One-pot friedlnder quinoline synthesis: Scope and limitations

Article abstract of DOI:10.1055/s-0029-1218701

A highly effective one-pot Friedlnder quinoline synthesis from o-nitroarylcarbaldehydes and ketones or aldehydes was developed and the scope and limitations of the method were examined. The o-nitroarylcarbaldehydes were reduced to o-aminoarylcarbaldehydes with iron in the presence of a catalytic amount of aqueous hydrochloric acid; the amino compounds were then condensed in situ with ketones or aldehydes to form mono- or disubstituted quinolines, respectively, in good-to-excellent yields (58-100%). Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218701

1678
PAPER
One-Pot Friedländer Quinoline Synthesis: Scope and Limitations
O
ne-Pot Friedländ
n
er
Q
uinoline
-
Synthes
H
is u Li,* David J. Beard, Heather Coate, Ayako Honda, Mridula Kadalbajoo, Andrew Kleinberg,
Radoslaw Laufer, Kristen M. Mulvihill, Anthony Nigro, Pawan Rastogi, Dan Sherman, Kam W. Siu,
Arno G. Steinig, Ti Wang, Doug Werner, Andrew P. Crew, Mark J. Mulvihill
Department of Cancer Chemistry, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, NY 11735, USA
Fax +1(631)8455671; E-mail: ali@osip.com
Received 4 January 2010
it is not applicable to aromatic ketones such as acetophe-
none.5 We therefore attempted to develop a method that
would permit the preparation of 2-aryl-substituted quino-
lines. As reported in our previous preliminary communi-
Abstract: A highly effective one-pot Friedländer quinoline synthe-
sis from o-nitroarylcarbaldehydes and ketones or aldehydes was de-
veloped and the scope and limitations of the method were
examined. The o-nitroarylcarbaldehydes were reduced to o-ami-
noarylcarbaldehydes with iron in the presence of a catalytic amount cation,5 we have discovered a practical one-pot
of aqueous hydrochloric acid; the amino compounds were then con-
Friedländer quinoline synthesis that uses inexpensive and
densed in situ with ketones or aldehydes to form mono- or disubsti-
readily available reagents such as iron powder, aqueous
tuted quinolines, respectively, in good-to-excellent yields (58–
hydrochloric acid, and solid potassium hydroxide. Our
100%).
method successfully condensed a variety of o-nitro alde-
Key words: quinolines, condensation, heterocycles, aldehydes,
ketones
hydes (or ketones) with various carbonyl co-reactants.
Herein, we report a study of the scope and limitations of
the one-pot Friedländer quinoline synthesis.
In a typical operation, 2-nitrobenzaldehyde was reduced
Quinolines are an important class of heterocycles that
with 4.0 equivalents of iron powder in the presence of 5
have long been used antimalarial agents,1 and more re-
mol% of aqueous hydrochloric acid in refluxing ethanol.
cently have been used as protein kinase inhibitors for the
The reduction was usually complete within 30–40 min-
treatment of cancer.2 These beneficial biological activities
utes (as monitored by thin-layer chromatography). After
continue to make quinolines attractive targets for both
this time, 1.0 equivalents of a carbonyl compound and 1.2
synthetic and medicinal chemists. Among the many meth-
equivalents of powdered potassium hydroxide were add-
ods available for constructing the quinoline ring, the
ed. The mixture was then stirred at reflux for a further 40–
Friedländer quinoline synthesis has proven to be a very
60 minutes to complete the condensation reaction. A clas-
powerful tool.3 This reaction typically requires two steps:
sical aqueous workup followed by chromatography over
silica gel or by recrystallization afforded the desired quin-
oline products. The results from the reactions of 2-ni-
trobenzaldehyde with various carbonyl compounds are
reduction of an o-nitro aldehyde or ketone I into an o-ami-
no aldehyde or ketone II followed by condensation of this
intermediate with a ketone or aldehyde III (Scheme 1).
Often the amino carbonyl intermediate II is unstable, es-
pecially when R2 = H, and it may undergo self-condensa-
tion. To overcome this potential problem and make this
century-old reaction more practical, several laboratories
have attempted to develop one-pot procedures involving
the use of II generated in situ.4,5 Of particular interest is
the one-pot method developed by Miller and McNaugh-
ton,4a which uses a tin(II) chloride/zinc chloride system to
convert o-nitro aldehydes or ketones into 2-monosubsti-
tuted or 2,3-disubstituted quinolines. This method works
well with a range of aliphatic ketones but, unfortunately,
summarized in Table 1.
Our one-pot procedure worked not only with aliphatic ke-
tones (entries 10–14), but also with a wide variety of other
ketones, including aromatic (entries 1–5), heteroaromatic
(entries 6–8), and a,b-unsaturated (entry 9) ketones, giv-
ing good-to-excellent yields of the corresponding quino-
lines. In the case of methyl pyruvate, the ester group was
hydrolyzed under the basic conditions present during the
condensation step, and the corresponding quinoline-2-
carboxylic acid was isolated as its hydrochloride salt after
R4
R2
R2
R2
(III)
R3
condensation
R4
R3
O
NO2
O
O
R1
R1
R1
reduction
N
NH2
I
II
IV
Scheme 1
SYNTHESIS 2010, No. 10, pp 1678–1686
x
x.
x
x
.
2
0
1
0
Advanced online publication: 12.03.2010
DOI: 10.1055/s-0029-1218701; Art ID: M00110SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Friedländer Quinoline Synthesis
1679
acidification of the reaction mixture (entry 15). Note that Our investigations next turned to the nature of the o-nitro-
an acetal group (entry 16) and an a,b-unsaturated ketone carboxaldehyde component, and the results are listed in
(entry 9) were unaffected by the reaction conditions, and Table 2.
that an aldehyde can be used as the carbonyl component
of III without observable self-condensation (entry 17),
In general, o-nitro carbaldehydes with electron-withdraw-
ing groups (entries 1, 4, 7–15) or with electron-donating
thereby allowing the introduction of an aryl group at the
groups (entries 2–3) both performed well under the reac-
3-position of the quinoline instead of the typical substitu-
tion conditions, affording good-to-excellent yields (58–
tions at the 2-position.
95%) in all cases. A lower yield (58%) was obtained with
Because a wide range of carbonyl components are com- 5-bromo-2-nitrobenzaldehyde (entry 1), because debro-
patible with this one-pot procedure, we prepared 2-(cy- mination occurred during the iron reduction stage. How-
clo)alkyl, 2-(het)aryl-, 2-styryl-, 2-carboxy-, 2,3-dialkyl-, ever, as expected, the chloro group was well tolerated
2-phenyl-3-methoxy-, 2-(dimethoxymethyl)-, and 3- (entries 7–15), and this can provide a handle for further
arylquinolines in generally good-to-excellent yields. palladium-mediated derivatization reactions of the quino-
When indan-1-one was used as the carbonyl component, line products. For example, we were able to convert 7-
the tetracyclic product 3e was obtained in 63% yield (en- chloroquinolines into 7-boronatoquinolines in high yields
try 5).
