CHAPTER – II 2,2-Bis(ethoxycarbonyl)vinyl (BECV) as a Versatile Amine Protecting...
Transcript of CHAPTER – II 2,2-Bis(ethoxycarbonyl)vinyl (BECV) as a Versatile Amine Protecting...
CHAPTER – II
2,2-Bis(ethoxycarbonyl)vinyl (BECV) as a Versatile Amine
Protecting group for Functional Group Transformations
Chapter II Introduction
20
INTRODUCTION
Protecting Groups
Protecting group (PG) is a small molecule, which has the capability to protecting
temporarily the host group from undergoing reaction, allowing the rest of the functional
groups present in the molecule to react without affecting the original reactivity and leave
from the host molecule without affecting the rest of the functional groups.
The protecting group could be called as an ideal protecting group, when it fulfills
the certain criteria. Thus, the protecting group should react with the desired functional
group quickly, should form the protected compound in good yield, the protected
compound should have good stability when stored for a long time. It should have a
minimum functional group to avoid side reaction during the course of the main reaction; it
should not create a new chiral centre at the molecule. At the time of deprotection, it should
cleave under mild reaction condition, should give good yield and the purification must be
simple. There are number of protecting groups available in the literature, for protecting
potentially interfering functional groups such as –OH, –SH, –COOH, –CHO, –C=O, –
NH2, etc.
In general alcoholic and phenolic hydroxyl groups and its sulphur analogues (thiols
and thiophenols) are protected as ethers or esters. Carboxylic acids are protected as esters
or amides. Adehydes and ketones are protected as acetals or ketals. The amino group was
protected as carbamates, amides or imines.
Attempting the synthesize of various complex molecules requires number of
selective functional group transformation involving the use of different reagents and
conditions. The existing protecting groups and available reaction conditions are not
enough to face these problems. Therefore, developing a new protecting groups and a new
conditions for the protection and deprotection of available protecting groups are needed.
Orthogonal Protecting Groups
During the synthesize of complex molecules, the starting material may have the
two or more same functional group (as in the carbohydrate). In this case, it is often
necessary to use same functional group at different times. This can be achieved by
Chapter II Introduction
21
choosing a variety of different protecting groups, which can be manipulated using
different reaction conditions. The development of such orthogonal protecting group
strategies makes it possible to remove one set of protecting groups, in any order, using
reagents and conditions that do not affect the other protecting groups in the molecule.
Consider the following molecule, which has three different amine group in a single
molecule protected by the different protecting groups A, B, C and D. The orthogonal
deprotection is the terminology, that the deprotecting condition of A, which will not affect
the other protecting groups B, C and D. Similarly, deprotecting condition of B, will not
affect the protecting groups A, C and D and vice versa (Figure 1).
BHN
COOR
NHDO
H
CHN
RO NHAH
Figure 1. Ideal molecule protected by different protecting group
Boons et al.1 synthesized highly branched disaccharide 2 from β-D-Man-(1→4)-D-
Man disaccharide 1 by the orthogonal protecting group strategy (Scheme 1).
OO O
HO OOHO
PolysaccharideOO HO
ODEIPS = diethylisopropylsilyl,Nap = methylnaphthylAll = allylLev =levulinoylBn = Benzyl
OO O
OBnOLev
ODEIPSO
OPh
NapOBnO
OAll
O OHHO
HOOH
O
H2N
OHOH
HO
O
OHHO
COOH
OLipid A
HO
O
HOHO
OH
HOOrthogonalDeprotection
Glycosylation
1 2
Scheme 1. Orthogonal protection/deprotection in synthesize of highly branched
isaccharide
To cleave the O-allyl group without affecting the levulinoyl, diethylisopropylsilyl,
methylnaphthyl and benzyl group, the allyl deprotecting agent PdCl2, NaOAc, AcOH,
H2O was used. To cleave the O-levulinoyl group without disturbing the allyl,
Chapter II Introduction
22
diethylisopropylsilyl, methylnaphthyl and benzyl group, the deprotecting agent hydrazine,
acetic acid in toluene and ethanol mixture was used. Similarly, to deptrotect O-DEIPS
without affecting the allyl, levulinoyl, methylnaphthyl and benzyl group, the deprotecting
reagents TBAF in acetic and THF was used and finally to cleave O-Nap orthogonally, the
reagent DDQ in DCM, water was used (Scheme 2).
OO O
OBnOLev
ODEIPSO
OPh
NapOBnO
OH
PdCl2, NaOAc, AcOH, H2O
OO O
OBnOH
ODEIPSO
OPh
NapOBnO
OAll
NH2NH2.AcOH Tol/EtOH
OO O
OBnOH
OHO
OPh
NapOBnO
OAll
TBAF, AcOH, THF
OO O
OBnOLev
ODEIPSO
OPh
HOBnO
OAll
DDQ, CH2Cl2, H2O
Scheme 2. Regents for orthogonal protection/deprotection
Amine Protecting Groups
Protection of amine group in presence of other functional groups is an important
transformation. This is because, during the synthesize of the natural products, new
chemical entity and the derivatives of existing molecules, the amine groups in the
molecules are more reactive to the most of the common reagents such as nucleophile,
electrophile, strong acid, strong base, Lewis acid, oixidizing agents etc. used.
Protecting groups in peptide synthesize
It is not as straight forward as mixing the amino acids together to form desired
peptides. For example, a mixture of alanine (Ala) and glycine (Gly) would give the
mixture of amides: Ala-Gly, Gly-Ala, Ala-Ala and Gly-Gly and higher polypeptides etc.
To control the coupling reaction, it is necessary to use protecting groups. By protecting the
amine group of one component and the carboxylic acid group of the other, a specific
amide bonds can be formed (Scheme 3).
Chapter II Introduction
23
COOH
R
HHN
CO2
R'
HH2N+
CO
R
HHN
HN H
CO2
R,
Protected amine Proected Acid Desired Peptide
Amine Protecting group
Acid Protecting group
Scheme 3. Schematic representation for protecting group in peptide synthesize
Even though, there is a number of amine protecting groups available in the
literature, many of protecting groups do not fulfill the conditions of an ideal amine
protecting groups and orthogonal character. So that, it could not be used in synthesize of
complex organic molecules.
Recently, a large number of amine protecting groups were reported in the
literature. Some of the prominent and novel amine protecting groups are given below.
Wright and Snider2 introduced (1-methyl)cyclopropyloxycarbonylcarbamate
(MPoc) as a amine protecting group. The MPoc group may be introduced to the amine by
reacting the p-nitroderivatives of MPoc 3 with the amine in the presence of triethylamine
in dichloromethane solution. The deprotection was achieved by hydrobromous acid in
presence of palladium catalyst (Scheme 4).
N O
O
R2
R1
NH
R2R1
NO2
O
O
O+
DeprotectionN O
O
R2
R1
NHR2
R1
HOBr, Pd
NEt3
CH2Cl2protection
3 4
4
Scheme 4. MPoc as amine protecting group
Tsunoda et al.3 successfully introduced and demonstrated that the 2-(1,3-dioxan-2-
yl)ethylsulfonyl- (Dios) group could be used for amine protection and activation. To
Chapter II Introduction
24
protect the amine with 2-(1,3-dioxan-2-yl)ethylsulfonyl group, 2-(1,3-dioxan-2-
yl)ethylsulfonyl (Dios) chloride (5) was used, which may be synthesized from 2-(2-
chloroethyl)-1,3-dioxane. Initially, 2-(2-chloroethyl)-1,3-dioxane was converted to the
corresponding sodium 2-(1,3-dioxan-2-yl)ethylsulfonate (Na2SO3, DME-H2O, reflux, 72
h) and then the sulfonate was treated with 2 equiv of PPh3 and 2.2 equiv of sulfuryl
chloride (CH2Cl2, 0 °C, 2 h). The deprotection was achieved with the trifluoroacetic acid
in water (Scheme 5).
N
O2SR2
R1
NH
R2R1 +
Protection
Deprotection
CF3COOH/H2ONH
R2
R1
O
O
SO2ClO
O
N
O2SR2
R1 O
O
NEt3
CH2Cl25
6
6
Scheme 5. Dios as amine protecting group
Chandrasekaran4 and Ramesh developed a new amine protecting group called but-
2-ynylbisoxycarbonyl- (Bbc) as a C2-symmetric reagent. The amine group was protected
by treatment with but-2-ynylbisoxycarbonyl chloride (7) in presence of sodium
bicarbonate in DCM. The deprotection was effected with the (PhCH2NEt3)2MoS4 in
acetonitrile solution (Scheme 6).
NH2
+
Protection
Deprotection
H3COOC
OO
Cl O
ClO
OOO
HN
O
NHCOOEtEtOOC
OOO
HN
O
NHCOOEtEtOOC
(PhCH2NEt3)2MoS4
NH2H3COOC
2NaHCO3
CH2Cl2
CH3CN
7 8
8
Scheme 6. Bbc as amine protecting group
Chapter II Introduction
25
Romieu et al.5 introduced aryldithioethyloxycarbonyl (Ardec) group for amine
protection. For protection, the 4-(phenyldisulfanyl)ethyl 4-nitrophenyl carbonate (9) was
treated with the corresponding amine in the presence of 5% sodium carbonate in
acetonitrile at 0oC to room temperature. For deprotection of the Ardec group the protected
amine was reduced with thiophenol (Scheme 7).
N O
O
H
RNH
HR
NO2
O
O
O+
5% Na2CO3
Protection
DeprotectionNH
R1
H
SS
Ar SS
Ar
N O
O
R1
H
SS
Ar
SH
CH3CN, 0 oC
9 10
10
Scheme 7. Ardec as amine protecting group
Winssinger and Pothukauri6developed a new protecting group, based on the azide
called azidomethyl carbamate (Azoc). The protection of the amine by Azoc needs,
formation of chloromethyl carbamate using the commercially available chloromethyl
chloroformate 11 followed by the azide displacement. The deprotection of Azoc group
was done with the trimethyl or tributyl phosphine (Scheme 8).
+Protection
Deprotection
Me3P or Bu3P
NH2Cl O
O
Cl NaN3
NH
O
O
N3
NH
O
O
N3NH2
11 12
12
Scheme 8. Azoc as amine protecting group
Enamine based protecting groups
Enamine based protecting groups are unique type of amine protecting groups.
Their preparation, deprotection and applications in organic synthesize are known over a
period of long time. However they are not very popular amine protecting groups as
carbamate based protecting groups. This could be due to some of the limitations in their
Chapter II Introduction
26
application in organic synthesize. A detailed literature survey on enamine based protecting
groups was made and salient features are given below.
Cross et al.7 used 5,5-dimethyl-3-oxo-1-cyclohexenyl- (Doc) as a amine protecting
group. It may be obtained from dimedone 13. This is one of the enamine based protecting
group for amine and amino acid. It is cleaved from the protected amines (14) by treatment
with either aqueous bromine or nitrous acid in excellent yield (Scheme 9).
NHR
O
Br2 or HNO2R-NH2
R-NH2
OH
O
O
O
+Protection
NHR
O
Deprotection
13 14
14
Scheme 9. Doc as amine protecting group
Southwick et al.8 developed the 1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl- (Nopy)
(15) as an amine protecting group. For the protection of the amine was stirred with NOPY-
OEt in acetonitrile solution. The deprotection was achieved in ammonia in methanol
solution (Scheme 10).
R-NH2N
OEt
O
O2N
i-Pr
PH 8-9+
N
HN
O
O2N
i-Pr
R
N
HN
O
O2N
i-Pr
R
R-NH2
Protection
Deprotection
NH3
MeOH
1516
16
Scheme 10. Nopy as amine protecting group
Bycroft et al.9 introduced a novel amine protecting group called 1-(4,4-dimethy1-
2,6-dioxocyclohexylidene)ethyl- (Dde) which was obtained from 2-(1-
Chapter II Introduction
27
hydroxyethylidene)-5,5-dimethylcyclohexane-1,3-dione (17) which in turn was prepared
by acylation of demedone with acetic anhydride in pyridine medium. Protection of the
amine by the Dde group was done by reacting the amine with the 2-(1-
hydroxyethylidene)-5,5-dimethylcyclohexane-1,3-dione in ethanolic solution. The
deprotecction of Dde needed addition of 2 % hydrazine (v/v) in DMF solution (Scheme
11).
Protection
CH3
O
OOH
R-NH2 +
O
ON
H
O
ON
H
R-NH2
CH3
CH3+
O
NH
N
CH3
Deprotection
EtOHreflux, 60 h
NH2NH2
17 18
1819
R
R
Scheme 11. Dde as amine protecting group
Chan et al. developed some new variants of Dde group in which the methyl group
was replaced by higher alkanes. The starting material, 2-(1-hydroxyalkylidene)-5,5-
dimethylcyclohexane-1,3-dione (21) was prepared by acylation of dimedone with the
DCC/DMAP with corresponding acid. The deprotection condition was little modified thus
1 % trifluoroacetic acid was used instead of hydrazine (Scheme 12).10
2120
Scheme 12. Dde variants as more versatile amine protecting groups
Latter, the hydrazine was replaced by the hydroxylamine hydrochloride in
imidazole. By changing the deprotection conditions, orthogonal deprotection was achieved
Chapter II Introduction
28
against some famous amine protection group like Fmoc etc. Various conditions and
reagents used for the deprotection for the Dde group are shown in the Scheme 13.
O
ON
H
CH3
R-NH2
NH2NH2
NH2OH.HCl
TFA
18
R
Scheme 13. Development of new deprotection conditions for Dde
Limitations of Dde as a protecting group
The stability of N-Dde towards 20% piperidine v/v -DMF is acceptable for most
applications, a small loss of Dde does occur during each deprotection cycle in the large
peptides synthesize, which can seriously compromise the purity of large peptides. Dde
undergoes intramolecular N to N' migration from a side chain or α-amino group to the ε-
amino function of lysine, resulting in the scrambling of the group within the peptide chain.
Recently, the N-Dde protecting group under certain conditions has been undergo both intra
and intermolecular N to N' migration, resulting in a number of resin-bound sequences.
During the removal of Dde protecting group (2% hydrazine solution in DMF) on Aloe and
Dde protected peptides, the formation of a side product of two mass units greater than the
expected free peptide was observed presumably arising from partial reduction of the Aloe
double bond. Dde protection group itself lacks emission, which hampers in situ monitoring
of the amine protection / deprotection progress by fluorescence spectroscopy.
