Parallel synthesis of strongly fluorescent polysubstituted 2,6-dicyanoanilines via microwave-promoted multicomponent reaction

Article abstract of DOI:10.1021/jo047823h

(Chemical Equation Presented) A facile parallel synthesis of polysubstituted 2,6-dicyanoanilines via microwave-promoted three-component reaction of aldehydes, ketones, and propanedinitrile in solution and also on polymer support has been developed. The screening for optical properties identified two new compounds with high fluorescence quantum yields.

Full text of DOI:10.1021/jo047823h

SCHEME 1. MW-Promoted Efficient Synthesis of
Polysubstituted 2,6-Dicyanoanilines
Parallel Synthesis of Strongly Fluorescent
Polysubstituted 2,6-Dicyanoanilines via
Microwave-Promoted Multicomponent
Reaction
Sun-Liang Cui, Xu-Feng Lin, and Yan-Guang Wang*
Department of Chemistry, Zhejiang University,
Hangzhou 310027, P.R. China
proached comprises a single donor and a single acceptor.
To obtain a long-lived charge separation, much attention
has been devoted to the investigation of the acceptor-
donor-acceptor (A-D-A) systems comprising one elec-
tron donor and two electron acceptors.4 This considerable
research effort is justified by the potential applications
of these molecular systems, which are the basis for
artificial photosynthetic systems,5 materials presenting
semiconducting or nonlinear optical properties,6 and
molecular electronic devices.7
orgwyg@zju.edu.cn
Received December 12, 2004
2,6-Dicyanoanilines are typical A-D-A systems. How-
ever, the investigation of the optical properties of this
system has rarely been documented.8 2,6-Dicyanoanilines
were reported to be prepared from arylidenemalonodini-
triles and 1-arylethylidenemalonodinitriles in the pres-
ence of piperidine.8a The reaction between propanedini-
trile and R,â-unsaturated ketones could also give 2,6-
dicyanoanilines, but the yields were very poor (5∼20%).9
To improve the utility of this process, we developed its
practical multicomponent variant described herein. The
R,â-unsaturated ketones are generated in situ from the
corresponding aldehydes and ketones, whereupon they
are captured by 2 equivalents of propanedinitrile, forming
the corresponding polysubstituted 2,6-dicyanoanilines
(Scheme 1). Performing both steps of this process under
microwave irradiation significantly reduces the reaction
time and increases the yields. As the starting point of
our exploration, we chose the reaction between aldehyde
1a and ketone 2c. A mixture of aldehyde, ketone and
propanedinitrile (2.5 equiv) was irradiated in the pres-
ence of a base, such as triethylamine or piperidine, for 2
min to give substituted 2,6-dicyanoaniline. The best
A facile parallel synthesis of polysubstituted 2,6-dicyano-
anilines via microwave-promoted three-component reaction
of aldehydes, ketones, and propanedinitrile in solution and
also on polymer support has been developed. The screening
for optical properties identified two new compounds with
high fluorescence quantum yields.
Coupled with the concomitant emergency of high-
throughput screening, combinatorial chemistry tech-
niques have evolved very rapidly over the past years and
are playing significant roles in the development of
modern synthetic organic chemistry.1 To date, the con-
cepts of combinatorial chemistry have been successfully
applied to development and improvement of novel phar-
maceutics, materials 1e and catalysts using rapid parallel
and mix-and-split synthesis in solution and also on
polymer supports. Lately, multicomponent reactions
(MCRs) involving domino process with at least three
different simple substrates has emerged as a powerful
strategy.2 This methodology allows molecular complexity
and diversity to be created by the facile formation of
several new covalent bonds in a one-pot transformation
quite closely approaching the concept of an ideal synthe-
sis and is particularly well adapted for combinatorial
synthesis.3
(4) (a) Dumur, F.; Gautier, N.; Gallego-Planas, N.; Sahin, Y.;
Levillain, E.; Mercier, N.; Hudhomme, P. J. Org. Chem. 2004, 69,
2164-2177. (b) Depaemelaere, S.; De Schryver, F. C.; Verhoeven, J.
W. J. Phys. Chem. A 1998, 102, 2109-2116. (c) Xiao, Y.; Qian, X. H.
Tetrahedron Lett. 2003, 44, 2087-2091.