Table 1 Reactions of 2-Nitrobenzaldehyde with Various Carbonyl Compounds
1) Fe (4.0 equiv), HCl (aq, 5 mol%),
EtOH, reflux
R1
R2
CHO
O
NO2
N
R1
2)
, KOH (s) (1.2 equiv), reflux
R2
1
3a–q
(2a–q)
Entrya
R1
H
R2
Ph
Ph
Ph
Product
Isolated yield (%)
1
2
3
4
3a
3b
3c
3d
99
OMe
Me
H
66b
92c
70
1,3-benzodioxol-5-yl
5
3e
63
6
7
H
H
H
H
H
2-pyridyl
3f
92
88
80
77
64
95
85
90d
91
95
90
87f
1-methylpyrrol-2-yl
2-thienyl
3g
3h
3i
8
9
(E)-2-phenylvinyl
Me
10
11
12
13
14
15
16
17
3j
(CH2)5
Et
3k
3l
Pr
H
t-Bu
3m
3n
3o
3p
3q
H
cyclopropyl
CO2Me (CO2H)e
CH(OMe)2
H
H
H
Ph
a All reactions were carried out on a 1.0-mmol scale. The reaction times for the reduction and condensation stages were 40 min and 30 min,
respectively, unless otherwise noted.
b 2 h for the reduction and 3 h for the condensation.
c 60 min for the reduction.
d 2 h for the condensation.
e Isolated as the HCl salt of the acid.
f 1 h for the reduction and 5 h for the condensation.
Synthesis 2010, No. 10, 1678–1686 © Thieme Stuttgart · New York

1680
A.-H. Li et al.
PAPER
under palladium-catalyzed conditions6 (results not Heteroaryl o-nitro carbaldehydes can also be smoothly
shown).
converted into the corresponding fused quinolinoid sys-
tems. This is exemplified by entry 6, in which a pyrazo-
lo[4,3-b]pyridine derivative was prepared in high yield
(82%). These results further demonstrate the broad appli-
cability of our one-pot method, which permits the prepa-
ration of quinoline derivatives functionalized on both the
phenyl and the pyridyl rings. Furthermore, the relatively
mild reaction conditions permit the introduction of func-
tional groups that can act as handles for further elabora-
tion of the quinoline products.
When a strongly electron-donating group, such as a dim-
ethylamino group, was present on the phenyl ring, both re-
duction and condensation stages took significantly longer
(5 h and 48 h compared with the usual 40 min and 30 min,
respectively; entry 3). This is attributed to the reduced
electrophilicity of the aldehyde group as a result of the
electron-rich nature of the phenyl ring to which the alde-
hyde is attached.7 A longer condensation time was also re-
quired for the naphthyl system (entry 5), possibly because
of steric effects.8
To extend the scope of our methodology, we attempted to
apply the usual reaction conditions to o-nitro ketone 7 to
Table 2 Reactions of Ketones with Various o-Nitrocarbaldehydes
R1
R2
1) Fe (4.0 equiv), HCl (aq, 5 mol%),
R4
R3
R4
CHO
EtOH, reflux
O
R3
NO2
N
1
2)
, KOH (s) (1.2 equiv), reflux
R
R2
4a–g
6a–o
(5a–j)
Entrya
R3/R4 or nitro aldehyde
Br/H
R2/R1
Ph/H
Ph/H
Ph/H
Ph/H
Product
6a
Isolated yield (%)
1
2
3
4
58
OCH2O
6b
82
Me2N/H
6c
67b
91c
CO2Me (CO2H)/H
6d
CHO
NO2
5
6
Ph/H
Ph/H
95d
N
6e
Me
Me
N
N
CHO
N
N
82
N
NO2
6f
7
8
Cl/H
Cl/H
Cl/H
Cl/H
Cl/H
Cl/H
Cl/H
Cl/H
Cl/H
2-FC6H4/H
2-ClC6H4/H
2-MeC6H4/H
Ph/Me
6g
87
68
76
75
84
81
71
65
78
6h
6i
9
10
11
12
13
14
15
6j
i-Pr/H
6k
6l
t-Bu/H
cyclopropyl/H
cyclobutyl/H
cyclohexyl/H
6m
6n
6o
a All reactions were carried out on a 1.0-mmol scale. The reaction times for the reduction and condensation stages were 40 min and 30 min,
respectively, unless otherwise noted.
b 5 h for the reduction and 48 h for the condensation.
c The product was isolated as the HCl salt of the acid.
d 8 equiv of iron and 16 mol% HCl(aq) [0.1 N] were used; 5 h for the reduction and 15 h for the condensation.
Synthesis 2010, No. 10, 1678–1686 © Thieme Stuttgart · New York

PAPER
One-Pot Friedländer Quinoline Synthesis
1681
O
O
O
Fe (4.0 equiv), HCl (aq, 5 mol%),
EtOH, reflux
Ph
(2a)
KOH (s) (1.2 equiv),
reflux
2 days
NO2
NH2
7
8
1) Fe (4.0 equiv), 0.1 N aq HCl (5 mol%), BuOH,
125 °C, MW, 45–90 min
2) 2a, KOH (1.2 equiv), 125 °C, MW, 5 h
Ph
N
20%
9
Scheme 2
introduce functionality at the 4-position of the quinoline together with undesired 2,3-disubstituted quinoline 12 in
ring (Scheme 2). In this case, the reduction stage took a ratio of approximately a 1:2.5. The preference for the
considerably longer (2 days compared with the usual 40 formation of compound 12 over compound 11, the former
min) to provide the amino ketone intermediate (8), and af- being obtained by reaction at the sterically more-hindered
ter the addition of acetophenone (2a), an additional two methylene group of ketone 10, is not currently under-
days were required for the condensation stage to reach a stood.11
conversion of about 40% (as judged by LC/MS). Howev-
er, microwave conditions and the use of higher-boiling
butan-1-ol as the solvent significantly reduced the reac-
To illustrate the scalability of our one-pot procedure, we
prepared 2-phenylquinoline-7-carboxylic acid (6d;
Table 2, entry 4) on a 10-gram scale. The desired product
tion times to 45–90 minutes for the reduction stage and to
was isolated in quantitative yield as the hydrochloride salt
five hours for the condensation stage. Unfortunately, the
(Scheme 4). On this larger scale, 10 equivalents of iron
reaction again stalled at about 40% conversion, and the
powder and 20 mol% of hydrochloric acid were used, and
desired product 9 was obtained in only 20% isolated yield.
the reaction times for both the reduction (1.5 h) and the
As an application of our method, we attempted to synthe- condensation (5 h) stages were markedly longer than for
size the 2-alkyl-substituted quinoline alkaloid 11, a natu- reactions on the smaller scale.
ral product isolated from the stem, root, bark, and leaves
The above examples demonstrate that our one-pot
Friedländer quinoline synthesis is an effective, practical,
and scalable procedure. A wide variety of (het)aryl o-nitro
carboxaldehydes with electron-withdrawing or electron-
of Galipea longiflora by Fournet and co-workers.9 The
first synthesis of this compounds was reported by Burnell
and co-workers10 in 1993 (Scheme 3).
Application of the conditions that we used for o-nitro car- donating substituents react smoothly with various carbon-
boxaldehydes to the commercially available starting ma- yl compounds, including aliphatic, (het)aromatic, or a,b-
terials 1 and 10 gave the desired natural product 11 unsaturated ketones, and even an aldehyde. A wide range
of functional groups, such as methoxy, chloro, fluoro, cy-
clopropyl, ester (hydrolyzed to acid), Michael acceptors,
and acetals are tolerated, enabling the preparation of a va-
1) Fe (4.0 equiv), HCl (aq, 5 mol%),
EtOH, reflux
CHO
riety of quinolines in good-to-excellent yields. However,
o-nitro ketones and other substrates with functional
groups that are sensitive to reduction, such as bromo, per-
formed poorly under these conditions, giving lower isolat-
ed yields of products.
