Direct solvent-free regioselective construction of pyrrolo[1,2-a][1,10] phenanthrolines based on isocyanide-based multicomponent reactions

Article abstract of DOI:10.1021/ol400191b

A novel efficient one-pot four-component regioselective synthesis of pyrrolo[1,2-a][1,10]phenanthrolines in excellent yields has been developed by 1,3-dipolar cycloaddition of aldehydes, malononitrile, and isocyanides with 1,10-phenanthroline under solvent-free conditions within 3 min without using any catalyst or activation. The products were preliminarily investigated as chromogenic and fluorescent sensors for Cu²⁺ ions.

Full text of DOI:10.1021/ol400191b

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Direct Solvent-Free Regioselective
Construction of
Pyrrolo[1,2‑a][1,10]phenanthrolines
Based on Isocyanide-Based
Multicomponent Reactions
Ming Li,*,†,‡ Xiu-Liang Lv,† Li-Rong Wen,*,† and Zhi-Qiang Hu†
State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry,
Molecular Engineering, Qingdao University of Science and Technology,
Qingdao 266042, P. R. China, and State Key Laboratory, Institute of Elemento-organic
Chemistry, Nankai University, Tianjin 300071, P. R. China
Liming928@qust.edu.cn; wenlirong@qust.edu.cn
Received January 22, 2013
ABSTRACT
A novel efficient one-pot four-component regioselective synthesis of pyrrolo[1,2-a][1,10]phenanthrolines in excellent yields has been developed
by 1,3-dipolar cycloaddition of aldehydes, malononitrile, and isocyanides with 1,10-phenanthroline under solvent-free conditions within 3 min
without using any catalyst or activation. The products were preliminarily investigated as chromogenic and fluorescent sensors for Cu2þ ions.
Rapid synthesis of complex molecules in a single opera-
tion without isolation of intermediates is one of the current
concerns of the scientific community that drives increasing
efforts.1 The multicomponent reaction (MCR) has thus
emerged as a powerful tool for this purpose.2 Isocyanide-
based multicomponent reactions (IMCRs) are among the
most popular multicomponent condensations due to their
diversity of bond-forming processes, functional group toler-
ance, and high levels of chemo-, regio-, and stereoselec-
tivities.3 Apart from their well-known and much exploited
reactivity in Passerini and Ugi reactions,4 isocyanides are
known to form zwitterions with activated acetylene com-
pounds such as dimethyl acetylenedicarboxylate (DMAD)
and develop novel protocols for the synthesis of hetero-
cycles.5 The success of these reactions provided us with a
conceptual framework for designing novel multicomponent
reactions.
† Qingdao University of Science and Technology.
‡ Nankai University.
(1) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115. (b) Ruijter, E.;Scheffelaar,
R.; Orru, R. V. A. Angew. Chem., Int. Ed. 2011, 50, 6234. (c) Groenendaal,
B.; Ruijter, E.; Orru, R. V. A. Chem. Commun. 2008, 5474. (d) Ganem, B.
´
Acc. Chem. Res. 2009, 42, 463. (e) Tejedor, D.; Garcıa-Tellado, F. Chem.
Soc. Rev. 2007, 36, 484. (f) Nair, V.; Menon, R. S.; Sreekanth, A. R.;
Abhilash, N.; Biju, A. T. Acc. Chem. Res. 2006, 39, 520.
(2) (a) Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem. Res. 2011, 44, 1156.
(b) Tietze, L. F.; Kinzel, T.; Brazel, C. C. Acc. Chem. Res. 2009, 42, 367.
ꢀ
(c) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439. (d) Ismabert,
N.; Lavilla, R. Chem.;Eur. J. 2008, 14, 8444. (d) Sunderhaus, J. D.;
Martin, S. F. Chem.;Eur. J. 2009, 15, 1300. (e) Wei, H.-L.; Yan, Z.-Y.;
Niu, Y.-L.; Li, G.-Q.; Liang, Y.-M. J. Org. Chem. 2007, 72, 8600.