(5) (a) Fox, M. A., Chanon, M., Eds. Photoinduced Electron Transfer;
Elsevier: Amsterdam, 1988. (b) Kurreck, H.; Huber M. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 849-866.
(6) (a) Prasad, P. N.; Williams, D. J. Introduction to Nonlinear
Optical Effects in Molecules and Polymers; Wiley: New York, 1991.
(b) Nalwa, H. S. Adv. Mater. 1993, 5, 341-358. (c) Long, N. J. Angew.
Chem., Int. Ed. Engl. 1995, 34, 21-38. (d) Wong, M. S.; Bosshard, C.;
Pan, F.; Gu¨nter, P. Adv. Mater. 1996, 8, 677-680.
In the past decades, photoinduced intramolecular
electron transfer has been a subject of extensive study.
The molecule in which electron transfer can be ap-
* To whom correspondence should be addressed. Tel: +86-571-
87951512. Fax: +86-571-87951512.
(1) (a) Nefzi, A.; Ostresh, J. M.; Yu, J. P.; Houghten, R. A. J. Org.
Chem. 2004, 69, 3603-3609. (b) Dolle, R. E. J. Comb. Chem. 2000, 2,
383-433. (c) Hall, D. G.; Manku, S.; Wang, F. J. Comb. Chem. 2001,
3, 125-150. (d) Dolle, R. E. J. Comb. Chem. 2001, 3, 477-577. (e)
Schiedel, M.-S.; Briehn, C. A.; Ba¨uerle, P. Angew. Chem., Int. Ed. 2001,
40, 4677-4680.
(2) (a) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der Eycken,
E. Org. Lett. 2004, 6, 4223-4225. (b) Hayes, J. F.; Shipman, M.; Twin,
H. J. Org. Chem. 2002, 67, 935-942. (c) Byk, G.; Kabahn, E. J. Comb.
Chem. 2004, 6, 596-603. (d) Marcaccini, S.; Miguel, D.; Torroba, T.;
Garcia-Valverge, M. J. Org. Chem. 2003, 68, 3315-3318.
(3) de Meijere, A.; Nu¨ske, H.; Es-Sayed, M.; Labahn, T.; Schroen,
M.; Bra¨se, S. Angew. Chem., Int. Ed. Engl. 1999, 38, 3669-3672.
(7) (a) Metzger, R. M.; Panetta, C. New. J. Chem. 1991, 15, 209. (b)
Launay J. P. Molecular Electronics. In Granular Nanoelectronics;
Ferry, D. K., Ed.; Plenum Press: New York, 1991. (c) Petty, M. C.,
Bryce, M. R., Bloor, D., Eds. Introduction to Molecular Electronics;
Oxford University Press: New York, 1995.
(8) (a) Sepiol, J.; Milart, P. Tetrahedron 1985, 41, 5261-5265. (b)
Griffiths, J.; Lockwood, M.; Roozpeikar, B. J. Chem. Soc., Perkin Trans.
2 1977, 1608-1610.
(9) (a) Victory, P. J.; Borrell, J. I.; Vidal-Ferran, A. Heterocycles 1993,
36, 769-776. (b) Victory, P.; Borrel, J. I.; Vidal-Ferran, A.; Seoane,
C.; Soto, J. L. Tetrahedron Lett. 1991, 32, 5375-5378. (c) Victory, P.
J.; Borrell, J. I.; Vidal-Ferran, A.; Montenegro, E.; Jimeno, M. L.
Heterocycles 1993, 36, 2273-2279.
10.1021/jo047823h CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/02/2005
2866
J. Org. Chem. 2005, 70, 2866-2869

TABLE 1. Parallel Solution-Phase Synthesis of Polysubstituted 2,6-Dicyanoanilines
conditions were found to be 300 W irradiation power. The
product, 3-methyl-5-phenyl-2,6-dicyanoaniline (4m), has
been isolated in 56% yield (Table 1, entry 13). This
prompted us to extend our studies toward the incorpora-
tion of different aldehydes and ketones.
was carried out under the microwave irradiation for 2
min. The resulting PEG bound 2,6-dicyanoanilines 6 were
cleaved by NaOMe/MeOH to afford free polysubstituted
2,6-dicyanoanilines 7. As exemplified in Table 2, the
reactions proceeded smoothly to completion, and the
products were isolated in good yields (65-82%) and high
purities (89-98%).
