A new practical approach towards the synthesis of unsymmetric and symmetric 1,10-phenanthroline derivatives at room temperature

Article abstract of DOI:10.1039/c2cc17208a

An efficient method towards synthesis of 1,10-phenanthrolines is described. Through Lewis acid-catalyzed annulation reaction between 3-ethoxycyclobutanones and 8-aminoquinolines, a variety of unsymmetric and symmetric 1,10-phenanthroline derivatives were

Full text of DOI:10.1039/c2cc17208a

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COMMUNICATION
A new practical approach towards the synthesis of unsymmetric and
symmetric 1,10-phenanthroline derivatives at room temperaturew
Yongfeng Cheng,ab Xuesong Han,a Huangche Ouyanga and Yu Rao*a
Received 19th November 2011, Accepted 19th January 2012
DOI: 10.1039/c2cc17208a
An efficient method towards synthesis of 1,10-phenanthrolines is
described. Through Lewis acid-catalyzed annulation reaction
between 3-ethoxycyclobutanones and 8-aminoquinolines, a variety
of unsymmetric and symmetric 1,10-phenanthroline derivatives were
readily prepared with high regioselectivity at room temperature.
1,10-Phenanthroline derivatives represent an important class
of heterocycles that find extensive utility as chelating ligands in
coordination chemistry1 and building blocks in supramolecular
chemistry.2 Those compounds have also found interesting bio-
logical applications3 such as stabilizing the human telomerase
quadruplex DNA.
Due to the important applications of 1,10-phenanthrolines,
various synthetic methodologies had been developed.4 By far
the most prevalent strategies for constructing the 1,10-phenan-
throline skeleton are the classic annulation reactions such as
Friedlander,5 Doebner-Miller,6 Skraup7 syntheses, etc. More
¨
recently Povarov reaction8 and photochemical electrocyclic
reaction9 were also applied in its synthesis. However, these
methods usually suffered from one or more limitations which
include poor regioselectivity, low yield, high temperature, harsh
reaction conditions and tedious reaction procedures. A ready
synthesis of 1,10-phenanthrolines still remains a challenging
problem, therefore, the development of mild, practical and
complementary approaches to 1,10-phenanthroline derivatives
is highly desired.
Scheme 1 A new approach for construction of 1,10-phenanthrolines.
adopted as substrates in the reaction, theoretically a ‘3 + 3’
annulation between 3-ethoxycyclobutanones and 8-amino-
quinolines is possible. In contrast to forming pyrazoles
with substituted hydrazines, a formal cycloaddition between
3-ethoxycyclobutanones and 8-aminoquinolines could furnish
corresponding 1,10-phenanthroline derivatives as products
(Scheme 1a). Also, in principle, the respective substituted
8-aminoquinolines could be available through the same
protocol with 3-ethoxycyclobutanones and 2-azidoanilines
(Scheme 1b).
Serving as a versatile intermediate, 3-ethoxycyclobutanones
have been used to prepare various types of compounds such as
bicyclobutanes, silyloxy dienes and six-membered cyclic
compounds.10 In those studies, 3-ethoxycyclobutanones were
involved as a formal 1,4-dipole.11 Recently our group reported
the synthesis of pyrazoles through a ‘3 + 2’ annulation reaction
between 3-ethoxycyclobutanones and substituted hydrazines.12
Our studies demonstrated that 3-ethoxycyclobutanones can be
employed as a 1,3-dicarbonyl synthon for useful chemical
transformations. Based on these findings, we therefore envisioned
that if aromatic amines instead of substituted hydrazines were
To date, there are no reports in the literature that 3-ethoxy-
cyclobutanones could be employed as a 1,3-dicarbonyl synthon
to prepare 1,10-phenanthrolines. Herein we report the develop-
ment of an efficient approach toward regioselective synthesis of
unsymmetric and symmetric 1,10-phenanthrolines through
Lewis acid-catalyzed annulation reactions with 3-ethoxycyclo-
butanones and 8-aminoquinolines.
To test our hypothesis, a model study was initiated with 2,2-
cyclopentyl-3-ethoxycyclobutanone and 8-aminoquinoline
(Table 1). As a Lewis acid promoter, 0.2 equiv. of BF3ÁOEt2
was added to the reaction mixture. Delightfully the reaction
went to afford the desired product 3 (entry 1) in a yield of 18%
with complete regioselectivity after overnight stirring at room
temperature. Encouraged by this preliminary result, we started
a Department of Pharmacology and Pharmaceutical Sciences,
School of Medicine and School of Life Sciences, Tsinghua University,
Beijing, 100084, China. E-mail: yrao@mail.tsinghua.edu.cn
b Tianjin University of Traditional Chinese Medicine, Tianjin,
300193, China
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc17208a
c
2906 Chem. Commun., 2012, 48, 2906–2908
This journal is The Royal Society of Chemistry 2012

