Efficient synthesis of ferrocenylquinolines via the friedlaender reaction

Article abstract of DOI:10.1080/00397911.2010.519090

Acylferrocenes 2a-c reacted with ortho-aminoarylaldehydes 1a-e via the Friedlnder condensation reaction to afford the corresponding ferrocenylquinolines 3a-o in moderate yields in the presence of sodium ethoxide (30mmol%) under mild reaction conditions. U

Full text of DOI:10.1080/00397911.2010.519090

This article was downloaded by: [McGill University Library]
On: 28 February 2013, At: 13:26
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Efficient Synthesis of
Ferrocenylquinolines via the Friedländer
Reaction
Yuhua Long a , Haifeng Zhang a & Dingqiao Yang a
a School of Chemistry and Environment, South China Normal
University, Guangzhou, China
Accepted author version posted online: 04 Jul 2012.Version of
record first published: 13 Nov 2012.
To cite this article: Yuhua Long , Haifeng Zhang & Dingqiao Yang (2013): Efficient Synthesis of
Ferrocenylquinolines via the Friedländer Reaction, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 43:5, 619-634
To link to this article: http://dx.doi.org/10.1080/00397911.2010.519090
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 43: 619–634, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.519090
EFFICIENT SYNTHESIS OF FERROCENYLQUINOLINES
¨
VIA THE FRIEDLANDER REACTION
Yuhua Long, Haifeng Zhang, and Dingqiao Yang
School of Chemistry and Environment, South China Normal University,
Guangzhou, China
GRAPHICAL ABSTRACT
Abstract Acylferrocenes 2a–c reacted with ortho-aminoarylaldehydes 1a–e via the
Friedla¨nder condensation reaction to afford the corresponding ferrocenylquinolines 3a–o
in moderate yields in the presence of sodium ethoxide (30 mmol%) under mild reaction
conditions. Under the same reaction conditions, 1,10-diacetylferrocene 2d and
1,10-dipropionylferrocene 2e reacted with ortho-aminoaldehydes 1a–e to afford the corre-
sponding 1,10-bis(substituted quinolin-2-yl)ferrocene derivatives 3p–t. The structures of
compounds 3a–t were determined and characterized by infrared, 1H NMR, mass spec-
trometry, and elemental analysis. The crystal structures of 3e and 3q were determined by
x-ray crystallography.
Keywords Acylferrocene; ferrocenylquinoline; Friedla¨nder reaction; o-aminoarylalde-
hyde; sodium ethoxide catalysis
INTRODUCTION
The preparation of nitrogen-containing aromatic compounds such as
quinolines and pyrroles has been extensively studied for more than a century because
of their broad range of biological activities and many potential applications. Many
quinolines analogs have been developed as drugs to treat human diseases. Their
Received October 9, 2009.
Address correspondence to Dingqiao Yang, School of Chemistry and Environment, South China
Normal University, Guangzhou 510006, China. E-mail: yangdq@scnu.edu.cn
619

620
Y. LONG, H. ZHANG, AND D. YANG
bioactivities include antibacterial,[1] anticancer and antiplatelet,[2] antiasthmatic,[3]
anti-inflammatory,[4] and antihypertensive activities[5] and also inhibit tyrosine
kinase PDGF-RTK.[6] In addition to medicinal applications, quinoline derivatives
have been heavily investigated as ligands for advanced architecture materials
through self-assembly.[7,8]
The structural core of quinoline can be synthesized through many conventional
reactions such as Skraup, Doebner–Miller, Riehm, Combes, Conrad–Limbach, Knorr,
Friedla¨nder, Povarov, Camps, Niementowski, Gould–Jacobs, and Pfitzinger.[9] Many
other new synthetic methods for the synthesis of quinoline are currently under explo-
ration. For example, the reactions of aromatic imines with enolizable aliphatic aldehydes
in the presence of metal, acidic, and iodine catalysts also led to formation of quinoline
derivatives.[10] In addition, the Friedla¨nder reaction, although known for a long time,
was recently re-explored and is considered one of the most simple and straightforward
methods for the synthesis of quinolines. Friedla¨nder reaction involved the formation of
quinoline derivatives by condensation of ortho-aminoarylaldehydes or ortho-aminoar-
ylketones with an aldehyde or ketone containing a reactive a-methylene group. The
Friedla¨nder reaction is generally carried out either by refluxing an aqueous or alcoholic
solution of reactants in the presence of acids or bases or heating the reactants at high
temperatures without catalysts. Over the past few years, several catalysts such as
amines,[11] Brønsted acids,[12] Lewis acids,[13] base,[14] molecular iodine,[15] and proline[16]
have all been found to be effective for promoting Friedla¨nder condensation reactions. In
addition, microwave irradiation[17] and ionic liquid[18] have also been employed as
promoters. On the other hand, many transition-metal complexes,[19] such as ruthenium,
palladium, iron, rhodium, and iridium, were found to be effective catalysts for the
modified Friedla¨nder reaction.
In the light of recent studies,[20] the hybridized molecule between quinoline and
ferrocenyl moiety may possess promising biological activities and may find potential
medicinal application. For example, ferrocenes have antitumor activity because of
metabolic formation of ferricinium ions in situ.[21] In addition, its fascinating sand-
wich structure motifs have been widely used in organometallic chemistry, materials
science, and chiral ligands.[22]
Among extensively studied quinoline derivatives, we are interested in the syn-
thesis of ferrocenyl substituted quinolines because of their promising biological
activities and potential applications. In our previous work, we reported that sodium
ethoxide is an efficient catalyst in the synthesis of novel six-member ring-fused
quinoline derivatives via the Friedla¨nder reaction.[23] In this article, we reported
the efficient synthesis of substituted quinolin-2-yl- and 1,10-bis(substituted quino-
lin-2-yl)ferrocene derivatives 3a–t via Friedla¨nder reaction in the presence of sodium
ethoxide.
RESULTS AND DISCUSSION
The substrates ortho-aminoarylaldehyde 1a, 1b, and 1c, and ferrocenylketone
2a, 2b, 2c, 2d, and 2e were prepared according to the reported procedures.[24] At
the beginning of our study, we used ortho-aminobenzaldehyde 1a with acetylferro-
cene 2a for the condensation in the presence of catalyst (Table 1). For comparison,

EFFICIENT SYNTHESIS OF FERROCENYLQUINOLINES
621
Table 1. Catalysts studied in the Friedla¨nder annulation with ortho-aminobenzaldehyde (1a) and
acetylferrocene (2a)
Entry
Catalyst
Piperidine
NEt3
Time (h)
Yielda (%)
1
2
48
48
48
16
16
16
16
24
48
48
48
Trace
Trace
Nr
3
NH3 ꢁ H2O
K2CO3
KOH
4
56
67
5
6
C2H5ONa
C2H5ONab
C2H5ONac
IrCl3 ꢁ H2O
[Ir(cod)Cl]2
[Ir(cod)Cl]2=dppf
75
72
7
8
50
Nr
9
10
11
Trace
Trace
aIsolated yield after silica-gel column chromatography.
b100 mmol% EtONa was used.
c10 mmol% EtONa was used.
a variety of catalysts were screened, and the results are shown in Table 1. It can be
seen that all inorganic bases can promote the reaction to a certain degree, and
sodium ethoxide was the best. However, in the presence of an organic base such
as triethylamine and piperidine as well as the Ir complex, the reaction hardly pro-
ceeded, even after a long reaction time. The catalyst loading of sodium ethoxide
was then investigated. We found that greater amounts of the catalyst loading
(100 mmol%) did not improve the yields (Table 1, entry 7). When the catalyst loading
was decreased to 10 mmol%, a much longer reaction time was required with a yield
of 50% (Table 1, entry 8).
To optimize the reaction conditions, we conducted this reaction in different
solvents [EtOH, tetrahydrofuran (THF), H2O, CH3CN, and dioxane]. The results
demonstrated that ethanol was the best solvent (Table 2, entry 2). The reaction in
Table 2. (Quinolin-2-yl)ferrocene 3a was synthesized via the Friedla¨nder reaction in the presence of
sodium ethoxide (30 mmol%) in various solvents
Entry
Solvent
Reaction temp. (ꢀC)
Time (h)
Yield (%)
1
2
3
4
5
H2O
EtOH
THF
90
85
75
90
85
16
16
16
16
16
Nr
75
48
32
10
Dioxane
CH3CN