O
NO2
O
2)
(10), KOH (s), reflux
1
O
O
O
In summary, we have developed a highly versatile one-pot
Friedländer quinoline synthesis from o-nitro carbalde-
hydes and ketones/aldehydes and have tested its scope and
limitations. The method, which uses inexpensive, readily
available, and common reagents, is scalable and requires
+
O
O
N
N
11 (23%)
12 (57%)
Scheme 3
1) Fe (10.0 equiv), HCl (aq, 20 mol%),
EtOH, reflux, 1.5 h
CHO
NO2
HO
O
N
O
HCl
O
OMe
2)
(5a), KOH (s),
4e
6d
reflux, 5 h
100% (10 g scale)
Scheme 4
Synthesis 2010, No. 10, 1678–1686 © Thieme Stuttgart · New York

1682
A.-H. Li et al.
PAPER
3-Methoxy-2-phenylquinoline (3b)
Yield: 66%; Rf = 0.39 (EtOAc–hexanes, 1:4).
ate a variety of functional groups that can serve as handles IR (thin film, KBr): 3056, 2924, 2852, 1686 cm–1.
no moisture- or oxygen-free operations or complex work-
ups. The reaction conditions are sufficiently mild to toler-
1H NMR (400 MHz, CDCl3): d = 8.15–8.21 (m, 1 H), 8.00–8.06 (m,
2 H), 7.76 (dd, J = 1.3 Hz, 1 H), 7.57–7.64 (m, 1 H), 7.55 (t, J = 2.0,
1.5 Hz, 1 H), 7.53–7.55 (m, 1 H), 7.52 (d, J = 1.0 Hz, 1 H), 7.50 (t,
J = 1.5 Hz, 1 H), 7.47–7.49 (m, 1 H), 3.91–3.98 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 152.0, 151.7, 143.1, 137.9, 129.8,
129.4, 128.9, 128.7, 128.1, 126.9, 126.8, 126.3, 112.9, 55.5.
for further elaboration of the quinoline products.
Commercially available reagents, anhyd solvents, and HPLC-grade
solvents were used without further purification. Reactions were
monitored by TLC on silica gel 60 F254 (0.2 mm)-precoated alumi-
num foil/plastic. Flash chromatography was performed with silica
gel (400–230 mesh). IR spectra were recorded on a Perkin-Elmer
Spectrum 1000 FT-IR spectrometer as thin films using diffuse re-
flectance. 1H NMR and 13C NMR spectra were recorded with Vari-
an or Bruker instruments (400 MHz for 1H; 100 MHz for 13C) at r.t.
with TMS or the residual solvent peak as the internal standard. The
positions of lines or multiplets are given in ppm (d), and the cou-
pling constants (J) are given as absolute values in Hz. LC/MS anal-
ysis was performed using Hewlett Packard HP1100 (OpenLynx
LC-MS: detection: UV at 254 nM; column: XTerra MS C18, 5- par-
ticle size, 4.6 × 50 mm; mobile phase: 5-min gradient of MeCN and
0.01% HCO2H in H2O; flow rate: 1.3 mL/min). Mass spectra were
recorded on Micromass_ZQ200 (OpenLynx LC-MS) mass spec-
trometers by electrospray ionization (ESI). Melting points were de-
termined with a Mel-Temp II apparatus and are uncorrected.
Elemental analyses were carried out by Atlantic Microlab, Inc.,
Norcross, GA, USA.
MS (ESI): m/z = 236.18 [M + H]+.
HPLC: tR = 1.86 min (OpenLynx).
3-Methyl-2-phenylquinoline (3c)
Yield: 92%; Rf = 0.57 (EtOAc–hexanes, 1:10).
1H NMR (400 MHz, CDCl3): d = 8.16 (d, J = 8.6 Hz, 1 H), 8.03 (s,
1 H), 7.79 (d, J = 8.1 Hz, 1 H), 7.65–7.71 (m, 1 H), 7.58–7.64 (m, 2
H), 7.42–7.56 (m, 4 H), 2.48 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.0, 147.0, 141.0, 137.0, 129.2,
129.2, 128.8, 128.7, 128.3, 128.2, 127.6, 126.7, 126.4, 26.0.
MS (ESI): m/z = 220.20 [M + H]+.
HPLC: tR = 2.46 min (OpenLynx).
2-(1,3-Benzodioxol-5-yl)quinoline (3d)
Yield: 70%; mp 87–89 °C; Rf = 0.62 (EtOAc–hexanes, 1:4).
Quinolines; General Procedure
IR (thin film, KBr): 3056, 2893, 2778, 1596, 1487, 1444, 1247,
1038, 809, 512 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.41 (d, J = 8.6 Hz, 1 H), 8.11 (d,
J = 8.6 Hz, 1 H), 8.04 (d, J = 8.1 Hz, 1 H), 7.98 (d, J = 7.8 Hz 1 H),
7.82–7.90 (m, 2 H), 7.72–7.81 (m, 1 H), 7.53–7.62 (m, 1 H), 7.09
(d, J = 8.08 Hz, 1 H), 6.13 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 155.4, 148.6, 148.0, 147.3, 136.9,
132.9, 129.8, 128.9, 127.6, 126.7, 126.1, 121.6, 118.3, 108.4, 107.0,
101.4.
Fe powder (<10 mm, Aldrich; 223 mg, 4.0 mmol) and 0.1 M aq HCl
(0.5 mL, 0.05 mmol) were added sequentially to a solution of an o-
nitroarylcarbaldehyde 1 or 4a–g (1.0 mmol) in EtOH (3 mL), and
the resulting mixture was stirred vigorously at 95 °C (oil bath) while
the reaction was monitored (TLC). On completion of the reaction
(40 min–5 h), the carbonyl compound 2a–q, 5a–j, or 10 (1.0 mmol)
and powdered KOH (67.3 mg, 1.2 mmol) were added sequentially
in portions. (CAUTION! Potential exotherm; add the KOH slowly.)
The mixture was stirred at 95 °C while the reaction was monitored
(TLC). Upon completion of the reaction (30 min–48 h), the mixture
was cooled to r.t., diluted with CH2Cl2 (50 mL) and filtered through
a Celite pad. The filtrate was washed with H2O (10 mL) and the
aqueous phase was back-extracted with CH2Cl2 (2 × 15 mL). The
combined organic phases were dried (MgSO4), filtered, and concen-
trated in vacuo. The crude material was purified by chromatography
(silica gel, EtOAc–hexane or MeOH–CH2Cl2) to give the desired
quinoline products 3a–q, 6a–o, 11, or 12.
MS (ESI): m/z = 250.17 [M + H]+.
HPLC: tR = 2.87 min (OpenLynx).
11H-Indeno[1,2-b]quinoline (3e)
Yield: 63%; mp 164–166 °C; Rf = 0.5 (EtOAc–hexanes, 1:4).
IR (thin film, KBr): 2924, 1623, 1562, 1498, 1463, 1394, 1318, 905,
770, 732 cm–1.
For the carboxylic acid products (entry 15 in Table 1 and entry 4 in
Table 2), the workup was modified as follows. The inorganic solids
were removed by filtration of the warm mixture and the filtrate was
acidified to pH 1.0 with 4 M aq HCl. The solvents were removed on
a Rotovap, and H2O (10 mL) was added. The product was extracted
into THF (3 × 15 mL), dried (MgSO4), filtered, and concentrated in
vacuo to afford the desired acids as their HCl salts.
1H NMR (400 MHz, CDCl3): d = 8.30 (d, J = 7.1 Hz, 1 H), 8.21 (d,
J = 8.3 Hz, 1 H), 7.99 (s, 1 H), 7.64–7.74 (m, 2 H), 7.50 (m, 2 H),
7.45 (m, 2 H), 3.86 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 161.3, 147.7, 144.9, 140.1, 134.3,
130.8, 129.7, 128.8, 128.5, 127.6, 125.2, 121.8, 33.7.
