Furan ring opening - Pyridine ring closure: New route to quinolines under the Bischler-Napieralski reaction conditions

Article abstract of DOI:10.1055/s-0030-1260118

A new approach to highly functionalized quinolines is proposed. This approach is based on the electrophilic recyclization of 2-[2-(acylamino)benzyl] furans under the Bischler-Napieralski reaction conditions. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0030-1260118

PAPER
2629
Furan Ring Opening – Pyridine Ring Closure: New Route to Quinolines under
the Bischler–Napieralski Reaction Conditions
New
R
oute toQuin
l
olines
e
under the
B
x
ischler–Nap
a
ieralski Re
n
actionCondi
d
tions er V. Butin,*a Fatima A. Tsiunchik,a Olga N. Kostyukova,a Maxim G. Uchuskin,a Igor V. Trushkovb,c
a
Research Institute of Heterocyclic Compounds Chemistry, Kuban State Technological University, Moskovskaya st. 2,
Krasnodar 350072, Russian Federation
Fax +7(861)2596592; E-mail: alexander_butin@mail.ru; E-mail: av_butin@yahoo.com
Department of Chemistry, M.V. Lomonosov Moscow State University, Leninskie Gory 1/3, Moscow 119991, Russian Federation
Laboratory of Chemical Synthesis, Federal Research Center of Pediatric Hematology, Oncology and Immunology, Leninskii av. 117/2,
Moscow 117997, Russian Federation
b
c
Received 18 April 2011; revised 29 May 2011
azepines 2 under the Bischler–Napieralski reaction condi-
tions; however, we recently found that treatment of 2-
[2-(benzoylamino)-4,5-dimethoxybenzyl]-5-methylfuran
(1a) with phosphorus oxychloride yields the quinoline de-
rivative 3a (Scheme 2) instead of 2.18 Herein, we report
our overall results of investigations of this unusual trans-
formation.
Abstract: A new approach to highly functionalized quinolines is
proposed. This approach is based on the electrophilic recyclization
of 2-[2-(acylamino)benzyl]furans under the Bischler–Napieralski
reaction conditions.
Key words: furans, ring opening, ring closure, fused-ring systems,
quinolines, Bischler–Napieralski reaction
R1
O
The Bischler–Napieralski reaction1 is an efficient method
for the transformation of phenethylamines into 3,4-dihy-
droisoquinolines,2 and tryptamines into b-carbolines.3
The Bischler–Napieralski reaction has also been applied
in the annulation of the pyridine ring to other heterocyclic
compounds, i.e. thiophene,4 benzothiophene,4,5 pyrrole,6
thiazole,7 and carbazole.8 The appropriate choice of
aromatic fragment and linker opens the way to a wide va-
riety of nitrogen-containing heterocycles via Bischler–
Napieralski-like reactions. For example, benzazepine de-
rivatives were obtained using compounds with an amide
group separated from the benzene ring by a propylene
linker.9 Similarly, ortho-acylamino-substituted diphenyl-
methanes, diphenyl ethers, diphenylamines, and diphenyl
sulfides were transformed into dibenzazepines,10–12 dibenz-
oxazepines,11,12 dibenzodiazepines,12,13 and dibenzothia-
zepines,12,14 respectively (Scheme 1; X = –CH=CH–,
Y = CH2, O, NR2, S). This transformation is also efficient
for 2-[2-(carbamoylamino)benzyl]thiophenes (X = S,
Y = CH2).15 In contrast, the Bischler–Napieralski reaction
with 2-(2-aminoethyl)furans as a substrate affords the cor-
responding furopyridine derivatives in low to moderate
yield only.16 A single example of a high-yielding
Bischler–Napieralski cyclization for furan derivatives
was reported for 2-[2-(carbamoylamino)phenylthio]-5-
methoxycarbonylfurans (Scheme 1; X = O, Y = S)
wherein the substituents facilitate electrophilic attack at
the C(3) atom of the furan ring and hinder attack at the
C(2) atom.17
R1
N
NH
PPA
Q
Q
R
or POCl3
Y
X
X
Y
R
X = -CH=CH-, O, S
Y = CH2, O, NR2, S
Q = Alk, Ar, CO2Me
2
1
Scheme 1 Bischler–Napieralski-like reaction of substrates 1
O
Ph
MeO
MeO
NH
Ph
MeO
MeO
N
POCl3
O
O
3a
1a
Scheme 2 Phosphorus oxychloride induced transformation of 1a
into quinoline 3a
To study the new reaction more carefully, we synthesized
a series of substrates 1a–p by acylation of 2-(2-furylmeth-
yl)anilines 4 and 2-[di(2-furyl)methyl]anilines 5, which
were obtained according to Schemes 3 and 4, respective-
ly. Thus, Friedel–Crafts acylation of veratrole (1,2-
dimethoxybenzene, 6) with acyl chlorides 7a–c gave rise
to 2-(3,4-dimethoxybenzoyl)furans 8a–c. These ketones
were nitrated using fuming nitric acid in acetic acid which
afforded nitrobenzenes 9a–c.19 The obtained nitro ketones
9 were reduced with iron powder and acetic acid under re-
flux to the 2-furoylanilines 10a–c which then further re-
duced with sodium borohydride in the presence of
anhydrous aluminum chloride in tetrahydrofuran under
heating to reflux to yield the 2-(2-furylmethyl)anilines
4a–c.
Taking these results into account, it might be expected
that 2-[2-(acylamino)benzyl]furans 1 (X = O, Y = CH2)
should afford the corresponding furo[3,2-c][1]benz-
SYNTHESIS 2011, No. 16, pp 2629–2638
x
x.
x
x
.
2
0
1
1
Advanced online publication: 14.07.2011
DOI: 10.1055/s-0030-1260118; Art ID: Z41111SS
© Georg Thieme Verlag Stuttgart · New York

2630
A. V. Butin et al.
PAPER
MeO
MeO
MeO
fuming HNO3
AcOH, r.t.
Cl
AlCl3
R1
+
R1
O
benzene, heat
O
MeO
O
O
8a R1 = Me (72 %)
8b R1 = t-Bu (68 %)
7a R1 = Me
7b R1 = t-Bu
6
8c R1 = 4-BrC6H4 (75 %)
7c R1 = 4-BrC6H4
MeO
NO2
O
MeO
NH2
O
MeO
MeO
NH2
NaBH4, AlCl3
R1
Fe, AcOH
R1
R1
EtOAc, H2O
reflux
THF, 0 °C to reflux
O
O
O
MeO
MeO
9a R1 = Me (65%)
10a R1 = Me (87%)
4a R1 = Me (74%)
4b R1 = t-Bu (80%)
9b R1 = t-Bu (62%)
10b R1 = t-Bu (83%)
9c R1 = 4-BrC6H4 (68%)
10c R1 = 4-BrC6H4 (91%)
4c R1 = 4-BrC6H4 (83%)
Scheme 3 Synthesis of 2-(2-furylmethyl)anilines 4a–c
R1
O
R1
O
R
R
CHO
NO2
R
R
.
N2H4•H2O, Raney Ni
HClO4
+
R1
1,4-dioxane
65–70 °C
O
NO2
EtOH, reflux
O
NH2
O
R
R
R1
1 = t-Bu (92%)
R1
11a R1 = t-Bu
11b R1 = Me
5a R = H; R1 = t-Bu (86%)
13a R = H; R
12a R = H
12b R = OMe
13b R = OMe; R1 = t-Bu (94%)
13c R = H; R1 = Me (87%)
5b R= OMe; R1 = t-Bu (83%)
5c R = H; R1 = Me (88%)
Scheme 4 Synthesis of 2-[di(2-furyl)methyl]anilines 5a–c
Condensation of 2-(tert-butyl)furan (11a)20 and 2-methyl- These reactions have been referred to as ‘abnormal re-
furan (11b) with the commercially available 2-nitrobenz- sults’. On the other hand, electrophilic attack onto a sub-
aldehydes 12a,b in 1,4-dioxane in the presence of a stituted a-carbon atom of the furan ring is often preferable
catalytic quantity of perchloric acid, followed by reduc- to the corresponding attack onto an unsubstituted b-posi-
tion of the resulting bis(5-alkyl-2-furyl)(2-nitrophe- tion.24 The preferable site of attack is under kinetic or ther-
nyl)methanes 13a–c with hydrazine hydrate in the modynamic control. In the case of 1a–m, both factors
presence of Raney nickel, yielded anilines 5a–c.21
result in preferential a-attack. Indeed, formation of the
quinoline system conjugated to the enone moiety is, evi-
dently, more preferable than the alternative creation of
10H-furo[3,2-c][1]benzazepines due to the low aromatic-
ity energy of the furan ring and the nonaromatic nature of
the central azepine cycle in 2 (X = O, Y = CHR2).
