Suzuki-Miyaura cross-coupling reaction as the key step for the synthesis of some new 4′-aryl and alkyl substituted analogues of?amodiaquine and amopyroquine

Article abstract of DOI:10.1016/j.tet.2007.08.115

A versatile methodology for the synthesis of some new 4-aminoquinoquinoline antimalarial drugs, using Csp²-Csp² and Csp²-Csp³ Suzuki-Miyaura cross-coupling reactions as a key step, is presented. The proposed str

Full text of DOI:10.1016/j.tet.2007.08.115

Tetrahedron 63 (2007) 12791–12810
Suzuki–Miyaura cross-coupling reaction as the key step for the
synthesis of some new 40-aryl and alkyl substituted analogues
of amodiaquine and amopyroquine
y
z
*
Emilia Paunescu, Nicolas Matuszak and Patricia Melnyk
´
´
´
‘Chimie et Micronanotechnologies aꢀ Visee Therapeutique’, UMR CNRS 8161—Universites de Lille 1 et Lille 2—Institut
Pasteur de Lille, 1 rue du Professeur Calmette, B.P. 447, 59021 Lille Cedex, France
Received 13 July 2007; revised 31 August 2007; accepted 31 August 2007
Available online 6 September 2007
Abstract—A versatile methodology for the synthesis of some new 4-aminoquinoquinoline antimalarial drugs, using Csp2–Csp2 and Csp2–
Csp3 Suzuki–Miyaura cross-coupling reactions as a key step, is presented. The proposed strategy allowed the synthesis of 26 new amodiaquine
(AQ) and amopyroquine (ApQ) derivatives. These new compounds constitute the base of the development of a new library, designed in order
to obtain derivatives that present not only improved antimalarial activity, but also a better stability towards bioactivation in potentially toxic
metabolites.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
CQ-resistant strains. Though resistance to AQ is also devel-
oping, last WHO’s guidelines for treatment still recommend
the use of this drug in combination with other antimalarial
drugs.1 However, its hepatotoxicity, explained by the pre-
sence of the 4-hydroxyanilino moiety, which is believed to
undergo extensive metabolization to a quinonimine variant,
has limited its use in prophylaxis (Fig. 2). Moreover, meta-
bolic stability of AQ could be increased by the replacement
of the diethylamino group in the side chain by a pyrrolidine
moiety providing amopyroquine (ApQ) analogue, which is
more active than AQ against CQ-resistant strains P. falcipa-
rum. With the aim of diminishing the toxicity, great effort
has been made for the preparation of various AQ analogues.2
Among them, compounds bearing alkyl or aryl substituent in
Malaria is considered as one of the most widespread diseases
in the world with almost one-half of the world’s population
exposed to risk of infection and two million deaths each
year.1 Chloroquine (CQ, Fig. 1), a 4-aminoquinoline com-
pound, has been the mainstream drug in the fight against
Plasmodium falciparum since 1950s, but its efficacy was
eroded by the emergence of resistant parasites. The develop-
ment of new drugs that overcome the parasite resistance
mechanism is thus an important issue.
Amodiaquine (AQ, Fig. 1), another 4-aminoquinoline drug,
maintains an important antimalarial activity against many
R3
OH
N
HN
HN
NR1R2
Cl
Amodiaquine (AQ): NR1R2 = NEt2 - R3 = H
N
Cl
N
Chloroquine (CQ)
Amopyroquine (ApQ): NR1R2 = pyrrolidine - R3 = H
Tebuquine (TBQ): NR1R2 = NH-tBu - R3 = p-chlorophenyl
Figure 1. Structure of chloroquine, amodiaquine, and analogues.
* Corresponding author. Tel.: +33 3 20 87 12 19; fax: +33 3 20 87 12 33; e-mail: patricia.melnyk@ibl.fr
Present address: Organic Chemistry Department, ‘Babes-Bolyai’ University, Faculty of Chemistry and Chemical Engineering, 11 Arany Janos Str.,
y
RO-400028, Cluj-Napoca, Romania.
Present address: Drug Design and Discovery Center, CMFA, Universite Catholique de Louvain, Bruxelles, Belgium.
z
ꢁ
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.115

12792
E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
OH
O
N
N
HN
N
N
P450 [O]
Binding to cellular
proteins
HEPATOTOXICITY
Cl
Cl
N
amodiaquine quinon-imine
Figure 2. Metabolization of AQ through oxidative pathway.