Bycroft et. al.11 has successfully exploited 2-acetyl-4-nitroindane-1,3-dione (2-
Nde) or 2-acetyl-5-nitroindane-1,3-dione (4-Nde) as a primary amine protecting group
displaying some advanced versatility (Scheme 13). This Nde protecting group is regarded
as another variant of the Dde protecting group. The preparation of the Nde-OH is very
similar to the Dde. Here, 4-nitro-indan-1,3-dione (22) was acylated with the acetic
anhydride. After preparation of 2-acetyl-4-nitroindane-1,3dione (23), it was introduced in
to amine by refluxing with ethanol. The deprotection of Nde is also similar to the Dde, it
was deprotected by adding the hydrazine solution (Scheme 14).
Chapter II Introduction
29
O
O
Ac2O/DMAP
O
OCH3
OH
O
OCH3
OH
+EtOH, Heat
Protection
NH2-CH(R)-COOH
O
OCH3
NH R
COOHH
NO2 NO2
NO2 NO2
O
OCH3
NH R
COOHH
NO2
NH2-CH(R)-COOH
ONO2
NH
N
H3C
+Deprotection
NH2NH2
25
23
24
22
23
24
Scheme 14. Nde as amine protecting group
Lima et al.12 showed the use of 1,3-dimethyl-5-acetyl-barbituric acid (26) (Dab) as
an amine protecting group. For the protection of amines with the Dab, the amine was
refluxed with the 1,3-dimethyl-5-acetyl-barbituric acid (26) in THF solution. For the
deprotection, hydrazine in ethanol solution was used. To achieve improved versatility
ammonia or some primary amines was used (Scheme 15).
N N
O
OO
H3C OH
CH3H3C
R-NH2+N N
O
OO
H3C NH
CH3H3C
R
N N
O
OO
H3C NH
CH3H3C
R
R NH2
Deprotection
Protection
THF
NH2NH2
EtOH, rt
2726
27
Scheme 15. Dab as amine protecting group
Yang and Kuo13 developed coumarin-based triketone as a fluorescent protecting
group for primary amines. According to them, when primary amines or amino acids
Chapter II Introduction
30
reacted with 3-acetyl-4-methoxy-7-N,N-dimethylaminocoumarin (30), the resulting
compounds emit blue fluorescence with a quantum yield of 0.25-0.50 in methylenedi
chloride. These protected compounds display satisfactory acid/base stability and this
protecting group can be removed with 5% hydrazine hydrate in DMF within 5 min at
ambient temperature. Similar properties also found in the hydroxyl derivatives (29) which
can also reacted with amino acids and form the diketo compound (31) (Scheme 16).
O O
N O
N
H
O O
OMe O
N
CH3COCl, Et3N
CH2Cl20 oC
KCN, 18 Crown-6, rtO O
OH
N O O
OH O
N CH2N2
EtOAc, 0 oC
R1
R2OOC
MeOH, Et3Nrt
MeOH, Et3Nrt
O O
O N
N
H
R1
COOR2
5% NH2NH2.H2O/DMFrt
NH2
R1
R2OOC
Protection
Deprotection
H2N
R1
COOR2H2N
R1
COOR2
32
28 29 30
31
Scheme 16. Coumarin based triketone as amine protecting group
Tien et. al.14 demonstrated that, the protection of 2,7-dichloro-fluoren-9-
ylidenemethylene can be used as a protecting group for amino acids. For protection, (2,7-
dichloro-fluoren-9-ylidene)-methanol (33) was heated with the amino acid in presence of
sodium hydroxide in methanol. For the deprotection of 2,7-dichloro-9-
fluorenylmethyleneamine group 34, the N-protected compound was hydrogenated with the
Pd/C in ammonium acetate or TFA (Scheme 17).
Chapter II Introduction
31
OH
ClClHOOC NH2
R
Protection
+
NH
ClCl
R COOH
NH
ClCl
R COOH
HCOONH4, Pd/Cor TFA
NH2
R COOHDeprotection
NaOH
MeOH, Heat
3433
34
Scheme 17. 2,7-dichloro-fluoren-9-ylidenemethylene as amine protecting group
Gorbunova et al.15a has introduced 4,4,4-trifluoro-3-oxo-1-butenyl- (Tfav) group
for the protection of amine in amino acids. It is formed by reaction of an amine with the
starting material 4-ethoxy-1,1,1-trifiuoro-3-buten-2-one (35) in aqueous sodium
hydroxide. Primary amino acids form the Z-enamines whereas secondary amines such as
proline form the E-enamines. Deprotection is achieved with 1-6 N aqueous HCl in dioxane
at room temperature (Scheme 18).
OF
FFC2H5OR-NH2 +
OF
FFNH
R
1-6 N HClO
F
FFNH
R R-NH2
Protection
Deprotection
3635
36
Scheme 18. Tfav as amine protecting group
2,2- Bis(ethoxycarbonyl)vinyl- (BECV) as an amine protecting group
Apart from the use of 2,2-bis(ethoxycarbonyl)vinyl (37, BECV) group as a novel
building block, It was also used as an amine protecting group. BECV is an important
enamine type amine protecting group. Alaiz et al.15b protected the amino group of the
amino acid with by treatment with BECV in the presence of base at room temperature.
After making the vinylamine derivatives 38, the acid group was converted to its 4-
(phenylazo)phenacyl esters 39 by treatment with corresponding alkyl bromide in
Chapter II Introduction
32
triethylamine. The deprotection was done with the bromine in chloroform solutions
(Scheme19).
NH
O
O
OEt OEt
OO
CHCl3, rt75%
O
NN
NH3Br
O
O
O
NN
+ -
O
NN
Br
acetone, NEt3, rt, 30 min, 70%
NH
O
OH
OEt OEt
OO
1. KOH, rt, 5 min2. 1N HCl. rt, 80%
EtO
EtO
O O
OEt+
NH2
OH
O
Protection
Deprotection
Br2
40
3738
39
Scheme 19. BECV as amine protecting group
Mellet et al.16a,b used the BECV group as a protecting group for preparation per-
acetyl aminoaldose derivatives (Scheme 20). The amine group 41 was protected as HN-
BECV group by treatment refluxing with the corresponding amine. After the entire
conversion of the amine into N-protected amine 42 the hydroxyl functional group was
converted in to its acetate, then, the N-protected amine was obtained by treatment with wet
the chlorine in chloroform.
Chapter II Introduction
33
CHCl3, Cl20-5 oC, > 3 h O
AcO
AcOOMe
AcO
NH2.HCl
OHO
HOOMe
OH
HN
EtO OEt
O O
OHO
HOOMe
OH
NH2
C2H5O
EtO OEt
O O
12 h, reflux+
(Ac)2O
OAcO
AcOOMe
OAc
HN
EtO OEt
O O
Pyridine
Protection
Deprotection
43
3741
42
42
Scheme 20. Modified deprotection condition for BECV group
Limitations of BECV as amine protecting group
The existing protection and deprotection conditions for using BECV group has
some disadvantages such as longer reaction time and high temperature. Usage of strong
inorganic base and strong mineral acids creates possibility for recemisation, during the
deprotection stage, harmful reagents such as CHCl3 saturated with Cl2 or Br2 was used.
Due to these reagents sensitive and oxidizible groups gave unidentified products.
O-to N- migration of acyl group was observed and amines are obtained as hydrochloride
or bromide salts. The reaction was carried out at 0 oC at first and later at 50 oC for several
hours. This method can’t be used for substrate with aromatic ring and unsaturated bonds.
There was no systematic study on aromatic and aliphatic amines, peptide synthesize and
also no study was made on orthogonality of this protecting group with existing familiar
amine protecting groups.
Chapter II Present Work
34
PRESENT WORK
The carbamate derivatives occupy a prominent position in the ranks of commonly
used amine protecting groups (PGs). The advantage of carbamate PGs, such as Boc, Cbz,
Fmoc and its recent variants Alloc, Troc and Azoc6 over other amine PGs is that the
cleavage condition can be varied considerably, depending on the choice of alkyl
component used. These PGs are useful for the synthesize of peptides, aminoglycosides and
functionalized aromatic amines. However, some of the reagents used for the carbamate
protection such as Fmoc-Cl are expensive and moisture-sensitive.17 Moreover, these
reagents are CO2- and COCl2-based chemicals18 are difficult to prepare as special
precaution is needed for preparation even on the industrial scale. Despite these drawbacks,
the use of carbamate PGs is being continued, due to a lack of alternative PGs that meet the
required standards.17 Hence, there is a clear need to develop alternative amine protecting
groups.
The primary amine protecting group, 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)
ethyl (Dde)9 introduced as an alternate to the carbamates has become a valuable tool for
the construction of cyclic side-chain modified peptides and peptide nucleic acid-peptide
conjugates.10 The Dde group is fully orthogonal to the Fmoc protecting group.19 Later,
some of its variants were introduced to overcome its drawbacks such as intramolecular N-
N'-migration10,19 stability towards Fmoc deprotection condition20 and lack of fluorescence
emission.21 The types of reactions carried out using the Dde protected amines are only
limited. These include amide or carbamate bond formation as in peptides and
polyamines,22 reactions involving the use of mild reagents such as tertiary amine,
secondary amine, inorganic base (Cs2CO3)20 and 1% TFA. The reason for this limited
study may be due to the presence of sterically hindered but acidic protons in the 1,3-
cyclohexanedione ring system of Dde group which may lead to side reactions if strong
bases such as NaH, LDA and NaOH are used. Another reason as observed by Bycroft11 is
that the development of Dde was to a large extent influenced by the availability of
dimedone and its conversion to 2-acetyl-5,5-dimethyl-cyclohexane-1,3-dione by acylation
reaction. We found that the 2,2-bis(ethoxycarbonyl)vinyl- (BECV) group, an ester type
variant of Dde, met some of the essential requirements of an amine PG. We herein present
our results (Scheme 21).
Chapter II Present Work
35
R-NH2
EtOH / rtEtOH / rtH2NNH2
R = Aromatic or Aliphatic sub units
EtO COOEt
COOEt
OH
NR
EtO
O OEt
Scheme 21. Schematic representation of protection and deprotection of BECV
In the course of our attempt to synthesize novel heterocycles we observed a facile
derpotection of BECV group on 44 in the presence of ethylenediamine in ethanol to give
product 44a in quantitative yield (99%) at room temperature (Scheme 22).
NH
OEtO
OEt
O
NH2
H3CO H3CO
44
44a
H2NNH2
EtOH, rt, 20 min. 99%
Scheme 22. Deprotection of BECV by ethylenediamine
The use of readily available organic reagent ethylenediamine, simple reaction
condition and the high yield of the deprotected product provided the scope for further
development of the techniques used. A complete literature review revealed that the BECV
group was used as an amine PG in the synthesize of amino acid esters15a and
aminoglycosides.16 However, no further reports were made mainly because, the amine
protection needs the use of strong base KOH and the deprotection involves the use of
harmful reagents, such as 4% solutions of Br2 or Cl2 in CHCl3 (wet). The reaction time is
usually long (12 h at 40 °C). Side reactions were observed for compounds containing
unsaturation, acid sensitive functional groups, easily oxidizable groups, which led to the
formation of carbon-to-nitrogen migration and complex mixture of unidentified products.
Further, there was no study on the use of BECV group for selective functional group
transformations on different class of organic compounds.
Chapter II Present Work
36
Table 1. Standardization of the reaction conditions for deprotection
NH
OEtO
OEt
OConditions
NH2
H3COH3CO
44 44a
S.No. Solvent Reagent Amount of reagent
Time Yield in %
1 THF H2N-CH2-CH2-NH2 4.0 mol 1.0 h 89
2 Toluene H2N-CH2-CH2-NH2 4.0 mol 3 h 91
3 Diethyl ether H2N-CH2-CH2-NH2 4.0 mol 2.5 h 95
4 Chloroform H2N-CH2-CH2-NH2 4.0 mol 1.5 h 92
5 Water H2N-CH2-CH2-NH2 4.0 mol 24 h 15
6 DMF H2N-CH2-CH2-NH2 4.0 mol 2.5 h 90
7 Acetonitrile H2N-CH2-CH2-NH2 4.0 mol 20 min. 95
8 Ethanol H2N-CH2-CH2-NH2 4.0 mol 20 min. 99
9 Ethanol 1,2-diaminobenzene 4.0 mol > 2 h No reaction
10 Ethanol H2N-NH2 4.0 mol 5 min. 98
11 Ethanol NH3 4.0 mol >24 h 35
12 Ethanol H2N-CH2-CH2-NH2 0.1 mol > 30 h 10
13 Ethanol H2N-CH2-CH2-NH2 0.5 mol 30 h 30
14 Ethanol H2N-CH2-CH2-NH2 1.0 mol >24 h 68
15 Ethanol H2N-CH2-CH2-NH2 2.0 mol 20 h 81
This encouraged us to undertake a complete study on the use of BECV as a protecting
group. In order to standardize the reaction condition, we examined different solvents,
reaction temperature and the use of other amines as deprotecting agents (Table 1).
With the use of less than 4 equiv. of ethylenediamine in ethanol, the deprotection
reaction is very slow (>24 h).23 By comparing the reaction times of various solvents
CHCl3 (1.5 h), CH3CN (20 min.), H2O (>24 h) studied, EtOH (20 min.) was found to be
suitable in terms of quick reaction time and eco-friendliness. With NH3, the reaction was
very slow (>24 h),24 with NH2-NH2 it was very fast (5 min.),25 and with 1,2-
diaminobenzene no reaction was observed (>2 h). However, the use of NH2-NH2, may
create conditions that are too harsh for selective functional group transformations. We
Chapter II Present Work
37
therefore decided to use the more moderate reagent, 4 equiv. ethylenediamine in ethanol,
for the remainder of the study.
According to the literature, the BECV group may typically be introduced to amines
by heating a neat mixture of an amine and Diethyl EthoxyMethyleneMalonate (DEMM)
between 100-120 °C,26 or in some cases heating to reflux in ethanol.27,28 However, we
observed that, the coupling reaction of the BECV group with a variety of aromatic,
aliphatic amines takes place with one equiv. of DEMM just by stirring it in ethanol at
room temperature. In the case of amino acids, the use of NEt3 (1 equiv.) was sufficient to
introduce the BECV group to amine at room temperature. The starting material, DEMM,
can be easily synthesized in the laboratory following a simple procedure reported in
literature.29
In order to investigate the electronic influence of the aromatic ring substituents on
protection and deprotection, we used anilines 44a-50a (Table 2). The BECV group was
introduced in presence of ethanol at room temperature to afford an excellent yield of
products 44-50. The higher the electron-withdrawing strength of the substituent in the
aromatic ring, slower the rate of coupling. In general, compounds that undergo the
coupling reaction slowly are also characterized by slow deprotection. Both protection and
deprotection occurred under these conditions in excellent yield. The presence of highly
UV active chromophore in BECV group is an added advantage for monitoring the reaction
by TLC.
The compound 45 crystallised as a single crystal in EtOAc shows an intra
molecular hydrogen bond existing between N-H and the ester carbonyl group. Thus there
exists a close proximity between ester carbonyl and NH group (Figure 2).