MS (ESI): m/z = 218.20 [M + H]+.
HPLC: tR = 3.32 min (OpenLynx).
2-Phenylquinoline (3a)
Yield: 99%; mp 84–85 °C.
2-Pyridin-2-ylquinoline (3f)
Yield: 92%; mp 95.5–97.0 °C.
IR (thin film, KBr): 3057, 1615, 1596, 1582, 1153, 1508, 1490,
1319, 1074 cm–1.
IR (thin film, KBr): 3054, 1595, 1555, 1502, 1419, 1237, 1123,
1088, 993, 957, 944, 741, 713, 623 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.74–8.76 (m, 1 H), 8.68 (d,
J = 8.4 Hz, 1 H), 8.58 (d, J = 8.8 Hz, 1 H), 8.30 (d, J = 8.4 Hz, 1 H),
8.21 (d, J = 8.4 Hz, 1 H), 7.86–7.90 (m, 2 H), 7.74–7.76 (m, 1 H),
7.56–7.59 (m, 1 H), 7.37–7.38 (m, 1 H).
1H NMR (400 MHz, CDCl3): d = 8.15–8.28 (m, 4 H), 7.85 (d,
J = 8.1 Hz, 1 H), 7.70–7.78 (m, 1 H), 7.53–7.57 (m, 3 H), 7.46–7.51
(m, 1 H), 7.43 (d, J = 8.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 157.4, 136.8, 129.8, 129.7, 129.4,
128.9, 127.6, 127.5, 127.2, 127.2, 126.3, 119.0.
MS (ESI): m/z = 206.20 [M + H]+.
13C NMR (100 MHz, CDCl3): d = 156.3, 156.2, 149.2, 147.9, 136.9,
136.8, 129.8, 129.6, 128.3, 127.6, 126.7, 124.0, 121.8, 118.9.
HPLC: tR = 3.68 min (OpenLynx).
Synthesis 2010, No. 10, 1678–1686 © Thieme Stuttgart · New York

PAPER
One-Pot Friedländer Quinoline Synthesis
1683
MS (ESI): m/z = 207.14 [M + H]+.
HPLC: tR = 3.28 min (OpenLynx).
3-Ethyl-2-propylquinoline (3l)
Yield: 85%; Rf = 0.68 (EtOAc–hexanes, 3:7).
IR (thin film, KBr): 3058, 2962, 1490, 1420, 1209, 1148, 908, 747,
616 cm–1.
2-(1-Methyl-1H-pyrrol-2-yl)quinoline (3g)
Yield: 88%; mp 51–52 °C; Rf = 0.52 (EtOAc–hexanes, 1:4).
IR (thin film, KBr): 1615, 1600, 1235 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.07 (d, J = 8.8 Hz, 1 H), 8.02 (dd,
J = 8.5, 1.14 Hz, 1 H), 7.76 (dd, J = 8.0, 1.4 Hz, 1 H), 7.71 (d,
J = 8.6 Hz, 1 H), 7.67 (ddd, J = 8.5, 7.0, 1.5 Hz, 1 H), 7.46 (ddd,
J = 8.0, 6.9, 1.3 Hz, 1 H), 6.80–6.83 (m, 1 H), 6.79 (dd, J = 3.9, 1.9
Hz, 1 H), 6.23 (dd, J = 3.9, 2.7 Hz, 1 H), 4.22 (s, 3 H).
1H NMR (400 MHz, CDCl3): d = 8.04 (d, J = 8.3 Hz, 1 H), 7.86 (s,
1 H), 7.72 (d, J = 8.1 Hz, 1 H), 7.55–7.65 (m, 1 H), 7.44 (t, J = 7.6
Hz, 1 H), 2.91–3.04 (m, 2 H), 2.84 (q, J = 7.3 Hz, 2 H), 1.76–1.94
(m, 2 H), 1.34 (t, J = 7.6 Hz, 3 H), 1.08 (t, J = 7.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 162.0, 146.2, 135.4, 134.1, 128.5,
128.3, 127.4, 126.9, 125.6, 37.7, 25.2, 22.9, 14.4, 14.4.
MS (ESI): m/z = 200.21 [M + H]+.
13C NMR (100 MHz, CDCl3): d = 152.3, 147.7, 135.9, 132.3, 129.4,
129.1, 127.7, 127.5, 126.1, 125.5, 120.2, 112.4, 107.9, 37.7.
HPLC: tR = 2.34 min (OpenLynx).
MS (ESI): m/z = 209.25 [M + H]+.
2-tert-Butylquinoline (3m)
Yield: 90%; Rf = 0.73 (EtOAc–hexanes, 1:4).
HPLC: tR = 2.70 min (OpenLynx).
1H NMR (400 MHz, CDCl3): d = 8.07 (d, J = 8.8 Hz, 2 H), 7.77 (d,
J = 8 Hz, 1 H), 7.67 (m, 1 H), 7.53 (d, J = 8.8 Hz, 1 H), 7.48 (m, 1
H), 1.49 (s, 9 H).
2-(2-Thienyl)quinoline (3h)
Yield: 80%; mp 130–132 °C; Rf = 0.44 (EtOAc–hexanes, 1:4).
IR (thin film, KBr): 3100, 3059, 1613, 1592, 1551, 1526, 1498,
1426, 1316, 1242, 1227, 1143, 1121, 1057, 905, 820, 719 cm–1.
13C NMR (100 MHz, CDCl3): d = 169.3, 147.5, 135.9, 129.5, 129.0,
127.3, 126.5, 125.7, 118.2, 77.4, 76.8, 38.2, 30.2.
1H NMR (400 MHz, CDCl3): d = 8.11 (d, J = 8.0 Hz, 1 H), 8.09 (d,
J = 7.6 Hz, 1 H), 7.77 (d, J = 8.8 Hz, 1 H), 7.70–7.77 (m, 2 H), 7.68
(ddd, J = 8.4, 6.8, 1.6 Hz, 1 H), 7.47 (ddd, J = 8.0, 6.8, 1.2 Hz, 1 H),
7.46 (dd, J = 5.2, 1.2 Hz, 1 H), 7.15 (dd, J = 5.2, 4.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 152.4, 148.2, 145.5, 136.8, 129.9,
129.4, 128.7, 128.2, 127.6, 127.3, 126.2, 126.1, 117.8.
MS (ESI): m/z = 186.24 [M + H]+.
HPLC: tR = 2.18 min (OpenLynx).
2-Cyclopropylquinoline (3n)
Yield: 91%; Rf = 0.47 (EtOAc–hexanes, 1:4).
IR (thin film, KBr): 3056, 3006, 1616, 1600, 1504, 1425, 1302,
1213, 1204, 1166, 1082, 1022, 951, 909, 819, 751, 619 cm–1.
MS (ESI): m/z = 212.14 [M + H]+.
HPLC: tR = 3.74 min (OpenLynx).
1H NMR (400 MHz, CDCl3): d = 7.99 (d, J = 8.6 Hz, 1 H), 7.96 (d,
J = 8.4 Hz, 1 H), 7.73 (dd, J = 1.2, 8.0 Hz, 1 H), 7.64 (ddd, J = 1.2,
7.0, 8.8 Hz, 1 H), 7.42 (ddd, J = 1.2, 7.0, 8.0 Hz, 1 H), 7.16 (d,
J = 8.4 Hz, 1 H), 2.28–2.20 (m, 1 H), 1.18–1.12 (m, 2 H), 1.12–1.05
(m, 2 H).
