Microwave-assisted synthesis of 4,4′-diaminotriphenylmethanes

Article abstract of DOI:10.1016/j.tetlet.2004.12.091

A fast, efficient and versatile route of synthesis of 4,4′- diaminotriphenylmethanes under microwave irradiation, suitable for parallel library syntheses were developed.

Full text of DOI:10.1016/j.tetlet.2004.12.091

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1119–1122
Microwave-assisted synthesis of 4,40-diaminotriphenylmethanes
a
D. Guzman-Lucero, J. Guzman, D. Likhatchev and R. Martınez-Palou
a
b
a,
*
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a
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Programa de Ingenierıa Molecular. Instituto Mexicano del Petroleo. Eje Cetral Lazaro Cardenas No. 152,
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´
07730 Mexico, D.F., Mexico
Instituto de Investigacion en Materiales, UNAM, Apdo. Postal 70-360, Coyoacan, 04510, Mexico, D.F., Mexico
b
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Received 19 November 2004; revised 14 December 2004; accepted 17 December 2004
Abstract—A fast, efficient and versatile route of synthesis of 4,40-diaminotriphenylmethanes under microwave irradiation, suitable
for parallel library syntheses were developed.
Ó 2004 Elsevier Ltd. All rights reserved.
Diaminotriphenylmethanes (DTMs) have received con-
siderable attention because these kind of compounds
are widely used as dyes1 and as antifungal agents in
commercial fish hatcheries.2 These compounds have also
been employed as precursors in high performance poly-
mer synthesis,3 in host–guest chemistry4 and in materials
science.5 Several DTMs have been evaluated as copper
corrosion inhibitors.6 DTMs present a number of inter-
esting structural properties in solid and solution that
have been much studied.7
namely, long reaction times (1.5–8 h) and the use of cor-
rosive acids or toxic metallic compounds that result in
generation of waste streams, complicated workup proce-
dures, byproducts and isomeric mixtures and, conse-
quently, low yields.
Microwave-assisted organic synthesis is a fast growing
area of research, due to the generally short reaction
times, high purities and yields of the resulting products
compared to conventional methods.13
Different methods for the preparation of the aforemen-
tioned compounds have been described such as from
4,40-diaminodiphenylmethanes and amines,8 by conden-
sation of amines and anilines in acid medium9 or using
zeolites10 and also by oxidative coupling of anilines with
metal catalyst11 or clay-mediated microwave-assisted
chemistry from N,N-disubstituted anilines, in which
DTMs are obtained in low to modest yields.12 Most of
these protocols, however, suffer from drawbacks,
Herein, we report a fast, efficient and versatile method-
ology for synthesizing DTMs focused in microwave
(MW), using aniline hydrochloride as catalyst in sol-
vent-free conditions (Scheme 1).
After some experimentation with respect to molar ratio
of reagents and catalyst, irradiation time and power
level of MW, we have found a set of conditions for
the synthesis of DTMs (1a–r).
R2 R3
N
R3 R2
N
R1
R1
R3
R5
O
H
R2
PhNH2.HCl
MW
+
N
R4
R1
1
R4
3
2
R5
Scheme 1. Microwave synthesis of 4,40-diaminotriphenylmethanes.
Keywords: Diaminotriphenylmethanes; Microwave; Parallel synthesis.
*
Corresponding author. Tel.: +52 55 91757395; fax: +52 55 91756239; e-mail: rpalou@imp.mx
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.091