Chapter II Present Work
38
Figure 2. ORTEP diagram for compound 45
Multifunctional anilines are useful starting materials for the synthesize of
important heterocycles.30 In many instances, functional groups, such as –OH, -SH, –
COOH and also -NH2 must be selectively manipulated over an amine group. We
investigated the compatibility of the BECV group with several potentially competing
functional groups (Table 3). In our study, the starting materials 51a-57a were prepared in
very good yield. Apart from 51a, in which two BECV groups were introduced, the yield is
excellent and the reaction time was short. This shows clearly that by keeping the
competing functional groups –NH2, –OH, –SH, and –COOH unprotected, anilines can be
protected selectively.
The selectively protected anilines were then subjected to functional group
transformations. Acylation and alkylation carried out separately on substrate 51a, yielded
51c, 51e and 51g. On selective deprotection of the BECV group, high yields of 51d, 51f
and 51h were obtained very quickly, after 1.30 h, 15 min. and 15 min. respectively.
Substrate 52a with a sterically encumbered ortho-amino substituent also behaved in a
similar way, demonstrating that one amino group may be selectively functionalized over
another in very high yield. The hydroxyl group in 53a was alkylated, using allyl bromide
and benzyl bromide and esterified using benzoyl chloride and acetyl chloride, each in turn,
thus obtaining compounds 53b, 53d, 53f and 53g respectively. The BECV group was
deprotected under standard conditions to obtain high yields of the corresponding anilines
53c, 53e, and 53h after a short reaction time. This shows that the –OH group can be
selectively functionalized in a substituted aniline.
Chapter II Present Work
39
Table 2. Electronic effect of aromatic substituents on Protection / Deprotection
H3CO
NH
OEt
O
OEtO
NH
OEt
O
OEtO
NH
OEt
O
OEtO
Cl
NH
OEt
O
OEtO
O2N
NH
OEt
O
OEtO
H3CO
NH2
NH2
NH2
Cl
NH2
O2N
NH2
N
NH2
H3CO
NH2
NH2
NH2
Cl
NH2
O2N
NH2
N
NH2
Starting MaterialR = Aninlines
Products Products
Protection
Time Yield
20 min
5 h
98%
99%
95%
98%
95%
15 min 99%
6 h
6 h
6 h
Deporotection
Time Yield
30 min
2.15 h
2.30 h
5 h
95%
95%
90%
95%
1.30 h 95%
20 min 99%
S.No.
1
2
3
4
5
6
44a
45a
46a
47a
48a
49a
44
45
46
47
48
49
R-NH2
rt
+
H2NNH2
R-NH2
44-5037
44a-50a OC2H5
OC2H5
O
C2H5O
O
NH
OC2H5
O
C2H5O
O
REtOH
rtEtOH
B
O
O
NH2
O
O
NH2
O
O
NH2
7
50a 50
7 h 6 h92%
N
NH
OEt
O
OEtO
90%
However, in the case of compound 53f, the ethylenediamine deprotected the Ac- group
instead of the BECV group. The same result was observed even with the milder reagent
such as aq.NH3. Similar is the case with 2-aminophenol (54).
Chapter II Present Work
40
Following the same strategy, 2-aminothiophenol (55) can be selectively alkylated
on thiol using ethyl bromide to obtain a very good yield of 2-aminothiphenol ethyl ether
(55c). Similarly, the 4-aminobenzoic acid derivative 56a was selectively esterified with
allyl bromide and methyl iodide to obtain excellent yields of 56b and 56d. On
deprotection, compounds 56c and 56e were obtained, in which the allyl and alkyl ester
remained unaffected. A similar observation was also made using 2-aminobenzoic acid
(57). This serves as a method for the selective functionalization of the –SH and –COOH
groups in the presence of –NH2 under very mild conditions.
A number of heterocyclization can be envisaged from many of the bifunctional
molecules discussed. However, these heterocylcization reactions require very high
temperature. For example in the synthesize of, 7-Chloro-6-fluoro-1H-quinolin-4-one, a
crucial intermediate for the drug norfloxacin31 and bipyridine,32 the heterocyclisation was
carried out at <200 °C. We did not observe any of such cyclized products under our
experimental conditions. All the substrates show very good stability at room temperature
and in light.
Chapter II Present Work
41
Table 3. Selective Protection / Functional Group Transformation (FGT) / Deprotection of Multifunctional Aromatic Compounds
Entry
1
2
3
15 min (99%)
1.30 h (80%)
Time(Yield)viii
AcHN NHR
HN NHR
NHR
NH2
NHR
HN
15 min (99%)
Product
51c
51e
53b
H2N NH2
51
NH2
NH2
53
Starting Material Product
51a
15 mim (99%)N NHR51g
53a
Time (Yield) Time(Yield)Product
Selective ProductionSelective Functional Group Transformation Selective Deprotection
51b
5 min (17%)
10 min (98%)
(77%) 1.30 h (80%)i
24 h (78%)ii
24 h (20%)ii
24 h (77%)ii
AcHN NH2
HN NH2
NH2
HN
51d
51f
53c
N NH2
51h
FGNH2
OEt
COOEt
COOEt Selective Functional Group Transformation
+
SelectiveProtection
H2NNH2
SFGTNH2H
NCOOEt
COOEt
FG
HN
COOEt
COOEt
SFGTi-vii/rt37
NHRRHN
NHRH2N
NHR4
5
1.30 h (90%)
1.30 h (95%)
HO
NHRBnO
NHRO
52b
53d
NH2HO
52 52a
15 min (99%) 3 h (85%)iii
12 h (92%)iv NH2BnO
NH2O
52c
53e
EtOHrt
EtOHrt
B
Chapter II Present Work
42
15 min (99%)
1 h (75%)NHRBzO
NHR
OH
NHR
O
NHR
SH
NHR
S
9 2 h (98%)
53g
57b
54b
NH2
OH
NH2
SH
57
54
7
8
57a
54a
15 min (99%)
20 min (98%)
1 h (99%)v
12 h (99%)ii
24 h (85%)ii
NH2BzO
NH2
O
NH2
S
53h
57c
54c
10 NHRHOOC NHRCO
O
NHRH3COOC
NHR
COOH
NHR
COOCH3
2 h (90%)
2.15 h (95%)
2.30 h (96%)
11
55b
56bNH2HOOC
NH2
COOH
55
56
55a
56d
56a
12
4.30 h (99%)
5.0 h (98%)
36 h (85%)vi
2 h (98%)vii
2 h (98%)vii
NH2CO
O
NH2H3COOC
NH2
COOCH3
55c
56e
56c
Where R = -CH=C(COOCH2CH3)2 = BECV; FGT = Functional Group Transformations; Reaction Conditions for Functional GroupTransformations i) N(C2H5)3, CHCl3, CH3COCl ii) K2CO3 , Acetone, C2H5Br iii) KOH, Acetone, Allyl bromide iv) K2CO3, CHCl3, Benzyl bromide v) N(C2H5)3, CHCl3, Benzoyl chloride vi) K2CO3, Acetone, Allyl bromide vii) K2CO3, Acetone, Methyl iodide viii) Ethanol,Ethylenediamine, rt.
6 5 min (95%)NHRAcO
53f
30 min (99%)i NHRHO
53a
Chapter II Present Work
43
The compound 56d was prepared by alkylation of the corresponding acid 56a. The
single crystal structure obtained for the compound 56d further confirms that during
alkylation reaction NH group is not affected (Figure 3).
Figure 3. ORTEP diagram for compound 56a
We then checked the versatility of this PG strategy on aliphatic amines.
Benzylamine reacted instantly and quantitatively to yield the compound 2-(benzylamino-
methylene)-malonic acid diethyl ester (Scheme 23). The deprotection was completed after
45 min. yielding benzylamine (98%). In order to study selective functional group
transformation on aliphatic amines (Scheme 24), we used 2-aminobutanol (58). Following
treatment with DEMM the selective protection of –NH2 group in the presence of free –OH
produced very high yields of 58a. On treatment with benzoyl chloride/NEt3 (Scheme 25),
acetyl chloride/NEt3 (Scheme 26), and ethyl bromide/NaH (Scheme 27) in separate
experiments, compound 58a yielded the corresponding esters 59 and 60 and ether 61.
These compounds on selective deprotection at room temperature gave the –OH
functionalized amines 59a and 61a in excellent yield. In a similar manner to phenyl
acetate 53f, its aliphatic equivalent 60 also underwent acetyl deprotection to yield the
starting material 58a. The hydroxyl group of aliphatic amino alcohols can thus be
selectively functionalized. This result when compared with deprotection aromatic ester
57b, shows that while esters of aromatic acids can survive, but, esters of aliphatic acid are
not stable under the present deprotection condition. All the compounds remained optically
active.
Chapter II Present Work
44
NH
OEtO
O
OEt
EtOH, rt
H2N NH2
45 min. 98%
NH2
Scheme 23. Deprotection of BECV from benzylamine
BECV-OEt
rt, 30 min 98%H NH2
OH
58
58a
H NHH3C OH
O OEt
O
OEt
Scheme 24. Selective protection of aliphatic amine in presence of alcohol
A key test of any amine protecting group is its applicability to amino acid-related
functional group transformation.4 With this in mind, we investigated the compatibility of
the BECV group with amino acid esterification.
H NHH3C OH
58a
O OEt
O
OEt
O
Cl+
H NHH3C O
59
O OEt
O
OEt
O
1h, 99%
EtOH, rt
H2N NH2
1h 94%
H NH2
H3C O
59a
O
Et3N
CHCl3, rt
H NHH3C O
59
O OEt
O
OEt
O
Scheme 25. Selective O-benzoylation followed by deprotection
H NHH3C OH
58a
O OEt
O
OEt
H3C
O
Cl+
H NHH3C O
60
O OEt
O
OEt
O
CH3
H2N NH258a
Et3N
EtOH, rt1 h, 70%
CHCl3, rt1 h, 99%
Scheme 26. O-acylation of aliphatic alcohols in presence of BECV
Chapter II Present Work
45
H NHH3C OH
58a
O OEt
O
OEt
H3C Br+H NH
H3C O
61
O OEt
O
OEt
CH3H2N NH2
H NH2
H3C O CH3
61a
NaH
DMF, rt24 h, 70 %
EtOH, rt1 h, 90 %
Scheme 27. Selective O-alkylation followed by deprotection
Protection of the amine group in amino acids (62-64) could be carried out at room
temperature in the presence of NEt3 as a base to achieve good yields of 62a-64a (Schemes
28-30). Further treatment with SOCl2/CH3OH provided excellent yields of the
corresponding methyl esters 62b-64b. The BECV group was tolerant to the reagent
SOCl2/CH3OH. The deperotection as usual gave amino acid esters 62c-64c in excellent
yield. Optical rotation values were recorded for all the compounds and compared with the
reported values,15a which confirmed that the deprotection condition does not affect the
chiral centre.
COOH
NH2+
OEt
OEt
O
EtO
O
EtOH, rt, 30 min, 96%
COOH
HN
O
OEt OEt
O
or SOCl2/MeOHrt, 30 min. 95%
COOCH3
HN
O
OEt OEt
O
NH2H2N
EtOH, rt, 2.5 h, 95%
COOCH3
NH2
6262a
62b 62c
CH3I , K2CO3 , Acetone
rt, 24 h, 70%
Et3N
37
Scheme 28. Preperation of phenylalanine methyl ester
CH3
H3C COOH
NH2
+
OEt
OEt
O
EtO
OCH3
H3C COOH
HN
O
OEt OEt
O
CH3
H3C COOCH3
HN
O
OEt OEt
O
NH2H2N
EtOH, rt, 2.15 h, 90%
CH3
H3C COOCH3
NH2
63
63a
63b 63cor SOCl2/MeOHrt, 30 min. 95%
CH3I , K2CO3 , Acetone
rt, 24 h, 72%
Et3N
EtOH rt, 30 min, 95%
37
Scheme 29. Preperation of leucine methyl ester
Chapter II Present Work
46
S COOH
NH2
+
OEt
OEt
O
EtO
O
EtOH, rt, 30 min, 90%
S COOH
HN
O
OEt OEt
O
S COOCH3
HN
O
OEt OEt
O
NH2H2N S COOCH3
NH2
H3C
H3C
H3C
H3C
EtOH, rt, 2.15 h, 90%
6464a
64b64cor SOCl2/MeOH
rt, 30 min. 95%
CH3I , K2CO3 , Acetone
rt, 24 h, 68%
Et3N
37
Scheme 30. Preparation of methionine methyl ester
The main purpose of the amine PG is to suppress its nucleophilic character,
primarily by delocalization of the lone pair of electrons.18 It is important to note that after
the introduction of the BECV group, the aniline or aliphatic amine still possess a –NH
proton but did not undergo alkylation or acylation even with highly active reagents such as
ethyl bromide/NaH, benzyl bromide/K2CO3 and acetylchloride/NEt3. Thus, we strongly
believe that the BECV group is effective in masking the nucleophilic behaviour of
nitrogen lone pair. In the 1H-NMR spectra of the NH-BECV protected aniline, the peaks
corresponding to BECV group were observed at approximate δ values ≅ 1.33, 4.33, 8.45,
11.00 ppm. These characteristic peaks do not interfere with the spectral interpretation.
We also studied the orthogonal stability of the BECV group using the common
amine protecting groups Boc, Cbz, and Fmoc, as shown in Schemes 31-34.
A mixture of NH-BECV protected phenylalanine (62b) and compound 65 or
compound 66 or compound 67 were treated with ethylenediamine (4 equiv.) in ethanol
separately. While Boc- and Cbz- were stable, Fmoc- was labile. However, when 62b was
treated with 4 equiv. of piperazine in ethanol as the reagent the deprotection of Fmoc took
place exclusively without affecting the BECV group. This clearly establishes that the
BECV group shows orthogonal stability against Fmoc, Cbz and Boc protecting groups.
COOCH3
NHBoc+
NH2NH2
EtOH, rt2.30 h
65 (98%)
COOCH3
HN
O
OEt OEt
O
62b
65
COOCH3
NHBoc
COOCH3
NH2
62c
+
Scheme 31. Orthogonal deprotection of BECV in presence of BOC
Chapter II Present Work
47
COOCH3
NHCbz+
NH2NH2
EtOH, rt2.30 h
66 (98%)
COOCH3
HN
O
OEt OEt
O
62b
66
COOCH3
NHCbz
COOCH3
NH2
62c (95 %)
+
Scheme 32. Orthogonal deprotection of BECV in presence of Cbz
COOCH3
NHFmoc+
NH2NH2
EtOH, rt2.30 h
67 (15%)
COOCH3
HN
O
OEt OEt
O
62b
67
COOCH3
NHFmoc
COOCH3
NH2
+
62c
Scheme 33. Deprotection of BECV and Fmoc in ethylenediamine
5% piperazine
EtOH, rt30 min
COOCH3
NHFmoc+
COOCH3
HN
O
OEt OEt
O
62b
67
COOCH3
NH2
+
62c (98%)
COOCH3
HN
O
OEt OEt
O
62b
Scheme 34. Orthogonal deprotection of Fmoc in presence of BECV
In order to check the stability of BECV group towards basic and acidic
conditions10 compounds 62b-64b were treated with 10% TFA in CH2Cl2, 10% aq.HCl and
20% piperazine in DMF separately at room temperature. All the compounds displayed
excellent acid/base stability for more than 24 h. In addition as discussed above the BECV
was also stable towards bases such as NaH, KOH, K2CO3, NEt3. This implies that the NH-
BECV group is adaptable to reactions involving both strong acids as well as base.