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Table 1 Optimization of the reaction conditions
Entry
Catalyst
Condition
Yielda (%)
1
2
3
4
5
6
7
8
BF3ÁOEt2
BF3ÁOEt2
BF3ÁOEt2
BF3ÁOEt2
TfOH
Sc(OTf)3
TMSOTf
TiCl4
0.2 eq., DCM, rt, 12 h
0.5 eq., DCM, rt, 12 h
0.8 eq., DCM, rt, 12 h
1.0 eq., DCM, rt, 24 h
1.0 eq., DCM, rt, 24 h
1.0 eq., DCM, rt, 24 h
1.0 eq., DCM, rt, 24 h
0.5 eq., DCM, rt, 24 h
1.0 eq., DCM, rt, 24 h
1.0 eq., DCM, rt, 48 h
1.2 eq., DCM, rt, 48 h
1.0 eq., DCE, rt, 48 h
1.0 eq., DMSO, rt, 24 h
1.0 eq., Toluene, rt, 24 h
1.0 eq., MeCN, rt, 24 h
1.0 eq., MeOH, rt, 24 h
18
55
52
74b
63
0
58
0
0
9
SnCl4
10
11
12
13
14
15
16
BF3ÁOEt2
BF3ÁOEt2
BF3ÁOEt2
BF3ÁOEt2
BF3ÁOEt2
BF3ÁOEt2
BF3ÁOEt2
87b
73
70
0
0
57
50
a
b
Conversion ratios. Isolated yields.
to optimize the reaction conditions. After a comprehensive
screening, we found that BF3ÁOEt2 was superior over other
Lewis acids, such as TMSOTf, TfOH etc., with a high level of
efficiency. But SnCl4, TiCl4 and Sc(OTf)3 were ineffective in
promoting this reaction. Generally, 1.0 equiv. amount of BF3Á
OEt2 was necessary to effectively promote the reaction. Smaller
Lewis acid loadings slow reaction rates and give rise to low
conversion ratios. It was observed that, besides DCM, the
reaction also proceeded smoothly in other solvents, such as DCE,
MeCN and MeOH, and gave product 3 in fair yields. However,
DMSO and toluene did not work in this case. Commonly
extending reaction time could improve yields. Typically the
reaction will proceed to completion within 48 hours in a clean
manner at room temperature (entry 10).
Scheme 2 Reaction scope for synthesis of unsymmetric 1,10-phenan-
throlines. a Isolated yields. b Yields in 24 h.
Having identified these optimal conditions, we set out to
explore the scope of this new reaction. As shown in Scheme 2, a
variety of 3-ethoxycyclobutanones were reacted with 8-amino-
quinoline in the presence of BF3ÁOEt2. The scope of the alkyl
substituents was found to be very broad. The ethyl, propyl, benzyl
and cyclohexyl groups, as well as the sterically demanding
isopropyl and 1-ethylpropyl groups were well tolerated. Different
3-ethoxycyclobutanones produced the corresponding 2-alkyl-1,10-
phenanthroline products smoothly in good to excellent yields
(compounds 4–17, Scheme 2). Especially noteworthy is the
synthesis of 1,10-phenanthrolines containing 2,3-disubstituents
(Scheme 2, compounds 13 and 14), since it is difficult to access
these compounds by conventional methods. Notably, only one
single product was isolated in all cases, no other regioisomer
was obtained.
Scheme 3 Synthesis of symmetric 1,10-phenanthrolines. a Isolated yields.
As illustrated in Scheme 3, this approach was successfully
employed in the synthesis of symmetric 1,10-phenanthroline
derivatives. The optimum reaction conditions proved to be
compatible with 2-azidoaniline which reacted with a variety of
3-ethoxycyclobutanones to readily provide different multi-
substituted quinolines (compounds 19–21). Following that,
a sequential chemical transformation including the Staudinger
reduction and second annulation with 3-ethoxycyclobuta-
nones afforded corresponding 1,10-phenanthroline products
in good yields. It is remarkable that this method can facilely
furnish 1,10-phenanthroline compound 26 containing 2,3,8,9-
tetrasubstituents which is synthetically challenging with usual
c
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Scheme 4 Plausible mechanism.
approaches. In general, these reactions showed great reactivity
and satisfactory yields as well. In particular, a consistent
complete regioselectivity of the reaction was observed. Only
single isomers were obtained in all examples.
A plausible mechanism for this new reaction is demonstrated
in Scheme 4. Upon activation of the possible in situ-generated
imine intermediate II from 2,2-disubstituted 3-ethoxycyclobu-
tanone (I), with Lewis acids, the more substituted C2–C3 bond
of hydrazone intermediate is broken down preferentially to
form a zwitterionic intermediate III. Subsequently the inter-
mediate III ring-closes to form the less strained six-membered
ring intermediate IV. Following this intramolecular cyclization,
an electron transfer provides intermediate V. Finally, elimina-
tion of one molecule of EtOH from V and a proton transfer
furnish the 1,10-phenanthroline product VII.
In summary, a practical protocol has been developed for the
ready synthesis of functionalized 1,10-phenanthrolines from
easily accessible starting materials at room temperature. This
method has been found to be generally useful for the preparation
of a variety of substituted 1,10-phenanthrolines some of which
are difficult to synthesize via conventional approaches. The
reaction demonstrates excellent reactivity, complete regio-
selectivity and high yields. By employing 3-ethoxycyclobutanones
as synthons for Lewis acid-catalyzed union with substituted
8-aminoquinolines, we have shown, for the first time, that this
masked 1,3-dicarbonyl synthon acts as a three-carbon synthon of
3-ethoxycyclobutanones in the preparation of unsymmetric and
symmetric 1,10-phenanthroline derivatives. Further studies using
newly synthesized 1,10-phenanthrolines as novel ligands in transi-
tion metal-catalyzed reactions are currently under investigation.
This work was supported by the national ‘973’ grant from the
Ministry of Science and Technology (grant # 2011CB965300),
National Natural Science Foundation of China (grant #
21142008) and Tsinghua University 985 Phase II funds.
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2908 Chem. Commun., 2012, 48, 2906–2908
This journal is The Royal Society of Chemistry 2012