(f) Duan, X.-H.; Liu, X.-Y.; Guo, L.-N.; Liao, M.-C.; Liu, W.-M.;
Liang, Y.-M. J. Org. Chem. 2005, 70, 6980. (g) Jiang, B.; Tu, S.-J.; Kaur,
P.; Wever, W.; Li, G.-G. J. Am. Chem. Soc. 2009, 131, 11660. (h) Jiang,
B.; Rajale, T.; Wever, W.; Tu, S.-J.; Li, G.-G. Chem.;Asian J. 2010, 5,
2318. (i) Lin, X.-F.; Mao, Z.-J.; Dai, X.-X.; Lu, P.; Wang, Y.-G. Chem.
Commun. 2011, 47, 6620. (j) Hong, D.; Zhu, Y.-X.; Li, Y.; Lin, X.-F.; Lu,
P.; Wang, Y.-G. Org. Lett. 2011, 13, 4668. (k) Zhu, Y.-X.; Yin, G.-W.;
Hong, D.; Lu, P.; Wang, Y.-G. Org. Lett. 2011, 13, 1024. (l) Sun, J.; Xia,
E.-Y.; Wu, Q.; Yan, C.-G. Org. Lett. 2010, 12, 3678.
€
(3) (a) Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112,
€
3083. (b) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
(c) Sadjadi, S.; Majid, M. H. Tetrahedron 2011, 67, 2707.
€
(4) (a) Ugi, I.; Steinbruckner, C. Angew. Chem. 1960, 72, 267.
€
(b) Domling, A. Chem. Rev. 2006, 106, 17. (c) Zhu, J. Eur. J. Org. Chem.
2003, 1133. (d) Grassot, J. M.; Masson, G.; Zhu, J.-P. Angew. Chem., Int.
Ed. 2008, 47, 947.
r
10.1021/ol400191b
XXXX American Chemical Society

1,10-Phenanthroline and its derivatives possess a variety
of uses, especially as biologically active compounds and
chelating agents.6 So far, pyrrolo[1,2-a][1,10]phenanthroline
derivatives are mostly promising candidates for solid-state
device technology,7 particularly organic light emitting diodes
(OLEDs);8 no utility as a probe for metal ions has been
reported. From a synthetic point of view, to date, methods
for obtaining pyrrolo[1,2-a][1,10]phenanthrolines are very
limited. The most useful synthetic approaches were based on
1,3-dipolar cycloaddition reactions of 1,10-phenanthroli-
nium N-ylides with activated alkynes and alkenes.9 Consid-
ering the growing interest for these compounds, and based
on our previous endeavors in exploring novel and practical
multicomponent reactions,10 herein, we report a novel dis-
placement strategy involving the reactions of zwitterions
generated in situ from isocyanides, aldehydes, and malono-
nitrile with 1,10-phenanthroline to rapidly construct novel
pyrrolo[1,2-a][1,10]phenanthrolines, which have not been so
far reported as a selective chemosensor for determination of
Cu2þ. To the best of our knowledge, this is so far the first
synthetic application of isocyanides to construct pyrrolo-
[1,2-a][1,10]phenanthrolines.
Our investigation started with the reaction of isocyano-
cyclohexane 1a, malononitrile 2, 4-fluorobenzaldehyde 3a,
and 1,10-phenanthroline 4 at room temperature in acet-
onitrile. A variety of molecular ratios, temperature, sol-
vents, and bases were screened (Table 1), and the results
showed that protic solvents were less efficient (Table 1,
entries 5ꢀ7); even in trifluoroethanol a complicated mix-
ture was observed. Interestingly, when dichloromethane
was accidentally decreased from 2 to 1 mL, the product 5a
was directly separated out in 82% yield within 10 h.
Inspired by this result, and considering that the solvent-
free reaction (SFR)3,4,11,12 is an important synthetic pro-
cedure from the viewpoint of green and sustainable chem-
istry, the solvent-free conditions at 40 °C in an oil bath
were attempted. Excitingly, a breakthrough result was
achieved; the starting materials were completely consumed
in 2 min affording the desired compound 5a in 95%
isolated yield (Table 1, entry 9). The best results were
obtained in the molecular ratio 1:1.2:1.2:1 for 1a/2/3a/4 at
40 °C under solvent-free conditions (for details, see Table
S1 in the Supporting Information (SI)).
