Synthesis of 1H-pyrrolo[3,2-c]quinoline derivatives via palladium-catalyzed heteroannulation of 2-aryl-3-iodo-4-(phenylamino)quinolines and 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinolines

Article abstract of DOI:10.1016/j.tet.2010.06.018

Palladium(0)/copper iodide catalyzed Sonogashira cross-coupling of 2-aryl-3-iodo-4-(phenylamino)quinolines with terminal alkynes afforded series of 1,2,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines in a single-step operation. Conversely, the 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives were found to undergo PdCl₂(PPh₃)₂/CuI catalyzed intramolecular Heck reaction to yield the corresponding 1,3,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines.

Full text of DOI:10.1016/j.tet.2010.06.018

Tetrahedron 66 (2010) 6040e6046
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 1H-pyrrolo[3,2-c]quinoline derivatives via palladium-catalyzed
heteroannulation of 2-aryl-3-iodo-4-(phenylamino)quinolines and
4-(N,N-allylphenylamino)-2-aryl-3-iodoquinolines
*
Malose J. Mphahlele , Lehlohonolo G. Lesenyeho, Hlamulo R. Makelane
Department of Chemistry, College of Science, Engineering and Technology, University of South Africa, PO Box 392, Pretoria 0003, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium(0)/copper iodide catalyzed Sonogashira cross-coupling of 2-aryl-3-iodo-4-(phenylamino)
quinolines with terminal alkynes afforded series of 1,2,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines in
a single-step operation. Conversely, the 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives
were found to undergo PdCl2(PPh3)2/CuI catalyzed intramolecular Heck reaction to yield the corre-
sponding 1,3,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines.
Received 9 February 2010
Received in revised form 20 May 2010
Accepted 7 June 2010
Available online 12 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
2-Aryl-3-iodo-4-(phenylamino)quinolines
4-(N,N-Allylphenylamino)-2-aryl-3-
iodoquinolines
Sonogashira reaction
Intramolecular Heck reaction
1H-Pyrrolo[3,2-c]quinolines
1. Introduction
formation and metal exchange.7 The Sonogashira reaction, which
involves palladium catalyzed coupling of terminal acetylenes with
Polynuclear heterocycles derived from quinolines represent an
important class of compounds and have attracted a great deal of at-
tention in recent years because of their wide range of pharmaco-
logical properties.1 During our research on the development of
polysubstituted quinolines,2,3,4 we became interested in the syn-
thesis of annulated quinoline derivatives based on the framework of
1H-pyrrolo[3,2-c]quinolines A (Fig. 1). This moiety forms the core
structural unit of a number of biologically interesting compounds,
such as gastric acid secretion inhibitors1,5 and antitumour agents.6
Iodofunctionalized organic molecules have established themselves
as versatile intermediates in synthetic organic chemistry based on
the ability of iodo substituents to facilitate carbonecarbon bond
aryl orheteroaryl halides has become an important tool forCeC bond
formationreaction.8 Theexperimentalsimplicity, highproductyields
and tolerance to a broad range of functional groups have made this
reaction one of the most convenient and versatile methods for
the synthesis of alkynylquinolines,9 which are important precursors
for the synthesis of polysubstituted quinolines.10,11 Palladium
acetate-catalyzed heteroannulation of 4-arylamino-3-iodoquino-
lines with internal alkynes in the presence of potassium acetate
(2 equiv) and lithium chloride (1 equiv) in refluxing dimethyl-
formamide (DMF) previously afforded 2-substituted 1-H-pyrrolo
[3,2-c]quinoline derivatives.10 Dichlorobis(triphenylphosphine)pal-
ladium(II) (PdCl2(PPh3)2)/copper iodide (CuI) catalyzed Sonogashira
reaction of 3-iodo-2-methyl-4-quinolinylamine with 1-hexyne in
the presence of triethylamine in THF at room temperature followed
by cyclization of the resulting 3-(1-hexynyl)-2-methyl-4-quinoli-
nylamine using KH in refluxing N-methylpyrrolidinone (NMP)
afforded 2-butyl-4-methyl-1H-pyrrolo[3,2-c]quinoline A (R1,3¼H,
R2¼Bu, R4¼Me).11 Series of 1,4-disubstituted pyrrolo[3,2-c]quino-
lines were also recently prepared in 52e94% yield via iron-catalyzed
cross-couplingof4-chloropyrrolo[3,2-c]quinolinewith alkyl andaryl
magnesium halides in a tetrahydrofuran (THF)/NMP mixture.12
Although several methods have been described in literature for
the synthesis of pyrrolo[3,2-c]quinolines, corresponding data for the
R1
N
R2
R3
R4
N
A
Figure 1. Generalized structure of polysubstituted 1H-pyrrano[3,2-c]quinolines.
* Corresponding author. Tel.: þ27 12 429 8805; fax: þ27 12 429 8549; e-mail
address: mphahmj@unisa.ac.za (M.J. Mphahlele).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.018

M.J. Mphahlele et al. / Tetrahedron 66 (2010) 6040e6046
6041
synthesis of fully aromatized pyrrolo[3,2-c]quinoline derivatives is
considerably less well documented.5,10e12 Prompted by the scant
attention paid in literature to the synthesis of polysubstituted 1H-
pyrrolo[3,2-c]quinolines, we decided to investigate the possibility of
direct one-pot synthesis of 1,2,3-trisubstituted 1H-pyrrolo[3,2-c]
quinolines from 2-aryl-3-iodo-4-(N-phenylamino)quinolines using
terminal alkynes as model for CeC bond formation. Moreover, the
synthesis of 1,3,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines using
4-(N,N-allylphenylamino)-2-aryl-3-iodoquinolines derived from
2-aryl-3-iodo-4-(N-phenylamino)quinolines was also investigated.
formation and metal exchange reactions. Inthisinvestigation, we first
subjected the previously described 2-aryl-4-chloro-3-iodoquinolines
14 to aminobenzene (aniline) in refluxing ethanol and isolated the
corresponding hitherto unknown 2-aryl-3-iodo-4-(phenylamino)
quinolines 2 in good yields (Scheme 1). Whereas allylation of
(4-arylamino)-3-iodoquinolines is reported to be complicated by
quartenarization,10 we were able to effect selective 4-N allylation of
2-aryl-4-(arylamino)-3-iodoquinolines 2 using allyl bromide in the
presence of sodium hydride in DMF to afford previously undescribed
4-(N,N-allylphenylamino)-2-aryl-3-iodoquinolines 3aed with no
traces of the quartenarization products (Scheme 1).
With the 2-aryl-3-iodo-4-(phenylamino)quinolines
2 and
2. Results and discussion
their 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives
3 in hands, we explored their reactivity towards palladium-
catalyzed reactions. Accordingly, systems 2 were first exposed to
PdCl2(PPh3)2/CuI catalyzed Sonagashira cross-coupling with phe-
nylacetylene in THF or DMF at room temperature in the presence of
triethylamine for 24 h, but we isolated the starting material un-
changed. Complete conversion of 2 to 1,2,4-trisubstituted 1H-pyr-
rolo[3,2-c]quinoline derivatives 5 was however observed by thin
layer chromatography (TLC) within 3 h when the reaction mixture
was performed in DMF at 120 ꢀC. We were concerned about the low
yields (<40%), which are presumably due to some decomposition as
observed by TLC of the reaction mixtures and the crude products.