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D. Guzman-Lucero et al. / Tetrahedron Letters 46 (2005) 1119–1122
1120
Table 1. 4,40-Diaminotriphenylmetanes (3a–q) synthesized via Scheme 1
Entry
R1
R2
R3
R4
R5
Product
Mp (°C)
Reaction time (min)
Yielda (%)
Yieldb (%)
1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
1a
1b
1c
1d
1e
1f
130–131
202–203
126–127
131–132
66–67
3
2
2
2
2
4
4
4
2
4
2
4
3
2
2
3
2
3
91
90
87
85
85
89
82
67
75
90
80
74
78
81
83
81
80
86
75
65
62
72
66
65
74
28
78
60
35
74
66
65
70
76
73
84
2
H
H
4-OH
4-OMe
4-OPr
4-t-Bu
4-F
H
3
H
H
H
4
H
H
H
5
H
H
H
6
H
H
H
139–140
68–69
83–84
7
H
H
4-CF3
4-NO2
4-NMe2
4-Et
H
1g
1h
1i
8
H
H
H
9
H
H
H
146–147
126–127
174–175
137–138
119–120
62–63
10
11
12
13
14
15
16
17
18
H
H
H
1j
H
H
2-OMe
3-CF3
4-OH
H
6-OMe
5-CF3
H
1k
1l
H
H
H
2-Me
2-OMe
2-OMe
H
1m
1n
1o
1p
1q
1r
H
H
H
4-OH
4-F
H
111–112
163–164
60–61
Me
Me
Me
H
H
4-OMe
4-NMe2
H
H
H
210–211
a Isolated yields using MW at power 100 W and 90 °C.
b Using alternative heating method (oil bath at 150 °C), employing 2 (0.35 mol), 3 (0.1 mol) and aniline hydrochloride (10% w/w respect to 3) during
2 h under nitrogen atmosphere.
We have found that using microwave-promoted synthe-
sis, the reactions can be carry out in an open vessel and
non excess of aniline is required to obtain good yields.
Synthesis of these compounds using analogue methodol-
ogy, employing conventional heating, requires a large
excess of highly toxic anilines, which are used as reagent
and solvent as well. Additionally traditional syntheses
have been carried out in inert atmosphere.3
Good isolated yields were obtained with all aryl alde-
hydes tested, demonstrating that electro-withdrawing
(entries 7, 8, 12 and 16) and electro-donating groups
(entries 2–5, 9–11, 15, 17 and 18), in addition to ortho
(entry 11) and meta substituents (entry 12), are well tol-
erated. The reaction was also well performed with ortho
substituted anilines such as toluidine and anisidine
(entries 13–15) and with N-substituted amines, such as
N-methyl aniline (entries 16 and 17) and N,N0-dimethyl-
aniline (entry 18).
Microwave irradiations were carried out utilizing con-
trolled single-mode MW (MIC-I, max. power 600 W,
from SEV, Mexico)14 using a 50 mL open reaction
tubes, with temperature and magnetical stirring
controls.
These reactions shown high regioselectivity, the regio-
isomer 4,40-diamino was almost exclusively detected in
the reaction mixture (>94% in all cases).
The reactions were monitored by TLC and IR and com-
pared with the compounds prepared by traditional
methods. The mass spectrometry molecular weight
determination and 1H and 13C NMR were in agreement
with the structures 1a–r in Table 1.
The fact that readily available aryl aldehydes and
amines are used along with the versatility of this syn-
thetic method and short reaction time required, makes
this approach a feasible protocol for generation of a
large library of DTM immediately available for screen-
ing, considering that compounds are obtained with puri-
ties higher than 85% before the purification process.15 In
all cases the main byproducts were 4,20- and 2,40-
diaminotriphenylmethanes.
The NMR spectrum of 1k shown that this compound
exists as a mixture of rotomers in dynamic equilibrium
at room temperature, while for 1r (crystal violet) the sig-
1
nal for the methyne proton is not present in H NMR
and signals suggest that for this compound an ionic
structure is favourable, as is well known for 4,40,400-
N,N0,N00-disubstituted analogues.7d
All compounds can be recrystallized from benzene or
toluene, but this operation is complicated because the
crude mixtures and some pure products are so strongly
colored in solution that is very difficult to see when
the solid dissolves and when crystals form.
N
N
A comparison between thermal heating (TH), using a
thermostated oil bath preheated at 90 °C and MW pro-
cedure for entry 1 (Table 1), with similar profile of raises
in temperature and reaction time is shown in Figure 1.
Cl
When the catalyst is used in less rate than 10% w/w
respect to the aldehyde or non catalyst is used the imine
formation (Schiff base) is the favourable or almost the
N
1r