Table 1. Optimization of Reaction Conditions for 5aa
temp
t
yieldb
(%)
entry
solvent
CH3CN
(°C)
(h)
1
2
3
4
5
6
7
8
9
10
rt
40
rt
rt
rt
rt
rt
rt
40
50
16
72
CH3CN
10
62
CH3CN
12
72c
71d
60
CH3CN
12
CH3CH2OH
CH3OH
24
10
68
CF3CH2OH
CH2Cl2
15
mixture
82e
95
10
f
;
2 min
2 min
f
;
90
a Reaction of cycloisocyanide 1a (1.0 mmol), malononitrile 2
(1.2 mmol), 4-fluoroaldehyde 3a (1.2 mmol), and 1,10-phenanthroline
4 (1.0 mmol) was performed in 2 mL of solvent. b Isolated yield after
washing with acetonitrile. c Et3N was used as base. d PPh3 was used as
base. e In 1 mL of CH2Cl2. f Solvent-free conditions.
(5) (a) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.;
Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899. (b) Shaabani,
A.; Ghadari, R.; Sarvary, A.; Rezayan, A. H. J. Org. Chem. 2009, 74,
4372. (c) Esmaeili, A. A.; Hosseinabadi, R.; Habibi, A. Synlett 2010, 10,
1477. (d) Nair, V.; Menon, R. S.; Beneesh, P. B.; Sreekumar, V.; Bindu,
S. Org. Lett. 2004, 6, 767. (e) Zhu, X.; Xu, X.-P.; Sun, C.; Wang, H.-Y.;
Zhao, K.; Ji, S.-J. J. Comb. Chem. 2010, 12, 822. (f) Pillai, A. N.; Suresh,
C. H.; Nair, V. Chem.;Eur. J. 2008, 14, 5851.
To generate a small library of functionalized pyrrolo-
[1,2-a][1,10]phenanthrolines, we next utilized a variety of
substrates to explore the synthetic scope and generality of
this accelerated one-pot Knoevenagel condensationꢀ1,3-
dipolar cycloaddition cascade reaction under the optimal
conditions. Representative results are shown in Table 2.
Gratifyingly, the reactions of a wide range of aldehydes
3aꢀo with isocyanocyclohexane 1a, malononitrile 2, and
1,10-phenanthroline 4 proceeded smoothly. The results
showed that the process could tolerate both aromatic alde-
hydes with electronically different substituents (Table 2, en-
tries 1ꢀ14) and heteroaromatic aldehydes such as furan-2-
carbaldehyde (Table 2, entry 15). Unfortunately, some
(6) (a) Huang, W.; Wang, L.; Tanaka, H.; Ogawa, T. Eur. J. Inorg.
€
Chem. 2009, 1321. (b) Bolink, H. J.; Cappelli, L.; Coronado, E.; Gratzel,
M.; Nazeeruddin, M. K. J. Am. Chem. Soc. 2006, 128, 46. (c) Zong, R.;
Thummel, R. P. J. Am. Chem. Soc. 2004, 126, 10800. (d) White, T. A.;
Higgins, S. L. H.; Arachchige, S. M.; Brewer, K. J. Angew. Chem., Int.
Ed. 2011, 50, 12209.
(7) (a) Leontie, L.; Druta, I.; Danac, R.; Rusu, G. I. Synth. Met. 2005,
155, 138. (b) Prelipceanu, M.; Prelipceanu, O. S.; Leontie, L.; Danac, R.
Phys. Lett. A 2007, 368, 331.
(8) Prelipceanu, M.; Leontie, L.; Danac, R.; Prelipceanu, O. S.
Proceedings, Romanian Conference on Advanced Materials, September
11ꢀ14, 2006, Bucharest-Magurele, Romania, p 68.
(9) (a) Dumitrascu, F.; Mitan, C. I. Tetrahedron Lett. 2001, 42, 8379.