Mechanism of Deprotection of the BECV Group
After the deprotection we could isolate mono-BECV (E) as well as di-BECV (F)
protected ethylenediamine in addition to free aniline (G). Based on this we propose the
following mechanism (Scheme 35) for deprotection reaction. We have also observed that,
when mono-BECV protected ethylenediamine (E) was left at room temperature for longer
time it gets converted into di-BECV protected ethylenediamine (F) and free
ethylenediamine (B).
Chapter II Present Work
48
H2N NH2
OEt
OEt
O
O
RN OEt
OEt
O
O
RHN
H2NHN
H
H
RNH2 NH
HN
O OEt
OEt
O
EtO
O
EtO O
NH
NH2EtO
O
EtO O
++
EG
B C D
F
Scheme 35. Mechanism for Deprotection of BECV Group
Conclusion
In conclusion, we have developed a simple method for the selective protection of
amino group as NH-BECV and deprotection of the BECV group, at room temperature, on
various substrates such as anilines, aliphatic amines and amino acids. This method is
useful for selective functional group transformations of the OH, NH2, SH and COOH
groups in the presence of the NH2 group. The BECV protecting group is stable towards
both strong acids as well as strong bases except primary amine. The reagents DEMM and
ethylenediamine, used for protection and deprotection respectively, are readily available
at much cheaper price compared with the reagents required for the preparation of
carbamate derivatives or Dde protecting group. This study establishes BECV as a versatile
amine protecting group that makes use of component materials that are readily available,
selectively protect and deprotect under mild conditions and is stable under delicate
functional group transformations of varied applications in organic synthesize. In view of
these advantages the BECV group could be used as an amine protecting group in line with
the well established Dde, Fmoc, Cbz, and Boc protecting groups.
Chapter II Experimental
49
EXPERIMENTAL
Method A: General experimental procedure for protection of amines with 2,2-bis-
(ethoxycarbonyl)cinyl (BECV) group
To asolution of aniline or amine (1 equiv.) in ethanol (5 times w/v), diethyl
ethoxymethylenemalonate (1 equiv.) was added and stirred at room temperature (~28 °C).
After completion of the reaction, during a specific time, ethanol was evaporated under
reduced pressure to get corresponding NH-BECV protected amine or aniline in 77-99%
yield.
Method B: General experimental procedure for deprotection of BECV group from
N- 2,2-Bis(ethoxycarbonyl)vinyl protected aniline or amine
To a solution of NH-BECV protected aniline or amine (1 equiv.) in ethanol (5 times w/v),
ethylenediamine (4 equiv.) was added and stirred at room temperature. After completion
of the reaction, water was added (10 times w/v) and extracted with ethyl acetate (three
portions). Combined organic layer was dried (Na2SO4), evaporated under reduced pressure
and passed through a filter column (Silica gel, Hexane:EtOAc) to get the corresponding
aniline or amine in 75-99% yield.
1) Protection and deprotection of aromatic amines
Preparation of 2-[(4-Methoxy-phenylamino)-methylene]-malonic acid diethyl ester
(44)
OH3C
NH
OOC2H5
OOC2H5
The reaction was carried out according to Method A using 4-methoxyaniline (44a, 500
mg, 4.0 mmol), diethyl ethoxymethylenemalonate (820 μL, 4.0 mmol) and ethanol (2.5
mL). Conditions: room temperature, 15 min. The title compound 44 was obtained as a
colorless solid (1.17 g, 99%). Spectral data of the compound 44 was in agreement with the
values reported in the literature.1
Preparation of 4-methoxyaniline (44a)
Chapter II Experimental
50
The reaction was carried out according to Method B using compound 44 (500 mg, 1.7
mmol), ethylenediamine (455 μL, 6.8 mmol) in ethanol (2.5 mL). Conditions: room
temperature, 20 min. The title compound 44a (0.20 g, 99%) was obtained as a colorless
solid after passing through a short silica gel column (Hexane:EtOAc = 9:1). The spectral
data of the compound 44a was in agreement with authentic sample available from
commercial sources.
Preparation of 2-Phenylaminomethylene-malonic acid diethyl ester (45)
NH OCH2CH3
O
OOCH2CH3
The reaction was carried out according to Method A using aniline (45a) (0.500 g, 5.3
mmol) and diethyl ethoxymethylenemalonate (1.08 mL, 5.3 mmol) and ethanol (2.5 mL).
Conditions: room temperature, 20 min. The title compound 45 (1.38 g, 98%) was obtained
as a colorless liquid. The spectral data was in agreement with the values reported in the
literature.33
Preparation of aniline (45a)
The reaction was carried out according to Method B using compound 45 (0.500 g, 1.8
mmol), ethylenediamine (507 μL, 7.5 mmol) in ethanol (2.5 mL). Conditions: room
temperature, 30 min. Title compound 45a (0.16 g, 95%) was obtained as a brown liquid
after passing through a short silica gel column (Hexane/EtOAc, 9:1). The spectral data of
the compound 45a was in agreement with authentic sample available from commercial
sources.
Preparation of 2-[(2-Chloro-phenylamino)-methylene]-malonic acid diethyl ester (46)
NH OCH2CH3
O
OOCH2CH3Cl
The reaction was carried out according to Method A using 2-chloroaniline (46a) (0.500 g,
3.9 mmol) diethyl ethoxymethylenemalonate (792 μL, 3.9 mmol) and ethanol (2.5 mL).
Conditions: room temperature, 5 h. The title compound 46 (1.15 g, 99%) was obtained as
Chapter II Experimental
51
a pale white solid. Spectral data and melting point of the compound 46 was in agreement
with the values reported in the literature.34
Preparation of 2-chloroaniline (46a)
The reaction was carried out according to Method B using compound 46 (0.500 g, 1.6
mmol), ethylenediamine (449 μL, 6.7 mmol) in ethanol (2.5 mL). Conditions: room
temperature, 2.15 h. The title compound 46a (0.19 g, 90%) was obtained as a colorless
liquid after passing through a short silica gel column chromatography (Hexane/EtOAc =
9:1). The spectral data of the compound 46a was in agreement with authentic sample
available from commercial sources.
Preparation of 2-[(4-Nitro-phenylamino)-methylene]-malonic acid diethyl ester (47)
NH OCH2CH3
O
OOCH2CH3
O2N
The reaction was carried out according to Method A using 4-nitroaniline (47a, 0.500 g, 3.6
mmol), diethyl ethoxymethylenemalonate (731 μL, 3.6 mmol) and ethanol (2.5 mL).
Conditions: room temperature, 6 h. The title compound 47 (1.00 g, 95%) was obtained as
a pale yellow solid. The spectral data and melting point of the compound 47 was in
agreement with the values reported in the literature.27
Preparation of 4-nitroaniline (47a)
The reaction was carried out according to Method B using compound 47 (0.500 g, 1.6
mmol), ethylenediamine (433 μL, 6.4 mmol) in ethanol (2.5 mL). Conditions: room
temperature, 2.30 h. The title compound 47a (0.21 g, 95%) was obtained as a yellow solid
after through a short silica gel column (Hexane:EtOAc = 9:1). The spectral data of the
compound 47a was in agreement with authentic sample available from commercial
sources.
Chapter II Experimental
52
Preparation of 2-(Naphthalen-1-ylaminomethylene)-malonic acid diethyl ester (48)
NH OCH2CH3
O
OOCH2CH3
The reaction was carried out according to Method A using 1-aminonaphthalene [48a,
0.500 g, 3.4 mmol), diethyl ethoxymethylenemalonate (705 μL, 3.4 mmol) and ethanol
(2.5 mL). Conditions: room temperature, 6 h. The title compound 48 (1.07 g, 98%) was
obtained as a solid. The spectral data and melting point of the compound 48 was in
agreement with the values reported in the literature.35
Preparation of 1-aminonaphthylene (48a)
The reaction was carried out according to Method B using compound 48 (0.500 g, 1.5
mmol), ethylenediamine (426 μL, 6.3 mmol) and ethanol (2.5 mL). Conditions: room
temperature, 5.0 h. The title compound 48a (0.21 g, 95%) was obtained as a solid after
passing through a short silica gel column (Hexane: EtOAc = 9:1). The spectral data of the
compound 48a was in agreement with authentic sample available from commercial
sources.
Preparation of 2-(Pyridin-2-ylaminomethylene)-malonic acid diethyl ester [49]
NNH OCH2CH3
O
OOCH2CH3
The reaction was carried out according to Method A using 2-aminopyridine (49a, 0.500 g,
5.3 mmol), diethyl ethoxymethylenemalonate (1.07 mL, 5.3 mmol) and ethanol (2.5 mL).
Conditions: room temperature, 6 h. The title compound 49 was obtained as a pale white
solid in (1.33 g, 95%).18
Preparation of 2-aminopyridine (49a)
The reaction was carried out according to Method B using compound 49 (0.500 g, 1.8
mmol), ethylenediamine (505 μL, 7.5 mmol) and ethanol (2.5 mL). Conditions: room
temperature, 1.30 h. The title compound 49a (0.16 g, 95%) was obtained as a solid after
passing through a short silica gel column (Hexane:EtOAc = 9:1). The spectral data of the
compound 49a was in agreement with authentic sample available from commercial
sources.
Chapter II Experimental
53
Preparation of 2-[(9,10-Dioxo-9,10-dihydro-anthracen-1-ylamino)-methylene]-
malonic acid diethyl ester (50)
NH OCH2CH3
O
OOCH2CH3O O
The reaction was carried out according to Method A using 1-aminoanthraquinone (50a,
0.500 g, 2.2 mmol), diethyl ethoxymethylenemalonate (452 μL, 2.2 mmol) and ethanol
(2.5 mL). Conditions: room temperature, 7 h. The title compound 50 (0.81 g, 92 %) was
obtained as a red solid. 1H NMR (200 MHz): δ 1.33-1.48 (m, 6H), 4.30 (q, J = 7.0 Hz,
2H), 4.50 (q, J = 7.0 Hz, 2H), 7.76-8.45 (m, 7H), 8.60 (d, J = 12.0 Hz, 1H), 13.46 (d, J =
12.0 Hz, 1H); 13C NMR (75 MHz): δ 14.31, 14.4, 60.4, 60.5, 92.6, 114.8, 116.1, 120.6,
125.2, 127.3, 146.5, 151.0, 166.9, 168.6; IR (KBr): 1282, 1607, 1728, 2924, 3421 cm-1;
Anal. calcd. for C22H19NO6: C, 67.17; H, 4.87; N, 3.56; O, 24.40; Found: C, 67.19; H,
4.53; N, 3.22.
Preparation of 1-aminoanthraquinone (50a)
The reaction was carried out according to Method B using compound 50 (0.500 g, 1.2
mmol), ethylenediamine (339 μL, 5.0 mmol) and ethanol (2.5 mL). Conditions: room
temperature, 6 h. The title compound 50a (0.25 g, 90%) was obtained as a dark red solid
after passing through a short silica gel column (Hexane/EtOAc = 9:1). The spectral data of
the compound 50a was in agreement with authentic sample available from commercial
sources.
2. Selective protection / Functional Group Interconversion / Derpotection of
multifunctional aromatic amines
Preparation of 2-[(4-Amino-phenylamino)-methylene]-malonic acid diethyl ester
(51a) and Preparation of 3-[4-(2,2-Bis-ethoxycarbonyl-vinylamino)-phenylamino]-2-
ethoxycarbonyl-acrylic acid ethyl ester (51b)
The reaction was carried out according to Method A using 1,4-diaminobenzene (51, 0.500
g, 4.6 mmol) diethyl ethoxymethylenemalonate (934 μL, 4.6 mmol) in ethanol (2.5 mL).
Conditions: room temperature, 5 min. Crude product was purified through column
Chapter II Experimental
54
chromatography (silica gel, Hexane: EtOAc = 8:2). First eluted was compound 51b (0.35
g, 17%).
NH OCH2CH3
O
OOCH2CH3
HNO
H3CH2CO
OH3CH2CO
51b: mp: 68 °C; 1H NMR (400 MHz, CDCl3): δ 1.31-1.40 (m, 12H), 4.22-4.34 (m, 8H),
7.15 (s, 4H), 8.46 (d, J = 13.6 Hz, 2H), 10.05 (d, J = 13.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3): δ 14.2, 14.4, 60.1, 60.4, 93.8, 118.5, 136.2, 151.5, 165.5, 169.0; IR (KBr): 463,
531, 756, 800, 920, 1031, 1099, 1232, 1258, 1302, 1348, 1383, 1412, 1453, 1525, 1597,
1640, 1683, 2854, 2926, 2982, 3271, 3443 cm-1; Anal. calcd. for C22H28N2O8: C, 59.92; H,
6.29; N, 6.25; Found: C, 60.01; H, 6.23; N, 6.27.
NH OCH2CH3
O
OOCH2CH3
H2N
Second eluetd was compound 51a (0.99 g, 77% yield) was obtained as a yellow solid. mp:
88 °C; 1H NMR (400 MHz, CDCl3): δ 1.29-1.39 (m, 6H), 3.69 (brs, 2H), 4.20-4.32 (m,
4H), 6.68 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 8.41 (d, J = 14.0 Hz, 1H), 10.94 (d,
J = 14.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.3, 14.4, 59.8, 60.1, 91.7, 115.9,
119.0, 131.0, 144.0, 152.6, 165.9, 169.2; IR (KBr): 407, 596, 699, 736, 804, 968, 1032,
1103, 1225, 1290, 1344, 1372, 1428, 1632, 1683, 2933, 2984, 3031, 3291, 3523 cm-1;
Anal. calcd. for C14H18N2O4: C, 60.42; H, 6.52; N, 10.07; Found: C, 60.47; H, 6.54; N,
10.25.