It is interesting for us to screen the polysubstituted
2,6-dicyanoanilines for their optical properties. The cor-
relation between optical properties (especially emission
wavelengths and the fluorescence quantum yields) and
the molecular structures can currently be described only
empirically, since no detailed theoretical predictions are
possible.11 A large number of compounds in a combina-
torial library should correlate to a better understanding
of the inherent structure-property relationships from
which specifically tailored materials can be produced.
From the library, two members 4p and 4u with the most
intensive fluorescence were selected. Maximum emission
wavelengths (λem ) 395-440 nm) were observed for these
two compounds in CH2Cl2, MeOH, and THF, while the
corresponding fluorescent quantum yields (Φf ) 0.08-
Using this three-component one-pot procedure, we
synthesized a parallel library containing 21 polysubsti-
tuted 2,6-dicyanoanilines (Table 1). The yields (50-63%)
are extensively increased as compared with the published
methods (5-20%).9 The crystallographic structure of
compound 4c was determined by X-ray diffraction (see
the Supporting Information), which is in accordance with
1
the H NMR, 13C NMR, and HRMS spectra.
In connection with our research on the liquid-phase
synthesis,10 we also synthesized the 2,6-dicyanoanilines
using poly(ethylene glycol) (PEG) as support (Scheme 2).
The PEG-bound aldehydes 510a were mixed with ketones
2 and 3 equivalents of propanedinitrile (3). NH4OAc was
used as the base. The one-pot three-component reaction
(10) (a) Lin, X. F.; Zhang, J.; Wang, Y. G. Tetrahedron Lett. 2003,
44, 4113-4115. (b) Wang, Y. G.; Zhang, J.; Lin, X. F.; Ding, H. F.
Synlett 2003, 1467-1468. (c) Shang, Y. J.; Wang, Y. G. Tetrahedron
Lett. 2002, 43, 2247-2249. (d) Wang, Y. G.; Lin, X. F.; Cui, S. L. Synlett
2004, 1175-1178. (e) Xia, M.; Wang, Y. G. Tetrahedron Lett. 2002,
43, 7703-7705.
(11) Schiedel, M.-S.; Briehn, C. A.; Ba¨uerle, P. Angew. Chem., Int.
Ed. 2001, 40, 4677-4680.
J. Org. Chem, Vol. 70, No. 7, 2005 2867

SCHEME 2. MW-Promoted Liquid-Phase Synthesis of Polysubstituted 2,6-Dicyanoanilines
TABLE 2. MW-Promoted Parallel Liquid-Phase
for generation of polysubstituted 2,6-dicyanoaninilines.
Using this one-pot protocol, the parallel synthesis of a
large number of unpublished fluorescent 2,6-dicyano-
aninilines in solution and also on soluble polymer support
was achieved. Furthermore, two compounds with high
fluorescent quantum yields were identified by screening
the library for optical properties.
Synthesis of 2,6-Dicyanoanilines Using PEG as Support
isolated puritya
product yield(%)
entry
R1
R2
(%)
1
2
3
4
5
6
7
8
9
C6H5 (2i)
C6H5 (2a)
H (2i)
7a
4c
7c
7d
7e
7f
7g
7h
7i
80
82
81
65
77
79
78
73
75
93
93
96
95
95
96
98
89
90
Me (2a)
4-MeC6H4 (2b) Me (2b)
Me (2c)
4-FC6H4 (2j)
H (2c)
H (2j)
(CH2)3 (2e)
(CH2)4 (2f)
Me (2d)
2-C6H4CH2CH2 (2g)
Experimental Section
Et (2d)
General Procedure for Microwave-Promoted Parallel
Synthesis of 2,6-Dicyanoanilines in solution. The appropri-
ate (see Table 1) aldehydes (10 mmmol), ketones (10 mmol),
propanedinitrile (25 mmol), and triethylamine (15 mmol) were
placed in five individual 25 mL glass bottles immersed in a Pyrex
crystallization dish filled with neutral alumina (500 g, 100-200
mesh). This setup was placed at the cavity of microwave
synthesizer. After irradiation at 300 W for 2 min, the reaction
mixture was cooled to room temperature and then dissolved in
CH2Cl2. The solution was washed with water, dried over
anhydrous Na2SO4 and evaporated in a vacuum. The crude
products were purified by a flash column chromatography on
silica gel with ethyl acetate-hexane (1:4, v/v) as eluent. All the
compounds were recrystallized from ethanol.
a Purity data were obtained on the basis of HPLC analysis for
the crude products.