(b) Danac, R.; Rotaru, A.; Drochioiu, G.; Druta, I. J. Heterocycl. Chem.
2003, 40, 283. (c) Dumitrascu, F.; Caira, M. R.; Draghici, C.; Caproiu,
M. T.; Badoiu, A. Molecules 2005, 10, 321. (d) Journal of Chemical
~
Crystallography 2005, 35, 361. (e) Dumitrascu, F.; Caira, M. R.; Draghici,
~
C.; Caproiu, M. T.; Brrbu, L. Revue Roumaine Chimie 2008, 53, 183.
(11) (a) Candeias, N. R.; Branco, L. C.; Gois, P. M. P.; Afonso,
C. A. M.; Trindade, A. F. Chem. Rev. 2009, 109, 2703. (b) Martins,
M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.; Machado, P. Chem.
Rev. 2009, 109, 4140. (c) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100,
(10) (a) Wen, L.-R.; Li, Z.-R.; Li, M.; Cao, H. Green Chem. 2012,
14, 707. (b) Li, M.; Cao, H.; Wang, Y.; Lv, X.-L.; Wen, L.-R. Org. Lett.
2012, 14, 3470. (c) Wen, L.-R.; Shi, Y.-J.; Liu, G.-Y.; Li, M. J. Org.
Chem. 2012, 77, 4252. (d) Li, M.; Shao, P.; Wang, S.-W.; Kong, W.; Wen,
L.-R. J. Org. Chem. 2012, 77, 8956. (e) Li, M.; Kong, W.; Wen, L.-R.;
Liu, F.-H. Tetrahedron 2012, 68, 4838. (f) Wen, L.-R.; Liu, C.; Li, M.;
Wang, L.-J. J. Org. Chem. 2010, 75, 7605. (g) Li, M.; Qiu, Z.-X.; Wen,
L.-R.; Zhou, Z.-M. Tetrahedron 2011, 67, 3638. (h) Li, M.; Hou, Y.-L.;
Wen, L.-R.; Gong, F.-M. J. Org. Chem. 2010, 75, 8522.
ꢀ
ꢀ
1025. (d) Galvez, J.; Galvez-Llompart, M.; Garcıa-Domenech, R. Green
´
Chem. 2010, 12, 1056. (e) Tan, J.-N.; Li, M.-H.; Gu, Y.-L. Green Chem.
2010, 12, 908. (f) Ramachary, D. B.; Jain, S. Org. Biomol. Chem. 2011, 9,
1277.
(12) Ugi, I.; Meyer, R. Angew. Chem., Int. Ed. 1962, 1, 8.
B
Org. Lett., Vol. XX, No. XX, XXXX

aliphatic aldehydes such as acetaldehyde, propionalde-
hyde, and butyraldehyde only gave trace products that
could not be isolated.
Scheme 1. Exploration of 1,4-Phthaldehyde 3p as Substrate
Table 2. Exploration of Substrate Scope for Synthesis of 5/6
formation zwitterions. According to the Mironov reac-
tion,13 the zwitterion was generated from 2-arylidene
malononitrile and 1,10-phenanthroline. However, in our
investigation, the zwitterion was generated from 2-aryli-
denemalononitrile and an isocyanide, which was con-
firmed by the X-ray single crystal diffraction analysis of
compounds 5l and 6a (Figure S1, SI).
entry
R2
product
t (min)
yielda (%)
1
4-FC6H4
5a
5b
5c
5d
5e
5f
2
95
93
90
90
88
90
90
86
88
85
84
82
83
80b
90
93
94
92
90
89
87
2
4-ClC6H4
4-BrC6H4
4-NO2C6H4
3-BrC6H4
2-FC6H4
2
3
2
4
2.5
2
5
Scheme 2. Plausible Mechanism
6
2
7
2-ClC6H4
2-BrC6H4
2-NO2C6H4
C6H5
5g
5h
5i
2
8
2
9
2.5
2
10
11
12
13
14
15
16
17
18
19
20
21
5j
4-MeC6H4
4-MeOC6H4
2-MeC6H4
4-OHC6H4
2-furnan
2-ClC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
C6H5
5k
5l
3
3
5m
5n
5o
6a
6b
6c
6d
6e
6f
3
3
2
2
2
2
2
2
4-MeOC6H4
2
a Isolated yield after washing by EtOH. b Yield after purification via
silica gel column chromatography.