Preparation of 2-[(4-Acetylamino-phenylamino)-methylene]-malonic acid diethyl
ester (51c)
NH OCH2CH3
O
OOCH2CH3
HNO
To a solution of 51a (0.500 g, 1.7 mmol) and triethylamine (375 μL, 2.6 mmol) in
chloroform (5 mL), acetyl chloride (211 μL, 2.6 mmol) was added slowly under nitrogen
atmosphere. After stirring at room temperature for 1.30 h, water (10 mL) was added and
Chapter II Experimental
55
extracted with chloroform (3 X 10 mL). The combined organic layer was dried (Na2SO4),
and evaporated under reduced pressure to get the title compound 51c (0.46 g, 80%) as a
yellow solid. Crude product was purified through column chromatography
(Hexane:EtOAc = 7:3); mp: 165 °C; 1H NMR (400 MHz, CDCl3): δ 1.30-1.38 (m, 6H),
2.17 (s, 3H), 4.21-4.33 (m, 4H), 7.06 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.93 (s,
1H), 8.45 (d, J = 14 Hz, 1H), 10.99 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
14.1, 14.3, 24.2, 60.0, 60.2, 93.0, 117.6, 121.2, 135.1, 135.2, 151.8, 165.7, 168.5, 168.9;
IR (KBr): 520, 624, 715, 801, 828, 919, 1030,1100,1238, 1225, 1312, 1367, 1411, 1441,
1478, 1520, 1540, 1629, 1672, 1698, 2362, 2909, 2931, 2983, 3070, 3150, 3238, 3325 cm-
1: Anal. calcd. for C16H20N2O5: C, 59.99; H, 6.29; N, 8.74; Found: C, 60.14; H, 6.41; N,
8.72.
Preparation of N-(4-Amino-phenyl)-acetamide (51d)
NHH2N
H3CO
The reaction was carried out according to Method B using compound 51c (0.500 g, 1.5
mmol), ethylenediamine (417 μL, 6.2 mmol) and ethanol (2.5 mL). Conditions: room
temperature, 1.30 h. The title compound 51d (0.18 g, 80%) was obtained after passing
through a short silica gel column (Hexane/EtOAc = 7:3). The data of the compound 51d
was in agreement with the values reported in the literature.36
Preparation of 2-[(4-Ethylamino-phenylamino)-methylene]-malonic acid diethyl ester
(51e) and 2-[(4-Diethylamino-phenylamino)-methylene]-malonic acid diethyl ester
(51g)
NH OCH2CH3
O
OOCH2CH3
HN
To a solution of 51a (0.500 g, 17 mmol) in acetone (5 mL), K2CO3 (0.372 g, 2.6 mmol)
was added and stirred for 1 h, followed by which ethyl bromide (201 μL, 2.6 mmol) was
added under nitrogen atmosphere. Stir the reaction mixture at room temperature for 24 h,
the acetone in reaction mixture was evaporated under reduced pressure. Water (10 mL)
was added and extracted with chloroform (3 X 10 mL). The combined organic layer was
dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by
Chapter II Experimental
56
column chromatography (silica gel, Hexane:EtOAc = 8:1). First eluted was the 2-[(4-
Ethylamino-phenylamino)-methylene]-malonic acid diethyl ester (51e, 0.42 g, 78%), a
greenish yellow solid and second eluted was 2-[(4-Diethylamino-phenylamino)-
methylene]-malonic acid diethyl ester (51g, 0.12 g, 20%) obtained as a yellow solid.
51e: mp: 52 °C; 1H NMR (400 MHz, CDCl3): δ 1.24-1.39 (m, 9H), 3.11-3.17 (m, 2H),
3.59 (brs, 1H), 4.20-4.32 (m, 4H), 6.59 (d, J = 6.8 Hz, 2H), 6.97 (d, J = 6.8 Hz, 2H), 8.41
(d, J = 13.6 Hz, 1H), 10.95 (d, J = 14.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.2,
14.4, 14.7, 38.5, 59.7, 60.0, 91.3, 113.3, 119.0, 129.7, 146.2, 152.6, 165.9, 169.2; IR
(KBr): 520, 562, 750, 809, 921, 995, 1033, 1098, 1180, 1272, 1310, 1377, 1434, 1477,
1526, 1606, 1632, 1678, 2865, 2929, 2981, 3030, 3163, 3260, 3374 cm-1; Anal. calcd. for
C16H22N2O4: C, 62.73; H, 7.24; N, 9.14; Found: C, 63.14; H, 7.21; N, 9.10.
NH OCH2CH3
O
OOCH2CH3
N
51g: mp: 80 °C; 1H NMR (400 MHz, CDCl3): δ 1.12 (t, J = 7.2 Hz, 6H), 1.28 (t, J = 7.2
Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H), 3.31 (q, J = 7.2 Hz, 4H), 4.17-4.29 (m, 4H), 6.62 (d, J =
7.2 Hz, 2H), 6.99 (d, J = 7.2 Hz, 2H), 8.39 (d, J = 14 Hz, 1H), 10.94 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 12.4, 14.3, 14.4, 44.5, 59.7, 60.0, 91.1, 112.6, 119.1,
128.3, 145.7, 152.6, 166.0, 169.4: IR (KBr): 518, 804, 916, 1030, 1095, 1155, 1255, 1313,
1414, 1446, 1479, 1524, 1570, 1612, 1641, 1686, 2928, 2979, 3183, 3264, 3441 cm-1:
Anal. calcd. for C18H26N2O4: C, 64.65; H, 7.84; N, 8.38; Found: C, 65.02; H, 7.84; N,
8.13.
Preparation of N-Ethyl-benzene-1,4-diamine (51f)
HN NH2
CH3
The reaction was carried out according to Method B using 51e (0.500 g, 1.8 mmol),
ethylenediamine (436 μL, 6.5 mmol) in ethanol (2.5 mL). Conditions: room temperature,
15 min. The title compound 51f (0.22 g, 99%) was obtained after passing through a short
silica gel column (Hexane:EtOAc = 8:2). The data of the compound 51f was in agreement
with the values reported in the literature.37
Chapter II Experimental
57
Preparation of N,N-Diethyl-benzene-1,4-diamine (51h)
N
NH2
CH3H3C
The reaction was carried out according to Method B using 51g (0.500 g, 1.4 mmol),
ethylenediamine (399 μL, 5.9 mmol) and ethanol (2.5 mL) Conditions: room temperature,
15 min. The title compound 51h (0.24 g, 99%) was obtained after passing through a short
silica gel column (Hexane:EtOAc = 8:2). The data of the compound 51h was in agreement
with the values reported in the literature. 37
Preparation of 2-[(2-Amino-phenylamino)-methylene]-malonic acid diethyl ester
(52a)
NH OCH2CH3
O
OOCH2CH3NH2
The reaction was carried out according to Method A using 1,2-diaminobenzene (52, 0.500
g, 4.6 mmol), diethyl ethoxymethylenemalonate (934 μL, 4.6 mmol). Conditions: room
temperature, 10 min. The title compound 52a (1.26 g, 98%) was obtained as a yellow
solid. mp: 78 °C; 1H NMR (400 MHz, CDCl3): δ 1.29-1.38 (m, 6H), 3.74 (brs, 2H), 4.19-
4.32 (m, 4H), 6.79-6.85 (m, 2H), 7.00-7.08 (m, 1H), 7.10 (d, J = 1.2 Hz, 1H), 8.40 (d, J =
13.6 Hz, 1H), 10.80 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.2, 14.2, 59.8,
60.1, 93.2, 117.4, 119.0, 119.9, 126.3, 127.6, 137.9, 154.0, 165.5, 169.0; IR (KBr): 544,
592, 654, 733, 833, 867, 909, 1000, 1028, 1071, 1222, 1310, 1383, 1414, 1467, 1504,
2983, 3036, 3140, 3250, 3352, 3408 cm-1; Anal. calcd. for C14H18N2O4: C, 60.42; H, 6.52;
N, 10.07; Found: C, 60.41; H, 6.49; N, 10.09.
Chapter II Experimental
58
Preparation of 2-[(2-Ethylamino-phenylamino)-methylene]-malonic acid diethyl ester
(52b)
NH OCH2CH3
O
OOCH2CH3NH
To a solution of 52a (0.500 g, 1.7 mmol) in acetone (5 mL), K2CO3 (0.372 g, 2.6 mmol),
was added, stirred at room temperature for 1 h, followed by which ethyl bromide (201 μL,
2.6 mmol) was added and stirred at room temperature for 24 h. After the reaction
completed acetone in reaction mixture was evaporated under reduced pressure. Water (10
mL) was added and extracted with chloroform (3 X 10 mL). The combined organic layer
was dried (Na2SO4) and evaporated under reduced pressure. The title compound 52b was
obtained as a greenish yellow solid (0.42 g, 77%). The crude product was purified through
column chromatography (silica gel, Hexane:EtOAc = 8:2); mp: 102 °C; 1H NMR (400
MHz, CDCl3): δ 1.19-1.24 (m, 6H), 1.30 (t, J = 7.2 Hz, 3H), 3.11 (q, J = 7.2 Hz, 2H), 3.56
(brs, 1H), 4.12-4.26 (m, 4H), 6.66-6.73 (m, 2H), 7.00-7.08 (m, 2H), 8.28 (d, J = 13.6 Hz,
1H), 10.55 (d, J = 13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.3, 14.3, 14.7, 38.5,
59.9, 60.2, 93.4, 112.4, 118.0, 120.3, 127.1, 127.3, 140.5, 155.2, 165.6, 169.1; IR (KBr):
526, 569, 673, 745, 796, 860, 1029, 1084, 1155, 1220, 1257, 1312, 1372, 1418, 1457,
1515,1617, 1660, 1708, 2848, 2887, 2929, 2978, 3074, 3254, 3337, 3446 cm-1; Anal.
calcd. for C16H22N2O4: C, 62.73; H, 7.24; N, 9.14; Found: C, 62.53; H, 6.24; N, 8.91.
Preparation of N-Ethyl-benzene-1,2-diamine (52c)
NH2
NH
H3C
The reaction was carried out according to Method B using compound 52b (0.500 g, 1.6
mmol), ethylenediamine (436 μL, 6.5 mmol) and ethanol (2.5 mL). Conditions: room
temperature, 15 min. The crude product was purified by column chromatography
(Hexane:EtOAc = 7:3) to get the title compound 52c (0.22 g, 99%). The data of the
compound 52c was in agreement with the values reported in the literature.38
Chapter II Experimental
59
Preparation of 2-[(4-Hydroxy-phenylamino)-methylene]-malonic acid diethyl ester
(53a)
NH OCH2CH3
O
OOCH2CH3
HO
The reaction was carried out according to Method A using 4-aminophenol (53, 0.500 g,
4.5 mmol), diethyl ethoxymethylenemalonate (925 μL, 4.5 mmol) and ethanol (2.5 mL).
Conditions: room temperature, 15 min. The title compound 53a was obtained as a white
solid (1.26 g, 99%). mp: 129 °C; 1H NMR (400 MHz, DMSO-D6): δ 1.22-1.28 (m, 6H),
4.09-4.22 (m, 4H), 6.80 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 8.30 (d, J = 14.0 Hz,
1H), 9.47 (s, 1H), 10.70 (d, J = 14.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.2, 14.3,
60.3, 60.3, 91.7, 116.5, 119.0, 131.9, 153.0, 154.4, 166.6, 169.0; IR (KBr): 710, 767, 803,
834, 869, 1010, 1031, 1092, 1218, 1354, 1379, 1415, 1463, 1517, 1591, 1622, 1657, 2520,
2619, 2744, 2876, 2933, 2982, 3036, 3200 cm-1; LCMS (TOF) [M+1]: 280.2; Anal. calcd.
for C14H17NO5: C, 60.21; H, 6.14; N, 5.02; Found: C, 60.45; H, 5.98; N, 5.12.
Preparation of 2-[(4-Allyloxy-phenylamino)-methylene]-malonic acid diethyl ester
(53b)
NH OCH2CH3
O
OOCH2CH3
O
To a solution of 53a (0.500 g, 1.7 mmol) in acetone (5 mL), KOH (0.150 g, 2.6 mmol)
was added and stirred at room temperature for 30 min. allyl bromide (232 μL, 2.6 mol)
was added and stirring continued till the completion of reaction at room temperature for 3
h. Water (5 mL) was added and extracted with ethyl acetate (3 X 10 mL). The combined
organic layer was dried with (Na2SO4) and evaporated under reduced pressure. Title
compound 53b was obtained a white solid (0.48 g, 85%) after passing the crude product
through column chromatography (silica gel, Hexane:EtOAc = 8:2) . mp: 48 °C; 1H NMR
(400 MHz, CDCl3): δ 1.28-1.37 (m, 6H), 4.19-4.31 (m, 4H), 4.52 (t, J = 4.8 Hz, 2H), 5.27
(d, J = 10.4 Hz, 1H), 5.39 (d, J = 17.2 Hz, 1H), 5.97-6.07 (m,1H), 6.90 (d, J = 8.8 Hz,
2H), 7.05 (d, J = 8.8 Hz, 2H), 8.41 (d, J = 14.0 Hz, 1H), 10.96 (d, J = 14.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3): δ 14.2, 14.3, 59.8, 60.1, 92.4, 115.7, 117.7, 118.6, 132.7, 132.8,
152.4, 156.0, 165.7, 169.0; IR (KBr): 516, 555, 758, 792, 945, 991, 1026, 1091, 1175,
Chapter II Experimental
60
1229, 1309, 1386, 1414, 1442, 1473, 1514, 1607, 1680, 2904, 2981, 3252 cm-1; Anal.
calcd. for C17H21NO5: C, 63.94; H, 6.63; N, 4.39; Found: C, 63.82; H, 6.55; N, 4.41.
Preparation of 4-Allyloxy-phenylamine (53c)
H2N O
The reaction was carried out according to Method B using 53b (0.500 g, 1.5 mmol),
ethylenediamine (418 μL, 6.2 mmol) and ethanol (2.5 mL). Conditions: room temperature,
1.30 h. The title compound 53c was obtained (0.21 g, 90%) after passing through a short
silica gel column (Hexane:EtOAc = 8:2). The spectral data of the compound 53c was in
agreement with the values reported in the literature.39
Preparation of 2-[(2-Benzyloxy-phenylamino)-methylene]-malonic acid diethyl ester
(53d)
NH OCH2CH3
O
OOCH2CH3
O
To a solution of 53a (0.500 g, 1.7 mmol) in chloroform (5 mL), K2CO3 (0.371 g, 2.6
mmol) was added, and stirred at room temperature for 1 h, followed by which benzyl
bromide (319 μL, 2.6 mmol) was added under nitrogen atmosphere. The reaction was
complete after 12 h stirring at room temperature; water (5 mL) was added and extracted
with chloroform (3 X 10 mL). The combined organic layer was dried (Na2SO4) and
evaporated under reduced pressure. The title compound 53d was obtained as a white solid
(0.60 g, 92%) after passing though column chromatography (silica gel, Hexane:EtOAc =
7:3) mp: 110 °C; 1H NMR (400 MHz, CDCl3): δ 1.29-1.39 (m, 6H), 4.20-4.32 (m, 4H),
5.04 (s, 2H), 6.96 (d, J = 9.2 Hz, 2H), 7.06 (d, J = 9.2 Hz, 2H), 7.32-7.42 (m, 5H), 8.43
(d, J = 13.6 Hz, 1H), 10.98 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.2,
14.3, 59.8, 60.1, 70.2, 92.4, 115.9, 118.6, 127.3, 127.9, 128.5, 132.8, 136.5, 152.4, 156.1,
165.7, 169.1; IR (KBr): 472, 521, 604, 700, 744, 796, 824, 870, 920, 996, 1090, 1121,
1171, 1223, 1309, 1339, 1381, 1413, 1441, 1476, 1511, 1608, 1679, 1979, 2983 cm-1;
Anal. calcd. for C21H23NO5: C, 68.28; H, 6.28; N, 3.79; Found: C, 68.15; H, 6.22; N,
3.79.
