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CHAPTER-3
Development and Application of New Methodologies for Synthesis of Bioactive Molecules176
3.1 INTRODUCTION:
3.2 LITERATURE SURVEY:
3.3 OBJECTIVE OF THE WORK:
3.4 DESIGN AND DEVELOPMENT:
3.5 EXPERIMENTAL:
3.6 RESULT AND DISCUSSION:
3.6.1 Mechanism:
3.7 APPLICATION:
3.8 SUMMERY AND CONCLUSION:
3.9 REFERENCES:
3.10 SPECTRA:
CHAPTER-3
Development and Application of New Methodologies for Synthesis of Bioactive Molecules177
3.1 INTRODUCTION:
The first synthetic dye discovered by Perkin, an English scientist working under
Hoffman, a German professor and even today the geographical focus of dye
production lies in Germany (BASF, Dystar), England (Avecia) and Switzerland
(Clariant, Ciba Specialties). Far Eastern countries, such as Japan, Korea and Taiwan,
as well as countries such as India, Brazil and Mexico also produce dyes.1
Dyes may be classified according to their chemical structure or by their usage or
application method. The former approach is adopted by practicing dye chemists, who
use terms such as azo dyes, anthraquinone dyes, triphenylmethane dyes and
phthalocyanine dyes. The later approach is used predominantly by the dye users, the
dye technologists, who speak of reactive dyes for cotton and dispersed dyes for
polyester. Very often, both terminologies are used, for example, an azo dispersed dye
for polyester and a phthalocyanine reactive dye for cotton.1
Triphenylmethane derivatives are hydrocarbons with the formula (R1-Ar-R2)3CH,
where R1 and R2 indicate different substituents, including hydrogen, halogen, alkyl
and alkoxy groups.1 The most important substituent is the amino group which is
present in diaminotriphenylmethane (DTM) compounds. Important dyes belonging to
this class include the well-known Leucomalachite Green and Crystal Violet, which are
some of the oldest synthetic dyes (Figure 1).1-2
Figure 1: Two examples of diaminotriphenylmethane (DTM) compounds
CHAPTER-3
Development and Application of New Methodologies for Synthesis of Bioactive Molecules178
The leuco forms of triarylmethane dyes are extensively used in biological
applications. They show photo toxicity toward tumor cells3 and also demonstrate
antifungal4a-c antitubercular5 anti-infective, and antimicrobial activity.6 Additionally,
they have been used for sterilization of trypanosome cruizi-infected blood,7a-b in
biotechnology process control,8-9 in dye-assisted laser inactivation of enzymes,10 in
wastewater treatment plants,11 and in the photo chemotherapy of neoplastic
diseases.12-14 In analytical chemistry, they are used as indicators in calorimetric and
titrimetric determinations,15 in detection of various heavy metals,16 and for the
detection of iodide17 and carboxylic acids.18 Diaminotriphenylmethane (DTM) dyes
are the most important group of triarylmethane dyes and were selected for the present
study due to their brilliance, high pictorial strength, and wide variety of applications.
Such as pressure-sensitive heat-sensitive materials, high-speed photo duplicating
copying paper, light-sensitive paper, ultrasonic recording paper, electrochemical heat-
sensitive recording paper, inks, crayons, typewriter ribbons, and photoimaging
systems.19 analysis of biological fluids, and wastewater treatment.20
Furthermore, they have particular structural properties in solid and solution phases.
This group includes a broad range of dyes such as Cresol Red, Bromocresol Green,
Light Green SF Yellowish, Victoria Blue BO, Ethyl Green, Brilliant Green,
Diaminotriphenylmethane, Fast Green FCF, Green S, Fuchsine Acid, Chlorophenol
Red, Crystal Violet Lactone, Fuchsine, Pararosaniline, Water Blue, Thymolphthalein,
Bromocresol Purple, and Aurin. (Figure 2) These compounds are usually soluble in
non-polar organic solvents and are insoluble in water.
CHAPTER-3
Development and Application of New Methodologies for Synthesis of Bioactive Molecules179
Figure 2
Because of the wide range of applications of DTMs, the development of new and
more efficient synthetic methods for their preparation is of great importance.
CHAPTER-3
Development and Application of New Methodologies for Synthesis of Bioactive Molecules180
3.2 LITERATURE SURVEY:
A wide range of approaches are available for the preparation of the aforementioned
compounds. Dyes has great influence in the field of chemistry as diagnostic agents,
colour forming agents, indicator in titration reaction, in paint and pigment industries
and high tech application as in solar cells.