TABLE 3. Fluorescence Data for Compounds 4p and 4u
in Different Solvents
in CH2Cl2
in MeOH
in THF
λex
λem
λex
λem
λex
λem
compd (nm) (nm) Φf (nm) (nm) Φf (nm) (nm) Φf
4p
4u
356 395 0.10 362 415 0.13 363 409 0.12
368 414 0.08 373 433 0.10 374 440 0.09
2,6-Dicyano-3-(4-methyloxycarbonylphenyl)-4-methyl-5-
phenylaniline (4c): colorless crystal needle; mp 210-213 °C;
1H NMR (CDCl3) δ 8.18 (d, J ) 8.20 Hz, 2H), 7.48 (m, 3H), 7.39
(d, J ) 8.20 Hz, 2H), 7.27 (t, J ) 7.84 Hz, 2H), 5.16 (bs, 2H),
3.95 (s, 3H), 1.73 (s, 3H) ppm; 13C NMR (CDCl3) δ 166.6, 151.1,
150.0, 149.6, 142.4, 137.6, 131.0, 130.4, 129.3, 129.1, 128.9, 128.6,
124.9, 115.6, 115.5, 98.7, 97.7, 52.6, 17.8 ppm; IR (KBr) ν 3457,
3345, 3245, 2950, 2223, 1718, 1644, 1560, 1436, 1278, 1116, 760,
702 cm-1; MS (ESI) m/z 366.2 ([M - H]+); HRMS (ESI) calcd
for C23H17N3O2 ([M + Na]+) 390.1213, found 390.1206.
2,6-Dicyano-3-(furan-2-yl)-4-methyl-5-phenylaniline (4h):
olivine crystal needle; mp 198-199 °C; 1H NMR (CDCl3) δ 7.62
(d, J ) 0.94 Hz, 1H), 7.50 (m, 3H), 7.27 (m, 2H), 6.80 (d, J )
3.25 Hz, 1H), 6.59 (m, 1H), 5.18 (bs, 2H), 1.96 (s, 3H) ppm; 13C
NMR (CDCl3) δ 151.2, 150.4, 148.9, 144.1, 138.5, 137.7, 129.3,
129.1, 128.7, 125.9, 116.1, 115.7, 113.8, 111.8, 98.6, 96.6, 18.2
ppm; IR (KBr) ν 3459, 3359, 3242, 2930, 2221, 1639, 1555, 1454,
1268, 1026, 770, 714, 594 cm-1; MS (ESI) m/z 298.1 ([M - H]+);
HRMS (ESI) calcd for C19H13N3O ([M + Na]+) 322.0951, found
322.0960.
0.13) were calculated based on 9,10-diphenylanthrance
(Table 3).12 In view of possible applications of these
compounds (e.g., as organic light-emitting diodes) the
NH2 substituted A-D-A systems are of interest since
these compounds can be transformed into more thermo-
stable derivatives through their amino groups. Also, the
subsequent step of the combinatorial development pro-
cess, namely structural optimization should be possible.
The application of combinatorial strategies for screening
and optimization of organic charge-transporting materi-
als in a spatially addressable library of organic light-
emitting diodes was reported by Schmidt et al.13
In conclusion, we have demonstrated a facile and
general microwave-enhanced three-component reaction
(12) Optically dilute measurements with refractive-index correc-
tions, maximal absorption of solutions e0.04. Measurements referenced
to 9,10-diphenylanthrance (Φf ) 0.90 ( 0.02); (a) Lakowicz, J. R., Ed.;
Principles of Fluorescence Spectroscopy, 2nd ed.; Kluwer Academic/
Plenum Publishers: New York, 1999. (b) Demas, J. N.; Grosby, G. A.