Chapter II Experimental
61
Preparation of 4-Benzyloxy-phenylamine (53e)
NH2
O
The reaction was carried out according to Method B using 53d (0.500 g, 1.3 mmol),
ethylenediamine (361 μL, 5.4 mmol) in ethanol (2.5 mL). Conditions: room temperature,
1.30 h. The title compound 53e (0.25 g, 95%) was obtained, after passing through a short
silica gel column (Hexane:EtOAc = 9:1). The data of the compound 53e was in agreement
with the values reported in the literature.39
Preparation of 2-[(4-Acetoxy-phenylamino)-methylene]-malonic acid diethyl ester
(53f)
NH OCH2CH3
O
OOCH2CH3
OO
To the solution of compound 53a (0.500 g, 1.7 mmol) and triethylamine (374 μL, 2.6
mmol) in chloroform (5 mL), acetyl chloride (190 μL, 2.6 mmol) was added under
nitrogen atmosphere. After stirring at room temperature for 30 min. water (5 mL) was
added and extracted with chloroform (3 X 10 mL). The combined chloroform layer was
dried (Na2SO4) evaporated under reduced pressure. The title compound 53f was obtained
as a white solid (0.56 g, 99%). mp: 64 °C; 1H NMR (400 MHz, CDCl3): δ 1.30-1.39 (m,
6H), 2.30 (s, 3H), 4.21-4.33 (m, 4H), 7.09-7.15 (m, 4H), 8.46 (d, J = 13.6 Hz, 1H), 11.02
(d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.2, 14.3, 20.9, 60.0, 60.3, 93.7,
118.0, 122.9, 136.9, 147.5, 152.0, 165.5, 168.9, 169.3; IR (KBr): 403, 490, 519, 592, 632,
799, 908, 1008, 1084, 1198, 1302, 1370, 1414, 1440, 1512, 1619, 1641, 1685, 1750, 2287,
2932, 2977, 3082 cm-1; ESIMS (TOF) [M+1]: 322.1; Anal. calcd. for C16H19NO6: C,
59.81; H, 5.96; N, 4.36; Found: C, 60.04; H, 6.01; N, 4.24.
Deprotection 2-[(4-Acetoxy-phenylamino)-methylene]-malonic acid diethyl ester (53f)
or Preparation (53a)
The reaction was carried out according to Method B using compound 53f (0.500 g, 1.5
mmol), ethylenediamine (416 μL, 6.2 mmol) and ethanol (2.5 mL). Conditions: room
Chapter II Experimental
62
temperature, 5 min. Compound 53a (0.41 g, 95%) was obtained after through a short silica
gel column chromatography (Hexane:EtOAc = 9:1).
Preparation of 2-[(4-Benzoyloxy-phenylamino)-methylene]-malonic acid diethyl ester
(53g)
NH OCH2CH3
O
OOCH2CH3
OO
To a solution of compound 53a (0.500 g, 1.7 mmol) and triethylamine (374 μL, 2.6 mmol)
in chloroform (5 mL), benzoyl chloride (311 μL, 2.6 mmol) was added under nitrogen
atmosphere. After stirring at room temperature 1.0 h, water (5 ml) was added and
extracted with chloroform (3 X 10 mL). The combined chloroform layer was dried
(Na2SO4) and evaporated under reduced pressure. The title compound 53g was obtained as
white solid (0.69g, 99%). mp: 79 °C; 1H NMR (400 MHz, CDCl3): δ 1.31-1.40 (m, 6H),
4.22-4.34 (m, 4H), 7.18-7.25 (m, 4H), 7.50-7.54 (m, 2H), 7.62-7.67 (m, 1H), 8.18-8.21
(m, 2H), 8.49 (d, J = 13.6 Hz, 1H), 11.05 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ 14.2, 14.3, 60.0, 60.3, 93.8, 118.1, 123.0, 128.5, 129.1, 130.1, 133.7, 137.0,
147.8, 152.0, 165.0, 165.5, 169.0 ; IR (KBr): 462, 526, 554, 708, 796, 870, 912, 1022,
1060, 1161, 1208, 1243, 1307, 1347, 1381, 1409, 1441, 1511, 1619, 1686, 1718, 2932,
2977 cm-1; Anal. calcd. for C21H21NO6: C, 65.79; H, 5.52; N, 3.65; Found: C, 65.68; H,
5.45; N, 3.50.
Preparation of Benzoic acid 4-amino-phenyl ester (53h)
NH2
O
O
The reaction was carried out according to Method B using compound 53g (0.500 g, 1.3
mmol), ethylenediamine (348 μL , 5.2 mmol) in ethanol (2.5 mL). Conditions: room
temperature 1 h. The title compound 53h was obtained passing through a short silica gel
column (Hexane:EtOAc = 9:1) (0.20 g, 75%). The data of the compound 53h was in
agreement with the values reported in the literature.40
Chapter II Experimental
63
Preparation of 2-[(2-Hydroxy-phenylamino)-methylene]-malonic acid diethyl ester
(54a)
NH OCH2CH3
O
OOCH2CH3OH
The reaction was carried out according to Method A using 2-aminophenol (54, 0.500 g,
4.5 mmol), diethyl ethoxymethylenemalonate (925 μL, 4.5 mmol) in ethanol (2.5 mL).
Conditions: room temperature, 15 min. The title compound 54a was obtained as a white
solid (1.26 g, 99%). mp: 139 °C; 1H NMR (400 MHz, DMSO-D6): δ 1.24-1.29 (m, 6H),
4.11-4.23 (m, 4H), 6.85-7.01 (m, 3H), 7.38-7.40 (d, J = 8 Hz, 1H), 8.52 (d, J = 14 Hz,
1H), 10.35 (s,1H) 11.01 (d, J = 14 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.1, 14.3,
60.3, 60.4, 92.5, 114.7, 116.0, 120.6, 125.0, 127.3, 146.3, 150.9, 166.7, 168.5; IR (KBr):
515, 591, 741, 809, 915, 981, 1038, 1092, 1214, 1313, 1397, 1469, 1524, 1578, 1632,
1661, 2717, 2767, 2979, 3157 cm-1; Anal. calcd. for C14H17NO5: C, 60.21; H, 6.14; N,
5.02; Found: C, 60.11; H, 6.26; N, 5.02.
Preparation of 2-[(2-Ethoxy-phenylamino)-methylene]-malonic acid diethyl ester
(54b)
NH OCH2CH3
O
OOCH2CH3O
To a solution of 54a (0.500 g, 1.7 mmol) in acetone (5 mL), K2CO3 (0.371 g, 2.6 mmol)
was added and stirred at room temperature for 1 h, later, ethyl bromide (200 μL, 2.6
mmol) was added and stirred at room temperature for 12 h. Acetone was evaporated under
reduced pressure, water (5 mL) was added and extracted with chloroform (3 X 10 mL).
The combined organic layers were dried (Na2SO4) and evaporated under reduced pressure.
The title compound 54b (0.54 g, 99%) was obtained as yellow solid. mp: 52 °C; 1H NMR
(400 MHz, CDCl3): δ 1.31-1.39 (m, 6H), 1.50 (t, J = 6.8 Hz, 3H), 4.14 (q, J = 7.2 Hz,
2H), 4.25 (q, J = 7.2 Hz, 2H), 4.33 (q, J = 7.2 Hz, 2H), 6.91-6.98 (m, 2H), 7.04-7.08 (m,
1H), 7.22-7.27 (m, 1H), 8.56 (d, J = 14 Hz, 1H), 11.13 (d, J = 14 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ 14.3, 14.3, 14.6, 59.9, 60.0, 64.4, 93.6, 112.3, 114.3, 121.0, 124.6, 128.9,
148.1, 150.3, 165.9, 168.2; IR (KBr): 562, 735, 813, 924, 987, 1041, 1095, 1116, 1227,
1263, 1338, 1381, 1425, 1506, 1581, 1613, 1644, 1685, 2897, 2932, 2980, 3241, 3413 cm-
Chapter II Experimental
64
1; Anal. calcd. for C16H21NO5: C, 62.53; H, 6.89; N, 4.56; Found: C, 62.26; H, 6.76; N,
4.42.
Preparation of 2-Ethoxy-phenylamine (54c)
NH2
O
The reaction was carried out according to Method B using compound 54b (0.500 g, 1.6
mmol), ethylenediamine (435 μL, 6.5 mmol) and ethanol (2.5 mL). Conditions: room
temperature, 15 min. The title compound 54c was obtained after passing through a short
silica gel column (Hexane:EtOAc = 8:2) (0.22 g, 99%). The data of the compound 54c
was in agreement with the values reported in the literature.41
Preparation of 2-[(2-Mercapto-phenylamino)-methylene]-malonic acid diethyl ester
(55a)
NH OCH2CH3
O
OOCH2CH3SH
55a
The reaction was carried out according to Method A using 2-aminothiophenol (55, 0.500
g, 3.9 mmol), diethyl ethoxymethylenemalonate (807 μL, 3.9 mmol) and ethanol (2.5 mL).
Conditions: room temperature, 20 min. The title compound 55a was obtained as a syrupy
liquid (1.1 g, 98%). Column chromatography (Hexane:EtOAc = 8:2); 1H NMR (200 MHz,
CDCl3): δ 1.26-1.50 (m, 6H), 4.21-4.36 (m, 4H), 6.94-7.41 (m, 4H), 8.36 (d, J = 14 Hz,
1H), 11.42 (d, J = 14 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.3, 14.4, 29.6, 60.2,
60.4, 95.5, 115.0, 124.3, 131.9, 137.3, 141.4, 149.7, 165.7, 167.7; IR (KBr): 458, 630,
752, 800, 861, 1024, 1094, 1157, 1250, 1306, 1370, 1418, 1447, 1478, 1584, 1611, 1655,
1736, 2904, 2933, 2980, 3064, 3370, 3468 cm-1; Anal. calcd. for C14H17NO4S: C, 56.93;
H, 5.80; N, 4.74; S, 10.86; Found: C, 60.34; H, 5.60; N, 4.11; S, 10.47.
Chapter II Experimental
65
Preparation of 2-[(2-Ethylsulfanyl-phenylamino)-methylene]-malonic acid diethyl
ester (55b)
NH OCH2CH3
O
OOCH2CH3S
To a solution of 55a (0.500 g, 1.6 mmol) in acetone (5 mL), K2CO3 (0.350 g, 2.5 mmol)
was added and stirred for 1 h, later ethyl bromide (189 μL, 2.5 mmol) was added and
stirred for 24 at room temperature, for the reaction to complete. Acetone was evaporated
under reduced pressure; water (5 mL) was added and extracted with chloroform (3 X 10
mL). The combined organic layers were dried (Na2SO4) and evaporated under reduced
pressure. The title compound 55b was obtained (0.46 g, 85%). Column chromatography
(Hexane:EtOAc = 8:2); 1H NMR (400 MHz, CDCl3): δ 1.13 (t, J = 7.6 Hz, 3H), 1.23-1.31
(m, 6H), 2.73 (q, J = 7.2 Hz, 2H), 4.17 (q, J = 7.2 Hz, 2H), 4.27 (q, J = 7.2 Hz, 2H), 6.97-
7.45 (m, 4H), 8.47 (d, J = 13.6 Hz, 1H), 11.46 (d, J = 14 Hz, 1H); 13C NMR (200 MHz,
CDCl3): δ 14.2, 14.3, 14.5, 29.5, 60.0, 60.2, 94.62, 114.4, 124.3, 129.4, 135.5, 140.7,
150.0, 165.8, 167.9; IR (KBr): 1582, 1608, 1656, 1691, 2928, 2978, 3079, 3362, 3463 cm-
1; Anal. calcd. for C16H21NO4S: C, 59.42; H, 6.54; N, 4.33; S, 9.91 Found: 59.42; H, 6.92;
N, 3.97; S, 9.56.
Preparation of 2-Ethylsulfanyl-phenylamine (55c)
NH2
S
The reaction was carried out according to Method B using 55b (0.500 g, 1.5 mmol),
ethylenediamine (413 μL, 6.1 mmol) and ethanol (2.5 mL). Conditions: room temperature,
2 h. The title compound 55c (0.22 g, 98%) was obtained after purification through column
chromatography (silica gel, Hexane:EtOAc = 7:3). The data of the compound 55c was in
agreement with the values reported in the literature.42
Chapter II Experimental
66
Preparation of 2-[(4-Carboxy-phenylamino)-methylene]-malonic acid diethyl ester
(56a)
NH OCH2CH3
O
OOCH2CH3
HOOC
The reaction was carried out according to Method A using 4-aminobenzoic acid (56, 0.500
g, 3.6 mmol), diethyl ethoxymethylenemalonate (843 μL, 3.6 mmol) and ethanol (2.5 mL).
Conditions: room temperature, 4.30 h. The title compound 56a was obtained as a white
solid (1.10 g, 99%) after purification through column chromatography (silica gel,
Hexane:EtOAc = 9:1). mp: 221 °C; 1H NMR (400 MHz, DMSO-D6): δ 1.26 (q, J = 6.8
Hz, 6H), 4.12-4.25 (m, 4H), 7.46 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 8.8 Hz, 2H), 8.44 (d, J =
13.6 Hz, 1H), 10.73 (d, J = 13.6 Hz, 1H), 12.85 (brs, 1H); 13C NMR (100 MHz, DMSO-
D6): δ 14.3, 14.4, 59.8, 60.0, 95.3, 117.1, 126.4, 131.2, 143.2, 150.0, 164.9, 166.9, 167.1;
IR (KBr): 548, 766, 807, 855, 927, 1025, 1098, 1122, 1179, 1239, 1372, 1416, 1447,
1480, 1570, 1594, 1640, 1683, 2545, 2684, 2906, 2985, 3084, 3172, 3265, 3430 cm-1;
Anal. calcd. for C15H17NO6: C, 58.63; H, 5.58; N, 4.56; Found: C, 58.62; H, 5.56; N, 4.46.