50-position, as tebuquine (TBQ), presented increased
activity upon CQ-resistant strains. 4-Aminoquinoline anti-
malarials are believed to exert their activity by inhibiting
hemozoin formation in the food vacuole, which is a crucial
heme detoxification process of the parasite.3
Because of the lower reactivity of alkylboronic acids, tri-
alkylboranes,8 alkylboronates, or alkylboronic acid esters9
are preferred as partners. The development and use of more
active catalytic systems, such as oxime-derived pallada-
cycles,10 or of ligands, i.e., ferrocenyldialkylphosphines,11
Tedicyp (cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinome-
thyl)cyclopentane)12 or i-Pr (N,N-bis-(2,6-diisopropylphe-
nyl)dihydroimidazolium chloride or tetrafluoroborate),13
allowed the realization of the Csp2–Csp3 cross-coupling
reactions using alkylboronic acids in good yields and even
with low catalyst loading.14
We describe here the synthesis of some novel AQ and ApQ
analogues in which the 40-hydroxyl function was replaced
with various aliphatic or aromatic groups (Fig. 3). We
hypothesize that the introduction of these substituents may
enhance interaction with heme via p–p stacking, thus inhib-
iting the formation of hemozoin. As low-cost preparation
and easy accessibility were the main criteria for the design
of new antimalarial compounds, we were interested in devel-
oping an efficient synthesis of aminoquinoline-biphenyl or
aminoquinoline-phenyl-alkyl moiety.
2. Results and discussion
Retrosynthetic analysis of the target compounds suggested
that aryl and alkyl R0 substituents could be introduced by
Suzuki–Miyaura cross-coupling reactions using bromides
1 and 2 as substrates (Scheme 1), allowing the convergent
introduction of the structural diversity in the last step. These
intermediates 1 and 2 were expected to be constructed from
nitro compounds 3 and 4 after reduction of the nitro function
and aromatic nucleophilic substitution with 4,7-dichloroqui-
noline. The aminomethylene side chain could be introduced
on the commercially available bromonitrobenzene. As we
anticipated that the reactivity of arylbromides 1 and 2 could
not be sufficient to obtain good yields, the synthetic steps
could be reversed and the target compounds could be also
obtained by performing Suzuki cross-coupling reaction on
bromo intermediates 3 and 4, followed by nitro reduction
and aromatic nucleophilic substitution.
R'
HN
NR2
Cl
N
R' = alkyl, aryl, heteroaryl
NR2 = NEt2 or pyrrolidine
Figure 3. Structure of target compounds.
Palladium-catalyzed cross-coupling of aryl halides with or-
ganoboronic acids, namely Suzuki–Miyaura cross-coupling
reaction, is a useful reaction for the formation of carbon–
carbon bonds, in particular for the synthesis of biaryls.4
Aryl–aryl bond in tebuquine was built using this cross-
coupling reaction.5 Usually, aromatic iodides or bromides
are involved in the coupling. Recently, efforts have been
focused on the development of efficient and selective cata-
lytic systems for Suzuki–Miyaura reaction allowing the use
of aryl chlorides.6
Thus, the first step was the synthesis of the key intermediates
3 and 4 (Scheme 2). The amino side chain was introduced
via a super-electrophilic Tscherniac amidomethylation of
the commercially available 4-bromonitrobenzene with N-
hydroxymethylphthalimide in trifluoromethanesulfonic
acid. The synthesis was performed according to Olah
et al.15 As the substrate was deactivated by the presence of
strong electron-withdrawing halogeno and nitro groups,
the use of a super acid (trifluoromethanesulfonic acid) as cat-
alyst and solvent was necessary. Bromo derivative of 2 equiv
was used in order to avoid the disubstitution side reaction.
The synthetic application of Suzuki–Miyaura cross-coupling
has been also extended to the formation of Csp2–Csp3 or
Csp3–Csp3 bonds.7
R'
Suzuki
Cl
Br
Br
Br
HN
N
HN
N
O2N
O2N
NR2
NR2
NR2
Cl
1 NR2 = NEt2
3 NR2 = NEt2
2 NR2 = pyrrolidine
4 NR2 = pyrrolidine
Scheme 1. Retrosynthetic scheme proposed for the obtainment of the 40-alkyl, aryl, and heteroaryl AQ and ApQ analogues.