13C NMR (100 MHz, CDCl3): d = 163.4, 148.0, 135.8, 129.2, 128.6,
127.4, 126.7, 125.1, 119.3, 18.1, 10.2.
2-[(E)-2-Phenylvinyl]quinoline (3i)
Yield: 77%; Rf = 0.43 (EtOAc–hexanes, 1:4).
1H NMR (400 MHz, CDCl3): d = 8.13 (d, J = 8.4 Hz, 1 H), 8.01 (d,
J = 8.8 Hz, 1 H), 7.72–7.62 (m, 5 H), 7.57 (d, J = 8.8 Hz, 1 H),
7.47–7.37 (m, 4 H), 7.34–7.30 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 156.0, 148.3, 136.6, 136.3, 134.5,
129.8, 129.3, 129.1, 128.8, 128.7, 127.6, 127.4, 127.3, 126.2, 119.3.
MS (ESI): m/z = 170.14 [M + H]+.
HPLC: tR = 1.79 min (OpenLynx).
2-Methylquinoline (3j)
Yield: 64%; Rf = 0.43 (EtOAc–hexanes, 1:4).
Quinoline-2-carboxylic Acid Hydrochloride (3o)
Yield: 95%; mp 150–153 °C (dec.).
IR (thin film, KBr): 1601, 1506, 1423, 1312, 1221, 813, 782, 741,
616 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.01–8.04 (m, 2 H), 7.75 (d,
J = 8.0 Hz, 1 H), 7.67 (m, 1 H), 7.64 (m, 1 H), 7.26 (d, J = 8.4 Hz,
1 H), 2.74 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 158.9, 147.8, 136.1, 129.4, 128.6,
127.5, 126.4, 125.6, 121.9, 25.3.
1H NMR (400 MHz, MeOH-d4): d = 8.53 (d, J = 8.3 Hz, 1 H), 8.21–
8.25 (m, 2 H), 8.03 (d, J = 8.3 Hz, 1 H), 7.85–7.89 (m, 1 H), 7.72–
7.76 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 167.7, 149.6, 148.1, 139.8, 132.1,
131.1, 130.3, 130.1, 129.2, 121.9.
MS (ESI): m/z = 174.06 [M + H]+.
HPLC: tR = 1.80 min (OpenLynx).
MS (ESI): m/z = 144.22 [M + H]+.
HPLC: tR = 0.89 min (OpenLynx).
2-(Dimethoxymethyl)quinoline (3p)
Yield: 90%; Rf = 0.37 (EtOAc–CHCl3, 1:5).
1,2,3,4-Tetrahydroacridine (3k)
Yield: 95%; Rf = 0.43 (EtOAc–hexanes, 1:4).
1H NMR (400 MHz, CDCl3): d = 7.97 (d, J = 8.4 Hz, 1 H), 7.70 (s,
1 H), 7.63 (d, J = 8.0 Hz, 1 H), 7.57 (dt, J = 2.4, 7.2 Hz, 1 H), 7.39
(dt, J = 1.2, 7.2 Hz, 1 H), 3.10 (t, J = 5.8 Hz, 2 H), 2.92 (t, J = 6.4
Hz, 2 H), 1.99–1.92 (m, 2 H), 1.87–1.82 (m, 2 H).
IR (thin film, KBr): 2932, 2830, 1601, 1504, 1102, 1067 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.22 (d, J = 8.3 Hz, 1 H), 8.16 (d,
J = 8.3 Hz, 1 H), 7.84 (d, J = 8.1 Hz, 1 H), 7.70–7.77 (m, 1 H), 7.68
(d, J = 8.3 Hz, 1 H), 7.53–7.60 (m, 1 H), 5.50 (s, 1 H), 3.48 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 157.7, 137.0, 129.5, 128.1, 127.6,
126.8, 124.8, 118.7, 105.1, 54.2.
13C NMR (100 MHz, CDCl3): d = 159.3, 146.7, 134.9, 130.9, 128.5,
128.3, 127.2, 126.9, 125.5, 33.6, 29.3, 23.3, 22.9.
MS (ESI): m/z = 204.21 [M + H]+.
MS (ESI): m/z = 184.21 [M + H]+.
HPLC: tR = 2.84 min (OpenLynx).
HPLC: tR = 1.86 min (OpenLynx).
Synthesis 2010, No. 10, 1678–1686 © Thieme Stuttgart · New York

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A.-H. Li et al.
PAPER
3-Phenylquinoline (3q)
Yield: 87%; mp 177–180 °C (HCl salt); Rf = 0.16 (CH2Cl2–
13C NMR (100 MHz, CDCl3): d = 160.7, 149.3, 141.0, 139.2, 134.5,
133.0, 131.7, 131.6, 130.7, 129.8, 129.5, 127.8, 122.9.
hexanes, 1:1).
MS (ESI): m/z = 250.15 [M + H]+.
IR (thin film, KBr): 3058, 3031, 1597, 1568, 1493, 1460, 1448,
1363, 1341, 1126, 1026, 954, 903, 786, 762, 696 cm–1.
HPLC: tR = 3.20 min (OpenLynx).
1H NMR (400 MHz, CDCl3): d = 9.19 (d, J = 2.2 Hz, 1 H), 8.31 (d,
J = 2.2 Hz, 1 H), 8.15 (d, J = 8.6 Hz, 1 H), 7.89 (dd, J = 1.8, 8.2 Hz,
1 H), 7.75–7.69 (m, 3 H), 7.58 (ddd, J = 1.2, 6.8, 8.2 Hz, 1 H), 7.56–
7.51 (m, 2 H), 7.47–7.42 (mc, 1 H).
13C NMR (100 MHz, CDCl3): d = 149.9, 147.3, 137.8, 133.8, 133.2,
129.3, 129.2, 129.1, 128.1, 128.0, 128.0, 127.4, 126.9.
2-Phenylbenzo[h]quinoline (6e)
Yield: 95%; mp 66–67 °C; Rf = 0.76 (EtOAc–hexanes, 1:4).
IR (thin film, KBr): 3050, 2360 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.37 (d, J = 7.2 Hz, 1 H), 8.51
(d, J = 8.4 Hz, 1 H), 8.44 (d, J = 7.6 Hz, 2 H), 8.31 (d, J = 8.4 Hz, 1
H), 8.06 (d, J = 8.0 Hz, 1 H), 7.90–7.97 (m, 2 H), 7.76–7.83 (m, 2
H), 7.61 (t, J = 7.4 Hz, 2 H), 7.53 (t, J = 7.2 Hz, 1 H).
MS (ESI): m/z = 206.14 [M + H]+.
HPLC: tR = 2.78 min (OpenLynx).
13C NMR (100 MHz, DMSO-d6): d = 137.2, 133.5, 130.9, 129.5,
128.9, 128.4, 128.0, 127.3, 127.1, 127.0, 125.3, 125.0, 123.9, 119.1.
7-Bromo-2-phenylquinoline (6a)
Yield: 58%; mp 122.0–123.5 °C.
1H NMR (400 MHz, CDCl3): d = 8.37 (s, 1 H), 8.15–8.21 (m, 5 H),
7.90 (d, J = 8.4 Hz, 1 H), 7.70 (d, J = 8.8 Hz, 1 H), 7.62 (dd,
J = 10.4, 1.6 Hz, 1 H), 7.46–7.56 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 158.2, 148.9, 139.1, 136.9, 132.1,
129.9, 129.8, 129.0, 128.8, 127.8, 125.9, 123.9, 119.4.