Treatment of anilines 4 and 5 with acyl chlorides in ben-
zene afforded the goal amides 1a–p (Table 1). When
amides 1a–m were refluxed in benzene or toluene in the
presence of phosphorus oxychloride, quinolines 3a–m
were obtained in low to good yields (Table 1).
The structures of compounds 3 were determined by anal-
ysis of 1H and 13C NMR spectra, mass spectroscopic data,
and elemental analysis, and proved unambiguously by
single-crystal X-ray analysis for compound 3a
(Figure 1).22 It needs to be pointed out that the exocyclic
C=C bond in quinolines 3a–i has the E configuration
(3J = 15.3–16.2 Hz), but the Z configuration for 3j–m
(3J = 11.7–12.0 Hz). Possibly, this can be explained by a
high-energy barrier for cis-trans isomerization due to
large steric effects preventing rotation around this C=C
bond in these compounds, even in protonated form.
Evidently, the formation of 3 proceeds via an electrophilic
attack of the amide-derived iminium ion onto the a- but
not the b-carbon atom of the furan. This attack is accom-
panied by furan ring opening and formation of the aromat-
ic quinoline system (Scheme 5). There are a few examples
of ipso attack by an electrophilic carbon atom in the
Bischler–Napieralski reaction and related processes.23
Figure 1 X-ray crystallographic structure of 3a
Synthesis 2011, No. 16, 2629–2638 © Thieme Stuttgart · New York

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New Route to Quinolines under the Bischler–Napieralski Reaction Conditions
2631
Table 1 Synthesis of Amides 1a–p and Quinolines 3a–m
R3
O
R
R
N
R3
NH2
R2
NH
R
R
R
R
R3COCl
POCl3
R1
R1
R1
benzene, r.t.
benzene or
toluene,
reflux
O
O
R2
O
R2
3a–m
4a–c
5a–c
1a–p
Entry
R
R1
R2
H
H
H
H
H
H
H
H
H
R3
Yield (%) of 1
Yield (%) of 3
a
b
c
d
e
f
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
Me
Ph
Me
72
65
76
80
68
87
63
74
75
79
87
84
76
85
90
73
61
34
68
56
82
42
45
75
72
52
69
54
25
–
Me
Me
2-O2NC6H4
2-thienyl
Ph
Me
t-Bu
t-Bu
t-Bu
4-BrC6H4
4-BrC6H4
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
Bn
g
h
i
CH2Cl
Ph
PhthNCH2CH2
Ph
j
5-t-BuFura
5-t-BuFura
5-t-BuFura
5-t-BuFura
5-t-BuFura
5-t-BuFura
5-MeFura
k
l
H
4-BrC6H4
4-O2NC6H4
4-MeOC6H4
4-O2NC6H4
4-Tol
H
m
n
o
p
H
OMe
OMe
H
–
4-O2NC6H4
–
a Fur = 2-furyl.
We have demonstrated the broad scope of this reaction. In could be employed in the reaction, giving similar yields of
general, transformation of furans 1e–g with a tert-butyl quinolines. At the same time, in some examples yields of
group at the C(5) position, and 1h,i with an aryl group, quinolines 3 are low or moderate. In the case of 3b,f,g, it
into quinolines 3 proceeds with better yields than that of is possibly explained by acid-catalyzed condensations
furans 1a–d containing a methyl group at this position. with participation of the a-carbon atom in the alkyl group
Both electron-enriched and electron-depleted benzamides at the C(2) atom of the quinoline, leading to the formation
R3
O
R3
R3
H
+
N
N
R
R
R
R
NH
POCl3
OP(O)Cl2
R
R1
R1
O
O
R
R2
2
O
R2
R2
R1
1
H+
OP(O)Cl2
H
H
N
R3
O
R3
N
OP(O)Cl2
R
R
N
R
R
R
R
R3
R1
R1
+
H
O
O
R2
R2
R2
R1
3
Scheme 5 The possible mechanism of quinoline 3 formation
Synthesis 2011, No. 16, 2629–2638 © Thieme Stuttgart · New York

2632
A. V. Butin et al.
PAPER
Ph
O
O
Ph
MeO
MeO
NH
N
Ph
NH
MeO
MeO
MeO
MeO
11b
O
POCl3
OH
TsOH, CH2Cl2
reflux
benzene
reflux
O
Br
Br
1q (81%)
Br
14
3q (36%)
Scheme 6 Synthesis of quinoline 3q
InfraLUM FT-801 instruments. Mass spectra were recorded on a
Kratos MS-30 instrument with 70-eV electron-impact ionization at
200 °C. Crystallographic measurements were performed at 293 K
on an Enraf Nonius CAD4 diffractometer. Melting points (uncor-
rected) were determined in capillaries with an Electrothermal 9100
capillary melting-point apparatus. Column chromatography was
performed on silica gel KSK (50–160 mm, LTD Sorbpolymer). All
reactions were carried out using freshly distilled and dried solvents.
of various byproducts. Recyclization of 1j–l proceeds
with satisfactory yield, accounting for the presence of the
second furyl group prone to acid-catalyzed transforma-
tions. In contrast, 3m was obtained in low yield only. We
believe this is a result of further product transformation by
intramolecular cyclizations with participation of the car-
bonyl group and the second furan ring, leading to salt-like
products and tar. Such secondary cyclizations were ob-
served previously in the recyclizations of other aryldifu-
rylmethanes.25 These byprocesses are especially efficient
for electron-enriched compounds and for substrates with
the small methyl group at the C(5) position of the furan
ring. Indeed, substrates 1n–p failed to give quinolines 3.
(3,4-Dimethoxyphenyl)(2-furyl)methanones 8a–c
Ketone 8a was synthesized according to a published method.19
Compounds 8b,c were obtained by a similar procedure.
(5-tert-Butyl-2-furyl)(3,4-dimethoxyphenyl)methanone (8b)
Yellow oil; yield: 68%. This compound was further used without
additional purification.
To check this proposition, we synthesized diaryl(fur-
yl)methane 1q by the alkylation of 2-methylfuran (11b)
with the corresponding benzhydrol 14. Treatment of 1q
with phosphorus oxychloride in benzene under reflux af-
fords quinoline 3q in 36% yield (Scheme 6).
[5-(4-Bromophenyl)-2-furyl](3,4-dimethoxyphenyl)methanone
(8c)
Pale yellow needles; yield: 75%; mp 130–131 °C (EtOH).
IR (KBr): 1631, 1599, 1508, 1469, 1307, 1273, 1237, 1137, 1031,
806 cm–1.
Thus, we have developed a principally new method for the
synthesis of polyfunctionalized quinolines26 by recycliza-
tion of 2-[2-(acylamino)benzyl]furans in the presence of
phosphorus oxychloride. In contrast to our previous
investigations19,21,25a wherein the same substrates were
transformed into indoles in the presence of Brønsted acids
via protonation of the furan ring followed by the interac-
tion of the electrophilic intermediate with the amide moi-
ety functioning as a nucleophile, in this novel approach
the amide function reacts as an electrophile and the furan
ring plays the role of nucleophile. Therefore, the appropri-
ate choice of acidic catalyst allows either indoles or quin-
olines to be synthesized from the same 2-[2-
(acylamino)benzyl]furans. Both kinds of products are in-
teresting, both in themselves and as precursors for the
preparation of various natural and non-natural physiolog-
ically active compounds.
1H NMR (300 MHz, DMSO-d6): d = 3.95 (s, 3 H, OCH3), 3.96 (s, 3
H, OCH3), 6.81 (d, J = 3.6 Hz, 1 H, HFur), 6.95 (d, J = 8.4 Hz, 1 H,
HAr), 7.29 (d, J = 3.6 Hz, 1 H, HFur), 7.55 (d, J = 8.7 Hz, 2 H, HAr),
7.58 (d, J = 2.1 Hz, 1 H, HAr), 7.65 (d, J = 8.7 Hz, 2 H, HAr), 7.73
(dd, J = 2.1, 8.4 Hz, 1 H, HAr).
13C NMR (75 MHz, DMSO-d6): d = 56.2, 56.3, 107.9, 110.3, 112.0,
122.0, 123.4, 124.1, 126.5 (2 C), 128.6, 130.2, 132.3 (2 C), 149.2,
152.1, 153.2, 156.8, 180.7.
MS (EI, 70 eV): m/z (%) = 388/386 (99/100) [M+], 314/312 (17/16),
225 (17), 165 (21), 77 (18), 43 (27).