Preparation of 2-[(4-Allyloxycarbonyl-phenylamino)-methylene]-malonic acid diethyl
ester (56b)
NH OCH2CH3
O
OOCH2CH3
O
O
To a solution of 56a (0.500 g, 1.6 mmol) in acetone (5 mL), K2CO3 (0.337 g, 2.4 mmol)
was added and stirred at room temperature for 1 h, followed by which allyl bromide (211
μL, 2.4 mmol) was added under nitrogen atmosphere. After 36 h of stirring at room
temperature, acetone was evaporated under reduced pressure; water (5 mL) was added and
extracted with of chloroform (3 X 10 mL). The combined organic layer was dried
(Na2SO4) and evaporated under reduced pressure. The title compound 56b was obtained as
white solid (0.58 g, 85%) after purification through column chromatography
(Hexane:EtOAc = 8:2); mp: 48 °C; 1H NMR (400 MHz, CDCl3): δ 1.32-1.40 (m, 6H),
4.24-4.34 (m, 4H), 4.80-4.83 (m, 2H), 5.28-5.43 (m, 2H), 6.00-6.07 (m, 1H), 7.18 (d, J =
8.8 Hz, 2H), 8.09 (d, J = 8.8 Hz, 2H), 8.54 (d, J = 13.6 Hz, 1H), 11.10 (d, J = 13.6 Hz,
1H); 13C NMR (100 MHz, CDCl3): δ 14.1, 14.3, 60.3, 60.6, 65.5, 95.4, 116.1, 118.3,
Chapter II Experimental
67
126.0, 131.6, 132.1, 142.9, 150.5, 165.3, 168.7; IR (KBr): 513, 612, 688, 764, 802, 850,
925, 976, 1025, 1094, 1168, 1240, 1363, 1412, 1443, 1472, 1594, 1636, 1681, 2901, 2938,
2983, 3143 cm-1; LCMS (TOF): Found [M+1]: 348.2; Anal. calcd. for C18H21NO6: C,
62.24; H, 6.09; N, 4.03; Found: 62.61; H, 6.39; N, 4.37.
Preparation of 4-Amino-benzoic acid allyl ester (56c)
NH2
OO
The reaction was carried out according to Method B using 56b (0.500 g, 1.4 mmol),
ethylenediamine (384 μL, 5.7 mmol) in ethanol (2.5 mL). Conditions: room temperature, 2
h. The title compound 56c (0.22 g, 90%) was obtained after passing through a short silica
gel column (Hexane:EtOAc = 9:1). The data of the compound 56c was in agreement with
the values reported in the literature.43
Preparation of 2-[(4-Methoxycarbonyl-phenylamino)-methylene]-malonic acid
diethyl ester (56d)
NH OCH2CH3
O
OOCH2CH3
O
O
To a solution of 56a (0.500 g, 1.6 mmol) in acetone (5 mL), K2CO3 (0.337 g, 2.4 mmol)
was added and stirred at room temperature for 1 h, methyl iodide (151 μL, 2.4 mmol) was
added. After stirring at room temperature for 2 h, acetone was evaporated under reduced
pressure; water (5 mL) was added and extracted with chloroform (3 X 10 mL). The
combined organic layers were dried (Na2SO4) evaporated under reduced pressure. The title
compound 56d was obtained as a white solid (0.51 g, 98%). mp: 80 °C; 1H NMR (400
MHz, CDCl3): δ 1.24-1.32 (m, 6H), 3.83 (s, 3H), 4.15-4.26 (m, 4H), 7.08 (d, J = 8.8 Hz,
2H), 7.97 (d, J = 8.8 Hz, 2H), 8.45 (d, J = 13.2 Hz, 1H), 11.01 (d, J = 13.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3): δ 14.1, 14.3, 52.0, 60.2, 60.5, 95.4, 116.1, 126.0, 131.1, 131.4,
131.5, 142.8, 150.4, 165.3, 166.1, 168.6; IR (KBr): 548, 766, 807, 855, 927, 1025, 1098,
1122, 1179, 1239, 1372, 1416, 1447,1480, 1570, 1594, 1640, 1683, 2545, 2684, 2906,
Chapter II Experimental
68
2985, 3084, 3172, 3265, 3430 cm-1; Anal. calcd. for C16H19NO6: C, 59.81; H, 5.96; N,
4.36; Found: C, 59.61; H, 5.98; N, 4.34
Preparation of 4-Amino-benzoic acid methyl ester (56e)
NH2
COOCH3
The reaction was carried out according to Method B using 56d (0.500 g, 1.5 mmol),
ethylenediamine (416 μL, 6.2 mmol) in ethanol (2.5 mL). Conditions: room temperature,
2.15 h. The title compound 56e (0.22 g, 95%) was obtained after passing through a short
silica gel column (Hexane;EtOAc = 7:3). The data of the compound 56e was in agreement
with the values reported in the literature.39
Preparation of 2-[(2-Carboxy-phenylamino)-methylene]-malonic acid diethyl ester
(57a)
NH OCH2CH3
O
OOCH2CH3COOH
The reaction was carried out according to Method A using 2-aminobenzoic acid (57, 0.500
g, 3.6 mmol), diethyl ethoxymethylenemalonate (843 μL, 3.6 mmol). Conditions: room
temperature, 5.0 h. The title compound 57a was obtained as a white solid (1.10 g, 98%).
mp: 146 °C; 1H NMR (400 MHz, CDCl3): δ 1.33-1.39 (m, 6H), 4.29 (q, J = 7.2 Hz, 2H),
4.38 (q, J = 7.2 Hz, 2H), 7.15 (t, J = 7.2 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.61 (t, J = 7.2
Hz, 1H), 8.16 (dd, J1 = 1.2 Hz, J2 = 8.0 Hz, 1H), 8.60 (d, J = 13.6 Hz, 1H), 10.70 (brs,
1H), 12.57 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.3, 14.3, 60.4, 60.5,
96.8, 115.1, 115.8, 123.1, 132.7, 135.2, 142.2, 149.1, 166.3, 166.7, 170.9; IR (KBr): 482,
578, 648, 672, 755, 792, 866, 917, 997, 1024,1095, 1147, 1246, 1307, 1352, 1382, 1425,
1501, 1567, 1611, 1638, 1680, 1716, 2904, 2935, 2987, 3105, 3221 cm-1; Anal. calcd. for
C15H17NO6: C, 58.63; H, 5.58; N, 4.56; Found: C, 58.54; H, 5.62; N, 4.36.
Chapter II Experimental
69
Preparation of 2-[(2-Methoxycarbonyl-phenylamino)-methylene]-malonic acid
diethyl ester (57b)
NH OCH2CH3
O
OOCH2CH3
OO
To the solution of 57a (0.500 g, 1.6 mmol) in acetone (5 mL), K2CO3 (0.337 g, 2.4 mmol)
was added and stirred at room temperature for 1 h, followed by which methyl iodide (151
μL, 2.3 mmol) was added under nitrogen atmosphere. After 2 h stirring at room
temperature acetone in reaction mixture was evaporated under reduced pressure, then
water (5 mL) was added and extracted with chloroform (3 X 10 mL). The combined
organic layers were dried (Na2SO4) and evaporated under reduced pressure. The title
compound 57b was obtained as white solid (0.51 g, 98%). mp.: 40 °C; 1H NMR (400
MHz, CDCl3): δ 1.32-1.40 (m, 6H), 3.99 (s, 3H), 4.27 (q, J1 = 7.2 Hz, 2H), 4.40 (q, J =
7.2 Hz, 2H), 7.12-7.16 (m, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.55-7.59 (m, 1H), 8.07 (dd, J1 =
1.6 Hz, J2 = 7.6 Hz, 1H), 8.60 (d, J = 13.6 Hz, 1H), 12.71 (d, J = 13.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ 00.92, 14.2, 14.3, 52.5, 60.2, 60.3, 96.5, 114.9, 116.7, 123.0, 131.9,
134.4, 141.6, 149.2, 166.0, 167.0, 167.1; IR (KBr): 460, 575, 690, 756, 818, 979, 1026,
1092, 1229, 1279, 1328, 1389, 1423, 1461, 1588, 1652, 1686, 1726, 2854, 2909, 2983,
3218, 3420 cm-1; Anal. calcd. for C16H19NO6: C, 59.81; H, 5.96; N, 4.36; Found: C,
59.80; H, 5.92; N, 4.29.
Preparation of 2-Amino-benzoic acid methyl ester [57c]
NH2
H3COOC
57c
The reaction was carried out according to Method B using 57b (0.500 g, 1.5 mmol),
ethylenediamine (416 μL, 6.2 mmol). Conditions: room temperature, 2.30 h. The title
compound 57c (0.22 g, 96%) was obtained after through a short silica gel column
(Hexane:EtOAc = 7:3). The spectral for the title compound 57c was in agreement with the
values reported in the literature.44
Chapter II Experimental
70
Selective protection, functional group interconversion and deprotecion of aliphatic
amines
Preparation of 2-[(1-Hydroxymethyl-propylamino)-methylene]-malonic acid diethyl
ester (58a)
H3C OHHN H
OH3CH2CO
O
H3CH2CO
The reaction was carried out according to Method A using (S)-(+)-2-amino-1-butanol (58,
0.500 g, 5.6 mmol), diethyl ethoxymethylenemalonate (1.13 mL, 5.6 mmol). Conditions:
room temperature, 30 min. The title compound 58a was obtained as a syrupy liquid (1.42
g, 98%). 1H NMR (400 MHz, CDCl3): δ 0.97 (t, J = 7.2 Hz, 3H), 1.26-1.35 (m, 6H), 1.51-
1.71 (m, 2H), 3.20-3.26 (m, 2H), 3.57-3.74 (m, 2H), 4.13-4.25 (m, 4H), 8.05 (d, J = 14.4
Hz, 1H), 9.14 (dd, J1 = 9.2 Hz, J2 = 13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 10.2,
14.2, 14.2, 24.5, 59.5, 59.7, 63.7, 64.7, 89.2, 159.7, 166.3, 169.3; IR (KBr): 465, 547, 674,
751, 805, 1030, 1074,1148, 1248, 1316, 1379, 1424, 1463, 1608, 1656, 1693, 2876, 2935,
2974, 3276, 3375, 3451 cm-1; [α]20D = -39.02 (c 1.00, CHCl3); Anal. calcd. for
C12H21NO5: C, 55.58; H, 8.16; N, 5.40. Found: C, 51.01, H, 8.0, N, 5.35.
Preparation of 2-[(1-Benzoyloxymethyl-propylamino)-methylene]-malonic acid
diethyl ester (59)
H3C OHN H
OH3CH2CO
O
H3CH2CO
O
To a solution of 58a (0.500 g, 1.9 mmol) in chloroform (5 mL), triethylamine (403 μL, 2.8
mmol), benzoyl chloride (335 μL, 2.8 mmol) was add under nitrogen atmosphere. After
stirring at room temperature for 1 h, water was added and extracted with chloroform (3 X
10 mL). The combined chloroform layer was dried (Na2SO4) and evaporated under
reduced pressure. The title compound 59 (0.69 g, 99%) was obtained as a syrupy liquid.
The reaction mixture was purified by column chromatography (silica gel, Hexane:EtOAc
= 8:2). 1H NMR (400 MHz, CDCl3): δ 1.05 (t, J = 7.2 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H),
Chapter II Experimental
71
1.34 (t, J = 6.8 Hz, 3H), 1.67-1.78 (m, 2H), 3.55-3.57 (m, 2H), 4.13-4.27 (m, 5H), 4.44
(dd, J1 = 4.0 Hz, J2 = 11.6 Hz, 1H), 7.38-7.59 (m, 3H), 8.01 (dd, J1 = 1.2 Hz, J2 = 3.2 Hz,
4H), 8.10 (d, J = 14 Hz, 1H), 9.26 (dd, J1 = 9.2 Hz, J2 = 12.8 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ 10.1, 14.2, 14.2, 24.8, 59.5, 59.8, 60.5, 66.5, 90.1, 126.1, 128.3, 129.3,
129.5, 133.2, 159.5, 165.7, 166.0, 169.2; IR (KBr):1606, 1651, 1687, 1720, 2936, 2975,
3267 cm-1; [α]20D = +112.45 (c 1.00, CHCl3); LCMS (TOF): Found: [M+1] 364.1; Anal.
calcd. for C19H25NO6: C, 62.80; H, 6.93; N, 3.85; Found: C, 62.87, H, 6.91, N, 3.79.
Preparation of Benzoic acid 2-amino-butyl ester (59a)
H3C OH2N H
O
The reaction was carried out according to Method B using 59 (0.500 g, 1.3 mmol),
ethylenediamine (367 μL, 5.5 mmol). Conditions: room temperature, 1 h. The title
compound 59a (0.24 g, 94%) was obtained as a solid after purification through column
chromatography (silica gel, Hexane:EtOAc = 3:7). The data of the compound 57c was in
agreement with the values reported in the literature.45
Preparation of 2-[(1-Acetoxymethyl-propylamino)-methylene]-malonic acid diethyl
ester (60)
H3C OHN H
OH3CH2CO
O
H3CH2CO
O
CH3
To the solution of 58a (0.500 g, 1.9 mmol) in chloroform (5 mL), triethylamine (403 μL,
2.8 mmol), acetyl chloride (205 μL, 2.8 mmol) was add under nitrogen atmosphere. After
1 h stirring at room temperature, water (10 mL) was added and extracted with chloroform
(3 X 10 mL). The combined chloroform layer was dried (Na2SO4) and evaporated under
reduced pressure. The title compound 60 was obtained as a syrupy liquid with (0.57 g,
99%) after purification through column chromatography (silica gel, Hexane:EtOAc = 8:2). 1H NMR (400 MHz, CDCl3): δ 1.00 (t, J = 7.6 Hz, 3H), 1.27-1.36 (m, 6H), 1.56-1.73 (m,
2H), 2.08 (s, 3H), 3.40-3.45 (m, 1H), 4.05-4.27 (m, 6H), 8.01 (d, J = 14 Hz, 2H), 9.14 (dd,
J1 = 9.6 Hz, J2 = 12.0 Hz, 1H); IR (KBr): 1608, 1652, 1687, 1744, 2976, 3270 cm-1; 13C
Chapter II Experimental
72
NMR (100 MHz, CDCl3): δ 10.0, 14.1, 14.2, 20.5, 24.7, 59.5, 59.7, 60.4, 65.9, 159.3,
166.0, 169.1, 170.5; [α]20D = +47.63 (c 1.00, CHCl3); Anal. calcd. for C14H23NO6: C,
55.80; H, 7.69; N, 4.65; Found: C, 55.82, H, 7.61, N, 4.74.
Deprotection of 2-[(1-Acetoxymethyl-propylamino)-methylene]-malonic acid diethyl
ester (60) or Preparation of compound (58a)
The reaction was carried out according to Method B using 60 (0.500 g, 1.6 mmol),
ethylenediamine (443 μL, 6.6 mmol). Conditions: room temperature, 1 h. The reaction
work up gave raise to the starting material 58a (0.30 g, 70%). For spectral data see the
experiment for preparation of 58a.
Preparation 2-[(1-Ethoxymethyl-propylamino)-methylene]-malonic acid diethyl ester
(61)
H3C OHN H
OH3CH2CO
O
H3CH2CO
CH3
To a solution of 58a (0.500 g, 1.9 mmol) in N,N-Dimethylformamide (5 mL), sodium
hydride (0.069 g, 2.8 mmol) was added at 0 ºC and stirred for 30 min. followed by which
ethyl bromide (215 μL, 2.9 mmol) was added under nitrogen atmosphere. After stirring for
24 h at room temperature, water was added and extracted with ethyl acetate (3 X 10 mL).
The combined chloroform layer was dried (Na2SO4) and evaporated under reduced
pressure. The title compound 61 was obtained as a syrupy liquid (0.38 g, 70%) after
purification through column chromatography (Hexane:EtOAc = 8:2). 1H NMR (400 MHz,
CDCl3): δ 0.89 (t, J = 7.6 Hz, 3H), 0.97 (t, J = 7.6 Hz, 3H), 1.25-1.36 (m, 6H), 1.50-1.68
(m, 2H), 3.35-3.50 (m, 6H), 4.15-4.27 (m, 4H), 8.06 (d, J = 14.4 Hz, 1H), 9.17 (dd, J1 =
8.4 Hz, J2 = 14.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 10.3, 13.8, 14.3, 14.4, 19.2,
25.0, 29.6, 31.5, 59.4, 59.6, 61.6, 71.3, 73.0, 89.2, 159.7, 166.2, 169.3; IR (KBr): 1606,
1652, 1068,1151, 1245, 2870 cm-1; [α]20D = +2.83 (c 1.00, CHCl3); Anal. calcd. for
C14H25NO5: C, 58.52; H, 8.77; N, 4.87; Found: C, 58.29; H, 8.82; N, 4.59.
Chapter II Experimental
73
Preparation of 1-Ethoxymethyl-propylamine (61a)
H3C OH2N H
CH3
The reaction was carried out according to Method B using 61 (0.500 g, 1.7 mmol),
ethylenediamine (465 μL, 6.9 mmol). Conditions: room temperature, 1 h. The title
compound 61a (0.18 g, 90%) was obtained after purification through a short silica gel
column (Hexane:EtOAc = 3:7). The data of the compound 61a was in agreement with the
values reported in the literature.46
Preparation of 2-[(1-Carboxy-2-phenyl-ethylamino)-methylene]-malonic acid diethyl
ester (62a)
HN
COOH
O
OEt
O
OEt
To the solution of (L)-Phenylalanine (62, 0.500 g, 3.0 mmol) in ethanol (5 mL),
triethylamine (421 μL, 3.0 mmol), was added and stirred at room temperature for 10 min.
diethyl ethoxymethylenemalonate (611 μL, 3.0 mmol) was added and stirred for 30 min. at
room temperature, the reaction mixture was neutralized with acetic acid, water (5 mL) was
added and extracted with ethyl acetate (3 X 10 mL). The combined ethyl acetate layer was
dried (Na2SO4) and evaporated under reduced pressure. The title compound 62a was
obtained as a syrupy liquid (0.97 g, 96%). 1H NMR (400 MHz, CDCl3): δ 1.13-1-20 (m,
6H), 3.03-3.21 (m, 2H), 3.96-4.11 (m, 4H), 4.63-4.68 (m, 1H), 7.17-7.31 (m, 5H), 7.79 (d,
J = 14 Hz, 1H), 9.18 (dd, J1 = 8.8 Hz, J2 = 14.4 Hz, 1H); 13C NMR (100 MHz, DMSO-
D6): δ 14.2, 14.4, 14.5, 20.9,58.9, 59.1, 59.9, 61.5, 89.5, 127.0, 128.6, 129.6, 136.3, 158.9,
165.1, 167.9, 172.1; IR (KBr): 439, 487, 539, 588, 619, 663, 699, 725, 799, 855, 917,
1030, 1058, 1113, 1180, 1333, 1387, 1404, 1439, 1477, 1497, 1512, 1620, 1650, 1719,
2985, 3082 cm-1; [α]20D = -225.79 (c 1.00, CHCl3); Anal. calcd. for C17H21NO6: C, 60.89;
H, 6.31; N, 4.18; Found: C, 60.37; H, 6.12; N, 4.22.
Chapter II Experimental
74
Preparation of 2-[(1-Carboxy-3-methyl-butylamino)-methylene]-malonic acid diethyl
ester (63a)
HN
COOH
O
OEt
O
OEt
To the solution of (L)-Leucine (63, 0.500 g, 3.8 mmol) in ethanol (5 mL), triethylamine
(531 μL, 3.8 mmol) was added and stirred at room temperature for 10 min. diethyl
ethoxymethylenemalonate (770 μL, 3.8 mmol) was added and stirred for 30 min. at room
temperature. The reaction mixture was neutralized with acetic acid, water (5 mL) was
added and extracted with ethyl acetate (3 X 10 mL), the combined ethyl acetate layers was
dried (Na2SO4) and evaporated under reduced pressure. The title compound 63a was
obtained as a syrupy liquid with (1.09 g, 96%). 1H NMR (400 MHz, CDCl3): δ 0.96 (t, J =
7.2 Hz, 6H), 1.26-1.35 (m, 6H), 1.72- 1.79 (m, 2H), 4.0-4.27 (m, 5H), 7.97 (d, J = 14 Hz,
1H), 9.32 (dd, J1 = 8.8 Hz, J2 = 14.0 Hz,1H); 13C NMR (100 MHz, CDCl3): δ 14.2, 14.3,
21.4, 22.7, 24.4, 41.7, 60.4, 91.0, 159.0, 166.7, 168.9, 174.5, 174.5; IR (KBr): 441, 563,
737, 801, 1028, 1069, 1148, 1219, 1373, 1604, 1655, 1721, 2360, 2959 cm-1; [α]20D = -
33.28 (c 1.00, CHCl3); Anal. calcd. for C14H23NO6: C, 55.80; H, 7.69; N, 4.65; O, 31.86;
Found: C, 55.92; H, 7.74; N, 4.34.
Preparation of 2-[(1-Carboxy-3-methylsulfanyl-propylamino)-methylene]-malonic
acid diethyl ester (64a)
HN
COOH
O
OEt
O
OEt
S
64a
To the solution of (L)-Methionine (64, 0.500 g, 3.3 mmol) in ethanol (5 mL),
triethylamine (467 μL, 3.3 mmol), was added and stirred at room temperature for 10 min.
diethyl ethoxymethylenemalonate (677 μL, 3.3 mmol) was added and stirred for 30 min. at
room temperature. The reaction mixture was neutralized with acetic acid, water (5 mL)
was added and extracted with ethyl acetate (3 x 10 mL), the combined ethyl acetate layers
was dried (Na2SO4) and evaporated under reduced pressure. The title compound 64a was
obtained as a syrupy liquid (0.96 g, 96%). 1H NMR (400 MHz, CDCl3): δ 1.17-1.28 (m,
Chapter II Experimental
75
6H), 2.03 (s, 3H), 2.16-2.20 (m, 1H), 2.43-2.61 (s, 3H), 4.104.27 (m, 5H), 7.95 (d, J = 14
Hz, 1H) 9.30 (dd, J1 = 8.8 Hz, J2 = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.0,
14.1, 15.0, 29.5, 31.7, 59.6, 60.1, 91.2, 159.1, 166.6, 168.8, 173.6; IR (KBr): 1609, 1659,
1736, 2924, 2981, 3274, 3364, 3463 cm-1; [α]20D = -105.03 (c 1.00, CHCl3); Anal. calcd.
for C13H21NO6S: C, 48.89; H, 6.63; N, 4.39; S, 10.04; Found: C, 48.92; H, 6.90; N, 4.18;
S, 10.26.
Preparation of 2-[(1-Methoxycarbonyl-2-phenyl-ethylamino)-methylene]-malonic
acid diethyl ester (62b)
HN
COOCH3
O
OEt
O
OEt
To a solution of 62a (0.500 g, 1.4 mmol) in methanol (5 mL), thionyl chloride (135 μL,
1.8 mmol) was added, stirred for 30 min. at room temperature. Neutralized with 5%
aq.NaHCO3, extracted with ethyl acetate (3 X 10 mL). The combined organic layers were
dried (NaSO4) and evaporated under reduced pressure. The title compound 62b was
obtained (0.51 g, 98%) as a syrupy liquid. 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J = 7.2
Hz, 3H), 1.32 (t, J = 6.8 Hz, 3H), 3.00-3.25 (m, 2H), 3.76 (s, 3H), 4.08-4.26 (m, 5H),
7.12-7.32 (m, 5H), 7.63 (d, J = 13.6 Hz, 1H), 9.38 (dd, J1 = 9.2 Hz, J2 = 13.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3): δ 14.0, 14.1, 14.2, 20.8, 39.9, 52.5, 59.7, 60.1, 63.0, 91.2,
127.3, 128.6, 129.2, 134.8, 158.0, 165.5, 168.4, 170.2, 170.9; IR (KBr): 1607, 1654, 1690,
1745, 2981, 3274 cm-1; [α]20D = -104.3 (c 1.00, CHCl3); Anal. calcd. for C18H23NO6: C,
61.88; H, 6.64; N, 4.01; Found: C, 61.59; H, 6.60; N, 4.12.
Preparation of 2-Amino-3-phenyl-propionic acid methyl ester (62c)
NH2
COOCH3
The reaction was carried out according to Method B using 62b (0.500 g, 1.4 mmol),
ethylenediamine (382 μL, 5.7 mmol). Conditions: room temperature, 2.30 h. The title
compound 62c (0.23 g, 90%) was obtained after purification through a short silica gel
column (Hexane:EtOAc = 4:6). The spectral data of the compound 62c is in agreement
with authentic sample available from commercial sources.
Chapter II Experimental
76
Preparation of 2-[(1-Methoxycarbonyl-3-methyl-butylamino)-methylene]-malonic
acid diethyl ester (63b)
HN
COOCH3
O
OEt
O
OEt
To a solution of 63a (0.500 g, 1.6 mmol) in methanol (5 mL), thionyl chloride (151 μL,
2.0 mmol) was added and stirred for 30 min. at room temperature. Neutralized with 5%
aq.NaHCO3, extracted with ethyl acetate (3 X 10 mL). The combined organic layer was
dried (Na2SO4) and evaporated under reduced pressure. The title compound 63b was
obtained (0.49 g, 95%) as a syrupy liquid. 1H NMR (400 MHz, CDCl3): δ 1.89 (t, J = 7.2
Hz, 6H), 1.25-1.36 (m, 6H), 1.65-1.75 (m, 3H), 3.77 (s, 3H), 3.99-4.05 (m, 1H), 4.16-4.28
(m, 4H), 7.93 (d, J = 14 Hz, 1H) 9.31 (dd, J1 = 9.6 Hz, J2 = 13.2 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ 14.2, 14.2, 21.4, 22.6, 24.3, 41.9, 52.5, 59.6, 59.8, 60.3, 91.1, 158.4,
165.8, 168.7, 171.4; IR (KBr): 470, 551, 748, 800, 859, 914, 1029, 1067, 1148, 1217,
1318, 1375, 1431, 1604, 1645, 1686, 1743, 2957 cm-1; [α]20D = -23.44 (c 1.00, CHCl3);
Anal. calcd. for C15H25NO6: C, 57.13; H, 7.99; N, 4.44; Found: C, 57.23; H, 7.78; N, 4.52.
Preparation of 2-Amino-4-methyl-pentanoic acid methyl ester (63c)
NH2
COOCH3
The reaction was carried out according to Method B using 63b (0.500 g, 1.5 mmol),
ethylenediamine (423 μL, 6.3 mmol). Conditions: room temperature, 2.15 h. The title
compound 63c (0.20 g, 90%) was obtained after passing through a short silica gel column
(Hexane:EtOAc = 4:6). The spectral data of the compound 63c was in agreement with
authentic sample available from commercial sources.
Chapter II Experimental
77
Preparation of 2-[(1-Methoxycarbonyl-3-methylsulfanyl-propylamino)-methylene]-
malonic acid diethyl ester [64b]
HN
COOCH3
O
OEt
O
OEt
S
To the solution of 64a (0.500 g, 1.5 mmol) in methanol (5 mL), thionyl chloride (142 μL,
1.9 mmol) was added, stirred for 30 min. at room temperature. Neutralized with 5%
aq.NaHCO3, extracted with ethyl acetate (3 X 10 mL). The combined organic layers were
dried (Na2SO4) and evaporated under reduced pressure. The title compound 64b was
obtained (0.49 g, 95%) as a syrupy liquid. 1H NMR (400 MHz, CDCl3): δ 1.20-1.30 (m,
6H,), 2.03 (s, 3H), 2.10-2.18 (m, 1H), 2.40-2.59 (m, 2H), 3.72 (s, 3H), 4.09-4.22 (m, 4H),
7.90 (d, J = 13.6 Hz, 1H), 9.29 (dd, J1 = 10.0 Hz, J2 = 12.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ 14.2, 14.3, 15.2, 29.5, 32.1, 52.8, 59.8, 60.0, 60.0, 91.7, 158.6, 165.7, 168.8,
170.9; IR (KBr): 1607, 1656, 1689, 1743, 2931, 2981, 3274, 3369, 3463 cm-1; [α]20D = -
23.88 (c 1.00, CHCl3); Anal. calcd. for C14H23NO6S: C, 50.43; H, 6.95; N, 4.20; S, 9.62;
Found: C, 50.72; H, 6.65; N, 4.18; S, 9.46.
Preparation of 2-Amino-4-methylsulfanyl-butyric acid methyl ester (64c)
NH2
COOCH3S
The reaction was carried out according to Method B using 64b (0.500 g, 1.4 mmol),
ethylenediamine (401 μL, 5.9 mmol). Conditions: room temperature, 2.15 h. The title
compound 64c (0.22 g, 90%) was obtained after purification through a short silica gel
column (Hexane:EtOAc = 4:6). The spectral data of the compound 64c was in agreement
with authentic sample available from commercial sources.
Chapter II Reference
78
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