622
Y. LONG, H. ZHANG, AND D. YANG
THF and dioxane afforded the expected product in 48% and 32% yields, respectively
(Table 2, entries 3 and 4). In CH3CN it gave the desired product in poor yield (10%),
and in water the product was not detected. These results promted us to
select 30 mmol% of sodium ethoxide as the catalyst and ethanol as the solvent for
further study.
We next examine the analogs of reagent 1a so as to understand the scope and
generality of the CH3CH2ONa-catalyzed Friedla¨nder reaction. The results of these
reactions are summarized in Table 3. As seen from Table 3, the electronic effects
of the substituted groups have an impact on the reaction results. The electron donor
group such as OCH3 was observed to give good yields (73% and 69%, respectively)
(Table 3, entries 2 and 3). When the substituted group was an electron-withdrawing
group such as 5-Cl or 3,5-dibromo, the yields were slightly lower (60% and 63%,
respectively) (Table 3, entries
electron-withdrawing functional group decreased the reactivity of the amino group
4
and 5). This may be because the
Table 3. Friedla¨nder condensation reaction of ortho-aminoarylaldehyde (1a–e) with acetylferrocene (2a)
in the presence of sodium ethoxide catalyst
Entry
1
Substrate 1
Product 3
Time (h)
16
Yield (%)
75
Mp (ꢀC)
143–145
3a
2
3b
16
73
141–143
3
4
3c
3d
16
8
69
60
171–172
154–155
5
3e
8
63
161–163

EFFICIENT SYNTHESIS OF FERROCENYLQUINOLINES
623
Table 4. Friedla¨nder condensation reaction of ortho-aminoarylaldehyde (1a–e) with acylferrocene (2b and
2c) in the presence of sodium ethoxide catalyst
Entry
Substrate 1
Substrate 2
Product 3
Yield (%)
Mp (ꢀC)
1
2
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
2b
2b
2b
2b
2b
2c
2c
2c
2c
2c
3f
3g
3h
3i
26
27
20
23
25
24
22
20
23
25
73–74
164–165
171–172
119–121
154–156
190–191
180–181
177–179
153–155
155–156
3
4
5
3j
6
3k
3l
7
8
3m
3n
3o
9
10
at the phenyl ring. The reaction involved the formation of an enamine followed by
aldol-type cyclization to yield the expected quinolines. In addition, steric effects also
influenced the reactivity: ortho-aminobenzaldehyde achieved greater yield up to 75%
(Table 3, entry 1) than those ortho-aminobenzaldehyde with substitutes (Table 3,
entries 2–5).
To further investigate the scope of this reaction, ferrocenylketones containing
a-methylene such as propionylferrocene 2b and phenylacetylferrocene 2c reacted
with various substituted ortho-aminoarylaldehydes 1a–e to produce a serial of quino-
line derivatives, and the results are summarized in Table 4. Surprisingly, we found
that the reaction is difficult to proceed and a library synthesis of quinoline 3 was
obtained in poor yields even after long reaction times. By comparison of the data
in Tables 3 and 4, it can be seen that the steric effects of the substituents on the
a-methylene group significantly influenced the reaction results. When the substituent
was methyl or phenyl, which have more steric hindrance, the reactivity obviously
decreased. Therefore, we afforded lower yields ranging from 20% to 27% (Table 4).
Finally, we also studied the reaction using the substrates of ferrocenyldiketone
such as 1,10-diacetylferrocene 2d and 1,10-dipropionylferrocene 2e with ortho-
aminoarylaldehyde to synthesize 1,10-bis(substituted quinolin-2-yl)ferrocenes in the
presence of sodium ethoxide catalyst, and the results are summarized in Table 5
and Scheme 1. It can be seen that ortho-aminoarylaldehyde 1 underwent
double Friedla¨nder condensations with 1,10-diacylferrocene 2d or 2e to afford
the corresponding 1,10-bis(substituted quinolin-2-yl)ferrocenes 3p–r and 3t.

624
Y. LONG, H. ZHANG, AND D. YANG
Table 5. Friedla¨nder condensation of ortho-aminoarylaldehyde (1a–c) with 1,10-dipropionylferrocene (2d)
in the presence of sodium ethoxide catalyst
Entry
Substrate 1
Product 3
Yield (%)
Mp (ꢀC)
1
2
3
1a
1b
1c
3p
3q
3r
43
58
55
209–211
226–228
224–226
Scheme 1. Friedla¨nder condensation of ortho-aminoarylaldehyde (1a) with 1,10-diacetylferrocene (2e) in
the presence of sodium ethoxide catalyst.
2-Amino-3,6-dimethoxylbenzaldehyde 1c and 2-amino-4,5-dimethoxylbenzaldehyde 1d
can react with 1,10-diacetylferrocene 2d smoothly to give the corresponding
1,10-bis[2-(5,8-dimethoxyquinolinyl)]ferrocene
3r
and
1,10-bis[2-(6,7-dimethoxy-
quinolinyl)]ferrocene in good yields (58% and 55%, respectively) (Table 5, entries 2
and 3). However, ortho-aminobenzaldehyde 1a reacted with 1,10-diacetylferrocene 2d
to give 1,10-bis(quinolin-2-yl)ferrocene in slightly lower yield 43% (Table 5, entry 1). This
may be because ortho-aminobenzaldehyde 1a forms
a polymer through a
self-condensation reaction. Also 1,10-dipropionylferrocene 2e reacted with ortho-amino-
benzaldehyde 1a to give monoquinolineferrocene 3s as a major product in 40% yield
and bisquinolineferrocene 3t as a minor product in 8% yield (Scheme 1).
Crystal structures of 3e and 3q obtained by solvent evaporation from solution
of dichloromethane and ethanol (v=v ¼ 1:1) are shown in Figs. 1 and 2, respectively.
EXPERIMENTAL
Melting points were obtained on a XT-4 microscopic melting-point apparatus
and are uncorrected. 1H NMR and 13C NMR spectra were recorded on a Varian XL

EFFICIENT SYNTHESIS OF FERROCENYLQUINOLINES
625
Figure 1. Crystal structure of compound 3e showing the atom labeling scheme. Hydrogen atoms have
been omitted for clarity. The data are as follows: Crystal system is triclinic, space group P-1 with unit cell
3
ꢀ
ꢀ
˚
˚
˚
dimensions of a ¼ 10.8239(15) A , b ¼ 11.3478(16) A, c ¼ 13.5025(19) A, a ¼ 89.332(2) , b ¼ 81.543(2) ,
ꢂ1
ꢀ
˚
c ¼ 89.446(2) , V ¼ 1640.3(4) A, Z ¼ 17. Absorption coefficient is 14.014 cm
.
400-MHz spectrometer (at 400 and 100 MHz, respectively) with SiMe4 as the internal
standard in CDCl3. Infrared (IR) spectra were recorded on a Perkin-Elmer 1730
Fourier transform (FT)–IR spectrometer as KBr pellets. Mass Spectrometry (MS)
data were obtained using a VGZAB-HS mass spectrometer. Elemental analysis
was performed on a Elemental Varioel spectrometer. Bruker Smart CCD Apex II
was used for single-crystal x-ray diffraction.
Figure 2. Crystal structure of compound 3q showing the atom labeling scheme. Hydrogen atoms have
been omitted for clarity, the data are as follows: Crystal system is orthorhombic, space group P with unit
3
ꢀ
ꢀ
ꢀ
˚
˚
˚
cell dimensions of a ¼ 15.387(9) A , b ¼ 21.783(12) A, c ¼ 15.387 A, a ¼ 90 , b ¼ 90 , c ¼ 90 , V ¼ 5157(4)
ꢂ1
˚
A, Z ¼ 8. Absorption coefficient is 0.627 cm
.