E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
12793
Br
Conditions of assay 9 provided the best results and were
further applied for the synthesis of the other target aryl com-
pounds using derivatives 1 and 2 as substrates and various
arylboronic acids. Results are presented in Table 2.
N
c
Br
Br
Br
O
a
b
3
N
NH2
NO2
Br
O
5
d
Unfortunately, only moderate yields were obtained. Parallel
experiments conducted on the bromo derivative 1 (possess-
ing a diethylaminomethyl side chain) provided even lower
yields of the coupled products. The substrates presented
incomplete conversion, and the unreacted bromo derivatives
raised important problems in the purification of the coupled
products. Some degradation of the reaction media was
observed in the case of the reactions conducted with sub-
strate 2 with para-acetylbenzene, 2-thiophene, and 2-furane-
boronic acids. Moreover, the conditions were completely
unsuccessful with alkylboronic acids. We could isolate the
expected 40-ethyl derivatives with low yields but with differ-
ent conditions of solvent, base, temperature, and quantities
of catalytic system (entry 12, Table 2). 40-Methyl derivatives
could not be obtained in those conditions.
NO2
NO2
NO2
N
6
4
NO2
Scheme 2. Synthesis of key intermediates 3 and 4. Reagents: (a) N-hydroxy-
methylphthalimide, CF3SO3H, rt, 24 h; (b) hydrazine hydrate, CH3CN,
reflux, 24 h; (c) ethylbromide, NaOH, CH3CN, 40 ꢀC, 48 h; (d) 1,4-dibro-
mobutane, K2CO3, CH3CN, reflux, 48 h.
Hydrazinolysis of compound 5 with hydrazine hydrate pro-
vided benzylamine 6, which was further reacted with the
appropriate bromide derivatives via nucleophilic substitution
reactions to yield compound 3 or 4.
Reduction of the bromo intermediates 3 and 4 with tin chlo-
ride in acidic media and regioselective nucleophilic aromatic
substitution of the chlorine atom in position 4 of the 4,7-
dichloroquinoline by the aniline compounds 7 and 8
(Scheme 3) allowed the synthesis of derivatives 1 and 2 in
good yields. The yield of the last step was considerably
enhanced by the use of 1 equiv of HCl. By protonating quino-
line nitrogen, the electrophilicity of carbon atom in position 4
of the quinoline nucleus was increased.
Low yields and difficulties encountered in the purification of
the coupling product (observed in the preliminary optimiza-
tion study) lead us to reconsider and develop alternative
synthetic pathway in which Suzuki–Miyaura cross-coupling
reaction was performed on the more reactive bromo sub-
strates 3 and 4, activated by the presence of an electron-
withdrawing nitro group in para position (Scheme 4).
A rapid optimization process run with compound 4 showed
that the experimental conditions used with compound 2
could be also successfully applied in this case. Results of
the obtained coupled intermediates 11a–m and 12a–m are
presented in Table 3.
The ability of derivative 2 to act as a substrate in Suzuki–
Miyaura cross-coupling reactions was further explored. First
a preliminary study was realized using derivative 2 and phe-
nylboronic acid in order to optimize the reaction conditions
(Table 1). Several catalytic systems were studied. No evolu-
tion was observed when N,N-bis-(2,6-diisopropylphenyl)di-
hydroimidazolium tetrafluoroborate (i-Pr$HBF4) was used.
The role of the solvent was also evaluated together with
the importance of additional compounds.
In this case, analogues of both the series (with a diethylamino
group and a pyrrolidine cycle) were obtained in moderate to
good yields by the cross-coupling reaction of intermediates 3
Br
R'
Br
Br
NR2
NR2
HN
HN
a
b
c
NR2
NR2
NH2
NO2
Cl
N
Cl
N
3 NR2 = NEt2
4 NR2 = pyrrolidine
7 NR2 = NEt2
8 NR2 = pyrrolidine
1 NR2 = NEt2
2 NR2 = pyrrolidine
9a-m NR2 = NEt2
10a-m NR2 = pyrrolidine
Scheme 3. Synthesis of target compounds via Suzuki cross-coupling reaction of intermediates 1 and 2. Reagents: (a) SnCl2, 1 M HCl, THF, reflux; (b) 4,7-
dichloroquinoline, HCl, CH3CN, reflux; (c) R0–B(OH)2, Pd(OAc)2, P(o-tol)3, TBAB, Na2CO3, toluene, EtOH, 60 ꢀC.
Table 1. Optimization of cross-coupling reaction of bromo derivative 2 with phenylboronic acid
Assay Catalytic system (equiv)
Base (equiv) Additive (equiv) Solvent
Temp (ꢀC) Reaction time (h) Yield (%)
1
2
3
4
5
6
7
8
Pd(PPh3)4 (0.075)
Pd(PPh3)4 (0.1)
Pd(PPh3)4 (0.075)
Pd(PPh3)4 (0.075)
PPh3 (0.1), Pd(OAc)2 (0.05)
P(o-tol)3 (0.1), Pd(OAc)2 (0.05)
P(o-tol)3 (0.15), Pd(OAc)2 (0.075) Na2CO3 (2)
P(o-tol)3 (0.15), Pd(OAc)2 (0.075) Na2CO3 (2)
Na2CO3 (1)
Na2CO3 (1)
Na2CO3 (2)
Cs2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
—
Toluene/EtOH/H2O, 3/2/1
Toluene/EtOH/H2O, 3/2/1
1,4-Dioxane/EtOH/H2O, 3/2/1 78
Toluene/EtOH/H2O, 3/2/1
Toluene/EtOH/H2O, 3/2/1
Toluene/EtOH/H2O, 3/2/1
Toluene/EtOH/H2O, 3/2/1
Toluene/EtOH/H2O, 3/2/1
Toluene/EtOH/H2O, 3/2/1
1,4-Dioxane
78
60
24
52
36
30
2
18
26
46
42
24
48
34
29
30
31
31
17
35
40
42
—
—
78
65
65
60
50
60
80
65
—
—
—
—
9
10
11
P(o-tol)3 (0.15), Pd(OAc)2 (0.075) Na2CO3 (2) TBAB (0.2)
i-Pr$HBF4 (0.05), Pd(OAc)2 (0.05) Cs2CO3 (2)
i-Pr$HBF4 (0.05), Pd(OAc)2 (0.05) Cs2CO3 (2)
—
—
1,4-Dioxane

12794
Table 2. Suzuki cross-coupling reaction of intermediate 2a
Assay Compd R0
Reaction Yield HPLC
E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
Table 3. Suzuki cross-coupling reactiona of intermediates 3 and 4
Compd R0
NR2
Reaction Yield HPLC
time (h) (%) purity (%)
time (h)
(%)
purity (%)
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10e
10f
10g
10h
10i
C6H5–
42
72
40
72
40
24
48
140
140
168
144
144
40
36
22
43
65
9
11
12
8
95
92
88
90
97
72
99
96
97
—
—
95
11a
12a
C6H5–
NEt2
40
43
75
95
95
p-CH3–C6H4–
p-(t-Bu)–C6H4–
p-CF3–C6H4–
p-CH3O–C6H4–
p-CH3CO–C6H4–
p-F–C6H4–
2-Thienyl–
2-Furyl–
Pyrrolidine 40
NEt2 16
Pyrrolidine 16
NEt2 40
Pyrrolidine 16
NEt2 40
Pyrrolidine 16
NEt2 120
Pyrrolidine 120
p-CH3CO–C6H4– NEt2 40
Pyrrolidine 40
NEt2 48
Pyrrolidine 48
NEt2 120
Pyrrolidine 140
NEt2 120
Pyrrolidine 140
NEt2 54
Pyrrolidine 310
NEt2 16
Pyrrolidine 16
NEt2 310
Pyrrolidine 170
NEt2 310
Pyrrolidine 240
11b
12b
p-CH3–C6H4–
p-(t-Bu)–C6H4–
p-CF3–C6H4–
p-CH3O–C6H4–
78
71
99
97
11c
12c
54
84
99
98
11d
12d
60
66
98
98
9
10
11
12
10l
10m
10m
Me
Et
Et
—
—
16b
11e
12e
45
59
99
98
a
R0–B(OH)2, Pd(OAc)2 7.5 mol %, P(o-tol)3 15 mol %, TBAB 20 mol %,
Na2CO3 2 equiv, toluene, EtOH, 60 ꢀC.
Pd(OAc)2 15 mol %, P(o-tol)3 30 mol %, K2CO3 2 equiv, THF, H2O, 70 ꢀC.