1) Ceric (IV) Ammonium Nitrate Catalyzed Synthesis of 4,4′-
Diaminotriarylmethane
Bardajee, G. R and et. Al. have been reported, one step synthesis of 4,4′-
dimethylaminotriarylmethanes in the presence of ceric(IV) ammonium nitrate as a
Lewis acid catalyst. The entitled compounds were prepared by the tandem regio-
selective electrophilic aromatic substitution reaction of N, N-dimethylaniline with aryl
aldehydes to form corresponding diaminotriarylmethane compounds. The synthetic
scheme is given in Scheme 3.121
Scheme 3.1: CAN catalysed synthesis of 4,4’-dimethylaminotriarylmethanes.
2) Synthesis using Montomorillonate K-10 22
Synthesis of triarylmethanes via Baeyer condensation dimethylaniline catalysed by of
aromatic aldehydes with N,N-dimethylenediamine catalysed by montmorillonite k-10.
Scheme 3.2
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Development and Application of New Methodologies for Synthesis of Bioactive Molecules181
3) Microwave mediated synthesis23
Guzman and et al have been reported a microwave mediated synthesis of DTM.
Scheme 3.3
4) Antimony chloride mediated synthesis of DTM24
A solvent-free one-step synthesis of various 4,4′-diaminotriarylmethane derivatives in
the presence of antimony trichloride as catalyst is described.
Scheme 3.4
5) Acid catalysed synthesis of DTM25
George et al have been reported the synthesis of DTM, is the reaction of arylaldehydes
with N,N-dimethylaniline in the presence of an acid such as sulfuric acid, HCl, p-
TSA.
Scheme 3.5
6) Bi(NO3)3•5H2O mediated synthesis of DTM26
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Development and Application of New Methodologies for Synthesis of Bioactive Molecules182
Recently, a synthesis of a variety of diaminotriarylmethane derivatives were
synthesized by the tandem Regio-selective electrophilic aromatic substitution reaction
of N,N-dimethylaniline with aryl aldehydes to form the corresponding
diaminotriarylmethane compounds.
Scheme 3.6
7) By using ZrOCl2•8H2O27
Solvent-free synthetic technique of diaminotriarylmethanes was reached by treating
N,N-dimethylaniline with some arylaldehydes over zirconium(IV) oxide chloride
(ZrOCl2•8H2O).
Scheme 3.7
Although different methods for the preparation of the aforementioned compounds
have been described, most of them however, suffer from drawbacks such as the use of
corrosive acids or toxic or hazardous chemicals, excess of solvents and harsh reaction
conditions, long reaction times which will result in generation of waste streams,
complicated workup procedures, byproducts and isomeric mixtures and consequently,
low yields. Therefore, there is still a need to search for a better catalyst with regards to
toxicity, selectivity, availability and operational simplicity for the synthesis of
triarylmethane compounds.
CHAPTER-3
Development and Application of New Methodologies for Synthesis of Bioactive Molecules183
3.3 OBJECTIVE OF THE WORK:
Iodine and iodine reagents have attracted increasing interest during the last decade
because of their selective, mild, and environmentally friendly properties as oxidizing
agents in organic synthesis. Investigation from our laboratories have revealed a series
of new paradigm for iodine reagent mediated reactions under mild conditions.28
Sodium dichloroiodate (I) {NaICl2} is nothing but a iodine reagent (non hypervalent
iodine compound) have recently attracted rising attention because of their selective,
mild, and environmentally friendly properties as oxidizing agents in organic
synthesis.39 So in this perspective, we develop a first novel synthetic utility of NaICl2
for synthesis of triaryl alkane compounds by aromatic C-C coupling, while the
developed method also useful for the preparation of diarylmethane compounds.
Sodium dichloroiodate is commercially available iodine reagent in a 50% water
solution and reported for the iodination of the aromatic ring at 40–70OC for 72 h.29
more recently we used this for the transformation of alcohol to aldehyde30a and
aldehyde to corresponding nitriles.30b While working on this reagent, we found that it
can be used for the regioselective carbon-carbon bond forming reaction. Relevant of
this methodology stems from the fact that all the aforementioned transformations are
quite fundamental in nature and can be easily applied to a multitude of synthetic
strategies.
CHAPTER-3
Development and Application of New Methodologies for Synthesis of Bioactive Molecules184
3.4 DESIGN AND DEVELOPMENT:
Although different methods for the preparation of the aforementioned compounds
have been described, most of them however, suffer from drawbacks such as the use of
corrosive acids or toxic or hazardous chemicals, as well as the inconvenience in
handling the reagents. Considering these restrictions, excess of solvents and harsh
reaction conditions, which will result in generation of waste streams, complicated
workup procedures, byproducts and isomeric mixtures and consequently, low yields.
Therefore, there is still a need to search for a better catalyst with regards to toxicity,
selectivity, availability and operational simplicity for the synthesis of triarylmethane
compounds.
In this contribution, we describe a new route for the preparation of DTM derivatives.
In addition, as our group has been working extensively on the development of novel
methodologies under mild conditions using iodine reagents. We observed that in the
presence of aqueous sodium dichloroiodate solution, N,N-dimethylaniline and
aromatic or aliphatic aldehydes, converted into either 4,4’-arylmethylene-bis-(N,N-
dimethylaniline) or 4,4’-alkylmethylene-bis-(N,N-dimethylaniline) (Scheme 3.9).
Scheme 3.9 Reaction of aryl and alkyl aldehydes with N,N-dimethylaniline in presence of NaICl2
Here, a first synthetic utility of NaICl2 (sodium dichloroiodate) for preparation of
triarylmethanes and diarylalkanes is described. In the presence of aqueous solution of
CHAPTER-3
Development and Application of New Methodologies for Synthesis of Bioactive Molecules185
NaICl2, the reaction of arenes with aromatic aldehydes gives corresponding
triarylmethane regioselectivly, in moderate to good yields. The method also useful for
the synthesis of diarylalkane derivatives by using aliphatic aldehydes.
3.5 EXPERIMENTAL:
General Experimental Procedure for synthesis of Triarymethanes using Iodine
Reagent:
Arylaldehydes (1 equiv), N, N-dimethylaniline (2 equiv) and aqueous NaICl2 (2 M, 10
ml, 0.5 equiv) was reflux in round bottom flask for 3-6 h. After completion of reaction
(TLC), the reaction mixture was quenched in water (10 mL) and further diluted with
dichloromethane (30 mL). The organic layer was separated and washed successively
with 10% aqueous solution of Na2S2O3 (2 x 20 mL), 10% aqueous solution of
NaHCO3 (2 x 15 mL), and finally with H2O (2 x 20 mL). Then organic layer was dried
over anhydrous Na2SO4 and concentrated under reduced pressure to give crude
product. Pure DTM as a green solid was obtained after silica gel column
chromatography (EtOAc: hexane, 1: 9).
Synthesis of Leucomalachite green:
Table 1, entry 1: 4,4’-(phenylmethylene)bis(N,N-dimethyleaniline)
Benzaldehyde 0.1g, (1 equiv), N, N-dimethylaniline 0.23g, (2 equiv) and aqueous was
treated by general procedure with NaICl2 0.104g, (2 M, 10 ml, 0.5 equiv) in round
bottom flask for 4h to gave the product with 75% yield (0.225 g); M.P. 92-93OC; 1H
NMR (CDCl3): δ 2.93 (s, 12H), 5.40 (s, 1H ), 6.66-7.25 (m, 13H,); IR (KBr, cm-1):
3075, 1611, 1532, 1459, 1347; 13C NMR (CDCl3): 148.91, 145.41, 132.81, 129.98,
129.86, 129.32, 128.02, 112.54, 112.41, 55.04, 40.79, 40.65
Table 1, entry 2: 4,4’-(4-fluorophenyl)methylene)bis(N,N-dimethylaniline)
4-fluro-benzaldehyde 0.1g,(1 equiv), N, N-dimethylaniline 0.19g, (2 equiv) and
aqueous was treated by general procedure with NaICl2 0.104g, (2 M, 10 ml, 0.5 equiv)
in round bottom flask for 5h to gave the product with 70% yield (0.195 g); M.P.100-
CHAPTER-3
Development and Application of New Methodologies for Synthesis of Bioactive Molecules186
101OC 1H NMR (CCl4, 60 MHz): 2.84(s, 12H), 5.21(s,1H), 6.41-7.33 (m, 12H); IR
(KBr, cm-1): 3075, 1611, 1532, 1459, 860
Table 1, entry 3: 4,4’-(4-chlorophenyl)methylene)bis(N,N-dimethylaniline)
4-chloro-benzaldehyde 0.1g,(1 equiv), N, N-dimethylaniline 0.17g, (2 equiv) and
aqueous was treated by general procedure with NaICl2 0.078g, (2 M, 10 ml, 0.5 equiv)
in round bottom flask for 5h to gave the product with 68% yield (0.175 g); M.P.256-
257OC; 1H NMR (CCl4, 60 MHz): 2.90 (s, 12H), 5.31 (s,1H), 6.53-7.42 (m, 12H); IR
(KBr, cm-1): 3074, 1615, 1531, 1462, 863
Table 1, entry 4: 4,4’-(4-nitrophenyl)methylene)bis(N,N-dimethylaniline)
4-nitro-benzaldehyde 0.1g, (1 equiv), N, N-dimethylaniline 0.16g, (2 equiv) and
aqueous was treated by general procedure with NaICl2 0.073g, (2 M, 10 ml, 0.5 equiv)
in round bottom flask for 3h to gave the product with 78% yield (0.192 g); M.P. 178-
179OC; 1H NMR (CCl4, 60 MHz): 2.86(s, 12H), 5.49(s,1H), 6.81(d, 1H), 8.00-
8.49(m, 11H); IR (KBr, cm-1): 3076, 1611, 1532, 1459, 1355, 860
Table 1, entry 5: 4,4’-(4-methylphenyl)methylene)bis(N,N-dimethylaniline)
4-methyl-benzaldehyde 0.1g, (1 equiv), N, N-dimethylaniline 0.20g, (2 equiv) and
aqueous was treated by general procedure with NaICl2 0.092g, (2 M, 10 ml, 0.5 equiv)
in round bottom flask for 6h to gave the product with 65% yield (0.185 g); 1H NMR
(CCl4, 60 MHz): 2.35 (s, 3H), 2.92(s, 12H), 5.48 (s,1H), 6.64(d, 4H), 7.05-7.15(m,
8H); IR (KBr, cm-1): 3070, 2960, 1609, 1530, 1455, 1350, 855
Table 1, entry 6: 4,4’-(4-methoxyphenyl)methylene)bis(N,N-dimethylaniline)
4-methoxy-benzaldehyde 0.1g, (1 equiv), N, N-dimethylaniline 0.17g, (2 equiv) and
aqueous was treated by general procedure with NaICl2 0.081g, (2 M, 10 ml, 0.5 equiv)
in round bottom flask for 6h to gave the product with 65% yield (0.171 g); M.P. 104-
105OC; 1H NMR (CCl4, 60 MHz): 2.90(s, 12H), 3.71(s, 3H), 5.49(s,1H), 6.62 (d,
4H),7.13(d, 4H), 7.52(d, 4H) 12H); IR (KBr, cm-1): 3410, 3075, 2931, 1611, 1532,
1459, 1317, 1270, 817
Table 1, entry 7: 4,4’-(pyridine-2-ylmethylene)bis(N,N-dimethylaniline)
CHAPTER-3
Development and Application of New Methodologies for Synthesis of Bioactive Molecules187
Pyridine-2-aldehyde 0.1g, (1 equiv), N, N-dimethylaniline 0.22g, (2 equiv) and
aqueous was treated by general procedure with NaICl2 0.10g, (2 M, 10 ml, 0.5 equiv)
in round bottom flask for 4h to gave the product with 60% yield (0.184 g); M.P. 169-
171OC; 1H NMR (CCl4, 60 MHz)): 2.94(s, 12H), 5.38(s,1H), 6.61(d, 6H), 7.04(d,
5H), 8.04(d,1H); IR (KBr, cm-1): 3075, 1611, 1532, 1459
Table 1, entry 8: 4,4’-(thiophen-2-ylmethylene)bis(N,N-dimethylaniline)
Thiophen-2-aldehyde 0.1g, (1 equiv), N, N-dimethylaniline 0.21g, (2 equiv) and
aqueous was treated by general procedure with NaICl2 0.098g, (2 M, 10 ml, 0.5 equiv)
in round bottom flask for 6h to gave the product with 80% yield (0.238 g); M.P. 83-
84OC; 1H NMR (CCl4, 60 MHz): 2.90(s, 12H), 5.50(s, 1H), 6.58-7.25 (m, 11H); IR
(KBr, cm-1): 3073, 1611, 1534, 1460, 1341,1200
Table 1, entry 9: 4,4’-(furan-2-ylmethylene)bis(N,N-dimethylaniline)
Furan-2-aldehyde 0.1g, (1 equiv), N, N-dimethylaniline 0.44g, (2 equiv) and aqueous
was treated by general procedure with NaICl2 0.11g, (2 M, 10 ml, 0.5 equiv) in round
bottom flask for 6h to gave the product with 75% yield (0.248 g); 1H NMR (CCl4, 60
MHz): 3.06 (s, 12H), 5.57(s, 1H), 6.08-7.58 (m, 11H); IR (KBr, cm-1): 3081, 1625,
1542, 1470, 1346,1210
Table 1, entry 10: 4,4’-(cyclohexylphenylmethylene)bis(N,N-dimethyleaniline)
Cyclohexaldehyde 0.1g, (1 equiv), N, N-dimethylaniline 0.37g, (2 equiv) and aqueous
was treated by general procedure with NaICl2 0.098g, (2 M, 10 ml, 0.5 equiv) in round
bottom flask for 4h to gave the product with 40% yield (0.119 g); M.P. 150-152OC; 1H NMR (CDCl3): 1.27-1.52(m, 10H), 2.35(m, 1H), 2.95(s, 12H), 4.19(d, 1H),
6.61(d, 4H), 7.25(d, 4H); IR (KBr, cm-1): 3061, 2926, 1611, 1532, 1440, 1347; 13C
NMR (CDCl3): 14.83, 133.90, 128.66, 128.54, 113.13, 112.99, 54.03, 41.61,
41.05, 32.35, 29.79, 25.57
Table 1, entry 11: 4,4’-(3-methylbutane-1,1-diyl)bis(N,N-dimethyleaniline)
3-methylbutanal 0.1g, (1 equiv), N, N-dimethylaniline 0.49g, (2 equiv) and aqueous
was treated by general procedure with NaICl2 0.12g, (2 M, 10 ml, 0.5 equiv) in round
bottom flask for 2h to gave the product with 60% yield (0.216 g); M.P. liquid
>250OC;1H NMR (CDCl3): 0.97 (t, 6H), 1.45(m, 1H), 1.89(t, 2H), 2.80(s, 12H),
CHAPTER-3
Development and Application of New Methodologies for Synthesis of Bioactive Molecules188
3.95(d, 1H), 6.69(d, 4H), 7.15(d, 4H); IR (KBr, cm-1): 3070, 2915, 1465, 1375, 800;
13C NMR (CDCl3): 149.05, 148.86, 134.76, 130.62, 129.50, 129.40, 128.40,
128.31, 113.26, 113.13, 46.85, 45.51, 43.30, 41.19, 41.06, 41.00, 40.93, 39.96,
29.77, 25.57, 22.81
Table 1, entry 12: 4,4’-(propane-1,1-diyl)bis(N,Ndimethyleaniline)
Propanaldehyde 0.1g, (1 equiv), N, N-dimethylaniline 0.41g, (2 equiv) and aqueous
was treated by general procedure with NaICl2 0.19g, (2 M, 10 ml, 0.5 equiv) in round
bottom flask for 2h to gave the product with 65% yield (0.316 g); B.P. 51-52OC;1H
NMR (CDCl3): 0.90(t, 3H), 1.95(m, 2H), 2.80(s, 12H), 3.90(t, 1H), 6.68(d, 4H),
7.15(d, 4H); IR (KBr, cm-1): 3070, 2980, 1462, 1370, 802; 13CNMR(CDCl3):
149.04, 130.33, 129.46, 129.35, 113.10, 112.96, 49.04, 41.14, 41, 40.88, 40.72 ,
39.88, 12.04
Table 1, entry 13: (E)-4,4’-(3-phenylprop-2-ene-1,1-diyl)bis(N,Ndimethyleaniline)
Cinnamaldehyde 0.1g, (1 equiv), N, N-dimethylaniline 0.28g, (2 equiv) and aqueous
was treated by general procedure with NaICl2 0.074g, (2 M, 10 ml, 0.5 equiv) in round
bottom flask for 5h to gave the product with 30% yield (0.071 g); 1H NMR (CDCl3):
2.95(s, 12H), 4.80(d, 1H), 6.60 (d, 1H), 6.80(d, 1H), 7.10(m, 8H), 7.21-7.60(m, 5H);
IR (KBr, cm-1): 3065, 2924, 1611, 1470, 1532, 801; 13CNMR,(CDCl3): 144.09,
136.34, 134.74, 130.08, 129.92, 128.48, 127.08, 116.78, 113.09, 52.79, 40.78
3.6 RESULT AND DISCUSSION:
From our investigations it was observed that N,N-dimethylaniline reacts smoothly
with arylaldehydes and heterocyclic aldehydes in the presence of NaICl2 to produce
the corresponding DTMs (Scheme 3.10) in good to excellent yields. At first we
focused on the reaction of benzaldehyde and N,N-dimethylaniline as a model reaction
under various reaction conditions (with solvent, solvent-free). Various protic and
aprotic solvents (Table no.2) were examined: The best results were obtained under
solvent-free conditions. It was also observed that under similar reaction conditions but
at room temperature slower reaction rate was observed.
CHAPTER-3
Development and Application of New Methodologies for Synthesis of Bioactive Molecules189
The general route for the synthesis of these compounds as shown below.
Scheme 3.10
Then, to explore the possibility of other reagents (Table no. 1) for conversion of
aldehydes into corresponding DTM, we also carried out the reaction with other iodine
reagents including ICl, DIB, and Iodine. Unlike the situation with sodium
dichloroiodate (Table no. 1, entry 4), no good yield was obtained. Hence from this
observation it was concluded that the sodium dichloroiodate was a best reagent for
this reaction.
Table 1: Reagent Studya
Entry Reagent Solvent Time (h)
Yieldb (%)
1 I2 CHCl3 8 50
2 ICl CHCl3 7 60
3 DIB CHCl3 12 25
4 NaICl2 CHCl3 6 75
aBenzaldehyde (1 equiv.) and N,N-dimethylaniline (2 equiv.) with different
iodine reagents, b isolated yield.
CHAPTER-3
Development and Application of New Methodologies for Synthesis of Bioactive Molecules190
Afterward, in solvent study, it was observed that, in chloroform reaction gave good
yield (Table 2 entry 4). But lower yields were observed in case of acetone, methanol
and dichloromethane (Table 2, entries 1-3). It was noteworthy that, when reaction
was carried out under solvent free condition, it gave good yield as compare the results
obtained from other solvents (Table 2, entry 6). And finally from this study it was
concluded that benzaldehyde (1equiv.) and N, N-dimethylamine (2 equiv) in solvent
free under reflux condition was good optimum condition.
Table 2: Solvent Studya
Entry Solvent Time (h)
Yieldb (%)
1 Acetone 12 20
2 Methanol 12 25
3 Dichloromethane 12 30
4 Chloroform 6 75
5 THF 12 30
6 Solvent free 4 85
aBenzaldehyde (1 equiv.) and N,N-dimethylaniline (2 equiv.) with different iodine reagents. bisolated
yield.
During reaction it was also, observed that N, N-dimethylaniline reacted with para-
formaldehyde at reflux temperature in presence of aqueous solution of sodium
dichloiodate and resulted in the formation of 4,4’-methylene-bis(N, N-
dimethylaniline) (Scheme 3.11) and thus provided an interesting rout for synthesis of
diphenylmethane compounds.
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Development and Application of New Methodologies for Synthesis of Bioactive Molecules191
Scheme 3.11 Reaction of Paraformaldehyde with N,N-dimethylaniline in presence of NaICl2
Next to evaluate scope of this method, these conditions were applied to variety of
aromatic and aliphatic aldehydes and the results are presented in Table 3. The results
clearly indicate that this method is suitable for electron withdrawing and donating
substituted aromatic substrates (Table 3, entries 2-6). In each case, good to excellent
yields of the desired 4,4’-arylmethylene-bis-(N,N-dimethylaniline) products were
isolated. Heterocyclic aromatic aldehyde compounds were also suitable for this
transformation (Table 3, entries 7- 9). A lowered reaction rate was observed in case
of aliphatic aldehydes (Table 3, entries 11, 12). Further investigations indicated that
α, β-unsaturated aldehydes are also suitable for this reaction (Table 3, entry 13)
without affecting the geometry of double bond.
Table 3: Reaction of N,N-dimethylaniline with aldehydes in presence of aqueous NaICl2 Scheme
3.12. a
Scheme 3.12
CHAPTER-3
Development and Application of New Methodologies for Synthesis of Bioactive Molecules192
Entry R-CHO Product Time
(h) Yieldb
(%)
1
4
75
2
5 70
3
5 68
4
3 78
5
6 65
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Development and Application of New Methodologies for Synthesis of Bioactive Molecules193
6
6 65
7
4 60
8
6 80
9
O
NCH3
CH3
N
CH3
H3C
6 75
10
4 40
11
2 60
CHAPTER-3
Development and Application of New Methodologies for Synthesis of Bioactive Molecules194
12 2 65
13
5 30
aReaction conditions: N,N’dimethylaniline (2 equiv), NaICl2 (0.5 equiv), aldehyde (1equiv). bIsolated
yields after column chromatography and structures were confirmed by comparison of IR and 1H NMR
with authentic materials.
So herein, we developed efficient and versatile methodology for synthesizing
diaminotriphenylmethanes as well as diamininodiphenylalkanes by using aqueous
sodium dichloroiodate reagent.
3.6.1 MECHANISM:
The plausible mechanism for this reaction can be proposed in (Figure 3), in which the
C-C coupling may be due to activation of the carbonyl group of the aldehyde by
NaICl2.
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Development and Application of New Methodologies for Synthesis of Bioactive Molecules195
Figure 3 . Plausible reaction mechanism
In this nucleophilic addition reaction, nucleophilic attack of N, N-dimethyleneamine
on electrophilic carbonyl carbon took place. Here the roll of NaICl2 is to increase the
electrophilicity of carbonyl group of aldehyde. Then, formation of intermediate 2, in
this chloride ion abstract a proton and ring get aromatized. In next step, the
intermediate 3 will again attacked by another mole of N, N-dimethylenediamine group.
And again by same way chloride ion pickup a proton, and another ring also get
aromatized, finally converted into Leucomalachite green compound.
CHAPTER-3
Development and Application of New Methodologies for Synthesis of Bioactive Molecules196
3.7 APPLICATION:
As discussed early in introduction, these type molecules have broad scope of
application like ink, it also Use in flexographic printing colours. Worldwide annual
sales of these dyes are approximately 1000 tones (Gessner & Mayer, 2000). Apart
from this application, these dyes are also have been used in medicinal field.
a) Synthesis of malachite green
This methodology can also be successfully used for the synthesis of malachite green.
Scheme 3.13
b) Synthesis of Michler’s base and Michler’s ketone
Here, we can be also applying for the synthesis of michler’s ketone. Michler base or
michler ketone is active ingredient in the synthesis of auramine. Worldwide annual
sales of these dyes are approximately 1000 tones (Gessner & Mayer, 2000). It is used
in flexographic printing colours.
Experimental: Step-1: Synthesis of Michler’s base (Spectra 14, 15)
Paraformaldehyde 0.1g,(1 equiv), N, N-dimethylaniline 0.49g,(2 equiv) and aqueous
was treated by general procedure with NaICl2 0.26g,(2 M, 0.5 equiv) in round bottom
flask for 8h to gave the solid product with 70% yield (0.195 g); M.P.90-91OC; 1H
NMR (CCl4, 60 MHz): 2.89(s, 12H), 3.81(s, 2H), 6.52-6.70 (d, 4H), 6.99-7.25 (d,
4H); IR (KBr, cm-1): 3350, 1601, 1513, 943, 792
Step-2: Synthesis of Michler’s Ketone (Spectra 16)
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Development and Application of New Methodologies for Synthesis of Bioactive Molecules197
Michler’s base 0.1g,(1 equiv), DIB 0.18g,(1.5 equiv) and sodium azide was added
catalytic in a 10ml of ACN:H2O system, at room temperature for an 1 h.50% yield
(0.0501g); M.P.172-174OC; 1H NMR (CCl4, 60 MHz): 2.85(s, 12H), 6.10-6.25 (d,
4H), 7.20-7.40 (d, 4H); IR (KBr, cm-1): 3080, 1610, 1700, 1535, 1462, 755
Scheme 3.14
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Development and Application of New Methodologies for Synthesis of Bioactive Molecules198
3.8 SUMMARY AND CONCLUSION:
Although different methods for the preparation of the aforementioned compounds
have been described, most of them however, suffer from drawbacks such as the use of
corrosive acids or toxic or hazardous chemicals, excess of solvents and harsh reaction
conditions, long reaction times which will result in generation of waste streams,
complicated workup procedures, byproducts and isomeric mixtures and consequently,
low yields. Therefore, there is still a need to search for a better catalyst with regards to
toxicity, selectivity, availability and operational simplicity for the synthesis of
triarylmethane compounds.
In summary, it has been demonstrated that NaICl2 is a mild and efficient catalyst for
the one-pot reaction of N,N-dimethylaniline with a variety of aryl and heteroaryl
aldehydes under solvent-free conditions to give substituted triarylmethanes. Using
NaICl2 as catalyst, even electron-rich benzaldehydes gave the corresponding products
in good yields. Operational simplicity, high yields, and the ability to prepare a wide
range of products are the advantages of this protocol.
In conclusion, a new reaction system using NaICl2 for C-C coupling has been
developed, which is capable of converting various aldehydes into corresponding
triphenyl and diphenyl compounds. The developed method is mild and gives moderate
to good yields of product for both aliphatic and aromatic substrates.
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Development and Application of New Methodologies for Synthesis of Bioactive Molecules199
3.9 REFERENCES:
1. K. Venkataraman, The Chemistry of Synthetic Dyes, 1st edition (Academic
Press, New York, 1952)
2. H.A. Lubs, The Chemistry of Synthetic Dyes and Pigments, 1st edition
(Reinhold Publishing Corporation, New York, 1955
3. Kandela, I. K.; Bartlett, J. A.; Indig, G. L.; Photochem. Photobiol. Sci., 2002, 1,
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4. a) Culp, S. J.; Beland, F. A.; J. Am. Coll. Toxicol. 1996, 15, 219 b) Alderman,
D. J.; J. Fish. Dis. 1985, 8, 289 c) Cho, B. P.; Yang, T.; Blankenship, L. R.;
Moody, J. D.; Churchwell, M.; Beland, F. A.; Culp, S. J.; Chem. Res. Toxicol.
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6. Duxbury, D. F.; Chem. Rev. 1993, 93, 381
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O.; Moraes-Souza, H.; Transfusion 1995, 35, 226 b) Dittrich, F.; Scholz, M.
Verfahren zum quantitativen Spurennachweis von Wasserstoffperoxid. German
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8. Babb, B. E.; Daniel, D. S. Compositions and elements containing
triarylmethane leuco dyes and methods using same. European Patent EP
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9. Jay, D. G.; Keshishian, H.; Nature 1990, 348, 548.
10. Zepp, R. G.; Skurlatov, Y. I.; Ritmiller, L. F.; Environ. Technol. Lett. 1988, 9,
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1996, 32, 49
12. Indig, G. L.; Chem. Lett. 1997, 243
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13. Fiedorowicz, M.; Pituch-Noworolska, A.; Zembala, M.; Photochem.
Photobiol. 1997, 65, 855
14. Muthyala, R.; Lan, X. The Chemistry of Leuco Triarylmethanes. In Chemistry
and applications of leuco dyes; Muthyala, R., Ed.; Plenum Press: New York,
1997; pp 125 ff
15. Smith, I. L. Analytical Applications of the Heavy Metal Induced Oxidation of
the Leuco Bases of Triphenylmethane Dyes. Ph.D. Thesis, The University of
Alabama, 1974. Chem. Abstr. 1974, 83, 71097m
16. Perez Ruiz, T.; Martinez Lozano, C.; Hernandez Lozano, M. An. Univ. Murcia
Cienc. 1984, 43, 251–268. Chem. Abstr. 1984, 103, 639831
17. Thakore, P. V.; Sci. Cult. 1989, 55, 105
18. Muthyala, R. In Chemistry and Applications of Leuco Dyes,Eds.: Katrizky, A.
R.; Sabongi, G. J., Plenum, New York, 1997
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R.; Sabongi, G. J., Plenum, New York, 1997
20. a) Maruyama, Y.; Ishikawa, M.; Satozono, H.; J. Am. Chem. Soc. 1996, 118,
6257 b) Alderman, D. J.; J. Fish. Dis. 1985, 8, 289 c) Cho, B. P.; Yang, T.;
Blankenship, L. R.; Moody, J. D.; Churchwell, M.; Beland, F.A.; Culp, S. J.;
Chem. Res. Toxicol. 2003, 16, 285 d) Kawai, H.; Nagamura, T.; J. Photochem.
Photobiol. A: Chem. 1995, 92, 105 e) Lueck, H. B.; McHale, J. L.; Edwards,
W. D.; J. Am. Chem. Soc. 1992, 114, 2342 f) Duxbury, D. F.; Chem. Rev. 1993,
93, 381
21. Bardajee, G. R.; Int.J. ChemTech Res. 2009, 1, 453
22. Zhan, H. Z.; Feng, Y. T.; Cheng-G. F.; Synthetic Communications, 1997, 27,
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P.; Molecules, 2008, 13, 986
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26. Bardajee, G. R.; Farnaz J.; Cent. Eur. J. Chem., 2009, 7, 138
27. Jafarpour, F.; Bardajee, G.; Pirelahi, H.; Dehnamaki, H.; Rahmdel, Sareh.;
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2179
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nthesis of Bio
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CHAPTE
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nthesis of Bio
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CHAPTE
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nthesis of Bio
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CHAPTE
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Table 3
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CHAPTE
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CHAPTE
Developm
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