Anal. Calcd for C19H15BrO4: C, 58.93; H, 3.90. Found: C, 58.61; H,
3.79.
(4,5-Dimethoxy-2-nitrophenyl)(2-furyl)methanones 9a–c;
General Procedure
Fuming HNO3 (5 mL) was added dropwise under efficient stirring
to a soln of the corresponding ketone 8 (15 mmol) in AcOH (25 mL)
at 3–5 °C. The reaction mixture was maintained at 5–7 °C for 20
min and at r.t. for 20 min (TLC monitoring). Then, it was poured
onto ice and the separated residue was collected by filtration and
washed with H2O until pH ~7. Compounds 9a,c were recrystallized
from the specified solvents. Product 9b was purified by column
chromatography on silica gel (CH2Cl2–PE, 1:3).
NMR spectra were recorded with a Bruker DPX 300 spectrometer
(300 MHz for 1H and 75 MHz for 13C NMR) at room temperature;
the chemical shifts (d) were measured in ppm with respect to the
solvent (CDCl3, 1H: 7.26 ppm, 13C: 77.13 ppm; DMSO-d6, 1H: 2.50
ppm, 13C: 39.7 ppm). Coupling constants (J) are given in hertz (Hz).
Multiplicities of signals are described as follows: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of
doublets, br = broadened. Abbreviations used for peak assignments
are as follows: Py = pyridyl, Ar = aryl, Fur = furyl, Th = thienyl. IR
spectra were measured as KBr plates on InfraLUM FT-02 and
(4,5-Dimethoxy-2-nitrophenyl)(5-methyl-2-furyl)methanone
(9a)19
Yellow solid; yield: 2.84 g (65%); mp 128–129 °C (EtOH–ace-
tone).
Synthesis 2011, No. 16, 2629–2638 © Thieme Stuttgart · New York

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New Route to Quinolines under the Bischler–Napieralski Reaction Conditions
2633
(5-tert-Butyl-2-furyl)(4,5-dimethoxy-2-nitrophenyl)methanone
(9b)
Yellow oil; yield: 3.10 g (62%). This compound was used in the fur-
ther transformations without additional purification.
13C NMR (75 MHz, CDCl3): d = 56.0, 56.7, 99.6, 107.7, 110.1,
114.3, 120.4, 123.0, 126.2 (2 C), 128.8, 132.3 (2 C), 140.5, 148.6,
152.9, 155.5, 155.8, 181.4.
MS (EI, 70 eV): m/z (%) = 403/401 (99/100) [M+], 388/386 (18/18),
218 (48), 164 (67), 136 (45), 43 (40).
[5-(4-Bromophenyl)-2-furyl](4,5-dimethoxy-2-nitrophe-
nyl)methanone (9c)
Yellow solid; yield: 4.41 g (68%); mp 189–190 °C (CH2Cl2–PE).
Anal. Calcd for C19H16BrNO4: C, 56.73; H, 4.01; N, 3.48. Found: C,
56.48; H, 4.00; N, 3.41.
IR (KBr): 1655, 1523, 1469, 1334, 1276, 1225, 1076, 1034, 868,
815, 789 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.98 (s, 3 H, OCH3), 4.04 (s, 3
H, OCH3), 6.77 (d, J = 3.6 Hz, 1 H, HFur), 6.99 (s, 1 H, HAr), 7.14 (d,
J = 3.6 Hz, 1 H, HFur), 7.52 (s, 4 H, HAr), 7.70 (s, 1 H, HAr).
2-(2-Furylmethyl)anilines 4a–c
Anilines 4a–c were synthesized according to a procedure published
previously.19 These compounds were used in the further transforma-
tions without additional purification.
2-[Di(2-furyl)methyl]anilines 5
13C NMR (75 MHz, DMSO-d6): d = 57.0, 57.1, 107.4, 108.7, 111.2,
121.5, 124.1, 126.9 (2 C), 128.4, 128.9, 132.6 (2 C), 140.9, 150.6,
151.4, 154.0, 157.8, 180.4.
Compounds 13a,b and 5a,b were synthesized according to a pub-
lished procedure,21 as were compounds 13c and 5c.25a
MS (EI, 70 eV): m/z (%) = 433/431 (1/1) [M+], 239/237 (100/100),
194 (35), 164 (53), 136 (65), 63 (37), 43 (35).
Amides 1a–p; General Procedure
A soln of an acyl chloride (7 mmol) in benzene (20–30 mL) was
added under stirring to a soln of an amine 4 or 5 (6 mmol) in ben-
zene (15 mL). The mixture was stirred at r.t. for 30–60 min (TLC
monitoring). Then, sat. aq NaHCO3 (50 mL) was added, and the
mixture was vigorously stirred for 30 min. The precipitate was col-
lected by filtration. The organic fraction was separated from the
aqueous fraction; the aqueous fraction was extracted with EtOAc
(3 × 25 mL). The combined organic phases were washed with H2O
(2 × 30 mL) and dried (Na2SO4). The solvent was evaporated under
reduced pressure. The residue and the precipitate were combined.
The crude product was purified by flash chromatography on silica
gel (CH2Cl2–PE, 1:8) and recrystallization (CH2Cl2–PE, 1:5).
Anal. Calcd for C19H14BrNO6: C, 52.80; H, 3.26; N, 3.24. Found: C,
52.71; H, 3.35; N, 3.28.
(2-Amino-4,5-dimethoxyphenyl)(2-furyl)methanones 10a–c;
General Procedure
A mixture of the corresponding nitro ketone 9 (15 mmol), iron pow-
der (10 g), AcOH (35 mL), H2O (50 mL), and EtOAc (10 mL) was
stirred under reflux for 6 h. After completion of the reaction, the
mixture was neutralized with NaHCO3 until pH 7 and filtered. The
residue was washed on the filter with EtOAc (3 × 150 mL). The or-
ganic layer was separated, and the aqueous layer was extracted with
EtOAc (3 × 150 mL). The combined extracts were dried (Na2SO4)
and concentrated under reduced pressure. The residue was recrys-
tallized (CH2Cl2–PE) to afford compound 10.
N-{4,5-Dimethoxy-2-[(5-methyl-2-furyl)methyl]phenyl}benz-
amide (1a)
White solid; yield: 1.52 g (72%); mp 115–116 °C.
(2-Amino-4,5-dimethoxyphenyl)(5-methyl-2-furyl)methanone
(10a)19
Yellow needles; yield: 3.41 g (87%); mp 120 °C.
IR (KBr): 3260, 1644, 1612, 1516, 1488, 1468, 1308, 1284, 1260,
1220, 1092, 712 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.25 (s, 3 H, CH3), 3.87 (s, 2 H,
CH2), 3.88 (s, 3 H, OCH3), 3.90 (s, 3 H, OCH3), 5.89 (d, J = 3.3 Hz,
1 H, HFur), 5.94 (d, J = 3.3 Hz, 1 H, HFur), 6.75 (s, 1 H, HAr), 7.44–
7.58 (m, 3 H, HAr), 7.61 (s, 1 H, HAr), 7.85–7.87 (m, 2 H, HAr), 8.38
(s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 13.5, 31.2, 55.9, 56.0, 106.4,
106.9, 108.1, 112.9, 122.0, 127.0 (2 C), 128.6 (2 C), 129.0, 131.7,
134.7, 146.3, 147.8, 151.3, 151.5, 165.5.
(2-Amino-4,5-dimethoxyphenyl)(5-tert-butyl-2-furyl)meth-
anone (10b)
Yellow needles; yield: 3.77 g (83%); mp 98–100 °C.
IR (KBr): 3417, 3305, 2939, 1630, 1584, 1570, 1524, 1502, 1465,
1402, 1322, 1250, 1143, 1021, 816 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.35 (s, 9 H, t-Bu), 3.84 (s, 3 H,
OCH3), 3.87 (s, 3 H, OCH3), 6.16 (d, J = 3.6 Hz, 1 H, HFur), 6.17 (s,
1 H, HAr), 7.10 (d, J = 3.6 Hz, 1 H, HFur), 7.64 (s, 1 H, HAr).
13C NMR (75 MHz, CDCl3): d = 28.9 (3 C), 33.1, 55.7, 56.4, 99.3,
104.9, 109.9, 114.2, 119.4, 140.1, 148.4, 152.1, 154.8, 168.0, 181.5.
MS (EI, 70 eV): m/z (%) = 351 (78) [M+], 247 (24), 246 (76), 105
(95), 77 (100), 59 (48), 43 (55).
Anal. Calcd for C21H21NO4: C, 71.78; H, 6.02; N, 3.99. Found: C,
71.61; H, 6.11; N, 3.81.