626
Y. LONG, H. ZHANG, AND D. YANG
General Procedure for the Synthesis of (Substituted
quinolin-2-yl)ferrocene 3a–O, and 1,1’-Bis(substituted quinolin-
2-yl)ferrocene 3p–3t
Sodium ethoxide (0.3 mmol) was added to a solution of o-aminoarylaldehyde 1
(1 mmol) and acylferrocene 2 (1 mmol) in absolute anhydrous ethanol (15 ml). The
solution was stirred at reflux for the designated time. The mixture was cooled to
room temperature. The solvent was removed under vacuum, and the residue was
purified by flash column chromatography on silica gel with petroleum ether = ethyl
acetate to afford the expected product.
(Quinolin-2-yl)ferrocene (3a)
Red brown solid; mp 143–145 ꢀC; IR (KBr, cmꢂ1): 3086, 3058, 2924, 2851,
1615, 1598, 1556, 1510, 1424, 1282, 1127, 1105, 1091, 907, 824, 757; 1H NMR
(400 MHz, CDCl3) d 8.04 (d, J ¼ 3.6 Hz, 1H, Ar-H), 8.03 (d, J ¼ 3.6 Hz, 1H,
Ar-H), 7.74 (d, J ¼ 8.8 Hz, 1H, Ar-H), 7.66 (t, J ¼ 8.4 Hz, 1H, Ar-H), 7.57 (d,
J ¼ 8.4 Hz, 1H, Ar-H), 7.46 (t, J ¼ 8.0 Hz, 1H, Ar-H), 5.07 (t, J ¼ 2.0 Hz, 2H, Fc-Ha),
), 4.47 (t, J ¼ 2.0 Hz, 2H, Fc-Hb), 4.06 (s, 5H, Fc-H); 13C NMR (100 MHz, CDCl3) d
159.3, 148.1, 135.3, 129.2, 128.9, 127.3, 126.5, 125.2, 119.3, 83.8, 70.3, 69.6, 67.8; MS
(ESI): m=z ¼ 314 [M þH]þ. Anal. calcd. for C19H15FeN: C, 72.87; H, 4.83; N, 4.47.
Found: C, 72.64; H, 4.59; N, 4.40.
(5,8-Dimethoxyquinolin-2-yl)ferrocene (3b)
Brown solid; mp 141–143 ꢀC; IR (KBr, cmꢂ1): 3086, 2933, 2833, 1617, 1600,
1
1570, 1518, 1478, 1459, 1399, 1304, 1257, 1164, 1105, 1079, 800, 724; H NMR
(400 MHz, CDCl3) d 8.44 (d, J ¼ 8.8 Hz, 1H, Ar-H), 7.62 (d, J ¼ 8.8 Hz, 1H,
Ar-H), 6.92 (d, J ¼ 8.4 Hz, 1H, Ar-H), 6.70 (d, J ¼ 8.4 Hz, 1H, Ar-H), 5.09 (s, 2H,
Fc-Ha), 4.45 (s, 2H, Fc-Hb), 4.05 (s, 8H, Fc-H, OCH3), 3.96 (s, 3H, OCH3); 13C
NMR (100 MHz, CDCl3) d 158.9, 149.2, 148.9, 140.5, 130.2, 119.7, 119.3, 108.0,
102.9, 84.3, 70.2, 69.6, 68.2, 56.6, 55.7; MS (ESI): m=z ¼ 374 [M þH]þ. Anal. calcd.
for C21H19FeNO2: C, 67.58; H, 5.13; N, 3.75. Found: C, 67.32; H, 5.39; N, 4.05.
(6,7-Dimethoxyquinolin-2-yl)ferrocene (3c)
Brown solid; mp 171–172 ꢀC; IR (KBr, cmꢂ1): 3079, 2985, 2927, 1617, 1596,
1499, 1465, 1432, 1337, 1244, 1215, 1160, 1002, 886, 853; 1H NMR (400 MHz,
CDCl3) d 7.87 (d, J ¼ 8.4 Hz, 1H, Ar-H), 7.44 (d, J ¼ 8.8 Hz, 1H, Ar-H), 7.39 (s,
1H, Ar-H), 6.99 (s, 1H, Ar-H), 5.00 (t, J ¼ 2.0 Hz, 2H, Fc-Ha), 4.42 (t, J ¼ 1.6 Hz,
2H, Fc-Hb), 4.05 (s, 5H, Fc-H), 4.04 (s, 3H, OCH3), 3.99 (s, 3H, OCH3); 13C
NMR (100 MHz, CDCl3) d 157.2, 152.4, 149.1, 145.2, 134.0, 122.0, 117.8, 108.2,
105.4, 84.6, 70.1, 69.7, 67.7, 56.2, 56.1; MS (ESI): m=z ¼ 374 [M þH]þ. Anal. calcd.
for C21H19FeNO2: C, 67.58; H, 5.13; N, 3.75. Found: C, 67.38; H, 5.32; N, 3.97.
(6-Chloroquinolin-2-yl)ferrocene (3d)
Brown solid; mp 154–155 ꢀC; IR (KBr, cmꢂ1): 3086, 3050, 2956, 2851, 1615,
1
1598, 1504, 1444, 1331, 1187, 1071, 854, 826; H NMR (400 MHz, CDCl3) d 7.93