J. Phys. Chem. 1971, 75, 991-1024.
(13) (a) Schmitz, C.; Posch, P.; Thelakkat, M.; Schmidt, H. W. Phys.
Chem. Chem. Phys. 1999, 1, 1777. (b) Schmitz, C.; Thelakkat, M.;
Schmidt, H. W. Adv. Mater. 1999, 11, 821-826.
2,6-Dicyano-3,5-di(4-methylphenyl)-4-methylaniline
1
(4i): white crystal needle; mp 251-253 °C; H NMR (CDCl3) δ
7.29 (d, J ) 8 Hz, 4H), 7.18 (d, J ) 8 Hz, 4H), 5.11 (bs, 2H),
2.41 (s, 6H), 1.76 (s, 3H) ppm; 13C NMR (CDCl3) δ 150.9, 150.0,
139.0, 135.0, 130.0, 128.5, 125.3, 116.0, 98.0, 21.6, 17.9 ppm; IR
(KBr) ν 3464, 3353, 3325, 2923, 2224, 1634, 1556, 1515, 1438,
2868 J. Org. Chem., Vol. 70, No. 7, 2005

1265, 1020, 815, 528 cm-1; MS (ESI) m/z 336.2 ([M - H]+);
HRMS (ESI) calcd for C23H19N3 ([M + Na]+) 360.1471, found
360.1473.
(m, 2H), 7.56 (m, 3H), 6.92 (bs, 2H), 6.88 (s, 1H), 3.93 (s, 3H)
ppm; 13C NMR (DMSO-d6) δ 166.2, 154.5, 150.5, 149.0, 142.3,
137.8, 130.8, 129.9, 129.8, 129.5, 129.1, 129.0, 118.9, 116.3, 116.1,
95.2, 94.4, 52.8 ppm; IR (KBr) ν 3396, 2922, 2214, 1725, 1621,
1300, 1122, 694 cm-1; MS (EI) m/z 353 (M+, 44.61); 57 (100);
HRMS (EI) calcd for C22H15N3O2 (M+) 353.1159, found 353.1158.
2,6-Dicyano-3-(4-methyloxycarbonylphenyl)-5-methyl-
aniline (7d): yellow powder; mp 230-231 °C; 1H NMR (CDCl3)
δ 8.16 (d, J ) 8.25 Hz, 2H), 7.60 (d, J ) 8.25 Hz, 2H), 6.73 (s,
1H), 5.28 (bs, 2H), 3.96 (s, 3H), 2.56 (s, 3H) ppm; 13C NMR
(CDCl3) δ 166.7, 152.8, 149.0, 148.3, 142.0, 131.3, 130.3, 128.7,
120.5, 115.9, 115.4, 97.5, 94.1, 52.6, 21.7 ppm; IR (KBr) ν 3477,
3357, 2920, 2221, 1720, 1647, 1295, 1109, 712 cm-1; MS (EI)
m/z 291 (M+, 72.69), 260 (100); HRMS (EI) calcd for C17H13N3O2
(M+) 291.1002, found 291.1002.
2,6-Dicyano-3-(4-methyloxycarbonylphenyl)-4-methyl-5-
ethylaniline (7h): yellow crystal; mp 177-178 °C; 1H NMR
(DMSO-d6) δ 8.08 (d, J ) 8.14 Hz, 2H), 7.45 (d, J ) 8.14 Hz,
2H), 6.49 (bs, 2H), 3.90 (s, 3H), 2.81 (q, J ) 7.42 Hz, 2H), 1.86
(s, 3H), 1.16 (t, J ) 7.45 Hz, 3H) ppm; 13C NMR (DMSO-d6) δ
166.3, 153.0, 151.5, 149.6, 143.4, 130.2, 129.9, 129.5, 122.7,
116.10, 116.07, 97.1, 95.5, 52.8, 26.7, 15.8, 13.9 ppm; IR (KBr)
ν 3451, 3368, 2926, 2218, 1724, 1647, 1277, 767 cm-1; MS (EI)
m/z 319 (M+, 100%); HRMS (EI) calcd for C19H17N3O2 (M+)
319.1315, found 319.1316.
2,6-Dicyano-3-(2-chlorophenyl)-4-methyl-5-ethylani-
line (4o): white crystal; mp 193-194 °C; 1H NMR (CDCl3) δ
7.53 (m, 1H), 7.41 (m, 2H), 7.20 (m, 1H), 5.07 (bs, 2H), 2.91 (q,
J ) 7.54 Hz, 2H), 1.92 (s, 3H), 1.27 (t, J ) 7.55 Hz, 3H) ppm;
13C NMR (CDCl3) δ 152.8, 150.2, 147.7, 136.9, 132.9, 130.6,
130.2, 130.2, 127.6, 125.3, 115.8, 115.4, 98.0, 96.6, 27.0, 15.3,
14.0 ppm; IR (KBr) ν 3472, 3346, 3241, 2970, 2228, 2212, 1641,
1569, 1461, 1294, 1238, 1061, 895, 766, 540 cm-1; MS (ESI) m/z
294.0 ([M - H]+); HRMS (ESI) calcd for C17H14ClN3 ([M + Na]+)
318.0768, found 318.0763.
2,6-Dicyano-5-(5-hydroxylmethyl)isoxazol-3-yl)-3-phen-
ylaniline (4u): yellowish solid; mp 226-228 °C; 1H NMR
(DMSO-d6) δ 7.64 (m, 2H), 7.55 (m, 3H), 7.10 (s, 1H), 7.01 (s,
1H), 6.95 (bs, 2H), 5.79 (t, J ) 5.79 Hz, 1H), 4.67 (d, J ) 5.95
Hz, 2H) ppm; 13C NMR (DMSO-d6) δ 174.8, 160.1, 154.7, 150.9,
137.5, 136.6, 130.1, 129.2, 129.0, 118.1, 116.1, 115.1, 102.3, 96.8,
93.4, 55.2 ppm; IR (KBr) ν 3469, 3414, 3343, 3245, 2932, 2227,
2212, 1644, 1585, 1435, 1291, 1040, 704, 594 cm-1; MS (ESI)
m/z 315.0 ([M - H]+); HRMS (EI) calcd for C18H12N4O2 (M+)
316.0954, found 316.0951.
General Procedure for Microwave-Promoted Parallel
Synthesis of 2,6-Dicyanoanilines on PEG Support. The
appropriate (see Table 2) PEG-supported aldehydes (10 mmmol),
ketones (20 mmol), propanedinitrile (30 mmol), and ammonium
acetate (10 mmol) were placed in five individual 25 mL glass
bottles immersed in a Pyrex crystallization dish. This setup was
placed at the cavity of microwave synthesizer. After irradiation
at 300 W for 2 min, the reaction mixtures were cooled to room
temperature. The polymer-supported products 6 were crystal-
lized from 2-propanol (30 mL), washed with diethyl ether, and
subsequently dried in a vacuum. The polymers 6 were treated
with 0.1 N NaOMe in anhydrous MeOH (10 mL) at room
temperature for 6 h. The detached PEG-OH was precipitated
by adding cold diethyl ether (30 mL) and filtered. The filtrates
were washed with brine, dried over anhydrous Na2SO4 and
evaporated in a vacuum to afford the corresponding crude
products. The pure products were obtained by recrystallization
from EtOH.
Acknowledgment. This work was financially sup-
ported by the 973 Project of Ministry of Science and
Technology (No.2002CB713808), the Natural Science
Foundation of Zhejiang Province (R404109), as well as
the Teaching and Research Award Program for Out-
standing Young Teachers in Higher Education Institu-
tions of MOE, P.R.C.
Supporting Information Available: Reaction condition
optimization. Experimental procedures. Spectral data for other
1
products. Copies of H and 13C NMR spectra for all products.
UV-vis absorption and fluorescence spectra for compounds
4p and 4u. X-ray structure details for compound 4c (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
2,6-Dicyano-3-(4-methyloxycarbonylphenyl)-5-phenyl-
aniline (7a): yellow powder; mp 274-275 °C; 1H NMR (DMSO-
d6) δ 8.12 (d, J ) 7.51 Hz, 2H), 7.83 (d, J ) 7.57 Hz, 2H), 7.67
JO047823H
J. Org. Chem, Vol. 70, No. 7, 2005 2869