Use of Dimedone to Avail Various Novel Aminomethylene Compounds

By Mehran Ali

Department of Chemistry The Islamia University of Bahawalpur Session 2012-2014

i

iii CONTENTS

Page No. CHAPTER 1: SUMMARY x Chapter 1 2 INTRODUCTION 2 1.1 Dimedone 2 1.2 Physical properties of Dimedone 2 1.3 Tautomeric forms of Dimedone 3 1.4 Hydrogen bonding 3 1.5 Dimedone-Synthesis 3 1.6 Some important Reactions of Dimedone 4 1.6.1 Hantzsch reaction 4 1.6.2 Tandem Aldol-Michael reactions 4 1.6.3 Unsymmetrical Hantzsch reaction 5 1.6.4 One-pot Knoevenagel and Michael addition reaction: 5 1.6.5 Biuret reaction 6 1.6.6 Begenilli reaction 6 1.7 Importance of Dimedone 7 1.7.1 Pharmaceutical applications 7 1.7.2 In flavours and fragrance 8 1.7.3 In Laser dye and Photoinitiator 9 1.7.4 Dimedone as a probe 9 1.7.5 Dimedone as a trapper 10 1.8 Medicinal importance 10 1.8.1 Antibacterial activity 12 1.8.2 Anticonvulsant activity 12 1.8.3 Antimicrobial activity 13 1.8.4 Antioxidant properties 13 1.8.5 Antituberculosis activity 15 1.8.6 Cardiovascular activity 16 1.9 Biological importance 16

viii Chapter 2 20 LITERATURE REVIEW 20 AIM OF PROJECT 40 Chapter 3 42 EXPERIMENTAL 42 3.1 Solvents and Reagents 42 3.2 Solvents 42 3.3 Melting Point 43 3.4 Spectroscopy 43 3.5 Chromatography 43 3.6 General Method for the production of various novel C-2 substituted dimedones 44 3.7 Data of Synthesized Compounds 45 Chapter 4 56 RESULT AND DISCUSSION 56 4.1 1HNMR 59 4.2 13CNMR 59 REFERENCES 66

ix

1 Chapter 1

INTRODUCTION 1.1 Dimedone

Dimedone (1) or Methone or 5,5-dimethyl-1,3-cyclohexanedione [1] is a highly reactive organic compound that is widely used in medicinal chemistry and organic synthesis. It is used as an active methylene compound as its most reactive centre i.e. C-2 is present between two strong electron withdrawing carbonyl groups. The C-2 of dimedone acts as a nucleophilic centre [2] while other less reactive sites i.e.C-1 and C-3 act as electrophilic centres. It is used in various organic reactions like knoevenagel condensation [3], Hantzsch reaction [4], Michael addition [3], Suzuki coupling [5] and Biginelli reaction [6] to form a number of useful products. It is also used as a precursor to form various biologically and pharmacologically active compounds that are used as anti-tumor [7], antibacterial [8], anti malarial [9], antifungal [10], antimicrobial [11] and antioxidant [12].

CH H3C 3 5 4 6 3 1 2 O O (1) 1.2 Physical properties of Dimedone

The physical parameters of dimedone (1) are given in the table as under.

Sr. No. Property State value

1 Molecular formula C8H12O2 [1] 2 Molecular mass 140.18[1] 3 Physical state Crystalline powder 4 Color Light yellow 5 Odor odorless 6 Decomposition point 147-150°C 7 Crystal structure Monoclinic[13]

2 1.3 Tautomeric forms of Dimedone

In solution form, dimedone (1) exists in two tautomeric forms i.e. enol (2) and keto (1) in (1:2) ratio in chloroform [14].

O OH

CH CH3 3 O O CH CH3 (1) 3 (2)

1.4 Hydrogen bonding

Dimedone (1) in its crystalline form, exists in polymeric (3) forms of enol linked by hydrogen bonding [1].

H- - - - O O

H3C CH3

H3C CH3 O- - - - O H (3)

1.5 Dimedone-Synthesis

Dimedone (1) was prepared by the reaction of malonic ester (4) and mesityl oxide (5) [15].

ONa EtOOC CH3 O EtOOC EtOH COOEt + H C CH NaOEt 3 3 H3C O (4) (5) H3C O OH

KOH H3C H C O HCl 3 OH CH3 CH3 (1)

(Scheme 1)

3 An unpredicted formation of dimedone (1) was described by Henshall et al. [16] by the hydrolysis of 6-hydro-3-cyano-2-keto-4,4,6-trimethylpiperidine (6) in the presence of aqueous acetic acid and sulphuric acid.

H3C CH3 H3C CH3 CN H2SO4(aq) COOH H3C -H2O H3C CH3COOH(aq) N O H3C COOH HO H O O (7) (6) (1)

(Scheme 2) 1.6 Some important Reactions of Dimedone

Dimedone is a well known organic molecule as it is an important part of almost every famous organic reaction and some of them are given as under.

1.6.1 Hantzsch reaction

Wang et al. [4] has reported a synthetic strategy for polyhydroquinoline derivatives (9) by a simple multi component coupling reaction of dimedone (1), aldehydes and ethyl acetate (8) in the presence of ammonium acetate via Hantzsch mechanism. The reaction was aided by a small amount of Yb(OTf)3 (5 mol %) as a catalyst. The beneficial aspects of this strategy include eco friendly conditions, simple handling, normal temperature and high yield of the product.

O O R O O Yb(OTf)3,5 mol 5% CO2Et 1eq. NH OAc H C 4 CH3 + H R + 3 O EtOH, r.t , 2-8 H, reflux H C N CH CH CO2Et 3 3 3 H3C H (1) (8) (9) (Scheme 3)

1.6.2 Tandem Aldol-Michael reactions

Barakat et al. [17] has demonstrated a facile synthesis of some novel zwitter ion derivatives (12) by a one pot three components condensation reaction of dimedone (1), aldehydes (11) and various barbituric acid derivatives (10) using diethylamine under aqueous media via Tendem Aldol Michael mechanism. The charming aspects of this reaction were eco friendly conditions, less reaction time, high yield of the desired

4 product, simple workup, easy handling and affordable conditions. The structure of the synthesized compounds was verified by using various identification techniques such as, IR, NMR, Mass Spectroscopy, CHN, elemental analysis and X-ray diffraction.

1 R O H H3C O O O N O O H3C 1 1 R R H2O,NHEt2 N 1 + N N + R CH R.T,Reflux - + 3 HO O O NH2Et2 CH3 O O (1) (10) (11) (12) 2 R 2 R

(Scheme 4)

1.6.3 Unsymmetrical Hantzsch reaction

Davoodina et al. [18] has described an environmentally benign mechanism for the synthesis of polyhydroquinolines (14) via a multi component unsymmetrical Hantzsch reaction. The reaction underwent by condensing dimedone (1) with ammonium acetate, aldehydes and ethyl acetoacetate (13) in the presence of small amount of tet‐rabutylammonium hexatungstate [TBA]2[W6O19] as a catalyst in solvent free environment. The present protocol has been associated with plenty of benefits like, high activity and reusability of the catalyst and high yield of the product formed.

O O R O

O O CH3 [TBA]2[W6O19] OEt CH 3 R H + + NH4OAc O + EtO O Solvent free H3C N CH3 CH3 o 110 C H3C H (1) (13) (14)

R= C6H5, 4-BrC6H4, 2-ClC6H4, 4-ClC6H4, 3-HOC6H4, 4-HOC6H4, 4-MeOC6H4, 4-MeC6H4

3-O2NC6H4 4-O2NC6H4 , 2-Furl, Et , n-Pr.

(Scheme 5)

1.6.4 One-pot Knoevenagel and Michael addition reaction: Kantevari et al. [19] described a method for the production of 9-aryl-1,8- dioxooctahydroxanthene (15) derivatives and 2-aryl-methylene bis(3-hydroxy-2- cyclohexene-1-one) (16) derivatives through a Knoevenagel and Michael addition type

5 mechanism. The reaction proceeded by reacting dimedone (1) with various kinds of aldehydes under solvent free environment, aqueous media or using acetonitrile ,utilizing

catalytic amounts of Silica supported perchloric acid ( HClO4–SiO2) and PPA–SiO2.

O O O Ar O O Ar CH3

H O H3C CH Knoevenegal CH CH3 3+ ArCHO H C 3 O 3 O condensation Michael addition H3C OH CH (1) CH3 O 3 H3C HClO -SiO PPA-SiO2 4 2 O Ar O O Ar O O Ar O

-H O 2 CH CH3 3 H3C H3C H3C O CH3 CH H3C CH3 O 3 H3C + H C OH OH (15) OH H CH3 3 (16)

Ar = C6H5 , 4-ClC6H4 , 4-NMe2C6H4 , 3,4,5-(OMe)3C6H2, 4-OMe C6H4, 4-BrC6H4 , 3-OMe C6H4

, 4-NO2C6H4 , 2-NO2C6H4 , 4-OH C6H4, 3-Cl C6H4 , 2,4-Cl2C6H4 , 3-OH C6H4 , 4-CH3C6H4

(Scheme 6)

1.6.5 Biuret reaction

Chassaing et al. [20] has described the formation of some unexpected products (18) by reacting different more or less active positions of dimedone (1) with benzofuroxan (17) in the presence of triethylamine.

H CH3 CH3 OH O O N N O Et3N CH3 + O N O N CH 3 O CH3 H3C (1) (17) (18)

(Scheme 7)

1.6.6 Begenilli reaction

Chebanov et al. [6] presented a sonication assisted synthesis of some novel pyrazoloquinazolinone derivatives (20) by a Begenelli type coupling mechanism. The

6 reaction was done by refluxing dimedone (1) with various aromatic aldehydes and phenylpyrazol derivatives (19) for 30 minutes using ethanol as solvent.

O N NH Ar O O N NH2 Sonication,EtOH N CH 3 H Ar + O + CH3 Reflux, 30 mins N CH3 H H C (1) (19) (20) 3

Ar = C6H5 , 4-MeC6H4 , 4-MeOC6H4, 4-BrC6H4, 4-NO2C6H4 , 2-MeOC6H4

(Scheme 8)

1.7 Importance of Dimedone

Dimedone (1) is a valuable compound that has vast applications in biological and pharmaceutical field respectively and is used in a variety of purposes as under.

1.7.1 Pharmaceutical applications

Dimedone (1) has been utilized in the preparation of substituted quinolines (21) [21] by a regioselective one pot two component method from formylated acetophenone and dimedone assisted by potassium bisulphate in aqueous media. Such type of compounds having quinoline groups show intense biological activities including anti asthmatic, anti infalammatory, anti hypertensiv and tyrosine kinase inhibiting agent. Among these 2-aryl- 5-oxo-7,7-dimethyl-5,6,7,8-tetrahydroquinoline (21) has interesting pharmaceutical activities like antimalarial, anti-HIV and anti-diabetic. It has been prepared by the following route.

7 O O O

Ar NMe 2 KHSO4/EtOH-HO2/60° C(2-3 Hours) R R NH OAc/MWI O 4 N Ar R 4-6 minutes R (1) (21)

R =CH3 Ar =C6H5 , 4-CH3C6H4 , 4-CH3OC6H4 , 4-NO2C6H4 , 4-ClC6H4 , 4-BrC6H4

KHSO4/EtOH-HO2/60°

(Scheme 9) 1.7.2 In flavours and fragrance

Létinois et al. [22] has described the selective hydrogenation of dimedone (1) up to the formation of monoketones (22) using Amberlyst 15® as an ion exchange resin and palladium as catalysts. The product formed has been used as building blocks for pharmaceutical industry and fragrance. This catalytic procedure has many advantages like, less by product formation, high catalytic activity, less salt formation and no formation of acids. The compound 3,3-dimethylcyclohexanone (22) which has been prepared by the selective reduction of dimedone (1) is widely used in industry as flavoring agent and fragrance. The compound (22) can be further used to synthesize 1- (3,3-dimethyl-1-cyclohexen-1-yl)-4-penten-1-one (23) which have a woody odor and has been widely used as odor-modifying , perfuming and taste-modifying agent.

O CH O O 2

H2-Pressure H3C H3C H3C O Catalytic Solvent H C H C H3C 3 (1) 3 (22) (23) (Scheme 21)

8 1.7.3 In Laser dye and Photoinitiator

1,8-dioxo-decahydroacridines (24) that are actually polyfunctionalized form of 1,4- dihydropyridines and reported to be prepared from dimedone (1) [23] , act as laser dyes, and also shown to be used as photoinitiators in industry.

2 R

O O

1 R 1 R 1 N 1 R R 3 R (24) 1 2 R = H , Me R = H , 3-NO2 , 4-Cl , 4-OH , 4-OMe

1.7.4 Dimedone as a probe

Dimedone (1) has been employed as a chemical probe for the chemoselective detection [24] of protein sulphenic acid (25) owing to its active methylene character. The C-2 carbon of dimedone makes a bond with the sulphur atom of the sulphenic acid to form a complex. These new reagents (26) are able to identify cysteine and other proteins that are sensitive to oxidation and allow the identification of the conditions of the cell. These labeled proteins can be further detected by mass spectroscopy and gel analysis [25].

O

H2N HOS O O CH O 3 H3C NH 2 H3C S NH H2N 2 H C O 3 O (25) (26)

(Scheme 22)

9 1.7.5 Dimedone as a trapper

Sakai et al. [26] reported the visual detection of formaldehyde by reacting dimdeone (1) with formaldehyde using ammonium acetate. The formation of a fluorescent compound of type (27) helped prove dimedone could be used as a trapper for aldehydes.

O O H H O H CH3 CH COONH CH O 3 4 3 O + H C H 3 N CH3 H3C H CH3 (1) (27)

(Scheme 23)

1.8 Medicinal importance

Dimedone (1) has been used in the preparation of benzodiazepine (28) nucleus which represents a wide range of heterocyclic compounds possessing extensive biological activities [27]. Some of them are used as hypnotic and neuroleptic agents, sedative, antidepressive and anticonvulsant agents. Many heterocyclic compounds which contain benzodiazepine nucleus were reported to have antiviral, anti inflammatory, anti-HIV and antitumor activities. Benzodiazepines were also used in the preparation of fused ring compounds like thiazolo, triazolo, pyrimido-benzodiazepines and imidazo. Benzotriazole derivatives (29) represent another class of heterocycles which possess wide range of medicinal importance. Compounds (28) and (29) have been prepared by reaction of dimedone (1) with substituted o-phenylenediamines by the following method.

10 H N X H - O 2 H N +Br NH 2 N O H N 2 X BrCN EtOH, N O EtOH H2N O H X (1) (28) NANO2 HCl N N N X

O (29)

(Scheme 24)

Li et al. [28] has developed a neat and green strategy for the preparation of some eleven dihydropyrano[3.2-b]chromenedione (31) by a simple and facile one pot multicomponent condensation reaction of dimedone (1), kojic acid (30) and aromatic aldehyde under solvent free environment employing alum as a green catalyst. Alum (KAl(SO4)2.12H2O) has been reported as an affordable, non toxic and efficient catalyst for carrying so many organic reactions like Pechman reaction, beginelli synthesis and for the preparation of many heterocyclic compounds like 1,3,4-oxadiazoles, 1,8-dioxo-octahydroxanthenes, 2- (hydroxymethyl)-7,7-dimethyl-10-aryl-7,8-dihydropyrano[3,2-b]chromene-4,9(6H,10H)- dione, 1,5-benzodiazepines and 1-H-spiro[isoindoline-1,2-quinazoline]-3,4’(3’H)-diones. The aim of this project was to prepare some kojic acid derivatives which are very important medicinally and biologically and reported to be showing activities like anti- inflammatory, antiproliferative, antioxidant, tyrosinase inhibitory, antibacterial, anticonvulsant, anti-HIV and anti-neoplastic activites.

O OH OH Ar O O O Alum + CH3 + ArCHO CH3 O OH 100 oC O CH3 CH3 O O (31) (1) (30)

Ar = C6H5, 4-Cl-C6H4, 4-F-C6H4, 4-NO2-C6H4, 3-NO2-C6H4, 2-Cl- C6H4, 2,4-Cl2-

C6H3, 2,4-Cl2-C6H3, 3,4,5-(MeO)3-C6H2, 2,5-(MeO)2-C6H , 4-Me-C6H4, 4-MeO-C

(Scheme 25)

11 1.8.1 Antibacterial activity

Saeed et al. [29-30] has developed and explained a methodology for the synthesis of Nine octahydroxanthen-1,8-dione derivatives (32) along with their bisdimedone intermediates (33). Bisdimedone derivatives were prepared by a simple condensation reaction of aldehyde with dimedone (1), while 9-substituted-1, 8-diketo octahydro xanthene was prepared by the cyclisations of corresponding bisdimedone intermediate. The structural proofs of the prepared compounds were given by 13C-NMR, 1H-NMR, UV and IR studies. For further confirmation the derivatives such as oxime and hydrazones of the corresponding compounds were prepared. The bisdimedone intermediates and the final products i.e. nine octahydroxanthen-1, 8-dione have been reported to possess a wide range of antibacterial activities especially against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. These also showed some antifungal activity against Candida albicans. Xanthene is present in many of the naturally occurring compounds and also in some dyes lilke 2,3,5,6-dibenzoylpyron. These have got significant importance owing to their biological and medicinal activities such as suppressing oriental fruit fly populations, antifungal activity, antischistosomal activity and antisnake venom activity.

O O O O H R H R

H3C CH3 H3C CH3 O H3C H C CH OH HO CH3 3 3 Bisdimedone derivative Octahydro Xanthene Derivatives (32) (33)

1.8.2 Anticonvulsant activity

Dimedone (1) has been employed in the manufacture of some 1,4-Dihydropyridine derivatives having good anticonvulsant activities. Some analogues of nifedipine having alkyl, aryl akyl and cyclo alkyl ester groups at C-3 and C-5 (35) along with 1-methyl-4- nitro-5-imidazolyl moiety at C-4 (34) have been reported to have more anticonvulsant activities than nifedipine [31].

12 N N

N CH3 N CH3 O2N O2N

2 1 COO(CH2)nR COO(CH2)nR COOR COOR

H3C N CH3 H3C N CH3 H H (34) (35) R1 = CH CH CH C H , CH C H (Cyclohexyl), R = CH3 , C6H5 2 2 2 6 5 2 6 11

CH2CH2C6H11(Cyclohexyl) 2 R = CH3 , CH3CH2

1.8.3 Antimicrobial activity

Dimedone (1) has been utilized in the production of so many medicinally important heterocyclic compounds and especially those having a bridgehead hydrazine ring have shown valuable antimicrobial and antifungal activities. Compounds of type (36) that has been prepared by the reaction of dimedone (1), phthalhydrazide and aromatic aldehyde, is used for this purpose.[32]

R

O

N O N

O CH3 CH (36) 3

1.8.4 Antioxidant properties

Some tetraketones (37) have been reported to have extensive lypoxgenase blocking activity and also act as strong antioxidants [33]. They have been found to have large number of biological activities such as dermatological disorders and tyrosinase blockers. Such type of compounds show lipoxygenase inhibiting and antioxidant properties in the range of 7.8-198.0 and 33.6-248.0 µM respectively. One of the best example of such type of compounds is 2,2′-Arylmethylene bis(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-ones (38) . This compound has been prepared from dimedone (1) by several ways.

13 O O O R O R

H C CH H3C CH3 3 3 H C H C O O CH 3 CH3 3 3 OH HO (37) (38) R= Aryl , alkyl

(Scheme 26) One way to synthesize these compounds is from the reaction of dimedome (1) with + aromatic aldehydes using tetraethyl ammonium bromide (Et4N Br-, TEAB) in water and also in the presence of pipridine.

O Ar O O

piperidine,(EtOH-H O),r.t or 2 H3C CH3 ArCHO + CH3 H3C CH O 3 TEAB, H2O, r.t OH HO CH3 (1) (39)

Ar = 4-ClC6H4, 4-O2NC6H4, 4-HOC6H4, 3,4-(CH3O)2C6H3, Piperonyl, 2-HOC6H4

(Scheme 27) Another method for the preparation of tetraketones (37) was given by Ramachary et al. [34] by the reaction of dimedone (1) with various aldehydes in the presence of S-proline and 1-(triphenylphosphanylidene)-propan-2-one in one pot reaction.

O O Ar O

(S)-Proline, MeOH,r.t CH ArCHO + 3 H3C CH3 O Ph3P=CHCOCH3 H3C CH3 CH3 OH HO (1) (39)

Ar = 4-ClC6H4, 4-O2NC6H4, 4-HOC6H4, 3,4-(CH3O)2C6H3, Piperonyl, 2-HOC6H4

(Scheme 28) Zhang et al. developed a green method for the synthesis of these compounds. L-histidine was used as a catalyst in ionic liquid (1-butyl-3-methylimidazolium tetrafluoroborate,

[bmim]BF4). Ionic liquid was used as a green alternative to organic solvents for this type of reactions.

14 O O Ar O

o [bmim]BF4, 60 C CH H C CH ArCHO + 3 3 3 O L-Histidine H3C CH3 CH3 OH HO (1) (39)

Ar = 4-ClC6H4, 4-O2NC6H4, 4-HOC6H4, 3,4-(CH3O)2C6H3, Piperonyl, 2-HOC6H4

(Scheme 29)

1.8.5 Antituberculosis activity

Dimedone (1) is employed in the production of 1,4-dihydropyridine derivatives by reacting it with ethylacetoacetate and aldehyde using MCM-41 as a catalyst under grinding methodology [31].1,4-dihydropyridine derivatives have been reported to have intense Antituberculosis activitiy specially against mycobacterium tuberculosis H37 strians. Many non-substituted, symmetrical and asymmetrical dihydropyridines derivatives were prepared for this purpose. Among them, which showed highest inhibiting effect against tuberclosis are, 4-(4-(Dimethylamino)phenyl)-1,4-dihydro- N3,N5-bis(2-methoxyphenyl)-2,6-dimethylpyridine-3,5-dicarboxamide (40) and 4-(2- Hydroxyphenyl)-1,4-dihydro-N3,N5-bis(3-nitro-phenyl)-2,6-dimethylpyridine-3,5- dicarboxamide.Theyshowed 93% and 92% inhibiting effects respectively. N3,N5-diaryl- 4-(4,5-dichloroimidazole-2-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbox-amides

(41) have shown promising inhibiting effects against mycobacterium tuberculosis H37 RV strain.

Cl Cl

1 N NH O Ar O O O H R R Ar-HN NH-Ar NH NH

H3C N CH3 H3C N CH3 H H (40) (41)

Ar = Chloropyridine-2-yl, 6-mthylpyridine-2-yl R = 3-Chloro, 3-Nitro, 4-Nitro Ar1 = 2-imidazolyl, 2-pyridyl

15 1.8.6 Cardiovascular activity

Dimedone (1) has been used in the preparation of some novel dihydropyridine derivatives possessing some phenylaminoimidazolyl moieties that have been screened for their antihypertensive activities and calcium antagonist activity. Some compounds of that series, especially those having ethyl (42) and phenyl (43) groups at C-3 and C-5 and 2- methylthio-1-phenylamino-5-imidazolyl at C-4 were found to be more active cardiovascular than all the previous one [31].

SCH3 SCH3 N N N NH N NH

H5C6OOC COOC6H5 H5C2OOC COOC2H5

H3C N CH3 H3C N CH3 H H (42) (43)

1.9 Biological importance

Gašparová and Lácová [36] have prepared some bio active chromene derivatives (45-46) by knoevenagel type condensation reaction of 3-formylchromone (44) with active methylene compounds e.g. dimedone (1) and some methyl compounds like barbituric acid or malonic acid. The reaction was activated by microwave irradiations and applying different solvent systems under reflux conditions. The final products obtained were further employed to synthesize different heterocyclic compounds which reported to show intense biological activities.

16 O CH O 3 O O AcONa CH3 O + CH3 O Ac2O , MWO R O O H H3C O (45) (44) (1) Ethanol or R = H , Me , Cl , NO2 Pyridine CH3 CH3 O O O O CH3 CH3

-H O 2 O O O O O O

O

H3C CH3 CH (46) H3C 3

(Scheme 30)

Dabiri et al. [37] has reported a facile and eco friendly mechanism for the preparation of some biologically vital spirooxindole derivatives (50-53) by a multicomponent reaction of dimedone (1), isatin (47) or acenaphthoquinone (48) and an active methylene reagent (49), applying small amount of Ammonium salts as catalyst under aqueous conditions. The benefits of this reaction were green conditions, short reaction time, outstanding yield of the product and affordable catalyst. Spirooxindoles have been reported to be associated with a number of biological and medicinal applications such as, anti-bacterial, antifungal, spasmolytic, anti-cancer, diuretic, antianaphylactic and anticoagulant activities.

O R O 1 H2N O R 2 CN R NH4Cl(20mol%) 1 R O X 2 + + R2 O X o R N H O, 80 C 1 H 2 O O (1) (47) 10 mins N (49) H (50) R = H , Me X = CN , CO Et 1 2 R = H , F 2

(Scheme 31)

17 H N O R1 O 2 R O O X 2 O CN NH Cl(20 mol%) R2 + 4 O O + R1 X

(1) (48) (49) (51) R = H , Me 1 X = CN , CO2Et R = H , F 2

(Scheme 32)

H C H O 3 N CH3 H C CH CN 3 3 NH4Cl (20mol%)

CH3 + 47 or 48 + O O Ph H O , 80 oC CH 2 O O (1) 3 (49) N 4 Hours H (52) or H H C 3 N CH3

H3C CH3

O O O

(53) (Scheme 33)

18