MS (EI, 70 eV): m/z (%) = 303 (100) [M+], 288 (21), 247 (21), 218
(38), 164 (77), 43 (39).
N-{4,5-Dimethoxy-2-[(5-methyl-2-furyl)methyl]phenyl}aceta-
mide (1b)
White solid; yield: 1.13 g (65%); mp 148–149 °C.
Anal. Calcd for C17H21NO4: C, 67.31; H, 6.98; N, 4.62. Found: C,
67.45; H, 7.08; N, 4.54.
IR (KBr): 3272, 1656, 1536, 1516, 1408, 1340, 1260, 1216, 1020
cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.98 (s, 3 H, CH3), 2.18 (s, 3
H, CH3), 3.68 (s, 3 H, OCH3), 3.69 (s, 3 H, OCH3), 3.80 (s, 2 H,
CH2), 5.86 (d, J = 3.0 Hz, 1 H, HFur), 5.92 (d, J = 3.0 Hz, 1 H, HFur),
6.72 (s, 1 H, HAr), 6.91 (s, 1 H, HAr), 9.26 (s, 1 H, NH).
(2-Amino-4,5-dimethoxyphenyl)[5-(4-bromophenyl)-2-fur-
yl]methanone (10c)
Yellow needles; yield: 5.49 g (91%); mp 184–185 °C.
IR (KBr): 3444, 3334, 1620, 1589, 1554, 1509, 1469, 1252, 1138,
810 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.83 (s, 3 H, OCH3), 3.89 (s, 3 H,
OCH3), 6.20 (s, 1 H, HAr), 6.79 (d, J = 3.6 Hz, 1 H, HFur), 7.21 (d,
J = 3.6 Hz, 1 H, HFur), 7.53 (d, J = 9.0 Hz, 2 H, HAr), 7.59 (s, 1 H,
HAr), 7.64 (d, J = 9.0 Hz, 2 H, HAr).
13C NMR (75 MHz, DMSO-d6): d = 13.2, 23.0, 29.4, 55.5, 55.7,
106.2, 106.8, 110.5, 113.1, 124.7, 128.9, 146.3, 147.0, 149.9, 151.9,
168.2.
MS (EI, 70 eV): m/z (%) = 289 (66) [M+], 247 (36), 246 (100), 231
(19), 204 (41), 189 (31).
Synthesis 2011, No. 16, 2629–2638 © Thieme Stuttgart · New York

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PAPER
N-{2-[(5-tert-Butyl-2-furyl)methyl]-4,5-dimethoxyphenyl}-2-
Anal. Calcd for C16H19NO4: C, 66.42; H, 6.62; N, 4.84. Found: C,
66.46; H, 6.66; N, 4.90.
chloroacetamide (1g)
Beige solid; yield: 1.38 g (63%); mp 96–97 °C.
N-{4,5-Dimethoxy-2-[(5-methyl-2-furyl)methyl]phenyl}-2-ni-
trobenzamide (1c)
Pale yellow solid; yield: 1.81 g (76%); mp 136–137 °C.
IR (KBr): 3236, 2960, 1676, 1648, 1612, 1548, 1516, 1464, 1404,
1212, 1100, 1004, 856, 796 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.23 (s, 9 H, t-Bu), 3.84 (s, 5 H,
OCH3 + CH2), 3.87 (s, 3 H, OCH3), 4.17 (s, 2 H, CH2), 5.83 (s, 2 H,
IR (KBr): 3234, 1652, 1525, 1348, 1259, 1218, 1099, 1021, 1001,
859, 790 cm–1.
HFur), 6.72 (s, 1 H, HAr), 7.35 (s, 1 H, HAr), 8.35 (br s, 1 H, NH).
1H NMR (300 MHz, DMSO-d6): d = 2.20 (s, 3 H, CH3), 3.71 (s, 3
H, OCH3), 3.75 (s, 3 H, OCH3), 3.91 (s, 2 H, CH2), 5.91 (d, J = 3.0
Hz, 1 H, HFur), 5.95 (d, J = 3.0 Hz, 1 H, HFur), 6.79 (s, 1 H, HAr), 7.03
(s, 1 H, HAr), 7.67–7.70 (m, 1 H, HAr), 7.71–7.77 (m, 1 H, HAr),
7.83–7.89 (m, 1 H, HAr), 8.11–8.14 (m, 1 H, HAr), 10.13 (s, 1 H,
NH).
13C NMR (75 MHz, DMSO-d6): d = 13.3, 29.3, 55.7 (2 C), 106.3,
107.0, 110.6, 113.1, 124.2, 126.0, 127.9, 129.2, 130.8, 132.8, 133.8,
146.8, 147.1, 147.3, 150.0, 151.9, 164.5.
13C NMR (75 MHz, CDCl3): d = 29.0 (3 C), 30.7, 32.5, 42.9, 56.0
(2 C), 102.5, 106.5, 108.1, 112.9, 122.7, 127.3, 147.0, 147.9, 150.6,
163.8, 164.3.
MS (EI, 70 eV): m/z (%) = 367/365 (33/100) [M+], 314 (23), 288
(63), 272 (47), 244 (56), 242 (99), 192 (23), 137 (20), 121 (28), 57
(27), 43 (74).
Anal. Calcd for C19H24ClNO4: C, 62.38; H, 6.61; N, 3.83. Found: C,
62.26; H, 6.63; N, 3.70.
MS (EI, 70 eV): m/z (%) = 396 (9) [M+], 379 (36), 319 (33), 281
(100), 247 (23), 246 (45), 120 (26), 95 (29), 43 (29).
N-(2-{[5-(4-Bromophenyl)-2-furyl]methyl}-4,5-dimethoxyphe-
nyl)benzamide (1h)
Anal. Calcd for C21H20N2O6: C, 63.63; H, 5.09; N, 7.07. Found: C,
63.64; H, 5.25; N, 7.06.
White solid; yield: 2.18 g (74%); mp 187–188 °C.
IR (KBr): 3284, 1640, 1612, 1528, 1476, 1448, 1404, 1216, 1204,
1072, 692 cm–1.
N-{4,5-Dimethoxy-2-[(5-methyl-2-furyl)methyl]phenyl}thio-
phene-2-carboxamide (1d)
Orange oil; yield: 1.71 g (80%). This compound was used in the fur-
ther transformations without additional purification.
1H NMR (300 MHz, CDCl3): d = 3.88 (s, 3 H, OCH3), 3.90 (s, 3 H,
OCH3), 4.00 (s, 2 H, CH2), 6.08 (d, J = 3.3 Hz, 1 H, HFur), 6.57 (d,
J = 3.3 Hz, 1 H, HFur), 6.80 (s, 1 H, HAr), 7.36–7.44 (m, 6 H, HAr),
7.48–7.54 (m, 2 H, HAr), 7.76–7.79 (m, 2 H, HAr), 8.04 (br s, 1 H,
NH).
13C NMR (75 MHz, CDCl3): d = 31.1, 56.0, 56.1, 106.6, 108.5,
108.8, 112.9, 120.9, 121.9, 124.9 (2 C), 126.9 (2 C), 128.6, 128.7 (2
C), 129.4, 131.7 (2 C), 131.8, 134.5, 146.6, 148.0, 152.2, 153.5,
165.7.
N-{2-[(5-tert-Butyl-2-furyl)methyl]-4,5-dimethoxyphe-
nyl}benzamide (1e)
White solid; yield: 1.60 g (68%); mp 119–120 °C.
IR (KBr): 3324, 1646, 1608, 1518, 1485, 1227, 1092, 1009, 854,
788 cm–1.
MS (EI, 70 eV): m/z (%) = 493/491 (16/16) [M+], 388/386 (64/64),
183 (31), 105 (88), 76 (100), 45 (36).
1H NMR (300 MHz, CDCl3): d = 1.21 (s, 9 H, t-Bu), 3.86 (s, 3 H,
OCH3), 3.91 (s, 5 H, OCH3 + CH2), 5.86 (d, J = 3.0 Hz, 1 H, HFur),
5.88 (d, J = 3.0 Hz, 1 H, HFur), 6.75 (s, 1 H, HAr), 7.41–7.47 (m, 2
H, HAr), 7.50–7.56 (m, 1 H, HAr), 7.61 (s, 1 H, HAr), 7.78–7.81 (m,
2 H, HAr), 8.14 (s, 1 H, NH).
Anal. Calcd for C26H22BrNO4: C, 63.43; H, 4.50; N, 2.84. Found: C,
63.43; H, 4.29; N, 2.72.