MS (ESI): m/z = 284 ([M + H]+, 79Br), 286 ([M + H]+, 81Br).
MS (ESI): m/z = 256.11 [M + H]+.
HPLC: tR = 4.52 min (OpenLynx).
3-tert-Butyl-1-methyl-5-phenyl-1H-pyrazolo[4,3-b]pyridine (6f)
Yield: 82%; mp 103–104 °C; Rf = 0.76 (EtOAc–hexanes, 5:95).
1H NMR (400 MHz, DMSO-d6): d = 8.09 (dt, J = 1.2, 7.4 Hz, 2 H),
7.73 (d, J = 7.3 Hz, 1 H), 7.63 (d, J = 7.3 Hz, 1 H), 7.46 (dt, J = 1.8,
7.4 Hz, 2 H), 7.37 (tt, J = 1.2, 7.4 Hz, 1 H), 3.99 (s, 3 H), 1.62 (s, 9
H).
13C NMR (100 MHz, DMSO-d6): d = 153.3, 150.4, 139.6, 139.3,
132.8, 128.3, 128.0, 126.6, 117.3, 116.5, 35.1, 33.2, 29.3.
MS (ESI): m/z = 266.23 [M + H]+.
HPLC: tR = 4.20 min (OpenLynx).
Anal. Calcd for C15H10BrN: C, 63.40; H, 3.55; N, 4.93; Br 28.12.
Found: C, 63.41; H, 3.41; N, 4.84; Br, 28.31.
6-Phenyl[1,3]dioxolo[4,5-g]quinoline (6b)
Yield: 82%; mp 110–112 °C; Rf = 0.25 (CH2Cl2–hexanes, 1:1).
HPLC: tR = 3.98 min (OpenLynx).
Anal. Calcd for C17H19N3: C, 76.95; H, 7.22; N, 15.84. Found: C,
76.75; H, 7.17; N, 16.11.
IR (thin film, KBr): 1792, 1772, 1683, 1652, 1616, 1230, 1171,
1037 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.11–8.04 (m, 2 H), 7.90 (d,
J = 8.6 Hz, 1 H), 7.63 (d, J = 8.3 Hz, 1 H), 7.51–7.44 (m, 2 H),
7.43–7.36 (m, 2 H), 6.96 (s, 1 H), 6.01 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 155.2, 150.7, 147.6, 146.5, 139.7,
135.4, 128.85, 128.71, 127.2, 124.0, 117.1, 106.1, 102.5, 101.6.
7-Chloro-2-(2-fluorophenyl)quinoline (6g)
Yield: 87%; mp 123.5 °C.
IR (thin film, KBr): 2957, 2931, 2866, 1610, 1598, 1497 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.24 (s, 1 H), 8.21 (d, J = 8.4 Hz,
1 H), 8.12 (dt, J = 1.6, 7.6 Hz, 1 H), 7.92 (dd, J = 8.6, 2.8 Hz, 1 H),
7.81 (d, J = 8.8 Hz, 1 H), 7.53 (dd, J = 8.8, 2.0 Hz, 1 H), 7.44–7.50
(m, 1 H), 7.34 (dt, J = 1.2, 7.6 Hz, 1 H), 7.19–7.25 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 162.1, 159.6, 154.98, 154.96,
148.6, 136.0, 135.5, 131.5, 131.5, 131.2, 131.2, 128.7, 128.7, 127.7,
127.5, 127.3, 125.6, 124.8, 124.7, 122.7, 122.6, 116.4, 116.2.
MS (ESI): m/z = 250.17 [M + H]+.
HPLC: tR = 2.63 min (OpenLynx).
N,N-Dimethyl-2-phenylquinolin-7-amine (6c)
Yield: 67%; Rf = 0.49 (EtOAc–CHCl3, 1:5).
IR (thin film, KBr): 3058, 3030, 1617, 1595 cm–1.
MS (ESI): m/z = 258.12 ([M + H]+, 35Cl), 261.06 ([M + H]+, 37Cl).
1H NMR (400 MHz, CDCl3): d = 8.13 (d, J = 7.3 Hz, 2 H), 8.07 (d,
J = 8.3 Hz, 1 H), 7.68 (d, J = 9.1 Hz, 1 H), 7.58 (d, J = 8.3 Hz, 1
H), 7.49–7.56 (m, 3 H), 7.42–7.49 (m, 1 H), 7.18 (dd, J = 9.1, 2.53
Hz, 1 H), 3.14 (s, 6 H).
HPLC: tR = 3.69 min (OpenLynx).
7-Chloro-2-(2-chlorophenyl)quinoline (6h)
Yield: 68%; mp 128 °C.
13C NMR (100 MHz, CDCl3): d = 40.8, 107.7, 115.5, 116.4, 120.2,
IR (thin film, KBr): 1611, 1598, 1499 cm–1.
127.8, 128.2, 128.9, 129.1, 136.4, 151.8, 157.9.
1H NMR (400 MHz, CDCl3): d = 8.21–8.29 (m, 2 H), 7.81 (dd,
J = 20.0, 8.6 Hz, 2 H), 7.68–7.74 (m, 1 H), 7.50–7.60 (m, 2 H),
7.38–7.47 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 158.3, 135.6, 135.6, 132.3, 131.7,
130.2, 130.1, 128.8, 128.6, 127.9,127.2, 125.5, 123.0.
MS (ESI): m/z = 249.16 [M + H]+.
HPLC: tR = 1.97 min (OpenLynx).
2-Phenylquinoline-7-carboxylic Acid Hydrochloride (6d)
Yield: 91%; mp 255 °C.
IR (thin film, KBr): 2924, 1682, 975, 760 cm–1.
1H NMR (400 MHz, MeOH-d4): d = 8.79-8.80 (m, 1 H), 8.45 (dd,
J = 0.8, 8.8 Hz, 1 H), 8.16-8.19 (m, 2 H), 8.14 (dd, J = 1.6, 8.4 Hz,
1 H), 8.10 (d, J = 8.8 Hz, 1 H), 8.02 (d, J = 8.4 Hz, 1 H), 7.50-7.59
(m, 3 H).
MS (ESI): m/z = 274.11 ([M + H]+, 35Cl), 276.10 ([M + H]+, 37Cl).
HPLC: tR = 3.63 min (OpenLynx).
7-Chloro-2-(2-methylphenyl)quinoline (6i)
Yield: 76%; mp 79 °C.
IR (thin film, KBr): 2961, 2927, 2862, 1611, 1598, 1497 cm–1.
Synthesis 2010, No. 10, 1678–1686 © Thieme Stuttgart · New York

PAPER
One-Pot Friedländer Quinoline Synthesis
1685
1H NMR (400 MHz, CDCl3): d = 8.22 (d, J = 8.1 Hz, 2 H), 7.82 (d,
1H NMR (400 MHz, CDCl3): d = 8.07 (br s, 2 H), 7.71 (d, J = 8.6
Hz, 1 H), 7.45 (d, J = 8.1 Hz, 1 H), 7.34 (d, J = 7.3 Hz, 1 H), 3.87
(br s, 1 H), 2.40–2.53 (m, 4 H), 2.07–2.21 (m, 1 H), 1.92–2.03 (m,
1 H).
13C NMR (100 MHz, CDCl3): d = 166.2, 148.1, 136.0, 135.1, 128.6,
128.1, 126.7, 125.1, 119.9, 42.6, 28.2, 18.3.