Encouraged by the success of this reaction, we employed
ethyl 2-isocyanoacetate 1b instead of cyclohexylisocyanide
1a to investigate this IMCR and found the reactions
involving 1b also proceeded well to afford the correspond-
ing products 6 in excellent yields (Table 2, entries 16ꢀ21).
Subsequently, the difunctional group 1,4-phthaldehyde
3p was also used to explore the scope of this reaction, and
theresultswerestill satisfactoryeventhoughlow yieldsand
a slightly longer reaction time were required (Scheme 1).
The above results revealed that the substituents on the
aromatic aldehydes had some influence on the yields of
products 5/6. The aromatic aldehydes with electron-
withdrawing groups such as fluoro, chloro, bromo, and nitro
groups (Table 2, entries 1ꢀ9 and 16ꢀ18) reacted faster and
gave higher yields than those with electron-rich groups such
as methyl and methoxyl groups (Table 2, entries 11ꢀ13 and
20). However, the position of the substituents did not exhibit
evident regularity in the reactivity of aromatic aldehydes.
It is worth mentioning that this new domino multi-
component procedure might involve two directions of
Although we have not experimentally established the
mechanism of the reaction, based on the above experi-
mental results, a plausible reaction scenario for the domino
cyclocondensation is presented in Scheme 2. The first step
is believedto be the Knoevenagel condensation between an
aldehyde 3 and malononitrile 2 to generate 2-arylidenema-
lononitrile which reacts with an isocyanide 1 to give a
highly reactive zwitterion intermediate [A], followed by its
trapping with 1,10-phenanthroline 4 to afford the inter-
mediate [B]. Next [C] and [D] were obtained by N-cycliza-
tion and aromatization with loss of HCN. Finally,
products 5/6 were received.
Selective detection of metal ions has been of great
interest because of their importance in biological and
(13) Mironov, M. A.; Ivantsova, M. N.; Mokrushin, V. S. Synlett
2003, 7, 943.
Org. Lett., Vol. XX, No. XX, XXXX
C

environmental processes. However, an inherent problem
exists in the detection of Cu2þ for fluorescent sensing
because of the likely quenching of fluorescence.14 Consid-
ering the great amount of interest in 1,10-phenanthrolines
as a ligand for metal complexes, we preliminarily studied
the photophysical behavior of representative compounds
5j and 6e in the presence of various metal ions in aqueous
solution, such as Cu2þ, Hg2þ, Mg2þ, Ba2þ, Naþ, Kþ, Agþ,
6e molecule, while with other metal ions no evident relevant
spectral changes were observed (Figure 2). The nonlinear
fitting of the titration curve assumed a 1:1 stoichiometry for
the 6eꢀCu2þ complex (Figure S4, SI). But 6e is suitable for
detecting the copper ion under the pH 6ꢀ7 conditions
(Figure S5, SI). From the fluorescence emission experiments
of 6b and 6f, it was found that the fluorescence intensity of
complexes could be decreased by the introdution of either
electron-withdrawing or -donating substituents compared to
unsubstituted 6e (Figure S6, SI).
Ca2þ, Cd2þ, Ce3þ, Co2þ, Ni2þ, Zn2þ, Pb2þ, and Al3þ
through UV/vis and fluorescence spectroscopy.
,
Figure 1. Visual appearance of solutions of 6e (10 μM) with
various metals (10 μM) in H2O/CH3CN (90:10 v/v) under
ambient light.
From Figure 1, we can observe clearly the metal-
dependent behavior of 6e; the product 6e showed strong
Cu2þ selectivity with an evident color change from yellow
to purple, while product 5j had no response to all ions.