13C NMR (75 MHz, CDCl3): d = 29.0 (3 C), 31.1, 32.5, 55.9, 56.0,
102.7, 106.5, 108.2, 112.8, 122.0, 127.0 (2 C), 128.6 (2 C), 128.7,
131.7, 134.6, 146.4, 147.8, 151.1, 163.8, 165.5.
MS (EI, 70 eV): m/z (%) = 393 (54) [M+], 289 (25), 288 (59), 232
(22), 121 (17), 105 (100), 76 (65), 57 (21).
N-(2-{[5-(4-Bromophenyl)-2-furyl]methyl}-4,5-dimethoxyphe-
nyl)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanamide
(1i)
White solid; yield: 2.65 g (75%); mp 209–210 °C.
IR (KBr): 3256, 1712, 1644, 1540, 1436, 1392, 1216, 924, 720
cm–1.
Anal. Calcd for C24H27NO4: C, 73.26; H, 6.92; N, 3.56. Found: C,
73.47; H, 6.90; N, 3.62.
1H NMR (300 MHz, DMSO-d6): d = 2.64–2.68 (m, 2 H, CH2), 3.68
(s, 3 H, OCH3), 3.69 (s, 3 H, OCH3), 3.86–3.91 (m, 2 H, CH2), 3.87
(s, 2 H, CH2), 6.09 (d, J = 3.3 Hz, 1 H, HFur), 6.80 (s, 1 H, HAr), 6.82
(d, J = 3.3 Hz, 1 H, HFur), 6.87 (s, 1 H, HAr), 7.50–7.57 (m, 4 H, HAr),
7.79–7.87 (m, 4 H, HAr), 9.48 (s, 1 H, NH).
N-{2-[(5-tert-Butyl-2-furyl)methyl]-4,5-dimethoxyphenyl}-2-
phenylacetamide (1f)
White solid; yield: 2.12 g (87%); mp 90–91 °C.
13C NMR (75 MHz, DMSO-d6): d = 29.4, 34.4, 34.5, 55.5, 55.7,
107.5, 108.7, 110.7, 113.0, 119.8, 123.0 (2 C), 124.6, 124.9 (2 C),
128.6, 129.6, 131.7 (2 C), 131.8 (2 C), 134.4 (2 C), 146.6, 147.2,
150.6, 154.4, 167.8 (2 C), 168.9.
MS (EI, 70 eV): m/z (%) = 590/588 (74/70) [M+], 388/386 (96/100),
185 (19), 160 (46), 147 (33), 103 (19), 76 (37), 59 (67), 55 (70), 43
(42).
IR (KBr): 3480, 2956, 1680, 1608, 1592, 1496, 1464, 1448, 1384,
1256, 1228, 1208, 1156, 1076, 1012, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.24 (s, 9 H, t-Bu), 3.59 (s, 2 H,
CH2), 3.69 (s, 2 H, CH2), 3.79 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3),
5.55 (d, J = 3.0 Hz, 1 H, HFur), 5.77 (d, J = 3.0 Hz, 1 H, HFur), 6.63
(s, 1 H, HAr), 7.16 (br s, 1 H, NH), 7.25–7.37 (m, 6 H, HAr).
13C NMR (75 MHz, CDCl3): d = 29.1 (3 C), 30.4, 32.5, 44.7, 56.0
(2 C), 102.5, 106.2, 108.3, 112.9, 122.0, 127.5, 128.3, 129.1 (2 C),
129.4 (2 C), 134.6, 146.6, 147.8, 150.7, 163.5, 169.3.
Anal. Calcd for C30H25BrN2O6: C, 61.13; H, 4.28; N, 4.75. Found:
C, 61.10; H, 4.40; N, 4.88.
MS (EI, 70 eV): m/z (%) = 407 (32) [M+], 288 (100), 192 (69), 165
(45), 91 (61), 43 (49).
N-{2-[Bis(5-tert-butyl-2-furyl)methyl]phenyl}benzamide (1j)27
Colorless needles; yield: 2.16 g (79%); mp 144–145 °C.
Anal. Calcd for C25H29NO4: C, 73.69; H, 7.17; N, 3.44. Found: C,
73.52; H, 7.08; N, 3.48.
Synthesis 2011, No. 16, 2629–2638 © Thieme Stuttgart · New York

PAPER
New Route to Quinolines under the Bischler–Napieralski Reaction Conditions
2635
N-{2-[Bis(5-tert-butyl-2-furyl)methyl]phenyl}-4-bromobenz-
amide (1k)27
Pale yellow cubes; yield: 2.79 g (87%); mp 155–156 °C.
Crystal data: C21H19NO3, monoclinic, space group P21/n;
a = 8.536(2) Å, b = 8.566(2) Å, c = 24.213(5) Å, b = 90.44(3)°,
V = 1770.4(6) Å3, Z = 4, Dcalcd = 1.251 g/cm3, F(000) = 704; 2473
reflections collected, 2290 unique (Rint = 0.0265); final R indices
(1180 observed collections, I > 2sI): R1 = 0.0292, wR2 = 0.0743;
final R indices (all data): R1 = 0.1012, wR2 = 0.0783.
N-{2-[Bis(5-tert-butyl-2-furyl)methyl]phenyl}-4-nitrobenz-
amide (1l)27
Colorless needles; yield: 2.52 g (84%); mp 159–160 °C.
(3E)-4-(6,7-Dimethoxy-2-methylquinolin-3-yl)but-3-en-2-one
(3b)
Yellow needles; yield: 129 mg (34%); mp 179–180 °C.
N-{2-[Bis(5-tert-butyl-2-furyl)methyl]phenyl}-4-methoxy-
benzamide (1m)27
White solid; yield: 2.21 g (76%); mp 134–135 °C.
IR (KBr): 1661, 1495, 1358, 1261, 1227, 1153, 1122, 1018, 969
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.42 (s, 3 H, CH3), 2.79 (s, 3 H,
CH3), 4.00 (s, 3 H, OCH3), 4.02 (s, 3 H, OCH3), 6.74 (d, J = 16.2
Hz, 1 H, =CH), 7.02 (s, 1 H, HAr), 7.35 (s, 1 H, HAr), 7.85 (d,
J = 16.2 Hz, 1 H, =CH), 8.16 (s, 1 H, HPy).
13C NMR (75 MHz, CDCl3): d = 23.1, 27.8, 55.9, 56.1, 105.0,
107.0, 122.1, 125.3, 128.6, 132.0, 139.4, 145.2, 149.6, 153.5, 155.1,
197.7.
N-{2-[Bis(5-tert-butyl-2-furyl)methyl]-4,5-dimethoxyphenyl}-
4-nitrobenzamide (1n)21
White solid; yield: 2.86 g (85%); mp 199–200 °C.
N-{2-[Bis(5-tert-butyl-2-furyl)methyl]-4,5-dimethoxyphenyl}-
4-methylbenzamide (1o)21
White solid; yield: 2.85 g (90%); mp 149–151 °C.
N-{2-[Bis(5-methyl-2-furyl)methyl]phenyl}-4-nitrobenzamide
(1p)
White solid; yield: 1.82 g (73%); mp 181–182 °C.
MS (EI, 70 eV): m/z (%) = 271 (60) [M+], 257 (23), 256 (100), 228
(39), 212 (60), 184 (22), 101 (33), 59 (51), 45 (62).
Anal. Calcd for C16H17NO3: C, 70.83; H, 6.32; N, 5.16. Found: C,
70.78; H, 6.15; N, 5.03.
IR (KBr): 3283, 1645, 1599, 1523, 1492, 1345, 1299, 1022, 851,
780, 753, 717 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.20 (s, 6 H, CH3), 5.48 (s, 1 H,
CH), 5.89 (d, J = 3.0 Hz, 2 H, HFur), 5.98 (d, J = 3.0 Hz, 2 H, HFur),
7.18–7.21 (m, 2 H, HAr), 7.33–7.39 (m, 1 H, HAr), 7.85 (d, J = 9.0
Hz, 2 H, HAr), 8.00–8.02 (m, 1 H, HAr), 8.26 (d, J = 9.0 Hz, 2 H,
HAr), 8.43 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 13.7 (2 C), 43.2, 106.6 (2 C), 109.1
(2 C), 123.8 (2 C), 124.8, 126.2, 128.3, 128.4, 130.2 (2 C), 130.7,
135.4 (2 C), 140.5, 149.8, 150.7 (2 C), 152.3 (2 C).
(3E)-4-[6,7-Dimethoxy-2-(2-nitrophenyl)quinolin-3-yl]but-3-
en-2-one (3c)
Yellow needles; yield: 360 mg (68%); mp 193–194 °C.