J = 8.6 Hz, 1 H), 7.48–7.59 (m, 3 H), 7.31–7.38 (m, 3 H), 2.43 (s, 3
H).
13C NMR (100 MHz, CDCl3): d = 160.9, 147.8, 139.8, 135.7, 135.6,
135.2, 130.6, 129.3, 128.4, 128.4, 128.2, 127.1, 125.7, 124.7, 122.2,
20.0.
MS (ESI): m/z = 254.14 ([M + H]+, 35Cl), 256.10 ([M + H]+, 37Cl).
MS (ESI): m/z = 218.12 ([M + H]+, 35Cl), 220.08 ([M + H]+, 37Cl).
HPLC: tR = 3.64 min (OpenLynx).
HPLC: tR = 3.36 min (OpenLynx).
7-Chloro-3-methyl-2-phenylquinoline (6j)
Yield: 75%; mp 106 °C.
7-Chloro-2-cyclohexylquinoline (6o)
Yield: 78%; mp 79 °C.
IR (thin film, KBr): 2961, 2931, 2866, 1613, 1598, 1497 cm–1.
IR (thin film, KBr): 2961, 2931, 2862, 1613, 1600, 1497 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.16 (br s, 1 H), 8.02 (s, 1 H), 7.73
(d, J = 8.6 Hz, 1 H), 7.54–7.64 (m, 2 H), 7.40–7.56 (m, 4 H), 2.48
(s, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.5, 146.9, 140.4, 136.7, 134.5,
129.6, 128.8, 128.5, 128.4, 128.3, 128.0, 127.5, 125.9, 20.4.
1H NMR (400 MHz, CDCl3): d = 8.06 (br s, 2 H), 7.71 (d, J = 8.1
Hz, 1 H), 7.45 (br s, 1 H), 7.33 (br s, 1 H), 2.91 (br s, 1 H), 2.03 (d,
J = 11.1 Hz, 2 H), 1.91 (dd, J = 9.6, 3.0 Hz, 2 H), 1.81 (d, J = 12.4
Hz, 1 H), 1.58–1.70 (m, 2 H), 1.48 (q, J = 12.6 Hz, 2 H), 1.28–1.40
(m, 1 H).
13C NMR (100 MHz, CDCl3): d = 167.9, 148.2, 136.1, 135.2, 128.6,
128.2, 126.6, 125.2, 120.0, 47.5, 32.7, 32.7, 26.5, 26.1.
MS (ESI): m/z = 253.86 ([M + H]+, 35Cl), 255.68 ([M + H]+, 37Cl).
HPLC: tR = 4.00 min (OpenLynx).
MS (ESI): m/z = 246.18 ([M + H]+, 35Cl), 248.14 ([M + H]+, 37Cl).
7-Chloro-2-isopropylquinoline (6k)
HPLC: tR = 3.91 min (OpenLynx).
Yield: 84%; mp 81–82 °C.
2-[2-(1,3-Benzodioxol-5-yl)ethyl]quinoline (11)
Yield: 23%; mp 60–63 °C; Rf = 0.39 (EtOAc–hexanes, 1:4).
IR (thin film, KBr): 2959, 2928, 2866, 1613, 1598, 1496, 1410
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.03–8.07 (m, 2 H), 7.70 (d,
J = 8.6 Hz, 1 H), 7.43 (dd, J = 8.6, 2.0 Hz, 1 H), 7.33 (d, J = 8.6 Hz,
1 H), 3.20–3.29 (m, 1 H), 1.39 (d, J = 7.1 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 188.3, 168.8, 148.1, 136.1, 135.0,
128.6, 128.1, 126.7, 125.3, 119.6, 37.2, 22.4.
1H NMR (400 MHz, CDCl3): d = 7.95–8.24 (m, 2 H), 7.82 (d,
J = 6.8 Hz, 1 H), 7.75 (br s, 1 H), 7.53 (br s, 1 H), 7.25 (br s, 1 H,
obscured), 6.77 (s, 1 H), 6.66–6.74 (m, 2 H), 3.24–3.37 (m, 2 H),
5.93 (s, 2 H), 3.08–3.16 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 161.7, 147.9, 147.5, 145.7, 136.2,
135.3, 129.4, 128.8, 127.5, 126.8, 125.8, 121.6, 121.3, 109.0, 108.1,
100.7, 41.2, 35.6.
MS (ESI): m/z = 206.12 ([M + H]+, 35Cl), 208.10 ([M + H]+, 37Cl).
MS (ESI): m/z = 277.88 [M + H]+.
HPLC: tR = 3.84 min (OpenLynx).
HPLC: tR = 1.97 min (OpenLynx).
2-tert-Butyl-7-chloroquinoline (6l)
Yield: 81%; mp 155–157 °C.
IR (thin film, KBr): 2959, 2924, 2859, 2358, 2332, 1116 cm–1.
3-(1,3-Benzodioxol-5-ylmethyl)-2-methylquinoline (12)
Yield: 57%; mp 126 °C; Rf = 0.24 (EtOAc–hexanes, 1:4).
1H NMR (400 MHz, CDCl3): d = 8.01–8.12 (m, 2 H), 7.70 (d,
J = 8.6 Hz, 1 H), 7.52 (d, J = 8.6 Hz, 1 H), 7.43 (dd, J = 8.6, 2.0 Hz,
1 H), 1.47 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 170.4, 147.8, 135.7, 134.8, 128.5,
128.4, 126.6, 124.8, 118.4, 38.3, 30.1.
1H NMR (400 MHz, CDCl3): d = 7.97–8.24 (m, 1 H), 7.83 (br s, 1
H), 7.75 (d, J = 8.1 Hz, 1 H), 7.69 (t, J = 7.1 Hz, 1 H), 7.47–7.55 (m,
1 H), 6.78 (d, J = 7.8 Hz, 1 H), 6.58–6.67 (m, 2 H), 5.96 (s, 2 H),
4.08 (s, 2 H), 2.71 (br s, 3 H).
13C NMR (100 MHz, CDCl3): d = 158.8, 147.9, 146.7, 135.7, 132.8,
132.6, 128.8, 128.8, 128.3, 127.2, 127.1, 125.8, 121.8, 109.3, 108.3,
101.0, 38.9, 23.5.
MS (ESI): m/z = 220.15 ([M + H]+, 35Cl), 222.18 ([M + H]+, 37Cl).
HPLC: tR = 4.35 min (OpenLynx).
MS (ESI): m/z = 277.97 [M + H]+.
7-Chloro-2-cyclopropylquinoline (6m)
Yield: 71%; mp 37 °C.
HPLC: tR = 1.47 min (OpenLynx).
IR (thin film, KBr): 1611, 1600, 1499 cm–1.
4-Methyl-2-phenylquinoline (9)
A tube containing a small stirring bar was charged with Fe powder
(<10 mm, Aldrich; 220 mg, 4.0 mmol), 1-(2-nitrophenyl)ethanone
(7; 160 mg. 1.0 mmol), n-BuOH (3 mL), and 0.1 M aq HCl (0.5 mL,
0.05 mmol). The mixture was heated with stirring in a microwave
reactor (CEM, 300 W, POWERMAX) at 125 °C for 1.5 h, then
cooled to r.t. A 6.7 M aq soln of KOH (0.18 mL, 1.2 mmol) was
added, followed by acetophenone (2a, 0.12 mL, 1.0 mmol). The
mixture was again heated with stirring in the microwave reactor at
125 °C for 5 h then cooled to r.t. and filtered. The metallic residue
was rinsed with MeOH, and the filtrate was concentrated in vacuo
and purified by preparative TLC [silica gel, EtOAc–hexanes (1:5)]
to give a pale yellow oil; yield: 44 mg (20%); Rf = 0.40 (EtOAc–
hexanes, 1:5).