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D. Guzman-Lucero et al. / Tetrahedron Letters 46 (2005) 1119–1122
1121
j.tetlet.2004.12.091. A supplementary data is provided,
which includes spectroscopic data (IR, NMR and MS)
of 1a–r. The supplementary data is available online with
the paper in Science Direct.
100
90
MW
80
70
60
50
40
30
20
TH
References and notes
0
50
100
t, sec.
150
200
1. (a) Gordon, P. F.; Gregory, P. Organic Chemistry in
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Figure 1. Temperature profile for the synthesis of 1a under TH and
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In conclusion, a solvent-free MW-assisted protocol for
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All reagents were purchase from Aldrich and used as
received, except aniline, which was distilled under vacuo
prior to be used. IR spectra were recorded on a Nicolet
FT-IR 5DX FT spectrometer using KBr as solid sup-
port. 1H NMR (200 MHz) and 13C NMR (50 MHz)
were determined on a Varian-Mercury 200 spectro-
meter using property solvent and TMS as internal
reference. MS spectra were obtained in a HP 6890
Plus spectrometer (70 eV). Microwave irradiations
were performed in a monomode MIC-I from SEV,
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Typical reaction conditions and representative spectros-
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w/w of aldehyde) were mixed thoroughly in a 50 mL
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bar. The mixture was irradiated during 4 min in a
MIC-I MW oven at power 100 W at 90 °C. The reaction
mixture was purified by recrystallization from toluene or
by silica gel flash chromatography column (hexane/ethyl
acetate gradient) to afford 90% of 1j as a white solid,
mp: 126–127 °C; IR (KBr) 3427, 3352, 3016, 2962,
2927, 2870, 1716, 1620, 1512, 1263, 1178, 1018,
7. (a) Maruyama, Y.; Ishikawa, M.; Satozono, H. J. Am.
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Berichte 1928, 61, 1294–1307, and Ref. 3.
´
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10. Alvaro, M.; Garcıa, H.; Sanjuan, A.; Espla, M. Appl.
819 cmꢀ1 1H NMR (200 MHz, CDCl3) d 1.18 (t,
;
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J = 7.2 Hz, 3H), 2.57 (q, J = 7.2 Hz, 2H), 3.4 (br s,
4H), 5.26 (s, 1H), 6.48, 6.83 (AB system, 8H), 7.01
(AB system, 4H); 13C NMR (50 MHz, CDCl3) d 15.9,
28.6, 54.9, 114.5, 127.0, 128.6, 129.4, 134.1, 140.9,
141.6, 143.7; MS (70 eV) 302 (M+, 40), 210 (42), 197
(58), 180 (60), 117 (39), 93 (100), 65 (72), 43 (85).
´
´
12. Lopez-Cortes, J. G.; Penieres-Carrillo, G.; Ortega-Alfaro,
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M. C.; Gutierrez-Perez, R.; Toscano, R. A.; Alvarez-
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13. (a) Microwaves in Organic Synthesis; Loupy, A., Ed.;
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14. Web page: www.sevmexico.com.
15. For recent examples of microwave-assisted combinatorial
synthesis see: (a) Georgsson, J.; Hallberg, A.; Larhed, M.
J. Comb. Chem. 2003, 5, 350–352; (b) Husemoen, G.;
Olsson, R.; Andersson, C.-M.; Harvey, S. C.; Hansen, C.
H. J. Comb. Chem. 2003, 5, 606–609; (c) Pottorf, R. S.;
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Acknowledgments
This work was realized within IMP project D00142.
Supplementary data
Supplementary data associated with this article can
be found, in the online version at, doi:10.1016/

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D. Guzman-Lucero et al. / Tetrahedron Letters 46 (2005) 1119–1122
1122
16. As example, when the reaction for obtaining 1i was carried
out using aniline (0.2 mol), p-dimethylaminobenzaldehyde
(0.1 mol) and aniline hydrochloride (3% w/w respect to
the aldehyde), the imine [4-(N,N0-dimethyl)-benzylid-
ene]phenylamine (4i) was obtained in 63% yield after
purification by sublimation to give an orange solid, mp:
229–230 °C; 1H NMR (200 MHz, DMSO-d6) d 2.99 (s,
6H), 6.76, 7.62 (AB system, 4H), 7.31–7.49 (m, 3H), 8.04
(d, J = 9.2 Hz, 2H), 8.66 (s, 1H); 13C NMR (50 MHz,
DMSO-d6) d 31.3, 104.6, 105.8, 111.0, 119.8, 121.7, 128.1,
130.0, 148.8, 149.5; MS (70 eV) 224 (100), 223 (82), 207
(12), 77 (11).
17. For examples of microwave-assisted imines synthesis see:
(a) Varma, R. S.; Dahiya, R.; Kumar, S. Tetrahedron Lett.
1997, 38, 2039–2042; (b) Varma, R. S.; Dahiya, R. Synlett
1997, 1245–1247; (c) Varma, R. S.; Dahiya, R. Tetrahe-
dron 1998, 54, 6293–6298; (d) Vass, A.; Dudas, J.; Varma,
R. S. Tetrahedron Lett. 1999, 40, 4951–4953.