IR (KBr): 1666, 1523, 1499, 1347, 1252, 1231, 1217, 856 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.22 (s, 3 H, CH3), 4.01 (s, 3 H,
OCH3), 4.04 (s, 3 H, OCH3), 6.71 (d, J = 15.9 Hz, 1 H, =CH), 7.11
(s, 1 H, HAr), 7.34 (d, J = 15.9 Hz, 1 H, =CH), 7.36 (s, 1 H, HAr),
7.49–7.52 (m, 1 H, HAr), 7.62–7.68 (m, 1 H, HAr), 7.72–7.78 (m, 1
H, HAr), 8.15–8.19 (m, 1 H, HAr), 8.33 (s, 1 H, HPy).
13C NMR (75 MHz, CDCl3): d = 27.7, 56.1, 56.2, 105.0, 107.7,
123.0, 124.8, 124.9, 128.8, 129.6, 132.0, 132.4, 133.2, 134.9, 138.8,
145.3, 148.8, 150.6, 153.9, 154.1, 197.5.
Anal. Calcd for C24H20N2O5: C, 69.22; H, 4.84; N, 6.73. Found: C,
69.24; H, 4.94; N, 6.91.
Quinolines 3a–m; General Procedure
A mixture of an amide 1 (1.4 mmol), POCl3 (7.5 mL), and benzene
(for the synthesis of 3a–i) or toluene (for the synthesis of 3j–m) (25
mL) was refluxed for 1.5 h. The reaction mixture was poured into
H2O (800 mL) and neutralized with a soln of NaOH (50 g) in H2O
(200 mL). The product was extracted with CH2Cl2 (3 × 150 mL).
The combined organic fractions were dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, 50–160 mm; CH2Cl2–PE, 1:3)
and recrystallization (CH2Cl2–PE, 1:4).
MS (EI, 70 eV): m/z (%) = 378 (97) [M+], 346 (51), 335 (37), 307
(34), 289 (100), 274 (41), 246 (44), 204 (36), 110 (42).
Anal. Calcd for C21H18N2O5: C, 66.66; H, 4.79; N, 7.40. Found: C,
66.89; H, 4.71; N, 7.45.
(3E)-4-[6,7-Dimethoxy-2-(2-thienyl)quinolin-3-yl]but-3-en-2-
one (3d)
Pale green-yellow needles; yield: 266 mg (56%); mp 210–211 °C.
IR (KBr): 1660, 1617, 1493, 1249, 1230, 1003, 887, 853, 745 cm–1.
(3E)-4-(6,7-Dimethoxy-2-phenylquinolin-3-yl)but-3-en-2-one
(3a)
Pale yellow needles; yield: 284 mg (61%); mp 200–201 °C.
1H NMR (300 MHz, CDCl3): d = 2.40 (s, 3 H, CH3), 4.02 (s, 3 H,
OCH3), 4.04 (s, 3 H, OCH3), 6.75 (d, J = 16.2 Hz, 1 H, =CH), 7.05
(s, 1 H, HAr), 7.17 (dd, J = 3.6, 5.1 Hz, 1 H, HTh), 7.32 (dd, J = 1.2,
3.6 Hz, 1 H, HTh), 7.41 (s, 1 H, HAr), 7.51 (dd, J = 1.2, 5.1 Hz, 1 H,
HTh), 7.97 (d, J = 16.2 Hz, 1 H, =CH), 8.18 (s, 1 H, HPy).
13C NMR (75 MHz, CDCl3): d = 27.3, 56.0, 56.2, 104.8, 107.5,
122.3, 124.5, 127.7, 128.3, 129.0, 129.2, 133.4, 141.9, 143.2, 145.5,
149.7, 150.2, 153.7, 198.0.
IR (KBr): 1664, 1616, 1588, 1496, 1432, 1392, 1260, 1228, 1212,
1132, 1008, 704 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.28 (s, 3 H, CH3), 4.03 (s, 3 H,
OCH3), 4.04 (s, 3 H, OCH3), 6.73 (d, J = 16.2 Hz, 1 H, =CH), 7.10
(s, 1 H, HAr), 7.46–7.54 (m, 4 H, HAr), 7.58–7.62 (m, 2 H, HAr), 7.66
(d, J = 16.2 Hz, 1 H, =CH), 8.30 (s, 1 H, HPy).
13C NMR (75 MHz, CDCl3): d = 26.9, 56.0, 56.2, 104.8, 107.9,
122.5, 124.8, 128.3 (3 C), 128.6, 129.7 (2 C), 132.8, 139.3, 142.0,
145.6, 150.2, 153.7, 157.1, 198.2.
MS (EI, 70 eV): m/z (%) = 339 (37) [M+], 296 (100), 281 (73), 264
(16), 252 (67), 236 (15), 222 (17), 209 (15), 45 (14).
Anal. Calcd for C19H17NO3S: C, 67.24; H, 5.05; N, 4.13. Found: C,
67.24; H, 4.88; N, 4.01.
MS (EI, 70 eV): m/z (%) = 333 (27) [M+], 290 (100), 275 (31), 274
(38), 246 (30), 217 (26), 101 (29), 59 (55), 43 (57).
(1E)-1-(6,7-Dimethoxy-2-phenylquinolin-3-yl)-4,4-dimethyl-
pent-1-en-3-one (3e)
Yellow solid; yield: 431 mg (82%); mp 114–115 °C.
Anal. Calcd for C21H19NO3: C, 75.66; H, 5.74; N, 4.20. Found: C,
75.37; H, 5.60; N, 4.19.
Synthesis 2011, No. 16, 2629–2638 © Thieme Stuttgart · New York

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A. V. Butin et al.
PAPER
IR (KBr): 1684, 1604, 1584, 1504, 1392, 1236, 1076, 1008 cm–1.
MS (EI, 70 eV): m/z (%) = 475/473 (21/21) [M+], 290 (100), 246
(28), 217 (32), 185/183 (33/33), 157/155 (29/29), 101 (35), 77 (40),
43 (32).
1H NMR (300 MHz, CDCl3): d = 1.21 (s, 9 H, t-Bu), 4.05 (s, 3 H,
OCH3), 4.06 (s, 3 H, OCH3), 7.07 (d, J = 15.6 Hz, 1 H, =CH), 7.14
(s, 1 H, HAr), 7.45–7.53 (m, 3 H, HAr), 7.56–7.60 (m, 3 H, HAr), 7.83
(d, J = 15.6 Hz, 1 H, =CH), 8.35 (s, 1 H, HPy).
Anal. Calcd for C26H20BrNO3: C, 65.83; H, 4.25; N, 2.95. Found: C,
66.07; H, 4.26; N, 3.19.
13C NMR (75 MHz, CDCl3): d = 26.2 (3 C), 43.2, 56.1, 56.3, 104.8,
108.0, 122.4, 122.6, 125.6, 128.5 (2 C), 128.6, 129.6 (2 C), 133.2,
139.5, 140.9, 145.4, 150.2, 153.6, 157.6, 203.7.
MS (EI, 70 eV): m/z (%) = 375 (13) [M+], 318 (100), 290 (16), 274
(18), 57 (13), 45 (27).
2-(2-{3-[(1E)-3-(4-Bromophenyl)-3-oxoprop-1-en-1-yl]-6,7-
dimethoxyquinolin-2-yl}ethyl)-1H-isoindole-1,3(2H)-dione (3i)
Pale yellow solid; yield: 576 mg (72%); mp 228–229 °C.
IR (KBr): 1700, 1660, 1592, 1496, 1388, 1308, 1244, 1212, 1164,
1108, 1032, 1008, 720 cm–1.
Anal. Calcd for C24H25NO3: C, 76.77; H, 6.71; N, 3.73. Found: C,
76.58; H, 6.76; N, 3.79.
1H NMR (300 MHz, DMSO-d6): d = 3.36–3.41 (m, 2 H, CH2), 3.88
(s, 3 H, OCH3), 3.92 (s, 3 H, OCH3), 3.98–4.03 (m, 2 H, CH2), 7.13
(s, 1 H, HAr), 7.26 (s, 1 H, HAr), 7.67–7.81 (m, 7 H, HAr + =CH), 7.99
(d, J = 8.7 Hz, 2 H, HAr), 8.03 (d, J = 15.3 Hz, 1 H, =CH), 8.75 (s,
1 H, HPy).
13C NMR (75 MHz, DMSO-d6): d = 33.1, 37.1, 55.6, 55.7, 105.5,
107.0, 121.9, 122.8 (2 C), 123.3, 125.2, 127.3, 130.4 (2 C), 131.6 (2
C), 131.7 (2 C), 132.8, 134.0 (2 C), 136.2, 139.9, 145.1, 149.5,
153.3, 155.3, 167.6 (2 C), 187.3.
(1E)-1-(2-Benzyl-6,7-dimethoxyquinolin-3-yl)-4,4-dimethyl-
pent-1-en-3-one (3f)
White solid; yield: 229 mg (42%); mp 183–185 °C.
IR (KBr): 1680, 1608, 1592, 1496, 1256, 1228, 1208, 1156, 1076,
1012, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.17 (s, 9 H, t-Bu), 3.99 (s, 3 H,
OCH3), 4.04 (s, 3 H, OCH3), 4.43 (s, 2 H, CH2), 6.98 (d, J = 15.3
Hz, 1 H, =CH), 7.04 (s, 1 H, HAr), 7.09–7.15 (m, 1 H, HAr), 7.18–
7.24 (m, 4 H, HAr), 7.41 (s, 1 H, HAr), 8.02 (d, J = 15.3 Hz, 1 H,
=CH), 8.14 (s, 1 H, HPy).
13C NMR (75 MHz, CDCl3): d = 26.2 (3 C), 42.8, 43.1, 56.0, 56.2,
105.1, 107.8, 122.4, 123.1, 126.2, 126.6, 128.5 (2 C), 128.7 (2 C),
132.5, 139.0, 139.6, 145.5, 150.0, 153.4, 157.5, 203.5.
MS (EI, 70 eV): m/z (%) = 572/570 (16/16) [M+], 388 (25), 387
(100), 240 (22), 183 (22), 77 (18), 43 (47).
Anal. Calcd for C30H23BrN2O5: C, 63.06; H, 4.06; N, 4.90. Found:
C, 63.02; H, 4.18; N, 4.89.
(1Z)-1-[4-(5-tert-Butyl-2-furyl)-2-phenylquinolin-3-yl]-4,4-di-
methylpent-1-en-3-one (3j)
Beige needles; yield: 318 mg (52%); mp 158–159 °C.
IR (KBr): 2968, 1680, 1616, 1556, 1076, 1004, 816, 768, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.77 (s, 9 H, t-Bu), 1.35 (s, 9 H, t-
Bu), 6.14 (d, J = 3.3 Hz, 1 H, HFur), 6.37 (d, J = 11.7 Hz, 1 H, =CH),
6.50 (d, J = 3.3 Hz, 1 H, HFur), 7.18 (d, J = 11.7 Hz, 1 H, =CH),
7.32–7.37 (m, 3 H, HAr), 7.46–7.51 (m, 1 H, HAr), 7.55–7.59 (m, 2
H, HAr), 7.65–7.70 (m, 1 H, HAr), 8.07–8.10 (m, 1 H, HAr), 8.14–
8.17 (m, 1 H, HAr).
13C NMR (75 MHz, CDCl3): d = 25.6 (3 C), 29.2 (3 C), 32.8, 42.9,
103.7, 114.7, 124.7, 125.1, 125.8, 126.5, 127.6 (2 C), 128.0, 129.0,
129.1, 129.9 (3 C), 134.5, 141.2, 141.6, 146.5, 147.4, 158.1, 165.4,
203.4.
MS (EI, 70 eV): m/z (%) = 389 (33) [M+], 332 (73), 304 (89), 298
(98), 91 (100), 57 (78), 43 (61).
Anal. Calcd for C25H27NO3: C, 77.09; H, 6.99; N, 3.60. Found: C,
77.23; H, 7.17; N, 3.62.
(1E)-1-[2-(Chloromethyl)-6,7-dimethoxyquinolin-3-yl]-4,4-
dimethylpent-1-en-3-one (3g)
Beige needles; yield: 219 mg (45%); mp 195–196 °C.
IR (KBr): 1680, 1608, 1592, 1500, 1432, 1392, 1256, 1228, 1208,
1164, 1080, 1008, 876 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25 (s, 9 H, t-Bu), 4.01 (s, 3 H,
OCH3), 4.02 (s, 3 H, OCH3), 4.90 (s, 2 H, CH2), 7.06 (s, 1 H, HAr),
7.20 (d, J = 15.3 Hz, 1 H, =CH), 7.37 (s, 1 H, HAr), 8.07 (d, J = 15.3
Hz, 1 H, =CH), 8.24 (s, 1 H, HPy).
13C NMR (75 MHz, CDCl3): d = 26.1 (3 C), 43.2, 45.4, 56.0, 56.2,
104.8, 107.5, 123.4, 123.7, 125.8, 132.9, 137.8, 145.0, 150.6, 152.7,
153.6, 203.5.
MS (EI, 70 eV): m/z (%) = 437 (52) [M+], 352 (37), 296 (100), 85
(16), 57 (92), 43 (76).
Anal. Calcd for C30H31NO2: C, 82.35; H, 7.14; N, 3.20. Found: C,
82.34; H, 7.29; N, 3.18.
MS (EI, 70 eV): m/z (%) = 349/347 (7/21) [M+], 292/290 (25/75),
262 (23), 256 (87), 227 (100), 212 (31), 59 (31), 57 (79), 45 (35), 43
(65).
(1Z)-1-[2-(4-Bromophenyl)-4-(5-tert-butyl-2-furyl)quinolin-3-
yl]-4,4-dimethylpent-1-en-3-one (3k)
Pale yellow solid; yield: 498 mg (69%); mp 196–197 °C.
Anal. Calcd for C19H22ClNO3: C, 65.61; H, 6.38; N, 4.03. Found: C,
65.39; H, 6.48; N, 4.12.
IR (KBr): 2964, 1680, 1608, 1560, 1528, 1484, 1360, 1272, 1072,
1004, 808, 800, 792, 768 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.80 (s, 9 H, t-Bu), 1.34 (s, 9 H, t-
Bu), 6.15 (d, J = 3.3 Hz, 1 H, HFur), 6.40 (d, J = 12.0 Hz, 1 H, =CH),
6.52 (d, J = 3.3 Hz, 1 H, HFur), 7.16 (d, J = 12.0 Hz, 1 H, =CH),
7.44–7.54 (m, 5 H, HAr), 7.67–7.73 (m, 1 H, HAr), 8.08–8.11 (m, 1
H, HAr), 8.16–8.19 (m, 1 H, HAr).
13C NMR (75 MHz, CDCl3): d = 25.6 (3 C), 29.1 (3 C), 32.9, 43.0,
103.8, 115.1, 122.5, 124.8, 125.1, 125.9, 126.9, 128.6, 129.5, 129.6,
130.7 (2 C), 131.6 (2 C), 135.0, 139.7, 141.2, 146.2, 147.0, 156.9,
165.6, 203.5.
(2E)-1-(4-Bromophenyl)-3-(6,7-dimethoxy-2-phenylquinolin-3-
yl)prop-2-en-1-one (3h)
Yellow needles; yield: 498 mg (75%); mp 183–184 °C.
IR (KBr): 1659, 1585, 1497, 1393, 1299, 1236, 1206, 1104 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.05 (s, 3 H, OCH3), 4.06 (s, 3 H,
OCH3), 7.14 (s, 1 H, HAr), 7.43 (d, J = 15.6 Hz, 1 H, =CH), 7.46–
7.53 (m, 4 H, HAr), 7.59–7.63 (m, 4 H, HAr), 7.83 (d, J = 8.7 Hz, 2
H, HAr), 7.95 (d, J = 15.6 Hz, 1 H, =CH), 8.41 (s, 1 H, HPy).
13C NMR (75 MHz, CDCl3): d = 56.1, 56.3, 104.9, 108.1, 122.5,
122.9, 125.4, 127.9, 128.5 (2 C), 128.7, 129.7 (2 C), 130.0 (2 C),
131.9 (2 C), 133.3, 136.6, 139.5, 143.7, 145.8, 150.3, 153.9, 157.7,
188.9.
MS (EI, 70 eV): m/z (%) = 517/515 (34/35) [M+], 376/374 (96/100),
57 (77), 43 (32).
Synthesis 2011, No. 16, 2629–2638 © Thieme Stuttgart · New York

PAPER
New Route to Quinolines under the Bischler–Napieralski Reaction Conditions
2637
Anal. Calcd for C30H30BrNO2: C, 69.77; H, 5.85; N, 2.71. Found: C,
69.66; H, 5.91; N, 2.59.
tered through a pad of silica gel and kept until crystallization of the
product.
White solid; yield: 4.10 g (81%); mp 194–195 °C.
(1Z)-1-[4-(5-tert-Butyl-2-furyl)-2-(4-nitrophenyl)quinolin-3-yl]-
4,4-dimethylpent-1-en-3-one (3l)
Yellow solid; yield: 364 mg (54%); mp 209–210 °C.