1H NMR (400 MHz, CDCl3): d = 7.93–8.03 (m, 2 H), 7.67 (d,
J = 8.6 Hz, 1 H), 7.39 (dd, J = 8.7, 1.9 Hz, 1 H), 7.20 (d, J = 8.3 Hz,
1 H), 2.23 (br s, 1 H), 1.06–1.23 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 164.7, 148.4, 135.5, 135.0, 128.6,
127.7, 126.1, 125.1, 120.0, 18.0, 10.7.
MS (ESI): m/z = 203.95 ([M + H]+, 35Cl), 205.95 ([M + H]+, 37Cl).
HPLC: tR = 3.62 min (OpenLynx).
7-Chloro-2-cyclobutylquinoline (6n)
Yield: 65%; mp 45 °C.
IR (thin film, KBr): 2959, 2871, 1615, 1600, 1497 cm–1.
Synthesis 2010, No. 10, 1678–1686 © Thieme Stuttgart · New York

1686
A.-H. Li et al.
PAPER
IR (thin film, KBr): 3059, 2920, 1683, 1597, 1508, 1409, 1348
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.13–8.31 (m, 3 H), 8.02 (d,
J = 8.1 Hz, 1 H), 7.70–7.79 (m, 2 H), 7.41–7.64 (m, 4 H), 2.79 (s, 3
Rosenfeld-Franklin, M.; Honda, A.; Mak, G.; Mulvihill, K.
M.; Nigro, A. I.; O’Connor, M.; Pirrit, C.; Steinig, A. G.;
Siu, K.; Stolz, K. M.; Sun, Y.; Tavares, P. A. R.; Yao, Y.;
Gibson, N. W. Bioorg. Med. Chem. 2008, 16, 1359. (g) Ji,
Q.-s.; Mulvihill, M. J.; Rosenfeld-Franklin, M.; Cooke, A.;
Feng, L.; Mak, G.; O’Connor, M.; Yao, Y.; Pirritt, C.; Buck,
E.; Eyzaguirre, A.; Arnold, L. D.; Gibson, N. W.; Pachter, J.
A. Mol. Cancer Ther. 2007, 6, 2158. (h) Mulvihill, M. J.;
Cooke, A.; Rosenfeld-Franklin, M.; Buck, E.; Foreman, K.;
Landfair, D.; O’Connor, M.; Pirritt, C.; Sun, Y.; Yao, Y.;
Arnold, L. D.; Gibson, N. W.; Ji, Q.-s. Future Med. Chem.
2009, 1, 1153.
H).
13C NMR (100 MHz, CDCl3): d = 156.9, 147.8, 145.0, 139.5, 133.0,
129.4, 129.2, 128.7, 127.6, 126.1, 123.6, 119.8, 19.0.
MS (ESI): m/z = 220.18 [M + H]+.
HPLC: tR = 3.53 min (OpenLynx).
2-Phenylquinoline-7-carboxylic Acid Hydrochloride (6d);
Scaled-Up Method
(3) (a) For a review, see: Cheng, C.-C.; Yan, S.-J. Org. React.
(N. Y.) 1982, 28, 37. For a recent paper on the mechanism,
see: (b) Muchowski, J. M.; Maddox, M. L. Can. J. Chem.
2004, 82, 461.
Fe powder (<10 mm, Aldrich; 21.05 g, 377 mmol), H2O (8 mL), and
concd HCl (0.63 mL, 7.5 mmol) were added consecutively to a so-
lution of methyl 4-formyl-3-nitrobenzoate (4e; 8.04 g, 38.4 mmol)
in EtOH (100 mL). The mixture was stirred at 95 °C for 1.5 h.
PhCOMe (5a, 4.4 mL, 37.7 mmol) and solid KOH (6.34 g, 113
mmol) were cautiously added, and the mixture was stirred at 95 °C
for another 5 h. The inorganic solids were removed by filtration of
the warm mixture, and the filtrate was acidified to pH 1.0 with 4 M
aq HCl. The solvents were removed on a Rotovap, and H2O (10 mL)
was added. The product was extracted with THF (3 × 100 mL) and
the extracts were dried (MgSO4), filtered and concentrated in vacuo
to afford the acid 6d as its HCl salt; yield: 10.9 g (quant). The ana-
lytical data were identical with those of the product from the small-
scale reaction.
(4) (a) McNaughton, B. R.; Miller, B. L. Org. Lett. 2003, 5,
4257. (b) Eckert, H. Angew. Chem. 1981, 93, 216.
(c) Motokura, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K.
Tetrahedron Lett. 2004, 45, 6029. (d) Cho, C. S.; Kim, B.
T.; Choi, H.-J.; Kim, T.-J.; Shim, S. C. Tetrahedron 2003,
59, 7997. (e) Martinez, R.; Ramon, D. J.; Yus, M. Eur. J.
Org. Chem. 2007, 1599. (f) Cho, C. S.; Ren, W. X.; Shim, S.
C. Tetrahedron Lett. 2006, 47, 6781. (g) Cho, C. S.; Ren,
W. X.; Shim, S. C. Bull. Korean Chem. Soc. 2005, 26, 1286.
(5) Li, A.-H.; Ahmed, E.; Chen, X.; Cox, M.; Crew, A. P.;
Dong, H.-Q.; Jin, M.; Ma, L.; Panicker, B.; Siu, K. W.;
Steinig, A. G.; Stolz, K. M.; Tavares, P. A. R.; Volk, B.;
Weng, Q.; Werner, D.; Mulvihill, M. J. Org. Biomol. Chem.
2007, 5, 61.
(6) Arnold, L. D.; Cesario, C.; Coate, H.; Crew, A. P.; Dong, H.;
Foreman, K.; Honda, A.; Laufer, R.; Li, A.-H.; Mulvihill, K.
M.; Mulvihill, M. J.; Nigro, A.; Panicker, B.; Steinig, A. G.;
Sun, Y.; Weng, Q.; Werner, D. S.; Wyle, M. J.; Zhang, T.
WO 2005097800, 2005; Chem. Abstr. 2005, 142, 405928.
(7) The Hammett substituent constant (s value) for the para-
Me2N group is –0.205, suggesting that it has an electron-
donating effect. See: Hammett, L. P. J. Am. Chem. Soc.
1937, 59, 96.
(8) Longer condensation times have also been reported for the
reaction of the intermediate 1-aminonaphthalene-2-
carboxaldehyde with 1,3-diacetylbenzene (31 h) and 2,6-
diacetylpyridine (17 h) under essentially the same reaction
conditions (KOH in refluxing EtOH); see: Riesgo, E. C.; Jin,
X.; Thummel, R. P. J. Org. Chem. 1996, 61 , 3017.
(9) (a) Fournet, A.; Vagneur, B.; Richomme, P.; Bruneton, J.
Can. J. Chem. 1989, 67, 2116. (b) Fournet, A.;
Hocquemiller, R.; Roblot, F.; Cavé, A.; Richomme, P.;
Bruneton, J. J. Nat. Prod. 1993, 56, 1547.
(10) Caron, S.; Desfossés, S.; Dionne, R.; Théberge, N.; Burnell,
R. H. J. Nat. Prod. 1993, 56, 138.
Acknowledgment
We thank OSI Cancer Chemistry and especially Viorica Lazarescu
and Raphael Rios for analytical support.
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Synthesis 2010, No. 10, 1678–1686 © Thieme Stuttgart · New York