After some experimentation we found the use of dioxane/water
(3:1, v/v) as solvent mixture at 80 ꢀC afforded products 5 within 4 h
with no traces of decomposed products (Scheme 2). The reaction in
dioxane/water mixture also proceeded well with 3-butyn-2-ol and
trimethylsilylacetylene.
Ourstrategyforexplorationof thestructuralfeatures necessaryfor
the synthesis of polysubstituted and annulated quinoline derivatives
withpotentialbiologicalactivityconsistsoftargeting2-aryl-4-chloro-
3-iodoquinolines as precursors. This approach takes advantage of
the ease of displacement of the 4-chloro atom by nucleophiles and
the potential for iodine to facilitate metal-catalyzed CeC bond
Ph
Cl
NHPh
N
I
(i)
I
I
(ii)
N
C6H4R
N
C6H4R
2a - d
% Yield of 2 % Yield of 3
N
C6H4R
1a - d
4-R
H
3a - d
a
b
c
86
78
93
68
85
80
60
F
Participation of copper(I) salts in the intramolecular cyclization
of the appropriately functionalized internal alkynes generated in
situ has been documented well in the literature.13e16 Mechanisti-
cally, the present one-pot coupling/cyclization process seems to
proceed through initial Pd(0) catalyzed coupling of 2 with copper(I)
acetylide generated in situ from terminal alkyne to afford the
Cl
d
OCH3 95
Scheme 1. Reagents (i) NH2Ph, EtOH, heat, 18 h; (ii) CH2]CHCH2Br, NaH, DMF, room
temperature, 12 h.
R'
NHPh
R'
Ph
NHPh
N
(i)
I
N
C6H4R
N
C6H4R
N
C6H4R
2a - d
4a - f
5a - f
4-R
R'
% Yield
58
5a
H
-C6H5
-C6H5
-C6H5
5b F
53
5c Cl
65
5d OCH3 -C6H5
63
5e
H
-CH(OH)CH3
-CH(OH)CH3
62
5f Cl
59
5g OMe -CH(OH)CH3
61
5h H
5i
-Si(CH3)3
-Si(CH3)3
75
F
65
5j OMe -Si(CH3)3
72
Scheme 2. Reagents (i) R0C^CH, PdCl2(PPh3)2, CuI, NEt3, dioxane/water (3:1, v/v), 80 ꢀC, 4 h.

6042
M.J. Mphahlele et al. / Tetrahedron 66 (2010) 6040e6046
incipient 2-aryl-3-(alkyl/arylethynyl)quinoline 4. We strongly
believe that nucleophilic attack on the triple bond by the amino
group affords the annulated derivative 5. To ascertain the
involvement of intermediates 4 in the proposed mechanism, we
subjected 1a to Sonogashira cross-coupling with phenylacetylene
to afford 4-chloro-2-phenyl-3-(phenylethynyl)quinoline 6a, which
was in turn, reacted with aniline in refluxing ethanol to yield 2-
phenyl-4-(phenylamino)-3-(phenylethynyl)quinoline 4a (Scheme
3). The latter was subjected to similar reaction conditions applied
to 2 above to afford 5a, thus confirming the involvement of the
incipient intermediate 4 in the proposed mechanism. To our
knowledge, the direct one-pot conversion of 2 to 5 described herein
represents the first example of the synthesis of 1,2,4-trisubstituted
1-H-pyrrolo[3,2-c]quinolines of potential biological application.
Such derivatives do not feature at all in a comprehensive review on
synthetic approaches to various azoloquinoline derivatives.1
cyclization of 4-allylamino-3-iodoquinoline to afford 6-methoxy-3-
methyl-1-(2-methylphenyl)-1H-pyrrolo[3,2-c]quinoline, however,
the generality of this method was not demonstrated.20 With these
considerations in mind, we subjected systems 3 to PdCl2(PPh3)2/CuI
catalytic system in DMF at 80 ꢀC and we isolated 1,4-diaryl-3-
methylpyrrolo[3,2-c]quinolines 7aed (Scheme 4).
Although intramolecular arylearyl bond formation of appro-
priately activated diarylamines to form carbazole moiety is well
precedented,21,22 systems 3 were found to undergo palladium-
catalyzed intramolecular Heck reaction with complete selectivity
over possible competitive intramolecular arylearyl coupling.
3. Conclusions
Sequential functionalization of 2-aryl-4-chloro-3-iodoquinolines
via nucleophilic displacement of 4-chloro atom with aniline and N-4
allylation of the resulting 2-aryl-3-iodo-4-(phenylamino)quinolines
yielded the corresponding 4-(N,N-allylphenylamino)-2-aryl-3-iodo-
quinolines. The 2-aryl-3-iodo-4-(phenylamino)quinolines partici-
pated well in Pd-mediated CeC bond forming reactions providing an
array of appropriately functionalized 1,2,4-trisubstituted pyrrolo
[3,2-c]quinolines 5 in a one-pot operation. Moreover, the 4-(N,N-
allylphenylamino)-2-aryl-3-iodoquinoline derivatives afforded the
1,3,4-trisubstituted pyrrolo[3,2-c]quinolines 6 via intramolecular
Heck cyclization. Thus, the Pd-Cu catalyzed cross-coupling reactions
described herein provide useful strategies for the synthesis of ana-
logues of 6-methoxy-3-methyl-1-(2-methylphenyl)-1H-pyrrolo[3,2-
c]quinoline, a known gastric acid secretion inhibitor against ethanol
induced gastric ulcer.1,5 Likewise, the 2-aryl-3-iodo-4-(phenylamino)
quinolines represent an important class of compounds with potent
immunostimulants and non-nucleoside HIV-1 inhibitors.23 The
2-aryl-4-chloro-3-iodoquinolines and their 4-arylamino derivatives
described in this investigation represent suitable candidates for
further studies of carbonecarbon bond forming reactions to generate
novel polysubstituted and polynuclear derivatives with potential
applications ranging from biology to materials.
Ph
NHPh
Ph
Cl
N
Ph
(ii)
Ph
N
N
(i)
(iii)
1a
N
C6H5
C6H5
C6H5
6a (74%)
4a (45%)
5a (55%)
Scheme 3. Reagents (i) PhC^CH, PdCl2(PPh3)2, CuI, NEt3; (ii) NH2Ph, EtOH, heat, 18 h;
(iii) PdCl2(PPh3)2, CuI, NEt3, dioxane/water (3:1, v/v), heat, 12 h.
Palladium-catalyzed intramolecular cyclization of nitrogen-
containing ortho-iodoaryl alkenes to indoles, indolines, oxindoles,
quinolines, isoquinolines and isoquinolones has been well in-
vestigated by Larock’s group.17 A one-pot palladium acetate/Xphos
catalyzed N-alkylation/Heck cyclization of 2-chloroanilines re-
cently yielded series of substituted indoles.18 The tandem Heck
coupling/isomerisation of iodinated N-allyl pyridines and pyrimi-
dines with 5% palladium acetate and triethylamine in toluene to
afford indole derivatives have also been described.19 Our interest in
the synthesis of polysubstituted 1-H-pyrrolo[3,2-c]quinolines
prompted us to also investigate the possibility of palladium cata-
lyzed intramolecular cyclization of the 4-(N,N-allylphenylamino)-
3-iodoquinolines 3. Previous attempts to synthesize 3-substituted
1-arylpyrrolo[3,2-c]quinolines via intramolecular Heck reaction of
4-allylarylamino-3-iodoquinolines led to low yields of the desired
products with limited functional group tolerance.6 Recourse to
literature revealed one example involving palladium catalyzed
4. Experimental
4.1. General
Melting points were recorded on a Thermocouple digital
melting point apparatus. IR spectra were recorded as powders
Scheme 4. Reagents (i) PdCl2(PPh3)2, CuI, NEt3, DMF, 80 ꢀC, 4 h.

M.J. Mphahlele et al. / Tetrahedron 66 (2010) 6040e6046
6043
using FTS 7000 Series Digilab Win-IR Pro ATR (attenuated total
reflectance) spectrometer. For column chromatography, Merck
Kieselgel 60 (0.063e0.200 mm) was used as stationary phase.
NMR spectra were obtained as CDCl3 solutions using a Varian
Mercury 300 MHz NMR spectrometer and the chemical shifts are
measured relative to the solvent peaks. Low and high-resolution
mass spectra were recorded at the University of Stellenbosch us-
ing a Waters API Q-TOF Ultima (double focusing high resolution)
instrument. The 2-aryl-4-chloro-3-iodoquinolines 1 used as sub-
strates in this investigation were prepared as described in our
previous communications.3,4
MHþ) 453; HRMS (ES): MHþ, found 453.0457. C22H18IN2Oþ re-
quires 453.0464.
4.3. Synthesis of the 4-(N,N-allylphenylamino)-2-aryl-3-
iodoquinolines 3. Typical procedure
4.3.1. 4-(N,N-Allylphenylamino)-3-iodo-2-phenylquinoline (3a). A
stirred solution of 3-iodo-2-phenyl-4-(phenylamino)quinoline 2a
(1.98 g, 4.69 mmol) in DMF (20 mL) was treated with NaH (0.22 g,
9.17 mmol) at room temperature. After 30 min, allyl bromide
(1.12 g, 9.0 mmol) was added to the reaction mixture and stirring
was continued for 12 h at room temperature. The mixture was
quenched with crushed ice and the resulting precipitate was
filtered, taken up into chloroform and dried (MgSO4). The solvent
was evaporated and the residue was purified by column chro-
matography to afford 3a as a solid (1.46 g, 68%), mp 116e117 ꢀC
(ethanol); Rf (20% ethyl acetate/hexane) 0.75; nmax (neat) 921,
4.2. Synthesis of the 4-aminophenyl-2-aryl-3-iodoquinolines
2. Typical procedure
4.2.1. 3-Iodo-2-phenyl-4-(phenylamino)quinoline (2a). 4-Chloro-3-
iodo-2-phenylquinoline (2.51 g, 6.84 mmol) and aniline (3.18 g,
34.2 mmol) in ethanol (50 mL) were heated at reflux for 18 h.
The solvent was evaporated under reduced pressure and the
residue was quenched with ice-cold water. The product was
taken up into chloroform and the organic solution was washed
with brine and then dried over anhydrous MgSO4. The solvent
was evaporated under reduced pressure and the residue was
recrystallized from ethanol to afford 2a as a solid (2.58 g, 86%),
mp 159e161 ꢀC (ethanol); nmax (neat) 929, 1073, 1264, 1399,
1241, 1392, 1481, 1498, 1557, 1598 cmꢁ1
; dH (300 MHz, CDCl3) 4.34
(dd, J 6.0 and 15.3 Hz, 1H), 4.52 (dd, J 6.0 and 15.3 Hz, 1H), 5.19 (d,
J 10.8 Hz, 1H), 5.33 (d, J 16.8 Hz, 1H), 6.09e6.23 (m, 1H), 6.58 (d, J
7.8 Hz, 2H), 6.79 (t, J 7.8 Hz, 1H), 7.20 (t, J 7.8 Hz, 2H), 7.43e7.54
(m, 4H), 7.66 (d, J 6.0 Hz, 2H), 7.73, (t, J 7.8 Hz, 1H), 7.82 (d, J
7.8 Hz, 1H), 8.19 (d, J 7.5 Hz, 1H); dC (75 MHz, CDCl3) 54.9, 100.4,
113.2, 118.2, 118.3, 124.4, 127.5, 127.6, 127.9, 128.7, 129.2, 129.3,
129.9, 130.4, 134.2, 143.2, 146.5, 149.0, 154.7, 164.0; m/z (100,
MHþ) 463; HRMS (ES): MHþ, found: 463.0675. C24H20INþ2 re-
quires 463.0671.
1486, 1564, 1599, 3363 cmꢁ1
; dH (300 MHz, CDCl3) 6.60 (s, 1H),
6.87 (d, J 7.8 Hz, 2H), 7.03 (t, J 7.8 Hz, 1H), 7.23e7.33 (m, 3H), 7.47
(t, J 7.8 Hz, 1H), 7.49 (d, J 7.5 Hz, 2H), 7.62 (d, J 9.3 Hz, 2H), 7.67
(d, J 7.5 Hz, 1H), 7.73 (d, J 7.5 Hz, 1H), 8.10 (1H, d, J 9.3 Hz); dC
(75 MHz, CDCl3) 90.4, 118.8, 121.1, 122.6, 124.9, 125.8, 128.0,
128.6, 129.0, 129.3, 129.7, 130.1, 143.6, 143.7, 148.3, 148.6, 162.4;
m/z (100, MHþ) 423; HRMS (ES): MHþ, found: 423.0360.
C21H16INþ2 requires 423.0358.
4.3.2. 4-(N,N-Allylphenylamino)-2-(40-fluorophenyl)-3-iodo-quino-
line (3b). (1.15 g, 85%), mp 160e162 ꢀC (ethanol); Rf (20% ethyl
acetate/hexane) 0.76; nmax (neat) 838, 936, 1158, 1211, 1394, 1481,
1596 cmꢁ1
; dH (300 MHz, CDCl3) 4.32 (dd, J 6.3 and 15.2 Hz, 1H),
4.51 (dd, J 6.3 and 15.3 Hz, 1H), 5.18 (d, J 9.3 Hz, 1H), 5.31 (d, J
16.8 Hz, 1H), 6.07e6.21 (m, 1H), 6.55 (d, J 9.3 Hz, 2H), 6.79 (t, J
7.8 Hz, 1H), 7.14e7.22 (m, 4H), 7.45 (t, J 7.8 Hz, 1H), 7.63e7.68 (m,
2H), 7.73 (t, J 7.8 Hz, 1H), 7.80 (d, J 7.8 Hz, 1H), 8.16 (d, J 7.8 Hz, 1H);
4.2.2. 2-(40-Fluorophenyl)-3-iodo-4-(phenylamino)quinoline (2b).
(1.46 g, 78%), mp 190e192 ꢀC (ethanol); nmax (neat) 835, 926, 1156,
2
dC (75 MHz, CDCl3) 54.9, 100.3, 113.2, 115.0 (d, JCF 21.7 Hz), 118.3,
1231,1486,1567,1600, 3367 cmꢁ1
;
dH (300 MHz, CDCl3) 6.58 (s,1H),
118.4, 124.5, 127.6, 127.8, 129.3, 129.9, 130.6, 131.4 (d, JCF 8.5 Hz),
3
4
6.86 (d, J 8.4 Hz, 2H), 7.04 (t, J 7.8 Hz, 1H), 7.14e7.33 (m, 5H), 7.59 (d,
J 7.5 Hz, 2H), 7.66 (t, J 8.7 Hz, 1H), 7.72 (d, J 7.5 Hz, 1H), 8.07 (d, J
134.1, 139.2 (d, JCF 3.4 Hz), 146.5, 149.0, 154.9, 162.9, 163.0 (d, 1JCF
246.7 Hz); m/z (100, MHþ) 481; HRMS (ES): MHþ, 481.0589.
8.4 Hz, 1H); dC (75 MHz, CDCl3) 90.1, 115.0 (d, JCF 21.6 Hz), 118.9,
C24H19FINþ2 requires 481.0587.
2
3
121.1, 122.8, 124.9, 125.9, 129.4, 129.6, 130.2, 131.1 (d, JCF 8.3 Hz),
4
1
139.7 (d, JCF 3.2 Hz), 143.6, 148.2, 148.7, 161.3, 162.9 (d, JCF
246.5 Hz); m/z (100, MHþ) 441; HRMS (ES): MHþ, found 441.0275.
C21H15IFNþ2 requires 441.0264.
4.3.3. 4-(N,N-Allylphenylamino)-2-(40-chlorophenyl)-3-iodoquino-
line (3c). (1.63 g, 80%), mp 119e122 ꢀC (ethanol); Rf (20% ethyl ac-
etate/hexane) 0.82; nmax(neat) 836, 1096, 1393, 1481, 1499, 1556,
1597 cmꢁ1
; dH (300 MHz, CDCl3) 4.32 (dd, J 6.3 and 16.8 Hz, 1H),
4.2.3. 2-(40-Chlorophenyl)-3-iodo-4-(phenylamino)quinoline (2c).
(2.66 g, 93%), mp 199e201 ꢀC (ethanol); nmax (neat) 829, 927, 1176,
4.52 (dd, J 6.3 and 16.8 Hz, 1H), 5.19 (d, J 10.8 Hz, 1H), 5.32 (d, J
16.8 Hz, 1H), 6.07e6.22 (m, 1H), 6.56 (d, J 7.8 Hz, 2H), 6.80 (t, J
7.8 Hz, 1H), 7.19 (t, J 7.8 Hz, 2H), 7.43e7.48 (m, 4H), 7.62 (d, J 9.0 Hz,
2H), 7.73 (t, J 7.5 Hz, 1H), 7.81 (d, J 9.3 Hz, 1H), 8.16 (d, J 7.8 Hz, 1H);
dC (75 MHz, CDCl3) 55.0, 99.9, 113.2, 118.3, 118.4, 124.5, 127.6, 127.8,
128.2, 129.3, 129.9, 130.6, 130.8, 134.1, 134.9, 141.5, 146.5, 149.1,
154.9, 162.7; m/z (100, MHþ) 497; HRMS (ES): MHþ, found
497.0273. C24H1935ClINþ2 requires 497.0282.
1243, 1397, 1494, 1566, 1600, 3369 cmꢁ1
; dH (300 MHz, CDCl3) 6.58
(s, 1H), 6.87 (d, J 7.8 Hz, 2H), 7.04 (t, J 7.8 Hz, 1H), 7.22e7.33 (m,
4H), 7.46 (d, J 7.8 Hz, 2H), 7.56 (d, J 9.3 Hz, 2H), 7.66 (t, J 7.5 Hz, 1H),
7.71 (d, J 7.8 Hz, 1H), 8.06 (d, J 7.8 Hz, 1H); dC (75 MHz, CDCl3) 89.7,
118.9, 121.1, 122.8, 124.9, 126.0, 128.3, 129.4, 129.7, 130.2, 130.6,
134.7, 142.0, 143.5, 148.3, 148.8, 161.2; m/z (100, MHþ) 457; 459
(23); HRMS (ES): MHþ, found: 456.9973. C21H1535ClINþ2 requires
456.9969.
4.3.4. 4-(N,N-Allylphenylamino)-3-iodo-2-(40-methoxyphenyl)quin-
oline (3d). (1.02 g, 60%), mp 110e112 ꢀC (ethanol); Rf (20% ethyl
acetate/hexane) 0.78; nmax (neat) 832, 1029, 1172, 1250, 1498,
4.2.4. 3-Iodo-2-(40-methoxyphenyl)-4-(phenylamino)quinoline
(2d). (2.70 g, 95%), mp 210e212 ꢀC (ethanol); nmax (neat) 829,
1597 cmꢁ1
; dH (300 MHz, CDCl3) 3.88 (s, 3H), 4.33 (dd, J 6.3 and
929, 1029, 1176, 1243, 1400, 1495, 1513, 1567, 1603, 3369 cmꢁ1
;
dH
15.3 Hz, 1H), 4.52 (dd, J 6.0 and 15.3 Hz, 1H), 5.18 (d, J 10.8 Hz,
1H), 5.32 (d, J 18.3 Hz, 1H), 6.08e6.22 (m, 1H), 6.56 (d, J 9.3 Hz,
2H), 6.78 (t, J 7.8 Hz, 1H), 7.02 (d, J 9.0 Hz, 2H), 7.19 (t, J 7.5 Hz,
2H), 7.43 (t, J 7.5 Hz, 1H), 7.65 (d, J 9.3 Hz, 2H), 7.71 (t, J 7.5 Hz,
1H), 7.79 (d, J 9.0 Hz, 1H), 8.17 (d, J 9.3 Hz, 1H); dC (75 MHz, CDCl3)
55.0, 55.3, 100.8, 113.2, 113.3, 118.2 (2ꢂC), 124.5, 127.3, 127.4,
129.3, 129.8, 130.4, 130.9, 134.2, 135.7, 146.5, 149.1, 154.7, 160.0,
(300 MHz, CDCl3) 3.88 (s, 3H), 6.56 (s, 1H), 6.86 (d, J 7.8 Hz, 2H),
7.01 (d, J 9.0 Hz, 2H), 7.02 (t, J 7.8 Hz, 1H), 7.23 (d, J 9.0 Hz, 2H),
7.27 (t, J 7.5 Hz, 1H), 7.59 (d, J 9.0 Hz, 2H), 7.65 (t, J 7.8 Hz, 1H),
7.72 (d, J 9.0 Hz, 1H), 8.08 (d, J 9.0 Hz, 1H); dC (75 MHz, CDCl3)
55.4, 91.0, 113.3, 118.7, 121.1, 122.5, 124.9, 125.7, 129.3, 129.7,
130.0, 130.6, 136.3, 143.7, 148.3, 148.5, 159.9, 162.1; m/z (100,

6044
M.J. Mphahlele et al. / Tetrahedron 66 (2010) 6040e6046
163.5; m/z (100, MHþ) 481; HRMS (ES): MHþ, 481.0580.
and 7.8 Hz, 1H), 7.38e7.66 (m, 8H), 7.95 (d, J 8.4 Hz, 2H), 8.03 (dd, J
1.5 and 8.2 Hz, 1H); dC (75 MHz, CDCl3) 22.7, 62.1, 101.0, 117.4, 118.8,
120.3, 125.0, 126.4, 128.6, 128.8, 128.9, 129.1, 129.4, 129.9, 130.0,
130.1, 130.5, 136.5, 138.8, 140.2, 144.2, 145.0, 154.6; m/z (100, MHþ)
365; HRMS (EI): MHþ, found 365.1662. C25H21N2Oþ requires
365.1654.
C25H23IN2Oþ requires 423.1893.
4.4. Sonogashira coupling of 2-aryl-3-iodo-4-(phenylamino)
quinolines (4). Typical procedure
4.4.1. 1,2,4-Triphenyl-1H-pyrrano[3,2-c]quinoline (5a). A mixture of
2a (0.20 g, 0.47 mmol), PdCl2(PPh3)2 (0.017 g, 0.024 mmol) and CuI
(0.005 g, 0.024 mmol) in dioxane/water (3:1, v/v; 20 mL) in a three-
necked flask equipped with a stirrer, condenser and rubber septum
was flushed with nitrogen gas for 20 min. Phenylacetylene (0.058 g,
0.57 mmol) and triethylamine (0.266 mL, 1.89 mmol) were added
sequentially to the flask via a syringe. The mixture was flushed for
additional 10 min and then refluxed at 80 ꢀC for 4 h under nitrogen
atmosphere and then allowed to cool. The cooled mixture was
added to a beaker containing ice-cold water and the product was
extracted into ethyl acetate and the combined organic extracts
were dried over MgSO4. The solvent was evaporated under reduced
pressure and the residue was passed through a column of silica gel
eluting with hexane/ethyl acetate mixture to afford (5a) as solid
(0.11 g. 58%), mp 210e212 ꢀC (ethanol); Rf (20% ethyl acetate/hex-
4.4.6. 4-(4-Chlorophenyl)-2-(1-hydroxyethyl)-1-phenyl-1H-pyrrano
[3,2-c]quinoline (5f). (0.101 g, 59%), mp 202e204 ꢀC (2-propanol);
Rf (30% ethyl acetate/hexane) 0.47; nmax (neat) 834,1009,1087,1310,
1444, 1499, 1567, 3210 cmꢁ1
; dH (300 MHz, CDCl3) 1.54 (d, J 6.6 Hz,
3H), 2.26 (br s, 1H), 4.71 (q, J 6.6 Hz, 1H), 6.88 (s, 1H), 6.90 (d, J
8.4 Hz, 1H), 7.14 (dt, J 1.2 and 7.8 Hz, 1H), 7.35e7.39 (1H, m),
7.45e7.52 (m, 4H), 7.58e7.66 (m, 3H), 7.95 (d, J 8.4 Hz, 2H), 8.19 (d, J
8.1 Hz, 1H); dC (75 MHz, CDCl3) 22.8, 62.0, 100.6, 117.4, 118.6, 120.3,
125.3, 126.5, 128.8, 128.9, 129.3, 129.8, 130.0, 130.1, 130.3, 130.4,
134.9, 136.6, 138.5, 138.6, 144.5, 144.8, 153.1; m/z (100, MHþ) 399;
HRMS (ES): MHþ, found 399.1261. C25H2035ClN2Oþ requires
399.1264.
4.4.7. 2-(1-Hydroxyethyl)-4-(4-methoxyphenyl)-1-phenyl-1H-pyr-
rano[3,2-c]quinoline (5g). (0.11 g, 61%), mp 221e223 ꢀC (ethanol);
Rf (30% ethyl acetate/hexane) 0.27; nmax (neat) 835, 1171, 1244, 1301,
ane) 0.90; nmax (neat) 807, 1028, 1315, 1349, 1371, 1499, 1564 cmꢁ1
;
dH (300 MHz, CDCl3) 7.10e7.20 (m, 3H), 72.3 (s, 5H), 7.43e7.61 (m,
9H), 8.13 (d, J 8.1 Hz, 2H), 8.27 (d, J 8.7 Hz, 1H); dC (75 MHz, CDCl3)
104.7, 117.6, 119.5, 120.4, 125.0, 126.3, 127.7, 128.1, 128.6, 128.8, 129.1,
129.3, 129.4, 129.5, 129.7, 130.6, 131.9, 136.6, 139.5, 140.3, 141.2,
145.2, 154.5; m/z (100, MHþ) 397; HRMS (ES): MHþ, found 397.1697.
C28H21Nþ2 requires 397.1705.
1440, 1501, 1606, 3170 cmꢁ1
; dH (300 MHz, CDCl3) 1.56 (3H, d, J
6.6 Hz), 1,98 (br s, 1H), 3.90 (s, 3H), 4.72 (q, J 6.6 Hz, 1H), 6.90 (d, J
7.5 Hz, 1H), 8.98 (s, 1H), 7.06e7.14 (m, 3H), 7.37e7.42 (m, 1H), 7.47
(t, J 7.5 Hz, 1H), 7.52e7.55 (m, 1H), 7.59e7.66 (m, 3H), 8.01 (d, J
8.4 Hz, 2H), 8.20 (d, J 8.4 Hz,1H); dC (75 MHz, CDCl3) 22.8, 55.4, 62.1,
101.0,114.0,117.3,118.7,120.3,124.8,126.3,128.9,129.4, 129.7, 129.9,
130.1, 130.3, 130.4, 132.8, 136.5, 138.8, 144.2, 145.0, 154.1, 160.3; m/z
(100, MHþ) 395; HRMS (ES): MHþ, found 395.1743. C26H23N2O2þ
requires 395.1746.
4.4.2. 4-(4-Fluorophenyl)-1,2-diphenyl-1H-pyrrano[3,2-c]quinoline
(5b). (0.100 g, 53%), mp 159e160 ꢀC (ethanol); Rf (20% ethyl ace-
tate/hexane) 0.94; nmax (neat) 838, 1154, 1221, 1499, 1598 cmꢁ1
; dH
(300 MHz, CDCl3) 7.06 (s,1H), 7.11 (dt, J 1.2 and 8.2 Hz,1H), 7.16 (dt, J
1.2 and 8.2 Hz, 1H), 7.23 (s, 5H), 7.26 (t, J 8.7 Hz, 2H), 7.41e7.45 (m,
2H), 7.48e7.56 (m, 4H), 8.11 (dd, J 5.4 and 9.0 Hz, 2H), 8.23 (dd, J 0.9
4.4.8. 1,4-Diphenyl-2-(trimethylsilyl)-1H-pyrrano[3,2-c]quinoline
(5h). (0.30 g, 75%), mp 160e163 ꢀC (ethanol); Rf (20% ethyl acetate/
2
and 8.2 Hz, 1H); dC (75 MHz, CDCl3) 104.4, 115.5 (d, JCF 21.3 Hz),
hexane) 0.87; nmax (neat) 838, 980, 1247, 1372, 1500, 1562 cmꢁ1
; dH
117.6,119.4,120.4,125.1,126.4,127.8,128.1,129.3,129.4,129.5,129.8,
(300 MHz, CDCl3) 0.09 (s, 9H), 7.00 (td, J 0.9 and 8.6 Hz, 1H), 7.14 (dt
J 1.5 and 7.7 Hz, 1H), 7.17 (s, 1H), 7.47e7.66 (m, 9H), 8.10 (dd, J 1.5
and 7.5 Hz, 2H), 8.25 (dd, J 0.6 and, 8.4 Hz, 1H); dC (75 MHz, CDCl3)
0.33, 114.4, 117.6, 119.9, 120.5, 124.9, 126.5, 128.6, 128.7, 129.1 (2ꢂC),
129.4, 129.6 (2ꢂC), 130.4, 139.2, 140.4, 141.6, 142.7, 145.1, 154.6; m/z
(100, MHþ) 392; HRMS (ES): MHþ, found 393.1789. C26H25N2Siþ
requires 393.1787.
130.5, 130.9 (d, 3JCF 8.3 Hz), 131.8, 136.4 (d, 4JCF 3.2 Hz), 139.4, 141.4,
1
145.1, 153.3, 163.4 (d, JCF 246.5 Hz); m/z (100, MHþ) 415; HRMS
(ES): MHþ, found 415.1602. C28H20FNþ2 requires 415.1611.
4.4.3. 4-(4-Chlorophenyl)-1,2-diphenyl-1H-pyrrano[3,2-c]quinoline
(5c). (0.105 g, 65%), mp 165e167 ꢀC (ethanol); Rf (20% ethyl acetate/
hexane) 0.93; nmax (neat) 839, 1223, 1450, 1500, 1600 cmꢁ1
; dH
(300 MHz, CDCl3) 7.08 (s, 1H), 7.10e7.22 (m, 2H), 7.25 (s, 5H),
7.43e7.56 (m, 7H), 8.09 (d, J 8.4 Hz, 2H), 8.25 (d, J 8.7 Hz, 1H); dC
(75 MHz, CDCl3) 104.3, 117.6, 119.4, 120.4, 125.2, 126.5, 127.8, 128.1,
128.8,129.3,129.4,129.5,129.8,130.4,130.5,131.7,134.9,136.7,138.7,
139.3, 141.4, 145.0, 153.0; m/z (100, MHþ) 431; HRMS (ES): MHþ,
found 431.1321. C28H2035ClNþ2 requires 431.1315.
4.4.9. 2-(4-Fluorophenyl)-2-(trimethylsilyl)-4-phenyl-1H-pyrrano
[3,2-c]quinoline (5i). (0.20 g, 65%), mp 185e187 ꢀC (ethanol); Rf
(20% ethyl acetate/hexane) 0.91; nmax (neat) 834, 933, 1221, 1503,
1597 cmꢁ1
; dH (300 MHz, CDCl3) 0.09 (s, 9H), 6.99 (dd, J 0.9, 8.6 Hz,
1H), 7.11 (1H, s), 7.13 (dt, J 1.5 and 7.7 Hz, 1H), 7.27 (t, J 8.4 Hz, 2H),
7.47e7.53 (m, 3H), 7.59e7.67 (m, 3H), 8.08 (dd, J 5.4 and 8.9 Hz, 2H),
2
8.20 (d, J 8.4 Hz, 1H); dC (75 MHz, CDCl3) 0.02, 114.1, 115.5 (d, JCF
4.4.4. 4-(4-Methoxyphenyl)-1,2-diphenyl-1H-pyrrano[3,2-c]quino-
21.4 Hz), 117.6, 119.7, 120.5, 125.0, 126.6, 129.3, 129.6, 129.7, 130.3,
line (5d). (0.120 g, 64%), mp 153e155 ꢀC (ethanol); Rf (20% ethyl
130.9 (d, 3JCF 8.3 Hz), 136.5 (d, 4JCF 2.9 Hz), 139.2, 141.5, 143.0, 145.0,
acetate/hexane) 0.78; nmax (neat) 832, 1029, 1246, 1501, 1605 cmꢁ1
;
153.5, 163.3 (d, JCF 246.5 Hz); m/z (100, MHþ) 411; HRMS (ES):
1
dH (300 MHz, CDCl3) 3.91 (s, 3H), 7.07e7.22 (m, 5H), 7.23e7.26 (m,
5H), 7.42e7.56 (m, 6H), 8.10 (d, J 7.0 Hz, 2H), 8.24(dd, J 0.9 and 8.6 Hz,
1H); dC (75 MHz, CDCl3) 55.4, 104.8, 114.0, 117.5, 119.4, 120.4, 124.7,
126.3,127.6,128.1,129.3,129.4,129.5,129.7,130.4,130.5,132.0,133.0,
136.6, 139.5, 141.1, 145.2, 154.0, 160.3; m/z (100, MHþ) 427; HRMS
(ES): MHþ, found 427.1831. C29H23N2Oþ requires 427.1810.
MHþ, found 411.1693. C26H24FN2Siþ requires 411.1693.
4.4.10. 4-(4-Methoxyphenyl)-2-(trimethylsilyl)-1-phenyl-1H-pyr-
rano[3,2-c]quinoline (5j). (0.37 g, 72%), mp 173e175 ꢀC (ethanol);
Rf (20% ethyl acetate/hexane) 0.75; nmax (neat) 840, 935, 981,
1174, 1249, 1509, 1608 cmꢁ1
; dH (300 MHz, CDCl3) 0.07 (s, 9H),
3.91 (s, 3H), 6.96 (d, J 8.4 Hz, 1H), 7.10 (dt, J 1.5 and 7.5 Hz, 1H),
7.11 (d, J 9.3 Hz, 2H), 7.16 (s, 1H), 7.47 (dt, J 1.5 and 7.5 Hz, 1H),
7.49 (dd, J 1.5 and 8.2 Hz, 2H), 7.57e7.66 (m, 3H), 8.09 (d, J 9.3 Hz,
2H), 8.20 (d, J 8.4 Hz, 1H); dC (75 MHz, CDCl3) 0.02, 55.4, 114.0,
114.5, 117.5, 119.8, 120.5, 124.7, 126.4, 129.3, 129.5, 129.6, 130.2,
130.5, 133.1, 139.2, 141.7, 142.6, 145.2, 154.3, 160.2; m/z (100, MHþ)
4.4.5. 2-(1-Hydroxyethyl)-1,4-diphenyl-1H-pyrrano[3,2-c]quinoline
(5e). (0.130 g, 62%), mp 183e185 ꢀC (ethanol); Rf (30% ethyl ace-
tate/hexane) 0.44; nmax (neat) 1071, 1364, 1494, 3389 cmꢁ1
; dH
(300 MHz, CDCl3) 1.56 (d, J 6.3 Hz, 3H), 1.98 (br s, 1H), 4.73 (q, J
6.3 Hz, 1H), 6.92 (dd, J 1.5 and 8.6 Hz, 1H), 6.97 (s, 1H), 7.13 (dt, J 1.2

M.J. Mphahlele et al. / Tetrahedron 66 (2010) 6040e6046
6045
423; HRMS (ES): MHþ, found 423.1879. C27H27N2OSiþ requires
423.1893.
saturated ammonium chloride and the resulting precipitate was
taken into ethyl acetate. The combined organic solution was
washed with brine and dried over MgSO4. The solvent was evap-
orated under reduced pressure and the residue was passed through
a column of silica gel eluting with ethyl acetate/hexane mixture to
afford 7a as a solid (0.11 g, 76%), mp 138e141 ꢀC (ethanol); Rf (20%
ethyl acetate/hexane) 0.75; nmax (neat) 976, 1370, 1433, 1497,
4.5. Indirect synthesis of 1,2,4-triphenyl-1H-pyrrano[3,2-c]
quinoline (5a)
4.5.1. 4-Chloro-2-phenyl-3-(phenylethynyl)quinoline (6a). A mix-
ture of 1a (1.00 g, 2.74 mmol), PdCl2(PPh3)2 (0.10 g, 0.14 mmol) and
CuI (0.03 g, 0.14 mmol) in a three-necked flask equipped with
a stirrer, condenser and rubber septum was flushed with nitrogen
gas for 20 min. Phenylacetylene (0.36 g, 3.30 mmol) and triethyl-
amine (8.0 mL) were added sequentially to the flask via a syringe.
The mixture was flushed for additional 10 min and then refluxed
for 2 h under nitrogen atmosphere. The cooled mixture was added
to a beaker containing ice-cold water and extracted with ethyl ac-
etate. The combined organic solution was dried over Mg2SO4, fil-
tered and then evaporated. The residue was purified by column
1557 cmꢁ1
; dH (300 MHz, CDCl3) 1.94 (3H, s), 7.00 (s, 1H), 7.21 (t, J
7.2 Hz, 1H), 7.35 (d, J 8.4 Hz, 1H), 7.46e7.62 (m, 9H), 7.66 (dd, J 1.6
and 6.6 Hz, 2H), 8.23 (d, J 8.4 Hz,1H); dC (75 MHz, CDCl3) 12.4,113.9,
117.4, 119.9, 120.6, 124.8, 126.5, 127.4, 127.9, 128.2, 128.7, 128.8,
129.2, 129.7, 130.2, 135.3, 140.9, 141.1, 144.2, 156.5; m/z 335 (100,
MHþ); HRMS (ES) MHþ, found 335.1549. C24H19Nþ2 requires
335.1548.
4.6.2. 4-(4-Fluorophenyl)-3-methyl-1-phenyl-1H-pyrrano[3,2-c]
quinoline (7b). (0.11 g, 75%), mp 123e125 ꢀC (ethanol); Rf (20%
ethyl acetate/hexane) 0.81; nmax (neat) 839, 977, 1219, 1371, 1499,
chromatography to afford 6a as
145e148 ꢀC; Rf (10% ethyl acetate/hexane) 0.44; nmax (neat) 822,
1070, 1234, 1345, 1400, 1442, 1474, 1492, 1563, 1599, 2213 cmꢁ1
dH
a solid (0.69 g; 74%), mp
1600 cmꢁ1
; dH (300 MHz, CDCl3) 1.93 (d, J 1.2 Hz, 3H), 7.01 (d, J
;
1.2 Hz, 1H), 7.16e7.36 (m, 3H), 7.34 (dd, J 0.9 and 8.3 Hz, 1H),
7.48e7.67 (m, 8H), 8.20 (dd, J 0.9 and 8.6 Hz, 1H); dC (75 MHz,
(300 MHz, CDCl3) 7.31e7.36 (m, 3H), 7.39e7.44 (m, 2H), 7.49 (m,
3H), 7.65 (dt, J 1.2 and 7.5 Hz, 1H), 7.77 (dt, J 1.5 and 7.7 Hz, 1H),
8.00e8.04 (m, 2H), 8.15 (dd, J 0.9 and 7.7 Hz, 1H), 8.27 (dd, J 0.9 and
8.6 Hz,1H); dC (75 MHz, CDCl3) 85.5, 100.6,116.4, 122.7, 124.4, 124.8,
127.8, 127.9, 128.4, 129.0, 129.2, 129.6, 130.0, 130.7, 131.5, 139.5,
145.1, 146.9, 159.8; m/z (100, MHþ) 340; HRMS (ES): MHþ, found
340.0888. C23H15N35Clþ requires 340.0893.
3
CDCl3) 12.5, 113.7, 114.9 (d, JCF 21.3 Hz), 117.4, 119.9, 120.6, 124.9,
3
126.6, 127.4, 128.8, 128.9, 129.8, 130.2, 131.0 (d, JCF 8.3 Hz), 135.4,
137.2 (d, 4JCF 3.2 Hz),140.8,144.2,155.4,163.0 (d, 1JCF 245.0 Hz); m/z:
353 (100, MHþ); HRMS (ES): MHþ, found 353.1449. C24H18FNþ2 re-
quires 353.1454.
4.6.3. 4-(4-Chlorophenyl)-3-methyl-1-phenyl-1H-pyrrano[3,2-c]
quinoline (7c). (0.12 g, 81%), mp 165e167 ꢀC (ethanol); Rf (20% ethyl
acetate/hexane) 0.85; nmax (neat) 825, 977, 1085, 1371, 1433, 1490,
4.5.2. 2-Phenyl-4-(phenylamino)-3-(phenylethynyl)quinoline 40a. A
mixture of 6a (0.18 g, 0.53 mmol) and aniline (0.05 g, 0.53 mmol) in
ethanol (20 mL) was heated at 80 ꢀC for 18 h and then evaporated
under reduced pressure. The residue was acidified with 2 M HCl
and then extracted into chloroform. The organic solution was
washed with saturated solution of Na2CO3, water and then dried
over MgSO4. The salt was filtered off and the organic solution was
evaporated under reduced pressure. The residue was purified by
column chromatography to afford (40a) as a solid (0.09 g, 45%), mp
175e176 ꢀC (EtOH); Rf (30% ethyl acetate/hexane) 0.57; nmax (neat)
1557, 1559 cmꢁ1
; dH (300 MHz, CDCl3) 1.95 (s, 3H), 7.01 (s, 1H), 7.20
(t, J 7.5 Hz, 1H), 7.34 (d, J 9.0 Hz, 1H), 7.47e7.62 (m, 10H), 8.20 (d, J
7.5 Hz, 1H); dC (75 MHz, CDCl3) 12.6, 113.6, 117.4, 119.7, 120.6, 125.1,
126.6, 127.3, 128.1, 128.8, 128.9, 129.6, 129.8, 130.1, 130.6, 134.4,
139.6, 140.7, 144.2, 155.1; m/z 369 (100, MHþ); HRMS (ES): MHþ,
found 369.1168. C24H1835ClNþ2 requires 369.1159.
4.6.4. 4-(4-Methoxyphenyl)-3-methyl-1-phenyl-1H-pyrrano[3,2-c]
quinoline (7d). (0.11 g, 74%), mp 175e177 ꢀC (2-propanol); Rf (20%
ethyl acetate/hexane) 0.58; nmax (neat) 826, 1030, 1169, 1245, 1434,
1261, 1354, 1400, 1485, 1529, 1560, 1599, 3182, 3225 cmꢁ1
; dH
(300 MHz, CDCl3) 7.06 (d, J 7.8 Hz, 2H), 7.09 (t, J 7.5 Hz, 1H), 7.14 (s,
1H), 7.20e7.33 (m, 8H), 7.46e7.55 (m, 3H), 7.64 (dt, J 1.5 and 7.5 Hz,
1H), 7.70 (d, J 8.4 Hz, 1H), 8.04 (dd, J 1.5 and 7.5 Hz, 2H), 8.11 (d, J
8.4 Hz, 1H); dC (75 MHz, CDCl3) 85.1, 101.3, 104.9, 119.2, 120.3, 122.8,
123.2, 124.4, 125.2, 127.9, 128.3, 128.5, 128.8, 129.2, 129.5, 130.0,
130.3, 131.1, 140.3, 143.3, 147.9, 149.0, 160.1; m/z (100, MHþ) 397;
HRMS (ES): MHþ, found 397.1695. C29H21Nþ2 requires 397.1705.
1495, 1607 cmꢁ1
; dH (300 MHz, CDCl3) 1.97 (d, J 1.2 Hz, 3H), 3.89 (s,
3H), 6.99 (d, J 1.2 Hz, 1H), 7.04 (d, J 9.0 Hz, 2H), 7.17 (dt, J 1.5 and
7.8 Hz, 1H), 7.33 (td, J 0.6 and 8.4 Hz, 1H), 7.47e7.53 (m, 2H),
7.55e7.62 (m, 5H), 8.20 (dd, J 0.6 and 8.1 Hz, 1H); dC (75 MHz,
CDCl3) 12.6, 55.4, 113.3, 114.0, 117.4, 120.0, 120.6, 124.7, 126.4, 127.4,
128.7, 128.8, 129.7, 130.2, 130.5, 133.8, 135.4, 140.9, 144.4, 156.3,
159.8; m/z 365 (100, MHþ); HRMS (ES): MHþ, found 365.1660.
C25H21N2Oþ requires 365.1654.
4.5.3. 1,2,4-Triphenyl-1H-pyrrano[3,2-c]quinoline (5a). A mixture of
40a (0.08 g, 0.20 mmol), PdCl2(PPh3)2 (0.01 g, 0.01 mmol), CuI
(0.02 g, 0.01 mmol) and triethylamine (0.1 mL, 0.06 mmol) in di-
oxane/water (3:1, v/v; 20 mL) was treated as described for the
synthesis of systems 5. Work-up and column chromatography
afforded 5a as a solid (0.04 g, 55%).
Acknowledgements
The authors are grateful to the University of South Africa
(UNISA) and the National Research Foundation (RSA) for financial
assistance. Mr. L.G.L. thanks UNISA for allowing him to pursue this
work as part of his M.Sc. program.
4.6. Heteroannulation of 4-(N,N-allylphenylamino)-2-aryl-3-
iodoquinolines (3). Typical procedure
References and notes
4.6.1. 3-Methyl-1,4-diphenyl-1H-pyrrano[3,2-c]quinoline
(7a). A
mixture of 3a (0.20 g, 0.43 mmol), PdCl2(PPh3)2 (0.015 g,
0.022 mmol) and CuI (0.004 g, 0.0022 mmol) in dry DMF (20 mL) in
a three-necked flask equipped with a stirrer, condenser and rubber
septum was flushed with nitrogen gas for 20 min. Triethylamine
(0.24 mL, 1.72 mmol) was added to the flask via a syringe and the
mixture was flushed for additional 10 min. The mixture was heated
at reflux for 4 h under nitrogen atmosphere and then allowed to
cool. The cooled mixture was added to a beaker containing ice-cold
1. Abass, M. Heterocycles 2005, 65, 901e965 and references therein.
2. Mphahlele, M. J.; El-Nahas, A. M. J. Mol. Struct. 2004, 688, 129e136.
3. Mphahlele, M. J.; Mtshemla, V. J. Chem. Res. 2008, 437e440.
4. Mphahlele, M. J.; Mtshemla, V. J. Heterocycl. Chem. 2008, 45, 1343e1350.
5. Brown, T. H.; Ife, R. J.; Keeling, D. J.; Laing, S. M.; Leach, C. A.; Parsons, M. E.;
Price, C. A.; Reavill, D. R.; Wiggall, K. J. J. Med. Chem. 1990, 33, 527e533.
6. Marquez, V. E.; Crauston, J. W.; Ruddon, R. W.; Kier, L. B.; Burckhalter, T. H. J.
Med. Chem. 1972, 15, 36e39.
7. For review on the use of iodofunctionalized system in metal-catalyzed CeC
formation see: Kirsch, G.; Hesse, S.; Comel, A. Curr. Org. Synth. 2004, 1, 47e63.

6046
M.J. Mphahlele et al. / Tetrahedron 66 (2010) 6040e6046
8. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467e4470.
9. Sonogashira, K. J. Organomet. Chem. 2002, 653, 46e49.
10. Kang, S. K.; Park, S. S.; Kim, S. S. Tetrahedron Lett. 1999, 40, 4379e4382.
11. Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schmid, B.; Knochel, P. Tetrahedron
2003, 59, 1571e1587.
16. Layek, L.; Rao, A. V. D.; Gajare, V.; Kalita, D.; Barange, D. P.; Islam, A.; Mokkanti,
K.; Pal, M. Tetrahedron Lett. 2009, 50, 4878e4881.
17. Larock, R. C.; Babu, S. Tetrahedron Lett.1987, 28, 5291e5294 and references therein.
18. Weinrich, M. L.; Beck, H. P. Tetrahedron Lett. 2009, 50, 6968e6972.
19. Kaim, L. E.; Gizzi, M.; Grimaud, L. Org. Lett. 2008, 10, 3417e3419.
20. Choi, J.-K.; Yum, E.K.; Kim, S.S.; Kang, S.K.; Cheon, H.G.; Kim, H.J. PCT Int. Appl.
WO 2000001696 A1 20000113, 2000.
12. Colacino, E.; Benakki, H.; Gunoum, F.; Martinez, J.; Lamaty, F. Synth. Commun.
2009, 39, 1583e1591.
13. Pal, M.; Subramanian, V.; Batchu, V. R.; Dager, I. Synlett 2004, 1965e1969.
14. Subramanian, V.; Batchu, V. R.; Barange, D.; Pal, M. J. Org. Chem. 2005, 70,
4778e4783.
15. Venkataraman, S.; Barange, D. K.; Pal, M. Tetrahedron Lett. 2006, 47,
7317e7322.
21. Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
581e590.
22. Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174e238.
23. Palacios, F.; Ochoa de Retana, A. M.; Oyarzabal, J. Tetrahedron 1999, 55,
5947e5964 and references cited therein.