IR (KBr): 3236, 1660, 1643, 1515, 1486, 1310, 1291, 1262, 1216,
1092, 1011, 714, 693 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.23 (s, 3 H, CH3), 3.74 (s, 3 H,
OCH3), 3.89 (s, 3 H, OCH3), 5.40 (s, 1 H, CH), 5.88 (d, J = 3.3 Hz,
1 H, HFur), 5.92 (d, J = 3.3 Hz, 1 H, HFur), 6.49 (s, 1 H, HAr), 7.00–
7.02 (m, 2 H, HAr), 7.36–7.44 (m, 4 H, HAr), 7.46–7.55 (m, 4 H,
HAr), 7.69 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 13.5, 46.6, 56.0, 56.1, 106.4,
109.0, 109.7, 113.0, 121.2, 125.4, 126.8 (2 C), 128.5, 128.6 (2 C),
130.2 (2 C), 131.7, 131.8 (2 C), 134.5, 139.3, 146.6, 148.3, 152.3,
152.5, 165.4.
IR (KBr): 2964, 1680, 1604, 1516, 1344, 1272, 1072, 1008, 808,
792, 772, 716 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.77 (s, 9 H, t-Bu), 1.35 (s, 9 H, t-
Bu), 6.17 (d, J = 3.3 Hz, 1 H, HFur), 6.42 (d, J = 12.0 Hz, 1 H, =CH),
6.53 (d, J = 3.3 Hz, 1 H, HFur), 7.22 (d, J = 12.0 Hz, 1 H, =CH),
7.52–7.58 (m, 1 H, HAr), 7.70–7.75 (m, 1 H, HAr), 7.78 (d, J = 9.0
Hz, 2 H, HAr), 8.12–8.17 (m, 2 H, HAr), 8.23 (d, J = 9.0 Hz, 2 H,
HAr).
13C NMR (75 MHz, CDCl3): d = 25.5 (3 C), 29.1 (3 C), 32.9, 43.1,
103.9, 115.4, 122.7 (2 C), 125.0, 125.2, 125.9, 127.3, 128.1, 129.7,
129.8, 130.9 (2 C), 135.0, 141.0, 145.9, 147.2, 147.4, 147.5, 156.0,
165.8, 203.6.
MS (EI, 70 eV): m/z (%) = 507/505 (79/76) [M+], 402/400 (79/76),
180 (30), 165 (78), 105 (100), 77 (50), 59 (56), 43 (58).
Anal. Calcd for C27H24BrNO4: C, 64.04; H, 4.78; N, 2.77. Found: C,
64.23; H, 4.94; N, 2.96.
MS (EI, 70 eV): m/z (%) = 482 (24) [M+], 398 (24), 381 (18), 341
(53), 325 (18), 85 (24), 57 (100), 43 (42).
(3Z)-4-[4-(4-Bromophenyl)-6,7-dimethoxy-2-phenylquinolin-3-
yl]but-3-en-2-one (3q)
Anal. Calcd for C30H30N2O4: C, 74.67; H, 6.27; N, 5.80. Found: C,
74.52; H, 6.30; N, 5.69.
A mixture of amide 1q (0.5 g, 1 mmol), POCl3 (5 mL), and benzene
(50 mL) was refluxed for 1.5 h. The reaction mixture was poured
into H2O (800 mL) and neutralized with a soln of NaOH (50 g) in
H2O (200 mL). The product was extracted with CH2Cl2 (3 × 150
mL). The combined organic fractions were dried (Na2SO4), filtered,
and concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (CH2Cl2–PE, 1:3) and re-
crystallization (CH2Cl2–PE).
(1Z)-1-[4-(5-tert-Butyl-2-furyl)-2-(4-methoxyphenyl)quinolin-
3-yl]-4,4-dimethylpent-1-en-3-one (3m)
Red-orange solid; yield: 163 mg (25%); mp 148–149 °C.
IR (KBr): 2966, 1684, 1607, 1514, 1249, 1182, 1073, 1005, 809,
758 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.79 (s, 9 H, t-Bu), 1.34 (s, 9 H, t-
Bu), 3.82 (s, 3 H, OCH3), 6.13 (d, J = 3.3 Hz, 1 H, HFur), 6.38 (d,
J = 12.0 Hz, 1 H, =CH), 6.48 (d, J = 3.3 Hz, 1 H, HFur), 6.89 (d,
J = 8.7 Hz, 2 H, HAr), 7.19 (d, J = 12.0 Hz, 1 H, =CH), 7.44–7.50
(m, 1 H, HAr), 7.52 (d, J = 8.7 Hz, 2 H, HAr), 7.63–7.68 (m, 1 H,
HAr), 8.04–8.07 (m, 1 H, HAr), 8.11–8.14 (m, 1 H, HAr).
13C NMR (75 MHz, CDCl3): d = 25.7 (3 C), 29.1 (3 C), 32.8, 42.9,
55.4, 103.6, 113.1 (2 C), 114.6, 124.5, 124.9, 125.7, 126.3, 128.9,
129.0, 129.7, 131.2 (2 C), 133.7, 134.4, 141.7, 146.5, 147.3, 157.7,
159.7, 165.2, 203.5.
Beige solid; yield: 176 mg (36%); mp 157–159 °C.
IR (KBr): 1692, 1616, 1500, 1464, 1452, 1428, 1352, 1212, 1184,
1144, 1016, 840 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.61 (s, 3 H, CH3), 3.78 (s, 3 H,
OCH3), 4.03 (s, 3 H, OCH3), 5.94 (d, J = 12.0 Hz, 1 H, =CH), 6.64
(d, J = 12.0 Hz, 1 H, =CH), 6.68 (s, 1 H, HAr), 7.18–7.21 (m, 2 H,
HAr), 7.34–7.42 (m, 3 H, HAr), 7.54–7.62 (m, 5 H, HAr).
13C NMR (75 MHz, CDCl3): d = 30.0, 55.8, 56.2, 103.1, 108.2,
121.1, 122.3, 126.1, 127.8 (3 C), 127.9 (2 C), 129.8 (2 C), 130.9,
131.6 (2 C), 135.9, 138.5, 140.5, 143.6, 144.2, 149.9, 152.5, 155.4,
198.3.
MS (EI, 70 eV): m/z (%) = 467 (42) [M+], 410 (27), 382 (37), 326
(93), 85 (64), 69 (22), 57 (100), 43 (68).
Anal. Calcd for C31H33NO3: C, 79.63; H, 7.11; N, 3.00. Found: C,
79.49; H, 7.24; N, 3.20.
MS (EI, 70 eV): m/z (%) = 489/487 (25/26) [M+], 446/444 (97/98),
430 (17), 257 (53), 105 (100), 77 (18), 43 (35).
Anal. Calcd for C27H22BrNO3: C, 66.40; H, 4.54; N, 2.87. Found: C,
66.37; H, 4.60; N, 2.67.
N-{2-[(4-Bromophenyl)(hydroxy)methyl]-4,5-dimethoxyphe-
nyl}benzamide (14)
Benzhydrol 14 was synthesized according to
a published
procedure19 and was used in the further transformations without ad-
ditional purification.
Acknowledgment
We thank the Russian Ministry of Education and Science (Federal
Special Program, procedure 1.3.1., state contract No. P 2347) and
the Council of President of the Russian Federation (grant MK-
4902.2010.3) for financial support of this work. The authors would
like to emphasize their special thanks to Dr. Valery E. Zavodnik for
the X-ray analysis.
White solid; mp 153–154 °C (EtOH–acetone).
1H NMR (300 MHz, DMSO-d6): d = 3.75 (s, 6 H, OCH3), 5.88 (s, 1
H, CH), 6.55 (br s, 1 H, OH), 7.05 (s, 1 H, HAr), 7.23 (d, J = 8.7 Hz,
2 H, HAr), 7.41 (s, 1 H, HAr), 7.43 (d, J = 8.7 Hz, 2 H, HAr), 7.49–
7.61 (m, 3 H, HAr), 7.80–7.83 (m, 2 H, HAr), 10.05 (s, 1 H, NH).
N-{2-[(4-Bromophenyl)(5-methyl-2-furyl)methyl]-4,5-
dimethoxyphenyl}benzamide (1q)
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reaction mixture was neutralized with aq NaHCO3 and dried
(Na2SO4). The mixture was concentrated to a volume of ca. 5–10
mL, and hexane (50 mL) was added. The resulting solution was fil-
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Synthesis 2011, No. 16, 2629–2638 © Thieme Stuttgart · New York

2638
A. V. Butin et al.
PAPER
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Synthesis 2011, No. 16, 2629–2638 © Thieme Stuttgart · New York