EFFICIENT SYNTHESIS OF FERROCENYLQUINOLINES
627
(d, J ¼ 8.8 Hz, 1H, Ar-H), 7.87 (d, J ¼ 8.4 Hz, 1H, Ar-H), 7.66 (d, J ¼ 2.0 Hz, 1H,
Ar-H), 7.54 (dd, J ¼ 2.5 Hz, J ¼ 6.8 Hz, 1H, Ar-H), 7.50 (d, J ¼ 8.4 Hz, 1H, Ar-H),
5.01 (t, J ¼ 2.0 Hz, 2H, Fc-Ha), 4.43 (t, J ¼ 2.0 Hz, 2H, Fc-Hb), 4.01 (s, 5H, Fc-H);
13C NMR (100 MHz, CDCl3) d 159.9, 146.6, 134.4, 130.8, 130.5, 130.1, 127.2,
126.1, 120.2, 83.4, 70.6, 69.6, 67.9; MS (ESI): m=z ¼ 348 [M þH]þ. Anal. calcd.
For C19H14ClFeN: C, 65.65; H, 4.06; N, 4.03. Found: C, 65.39; H, 4.26; N, 4.22.
(6,8-Dibromoquinolin-2-yl)ferrocene (3e)
Brown solid; mp 145–146 ꢀC; IR (KBr, cmꢂ1): 3086, 3050, 2920, 2847, 1617,
1590, 1502, 1458, 1313, 1281, 1187, 1107, 1005, 970, 861, 820; 1H NMR
(400 MHz, CDCl3) d 8.07 (s, 1H, Ar-H), 7.86 (d, J ¼ 8.4 Hz, 1H, Ar-H), 7.81 (s,
1H, Ar-H), 7.51 (d, J ¼ 8.8 Hz, 1H, Ar-H), 5.10 (d, J ¼ 1.6 Hz, 2H, Fc-Ha), 4.49
(d, J ¼ 1.6 Hz, 2H, Fc-Hb), 4.03 (d, J ¼ 0.8 Hz, 5H, Fc-H); 13C NMR (100 MHz,
CDCl3) d 161.6, 144.5, 136.1, 135.3, 129.8, 128.8, 126.1, 121.1, 118.5, 83.5, 71.4,
70.3, 68.8; MS (ESI): m=z ¼ 472 [M þH]þ. Anal. calcd. for C19H13Br2FeN: C,
48.45; H, 2.78; N, 2.97. Found: C, 48.22; H, 3.02; N, 3.19.
(3-Methylquinolin-2-yl)ferrocene (3f)
Brown solid; mp 73–74 ꢀC; IR (KBr, cmꢂ1): 3092, 3050, 2956, 2851, 1615, 1598,
1494, 1444, 1408, 1328, 1274, 1130, 1106, 1070, 1033, 876, 819, 755; 1H NMR
(400 MHz, CDCl3) d 8.02 (d, J ¼ 6.0 Hz, 1H, Ar-H), 7.83 (s, 1H, Ar-H), 7.68 (d,
J ¼ 8.0 Hz, 1H, Ar-H), 7.60 (t, J ¼ 7.6 Hz, 1H, Ar-H), 7.43 (t, J ¼ 7.2 Hz, 1H,
Ar-H), 5.09 (s, 2H, Fc-Ha), 4.44 (s, 2H, Fc-Hb), 4.09 (s, 5H, Fc-H), 2.76 (s, 3H,
CH3); 13C NMR (100 MHz, CDCl3) d 158.4, 146.7, 136.6, 129.2, 128.9, 128.4,
126.8, 126.5, 125.5, 85.3, 70.0, 69.8, 69.5, 21.4; MS (ESI): m=z ¼ 328 [M þH]þ. Anal.
calcd. for C20H17FeN: C, 73.41; H, 5.24; N, 4.28. Found: C, 73.21; H, 5.51; N, 4.47.
(3-Methyl-5,8-dimethoxyquinolin-2-yl)ferrocene (3g)
Brown solid; mp 164–165 ꢀC; IR (KBr, cmꢂ1): 3091, 2935, 2833, 1617, 1597,
1463, 1433, 1389, 1341, 1262, 1180, 1112, 1009, 876, 797; 1H NMR (400 MHz,
CDCl3) d 8.23 (s, 1H, Ar-H), 6.83 (d, J ¼ 8.4 Hz, 1H, Ar-H), 6.66 (d, J ¼ 8.4 Hz,
1H, Ar-H), 5.09 (t, J ¼ 2.0 Hz, 2H, Fc-Ha), 4.42 (t, J ¼ 1.6 Hz, 2H, Fc-Hb), 4.09 (s,
5H, Fc-H), 4.02 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 2.78 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3) d 157.5, 149.3, 148.3, 138.9, 131.5, 128.9, 119.9, 106.8, 102.8,
85.7, 70.1, 69.8, 69.4, 56.5, 55.7, 21.4; MS (ESI): m=z ¼ 388 [M þH]þ. Anal. calcd.
for C22H21FeNO2: C, 68.23; H, 5.47; N, 3.62. Found: C, 68.42; H, 5.55; N, 3.90.
(3-Methyl-6,7-dimethoxyquinolin-2-yl)ferrocene (3h)
Brown solid; mp 171–172 ꢀC; IR (KBr, cmꢂ1): 3087, 2949, 2826, 1617, 1597,
1497, 1462, 1336, 1341, 1237, 1146, 1019, 1009, 898, 818; 1H NMR (400 MHz,
CDCl3) d 7.67 (s, 1H, Ar-H), 7.35 (s, 1H, Ar-H), 6.92 (s, 1H, Ar-H), 5.01 (s, 2H,
Fc-Ha), 4.40 (s, 2H, Fc-Hb), 4.08 (d, J ¼ 0.8 Hz, 5H, Fc-H), 4.01 (s, 3H, OCH3),
3.97 (s, 3H, OCH3), 2.72 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) d 155.7,

628
Y. LONG, H. ZHANG, AND D. YANG
151.6, 149.2, 143.4, 135.4, 127.2, 122.2, 107.7, 104.2, 85.8, 69.6, 69.5, 69.3, 56.1, 55.9,
21.2; MS (ESI): m=z ¼ 388 [M þH]þ. Anal. calcd. for C22H21FeNO2: C, 68.23; H,
5.47; N, 3.62. Found: C, 67.96; H, 5.73; N, 3.48.
(6-Chloro-3-methylquinolin-2-yl)ferrocene (3i)
Brown solid; mp 119–121 ꢀC; IR (KBr, cmꢂ1): 3086, 2963, 2833, 1618, 1593, 1485,
1
1403, 1383, 1235, 1270, 1070, 886, 824; H NMR (400 MHz, CDCl3) d 7.94 (d,
J ¼ 8.8 Hz, 1H, Ar-H), 7.72 (s, 1H, Ar-H), 7.65 (s, 1H, Ar-H), 7.52 (d, J ¼ 8.8 Hz,
1H, Ar-H), 5.08 (s, 2H, Fc-Ha), 4.46 (s, 2H, Fc-Hb), 4.10 (s, 5H, Fc-H), 2.72 (s, 3H,
CH3); 13C NMR (100 MHz, CDCl3) d 158.9, 145.1, 135.6, 130.9, 130.4, 130.2, 129.3,
127.3, 125.2, 84.8, 70.0, 69.5, 21.4; MS (ESI): m=z ¼ 362 [M þH]þ. Anal. calcd. for
C20H16ClFeN: C, 66.42; H, 4.46; N, 3.87. Found: C, 66.12; H, 4.66; N, 3.72.
(6,8-Dibromo-3-methylquinolin-2-yl)ferrocene (3j)
Brown solid; mp 154–156 ꢀC; IR (KBr, cmꢂ1): 3456, 3369, 3086, 3050, 2923, 2851,
1
1608, 1584, 1481, 1442, 1396, 1318, 1267, 1106, 1033, 1070, 947, 890, 824; H NMR
(400 MHz, CDCl3) d 8.01 (s, 1H, Ar-H), 7.77 (s, 1H, Ar-H), 7.69 (s, 1H, Ar-H), 5.13
(s, 2H, Fc-Ha), 4.47 (s, 2H, Fc-Hb), 4.10 (s, 5H, Fc-H), 2.69 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3) d 160.3, 142.3, 135.6, 134.6, 131.0, 128.3, 128.3, 125.6, 118.2,
84.4, 70.6, 70.2, 69.7, 21.1; MS (ESI): m=z ¼ 486 [M þH]þ. Anal. calcd. for
C20H15Br2FeN: C, 49.53; H, 3.12; N, 2.89. Found: C, 49.30; H, 3.32; N, 3.12.
(3-Phenylquinolin-2-yl)ferrocene (3k)
Brown solid; mp 193–194 ꢀC; IR (KBr, cmꢂ1): 3101, 3057, 2925, 2854, 1729,
1620, 1589, 1485, 1441, 1272, 1106, 1088, 1019, 816, 755; 1H NMR (400 MHz, CDCl3)
d 8.10 (d, J ¼ 8.4 Hz, 1H, Qu-H), 7.87 (s, 1H, Qu-H), 7.74 (d, J ¼ 8.4 Hz, 1H, Qu-H),
7.68 (t, J ¼ 8.0 Hz, 1H, Qu-H), 7.50–7.44 (m, 4H, Ar-H), 7.40–7.37 (m, 2H, Ar-H,
Qu-H), 4.50 (t, J ¼ 2.0 Hz, 2H, Fc-Ha), 4.23 (t, J ¼ 1.8 Hz, 2H, Fc-Hb), 3.98 (s, 5H,
Fc-H); 13C NMR (100 MHz, CDCl3) d 157.9, 147.9, 141.3, 137.1, 134.7, 130.2,
129.7, 129.4, 128.7, 128.1, 127.8, 126.4, 126.2, 84.8, 71.0, 70.1, 69.9; MS (ESI):
m=z ¼ 390 [M þH]þ. Anal. calcd. for C25H19FeN: C, 77.14; H, 4.92; N, 3.60. Found:
C, 76.98; H, 5.16; N, 3.88.
(5,8-Dimethoxy-3-phenylquinolin-2-yl)ferrocene (3l)
Brown solid; mp 180–181 ꢀC; IR (KBr, cmꢂ1): 3086, 2934, 2832, 1616, 1589,
1
1496, 1461, 1384, 1368, 1269, 1230, 1110, 1002, 799; H NMR (400 MHz, CDCl3)
d 8.26 (s, 1H, Qu-H), 7.48-7.38 (m, 5H, C6H5-H), 6.95 (d, J ¼ 8.4 Hz, 1H, Qu-H),
6.69 (d, J ¼ 8.4 Hz, 1H, Qu-H), 4.55 (s, 2H, Fc-Ha), 4.22 (s, 2H, Fc-Hb), 4.11 (s,
3H, OCH3), 3.97 (s, 5H, Fc-H), 3.93 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3)
d 157.1, 150.0, 149.7, 141.6, 140.5, 134.4, 132.3, 130.3, 128.7, 128.1, 119.8, 109.4,
103.5, 85.3, 71.2, 70.3, 70.2, 57.9, 56.3; MS (ESI): m=z ¼ 450 [M þH]þ. Anal. calcd.
for C27H23FeNO2: C, 72.17; H, 5.16; N, 3.12. Found: C, 71.94; H, 4.96; N, 3.36.

EFFICIENT SYNTHESIS OF FERROCENYLQUINOLINES
629
(6,7-Dimethoxy-3-phenylquinolin-2-yl)ferrocene (3m)
Brown solid; mp 177–179 ꢀC; IR (KBr, cmꢂ1): 3086, 3057, 2932, 2826, 1662,
1591, 1496, 1448, 1386, 1338, 1278, 1151, 1010, 821, 702; 1H NMR (400 MHz,
CDCl3) d 7.01 (s, 1H, Qu-H), 7.42 (s, 4H, C6H5-H), 7.36 (s, 1H, C6H5-H), 7.35 (s,
1H, Qu-H), 6.97 (s, 1H, Qu-H), 4.44 (s, 2H, Fc-Ha), 4.18 (s, 2H, Fc-Hb), 4.08 (s,
3H, OCH3), 3.98 (s, 8H, Fc-H, OCH3); 13C NMR (100 MHz, CDCl3) d 154.7,
152.4, 149.4, 144.4, 141.2, 135.2, 132.5, 129.8, 128.1, 127.4, 121.3, 107.7, 104.7,
84.8, 70.2, 69.5, 69.1, 56.2, 56.0; MS (ESI): m=z ¼ 450 [M þH]þ. Anal. calcd. for
C27H23FeNO2: C, 72.17; H, 5.16; N, 3.12. Found: C, 71.94; H, 4.96; N, 3.36.
(6-Chloro-3-phenylquinolin-2-yl)ferrocene (3n)
Brown solid; mp 153–155 ꢀC; IR (KBr, cmꢂ1): 3094, 3057, 2925, 1603, 1585,
1494, 1472, 1405, 1365, 1269, 1184, 1106, 1001, 880, 827; 1H NMR (400 MHz,
CDCl3) d 8.02 (d, J ¼ 8.8 Hz, 1H, Qu-H), 7.78 (s, 1H, Qu-H), 7.71 (d, J ¼ 2.4 Hz,
1H, Qu-H), 7.60 (dd, J ¼ 2.0 Hz, J ¼ 2.8 Hz, 1H, Qu-H), 7.48–7.46 (m, 3H, C6H5-
H), 7.38–7.36 (m, 2H, C6H5-H), 4.49 (s, 2H, Fc-Ha), 4.25 (s, 2H, Fc-Hb), 3.99 (s,
5H, Fc-H); 13C NMR (100 MHz, CDCl3) d 157.9, 145.7, 140.2, 135.5, 134.9,
131.0, 130.4, 130.0, 129.4, 128.1, 127.7, 126.3, 125.8, 83.7, 70.5, 69.6; MS (ESI):
m=z ¼ 424 [M þH]þ. Anal. calcd. for C25H18ClFeN: C, 70.87; H, 4.28; N, 3.31.
Found: C, 70.62; H, 4.57; N, 3.59.
(6,8-Dibromo-3-phenylquinolin-2-yl)ferrocene (3o)
Brown solid; mp 155–156 ꢀC; IR (KBr, cmꢂ1): 3082, 2924, 2847, 1581, 1530,
1
1468, 1439, 1355, 1282, 1184, 1079, 1019, 1002, 881, 795, 701; H NMR (400 MHz,
CDCl3) d 8.10 (s, 1H, Qu-H), 7.85 (s, 1H, Qu-H), 7.76 (s, 1H, Qu-H), 7.45 (s, 3H,
C6H5-H), 7.34 (s, 2H, C6H5-H), 4.53 (s, 2H, Fc-Ha), 4.27 (s, 2H, Fc-Hb), 3.99 (s,
5H, Fc-H); 13C NMR (100 MHz, CDCl3) d 159.5, 143.0, 139.5, 135.7, 135.7, 135.4,
129.4, 129.1, 128.4, 128.0, 127.5, 125.7, 118.4, 83.4, 71.1, 70.0; MS (ESI): m=z ¼ 548
[M þH]þ. Anal. calcd. for C25H17Br2FeN: C, 54.89; H, 3.13; N, 2.56. Found: C,
55.01; H, 3.36; N, 2.80.
1,1’-Bis(quinolin-2-yl)ferrocene (3p)
Following the general procedure, using o-aminobenzaldehyde 1a (2 mmol),
1,10-diacetylferrocene 2d (1 mmol), and sodium ethoxide (0.6 mmol), 3p was obtained
as a brown solid; mp 209–211 ꢀC. IR (KBr, cmꢂ1): 3050, 2924, 2847, 1732, 1619,
1
1599, 1556, 1512, 1424, 1091, 1028, 908, 819, 749; H NMR (400 MHz, CDCl3) d
7.87 (d, J ¼ 8.4 Hz, 2H, Ar-H), 7.58 (d, J ¼ 3.6 Hz, 2H, Ar-H), 7.39 (s, 4H, Ar-H),
7.19 (d, J ¼ 8.4 Hz, 2H, Ar-H), 6.98 (d, J ¼ 8.4 Hz, 2H, Ar-H), 5.04 (s, 4H, Fc-Ha),
), 4.42 (s, 4H, Fc-Hb); 13C NMR (100 MHz, CDCl3) d 157.2, 148.0, 134.9, 129.0,
128.7, 127.4, 126.3, 125.0, 119.1, 85.6, 71.2, 68.9; MS (ESI): m=z ¼ 441 [M þH]þ.
Anal. calcd. for C28H20FeN2: C, 76.38; H, 4.58; N, 6.36. Found: C, 76.10; H,
4.83; N, 6.40.

630
Y. LONG, H. ZHANG, AND D. YANG
1,1’-Bis(5,8-dimethoxyquinolin-2-yl)ferrocene (3q)
Following the general procedure, using 2-amino-3,6-dimethoxybenzaldehyde
1b (2 mmol), 1,10-diacetylferrocene 2d (1 mmol), and sodium ethoxide (0.6 mmol),
3q was obtained as a orange solid; mp 226–228 ꢀC. IR (KBr, cmꢂ1): 3072, 3000,
1
2934, 2826, 1621, 1600, 1459, 1434, 1399, 1257, 1203, 1164, 1107, 1080, 799; H
NMR (400 MHz, CDCl3) d 7.98 (d, J ¼ 8.8 Hz, 2H, Ar-H), 7.28 (d, J ¼ 8.8 Hz,
2H, Ar-H), 6.83 (d, J ¼ 8.4 Hz, 2H, Ar-H), 6.59 (d, J ¼ 8.4 Hz, 2H, Ar-H), 4.99 (s,
4H, Fc-Ha), 4.35 (s, 4H, Fc-Hb), 4.01 (s, 6H, OCH3), 3.89 (s, 6H, OCH3); 13C
NMR (100 MHz, CDCl3) d 156.9, 149.1, 148.8, 140.4, 129.9, 119.5, 118.9, 107.8,
102.5, 85.7, 71.4, 69.5, 56.5, 55.6; MS (ESI): m=z ¼ 561 [M þH]þ. Anal. calcd. for
C32H28FeN2O4: C, 68.58; H, 5.04; N, 5.00. Found: C, 68.40; H, 5.20; N, 5.30.
1,1’-Bis(6,7-dimethoxyquinolin-2-yl)ferrocene (3r)
Following the general procedure, using 2-amino-4,5-dimethoxybenzaldehyde
1c (2 mmol), 1,10-diacetylferrocene 2d (1 mmol), and sodium ethoxide (0.6 mmol),
3r was obtained as a brown solid, mp 224–226 ꢀC. IR (KBr, cmꢂ1): 3086, 3000,
1
2936, 2833, 1621, 1598, 1500, 1466, 1432, 1337, 1245, 1203, 1129, 1029, 857; H
NMR (400 MHz, CDCl3) d 7.13 (d, J ¼ 8.4 Hz, 2H, Ar-H), 7.09 (s, 2H, Ar-H),
6.89 (d, J ¼ 8.4 Hz, 2H, Ar-H), 6.58 (s, 2H, Ar-H), 4.98 (t, J ¼ 1.6 Hz, 4H, Fc-Ha),
4.38 (t, J ¼ 2.0 Hz, 4H, Fc-Hb), 3.97 (s, 6H, OCH3), 3.95 (s, 6H, OCH3); 13C
NMR (100 MHz, CDCl3) d 154.4, 151.7, 148.5, 144.7, 133.1, 121.5, 117.2, 107.6,
104.9, 85.9, 70.7, 68.4, 56.0, 55.8; MS (ESI): m=z ¼ 561 [M þH]þ. Anal. calcd. for
C32H28FeN2O4: C, 68.58; H, 5.04; N, 5.00. Found: C, 68.83; H, 5.32; N, 4.76.
1-(3-Methylquinolin-2-yl)-1’-propionylferrocene (3s)
Following the general procedure, using o-aminobenzaldehyde 1a (2 mmol),
1,10-dipropionylferrocene 2e (1 mmol), and sodium ethoxide (0.6 mmol), 3 s was
obtained as a brown solid, mp 109–111 ꢀC. IR (KBr, cmꢂ1): 3050, 2975, 1672,
1
1596, 1494, 1450, 1409, 1376, 1246, 1050, 879, 756; H NMR (400 MHz, CDCl3) d
8.00 (d, J ¼ 8.4 Hz, 1H, Qu-H), 7.86 (s, 1H, Qu-H), 7.69 (d, J ¼ 8.0 Hz, 1H,
Qu-H), 7.61 (t, J ¼ 7.6 Hz, 1H, Qu-H), 7.45 (t, J ¼ 7.6 Hz, 1H, Qu-H), 5.13 (s, 2H,
Fc-Ha), 4.69 (s, 2H, Fc-Hb), 4.42 (d, J ¼ 16.0 Hz, 4H, Fc-H), 2.66 (s, 3H, CH3),
2.44 (q, J ¼ 7.2 Hz, 2H, CH2), 0.88 (t, J ¼ 7.2 Hz, 3H, CH2-CH3); 13C NMR
(100 MHz, CDCl3) d 204.7, 156.9, 146.8, 137.1, 129.4, 128.9, 128.8, 127.1, 126.8,
126.1, 87.0, 80.2, 73.5, 71.6, 71.4, 70.7, 32.9, 21.8, 8.1; MS (ESI): m=z ¼ 384 [M
þH]þ. Anal. calcd. for C23H21FeNO: C, 72.08; H, 5.52; N, 3.65. Found: C, 71.97;
H, 5.79; N, 3.39.
1,1’-Bis[(3-methylquinolin-2-yl)]ferrocene (3t)
Following the general procedure, using o-aminobenzaldehyde 1a (2 mmol),
1,10-dipropionylferrocene 2e (1 mmol), and sodium ethoxide (0.6 mmol), 3 t was
obtained as a brown solid, mp 229–230 ꢀC. IR (KBr, cmꢂ1): 3036, 2956, 2923,
1
1618, 1597, 1494, 1443, 1410, 1280, 1037, 887, 746; H NMR (400 MHz, CDCl3) d

EFFICIENT SYNTHESIS OF FERROCENYLQUINOLINES
631
7.89 (d, J ¼ 8.4 Hz, 2H, Ar-H), 7.56 (t, J ¼ 7.2 Hz, 2H, Ar-H), 7.39 (t, J ¼ 7.2 Hz, 2H,
Ar-H), 7.28 (d, J ¼ 8.0 Hz, 2H, Ar-H), 6.51 (s, 2H, Ar-H), 5.28 (s, 4H, Fc-Ha), 4.44
(s, 4H, Fc-Hb), 2.29 (s, 6H, CH3); 13C NMR (100 MHz, CDCl3) d 156.3, 146.1,
136.1, 128.5, 128.3, 128.1, 126.4, 126.4, 125.0, 86.3, 71.0, 70.5, 21.4; MS (ESI): m=
z ¼ 469 [M þH]þ. Anal. calcd. for C30H24FeN2: C, 76.93; H, 5.16; N, 5.98. Found:
C, 77.12; H, 5.45; N, 6.22.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China
(Nos. 2117208, 20772036, and 20802021) and the Natural Science Foundation of
Guangdong Province (Nos. 8251063101000002 and 7005804) for financial support.
REFERENCES
1. (a) Vaitilingam, B.; Nayyar, A.; Palde, P. B.; Monga, V.; Jain, R.; Kaur, S.; Singh, P. P.
Synthesis and antimycobacterial activities of ring-substituted quinoline carboxylic acid=
ester analogues, part 1. Bioorg. Med. Chem. 2004, 12, 4179–4188; (b) Chen, Y. L.; Fang,
K. C.; Sheu, J. Y.; Hsu, S. L.; Tzeng, C. C. Synthesis and antibacterial evaluation of cer-
tain quinolinone derivatives. J. Med. Chem. 2001, 44, 2374–2377.
2. (a) Lee, B. D.; Li, Z.; French, K. J.; Zhuang, Y.; Xia, Z.; Smith, C. D. Synthesis and
evaluation of dihydropyrroloquinolines that selectively antagonize p-glycoprotein. J.
Med. Chem. 2004, 47, 1413–1422; (b) Gopal, M.; Shenoy, S.; Doddamani, L. S. Antitumor
activity of 4-amino- and 8-methyl-4-(3-diethylamino propylamino)pyrimido[4’,5’:4,5]thie-
no(2,3-b) quinolines. J. Photochem. Photobiol. B 2003, 72, 69–78; (c) Fryatt, T.;
Pettersson, H. I.; Gardipee, W. T.; Bray, K. C.; Green, S. J.; Slawin, A. M.; Beall,
H. D.; Moody, C. J. Novel quinolinequinone antitumor agents: Structure–metabolism
studies with NAD(P)H: quinone oxidoreductase (NQO1). Bioorg. Med. Chem. 2004, 12,
1667–1687; (d) Ko, T. C.; Hour, M. J.; Lien, J. C.; Teng, C. M.; Lee, K. H.; Kuo, S.
C.; Huang, L. J. Synthesis of 4-alkoxy-2-phenylquinoline derivatives as potent antiplatelet
agents. Bioorg. Med. Chem. Lett. 2001, 11, 279–282.
3. (a) Larsen, R. D.; Corley, E. G.; King, A. O.; Carrol, J. D.; Davis, P.; Verhoeven, T. R.;
Reider, P. J.; Labelle, M.; Gauththier, J. Y.; Xiang, Y. B.; Zamboni, R. J. Practical route
to a new class of LTD4 receptor antagonists. J. Org. Chem. 1996, 61, 3398–3405; (b)
Zwaagstra, M. E.; Timmerman, H.; Van De Stolpe, A. C.; De Kanter, F. J.; Tamura,
M.; Wada, Y.; Zhang, M. Q. Synthesis and structure–activity relationships of carboxyfla-
vones as structurally rigid CysLT1 (LTD4) receptor antagonists. J. Med. Chem. 1998, 41,
1428–1438; (c) Von Sprecher, A.; Gerspacher, M.; Beck, A.; Kimmel, S.; Wiestner, H.;
Anderson, G. P.; Niederhauser, U.; Subramanian, N.; Bray, M. A. Synthesis and SAR
of a novel, potent, and structurally simple LTD4 antagonist of the quinoline class. Bioorg.
Med. Chem. Lett. 1998, 8, 965–970; (d) Doube, D.; Blouin, M.; Brideau, C.; Chan, C.;
Desmarais, S.; Ethier, D.; Falgueyret, J. P.; Friesen, R. W.; Girard, M.; Girard, Y.; Guay,
J.; Tagari, P.; Young, R. N. Quinolines as potent 5-lipoxygenase inhibitors: Synthesis and
biological profile of L-746,530. Bioorg. Med. Chem. Lett. 1998, 8, 1255–1260.
4. (a) Kalluraya, B.; Sreenivasa, S. Synthesis and pharmacological properties of some quino-
line derivatives. Farmaco 1998, 53, 399–404; (b) Roma, G.; Braccio, M. D.; Grossi, G.;
Mattioli, F.; Ghia, M. 1,8-Naphthyridines IV: 9-Substituted N,N-dialkyl-5-(alkylamino
or
cycloalkylamino)
[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides,
new

632
Y. LONG, H. ZHANG, AND D. YANG
compounds with anti-aggressive and potent anti-inflammatory activities. Eur. J. Med.
Chem. 2000, 35, 1021–1035.
5. (a) Morizawa, Y.; Okazoe, T.; Wang, S. Z.; Sasaki, J.; Ebisu, H.; Nishikawa, M.;
Shinyama, H. A novel trifluoromethanesulfonamidophenyl-substituted quinoline deriva-
tive, GA 0113: synthesis and pharmacological profiles. J. Fluor. Chem. 2001, 109, 83–
86; (b) Ferrarini, P. L.; Mori, C.; Badawneh, M.; Calderonem, V.; Greco, R.; Manera,
C.; Martinelli, A.; Nieri, P.; Saccomanni, G. Synthesis and beta-blocking activity of
(R,S)-(E)-oximeethers of 2,3-dihydro-1,8-naphthyridine and 2,3-dihydrothiopyrano
[2,3-b]pyridine: Potential antihypertensive agents, part IX. Eur. J. Med. Chem. 2000, 35,
815–826.
6. Maguire, M. P.; Sheets, K. R.; McVety, K.; Spada, A. P.; Zilberstein, A. A new series of
PDGF receptor tyrosine kinase inhibitors: 3-Substituted quinoline derivatives. J. Med.
Chem. 1994, 37, 2129–2137
7. Yadav, J. S.; Rao, P. P.; Sreenu, D.; Rao, R. S.; Kumar, V. N.; Nagaiah, K.; Prasad, A.
R. Sulfamic acid: An efficient, cost-effective, and recyclable solid acid catalyst for the
Friedla¨nder quinoline synthesis. Tetrahedron Lett. 2005, 46, 7249–7253.
8. (a) Hu, Y. Z.; Zhang, G.; Randolph, P. T. Friedla¨nder approach for the incorporation of
6-bromoquinoline into novel chelating ligands. Org. Lett. 2003, 5, 2251–2253; (b) Ohashi,
A.; Tsuguchi, A.; Imura, H.; Ohashi, K. Synergistic cloud point extraction behavior of
aluminum(III) with 2-methyl-8-quinolinol and 3,5-dichlorophenol. Anal. Sci. 2004, 20,
1091–1093; (c) Wang, H.; Liu, Z.; Liu, C.; Zhang, D.; Lu, Z.; Geng, H.; Shuai, Z.;
Zhu, D. Coordination complexes of 2-(4-quinolyl)nitronyl nitroxide with M(hfac)(2)
=
[M Mn(II), Co(II), and Cu(II)]: Syntheses, crystal structures, and magnetic characteriza-
tion. Inorg. Chem. 2004, 43, 4091–4098.
9. Kouznetsov, V. V.; Mendez, L. Y. V.; Gomez, C. M. M. Recent progress in the synthesis
of quinolines. Curr. Org. Chem. 2005, 9, 141–161.
10. (a) Igarashi, T.; Inada, T. I.; Sekioka, T.; Nakajima, T.; Shimizu, I. One-pot synthesis of
substituted quinolines by iridium-catalyzed three-component coupling reaction. Chem.
Lett. 2005, 34, 106–107; (b) Inada, T.; Nakajima, T.; Shimizu, I. One-step synthesis of
ethyl quinaldates by Lewis acid–catalyzed three-component coupling reaction of aromatic
amines, aliphatic aldehydes, and ethyl glyoxylate. Heterocycles 2005, 66, 611–619; (c)
Nakajima, T.; Inada, T.; Igarashi, T.; Sekioka, T.; Shimizu, I. Facile three-component
synthesis of substituted quinolines catalyzed by iridium(III) complex. Bull. Chem. Soc.
Jpn. 2006, 79, 1941–1949; (d) Tanaka, S.; Yasuda, M.; Baba, A. Practical and simple syn-
thesis of substituted quinolines by an HCl-DMSO system on a large scale: Remarkable
effect of the chloride ion. J. Org. Chem. 2006, 71, 800–803; (e) Lin, X. F.; Cui, S. L.;
Wang, Y. G.; Molecular iodine–catalyzed one-pot synthesis of substituted quinolines from
imines and aldehydes. Tetrahedron Lett. 2006, 47, 3127–3130.
11. Dormer, P. G.; Eng, K. K.; Farr, R. N.; Humphrey, G. R.; McWilliams, J. C.; Reider,
P. J.; Sager, J. W.; Volante, R. P. Highly regioselective Friedla¨nder annulations with
unmodified ketones employing novel amine catalysts: Syntheses of 2-substituted quino-
lines, 1,8-naphthyridines, and related heterocycles. J. Org. Chem. 2003, 68, 467–477.
12. (a) Fehnel, E. A. Friedla¨nder syntheses with o-aminoaryl ketones, I: Acid-catalyzed con-
densations of o-aminobenzophenone with ketones. J. Org. Chem. 1966, 31, 2899–2902;
(b) Strekowski, L.; Czarny, A.; Lee, H. The Friedlander synthesis of 4-(perfluoroalkyl)qui-
¨
nolines. J. Fluor. Chem. 2000, 104, 281–284; (c) Suzuki, M.; Iwasaki, H.; Fujikawa, Y.;
Kitahara, M.; Sakashita, M.; Sakoda, R. Synthesis and biological evaluations of
quinoline-based HMG-CoA reductase inhibitors. Bioorg. Med. Chem. 2001, 9, 2727–
2743; (d) Zhan, X. W.; Liu, Y. Q.; Wu, X.; Wang, S.; Zhu, D. B. New series of
blue-emitting and electron-transporting copolymers based on fluorene. Macromolecules
2002, 35, 2529–2537; (e) Wang, G. W.; Jia, C. S.; Dong, Y. W. Benign and highly efficient

