H2N

pyridine, O

R

N

HN

N

NO

O

O

R`

R`

1M HCl, 30-40%

O

R

N

HN

N

NO

O

R`

O

R`

55-85%

277 278279

280

Scheme 96 R= H, Me, OMe, Cl; R`= H, Me

2.3.13. TRIAZOLO[3,4-a]PHTHALAZINES

Cyclocondensation of 1-hydrazinophthalazine 281 with substituted ethyl benzoylpyruvates 282 gave

under neutral reaction conditions, 3-[2-oxo-2-(substituted phenyl)ethyl]-4H-as-triazino[3,4-a]phthalazin-

4-ones 283. Under acidic but otherwise identical conditions, depending on the substituent,

cyclocondensation gave 3-carbethoxy-s-triazolo[3,4-a]phthalazine 28479 (Scheme 97).

N

N

HN NH2

O

O

OEt

R

O

+neutral

N

N

NN

O

CH OH

R

acidicN

N

N N

CO2Et

284283281 282

Scheme 97 R = C6H4R1; R1 = 4-Me, 4-MeO, 3-MeO, 4-Cl


2.4. SEVEN MEMBERED RING

Cyclocondensation of ethyl 1,2,3,4-tetrahydro-1-oxo-2-naphthaleneglyoxylate with o-phenylenediamine

gave 78% 285 which was treated with hydroxylamine hydrochloride to give 82% 286. Amination of 285

by various amines and sulfa compounds gave 63-74% benzonaphtho-1,4-diazepines 287 (Scheme 98)

which were useful as bactericides.147

CO2Et

O

O

+

NH2

NH2 N

HN

CO2Et

NH2OH

N

HN

O

NHOH

RNH2

N

HN

O

HN

R

285

286

287Scheme 98 R = NHCH2CH2NEt2, N(CH2CH2OH)2, N(CH2CH2CH2OH)2, sulfanilamido-, sulfacetamido, 4-amino-N-2-pyrimidinyl-, 4-amino-N-2-(4,6-dimethyl-2-pyrimidinyl)benzenesulfonamido]-

Benzoylpyruvates 288, act as α-keto-ester on cyclodehydration with 289 led to intermediate β-enaminone

290 and then to 1,2-dihydrobenzo[e][1,4]oxazepin-3(5H)-one 291 by refluxing in acetic anhydride

(Scheme 99).148

O O

CO2Et

R

+

H2N

OH

Ph

Ph TsOH, benzene

50-84%

O HN

CO2Et

R

Ph

HO

Ph

Ac2O /

53-76%

O HN

R

Ph

Ph

O

O

288 289 290

291

Scheme 99 R= H, Me, Cl


DIFFERENT REACTIONS

The self-condensation reaction of β-acylpyruvates 292 in the presence of 1,4-diazabicyclo[2.2.2]octane

(DABCO) afforded 4,5,5-trisubstituted tetrahydrofuran-2,3-diones derivatives 294 (Scheme 100).149,150

N

N

O

R

OCO2Et

THF, rt, 3daysO

O

O

OR

O

R

CO2MeO

O

O

OR

O

R

CO2Me

H

N

N

292 293 294

Scheme 100 R = Me, Ph, 4-ClC6H4

6-(1-Methylhydrazino)isocytosine 295 cyclizes with α,γ-dioxo esters 296 to give pyrimido[4,5-

c]pyridazines 297, 298 and 1H-pyrimido[4,5-c]-1,2-diazepines 299 and 300, the latter being predominant

in each case (Scheme 101).151

NH2N

HN

O

NH2N

Me

O

R1

O

CO2R2+ MeOH

reflux

N

N NNH

H2N

O

Me

O

O

R1

HN

N NN

H2N

O

Me

OO R1

HN

N N N

R1O

H2N

Me

CO2R2HN

N N N

CO2R2O

H2N

Me

R1

+

+

299 300

297 298296

295

Scheme 101 R1 = Ph, 3-pyridyl; R2 = Me, Et

Cyclic monodithioacetals 301 of ethyl acetylpyruvate was prepared in 80% yield using boron trifluoride

etherate as the acid catalyst (Scheme 102).152

O

Me

O

CO2Et

HS(CH2)nSH

BF3 Me

O

CO2Et

SS

(H2C)n

301Scheme 102 n=2,3

OEt2


Tetracyclen 303 was prepared in 60% yield by reaction of bis(4,5-dihydro-1H-imidazol-2-yl)methane 302

with ethyl 2,4-dioxopentanoate (Scheme 103).153

N

NH

NHN

+

O

Me

O

CO2Et- H2O

- EtOH N N

NN

O

Me

303

Scheme 103

302

1,2,3-Triazolo-1,2,3-triazine salts 306 were prepared in 27-94% yields by cyclocondensation of the

corresponding 1-aminotriazole 304 with ethyl acylpyruvates 305 (Scheme 104).154

N

NN

NH2O

R3

O

CO2Et

R2

R

R1 +

HClO4N

NN

R

R1

CO2Et

R2

R3ClO4

304 305

306

Scheme 104 R = H, Ph; R1 = Ph; RR1 = CH:CHCH:CH; R2= H, Et; R3 = Me, Ph

The condensation of 2,5-diamino-4-methylamino-6-oxo-1,6-dihydropyrimidine 307 with ethyl

acetopyruvate gave 8,9-dimethylguanine 308 and isoxanthopterin 309 at pH 1, and 8-methyl-6-

acetonylisoxanthopterin 310 at pH 5 (Scheme 105).155

N

NH

O

NHMe

NH2

H2N

O

Me CO2Et

O

+N

NNH2N

HN

O

Me

Me +HN

N N

N

O

O

H2N

pH 1Me

Me

pH 5 HN

N N

N

O

O

H2N

Me

OMe

308 309

310

307

Scheme 105

Ethyl 2,4-dioxopentanoate was added to 3-hydroxy-4-thiacyclohexanone 311 in potassium hydroxide

several weeks followed by acidification with acetic acid and then treatment with sodium nitrite and finally

with Zn dust, to give ethyl 4,5,6,7-tetrahydro-2-methyl-1-aza-6-thiaindene-3-carboxylate 312 (Scheme

106).51


S

HO O

O

Me CO2Et

O

+

HN

S CO2Et

1.KOH

2.AcOH / NaNO2

3.Zn dust312311

Scheme 106

Ethyl (2-furoyl)pyruvate underwent Mannich alkylation to give the β-furoyl-β-(arylmethyl)pyruvate 313

(Scheme 107).62

O

O O

CO2Et + CH2O + ArNH2O

O O

CO2Et

NHAr

313Scheme 107

Ethyl 4-aryl-2,4-dioxobutanoates 314 undergo intramolecular Wittig reaction with a

vinyltriphenylphosphonium salt to yield cyclobutene derivative 315 which undergo electrocyclic ring-

opening reactions in boiling toluene to produced highly electron-deficient 1,3-dienes 316 in quantitative

yields (Scheme 108).156

C

C

CO2Me

CO2Me

+P(Ph)3 +

O O

CO2Et

X

CH2Cl2

O

X

CO2Et

CO2MeMeO2C

H

H

toluene

reflux

O

X78-87%

CO2Et

CO2Me

CO2Me

H

H

314 315

316

Scheme 108 X = H, Br, NO2

The mechanism involves addition-cyclization products apparently result from initial addition of

triphenylphosphine to the acetylenic ester and concomitant protonation of the 1:1 adduct 317, followed by

attack of the anion of 314 to vinyltriphenylphosphonium cation to form a phosphorane 318, which is

converted to strained carbocyclic ring system 316 (Scheme 109).156

C

HC

CO2Me

(Ph)3PCO2Me

O O

CO2Et

X

O O

CO2Et

X MeO2CCO2Me

P(Ph)3 316

318317

+

Scheme 109


Reaction of hydrazines 319, with ethyl 2,4-dioxo-4-phenylbutanoate in absolute ethanol at 60 °C gave

91% hydrazones 320 (Scheme 110).157

O

Ph

O

CO2Et+ PPh

Z

NH

Ph NH2

O

Ph CO2Et

P

Ph

Z

NH

Ph

NEtOH

60 °C

319 320

Scheme 110 Z = O, S

ACKNOWLEDGEMENTS

The authors would like to thank Abdelbasset A. Farahat, chemistry department, Georgia State University,

Atlanta, Georgia, USA for helping in data collection and refining.

REFERENCES

1. H. Moser, B. Boehner, and W. Foery, EP 268, 554 (Chem. Abstr., 1988, 110, 23879); T. Ishii, H.

Shimortori, Y. Tanaka, and K. Ishikawa, JP 01, 168, 675 (Chem. Abstr., 1989, 112, 35854); I.

Okada, K. Yoshida, and M. Sekine, JP 02, 292, 263 (Chem. Abstr., 1990, 114, 185497).

2. E. Sohn, R. Handle, H. Mildenberger, H. Buerstell, K. Bauer, and H. Bieringer, Ger. Patent 3, 633,

840 (Chem. Abstr., 1988, 110, 8202).

3. P. G. Baraldi, A. Barco, S. Benetti, S. Manfredini, G. P. Pollini, and D. Simoni, Tetrahedron,

1987, 43, 235.

4. J. M. J. Nolsoe and D. Weigelt, J. Heterocycl. Chem., 2009, 46, 1.

5. A. Cox, In Comprehensive Organic Chemistry; ed. by D. H. R. Barton, W. D. Ollis, I. O.

Sutherland, Pergamon Press, New York, 1969; Vol. 2, p. 702.

6. J. Zhang, S. Didierlaurent, M. Fortin, D. Lefrancois, E. Uridat, and J. P. Vevert, Bioorg. Med.

Chem. Lett., 2000, 10, 2575.

7. F. Wei, B.-X. Zhao, B. Huang, L. Zhang, C.-H. Sun, W.-L. Dong, D.-S. Shin, and J.-Y. Miao,

Bioorg. Med. Chem. Lett., 2006, 16, 6342.

8. N. W. Fadnavis and K. R. Radhika, Tetrahedron: Asymmetry, 2004, 15, 3443.

9. R. Braga, L. Hecquet, and C. Blonski, Bioorg. Med. Chem., 2004, 12, 2965.

10. Y. Pei and B. O. S. Wickham, Tetrahedron Lett., 1993, 34, 7509.

11. Y. Wakabayashi, A. Miyata, and H. Sato, JP 04149154(1992) (Chem. Abstr., 1992, 117, 170989).

12. S. Imaki, J. Takuma, and K. Endo, Jpn. Kokai Tokkyo Koho JP04069361 (1992) (Chem. Abstr.,

1992, 117, 7522).


13. S. Matsutani, K. Hirai, M. Tsutsumiuchi, and T. Mizui, JP 61134346 (1986) (Chem. Abstr., 1986,

105, 225805).

14. C. Musante and S. Fatutta, Gazz. Chim. Ital., 1958, 88, 879.

15. S. Fatutta, Gazz. Chim. Ital., 1959, 89, 964.

16. L. M. Oh, H. Wang, S. C. Shilcrat, R. E. Herrmann, D. B. Patience, P. G. Spoors, and J. Sisko,

Org. Proc. Res. Develop., 2007, 11, 1032.

17. K. M. Ghoneim, M. M. Badran, M. A. Shaaban, and S. El-Meligie, Egypt. J. Pharm. Sci., 1988, 29,

571 (Chem. Abstr., 1989, 111, 23436).

18. V. P. Gorbunova and N. N. Suvorov, Chem. Heterocycl. Compd. (N. Y., NY, U. S), 1977, 14, 754.

19. S. Ferro, A. Rao, M. Zappala, A. Chimirri, M. L. Barreca, M. Witriam, Z. Debyser, and P.

Monforte, Heterocycles, 2004, 63, 2727.

20. Y. A. Ibrahim, B. Al-Saleh, and A.-A. A. Mahmoud, Tetrahedron, 2003, 59, 8489.

21. F. Kipnis, I. Levy, and J. Ornfelt, J. Am. Chem. Soc., 1948, 70, 4265, Figure 1.

22. R. W. Hamilton, J. Heterocycl. Chem., 1976, 13, 545.

23. H. M. Faidallah, S. A. Basaif, E. M. Sharshira, and A.A-Ba-Oum, Egypt. J. Chem., 2002, 45, 905

(Chem. Abstr., 2004, 141, 410854).

24. G. A. Pinna, M. A. Pirisi, J.-M. Mussinu, G. Murineddu, G. Loriga, A. Pau, and G. E. Grella,

Farmaco, 2003, 58, 749.

25. F. Campagna, F. Palluotto, A. Carotti, and E. Maciocco, Farmaco, 2004, 59, 849.

26. J.-M. Mussinu, S. Ruiu, A. C. Mule, A. Pau, M. A. M. Carai, G. Loriga, G. Murineddu, and G. A.

Pinna, Bioorg. Med. Chem., 2003, 11, 251.

27. S. Patil, S. Kamath, T. Sanchez, N. Neamati, R. F. Schinazi, and J. K. Buolamwini, Bioorg. Med.

Chem., 2007, 15, 1212.

28. V. Blandin, J.-F. Carpentier, and A. Mortreux, Tetrahedron: Asymmetry, 1998, 9, 2765.

29. V. Blandin, J.-F. Carpentier, and A. Mortreux, Eur. J. Org. Chem., 1999, 8, 1787.

30. G. I. Chipens, V. A. Slavinskaya, A. K. Strautinya, D. R. Kreile, D. E. Sile, E. Kh. Korchagova,

and O. M. Galkin, Structure and Action of Inhibitors of Zinc-Containing Enzymes – Kinase II and

Encephalinase [in Russian], Zinatne, Riga (1990), p. 238.

31. V. Slavinska, D. Sile, E. Korchagova, and M. Katkevich, Synth. Commun., 1996, 26, 2229.

32. V. Slavinska, D. Sile, G. Rozenthal, G. Maurops, J. Popelis, M. Katkevich, V. Stonkus, and E.

Lukevics, Chem. Heterocycl. Compd. (N. Y., NY, U. S), 2006, 42, 570.

33. N. W. Fadnavis, K. R. Radhika, and D. A. Vedamayee, Tetrahedron: Asymmetry, 2006, 17, 240.

34. P. G. Baraldi, S. Manfredini, G. P. Pollini, R. Romagnoli, and V. Z. Simoni, Tetrahedron Lett.,

1992, 33, 2871.

35. R. Oehrlein and G. Baisch, PCT Int. Appl. WO 2002040438 (2002) (Chem. Abstr., 2002, 136,


385942).

36. S. Manfredini, D. Simoni, V. Zanirato, and A. Casolari, Tetrahedron Lett., 1988, 29, 3997.

37. D. W. Emerson, R. L. Titus, and R. M. Gonzaez, J. Org. Chem., 1991, 56, 5301.

38. A. Haider and H. Wyler, Helv. Chim. Acta, 1983, 66, 606.

39. F. Chen and L. Zhao, CN 1995006 (2007) (Chem. Abstr., 2007, 147, 18943).

40. T. Lu, T. Markotan, F. Coppo, B. Tomczuk, C. Crysler, S. Eisennagel, J. Spurlino, L. Gremminger,

R. M. Soll, E. C. Giardino, and R. Bone, Bioorg. Med. Chem. Lett., 2004, 14, 3727.

41. E. Matsumura, M. Ariga, and Y. Tohda, Tetrahedron Lett., 1979, 16, 1393.

42. A. N. Maslivets, O. P. Krasnykh, and Yu. S. Andreichikov, Zh. Organ. Kh., 1988, 24, 2233.

43. M. Dohrn and A. Thiele, Ber., 1931, 64B, 2863 (Chem. Abstr., 1932, 26, 1928).

44. Y. Chigira, M. Masaki, and M. Ohta, Chem. Pharm. Bull., 1969, 42, 228.

45. E. M. Afsah, H. A. Etman, W. S. Hamama, and A. F. Sayed, Boll. Chim. Farmaceutico, 1995, 134,

547 (Chem. Abstr., 1996, 124, 260756).

46. Yu. S. Andreichikov, V. L. Gein, and I. N. Anikina, Chem. Heterocycl. Compd. (N. Y., NY, U. S),

1985, 21, 1178 (Chem. Abstr., 1987, 107, 39766).

47. N. M. S. Hasanien, Studies on Claisen condensation and its products. M. Sc. Thesis, Faculty of

Science, Mansoura University, 1996.

48. A. G. Schering, M. Dohrn, and H. Nahme, Ger. 678, 152, 1939 (Chem. Abstr., 1939, 33, 7963).

49. D. W. Emerson, R. L. Titus, and M. D. Jones, J. Heterocycl. Chem., 1998, 35, 611.

50. M. K. A. Khan, K. J. Morgan, and D. P. Morrey, Tetrahedron, 1966, 22, 2095.

51. G. H. Cookson, J. Chem. Soc., 1953, 2789.

52. H. Takaya, S. Kojima, and S.-I. Murahashi, Org. Lett., 2001, 3, 421.

53. J. Vorkapic-Furac and M. Suprina, Z. Chemie, 1989, 29, 176 (Chem. Abstr., 1990, 112, 76847).

54. J. Büchi, H. R. Meyer, R. Hirt, F. Hunziker, E. Eichenberger, and R. Lieberherr, Helv. Chim. Acta,

1955, 79, 670.

55. L. M. Subramanian and G. S. Misra, Synthesis, 1984, 1063.

56. F. Arano, D. Catarzi, V. Colotta, G. Filacchioni, A. Galli, C. Costagli, and V.Carlá, J. Med. Chem.,

2002, 45, 1035.

57. T. Herk, J. Brussee, A. M. C. H. Nieuwendijk, P. A. M. Klein, A. P. Ijzerman, C. Stannek, A.

Burmeister, and A. Lorenzen, J. Med. Chem., 2003, 46, 3945.

58. T. Majid, C. R. Hopkins, B. Pedgrift, and N. Collar, Tetrahedron Lett., 2004, 45, 2137.

59. G. Szabo, J. Fischer, and A. Kis-Varga, Pharmazie, 2006, 61, 522.

60. H. Yoshida, K. Oomori, M. Yokoi, and K. Fuse, Jpn. Kokai Tokkyo Koho JP 07118238 (1995)

(Chem. Abstr., 1995, 123, 169615).

61. K. Harada, S. Nishino, and T. Harada, Jpn. Kokai Tokkyo Koho JP 2001335564 (2001) (Chem.


Abstr., 2001, 136, 5989).

62. R. M. Saleh and I. M. El-Deen, Rev. Roumain. de Chim., 1993, 38, 1333 (Chem. Abstr., 1994, 121,

108560).

63. G. J. Reddy, D. Latha, and K. S. Rao, Org. Prep. Proc. Int., 2004, 36, 494.

64. E. Sohn, H. Mildenberger, K. Bauer, and H. Bieringer, EP 333131 (1989) (Chem. Abstr., 1990,

112, 153721).

65. J. M. Smallheer, R. S. Alexander, J. Wang, S. Wang, S. Nakajima, K. A. Rossi, A. Smallwood, F.

Barbera, D. Burdick, J. M. Luettgen, R. M. Knabb, R. R. Wexler, and P. K. Jadhav, Bioorg. Med.

Chem. Lett., 2004, 14, 5263.

66. C. Tan, D. Shen, J. Weng, and D. Fan, Zhejiang Daxue Xuebao, Lixueban, 2005, 32, 204 (Chem.

Abstr., 2005, 144, 369957).

67. J. Yang and Y. Tian, Xiandai Nongyao, 2002, 1, 11 (Chem. Abstr., 2002, 138, 221511).

68. J. Yang and Y. Tian, CN 1305996 (2001) (Chem. Abstr., 2002, 137, 140519).

69. M. J. S. Dewar and F. E. King, J. Chem. Soc., 1945, 114.

70. C. Tan, D. Shen, J. Weng, and N. Sun, Zhejiang Gongye Daxue Xuebao, 2005, 33, 331 (Chem.

Abstr., 2005, 144, 294684).

71. B. Gu, W. Zhu, and W. Fan, Xiandai Nongyao, 2002, 1, 9 (Chem. Abstr., 2003, 139, 52927).

72. M. Nakagawa, S. Hara, and M. Sogawa, JP 04224565 (1992) (Chem. Abstr., 1992, 117, 251349).

73. F. Lepage and B. Hublot, EP 459887 (1991) (Chem. Abstr., 1992, 116, 128914).

74. J. L. Huppatz, Aust. J. Chem., 1983, 36, 135 (Chem. Abstr., 1983, 98, 160637).

75. S. C. McKeown, A. Hall, G. M. P. Giblin, O. Lorthioir, R. Blunt, X. Q. Lewell, R. J. Wilson, S. H.

Brown, A. Chowdhury, T. Coleman, S. P. Watson, I. P. Chessell, A. Pipe, N. Claytonb, and P.

Goldsmith, Bioorg. Med. Chem. Lett., 2006, 16, 4767.

76. N. Pommery, T. Taverne, A. Telliez, L. Goossens, C. Charlier, J. Pommery, J.-F. Goossens, R.

Houssin, F. Durant, and J.-P. He´nichart, J. Med. Chem., 2004, 47, 6195.

77. S. Barbey, L. Goossens, T. Taverne, J. Cornet, V. Choesmel, C. Rouaud, G. Gimeno, S.

Yannic-Arnoult, C. Michaux, C. Charlier, R. Houssin, and J.-P. Henichart, Bioorg. Med. Chem.

Lett., 2002, 12, 779.

78. A. C. Donohue, S. Pallich, and T. D. McCarthy, J. Chem. Soc., Perkin Trans. 1, 2001, 21, 2817.

79. A. Amer, K. Weisz, and H. Zimmer, Heterocycles, 1987, 26, 1853.

80. R. M. Saleh and I. M. El-Deen, J. Serbian Chem. Soc., 1991, 56, 595 (Chem. Abstr., 1992, 116,

106163).

81. B. F. Abdel-Wahab and A.-A. S. El-Ahl, Phosphorus, Sulfur Silicon Relat. Elem., (2009), in press.

82. B. F. Abdel-Wahab, H. A. Abdel-Aziz, and E. M. Ahmed, Arch. Pharm. (Weinheim, Ger), 2008,

341, 734.


83. B. F. Abdel-Wahab, H. A. Abdel-Aziz, and E. M. Ahmed, Monatsh. Chem., 2009, 140, 601.

84. A. Fruchier, B. Lupo, and G. Tarrago, Can. J. Chem., 1985, 63, 375.

85. J. Yuan, M. Gulianello, S. De Lombaert, R. Brodbeck, A. Kieltyka, and K. J. Hodgetts, Bioorg.

Med. Chem. Lett., 2002, 12, 2133.

86. D. J. P. Pinto, M. J. Orwat, S. Wang, J. M. Fevig, M. L. Quan, E. Amparo, J. Cacciola, K. A.

Rossi, R. S. Alexander, A. M. Smallwood, J. M. Luettgen, L. Liang, B. J. Aungst, M. R. Wright, R.

M. Knabb, P. C. Wong, R. R. Wexler, and P. Y. S. Lam, J. Med. Chem., 2001, 44, 566.

87. W. T. Ashton and G. A. A. Doss, J. Heterocycl. Chem., 1993, 30, 307.

88. J. R. Pruitt, D. J. P. Pinto, R. A. Galemmo, R. S. Alexander, K. A. Rossi, B. L. Wells, S.

Drummond, L. L. Bostrom, D. Burdick, R. Bruckner, H. Chen, A. Smallwood, P. C. Wong, M. R.

Wright, S. Bai, J. M. Luettgen, R. M. Knabb, P. Y. S. Lam, and R. R. Wexler, J. Med. Chem.,

2003, 46, 5298.

89. Z. J. Jia, Y. Wu, W. Huang, E. Goldman, P. Zhang, J. Woolfrey, P. Wong, B. Huang, U. Sinha, G.

Park, A. Reed, R. M. Scarborough, and B.-Y. Zhu, Bioorg. Med. Chem. Lett., 2002, 12, 1651.

90. D. Berta, M. Villa, A. Vulpeti, and E. Felder, Tetrahedron, 2005, 61, 10801.

91. P. Herold, A. F. Indolese, M. Studer, H. P. Jalett, U. Siegrist, and H. U. Blaser, Tetrahedron, 2000,

56, 6497.

92. A. Schmidt, T. Habeck, M. K. Kindermann, and M. Nieger, J. Org. Chem., 2003, 68, 5977.

93. S. Fustero, R. Roman, J. F. Sanz-Cervera, A. Simon-Fuentes, J. Bueno, and S. Villanova, J. Org.

Chem., 2008, 73, 8545.

94. S. Fustero, R. Román, J. F. Sanz-Cervera, A. Simon-Fuentes, A. C. Cunat, S. Villanova, and M.

Murgui, J. Org. Chem., 2008, 73, 3523.

95. Z.-X. Wang and H.-L. Qin, Green Chem., 2004, 6, 90.

96. A. Attayibat, S. Radi, A. Ramdani, Y. Lekchiri, B. Hacht, M. Bacquet, S. Willai, and M.

Morcellet, Bull. Korean Chem. Soc., 2006, 27, 1648.

97. G. Menozzi, L. Mosti, P. Schenone, D. Donnoli, F. Schiariti, and E. Marmo, Farmaco, 1990, 45,

167.

98. C. B. Barrett, R. J. S. Beer, G. M. Dodd, and A. Robertson, J. Chem. Soc., 1957, 4810.

99. V. P. Gorbunova and N. N. Suvorov, Chem. Heterocycl. Compd. (N. Y., NY, U. S), 1972, 9, 1374.

100. J. M. Fevig, J. Cacciola, J. Buriak, K. A. Rossi, R. M. Knabb, J. M. Luettgen, P. C. Wong, S. A.

Bai, R. R.Wexler, and P. Y. S. Lam, Bioorg. Med. Chem. Lett., 2006, 16, 3755.

101. D. Bierowska-Charytonowicz and M. Konieczny, Arch. Immun. Therap. Exp., 1976, 24, 871

(Chem. Abstr., 1977, 87, 53221).

102. A. Amer, N. Rashed, M. M. Abdel Rahman, and H. Zimmer, Heterocycles, 1987, 26, 1277.

103. A. K. Roy and S. Batra, Synthesis, 2003, 2325.


104. G. Biagi, I. Giorgi, O. Livi, V. Scartoni, L. Betti, G. Giannaccini, and M. L. Trincavelli, Eur. J.

Med. Chem., 2002, 37, 565.

105. P. G. Baraldi, A. Barco, S. Benetti, S. Manfredini, G. P. Pollini, and D. Simoni Tetrahedron Lett.,

1984, 25, 4313.

106. N. K. Kochetkov and S. D. Sokolov, "Advances in Heterocyclic Chemistry", ed. by A. R.

Katritzky, Academic Press, New York, 1963.

107. P. A. Pieper, D. Yang, H. Zhou, and H. Liu, J. Am. Chem. Soc., 1997, 119, 1809.

108. H. Henecka, Chem. Ber., 1949, 82, 36.

109. Y. Oka, K. Omura, A. Miyake, K. Itoh, M. Tomimoto, N. Tada, and S. Yuruga, Chem. Pharm.

Bull., 1975, 23, 2239.

110. J. Suh and Y. Hong, Arch. Pharm. Res., 1990, 13, 257.

111. A. Palani, S. Shapiro, J. W. Clader, W. J. Greenlee, S. Vice, S. McCombie, K. Cox, J. Strizki, and

B. M. Baroudy, Bioorg. Med. Chem. Lett., 2003, 13, 709.

112. L. Valgimigli, G. Brigati, G. F. Pedulli, G. A. DiLabio, M. Mastragostino, C. Arbizzani, and D. A.

Pratt, Chem. Eur. J., 2003, 9, 4997.

113. D. V. Sevenard, O. G. Khomutov, O. V. Koryakova, V. V. Sattarova, M. I. Kodess J. Stelten, I.

Loop, E. Lork, K. I. Pashkevich, and G.-V. Roschenthaler, Synthesis, 2000, 1738.

114. C. R. Hauser and R. M. Manyik, J. Org. Chem., 1953, 18, 588.

115. A. H. Abd-El-Rahman, F. A. Amer, E. M. Kandeel, and S. I. El-Desoky, Egypt. J. Chem., 1990, 31, 59.

116. J. Lee, H. J. Kim, S. Choi, H. G. Choi, S. Yoon, J.-H. Kim, K. Jo, S. Kim, S.-Y. Koo, M.-H. Kim,

J. I. Kim, S.-Y. Hong, M. S. Kim, S. Ahn, H.-S. Yoon, and H.-S. Cho, PCT Int Appl WO

2004/080979 (2004) (Chem. Abstr., 2004, 141, 277637).

117. M. M. Eid, M. A. Badawy, M. A. H. Ghazala, and Y. A. Ibrahim, J. Heterocycl. Chem., 1983, 20,

1709.

118. V. L. Gein, N. N. Kasimova, M. A. Panina, and E. V. Voronina, Pharm. Chem. J., 2006, 40, 410.

119. V. L. Gein, L. F. Gein, and I. A. Shevchenko, Russ. J. Gen. Chem., 2003, 73, 661.

120. S. A. Abdel-Hady, M. A. Badawy, A. M. Kadry, and Y. A. Ibrahim, Sulfur Lett., 1988, 8, 153.

121. Y. A. Ibrahim, S. A. L. Abdel-Hady, M. A. Badawy, and M. A. H. Ghazala, J. Heterocycl. Chem.,

1982, 19, 913.

122. Y. S. Andreichikov, S. V. Kol’tsova, I. A. Zhikina, and D. D. Nekrasov, Russ. J. Org. Chem.,

1999, 35, 1538.

123. H. Sheibani, M. R. Islami, H. Khabazzadeh, and K. Saidi, Tetrahedron, 2004, 60, 5931.

124. C. Cano, P. Goya, J. A. Paez, R. Giron, and E. Sanchez, Bioorg. Med. Chem., 2007, 15, 7480.

125. H. K. Ibrahim, S. H. El-Tamany, R. F. El-Shaarawy, and I. M. El-Deen, Macedonian J. Chem.

Eng., 2008, 27, 65.


126. O. Migliara, S. Petruso, and V. Sprio, J. Heterocycl. Chem., 1979, 16, 577.

127. G. Auzzi, L. Cecchi, A. Costanzo, and L. Pecori Vettori, Farmaco, 1979, 34, 898.

128. G. Auzzi, L. Cecchi, A. Costanzo, L. Pecori Vettori, F. Bruni, R. Pirisino, and G. B. Ciottoli,

Farmaco, 1979, 34, 478.

129. R. Balicki, Polish J. Chem., 1983, 57, 1251 (Chem. Abstr., 1985, 103, 87802).

130. O. Migliara, S. Petruso, and V. Sprio, J. Heterocycl. Chem., 1979, 16, 1105.

131. M. P. Giovannoni, C. Vergelli, C. Ghelardini, N. Galeotti, A. Bartolini, and V. Dal Piaz, J. Med.

Chem., 2003, 46, 1055.

132. T. Mulamba, R. El Boukili-Garre, D. Seraphin, E. Noe, C. Charlet-Fagnere, J. Henin, J. Laronze, J.

Sapi, and R. Barret, Heterocycles, 1995, 41, 29.

133. I. M. El-Deen and F. F. Mahmoud, Phosphorus, Sulfur and Silicon Relat. Elem., 2000, 165, 205.

134. D. G. Markees, J. Heterocycl. Chem., 1989, 26, 29.

135. R. B. Palkar and H. E.Master, Indian J. Heterocycl. Chem., 2000, 10, 37.

136. I. V. Mashevskaya, R. R. Makhmudov, G. A. Aleksandrova, O. V. Golovnina, A. V. Duvalov, and

A. N. Maslivets, Pharm. Chem. J., 2001, 35, 196.

137. K. S. Bozdyreva, I. V. Smirnova, and A. N. Maslivets, Russ. J. Org. Chem., 2005, 41, 1081.

138. N. Rashed, A. M. El-Massry, E. H. El-Ashry, and A. Amer, J. Heterocyl. Chem., 1990, 27, 691.

139. M. Xia, B. Wu, and G.-F. Xiang, Synth. Commun., 2008, 38, 1268.

140. D. G. Orphanos and A. Taurins, Can .J. Chem., 1966, 44, 1795.

141. Z. G. Aliev, O. P. Krasnykh, A. N. Maslivets, and L. O. Atovmyan, Russ. Chem. Bull., 2000, 49,

2045.

142. V. L. Gein, N. A. Rassudikhina, and E. V. Voronina, Pharm. Chem. J., 2006, 40, 554.

143. A. Atfah and J. Hill, J. Chem. Soc., Perkin Trans. 1, 1989, 221.

144. G. A. M. Giardina, M. Artico, S. Cavagnera, A. Cerri, E. Consolandi, S. Gagliardi, D. Graziani, M.

Grugni, D. W. P. Hay, M. A. Luttmann, R. Mena, L. F. Raveglia, R. Rigolio, H. M. Sarau, D. B.

Schmidt, G. Zanoni, and C. Farina, Farmaco, 1999, 54, 364.

145. M. C. Venuti, Synthesis, 1982, 61.

146. S. A. L. Abdel-Hady, M. A. Badawy, M. A. N. Mosselhi, and Y. A. Ibrahim, J. Heterocycl. Chem.,

1985, 22, 801.

147. A. Zayed and J. Metri, Egypt. J. Chem., 1981, 24, 481 (Chem. Abstr., 1983, 99, 70679).

148. N. V. Kolotova, V. O. Kozminykh, E. V. Dolbilkina, and E. N. Kozminykh, Russ. Chem. Bull.,

1998, 47, 2246.

149. H. J. Lee, T. Y. Kim, and J. N. Kim, Synth. Commun., 1999, 29, 4375.

150. J. N. Kim, H. J. Lee, K. Y. Lee, H. R. Kim, and E. K. Ryu, Bull. Korean Chem. Soc., 1999, 20,

1375 (Chem. Abstr., 2000, 133, 73900).


151. W. R. Mallory, R. W. Morrison, and V. L. Styles, J. Org. Chem., 1982, 47, 667.

152. M. T. Barros, C. F. G. C. Geraldes, C. D. Maycock, and M. I. Silva, Tetrahedron, 1988, 44, 2283.

153. H. Meyer and J. Kurz, Liebigs Ann. Chem., 1978, 1491.

154. V. A. Chuiguk, G. N. Poshtaruk, and V. A. Goroshko, Ukrainskii Khim. Zh. (Russ. Ed.), 1981, 47,

76 (Chem. Abstr., 1981, 94, 175002).

155. G. B. Barlin and W. Pfleiderer, Chem. Ber., 1969, 102, 4032 (Chem. Abstr., 1970, 72, 43613).

156. I. Yavary and A. R. Samzadeh-Kermani, Tetrahedron Lett., 1998, 39, 6343.

157. F. V. Bagrov, T. V. Vasil'eva, and D. F. Bagrov, Zh. Obsh. Khim., 1994, 64, 1475 (Chem. Abstr.,

1995, 123, 9523).

Kamal M. Dawood was born in 1965 in Kafr-Elsheikh, Egypt. He graduated from Cairo University, Egypt in 1987 then he carried out his MSc and PhD studies under the supervision of Professor Ahmad Farag, Cairo University. He received his PhD in 1995 in the applications of hydrazonoyl halides in heterocyclic chemistry. In 1997 he was awarded the UNESCO Fellowship for one year at Tokyo Institute of Technology (TIT) and collaborated with Prof. T. Fuchigami in the field of ‘Electrochemical Partial Fluorination of Heterocyclic Compounds’. In 1999, he was awarded the JSPS (Japan Society for Promotion of Science) Fellowship for two years and worked again with Professor Fuchigami at TIT in the same field.. He was awarded the Alexander von Humboldt Fellowship at Hanover University in 2004-2005 with Prof. A. Kirschning in the field of polymer supported palladium catalysed cross coupling reactions and in 2007 and 2008 with Prof. Peter Metz at TU-Dresden, Germany, and in the field of total synthesis of natural products. In 2002 he promoted to Associate Professor and in May 2007 he was appointed as Professor of Organic chemistry, Faculty of Science, Cairo University. In 2002 he received the Cairo University Award in Chemistry and in 2007 he received the State-Award in Chemistry.

Hassan Abdel-Gawad is an associate professor of organic chemistry at National Research Centre. He was born in 1968 in Giza, Egypt and received B.S. degree (1990) M.S. degree (1996) and Ph.D. degree (2001) from Cairo University under the supervision of Professors Issa M. I. Fakhr and N. A. Kassab. His current research interests covers the synthesis of the insecticides either radiolabelled or nonelabelled, extraction, isolation, and identification of their metabolites. In addition to, the synthesis of heterocycles.

Hanan A. Mohamed is a 2nd year Ph.D. candidate and a research associate of organic chemistry at National Research Centre. She obtained both B.S. degree (2001) and M.S (2006) from Cairo University under the direction of Prof. Kamal M. Dawood. Her current research interests lie in the area of the synthesis of biologically active new heterocycles.


Bakr F. Abdel-Wahab is a researcher of organic chemistry at National Research Centre. He was born in 1978 in Mansoura, Egypt and received both B.S. degree (1999) and M.S. degree (2003) from Mansoura University (Professor Fathy A. Amer), and his Ph.D. degree (2007) from Ain-Shams University under the direction of Professor Mahr A. El-Hashash (D.Sc), his current research interests covers the development and mechanistic understanding of organic reactions and their applications in medicinal chemistry. He is the author of over 17 international scientific papers and 6 reviews in heterocyclic chemistry.


Date post:	08-Nov-2016
Category:	Documents
Upload:	kamal
View:	234 times
Download:	0 times

Utility of 2,4-Dioxoesters in the Synthesis of New Heterocycles

Documents