lewis acid mediated selective monohydrolysis of geminal...

CHAPTER – III

Lewis Acid Mediated Selective Monohydrolysis of Geminal Diesters - Synthesize of Functionalized Malonic acid Half esters

Chapter III Inroduction

81

INTRODUCTION

Hydrolysis of esters is one of the most fundamental reactions in organic chemistry.

Alkaline hydrolysis or saponification of esters using a base such as NaOH in aqueous

alcohol is a well-known and important method for hydrolysis of an ester. Partial

hydrolysis of diesters produces molecules which have both a carboxylic and an ester group

is called half ester. The Half esters are given different names in the literature which

includes, hemi ester, mono acid, mono ester etc.

COOH

COOR

Half esters

Figure 1. Structure of half esters

Half esters are versatile building blocks and synthons which is useful in the

synthesize of variety of natural products, bioactive compounds and intermediates.

Different types of half esters are known in the literature. Half esters, depending

upon the position of the ester and acid group, could be classified as geminal, vicinal,

vinylic, aromatic and normal half esters. These half esters based on the type, shows

different properties and application in various chemical reactions. Structure of some of the

common half esters is shown Figure 2.

COOH

COOR

COOH

COOR

COOH

COOR

HOOC COOR

R''R'

COOH

COOR

COOR

COOH

COOR

COOH

COOH

COOR

COOH

COOR

8

Figure 2. Different types of half esters


82

Organic Intermediates

In the synthesis of(-)-virantmycin1

In the synthesis of

bicyclic compounds11

O

O O

O

O

synthesis of tricarbonyl compound8

alphaamino acid

OH

NHCbz

O

NBoc

Boc

β−amino acid

H2N

R

O

NHBn

O O

OHO

O

H

COORCOOH

OHC H COOH

COOR

Half esters

Building Blocks

3-Aza-6,8-dioxabicyclo[3.2.1]octane-7-carboxylic Acid38

EtOOC COOH

COOEt

alkylated alcoholsO

O COOH

COOCH3

N

OO

OCH3

O

H3C

O

Bn

OO

CH3

HO

HO

O

O OH

O

Natural Products 39

Figure 3. Half ester and their applications in organic synthesize

Geminal half esters are a sub-class in half esters in which both the carbonyl groups,

namely ester and carboxylic acid are attached to the same carbon. This makes the central

carbon susceptible for nucleophilic attack and the protons attached to it become more

acidic. Among the different half esters known, geminal half esters finds unique application

in organic synthesize. Since half ester contains both the ester and acid groups the

difference in reactivity could be exploited for functionalizing these half esters and used as

a novel building block in the synthesize of valuable intermediates, bio-active compounds,

etc. Some of the important applications of the half esters are given below.

Applications of Half-esters

In the synthesize of amino acid derivatives

Back et al.1 developed a convenient and versatile enantioselective synthesize of

biologically important α-quaternary amino acid derivatives using half ester. The half esters

were converted to its corresponding N-Cbz-protected amino acids 4 or C-methyl-protected


83

amino acid 3 via the intermediate isocyanates 2 by Curtius rearrangement (DPPA and

Et3N) (Scheme 1).

H3COOC COOH

R'RDPPAEt3N

H3COOC NCO

R'R

H2, Pd-C

PhCH2OH

H3COOC NHCbz

R'R

H3COOC NH2

R'R

HOOC NHCbz

R'R

(R)-(+)-2-phenyl- ethylamine

H3COOC NH

R'R

OHN

PhH

H3C

KOH-MeOH

1 2

3

4

Scheme 1. Synthesize of α-quaternary amino acid derivatives

Similarly, Appella et al.2 used the N-Boc protected amino diethyl malonate half

ester in the synthesize N(α)-Boc2-N(β)-Cbz-2,3-diaminopropionic acid.

Guanti et al.3 synthesized α-amino acid derivatives by the use of half esters. The

half esters of the norbornene 5 was reacted with the ethylchloroformate and sodium azide

to form the azide derivative, which was further converted into to bromo derivative by

adding the bromine in dichloromethane solution. The azide derivative 6 was reacted with

the p-methoxybenzylalcohol to form the PMB protected amino derivative 7. NH group

was substituted with the benzyl group to form the N-Bn derivative. Cleavage of the PMB

and benzylester with the TFA and NaOH produced the N-Bn amino acid derivatives. On

further reaction with the aldehyde and the isocyanide the substituted amino acid was

produced (Scheme 2).


84

O

COOHCOOBn

O

CON3

COOBnBr2

O

NH-MeOZCOOBn

O

N

BnMeOZ

COOBn

O

NH2

Bn

COO

O Cl

O

H3C

2. NaN3(aq.)

1.H3CO

OH

Toluene/reflux

3. Br2

1.

2. Zn, TiCl4

TFANaH, Benzylbromide

DMF aq.NaOH

NH

R

O

NHBn H2N

R

O

NHBnPd black

5 6

7

89

Scheme 2. Synthesize of β-amino acid derivatives

Pellicciari et al.4 synthesized, 1-aminospiro[2.2]pentyl-1,4-dicarboxylic acids from

the corresponding half ester. The half esters 10, 10a on reaction with the ethyl

chloroformate and sodium azide gives rise to the isocynate derivative, which on hydrolysis

with tertiary butanol forms the N-Boc protected amino acid derivatives 11, 11a. Further

transformation produces the target molecule in good yield (Scheme 3).

COOCH3

COOH

t-BuOOC

COOH

COOCH3

t-BuOOC

H3C O Cl

O

NaN3

t-Bu-OH

+

COOCH3

NHBoc

t-BuOOC

NHBoc

COOCH3

t-BuOOC

+10

11

10a 11a

Scheme 3. Synthesize of 1-aminospiro[2.2]pentyl-1,4-dicarboxylic acids

In the synthesize of β-amino esters and β-hydroxy ester

Baudoux et al 5. synthesized the β-hydroxy esters 13 and β-amino esters 14 using

the half ester 12 of diethyl malonate by the decarboxylative nuclophile additions of imine

or aldehyde to mono ester of diethyl malonate respectively (Scheme 4).


85

O OH

EtO O

CHO

O

Ar

O

EtO

OH

O H -CO2

-NR3

EtO

O

OH

O NEt3 EtO

OHO

O OH

EtO O

CHNTs

O

Ar

O

EtO

NHTs

O H

-CO2

-NR3EtO

O

OH

O NEt3 EtO

NHTsO

HNEt3

HNEt3

1213

1412

Scheme 4. Synthesize of β-hydroxy esters and β-amino esters

In the synthesize of alkylated alcohols:

Williams et al 5. synthesized alkylated alcohols ester using the diethylmalonate half

ester. The malonate half esters 12 were alkylated using alcohols by decarboxylative

reaction, using Ru(PPh3)3Cl2 as catalyst through borrowing hydrogen pathway. The benzyl

alcohols reacted with the monoethyl malonate in the presence of Ru(PPh3)3Cl2 as a

catalyst and pyrrolidine as a organocatalyst in toluene to produce ethyldihydrocinamate 16

in good yield with small amount of ethyl cinnamate 17 (Scheme 5).

OH+

Ru(PPh3)3Cl2

30 mol% PyrrolidinePhMe, Reflux

EtOOC COOH

COOEt COOEt+

12 1516 17

Scheme 5. Synthesize of alkylated alcohols ester

In the synthesize of cyclic ester

Besten et al.7 synthesized ethyl-2-vinylcyclopropane-1-carboxylate 21 from the

half ester of diacid 20, 2-alkenyl cyclopropane-1,l-dicarboxylic acid 18. Simple heating of

the diacid, 2-vinyl-cyclopropane-1,l-dicarboxylic acid 18 will not give the decarboxylative

product instead of that it will produce cyclic lactone 19. However, half ester of 2-alkenyl

cyclopropane-1,l -dicarboxylic acid 20 underwent the decarboxylation to produce the

desired ethyl 2-vinylcyclopropane-1-carboxylate 21. This method was considered as a best

method compared with the previously reported synthesize of cyclopropyl ethyl ester from

the ethyldiazoacetate and 1,3 butadiene (Scheme 6).


86

COOH

COOH Heat

COOH

COOEt

O

COOEtHeat

O

18 19

20 21

Scheme 6. Synthesize of ethyl-2-vinylcyclopropane-1-carboxylate

In the synthesize of tricarbonyl compounds

Scott and Ryu8 synthesized 1,3-acetonedicarboxylic acid diesters 23 from the

malonic acid benzyl half ester 22 by reaction with N-hydroxysuccinimidyl ester forming

reagent. This reaction proceeds through the self-condensation of malonic acid half

oxyesters. This could be considered as a model for the decarboxylative Claisen

condensation in polyketide biosynthesize. Further this method does not require any

divalent metal chelator or a special coordinating solvents (Scheme 7).

O

O

OH

O

O

O O

O

O

1.2 equiv. TSTU, DPEA, DMF

22 23

Scheme 7. Synthesize of 1,3-acetonedicarboxylic acid diesters

In the Synthesize of alcohol by selective reduction

Periyasamy and Kanth9 selectively reduced the acid group present in the half ester

24 and 26 by NaBH4 to produce corresponding alcohol 25 and 27. For the preparation of

the alcohol, a solution of half ester in THF was added slowly to a suspension of sodium

borohydride in THF and the mixture was stirred until gas evolution ceases. Further, iodine

in THF was added slowly at the room temperature for completion of the acid reduction

(Scheme 8).


87

COOCH3

COOH

COOCH3

COOH

NaBH4, THFCOOCH3

CH2OHI2

NaBH4, THF

I28

24 25

26 27

COOCH3

CH2OH8

Scheme 8. Synthesize of mono alcohols by selective reduction of half ester-1

Bols10et al. reduced the acid group in a monoester 28 into corresponding alcohol

29 using BH3 in THF solution, which was employed for the synthesize of

isogalactofagomine (Scheme 9).

NBoc

OH

COOHH3COOC

NBoc

OH

H3COOC

OHBH3-THF

0 oC

99%

28 29

Scheme 9. Synthesize of mono alcohols by selective reduction of half ester-2

In the synthesize of alkoxycarbonylbicyclic derivatives

Niwayama and Liu11 asymmetrically synthesized 6-formyl-1-alkoxycarbonyl

bicyclo[3.1.0]hex-2-ene-2-carboxylic acids 31 via a rearrangement reactions of some

norborenyl half ester. Treatment of Pig Liver Eesterase on the diester 30 at pH=8 in

phosphate buffer gave the rearranged product through in situ formation of mono acid to

produced a alkoxy carbonyl bicyclic compounds 31 (Scheme 10).

O COOR1COOR2 pH=8

Phosphate buffer

O

COOR

O

-O

-O

COOR

O

O

H+H

COOR1COOH2

OHC H

PLE

30

31

Scheme 10. Asymmetric synthesize of 6-formyl-1-alkoxycarbonyl bicyclo[3.1.0]hex-2-

ene-2-carboxylic acids

In the synthesize of α, β or α, β, γ unsaturated ester

List et al.12 synthesized, α, β or, β, γ unsaturated esters in the presence of amino

acids like proline and some bases as co-catalyst, the two equivalent half ester of diethyl


88

malonate 12 was reacted with a long chain aldehyde 32 to produce α, β or, β, γ unsaturated

esters 33 or 34. Not unexpectedly, when pentanedial 35 reacted with three equivalents of

half ester 12 produced a cyclic unsaturated ester 36 (Scheme 11).

n-BuCHOHOOC COOEt

COOEtn-Pr

COOEtn-Bu

γ,

α β,

+Amino Acid Catalyst

BaseDMF

1 equiv.2 equiv.

+

CHO

CHOHOOC COOEt

3 equiv.

DMAP20 mol%

DMF, 25 oC+

COOEt

OH

β

12 32

33

34

12 3536

Scheme 11. Synthesize of α, β or, β, γ unsaturated esters from aldehydes

3. 2 Methods of synthesize of half ester

Base mediated monohydrolysis of diester

Durham13 et al. hydrolysed one of the ester group of long chain terminal diesters

37 to produce a half ester 38 using Ba(OH)2 as a base in aqueous medium. (Scheme 12).

H3COOC COOCH39

Ba(OH)2

aq. HClH3COOC COOH

9

37 38

Scheme 12. Synthesize of half esters by Ba(OH)2

Niwayama14 selectively hydrolysed the symmetric diesters 39, 41, 43 and 45 to

form the mono ester or half ester 40, 42, 44 and 46 by treatment with aqueous sodium

hydroxide in THF at 0oC (Scheme 13).


89

COOCH2CH3

PhCOOCH2CH3

COOCH2CH3

COOCH2CH3

THF / aq. NaOH

0 oC, 0.5-1 h

THF / aq. NaOH

0 oC, 0.5-1 h

COOCH2CH3

PhCOOH

COOH

COOCH2CH3

H3CO OCH3

OO

EtO OEt

OO

CH3

THF / aq. KOH

0 oC, 0.5-1 h

THF / aq. KOH

0 oC, 0.5-1 h

H3CO OH

OO

EtO OH

OO

CH3

39 40

41 42

43 44

45 46

Scheme 13. Synthesize of half esters by aq. NaOH or KOH in THF medium

This methodology is useful for preparation of variety of half esters and the reaction

time is short, (0.5-1 h). Since carboalkoxy groups are the most hydrophilic parts and

therefore are expected to be facing the interface between THF and water, the

monohydrolysis is expected to occur at this interface selectively.

Niwayama15 also developed a highly efficient selective monohydrolysis of

symmetric diesters especially for monohydrolysis of several dialkyl malonates and their

derivatives. This has great industrial importance. With the 0.8-1.2 equivalent of aqueous

KOH and a co-solvent, THF or acetonitrile at 0 oC the hydrolysis occurs smoothly. The

reaction takes place without any decarboxylation.

Similarly Pellicciari et al.4 hydrolysed the geminal diester 47 present in the spiro

compound using NaOH as a base (Scheme 14).

COOCH3

COOCH3

t-BuOOC

NaOH / CH3OH

72 h, 78%COOCH3

COOH

t-BuOOC47 10

Scheme 14. Synthesize of half esters by NaOH in methanol


90

Enzyme mediated Monohydrolysis of diesters

Kedrowshi16 synthesized the half ester by the enzyme hydrolysis method. The

disubtituted dimethyl malonate 48 was subjected to hydrolysis with the Pig Liver Esterase

(PLE) at pH 7.2 phosphate buffer to produce the corresponding monoester 49 (Scheme

15).

HOOC COOMe

Met-BuS

MeOOC COOMe

Met-BuSPig Liver Esterase (PLE)

pH 7.2 phosphate ester

97%, 91% ee48 49

Scheme 15. Synthesize of half esters by Pig Liver Esterase

Back et al.1 used porcine liver esterase (PLE) to prepare a half esters of

disubtiteuted dimethyl malonate 51. The reaction in general gives product in 86% yield

with 95% ee. This desymmetrization reaction is convenient for the preparation of half

ester under mild condition (Scheme 16).

O O

OO

O porcine liveresterase (PLE)

O O

OHO

O

86% , 95% ee

50 51

Scheme 16. Synthesize of half esters by Porcine Liver Esterase

Bols et al.10 hydrolysed the 1,3-diester 52 using the different types of esterase to

get a mono ester 28. This mono ester was used an important intermediate for the

synthesize of optically pure isogalactofagomine from achiral starting material (Scheme

17).

N

COOCH3H3COOC

OH

Boc

Lipase M(Murcor javanicus))

N

COOHH3COOC

OH

BocH2O

52 28

Scheme 17. Synthesize of half esters by murcor javanicus


91

Synthesize of half esters using protection and deprotection methods

For the synthesize of special amino acid derivative Englund et al.2 used half ester a

commercially available amino acid mono benzyl ester intermediate. This mono benzyl

ester 53 was converted into its methyl benzyl ester 54 by reaction with the methyl iodide.

After making the necessary substitutions at the other site of the molecule, the benzyl ester

was cleaved by treatment with Pd- C and hydrogen to produce the mono methyl ester 56

(Scheme 18).

OH

O Ph

O

O

H2NOCH3

O Ph

O

O

H2N

1 equiv. DMAP

1.5 equiv. Boc2O

OCH3

O Ph

O

O

NBoc

Boc

Pd/C, H2

50 psiOCH3

OH

O

O

NBoc

Boc

K2CO3, CH3I

5354

55 56

Scheme 18. Synthesize of half esters by multistep protection and deprotection

Lewis acid mediated ring opening of cyclic anhydrides

Sabitha et al.17 prepared a variety of half esters by the ring opening of cyclic

anhydrides by the Lewis acids. The half ester produced by this method was achiral. When

BF3.OEt2, AlCl3 or FeCl3 was treated with the cyclic anhydrides in the presence of

alcohols, like methanol and ethanol, the corresponding pure half ester were obtained

spontaneously in excellent yield. With this method the homophthalic anhydride 57, tetralic

anhydride 59 and phenylitaconic anhydride 61 produced regio-selective ring opening

products 58, 60 and 62 without affecting the aromatic acid (Scheme 19).


92

O

O

O

O

O

O

O

O

O

Ph

MeOH or EtOH

BF3.Et2O or AlCl3 or FeCl3

MeOH or EtOH

BF3.Et2O or AlCl3 or FeCl3

MeOH or EtOH

BF3.Et2O or AlCl3 or FeCl3 COOH

COOR

Ph

COOR

COOH

COOH

COOR

R= Me or Et

O

O

O

R-OH, LA

rt COOR

57 58

59

60

6162

COOH

Scheme 19. Synthesize of half esters by ring opening of anhydrides using Lewis acids

Lewis base mediated ring opening of cyclic anhydrides

Guanti et al.3 prepared norboronene derivatives mono benzylester 5 from by ring

opening of corresponding anhydride 63 using optically active Lewis base (+)-quinine

(Scheme 20).

O

O

O

O

(+)-quinine, PhCH2OHCCl4

PhMe, -55 oC, 95%

O

COOHCOOBn

63 5

Scheme 20. Synthesize of half esters by ring opening of anhydrides by (+)-quinine

By oxidative cleavage of suitable alkenes

Henry and Weinreb18 obtained the half ester during the oxidative scission of

alkenes. Here, the alkene suitably substituted with the diester 64 was cleaved using the

Jones reagent and osmium tetraxide to form the corresponding bis-half ester 65 (Scheme

21).


93

COOCH3

COOCH3

Jones reagent

OsO4

HOOC

HOOC

COOCH3

COOCH3

64 65

Scheme 21. Synthesize of half esters by scission of double bond

Yand and Zhang19 obtained the half ester of long chain hydrocarbon 67 as one of

the products by the oxidative cleavage of double bond 66 using the RuCl and oxone as the

catalyst (Scheme 22).

H3CO

O

8

RuClOxone

NaHCO3

CH3CNH2O

H3CO

O

COOH

8

alcohols and aldehyde derivatives+

66 67

Scheme 22. Synthesize of half esters by cleavage of terminal double bond

Reductive Cleavage of C-C bond

Otera and Sato20 demonstrated that when reduction of suitably allyl substituted

ester 68 with the ammonium formate and palladium acetate-triphenyl phosphine in

dioxane was carried out at reflux temperature, all group gets deprotected followed by

which decarboxylation takes place to give the half ester 69 in 100 % yield (Scheme 23).

H3C COOEt

COOCH2CH=CH2H2C=HCH2COOC HCOONH4-Pd(OAc)2-PhPh3

Dioxane, reflux, 3 h H3C COOEt

COOH

68 69

Scheme 23. Synthesize of half esters by reductive cleavage of double bond

As described earlier there are a large number of methods known in the literature

for the synthesize of half esters. Geminal half esters are known only to be synthesized by

hydrolysis of geminal diester either using a base12 or an enzyme11 but there is no report

availabe on the use of Lewis acid.

Chapter III Present Work

94

PRESENT WORK

Ester hydrolysis remains as an integral functional group transformation21 in

multistep synthesize of several natural products, pharmaceuticals, fine chemicals and

novel organic materials. It can also be considered as a deprotection step to unmask a

carboxyl group. The half esters of malonates are important building blocks used in the

synthesize of substituted α-amino acids,1 doubly homologated ester,6 tricarbonyl

compound,8 alcohols,9 β-amino ester and β-hydroxyester.5

Methods known for preparation of half esters or hemiesters such as alkaline

hydrolysis,22,23 multistep protection and deprotection,2 ring opening of anhydrides,3,17 and

enzymatic hydrolysis10,16 have some practical disadvantages. The saponification involves

the use of strong bases such as NaOH or KOH14,22,24 which may seriously affect sensitive

functional groups. Ring opening of anhydride using Lewis acid or Lewis base needs

preparation of suitable anhydrides as starting material. The enzyme hydrolysis depends of

availability of suitable enzyme and the stereochemistry varies based on substrate and

takes long reaction time. Geminal half esters are a class of half esters known only to be

synthesized by hydrolysis of geminal diester either using a base14,22,24 or an enzyme10,16

but there was no report availabe on the use of Lewis acid.

As we explained in Chapter-2, the bis-ethoxycarbonylvinyl (BECV) group could

be used as a versatile amine protecting group for selective functional group

transformations.13 In this direction, we examined reactivity of diester part of the N-BECV

amine group towards different Lewis acids (Table 1). AlCl3 did not catalyze the reaction at

room temperature (Scheme 24), even after using more than stiochiometric quantity (2.5

equiv.) of the reagent, and the reaction took place only after heating at reflux in 1, 2-

dichloroethane (entry 7) to give the product 71a, in high yield. Lewis acids such as ZnCl2,

SnCl4, Yb(OTf)3, FeCl3 or CuSO4 were ineffective.

NH

COOCH2CH3

NH

COOCH2CH3 COOCH2CH3

COOH70a 71a

AlCl3

ClCH2CH2Cl reflux, 30 min

92% Scheme 24. AlCl3 mediated monohydrolysis of geminal diester


95

Table 1. Optimization of reaction condition for the Lewis acid mediated monohydrolysis of geminal diester

NH

COOCH2CH3

NH

COOCH2CH3 COOCH2CH3

COOH70a 71a

Conditions

S.No. Catalyst No of equiv.

Solvent Temp. Time Yield in %

1 AlCl3 0.1 CHCl3 rt 24 h 0 1 AlCl3 1.0 CHCl3 rt 24 h 0 2 AlCl3 2.5 CHCl3 rt 24 h 0 3 AlCl3 1.0 DCE rt 24 h 0 4 AlCl3 1.0 CHCl3 reflux 1.0 h 52 5 AlCl3 2.5 CHCl33 reflux 1.0 h 60 6 AlCl3 1.0 DCE reflux 1.0 h 72 7 AlCl3 2.0 DCE reflux 1.0 h 81 8 SnCl4 1.0 DCE rt 1.0 h 0 9 SnCl4 2.0 DCE reflux 1.0 h 0

10 FeCl3 0.5 CHCl3 reflux 1.0 h 0 11 FeCl3 1.5 CHCl3 rt 3.0 h 0 12 CuSO4 2.0 CHCl3 reflux 3.0 h 0 13 ZnCl2 2.0 CHCl3 reflux 3.0 h 0 14 Yb(OTf)3 0.1 CHCl3 reflux 3.0 h 0 15 BF3.OEt2 1.0 CHCl3 rt 30 min 92 16 BF3.OEt2 0.5 CHCl3 rt 25 min 51 17 BF3.OEt2 0.1 CHCl3 rt 25 min 10 18 BF3.OEt2 1.0 Toluene rt 30 min 80 19 BF3.OEt2 1.0 ACN rt 30 min 70 20 BF3.OEt2 1.0 THF rt 4.0 h 45 21 BF3.OEt2 1.0 None rt 30 min 76 22 BF3.OEt2 1.0 DMF rt 4.0 h 0 23 BF3.OEt2 2.0 DMF rt 30 min 8

In order to avoid the reaction taking place at reflux temperature, we further

examined milder reaction conditions. BF3.OEt2 (1 equiv.) selectively hydrolyzed one of

the ester group in 2-phenylaminomethylene-malonic acid diethyl ester 70a in very short

time, at room temperature to give a functionalized malonic acid half ester 71a (Scheme

25). With less than stiochiometric quantity of the reagent, the reaction was not completed.

Among the different solvents examined, CHCl3 gave high yield of the product, where as

solvents such as CH3CN, CH3NO2, THF and DMF gave low yield of the product. Based

on these results it was decided to use the mild reaction condition, BF3.OEt2 (equiv.) in

CHCl3 at room temperature for further studies.


96

NH

COOCH2CH3

NH

COOCH2CH3 COOCH2CH3

COOH70a 71a

BF3.Et2O

CHCl3, 30 min92%

Scheme 25. BF3.OEt2 mediated mono hydrolysis of germinal diesters

Interestingly, BF3.OEt2 does not hydrolyse geminal diester with no neighbouring

heteroatom25,26 or a mono ester even in the presence of α or β nitrogen atom.27Moreover,

there are only isolated examples on the use of Lewis acids for ester hydrolysis as in the

case of BF3.OEt2 mediated hydrolysis of t-butyl ester,28 hydrolysis of ethyl ester vicinal to

carbonyl28 and ZnBr230 or LiBr31 mediated selective hydrolysis of dissimilar esters lying

far apart. Further, there is no report on participation of a neighbouring group in Lewis acid

mediated hydrolysis of a geminal diester. Thus, we realised that this observation is the first

Lewis acid mediated selective monohydrolysis of a geminal diester to give half ester. This

prompted us to make a further study on this subject. To standardize the reaction condition

diethyl 2-phenylaminomethylene malonate 70a was treated with different Lewis acids and

the results are summarised in Table 1. Among the different Lewis acids examined by us

BF3.OEt2 was found to have advantages such as work up procedure is simple, maintains

homogeneous reaction mixture, achieves coordination with the neigbouring functional

groups easily and the reagent available in the form of liquid is easy to handle.

To check the versatility of this method and electronic influence of subtituents on

aromatic ring, different N-2,2-bis(ethoxycarbonyl)vinylamine derivatives were prepared32

and subjected to the hydrolysis and the results are summarized in Table 2. With electron

donating -OCH3, 4-OBn and 4-CH3 substituent on the phenyl ring 70b-f the rate of

hydrolysis was fast compared to the unsubstituted aniline (70a, 30 min). Presence of –

OCH3 substituent (Table 1, entry 3-5) at para, ortho or meta position did not bring any

change in the reaction rate. Inductively electron withdrawing –Cl, –NO2 and –COCH3

subsituents in compounds 70g-70m lead to slow reaction. The naphthyl derivative 70n,

behaved similar to a subtituent containing electron wtihdrawing group. This suggests that,

the substituent effect is mainly electronic in nature and not steric. The pyridine derivatives

70o-70p underwent hydrolysis successfully in 45 min without forming a complex with

BF3.OEt2. High yield of the monoester was obtained with almost all the compounds. The

functional groups such as ether, ketone, nitro and pyridine ring remained stable under the

hydrolysios reaction condition.


97

Table 2. Electronic influence of subtitutents in the BF3.OEt2 catlysed monohydrolysis

of N-aryl-2,2-bis(ethoxycarbonyl) vinylamine derivatives

RNH

COOCH2CH3

RNHrt, CHCl3

COOCH2CH3 COOCH2CH3

COOH

BF3.OEt2

S. No. Time Yield Product

1 30 min 92 NH

O OH

OCH2CH3

O

2 20 min 90

H3C

NH

O OH

OCH2CH3

O

3 25 min 90

H3CO

NH

O OH

OCH2CH3

O

4 25 min 89NH

O OH

OCH2CH3

O

OCH3

5 25 min 89NH

O OH

OCH2CH3

O

OCH3

6 25 min 91NH

O OH

OCH2CH3

O

O

7 2 h 81NH

O OH

OCH2CH3

O

Cl

8 2.15 h 80NH

O OH

OCH2CH3

O

NH

O OCH2CH3

OCH2CH3

O

H3C

NH

O OCH2CH3

OCH2CH3

O

H3CO

NH

O OCH2CH3

OCH2CH3

O

NH

O OCH2CH3

OCH2CH3

O

OCH3

NH

O OCH2CH3

OCH2CH3

O

OCH3

NH

O OCH2CH3

OCH2CH3

O

O

NH

O OCH2CH3

OCH2CH3

O

Cl

NH

O OCH2CH3

OCH2CH3

O

Substrate (R)

70a

70b

70c

70d

70e

70f

70g

1h

71a

71b

71c

71d

71e

71f

71g

71h

Cl Cl


98

S. No. Time Yield Product

9

10

11

12

13

14

15

16

Substrate (R)

NH

O OCH2CH3

OCH2CH3

O

O2N

NH

O OCH2CH3

OCH2CH3

O

NH

O OCH2CH3

OCH2CH3

O

NH

O OCH2CH3

OCH2CH3

O

NH

O OCH2CH3

OCH2CH3

O

NH

O OCH2CH3

OCH2CH3

O

N

NH

O OCH2CH3

OCH2CH3

O

N

NH

O OCH2CH3

OCH2CH3

O

Cl

NO2

NO2

O

H3C

NH

O OH

OCH2CH3

O

O2N

NH

O OH

OCH2CH3

O

NH

O OH

OCH2CH3

O

NH

O OH

OCH2CH3

O

NH

O OH

OCH2CH3

O

NH

O OH

OCH2CH3

O

N

NH

O OH

OCH2CH3

O

N

NH

O OH

OCH2CH3

O

Cl

NO2

NO2

O

H3C

78

83

83

85

80

85

60

64

2.15 h

2. 20 h

2.30 h

2.20 h

2.30 h

2.20 h

45 min

45 min

70i

70j

70k

70l

70m

70n

70o

70p

71i

71j

71k

71l

71m

71n

71o

71p

Single crytal obtained, for the compounds 71b, 71g, 71k, all crystalised from EtOAc

shows very clearly that under the BF3.OEt2 mediated hydrolysis the ester group adjacent to

the –NH group gets hydrolysed selectively leading to E configuration.


99

Figure 4. ORTEP for compound 71g

Figure 5. ORTEP for compound 71b


100

Figure 6. ORTEP for compound 71k

Versatility of this monohydrolysis method on aliphatic substrates was checked

using compounds 72, 73 and 74. The 2-(benzylamino-methylene)-malonic acid diethyl

ester 72 reacted with BF3.OEt2 within 30 min. to give the mono ester 72a in very high

yield ( Scheme 26).

NH

COOC2H5

COOC2H5

BF3.Et2O

CHCl3, rt30 min, 89%

NH

COOC2H5

COOH

72 72a

Scheme 26. BF3.OEt2 mediated monohydrolysis of N-BECV benzyl amine

The diamino tetraester 73, on treatment with BF3.OEt2 gave the mono hydrolysis

product 73a in 40% yield. In addition, an unidentified solid mass, insoluble in polar

organic solvents, such as DMSO and water, was obtained.33 Interestingly, the tetra ester 74

gave symmetric and highly functionalized malonate bis-half ester 74a, containing several

potential chelating functional groups, in high yield (Schemes 27 and 28).


101

73 73a

BF3.OEt2

CHCl3rt, 35 min, 40%

HN NH

OC2H5

O

OC2H5O

C2H5O

O

OC2H5O

HN NH

OH

O

OC2H5O

C2H5O

O

OC2H5O

OC2H5

O

OC2H5

O

C2H5OH2N NH2 +rt, 5 min, 99%

2 equiv.

Scheme 27. BF3.OEt2 mediated monohydrolysis of Bis-N-BECV ethylenediamine

OC2H5

O

OC2H5

O

C2H5O+EtOH

rt, 7 min, 98%

74a

CHCl3, rt, 35 min, 80%

BF3.OEt2HN NH

O

O

OC2H5

OC2H5

O

C2H5O

OC2H5O

HN NH

O

O

OH

OC2H5

O

HO

OC2H5O

74

H2N NH2

2 equiv.

Scheme 28. BF3.OEt2 mediated monohydrolysis of Bis-N-BECV 1,2-diaminopropane

Chemical intramolecular reactions resemble intracomplex reactions of enzymes,

hence the study of neighbouring group participation in a reaction gains lot of

significance.34 Neighboring group participation by nitrogen in ester hydrolysis is known as

in the case of LiBr,31 NaOH mediated ester hydrolysis and in acetalysis of 4-

(acetoxyphenyl) imidazle. Thus, the role of nitrogen atom and compatibility of similar

ester groups in the ester hydrolysis was examined. In this direction, when compounds 75-

7932 subjected to BF3.OEt2 catalysed hydrolysis, only the geminal diester underwent

reaction and the corresponding half esters 75a, 76a and 77a-79a were obtained as the

exclusive products in very good yield (Scheme 29).


102

NH

COOH

K2CO3, C2H5Br

Acetonert, 24 h, 80%

BF3·OEt2

CHCl3rt, 1.40 h, 81%

OH3CH2CO

OOC2H5 NH

CO2C2H5

OH3CH2CO

OOC2H5

NH

CO2C2H5

OH3CH2CO

OOH

75

75a Scheme 29. BF3.OEt2 mediated selective mono hydrolysis of N-BECV in presence of

similar aromatic esters-1

NH

K2CO3, C2H5Br

BF3·OEt2

Acetonert, 24 h, 83%

CHCl3rt, 1.35 h 85%,

OH3CH2CO

OOC2H5

NH

OH3CH2CO

OOC2H5

NH

OH3CH2CO

OOH

HOOC C2H5O2C

C2H5O2C

76

76a Scheme 30. BF3.OEt2 mediated selective mono hydrolysis of N-BECV in presence of

similar aromatic esters-2

In case of compound 75, the distance between nitrogen and the vinyl ester as well

as the aromatic ester was almost the same. Similarly in compounds 78 and 79, an aliphatic

ester group lies very close to the reactive site (Schemes 31-33). In all these cases, only the

amino vinlyl ester underwent hydrolysis and other ester groups remained unaffected.

COOCH3

NH

COOCH2CH3

COOCH2CH3CHCl3

rt, 20 min, 79%

BF3.OEt2 COOCH3

NH

COOH

COOCH2CH3

77 77a Scheme 31. BF3.OEt2 mediated selective mono hydrolysis of N-BECV in presence of

similar aliphatic esters in half ester of N-BECV pheylalanine methyl ester


103

COOCH3

NH

COOCH2CH3

COOCH2CH3CHCl3

rt, 20 min, 80%

BF3.OEt2CH3

H3C

COOCH3

NH

COOH

COOCH2CH3

CH3

H3C


similar aliphatic esters in half ester of N-BECV leucine methyl ester

COOCH3

NH

COOCH2CH3

COOCH2CH3CHCl3

rt, 25 min, 78%

BF3.OEt2S

H3C

COOCH3

NH

COOH

COOCH2CH3SH3C


similar aliphatic esters in half ester of N-BECV methionine methyl ester

This highly selective ester hydrolysis was further confirmed from the crystal

structure of compound 75a and 77a (Figure 4). The carboxylic acid and the vinyl amine

were found lying on the same side of the double bond, giving rise to E configuration.

These observations summarizes that, the amine nitrogen, neighboring to the vinyl ester

should participate in the hydrolysis. Thus the position and connectivity of ester group is

important for the hydrolysis reaction.

Figure 7. ORTEP for compound 75a


104

Figure 8. ORTEP for compound 77a

Further, to estabilish the role of intramolecular nitrogen atom, geminal diesters 80-

83 and diesters 84 and 85 were subjected to hydrolysis under current experimental

conditions (Scheme 33). None of these esters underwent hydrolysis which confirms that

the presence of NH group at neighbouring position to the ester is important for the

hydrolysis reaction.

O

OC2H5

O

OC2H5

O

OC2H5

O

OC2H5

OOC2H5

OOC2H5

OOC2H5

OOC2H5

OOC2H5

OOC2H5

Ph

Ph

80

84 85

81 82

83 R = -NO2, -OCH3

OOC2H5

OOC2H5

R

C2H5O

Scheme 33. Diesters failed to undergo BF3.OEt2 mediated ester hydrolysis

With less than one equivalenmt of BF3.OEt2 the reaction was not complete. This

infers that, for removel of each ethyl group, more probably in the form of ethylfluoride,

one molecule of BF3.OEt2 is necessary. Based on these results a suitable mechanism is

proposed as shown in (Scheme 34).


105

N

O

O

O O

CH3

CH3

R

BFF F

H

N

O

O

O O

CH3R

BF

F

HH2ON

H

O

O

O OH

CH3R

Intermediate formation

Half ester

Geminar diester

BF3.OEt2NH

O

O

O O

CH3

CH3

R N

O

O

O O

CH3

CH3

R

BFF

H

F

-CH3CH2F

Scheme 34. Plausible mechanism of the reaction

BF3.OEt2 might prefer to coordinate with more nucleophilic nitrogen and an

adjacent carbonyl instead of both carbonyl groups35,36 to give rise to boron anion which

stabilizes itself by loss of fluoride ion, which in turn attacks the ethyl group.37 This is an

intramolecular reaction in which a six membered intermediate is involved.

Conclusison

In conclusion, a new method for selective mono hydrolysis of geminal diesters by

Lewis acid was developed. Neighboring group participation by nitrogen in the Lewis acid

mediated ester hydrolysis was established. This new synthetic technique is stable towards

alkyl ether, aryl ether, thio ether, ester, ketone, pyridine functional groups and no

racemization or isomerization tookplace. This reaction is specific to the geminal diester

and aromatic or aliphatic esters remain unaffected. This very mild and highly selective

procedure enables the synthesize of highly functionalized malonic acid half ester. This

chemoselective Lewis acid hydrolysis of ester functional groups should be of general

utility for the synthesize of mutifunctional and highly substituted malonate derivatives.

Chapter III Experimental

106

EXPERIMENTAL

General procedure for monohydrolysis of geminal diesters

To a solution of 2-[(aryl/alkyl-amino)-methylene]-malonic acid diethyl ester (1.0

equiv.) in CHCl3 (3 times w/v), BF3.OEt2 (1.0 equiv.) was added and stirred at room

temperature. Completion of the reaction was determined by TLC, followed by which the

reaction mixture was quenched with water (1 time w/v) and extracted with chloroform

(three portions mL). The combined organic layer was dried (anhyd. Na2SO4) and

evaporated in rotary evaporator under vacuum. The crude product obtained was passed

through a short silica gel column using a suitable eluent to get corresponding product.

Preparation of 2-phenylaminomethylene-malonic acid monoethyl ester (71a)

NH

O

OH

OC2H5

O

To a solution of 2-phenylaminomethylene-malonic acid diethyl ester32 (70a, 500

mg, 1.8 mmol) in chloroform (1.5 mL), BF3.OEt2 (477 μL, 1.8 mmol ) was added and

stirred at room temperature for 30 min. Completion of the reaction was determined by

TLC, followed by which the reaction mixture was quenched with water and extracted with

chloroform (3x5 mL). The combined organic layer was dried (anhyd. Na2SO4) and

evaporated in rotary evaporator under vacuum to get a 2-phenylaminomethylene-malonic

acid monoethyl ester (71a) in 0.41 g (92%) yield as white solid. mp: 114 °C; 1H NMR

(400 MHz, CDCl3) δ: 1.30 (t, J = 6.8 Hz, 3H), 4.27 (q, J = 14.0 and J = 7.2 Hz, 2H), 7.11-

7.19 (m, 3H), 7.32-7.36 (m, 2H), 8.43 (d, J = 14.0 Hz, 1H), 11.62 (d, J = 12.8 Hz, 1H),

12.92 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ:14.3, 61.4, 89.5, 117.8, 126.0, 129.9,

138.5, 151.6, 169.9, 170.7; IR (KBr) ν: 3180, 2983, 2934, 1695, 1624, 1476, 1449, 1271,

1094, 821, 690, 568 cm-1; Mass: m/z calcd. for C12H13NO4: 235.08; Found: 236.1 (M+1);

Anal. calcd. for C12H13NO4, Elemental Analysis: C, 61.27; H, 5.57; N, 5.95; Found: C,

61.30; H, 5.55; N, 5.98.


107

Preparation of 2-(p-tolylamino-methylene)-malonic acid monoethyl ester (71b)

NH

O

OH

OC2H5

O

H3C

To a solution of 2-(p-tolylamino-methylene)-malonic acid diethyl ester32 (70b, 500





evaporated in rotary evaporator under vacuum to get a 2-(p-tolylamino-methylene)-

malonic acid monoethyl ester (71b) in 0.40 g (90%) yield as white solid. mp: 92 °C; 1H

NMR (400 MHz, CDCl3) δ: 1.35 (t, J = 7.2 Hz, 3H), 2.33 (s, 3H), 4.32 (q, J = 14.4 and J =

7.2 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 8.44 (d, J = 13.6 Hz, 1H),

11.62 (d, J = 13.2 Hz, 1H), 13.0 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ:14.3, 20.7,

61.3, 89.0, 177.7, 130.3, 135.9, 136.0, 151.6, 169.9, 170.7; IR (KBr) ν: 3183, 2978, 2688,

1696, 1630, 1512, 1473, 1407, 1268, 1205, 1089, 1017, 887, 831, 811 cm-1; Mass: m/z

calcd. for C13H15NO4: 249.10; Found: 250.2 (M+1); Anal. calcd. for C13H15NO4,

Elemental Analysis: C, 62.64; H, 6.07; N, 5.62; Found: C, 62.62; H, 6.08; N, 5.60.

Preparation of 2-[(4-4ethoxy-phenylamino)-methylene]-malonic acid monoethyl ester

(71c):

NH

O

OH

OC2H5

O

H3CO

To a solution of 2-[(4-methoxy-phenylamino)-methylene]-malonic acid diethyl

ester32 (70c, 500 mg, 1.7 mmol) in chloroform (1.5 mL), BF3.OEt2 (428 μL, 1.7 mmol )

was added and stirred at room temperature for 25 min. Completion of the reaction was

determined by TLC, followed by which the reaction mixture was quenched with water and

extracted with chloroform (3x5 mL). The combined organic layer was dried (anhyd.

Na2SO4) and evaporated in rotary evaporator under vacuum to get a 2-[(4-methoxy-

phenylamino)-methylene]-malonic acid monoethyl ester (71c) in 0.40 g (90%) yield as

white solid. mp: 110 °C; 1H NMR (400 MHz, CDCl3) δ:1.35 (t, J = 7.2 Hz, 3H), 3.80 (s,

3H), 4.31(q, J = 14.0 and 6.8 Hz, 2H), 6.92 (d, J = 9.2 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H),


108

8.37 (d, J = 13.6 Hz, 1H), 11.63 (d, J = 13.6 Hz, 1H), 12.97 (brs, 1H); 13C NMR (100

MHz, CDCl3) δ:14.3, 55.5, 61.2, 88.7, 115.0, 119.4, 131.9, 151.9, 157.9, 170.1, 170.7; IR

(KBr) ν: 3172, 2998, 2954, 2831, 2708, 1694, 1632, 1516, 1474, 1431, 1329, 1281, 1205,

1101, 1027, 837, 548, 441 cm-1; Mass: m/z calcd. for C13H15NO5: 265.09; Found: 266.2

(M+1); Anal. calcd. for C13H15NO5, Elemental Analysis: C, 58.86; H, 5.70; N, 5.28;

Found: C, 58.85; H, 5.73; N, 5.30.

Preparation of 2-[(2-Methoxy-phenylamino)-methylene]-malonic acid monoethyl

ester (71d)

NH

O

OH

OC2H5

O

OCH3


ester32 (70d, 500 mg, 1.7 mmol) in chloroform (1.5 mL), BF3.OEt2 (428 μL, 1.7 mmol )





phenylamino)-methylene]-malonic acid monoethyl ester (71d) in 0.40 g (89%) yield as

white solid. mp: 132 °C; 1H NMR (400 MHz, CDCl3) δ:1.36 (t, J = 7.2 Hz, 3H), 3.91 (s,

3H), 4.32 (q, J = 14.4 and J = 7.2 Hz, 2H), 6.93-7.0 (m, 2H), 7.13-7.17 (m, 1H), 7.22-

7.24 (m, 1H), 8.51 (d, J = 14.4 Hz, 1H), 11.87 (d, J = 13.6 Hz, 1H), 12.94 (brs, 1H); 13C

NMR (100 MHz, CDCl3) δ:14.3, 55.8, 61.3, 89.5, 111.4, 115.0, 121.0, 126.1, 127.8,

149.4, 150.3, 169.6, 170.7; IR (KBr) ν: 3155, 2981, 2938, 2843, 2721, 1698, 1612, 1583,

1467, 1383, 1277, 1098, 995, 865, 756, 587, 558, 529, 413 cm-1; Mass: m/z calcd. for

C13H15NO5: 265.09; Found: 266.2 (M+1); Anal. calcd. for C13H15NO5, Elemental

Analysis: C, 58.86; H, 5.70; N, 5.28; Found: C, 58.87; H, 5.72; N, 5.29.


109

Preparation of 2-[(3-Methoxy-phenylamino)-methylene]-malonic acid monoethyl

ester (71e)

NH

O

OH

OC2H5

O

OCH3


ester32 (70e, 500 mg, 1.7 mmol) in chloroform (1.5 mL), BF3.OEt2 (428 μL, 1.7 mmol )





phenylamino)-methylene]-malonic acid monoethyl ester (71e) in 0.40 g (89%) yield as

white solid. mp: 102 °C; 1H NMR (400 MHz, CDCl3) δ: 1.36 (t, J = 6.8 Hz, 3H), 3.82 (s,

3H), 4.33 (q, J = 14.4 and J = 7.2 Hz, 2H), 6.69 (t, J = 2.4 Hz, 1H), 6.73-6.78 (m, 2H),

7.29 (t, J = 8.0 Hz, 1 H), 8.46 (d, J =14.0 Hz, 1H), 11.62 (d, J = 13.2 Hz, 1H), 12.99 (brs,

1H); 13C NMR (100 MHz, CDCl3) δ:14.3, 55.4, 61.4, 89.6, 104.1 109.8, 111.1 130.7,

139.6, 151.5, 160.8, 169.8, 170.6; IR (KBr) ν: 3202, 2992, 2739, 1703, 1635, 1598, 1439,

1389, 1286, 1157, 1106, 1053, 845, 811, 789; Mass: m/z calcd. for C13H15NO5: 265.09;

Found: 266.2 (M+1); Anal. calcd. for C13H15NO5, Elemental Analysis: C, 58.86; H, 5.70;

N, 5.28; Found: C, 58.88; H, 5.72; N, 5.32.

Preparation of 2-[(4-Benzyloxy-phenylamino)-methylene]-malonic acid monoethyl

ester (71f)

NH

O

OH

OC2H5

O

O

To a solution of 2-[(4-benzyloxy-phenylamino)-methylene]-malonic acid diethyl

ester32 (70f, 500 mg, 1.3 mmol) in chloroform (1.5 mL), BF3.OEt2 (340 μL, 1.3 mmol )




Na2SO4) and evaporated in rotary evaporator under vacuum to get a 2-[(4-benzyloxy-


110

phenylamino)-methylene]-malonic acid monoethyl ester (71f) in 0.42 g (91%) yield as

white solid. mp: 90 °C; 1H NMR (400 MHz, CDCl3) δ: 1.36 (t, J = 7.2 Hz, 3H), 4.32 (q, J

= 14.0 and J = 6.8 Hz, 2H), 5.07 (s, 2H), 7.00 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H),

7.34-7.41 (m, 5H), 8.38 (d, J = 14.0 Hz, 1H), 11.65 (d, J = 13.2 Hz, 1H), 12.99 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ: 14.4, 61.3, 70.4, 88.8, 116.1, 119.5, 127.4, 128.1, 128.6,

132.2, 136.4, 151.9, 170.1; IR (KBr) ν: 2978, 2920, 2840, 1683, 1634, 1613, 1515, 1417,

1260, 1226, 1094, 1024, 803 cm-1; Mass: m/z calcd. for C19H19NO5: 341.12; Found: 342.6

(M+1); Anal. calcd. for C19H19NO5, Elemental Analysis: C, 66.85; H, 5.61; N, 4.10;

Found: C, 66.83; H, 5.59; N, 4.08.

Preparation of 2-[(4-Chloro-phenylamino)-methylene]-malonic acid monoethyl ester

(71g)

NH

O

OH

OC2H5

O

Cl

To a solution of 2-[(4-chloro-phenylamino)-methylene]-malonic acid diethyl ester

ester32 (70g, 500 mg, 1.6 mmol) in chloroform (1.5 mL), BF3.OEt2 (422 μL, 1.6 mmol )

was added and stirred at room temperature for 2.0 h. Completion of the reaction was



Na2SO4) and evaporated in rotary evaporator under vacuum to get a 2-[(4-chloro-

phenylamino)-methylene]-malonic acid monoethyl ester (71g) in 0.36 g (81%) yield as

white solid. mp: 152 °C; 1H NMR (400 MHz, CDCl3) δ: 1.36 (t, J = 7.2 Hz, 3H), 4.33 (q,

J = 14.4 and J = 7.2 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 8.42 (d, J

= 13.6 Hz, 1H), 11.68 (d, J = 13.2 Hz, 1H), 12.97 (brs, 1H); 13C NMR (100 MHz, CDCl3)

δ:14.3, 61.5, 90.0, 118.9, 129.9, 131.2, 137.1, 151.3, 169.7, 170.4 ; IR (KBr) ν: 3062,

2981, 2900, 1681, 1638, 1616, 1576, 1496, 1437, 1407, 1258, 1240, 1089, 1027, 827, 802,

511, 427 cm-1; Mass: m/z calcd. for C12H12ClNO4: 269.04; Found: 270.1 (M+1); Anal.

calcd. for C12H12ClNO4, Elemental Analysis: C, 53.44; H, 4.49; N, 5.19; Found: C, 53.47;

H, 4.50; N, 5.22.


111

Preparation of 2-[(2-chloro-phenylamino)-methylene]-malonic acid monoethyl ester

(71h)

NH

O

OH

OC2H5

O

Cl

To a solution of 2-[(2-Chloro-phenylamino)-methylene]-malonic acid diethyl ester

ester32 (70h, 500 mg, 1.6 mmol) in chloroform (1.5 mL), BF3.OEt2 (422 μL, 1.6 mmol )





phenylamino)-methylene]-malonic acid monoethyl ester (71h) in 0.36 g (80%) yield as

white solid. mp: 117 °C; 1H NMR (400 MHz, CDCl3) δ:1.36 (t, J = 7.2 Hz, 3H), 4.33 (q, J

= 14.0 and J = 7.2 Hz, 2H), 7.11-7.15 (m, 1H), 7.32-7.34 (m, 2H), 7.41-7.44 (m, 1H), 8.49

(d, J = 13.2 Hz, 1H), 12.06 (d, J = 12.8 Hz, 1H), 12.91 (brs, 1H); 13C NMR (100 MHz,

CDCl3) δ:14.2, 61.6, 90.0, 116.3, 124.5, 126.2, 128.0, 130.3, 135.6, 150.7, 169.4, 170.4;

IR (KBr) ν: 3144, 3072, 2982, 2734, 1709, 1604, 1444, 1381, 1322, 1273, 1102, 984, 854,

816, 761, 686, 583, 448 cm-1; Mass: m/z calcd. for C12H12ClNO4: 269.04; Found: 270.2

(M+1); Anal. calcd. for C12H12ClNO4, Elemental Analysis: C, 53.44; H, 4.49; N, 5.19;

Found: C, 53.46; H, 4.48; N, 5.20.

Preparation of 2-[(3-chloro-phenylamino)-methylene]-malonic acid monoethyl ester

(71i)

NH

O

OH

OC2H5

O

Cl

To a solution of 2-[(3-chloro-phenylamino)-methylene]-malonic acid diethyl

ester32 (70i, 500 mg, 1.6 mmol) in chloroform (1.5 mL), BF3.OEt2 (422 μL, 1.6 mmol )





phenylamino)-methylene]-malonic acid monoethyl ester (71i) in 0.35 g (78%) yield as


112

white solid. mp: 108 °C; 1H NMR (400 MHz, CDCl3) δ: 1.38 (t, J = 7.2 Hz, 3H), 4.35 (q, J

= 14.4 and J = 7.2 Hz, 2H), 7.06-7.08 (m, 1H), 7.18-7.19 (m, 2H), 7.31-7.35 (m, 1H), 8.44

(d, J = 13.6 Hz, 1H), 11.68 (d, J = 12.8 Hz, 1H), 12.98 (brs, 1H) ; 13C NMR (100 MHz,

CDCl3) δ:14.3, 61.7, 90.4, 116.2, 117.7, 125.9, 131.0, 135.7, 139.6, 151.2, 169.7, 170.4 ;

IR (KBr) ν: 3174, 2994, 2739, 1721, 1642, 1598, 1457, 1383, 1328, 1290, 1102, 995, 914,

859, 819, 778 cm-1; Mass: m/z calcd. for C12H12ClNO4: 269.04; Found: 270.1 (M+1);

Anal. calcd. for C12H12ClNO4, Elemental Analysis: C, 53.44; H, 4.49; N, 5.19; Found: C,

53.42; H, 4.51; N, 5.17.

Preparation of 2-[(4-nitro-phenylamino)-methylene]-malonic acid monoethyl ester

(71j)

NH

O

OH

OC2H5

O

O2N

To a solution of 2-[(4-nitro-phenylamino)-methylene]-malonic acid diethyl ester

(70j, 500 mg, 1.6 mmol) in chloroform (1.5 mL), BF3.OEt2 (408 μL, 1.6 mmol ) was

added and stirred at room temperature for 2.20 h. Completion of the reaction was



Na2SO4) and evaporated in rotary evaporator under vacuum to get a 2-[(4-nitro-

phenylamino)-methylene]-malonic acid monoethyl ester (71j) in 0.37 g (83%) yield as

yellow solid. mp: 190 °C; 1H NMR (400 MHz, CDCl3) δ: 1.40 (t, J = 6.8 Hz, 3H), 4.39 (q,

J = 14.0 and J = 7.2 Hz, 2H), 7.31(d, J = 8.8 Hz, 2H), 8.30 (d, J = 8.4 Hz, 2H), 8.54 (d, J

= 13.2 Hz, 1H), 11.93 (d, J = 12.4 Hz, 1H), 12.97 (brs, 1H); 13C NMR (100 MHz, CDCl3)

δ: 14.3, 62.1, 92.6, 117.3, 125.9, 143.6, 144.7, 150.2, 169.3, 170.0 ; IR (KBr) ν: 3172,

2985, 2920, 1698, 1629, 1587, 1519, 1455, 1421, 1372, 1297, 1095, 845, 814 cm-1; Mass:

m/z calcd. for C12H12N2O6: 280.06; Found: 281.3 (M+1); Anal. calcd. for C12H12N2O6,



113

Preparation of 2-[(2-Nitro-phenylamino)-methylene]-malonic acid monoethyl ester

(71k)

NH

O

OH

OC2H5

O

NO2

To a solution of 2-[(2-nitro-phenylamino)-methylene]-malonic acid diethyl ester32

(70k, 500 mg, 1.6 mmol) in chloroform (1.5 mL), BF3.OEt2 (408 μL, 1.6 mmol ) was





phenylamino)-methylene]-malonic acid monoethyl ester (71k) in 0.37 g (83%) yield as

yellow solid. mp: 158 °C; 1H NMR (400 MHz, CDCl3) δ:1.39 (t, J = 7.2 Hz, 3H), 4.38 (q,

J = 14.4 and J = 7.2 Hz, 2H), 7.30-7.35 (m, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.72-7.76 (m,

1H), 8.27 (d, J = 8.4 Hz, 1H), 8.56 (d, J = 13.2 Hz, 1H), 12.79 (brs, 1H), 13.25 (d, J =

11.6 Hz, 1H),; 13C NMR (100 MHz, CDCl3) δ: 14.2, 62.0, 93.8, 117.5, 124.9, 126.7,

134.7, 135.8, 138.0, 150.0, 168.1, 170, 1; IR (KBr) ν: 3182, 3086, 2988, 2905, 1684,

1652, 1587, 1518, 1422, 1345, 1295, 1228, 847, 827, 743 cm-1; Mass: m/z calcd. for

C12H12N2O6: 280.06; Found: 281.2 (M+1); Anal. calcd. for C12H12N2O6, Elemental


Preparation of 2-[(3-Nitro-phenylamino)-methylene]-malonic acid monoethyl ester

(71l)

NH

O

OH

OC2H5

O

NO2

To a solution of 2-[(3-nitro-phenylamino)-methylene]-malonic acid diethyl ester32

(70l, 500 mg, 1.6 mmol) in chloroform (1.5 mL), BF3.OEt2 (408 μL, 1.6 mmol ) was





phenylamino)-methylene]-malonic acid monoethyl ester (71l) in 0.38 g (85%) yield as


114

yellow solid. mp: 177 °C; 1H NMR (400 MHz, CDCl3) δ:1.40 (t, J = 6.8 Hz, 3H), 4.39 (q,

J = 14.0 and J = 6.8 Hz, 2H), 7.49-7.52 (m, 1H), 7.61 (t, J = 8.0 Hz, 1H), 8.05-8.09 (m,

2H), 8.53 (d, J = 13.2 Hz, 1H), 11.91 (d, J = 13.2 Hz, 1H), 12.99 (brs, 1H); 13C NMR (100

MHz, CDCl3) δ:14.3, 62.0, 91.6, 111.8, 120.1, 123.9, 131.0, 139.7, 149.2, 150.8, 169.6,

170.2; IR (KBr) ν: 3141, 2986, 2924, 2853, 1701, 1616, 1581, 1440, 1273, 1102, 820, 734

cm-1; Mass: m/z calcd. for C12H12N2O6: 280.06; Found: 281.3 (M+1); Anal. calcd. for

C12H12N2O6, Elemental Analysis: C, 51.43; H, 4.32; N, 10.00; Found: C, 51.42; H, 4.30;

N, 10.00.

Preparation of 2-[(4-Acetyl-phenylamino)-methylene]-malonic acid diethyl ester

(70m)

NH

O

OC2H5

OC2H5

O

O

H3C

To the solution of 4-Aminoacetophenone (1.0 g, 7.3 mmol) in ethanol (3 mL),

diethyl ethoxymethylenemalonate (1.48 mL, 7.3 mmol) was added and stirred at room

temperature for 3.0 h. The ethanol in reaction mixture was evaporated in rotator

evaporator under vacuum to get a 2-[(4-acetyl-phenylamino)-methylene]-malonic acid

diethyl ester (70m) in 2.03 g (90%) as pale yellow solid. mp: 84 °C; 1H NMR (400 MHz,

CDCl3) δ: 1.32-1.39 (m, 6H), 2.58 (s, 3H), 4.23-4.34 (m, 4H), 7.17 (d, J = 8.8 Hz, 2H),

7.98 (d, J = 8.8 Hz, 2H), 8.53 (d, J = 13.2 Hz, 1H), 11.10 (d, J = 13.2 Hz, 1H); 13C NMR

(100 MHz, CDCl3) δ: 14.2, 14.3, 26.4, 60.4, 60.7, 95.7, 116.3, 130.5, 133.3 , 143.0, 150.4,

165.4, 168.7, 196.4; IR (KBr) ν: 3270, 2984, 2903, 1686, 1645, 1595, 1569, 1410, 1349,





115

Preparation of 2-[(4-acetyl-phenylamino)-methylene]-malonic acid monoethyl ester

(71m)

NH

O

OH

OC2H5

O

O

H3C

To a solution of 2-[(4-acetyl-phenylamino)-methylene]-malonic acid diethyl ester

(70m, 500 mg, 1.6 mmol) in chloroform (1.5 mL), BF3.OEt2 (412 μL, 1.6 mmol ) was




Na2SO4) and evaporated in rotary evaporator under vacuum to get a 2-[(4-acetyl-

phenylamino)-methylene]-malonic acid monoethyl ester (71m) in 0.39 g (86%) yield as

white solid. mp: 145 °C; 1H NMR (400 MHz, CDCl3) δ: 1.32 (t, J = 7.2 Hz, 3H), 2.52 (s,

3H), 4.30 (q, J = 14.4 and J = 7.2 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 8.8 Hz,

2H), 8.48 (d, J = 13.2 Hz, 1H), 11.73 (d, J = 13.2 Hz, 1H), 12.92 (brs, 1H); 13C NMR (100

MHz, CDCl3) δ:14.2, 26.4, 61.8, 91.2, 117.0, 130.4, 134.2, 142.1, 150.6, 169.5, 170.3,

196.3; IR (KBr) ν: 3463, 3373, 3265, 2984, 2924, 1740, 1686, 1645, 1595, 1567, 1244,

1095, 1025, 794, 591 cm-1; Mass: m/z calcd. for C14H15NO5: 277.09; Found: 278.3 (M+1);

Anal. calcd. for C14H15NO5, Elemental Analysis: C, 60.64; H, 5.45; N, 5.05; Found: C,

60.65; H, 5.43; N, 5.06.

Preparation of 2-(Naphthalen-2-ylaminomethylene)-malonic acid monoethyl ester

(71n)

NH

O

OH

OC2H5

O

To a solution of 2-(naphthalen-2-ylaminomethylene)-malonic acid diethyl ester32

(70n, 500 mg, 1.6 mmol) in chloroform (1.5 mL), BF3.OEt2 (401 μL, 1.6 mmol ) was




Na2SO4) and evaporated in rotary evaporator under vacuum to get a 2-(naphthalen-2-

ylaminomethylene)-malonic acid monoethyl ester (71n) in 0.38 g (85%) yield as white


116

solid. mp: 98 °C; 1H NMR (400 MHz, CDCl3) δ: 1.38 (t, J = 7.2 Hz, 3H), 4.36 (q, J = 14.4

and J = 7.2 Hz, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.56-7.64 (m, 2H),

7.77 (d, J = 8.4 Hz, 1H), 7.89-7.91 (m, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.62 (d, J = 13.2 Hz,

1H), 12.46 (d, J = 12.8 Hz, 1H), 13.05 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ: 14.3,

61.4, 90.3, 114.2, 120.7, 125.5, 125.7, 126.7, 127.0, 127.4, 128.5, 134.1, 135.0, 153.5,

170.4, 170.7; IR (KBr) ν: 3144, 3065, 2983, 2927, 2731, 1698, 1595, 1593, 1434, 1404,

1331, 1285, 1196, 1110, 1082, 813, 766 cm-1; Mass: m/z calcd. for C16H15NO4: 285.10;

Found: 286.1 (M+1) ; Anal. calcd. for C16H15NO4, Elemental Analysis: C, 67.36; H, 5.30;

N, 4.91; Found: C, 67.37; H, 5.29; N, 4.90.

Preparation of 2-(pyridin-2-ylaminomethylene)-malonic acid monoethyl ester (71o)

NH

O

OH

OC2H5

O

N

To a solution of 2-(pyridin-2-ylaminomethylene)-malonic acid diethyl ester32

(70o, 500 mg, 1.9 mmol) in chloroform (1.5 mL), BF3.OEt2 (476 μL, 1.9 mmol ) was

added and stirred at room temperature for 45 min. Completion of the reaction was



Na2SO4) and evaporated in rotary evaporator under vacuum to get a 2-(pyridin-2-

ylaminomethylene)-malonic acid monoethyl ester (71o) in 0.26 g (60%) yield as white

solid. mp: 86 °C; 1H NMR (400 MHz, CD3OD) δ: 1.38 (t, J = 7.2 Hz, 3H), 4.37 (q, J =

14.0 and J = 6.8 Hz, 2H), 7.64-7.7.67 (m, 1H), 7.88-7.91 (m, 1H), 8.29-8.33 (m, 1H), 8.99

(s, 1H), 9.31-9.34 (m, 1H); 13C NMR (100 MHz, CD3OD) δ: 14.6, 62.3, 105.7, 120.3,

125.2, 130.6, 143.6, 153.2, 155.5, 156.7, 165.1; IR (KBr) ν: 3094, 2978, 1732, 1710, 1627,

1573, 1483, 1293, 1147, 1119, 1020, 784 cm-1; Mass: m/z calcd. for C11H12N2O4: 236.07;

Found: 237.2 (M+1); Anal. calcd. for C11H12N2O4, Elemental Analysis: C, 55.93; H, 5.12;

N, 11.86; Found: C, 55.92; H, 5.10; N, 11.88.


117

Preparation of 2-(pyridin-3-ylaminomethylene)-malonic acid monoethyl ester (71p)

NH

O

OH

OC2H5

O

N

To a solution of 2-(pyridin-3-ylaminomethylene)-malonic acid diethyl ester32

(70p, 500 mg, 1.9 mmol) in chloroform (1.5 mL), BF3.OEt2 (476 μL, 1.9 mmol ) was

added and stirred at room temperature for 45 min. Completion of the reaction was



Na2SO4) and evaporated in rotary evaporator under vacuum to get a 2-(pyridin-3-

ylaminomethylene)-malonic acid monoethyl ester (71p) in 0.28 g (64%) yield as white

solid. mp: 202 °C; 1H NMR (400 MHz, CDCl3) δ: 1.39 (t, J = 7.2 Hz, 3H), 4.36 (q, J =

14.4 and J = 7.2 Hz, 2H), 7.260 (s, 1H), 7.268 (s, 3H), 8.46 (d, J = 13.6 Hz, 1H), 11.78 (d,

J = 14.0 Hz, 1H) 12.99 (brs, 1H); 13C NMR (100 MHz, CD3OD) δ:14.3, 29.6, 61.6, 90.3,

119.2, 136.3, 151.1, 169.9; IR (KBr) ν: 3420, 3181, 2985, 2913, 1698, 1621, 1464, 1432,

1329, 1271, 1097, 823, 804 cm-1; Mass: m/z calcd. for C11H12N2O4: 236.07; Found: 237.1

(M+1); Anal. calcd. for C11H12N2O4, Elemental Analysis: C, 55.93; H, 5.12; N, 11.86;

Found: C, 55.90; H, 5.15; N, 11.82.

Preparation of 2-(benzylamino-methylene)-malonic acid monoethyl ester (72a)

NH

O

OH

OC2H5

O

To a solution of 2-(benzylamino-methylene)-malonic acid diethyl ester32 (72, 500





evaporated in rotary evaporator under vacuum to get a 2-(benzylamino-methylene)-

malonic acid monoethyl ester (72a) in 0.40 g (89%) yield as white solid. mp: 98 °C; 1H

NMR (400 MHz, CDCl3) δ: 1.24 (t, J = 7.2 Hz, 3H), 4.19 (q, J = 14.0 and J = 7.2 Hz, 2H),

4.49 (d, J = 6.0 Hz, 2H), 7.17-7.19 (m, 2H), 7.24-7.33 (m, 3H), 7.99 (d, J = 14.4 Hz, 1H),

10.09 (brs, 1H), 12.84 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ: 14.3, 53.6, 61.0, 87.1,


118

127.2, 128.3, 129.0, 135.7, 158.8, 170.2, 170.8; IR (KBr) ν: 3190, 2984, 2905, 2710, 1685,

1599, 1435, 1396, 1281, 1215, 1101, 854, 747 cm-1; Mass: m/z calcd. for C13H15NO4:

249.10; Found: 250.2 (M+1); Anal. calcd. for C13H15NO4, Elemental Analysis: C, 62.64;

H, 6.07; N, 5.62; Found: C, 62.65; H, 6.09; N, 5.60.

Preparation of 3-[2-(2,2-Bis-ethoxycarbonyl-vinylamino)-ethylamino]-2-

ethoxycarbonyl-acrylic acid ethyl ester (73)

HN NH

OC2H5

O

OC2H5O

C2H5O

O

OC2H5O

To the solution of ethylenediamine (1.11 mL, 16 mmol) in ethanol (3 mL), diethyl

ethoxymethylenemalonate (6.66 mL, 33 mmol) was added and stirred at room temperature

for 5 min. The ethanol in reaction mixture was evaporated in rotator evaporator under

vacuum to get a 3-[2-(2,2-bis-ethoxycarbonyl-vinylamino)-ethylamino]-2-ethoxycarbonyl-

acrylic acid ethyl ester (73) in 6.59 g (99%) as white solid. mp: 121 °C; 1H NMR (400

MHz, CDCl3) δ: 1.24-1.33 (m, 12H), 3.51 (t, J = 2.8 Hz, 4H), 4.14-4.26 (m, 8H), 7.92 (d,

J = 14.0 Hz, 2H), 9.22 (t, J = 13.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ:14.2, 14.3,

49.8, 59.7, 60.0, 91.4, 159.8, 165.5, 169.1 ; IR (KBr) ν: 3246, 3173, 2982, 2934, 2898,

1634, 1598, 1429, 1306, 1273, 1210, 1096, 1024, 912, 800, 746, 655 cm-1; Mass: m/z

calcd. for C18H28N2O8: 400.18; Found: 400.3 (M+1); Anal. calcd. for C18H28N2O8,

Elemental Analysis: C, 53.99; H, 7.05; N, 7.00; Found: C, 54.01; H, 7.03; N, 7.01

Preparation of 3-[2-(2,2-bis-ethoxycarbonyl-vinylamino)-ethylamino]-2-

ethoxycarbonyl-acrylic acid (73a)

HN NH

OH

O

OC2H5O

C2H5O

O

OC2H5O

To a solution of 3-[2-(2,2-bis-ethoxycarbonyl-vinylamino)-ethylamino]-2-

ethoxycarbonyl-acrylic acid ethyl ester (73, 500 mg, 1.2 mmol) in chloroform (1.5 mL),

BF3.OEt2 (628 μL, 2.4 mmol ) was added and stirred at room temperature for 35 min.

Completion of the reaction was determined by TLC, followed by which the reaction

mixture was quenched with water and extracted with chloroform (3x5 mL). The combined

organic layer was dried (anhyd. Na2SO4) and evaporated in rotary evaporator under


119

vacuum to get a 3-[2-(2,2-bis-ethoxycarbonyl-vinylamino)-ethylamino]-2-ethoxycarbonyl-

acrylic acid (73a) in 0.18 g (40%) yield as white solid. mp: 141 °C; 1H NMR (400 MHz,

CDCl3) δ: 1.24-1.33 (m, 9H), 3.58 (s, 4H), 4.12-4.26 (m, 6H), 7.86-7.94 (m, 2H), 9.23 (t, J

= 6.8 Hz, 1H), 9.98 (t, J = 6.8 Hz, 1H) 12.88 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ:

14.22, 14.25, 14.32, 49.3, 50.5, 59.8, 60.0, 61.1, 87.7, 91.3, 159.3, 159.9, 165.5, 169.1,

170.1, 170.6; IR (KBr) ν: 3292, 2984, 2927, 2898, 1682, 1609, 1439, 1400, 1342, 1281,

1103, 1043, 829, 800 cm-1; Mass: m/z calcd. for C16H24N2O8: 372.15; Found: 373.2 (M+1)

; Anal. calcd. for C16H24N2O8, Elemental Analysis: C, 51.61; H, 6.50; N, 7.52; Found: C,

51.62; H, 6.52; N, 7.50.

Preparation of 3-[3-(2,2-Bis-ethoxycarbonyl-vinylamino)-propylamino]-2-

ethoxycarbonyl-acrylic acid ethyl ester (74)

HN NH

O

O

OC2H5

OC2H5

O

C2H5O

OC2H5O

To the solution of 1,3-propanediamine (1.12 mL, 13 mmol) in ethanol (3 mL),

Diethyl ethoxymethylenemalonate (5.45 mL, 26 mmol) was added and stirred at room

temperature for 7 min. The ethanol in reaction mixture was evaporated in rotator

evaporator under vacuum to get a 3-[3-(2,2-bis-ethoxycarbonyl-vinylamino)-

propylamino]-2-ethoxycarbonyl-acrylic acid ethyl ester (74) in 5.47 g (98%) as white

solid. mp: 93 °C; 1H MR (400 MHz, CDCl3) δ: 1.24-1.33 (m, 12H), 1.88-1.95 (m, 2H),

3.39 (q, J = 13.2 and 6.8 Hz, 4H) 4.12-4.23 (m, 8H), 7.94 (d, J = 14.0 Hz, 2H), 9.19 (t, J

= 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ:14.2, 14.3, 31.6, 46.3, 59.6, 59.9, 90.3,

159.7, 165.7, 169.3; IR (KBr) ν: 3264, 2978, 2934, 1700, 1666, 1602, 1393, 1374, 1218,

1096, 1065, 1035, 814 cm-1; Mass: m/z calcd. for C19H30N2O8: 414.20; Found: 414.3

(M+1); Anal. calcd. for C19H30N2O8, Elemental Analysis: C, 55.06; H, 7.30; N, 6.76;

Found: C, 55.04; H, 7.32; N, 6.74.


120

Preparation of 3-[3-(2-Carboxy-2-ethoxycarbonyl-vinylamino)-propylamino]-2-

ethoxycarbonyl-acrylic acid (74a)

HN NH

O

O

OH

OC2H5

O

HO

OC2H5O

To a solution of 3-[3-(2,2-bis-ethoxycarbonyl-vinylamino)-propylamino]-2-

ethoxycarbonyl-acrylic acid ethyl ester (74, 500 mg, 1.2 mmol) in chloroform (1.5 mL),

BF3.OEt2 (607 μL, 2.4 mmol ) was added and stirred at room temperature for 35 min.




vacuum to get a 3-[3-(2-carboxy-2-ethoxycarbonyl-vinylamino)-propylamino]-2-

ethoxycarbonyl-acrylic acid (74a) in 0.35 g (80%) yield as white solid. mp: 42 oC; 1H

NMR (400 MHz, CDCl3) δ: 1.32 (t, J = 7.2 Hz, 6H), 2.01-2.08 (m, 2H), 3.51 (q, J = 13.2

and J = 6.4 Hz, 4H) 4.25 (q, J = 14.4 and J = 7.2 Hz, 4H), 7.95 (d, J = 14.0 Hz, 2H), 9.92

(t, J = 6.4 Hz, 2H), 12.91 (brs, 2H); 13C NMR (100 MHz, CDCl3) δ: 14.3, 30.7, 46.8, 61.1,

87.3, 158.8, 170.3, 170.6; IR (KBr) ν: 3226, 2984, 2942, 2739, 1696, 1614, 1439, 1403,

1298, 1273, 1149, 1020, 852, 814 cm-1; Mass: m/z calcd. for C15H22N2O8: 358.14; Found:

359.2 (M+1) Anal. calcd. for C15H22N2O8, Elemental Analysis: C, 50.28; H, 6.19; N, 7.82;

Found: C, 50.27; H, 6.17; N, 7.80.

Preparation of 2-[(2-Ethoxycarbonyl-phenylamino)-methylene]-malonic acid diethyl

ester (75)

NH

O OC2H5

O

OC2H5

C2H5O O

To the solution of 2-[(2-carboxy-phenylamino)-methylene]-malonic acid diethyl

ester32 (1.0 g 3.2 mmol) in acetone (15 mL), anhyd. K2CO3 (0.54 mg, 3.9 mmol) was

added and stirred for an hour, ethyl bromide (315 μL, 4.2 mmol) was added and stirred for

24 h. Completion of the reaction was determined by TLC. Followed by which, the acetone

in the reaction mixture was evaporated in rotary evaporator under vacuum, water (10 mL)

was added to the reaction mixture, and extracted with ethyl acetate (3x5 mL). The

combined organic layer was dried (anhyd. Na2SO4) and evaporated in rotary evaporator


121

under vacuum to get a 2-[(2-ethoxycarbonyl-phenylamino)-methylene]-malonic acid

diethyl ester (75) in 0.87 g (80%) as a white solid. mp: 70 °C; 1H NMR (400 MHz,

CDCl3) δ: 1.32-1.41 (m, 9H), 4.24 (q, J = 14.4 and J = 7.2 Hz, 2H), 4.35-4.47 (m, 4H),

7.09-7.13 (m, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.52-7.56 (m, 1H), 8.06 (dd, J = 8.0 and 1.6,

1H), 8.57 (d, J = 13.6 Hz, 1H), 12.69 (d, J = 13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)

δ:14.19, 14.30, 14.33, 60.21, 60.36, 61.47, 96.4, 114.9, 117.0, 123.0, 131.8, 134.2, 141.6,

149.3, 166.0, 166.6, 167.1; IR (KBr) ν: 3397, 3219, 2980, 2933, 2898, 1707, 1666, 1587,

1379, 1311, 1252, 1080, 1035, 757, 697, 655 cm-1; Mass: m/z calcd. for C17H21NO6:

335.13; Found:136.1 (M+1); Anal. calcd. for C17H21NO6, Elemental Analysis: C, 60.89;

H, 6.31; N, 4.18; Found: C, 60.92; H, 6.29; N, 4.20.

Preparation of 2-[(2-ethoxycarbonyl-phenylamino)-methylene]-malonic acid

monoethyl ester (75a)

NH

O OH

O

OC2H5

C2H5O O

To a solution of 2-[(2-ethoxycarbonyl-phenylamino)-methylene]-malonic acid

diethyl ester (75, 500 mg, 1.4 mmol) in chloroform (1.5 mL), BF3.OEt2 (375 μL, 1.4

mmol) was added and stirred at room temperature for 1.20 h. Completion of the reaction

was determined by TLC, followed by which the reaction mixture was quenched with water

and extracted with chloroform (3x5 mL). The combined organic layer was dried (anhyd.

Na2SO4) and evaporated in rotary evaporator under vacuum to get a 2-[(2-ethoxycarbonyl-

phenylamino)-methylene]-malonic acid monoethyl ester (75a) in 0.37 g (81%) yield as

white solid. mp: 118 °C; 1H NMR (400 MHz, CDCl3) δ:1.36-1.43 (m, 6H), 4.35 (q, J =

14.4 and J = 7.2 Hz, 2H), 4.50 (q, J = 14.0 and J = 7.2 Hz, 2H), 7.22-7.24 (m, 1H), 7.38

(d, J = 8.4 Hz, 1H), 7.58-7.62 (m, 1H), 8.11 (dd, J = 7.6 and 1.2 Hz, 1H), 8.59 (d, J = 13.6

Hz, 1H), 12.83 (brs, 1H), 13.25 (d, J = 13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ:

14.29, 14.34, 61.5, 61.8, 91.7, 115.7, 118.9, 124.5, 132.2, 134.1, 140.3, 150.1, 165.9,

168.2, 170.7; IR (KBr) ν: 3137, 2987, 2909, 2799, 1721, 1708, 1615, 1591, 1438, 1317,

1248, 1208, 1097, 1084, 996, 852, 836, 750, 691, 587, 481 cm-1; Mass: m/z calcd. for




122

Preparation of 2-[(4-ethoxycarbonyl-phenylamino)-methylene]-malonic acid diethyl

ester (76)

NH

O OC2H5

O

OC2H5C2H5O

O

To the solution 2-[(4-carboxy-phenylamino)-methylene]-malonic acid diethyl

ester32 (1.0 g 3.2 mmol) in acetone (15 mL), anhyd. K2CO3 (0.54 g, 3.9 mmol) was added

and stirred for an hour, ethyl bromide (315 μL, 4.2 mmol) was added and stirred for 24 h.

Completion of the reaction was determined by TLC. Followed by which, the acetone in

the reaction mixture was evaporated in rotary evaporator under vacuum, water (10 mL)

was added to the reaction mixture, and extracted with ethyl acetate (3x5 mL). The

combined organic layer was dried (anhyd. Na2SO4) and evaporated in rotary evaporator

under vacuum to get a 2-[(4-ethoxycarbonyl-phenylamino)-methylene]-malonic acid

diethyl ester (76) in 0.90 g (83%) as a white solid. mp: 54 °C; 1H NMR (400 MHz,

CDCl3) δ: 1.31-1.40 (m, 9H), 4.22-4.38 (m, 6H), 7.14 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.8

Hz, 2H), 8.52 (d, J = 13.6 Hz, 1H), 11.07 (d, J = 13.2 Hz, 1H); 13C NMR (100 MHz,

CDCl3) δ:14.1, 14.2, 14.3, 60.2, 60.5, 60.9, 95.3, 116.1, 126.4, 131.4, 142.7, 150.5, 165.3,

165.6, 168.6; IR (KBr) ν: 3137, 2988, 2938, 2906, 1717, 1683, 1642, 1596, 1574, 1445,


C17H21NO6: 335.13; Found: ; 336.2 (M+1); Anal. calcd. for C17H21NO6, Elemental


Preparation of 2-[(4-ethoxycarbonyl-phenylamino)-methylene]-malonic acid

monoethyl ester (76a)

C2H5O

O

NH

O

OC2H5

OHO

To a solution of 2-[(4-ethoxycarbonyl-phenylamino)-methylene]-malonic acid

diethyl ester (76, 500 mg, 1.4 mmol) in chloroform (1.5 mL), BF3.OEt2 (375 μL, 1.4

mmol) was added and stirred at room temperature for 1.35 h. Completion of the reaction




123

Na2SO4) and evaporated in rotary evaporator under vacuum to get a 2-[(4-ethoxycarbonyl-

phenylamino)-methylene]-malonic acid monoethyl ester (76a) in 0.39 g (85%) yield as

white solid. mp: 125 °C; 1H NMR (400 MHz, CDCl3) δ:1.37-1.41 (m, 6H), 4.34-4.40 (m,

4H), 7.23 (d, J = 8.8 Hz, 2H), 8.09 (d, J = 8.8 Hz, 2H), 8.54 (d, J = 13.2 Hz, 1H), 11.80 (d,

J = 13.6 Hz, 1H), 12.99 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ:14.2, 14.3, 61.1, 61.7,

91.0, 116.9, 127.6, 131.5, 141.9, 150.7, 165.5, 169.6, 170.3; IR (KBr) ν: 3197, 2980, 1706,

1647, 1601, 1460, 1364, 1321, 1268, 1176, 1097, 1019, 803, 692, 411 cm-1; Mass: m/z

calcd. for C15H17NO6: 307.10; Found: 308.3 (M+1); Anal. calcd. for C15H17NO6,


Preparation of 2-[(1-methoxycarbonyl-2-phenyl-ethylamino)-methylene]-malonic

acid monoethyl ester (77a)

NH

O OH

O

OC2H5COOCH3

To a solution of 2-[(1-methoxycarbonyl-2-phenyl-ethylamino)-methylene]-malonic

acid diethyl ester (77, 500 mg, 1.4 mmol) in chloroform (1.5 mL), BF3.OEt2 (360 μL, 1.4

mmol) was added and stirred at room temperature for 20 min. Completion of the reaction



Na2SO4) and evaporated in rotary evaporator under vacuum to get a 2-[(1-

methoxycarbonyl-2-phenyl-ethylamino)-methylene]-malonic acid monoethyl ester (77a)

in 0.36 g (79%) yield as white solid. mp: 82 °C; [α]27D -123.1 (c 1.00, CHCl3);

1H NMR

(400 MHz, CDCl3) δ: 1.24 (t, J = 6.8 Hz, 3H), 3.02-3.08 (m, 1H), 3.29-3.33 (m, 1H), 3.80

(s, 3H), 4.10-4.26 (m, 3H), 7.16-7.18 (m, 2H), 7.25-7.35 (m, 3H), 10.15 (t, J = 9.6 Hz,

1H), 12.78 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ:14.1, 39.6, 52.9, 60.9 63.5, 87.8,

127.5, 128.9, 129.3, 134.7, 157.8, 169.6, 169.7, 170.5; IR (KBr) ν: 3195, 2984, 2746,

1743, 1700, 1606, 1454, 1400, 1378, 1219, 1088, 1000, 870, 770, 709 cm-1; Mass: m/z

calcd. for C16H19NO6: 321.12; Found: 322.3; Anal. calcd. for C16H19NO6, Elemental



124

Preparation of 2-[(1-methoxycarbonyl-3-methyl-butylamino)-methylene]-malonic

acid monoethyl ester (78a)

NH

O OH

O

OC2H5COOCH3CH3

H3C

To a solution of 2-[(1-methoxycarbonyl-3-methyl-butylamino)-methylene]-

malonic acid diethyl ester32 (78, 500 mg, 1.5 mmol) in chloroform (1.5 mL), BF3.OEt2

(398 μL, 1.5 mmol) was added and stirred at room temperature for 20 min. Completion of

the reaction was determined by TLC, followed by which the reaction mixture was

quenched with water and extracted with chloroform (3x5 mL). The combined organic

layer was dried (anhyd. Na2SO4) and evaporated in rotary evaporator under vacuum to get

a 2-[(1-methoxycarbonyl-3-methyl-butylamino)-methylene]-malonic acid monoethyl ester

(78a) in 0.36 g (80%) yield as colorless syrupy liquid. [α]26D -12.0 (c 1.00, CHCl3);

1H

NMR (400 MHz, CDCl3) δ: 0.91 (t, J = 6.4 Hz, 6H), 1.27 (t, J = 7.2 Hz, 3H), 1.60-1.72

(m, 3H), 3.72 (s, 3H), 4.02-4.08 (m, 1H), 4.21 (q, J = 14.4 and 7.2 Hz, 2H), 7.92 (d, J =

14.0 Hz, 1H), 9.97 (dd, J = 12.4 and 9.6 Hz, 1H), 12.82 (brs, 1H); 13C NMR (100 MHz,

CDCl3) δ:14.1, 21.2, 22.5, 24.3, 41.3, 52.6, 60.3, 60.9, 87.7, 157.8, 169.6, 170.5, 170.8; IR

(KBr) ν: 2956, 2920, 2855, 1743, 1707, 1606, 1454, 1400, 1281, 1215, 1150, 1096, 772

cm-1; Mass: m/z calcd. for C13H21NO6: 287.137; Found:; Anal. calcd. for C13H21NO6,


Preparation of 2-[(1-methoxycarbonyl-3-methylsulfanyl-propylamino)-methylene]-

malonic acid monoethyl ester (79a)

NH

O OH

O

OC2H5COOCH3

SH3C

To a solution of 2-[(1-methoxycarbonyl-3-methylsulfanyl-propylamino)-

methylene]-malonic acid diethyl ester32 (79, 500 mg, 1.5 mmol) in chloroform (1.5 mL),

BF3.OEt2 (377 μL, 1.5 mmol) was added and stirred at room temperature for 25 min.




vacuum to get a 2-[(1-Methoxycarbonyl-3-methylsulfanyl-propylamino)-methylene]-

malonic acid monoethyl ester (79a) in 0.35 mg (78%) yield as colorless syrupy liquid.


125

[α]25D -58.1 (c 1.00, CHCl3);

1H NMR (400 MHz, CDCl3) δ: 1.31 (t, J = 6.8 Hz, 3H), 2.08

(s, 3H), 2.19-2.27 (m, 1H), 2.44-2.52 (m, 1H), 2.61-2.68 (m,1H), 3.78 (s, 3H), 4.23-4.34

(m, 3H), 7.98 (d, J = 13.6 Hz, 1H), 10.02 (t, J = 12.0 Hz, 1H), 12.84 (brs, 1H); 13C NMR

(100 MHz, CDCl3) δ:14.2, 15.0, 29.5, 31.4, 52.9, 60.1, 61.1, 88.3, 158.2, 169.8, 170.3,

170.5; IR (KBr) ν: 2956, 2923, 2847, 1743, 1703, 1605, 1454, 1400, 1269, 1168, 1089,

807 cm-1; Mass: m/z calcd. for C12H19NO6S: 305.09; Found: 306.2; Anal. calcd. for

C12H19NO6S, Elemental Analysis: C, 47.20; H, 6.27; N, 4.59; S, 10.50; Found: C, 47.22;

H, 6.30; N, 4.61; S, 10.52.

13 12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

-0.0

00

1.2

92

1.3

09

1.3

27

4.2

50

4.2

68

4.2

85

4.3

03

7.1

18

7.1

20

7.1

34

7.1

39

7.1

42

7.1

45

7.1

60

7.1

64

7.1

80

7.1

82

7.1

85

7.1

93

7.3

28

7.3

47

7.3

49

7.3

68

8.4

21

8.4

56

11.6

1111

.643

12.9

26

3.0

4

2.0

5

3.1

72

.05

1.0

0

1.0

0

1.0

0

NAME 10122009-1aiganEXPNO 26PROCNO 1Date_ 20091012Time 14.15INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zg30TD 65536SOLVENT CDCl3NS 16DS 2SWH 8223.685 HzFIDRES 0.125483 HzAQ 3.9846387 secRG 181DW 60.800 usecDE 6.50 usecTE 292.2 KD1 1.00000000 secTD0 1

======== CHANNEL f1 ========NUC1 1HP1 14.00 usecPL1 -1.00 dBPL1W 12.39612865 WSFO1 400.1324710 MHzSI 32768SF 400.1300326 MHzWDW EMSSB 0LB 0.30 HzGB 0PC 1.00

Ani-HyPROTON CDCl3

NH

O

OH

OC2H5

O

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

14.

37

61.

48

76.

68

77.

00

77.

32

89.

59

117

.83

126

.01

129

.94

138

.50

151

.64

169

.93

170

.69

NAME 10122009-1aiganEXPNO 32PROCNO 1Date_ 20091012Time 16.21INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zgpg30TD 65536SOLVENT CDCl3NS 1024DS 4SWH 24038.461 HzFIDRES 0.366798 HzAQ 1.3631988 secRG 2050DW 20.800 usecDE 6.50 usecTE 292.0 KD1 2.00000000 secD11 0.03000000 secTD0 1

======== CHANNEL f1 ========NUC1 13CP1 9.00 usecPL1 -2.00 dBPL1W 55.73500443 WSFO1 100.6228298 MHz

======== CHANNEL f2 ========CPDPRG2 waltz16NUC2 1HPCPD2 80.00 usecPL2 -1.00 dBPL12 14.14 dBPL13 15.00 dBPL2W 12.39612865 WPL12W 0.37956488 WPL13W 0.31137666 WSFO2 400.1316005 MHzSI 32768SF 100.6127723 MHzWDW EMSSB 0LB 1.00 HzGB 0PC 1.40

Ani-HyC13CPD CDCl3

NH

O

OH

OC2H5

O

14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

1.33

71.

355

1.37

3

3.80

84.

291

4.30

84.

326

4.34

4

6.90

96.

932

7.11

07.

132

8.36

08.

394

11.6

1611

.650

12.9

79

3.07

3.11

2.06

2.06

2.03

1.00

1.01

1.00

NAME 01212010-1aiganEXPNO 2PROCNO 1Date_ 20100121Time 10.30INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zg30TD 65536SOLVENT CDCl3NS 16DS 2SWH 8223.685 HzFIDRES 0.125483 HzAQ 3.9846387 secRG 71.8DW 60.800 usecDE 6.50 usecTE 295.6 KD1 1.00000000 secTD0 1


p-Anis-HyPROTON CDCl3

NH

O

OH

OC2H5

O

H3CO

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

14.3

4

55.5

5

61.2

9

76.6

877

.00

77.3

2

88.7

4

115.

05

119.

46

131.

94

151.

98

157.

90

170.

10

170.

76




p-Anis-HyC13CPD CDCl3

NH

O

OH

OC2H5

O

H3CO

14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

1.35

11.

369

1.38

7

4.31

34.

331

4.34

84.

366

7.11

77.

123

7.13

27.

137

7.13

87.

143

7.15

27.

159

7.32

27.

328

7.33

87.

340

7.41

87.

438

7.44

08.

476

8.50

9

12.0

47

12.0

79

12.9

16

3.03

2.04

1.01

2.05

1.00

1.00

1.00

0.96



2-Cl-Ani-Cop--HyPROTON CDCl3

NH

O

OH

OC2H5

O

Cl

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

14.

28

61.

65

76.

68

77.

00

77.

32

91.

00

116

.35

124

.59

126

.21

128

.08

130

.39

135

.67

150

.70

169

.43

170

.41




2-Cl-Ani-Cop-HyC13CPD CDCl3

NH

O

OH

OC2H5

O

Cl

15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

1.3

80

1.3

98

1.4

15

4.3

56

4.3

74

4.3

92

4.4

10

7.2

60

7.3

09

7.3

11

7.3

29

7.3

48

7.3

50

7.4

96

7.5

17

7.7

20

7.7

23

7.7

41

7.7

59

7.7

62

8.2

69

8.2

90

8.5

53

8.5

86

12.

79

913.

24

413.

27

3

3.0

1

2.0

6

1.0

31

.05

1.0

4

0.9

91

.00

0.9

5

1.0

3



2.nit.ani-HyPROTON CDCl3

NH

O

OH

OC2H5

O

NO2

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

14.2

6

62.0

6

76.6

877

.00

77.3

2

93.8

8

117.

58

124.

9312

6.72

134.

7713

5.81

138.

05

150.

04

168.

1017

0.13




2-Nit.Ani-HyC13CPD CDCl3

NH

O

OH

OC2H5

O

NO2

14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

1.3

09

1.3

27

1.3

45

2.5

29

4.2

75

4.2

93

4.3

11

4.3

28

7.1

85

7.2

07

7.9

37

7.9

59

8.4

71

8.5

04

11.7

1811

.751

12.9

27

3.0

7

3.0

3

2.0

2

2.0

9

2.0

4

1.0

0

1.0

0

0.9

4



4-Acy-Ani--HyPROTON CDCl3

NH

O

OH

OC2H5

O

O

H3C

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

14.2

9

26.4

1

61.8

1

76.6

877

.00

77.3

2

91.2

1

117.

08

130.

4413

4.20

142.

10

150.

60

169.

5417

0.31

196.

34NAME 12212009-2aiganEXPNO 36PROCNO 1Date_ 20091221Time 16.55INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zgpg30TD 65536SOLVENT CDCl3NS 512DS 4SWH 24038.461 HzFIDRES 0.366798 HzAQ 1.3631988 secRG 2050DW 20.800 usecDE 6.50 usecTE 294.5 KD1 2.00000000 secD11 0.03000000 secTD0 1



4-Acy-Ani-Cop-HyC13CPD CDCl3

NH

O

OH

OC2H5

O

O

H3C

14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

1.3

65

1.3

83

1.4

01

4.3

36

4.3

54

4.3

72

4.3

90

7.2

60

7.3

71

7.3

90

7.4

88

7.5

08

7.5

28

7.5

60

7.5

63

7.5

77

7.5

80

7.5

83

7.5

96

7.6

01

7.6

07

7.6

20

7.6

23

7.6

27

7.6

40

7.6

44

7.7

62

7.7

83

7.8

91

7.8

94

7.9

14

8.0

64

8.0

85

8.6

06

8.6

39

12.

445

12.

477

13.

055

3.0

4

2.0

5

1.0

11.0

12.0

71.0

11.0

11.0

21.0

0

1.0

2

1.0

1



1-Naph.Amine-HYPROTON CDCl3

NH

O

OH

OC2H5

O

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

14.3

8

61.4

9

76.6

877.0

077.3

2

90.3

3

114.2

8120.7

7125.5

0125.7

9126.7

6127.0

8127.4

1128.5

8134.1

9135.0

9

153.5

5

170.4

3170.7

4




Naph.Amine-HyC13CPD CDCl3

NH

O

OH

OC2H5

O

15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

1.368

1.386

1.404

3.292

3.296

3.300

3.304

3.308

4.350

4.367

4.385

4.403

4.866

7.640

7.643

7.657

7.660

7.675

7.678

7.884

7.886

7.886

7.888

7.906

7.907

7.908

7.910

8.291

8.294

8.308

8.312

8.316

8.330

8.334

8.996

9.318

9.320

9.322

9.323

9.336

9.337

9.339

9.341

3.0

8

2.0

9

1.0

31.0

4

1.0

5

1.0

21.0

0

NAME 051810-aiganEXPNO 16PROCNO 1Date_ 20100518Time 14.19INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zg30TD 65536SOLVENT MeODNS 16DS 2SWH 8223.685 HzFIDRES 0.125483 HzAQ 3.9846387 secRG 256DW 60.800 usecDE 6.50 usecTE 292.7 KD1 1.00000000 secTD0 1


2-Am.Py-CyPROTON MeOD

NH

O

OH

OC2H5

O

N

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

14.6

0

48.3

648.5

748.7

949.0

049.2

149.4

249.6

462.3

0

105.7

2

120.3

5

125.2

7

130.6

4

143.6

1

153.2

0155.5

5156.7

9

165.1

3

NAME 05182010-aiganEXPNO 34PROCNO 1Date_ 20100518Time 21.57INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zgpg30TD 65536SOLVENT MeODNS 1536DS 4SWH 24038.461 HzFIDRES 0.366798 HzAQ 1.3631988 secRG 2050DW 20.800 usecDE 6.50 usecTE 294.5 KD1 2.00000000 secD11 0.03000000 secTD0 1



2-Am.Py-CyC13CPD MeOD

NH

O

OH

OC2H5

O

N

13 12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

-0.0

00

1.2

31

1.2

49

1.2

67

4.1

67

4.1

85

4.2

02

4.2

20

4.4

90

4.5

05

7.1

77

7.1

93

7.1

97

7.2

48

7.2

51

7.2

57

7.2

66

7.2

73

7.2

80

7.2

84

7.2

87

7.2

98

7.3

12

7.3

16

7.3

29

7.3

33

7.3

38

7.9

73

8.0

09

10.

096

12.

841

3.1

5

2.0

42.0

5

2.1

53.0

8

1.0

0

1.0

0

0.9

6

NAME Mar25-2011-3aiganEXPNO 4PROCNO 1Date_ 20110325Time 23.23INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zg30TD 65536SOLVENT CDCl3NS 16DS 2SWH 8223.685 HzFIDRES 0.125483 HzAQ 3.9846387 secRG 128DW 60.800 usecDE 6.50 usecTE 290.9 KD1 1.00000000 secTD0 1


Benzylamine-HyPROTON CDCl3

NH

O

OH

OC2H5

O

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

14.3

2

53.6

1

60.9

9

76.6

877

.00

77.3

2

87.1

3

127.

26

128.

35

129.

05

135.

71

158.

85

170.

22

170.

80

NAME Mar25-2011-3aiganEXPNO 5PROCNO 1Date_ 20110325Time 23.55INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zgpg30TD 65536SOLVENT CDCl3NS 512DS 4SWH 24038.461 HzFIDRES 0.366798 HzAQ 1.3631988 secRG 1620DW 20.800 usecDE 6.50 usecTE 292.6 KD1 2.00000000 secD11 0.03000000 secTD0 1



Benzylamine-HyC13CPD CDCl3

NH

O

OH

OC2H5

O

12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

1.24

21.

259

1.27

71.

301

1.31

91.

337

3.49

53.

502

3.51

04.

129

4.14

74.

165

4.18

34.

192

4.21

04.

228

4.24

5

7.26

0

7.89

87.

932

9.20

99.

226

9.24

3

13.5

3

4.17

8.91

2.00

2.01

NAME Mar31-2011-1aiganEXPNO 7PROCNO 1Date_ 20110331Time 10.49INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zg30TD 65536SOLVENT CDCl3NS 16DS 2SWH 8223.685 HzFIDRES 0.125483 HzAQ 3.9846387 secRG 80.6DW 60.800 usecDE 6.50 usecTE 291.8 KD1 1.00000000 secTD0 1


EN-Di-Di-Cop.31/3/11PROTON CDCl3

HN NH

OC2H5

O

OC2H5O

C2H5O

O

OC2H5O

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

14.2

514

.33

49.8

7

59.7

460

.03

76.6

877

.00

77.3

2

91.4

2

159.

82

165.

59

169.

15

NAME Apr01-2011-1aiganEXPNO 22PROCNO 1Date_ 20110401Time 13.23INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zgpg30TD 65536SOLVENT CDCl3NS 512DS 4SWH 24038.461 HzFIDRES 0.366798 HzAQ 1.3631988 secRG 36DW 20.800 usecDE 6.50 usecTE 295.3 KD1 2.00000000 secD11 0.03000000 secTD0 1



En-Di-Cop.31/3/11C13CPD CDCl3

HN NH

OC2H5

O

OC2H5O

C2H5O

O

OC2H5O

13 12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

1.24

01.

257

1.27

61.

294

1.30

01.

312

1.31

81.

336

3.58

14.

124

4.14

24.

160

4.17

74.

185

4.20

34.

209

4.22

14.

227

4.23

94.

245

4.26

3

7.26

07.

867

7.90

27.

914

7.94

9

9.21

59.

232

9.24

89.

967

9.98

410

.000

12.8

84

9.54

4.00

6.20

2.08

1.03

1.01

1.00

NAME Mar25-2011-3aiganEXPNO 6PROCNO 1Date_ 20110325Time 23.59INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zg30TD 65536SOLVENT CDCl3NS 16DS 2SWH 8223.685 HzFIDRES 0.125483 HzAQ 3.9846387 secRG 144DW 60.800 usecDE 6.50 usecTE 291.4 KD1 1.00000000 secTD0 1


Ethylenediamine-HyPROTON CDCl3

HN NH

OH

O

OC2H5O

C2H5O

O

OC2H5O

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

14.2

214

.25

14.3

2

49.3

750

.51

59.8

060

.01

61.1

2

76.6

877

.00

77.3

2

87.7

491

.39

159.

3015

9.97

165.

5216

9.17

170.

1217

0.60

NAME Mar25-2011-3aiganEXPNO 7PROCNO 1Date_ 20110326Time 0.32INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zgpg30TD 65536SOLVENT CDCl3NS 512DS 4SWH 24038.461 HzFIDRES 0.366798 HzAQ 1.3631988 secRG 32DW 20.800 usecDE 6.50 usecTE 292.8 KD1 2.00000000 secD11 0.03000000 secTD0 1



Ethylenediamine-HyC13CPD CDCl3

HN NH

OH

O

OC2H5O

C2H5O

O

OC2H5O

14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

1.3

021

.320

1.3

372

.015

2.0

332

.038

2.0

502

.067

2.0

843

.487

3.5

033

.520

3.5

374

.230

4.2

484

.266

4.2

84

7.2

60

7.9

357

.970

9.9

099

.925

9.9

41

12

.91

3

6.0

4

2.0

8

4.0

5

4.0

4

2.0

0

2.0

1

1.9

9

NAME Feb16-2011-1aiganEXPNO 55PROCNO 1Date_ 20110216Time 21.35INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zg30TD 65536SOLVENT CDCl3NS 16DS 2SWH 8223.685 HzFIDRES 0.125483 HzAQ 3.9846387 secRG 228DW 60.800 usecDE 6.50 usecTE 291.1 KD1 1.00000000 secTD0 1


PropDiAm-Cop-HyPROTON CDCl3

HN NH

O

O

OH

OC2H5

O

HO

OC2H5O

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

14.3

3

30.7

9

46.8

7

61.1

5

76.6

877

.00

77.3

2

87.3

0

158.

88

170.

3317

0.67

NAME Feb16-2011-1aiganEXPNO 56PROCNO 1Date_ 20110216Time 22.35INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zgpg30TD 65536SOLVENT CDCl3NS 1024DS 4SWH 24038.461 HzFIDRES 0.366798 HzAQ 1.3631988 secRG 2050DW 20.800 usecDE 6.50 usecTE 293.4 KD1 2.00000000 secD11 0.03000000 secTD0 1



PropDiAm-Cop-HyC13CPD CDCl3

HN NH

O

O

OH

OC2H5

O

HO

OC2H5O

14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

1.30

31.

321

1.33

91.

342

1.36

01.

375

1.37

71.

392

1.41

04.

221

4.23

94.

257

4.27

54.

351

4.36

94.

387

4.40

54.

416

4.43

44.

452

4.47

07.

095

7.09

77.

115

7.13

37.

136

7.26

07.

366

7.38

67.

524

7.52

87.

546

7.56

47.

567

8.05

08.

054

8.07

08.

074

8.56

28.

596

12.6

8012

.713

9.02

2.00

4.03

1.02

1.01

1.02

1.00

1.00

1.00



2-Aninobenzoic Acid-Cop-Et-EsterPROTON CDCl3

NH

O OC2H5

O

OC2H5

C2H5O O

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

14.1

914

.30

14.3

3

60.2

160

.36

61.4

7

76.6

877

.00

77.3

2

96.4

2

114.

9511

7.03

123.

01

131.

8513

4.27

141.

66

149.

30

166.

0616

6.62

167.

14




2-Aniobenzoic acid-Cop-Et-Ester-C13C13CPD CDCl3

NH

O OC2H5

O

OC2H5

C2H5O O

Chapter III Reference

126

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lewis acid mediated selective monohydrolysis of geminal...

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