EFFICIENT SYNTHESIS OF FERROCENYLQUINOLINES
633
synthesis of quinolines from 2-aminoarylketone or 2-aminoarylaldehyde and carbonyl
compounds mediated by hydrochloric acid in water. Tetrahedron Lett. 2006, 47,
1059–1063; (f) Sliskovic, D. R.; Picard, J. A.; Roark, W. H.; Roth, B. D.; Ferguson, E.;
Krause, B. R.; Newton, R. S.; Sekerke, C.; Shaw, M. K. Inhibitors of cholesterol bio-
synthesis, 4: trans-6-[2-(Substituted quinolinyl)ethenyl=ethyl]tetrahydro-4-hydroxy-2H-
pyran-2-ones, a novel series of HMG-CoA reductase inhibitors. J. Med. Chem. 1991,
34, 367–373; (g) Manikumar, G.; Wadkins, R. M.; Bearss, D.; Von Hoff, D. D.; Wania,
M. C.; Walla, M. E.; Manikumar, G. Camptothecin analogs with bulky, hydrophobic
substituents at the 7-position via a Grignard reaction. Bioorg. Med. Chem. Lett. 2004,
14, 5377–5381.
13. (a) Zolfigol, M. A.; Salehi, P.; Ghaderi, A.; Shiri, M. A catalytic and green procedure for
Friedla¨nder quinoline synthesis in aqueous media. Catal. Commun. 2007, 8, 1214–1218;
(b) Atechian, S.; Nock, N.; Norcross, R. D.; Ratni, H.; Thomas, A. W.; Verron, J.;
Masciadri, R. New vistas in quinoline synthesis. Tetrahedron 2007, 63, 2811–2823; (c)
Bose, D. S.; Kumar, R. K. An efficient, high-yielding protocol for the synthesis of func-
tionalized quinolines via the tandem addition=annulation reaction of ortho-aminoaryl
ketones with a-methylene ketones. Tetrahedron Lett. 2006, 47, 813–816; (d) Cho, C. S.;
Ren, W. X.; Shimet, S. C. A copper(II)-catalyzed protocol for modified Friedlander
¨
quinoline synthesis. Tetrahedron Lett. 2006, 47, 6781–6785.
14. (a) Yang, D. Q.; Guo, W.; Cai, Y. P.; Jiang, L. S.; Jiang, K. L.; Wu, X. B. Efficient syn-
thesis of novel six-member ring-fused quinoline derivatives via the Friedla¨nder reaction.
Heteroatom Chem. 2008, 19, 229–233; (b) Nourry, A.; Legoupy, S.; Huet, F. Synthesis
of new lavendamycin analogues. Tetrahedron 2008, 64, 2241–2250.
15. (a) Zora, M.; Velioglu, O. Synthesis of ferrocenyl quinolines. J. Organomet. Chem. 2008,
693, 2159–2162; (b) Wu, J.; Xia, H. G.; Gao, K. Molecular iodine: A highly efficient cata-
lyst in the synthesis of quinolines via Friedlander annulation. Org. Biomol. Chem. 2006, 4,
¨
126–129(c) Wang, X. S.; Li, Q.; Yao, C. S.; Tu, S. J. An efficient method for the synthesis
of benzo[f]quinoline and benzo[a]phenanthridine derivatives catalyzed by iodine by a
three-component reaction of arenecarbaldehyde, naphthalen-2-amine, and cyclic ketone.
Eur. J. Org. Chem. 2008, 20, 3513–3518.
16. Jiang, B.; Dong, J. J.; Jin, Y.; Du, X. L.; Xu, M. The first proline-catalyzed Friedla¨nder
annulation: Regioselective synthesis of 2-substituted quinoline derivatives. Eur. J. Org.
Chem. 2008, 16, 2693–2696.
17. (a) Loupy, A.; Perreux, L.; Liagre, M.; Burle, K.; Moneuse, M. Reactivity and selectivity
under microwaves in organic chemistry: Relation with medium effects and reaction
mechanisms. Pure Appl. Chem. 2001, 73, 161–166; (b) Song, S. J.; Cho, S. J.; Park, D.
K.; Kwon, T. W.; Jenekhe, S. A. Microwave-enhanced solvent-free synthesis of a library
of quinoline derivatives. Tetrahedron Lett. 2002, 44, 255–257.
18. Palimkar, S. S.; Siddiqui, S. A.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. Ionic liquid–
promoted regiospecific Friedla¨nder annulation: Novel synthesis of quinolines and fused
polycyclic quinolines. J. Org. Chem. 2003, 68, 9371–9378.
19. (a) Cho, C. S.; Oh, B. H.; Kim, J. S.; Kim, T. J.; Shim, S. C. Synthesis of quinolines via
ruthenium-catalyzed amine exchange reaction between anilines and trialkylamines. Chem.
Commun. 2000, 19, 1885–1886; (b) Cho, C. S.; Ren, W. X.
¨
A recyclable
palladium-catalyzed modified Friedlander quinoline synthesis. J. Organomet. Chem.
2007, 692, 4182–4186; (c) Taguchi, K.; Sakaguchi, S.; Ishii, Y.; Synthesis of quinolines
from amino alcohol and ketones catalyzed by [IrCl(cod)]2 or IrCl3 under solvent-free con-
ditions. Tetrahedron Lett. 2005, 46, 4539–4524
20. (a) Hillard, E.; Vessieres, A.; Thouin, L.; Jaouen, G.; Amatore, C. Ferrocene-mediated
proton-coupled electron transfer in a series of ferrocifen-type breast-cancer drug candi-
dates. Angew. Chem., Int. Ed. 2006, 45, 285–290; (b) Top, S.; Vessieres, A.; Leclercq,

634
Y. LONG, H. ZHANG, AND D. YANG
G.; Quivy, J.; Tang, J.; Vaissermann, J.; Huche, M.; Jaouen, G. Synthesis, biochemical
properties, and molecular modeling studies of organometallic specific estrogen receptor
modulators (SERMs), the ferrocifens and hydroxyferrocifens: Evidence for an antiproli-
ferative effect of hydroxyferrocifens on both hormone-dependent and hormone-
independent breast cancer cell lines. Chem. Eur. J. 2003, 9, 5223–5236; (c) Wang, R.;
Hong, X.; Shan, Z. X. A novel, convenient access to acylferrocenes: Acylation of ferro-
cene with acyl chlorides in the presence of zinc oxide. Tetrahedron Lett. 2008, 49, 636–639.
21. Zora, M.; Velioglu, O. Synthesis of ferrocenyl quinolines. J. Organomet. Chem. 2008, 693,
2159–2162.
22. Gomez Arrayas, R.; Adrio, J.; Carretero, J. C. Recent applications of chiral ferrocene
ligands in asymmetric catalysis. Angew. Chem., Int. Ed. 2006, 45, 7674–7715.
23. Yang, D. Q.; Jiang, K. L.; Li, J. N.; Xu, F. Synthesis and characterization of quinoline
derivatives via the Friedla¨nder reaction. Tetrahedron 2007, 63, 7654–7658.
24. (a) Wang, R.; Hong, X.; Shan, Z. X. A novel, convenient access to acylferrocenes: Acyla-
tion of ferrocene with acyl chlorides in the presence of zinc oxide. Tetrahedron Lett. 2008,
49, 636–639; (b) Rosenblum, M.; Woodward, R. B. The structure and chemistry of ferro-
cene, III: Evidence pertaining to the ring rotational barrier. J. Am. Chem. Soc. 1958, 80,
5443–5449