The UV/vis absorption spectra of 6e (10 μM) in CH3CN
and upon addition of 3 equiv of various perchlorate salts of
metal ions (Figure S2, SI) show that 6eꢀCu2þ has a band
in the visible region, λmax = 549 nm, ε = 1.45 ꢁ 104 Mꢀ1
cmꢀ1. The IR and NMR spectra of the 6bꢀCu2þ complex
suggested that compounds 6 could bind Cu2þ as a N,N,N
ligand in a tridentate fashion, while the ester group did not
participate in the coordination (Figure S3, SI). N-Cyclo-
hexyl substituted pyrrolo[1,2-a]phenanthroline deriva-
tives 5 could not act as a tridentate ligand to coordinate
with Cu2þ, which may be due to the steric effect of the
cyclohexyl group. A similar observation was obtained with
compounds 6b and 6f, bearing an electron-withdrawing
and -donating substituent on the 10-aryl ring, respectively.
This feature of 6e allows visual detection of Cu2þ under
ambient light, configuring 6 as a potential sensor for the
Figure 2. Fluorescence profiles of 6e (10 μM) upon addition of vari-
ous metal ions (3 equiv) in H2O/CH3CN (90:10 v/v) (λex =375nm).
In summary, a novel rapid and direct synthesis of
pyrrolo[1,2-a][1,10]phenanthrolines has been developed
by cyclization of aldehydes, malononitrile with isocyanide,
and 1,10-phenanthroline under solvent-free conditions
within 3 min without using any catalyst or activation. This
is the first example of a synthesis of pyrrolo[1,2-a]-
[1,10]phenanthrolines involving the reactions of zwitter-
ions generated in situ from isocyanides, aldehydes, and
malononitrile with phenanthroline. Furthermore, our pro-
ducts 6 displayed a selective colorimetric and fluorescene
change upon the addition of Cu2þ over a wide range of
testedmetal ionsin H2O/acetonitrile (90:10 v/v), indicating
that compounds 6 could be used as a potential sensor for
the naked-eye detection of Cu2þ and may contribute to the
naked-eye detection of Cu2þ
.
development of a more useful fluorescent sensor for Cu2þ
.
We next performed fluorescence emission experiments
with compound 6e. The results were consistent with
the above observations. 6e has almost no fluoresence,
but the complex with Cu2þ shows an enhanced fluores-
cence (λem = 422 nm) with an emission maxima blue shift
relative to 6e (λem = 460 nm), which may be subject to
that after the chelation with Cu2þ the lowest excited singlet
state was changed to the S1(ππ*) state from S1(nπ*) of the
Acknowledgment. This work was financially supported
by the National Natural Science Foundation of China
(Nos. 20872074 and 21072110), the Natural Science Foun-
dation of Shandong Province (No. ZR2012BM003).
Supporting Information Available. Experimental and
characterization details, 1H and 13C NMR spectra of all
new compounds and complex 6b-Cu2þ, UV/vis spectra of
6e with metal ions, fluorescence emission spectra of 6e
upon titration with Cu2þ, and crystal data for 5l and 6a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) (a) Que, E. L.; Domaille, D. W.; Chang, C. J. Chem. Rev. 2008,
108, 1517. (b) Liu, J. W.; Lu, Y. J. Am. Chem. Soc. 2007, 129, 9838.
(c) Nez, R. M.; Zapata, F.; Caballero, A.; Espinosa, A. Org. Lett. 2006,
8, 3235. (d) Wu, C.; Bian, Q.-N.; Zhang, B.-G.; Cai, X.; Zhang, S.-D.;
Zheng, H.; Yang, S.-Y.; Jiang, Y.-B. Org. Lett. 2012, 14, 4198.
(e) Martorana, A.; Pace, A.; Buscemi, S.; Piccionello, A. P. Org. Lett.
2012, 14, 3240. (f) Liu, Z.-P.; Zhang, C.-L.; Wang, X.-Q.; He, W.-J.;
Guo, Z.-J. Org. Lett. 2012, 14, 4378. (g) Li, G.-K.; Xu, Z.-X; Chen,
C.-F.; Huang, Z.-T. Chem. Commun. 2008, 1774.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX