lewis acid mediated selective monohydrolysis of geminal...
TRANSCRIPT
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
Chapter III Inroduction
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
Chapter III Inroduction
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).
Chapter III Inroduction
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).
Chapter III Inroduction
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).
Chapter III Inroduction
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).
Chapter III Inroduction
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
Chapter III Inroduction
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).
Chapter III Inroduction
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
Chapter III Inroduction
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
Chapter III Inroduction
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).
Chapter III Inroduction
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).
Chapter III Inroduction
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
Chapter III Present Work
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.
Chapter III Present Work
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.
Chapter III Present Work
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
Chapter III Present Work
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.
Chapter III Present Work
99
Figure 4. ORTEP for compound 71g
Figure 5. ORTEP for compound 71b
Chapter III Present Work
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).
Chapter III Present Work
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).
Chapter III Present Work
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
Chapter III Present Work
103
COOCH3
NH
COOCH2CH3
COOCH2CH3CHCl3
rt, 20 min, 80%
BF3.OEt2CH3
H3C
COOCH3
NH
COOH
COOCH2CH3
CH3
H3C
78 78a Scheme 32. BF3.OEt2 mediated selective mono hydrolysis of N-BECV in presence of
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
79 79a Scheme 32. BF3.OEt2 mediated selective mono hydrolysis of N-BECV in presence of
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
Chapter III Present Work
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).
Chapter III Present Work
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.
Chapter III Experimental
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
mg, 1.8 mmol) in chloroform (1.5 mL), BF3.OEt2 (453 μL, 1.8 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-(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),
Chapter III Experimental
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
To a solution of 2-[(2-methoxy-phenylamino)-methylene]-malonic acid diethyl
ester32 (70d, 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-[(2-methoxy-
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.
Chapter III Experimental
109
Preparation of 2-[(3-Methoxy-phenylamino)-methylene]-malonic acid monoethyl
ester (71e)
NH
O
OH
OC2H5
O
OCH3
To a solution of 2-[(3-methoxy-phenylamino)-methylene]-malonic acid diethyl
ester32 (70e, 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-[(3-methoxy-
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 )
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-benzyloxy-
Chapter III Experimental
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
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-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.
Chapter III Experimental
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 )
was added and stirred at room temperature for 2.15 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-chloro-
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 )
was added and stirred at room temperature for 2.15 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-[(3-chloro-
phenylamino)-methylene]-malonic acid monoethyl ester (71i) in 0.35 g (78%) yield as
Chapter III Experimental
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
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-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,
Elemental Analysis: C, 51.43; H, 4.32; N, 10.00; Found: C, 51.42; H, 4.32; N, 10.02.
Chapter III Experimental
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
added and stirred at room temperature for 2.30 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-nitro-
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
Analysis: C, 51.43; H, 4.32; N, 10.00; Found: C, 51.42; H, 4.30; N, 10.3.
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
added and stirred at room temperature for 2.20 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-[(3-nitro-
phenylamino)-methylene]-malonic acid monoethyl ester (71l) in 0.38 g (85%) yield as
Chapter III Experimental
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,
1243, 1184, 1095, 1027, 956, 830, 795, 753, 650, 469 cm-1; Mass: m/z calcd. for
C16H19NO5: 305.12; Found: 306.2 (M+1); Anal. calcd. for C16H19NO5, Elemental
Analysis: C, 62.94; H, 6.27; N, 4.59; Found: C, 62.92; H, 6.26; N, 4.60.
Chapter III Experimental
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
added and stirred at room temperature for 2.30 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-[(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
added and stirred at room temperature for 2.30 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-(naphthalen-2-
ylaminomethylene)-malonic acid monoethyl ester (71n) in 0.38 g (85%) yield as white
Chapter III Experimental
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
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-(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.
Chapter III Experimental
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
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-(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
mg, 1.8 mmol) in chloroform (1.5 mL), BF3.OEt2 (453 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-(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,
Chapter III Experimental
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
Chapter III Experimental
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.
Chapter III Experimental
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.
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 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
Chapter III Experimental
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
C15H17NO6: 307.10; Found: 308.2 (M+1); Anal. calcd. for C15H17NO6, Elemental
Analysis: C, 58.63; H, 5.58; N, 4.56; Found: C, 58.60; H, 5.61; N, 4.55.
Chapter III Experimental
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,
1246, 1175, 1092, 1021, 848, 806, 766, 689, 512, 409 cm-1; Mass: m/z calcd. for
C17H21NO6: 335.13; Found: ; 336.2 (M+1); Anal. calcd. for C17H21NO6, Elemental
Analysis: C, 60.89; H, 6.31; N, 4.18; Found: C, 60.90; H, 6.30; N, 4.19.
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
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.
Chapter III Experimental
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,
Elemental Analysis: C, 58.63; H, 5.58; N, 4.56; Found: C, 58.59; H, 5.60; N, 4.54.
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
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-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
Analysis: C, 59.81; H, 5.96; N, 4.36; Found: C, 59.80; H, 5.94; N, 4.38.
Chapter III Experimental
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,
Elemental Analysis: C, 54.35; H, 7.37; N, 4.88; Found: C, 54.38; H, 7.41; N, 4.85.
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.
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-methylsulfanyl-propylamino)-methylene]-
malonic acid monoethyl ester (79a) in 0.35 mg (78%) yield as colorless syrupy liquid.
Chapter III Experimental
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
======== CHANNEL f1 ========NUC1 1HP1 14.00 usecPL1 -1.00 dBPL1W 12.39612865 WSFO1 400.1324710 MHzSI 32768SF 400.1300056 MHzWDW EMSSB 0LB 0.30 HzGB 0PC 1.00
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
NAME 01212010-1aiganEXPNO 4PROCNO 1Date_ 20100121Time 11.12INSTRUM 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 296.8 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 100.6127734 MHzWDW EMSSB 0LB 1.00 HzGB 0PC 1.40
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
NAME 12212009-1aiganEXPNO 17PROCNO 1Date_ 20091221Time 12.05INSTRUM 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 292.1 KD1 1.00000000 secTD0 1
======== CHANNEL f1 ========NUC1 1HP1 14.00 usecPL1 -1.00 dBPL1W 12.39612865 WSFO1 400.1324710 MHzSI 32768SF 400.1300058 MHzWDW EMSSB 0LB 0.30 HzGB 0PC 1.00
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
NAME 12232009-1aiganEXPNO 16PROCNO 1Date_ 20091223Time 13.33INSTRUM 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 293.2 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 100.6127771 MHzWDW EMSSB 0LB 1.00 HzGB 0PC 1.40
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
NAME 05242010-2aiganEXPNO 2PROCNO 1Date_ 20100524Time 15.42INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zg30TD 65536SOLVENT CDCl3NS 16DS 2SWH 8223.685 HzFIDRES 0.125483 HzAQ 3.9846387 secRG 287DW 60.800 usecDE 6.50 usecTE 294.7 KD1 1.00000000 secTD0 1
======== CHANNEL f1 ========NUC1 1HP1 14.00 usecPL1 -1.00 dBPL1W 12.39612865 WSFO1 400.1324710 MHzSI 32768SF 400.1300058 MHzWDW EMSSB 0LB 0.30 HzGB 0PC 1.00
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
NAME 05252010-2aiganEXPNO 31PROCNO 1Date_ 20100525Time 20.37INSTRUM 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 296.6 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 100.6127756 MHzWDW EMSSB 0LB 1.00 HzGB 0PC 1.40
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
NAME 12212009-1aiganEXPNO 15PROCNO 1Date_ 20091221Time 11.37INSTRUM 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 292.1 KD1 1.00000000 secTD0 1
======== CHANNEL f1 ========NUC1 1HP1 14.00 usecPL1 -1.00 dBPL1W 12.39612865 WSFO1 400.1324710 MHzSI 32768SF 400.1300261 MHzWDW EMSSB 0LB 0.30 HzGB 0PC 1.00
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
======== 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 100.6127760 MHzWDW EMSSB 0LB 1.00 HzGB 0PC 1.40
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
NAME 04292010-2aiganEXPNO 10PROCNO 1Date_ 20100429Time 14.52INSTRUM 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 295.9 KD1 1.00000000 secTD0 1
======== CHANNEL f1 ========NUC1 1HP1 14.00 usecPL1 -1.00 dBPL1W 12.39612865 WSFO1 400.1324710 MHzSI 32768SF 400.1300056 MHzWDW EMSSB 0LB 0.30 HzGB 0PC 1.00
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
NAME 04292010-2aiganEXPNO 14PROCNO 1Date_ 20100429Time 16.24INSTRUM 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 297.5 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 100.6127698 MHzWDW EMSSB 0LB 1.00 HzGB 0PC 1.40
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
======== CHANNEL f1 ========NUC1 1HP1 14.00 usecPL1 -1.00 dBPL1W 12.39612865 WSFO1 400.1324710 MHzSI 32768SF 400.1300073 MHzWDW EMSSB 0LB 0.30 HzGB 0PC 1.00
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
======== 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 100.6126271 MHzWDW EMSSB 0LB 1.00 HzGB 0PC 1.40
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
======== CHANNEL f1 ========NUC1 1HP1 14.00 usecPL1 -1.00 dBPL1W 12.39612865 WSFO1 400.1324710 MHzSI 32768SF 400.1300325 MHzWDW EMSSB 0LB 0.30 HzGB 0PC 1.00
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
======== 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 100.6127740 MHzWDW EMSSB 0LB 1.00 HzGB 0PC 1.40
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
======== CHANNEL f1 ========NUC1 1HP1 14.00 usecPL1 -1.00 dBPL1W 12.39612865 WSFO1 400.1324710 MHzSI 32768SF 400.1300056 MHzWDW EMSSB 0LB 0.30 HzGB 0PC 1.00
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
======== 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 100.6127720 MHzWDW EMSSB 0LB 1.00 HzGB 0PC 1.40
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
======== CHANNEL f1 ========NUC1 1HP1 14.00 usecPL1 -1.00 dBPL1W 12.39612865 WSFO1 400.1324710 MHzSI 32768SF 400.1300059 MHzWDW EMSSB 0LB 0.30 HzGB 0PC 1.00
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
======== 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 100.6127728 MHzWDW EMSSB 0LB 1.00 HzGB 0PC 1.40
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
======== CHANNEL f1 ========NUC1 1HP1 14.00 usecPL1 -1.00 dBPL1W 12.39612865 WSFO1 400.1324710 MHzSI 32768SF 400.1300058 MHzWDW EMSSB 0LB 0.30 HzGB 0PC 1.00
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
======== 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 100.6127704 MHzWDW EMSSB 0LB 1.00 HzGB 0PC 1.40
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
NAME 11272009-1aiganEXPNO 1PROCNO 1Date_ 20091127Time 10.10INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zg30TD 65536SOLVENT CDCl3NS 16DS 2SWH 8223.685 HzFIDRES 0.125483 HzAQ 3.9846387 secRG 57DW 60.800 usecDE 6.50 usecTE 291.7 KD1 1.00000000 secTD0 1
======== CHANNEL f1 ========NUC1 1HP1 14.00 usecPL1 -1.00 dBPL1W 12.39612865 WSFO1 400.1324710 MHzSI 32768SF 400.1300056 MHzWDW EMSSB 0LB 0.30 HzGB 0PC 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
NAME 11272009-1aiganEXPNO 21PROCNO 1Date_ 20091127Time 13.34INSTRUM 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 292.7 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 100.6127764 MHzWDW EMSSB 0LB 1.00 HzGB 0PC 1.40
2-Aniobenzoic acid-Cop-Et-Ester-C13C13CPD CDCl3
NH
O OC2H5
O
OC2H5
C2H5O O
Chapter III Reference
126
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J. Org. Chem. 2009, 75, 1612.
2. Englund, E. A.; Gopi, H. N.; Appella. D.H. Org. Lett, 2004, 6, 213.
3. Basso, A.; Banfi, L.; Riva, R.; Guanti, G. J. Org. Chem. 2005, 70, 575.
4. Pellicciari, R.; Marinozzi, M.; Camaioni, E.; Nunez, M. C.; Costantino, G.; Gasparini, F.; Giorgi, G.; Macchiarulo, A.; Subramanian. J. Org. Chem. 2002, 67, 5497.
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