11f
12f
39
70
98
97
b
11g
12g
p-F–C6H4–
2-Thienyl–
2-Furyl–
o-F–C6H4–
p-Cl–C6H4–
Meb
34
38
97
99
and 4 with a series of aryl and heteroarylboronic acids. An
improvement of yields was observed in the case of reactions
run with benzeneboronic acids substituted in para position
with hydrophobic groups. Also, in most cases, better results
were obtained when cross-coupling reactions were con-
ducted on substrate 4, with a pyrrolydinylmethyl side chain.
The presence of carbonyl (entry f, Table 3) and ether groups
(entry e, Table 3) in para position of the arylboronic acid was
well tolerated.
11h
12h
15
43
96
97
11i
12i
16
40
98
97
11j
12j
16
0
99
—
11k
12k
64
58
98
98
11l
12l
68
73
98
>99
The system seemed to be more sensitive to the presence of
ortho groups on the boronic acid. This effect may be due
to the fact that the bromo partner is also substituted in ortho
position and thus steric hindrance at the reaction center is
favored. Thus, in the case of the cross-coupling reaction re-
alized on substrate 3 the coupled product was isolated with
a very low yield, whereas in the case of the reaction realized
on substrate 4 the coupled product was not obtained (entry l,
Table 3).
11m
12m
Etb
68
48
93
94
a
R0–B(OH)2, Pd(OAc)2 7.5 mol %, P(o-tol)3 15 mol %, TBAB 20 mol %,
Na2CO3 2 equiv, toluene, H2O, EtOH, 60 ꢀC.
Experimental conditions for alkylboronic acids: THF/H2O, 10/1 as
solvent; K2CO3 as base; 75 ꢀC.
b
may act as a hydrogen donor, and the formation of a hetero-
aromatic cycle may favor this side reaction.16–19
The important side reaction observed in some cases is the
debromination of starting material as shown by the isolation
of 5–10% yields of (5-nitro-benzyl)-diethylamine or 1-(5-
nitro-benzyl)-pyrrolidine, reducing thus the conversion of
substrates 3 and 4 into the desired coupled product. In the
cross-coupling reactions with the heteroaromatic boronic
acids the conversion of the brominated substrates in the
coupled products was lower, probably because of the lower
reactivity and thermal stability of these boronic acids.
This reaction proved to be time dependant as the pyrrole
coupled derivative become predominant if the reaction is
continued for further 24 h (Table 4).
This strategy could be also applied for Csp2–Csp3 cross-
coupling of substrates 3 and 4 with methyl and ethylboronic
acids, which lead to the expected coupled compounds with
good yields around 70%. Nevertheless different experimen-
tal conditions appeared necessary in that case.
In the case of some analogues with a pyrrolidine in the amino
side chain, a side reaction of dehydrogenation of the pyrro-
lidine cycle to pyrrole was also observed. As a possible
explanation, we suspect that in the reaction conditions
used (oxidant character of the medium) the pyrrolidine cycle
Intermediates 11a–m and 12a–m were subjected to a two-step
reaction sequence (Scheme 4), consisting in the reduction of
the nitro group and the substitution of the chlorine atom in
the 4-position of the 4,7-dichloroquinoline with aniline
R'
Br
R'
R'
NR2
NR2
NR2
HN
b
a
c
NR2
NO2
NO2
NH2
13a-m NR2 = NEt2
Cl
N
11a-m NR2 = NEt2
12a-m NR2 = pyrrolidine
9a-m NR2 = NEt2
3 NR2 = NEt2
4 NR2 = pyrrolidine
14a-m NR2 = pyrrolidine
10a-m NR2 = pyrrolidine
Scheme 4. Synthesis of target compounds via Suzuki cross-coupling reaction of aromatic bromides 3 and 4. Reagents: (a) R0–B(OH)2, Pd(OAc)2, P(o-tol)3,
TBAB, Na2CO3, toluene, EtOH, 60 ꢀC; (b) SnCl2, HCl, THF, reflux; (c) 4,7-dichloroquinoline, HCl, acetonitrile, reflux.

E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
12795
Table 4. Dehydrogenation of pyrrolidine amino side chain during Suzuki cross-coupling reaction of intermediates 4
Ar
Ar
Br
Pd(OAc)2, P(o-tol)3
N
TBAB
N
N
+
+
Ar B(OH)2
60 °C
toluène, EtOH
Na2CO3 aq
NO2
NO2
NO2
4
12b-d
12'b-d
Ar
Reaction time (h)
Yield of 12 (%)
Yield of 120 (%)
p-CH3–C6H4–
16
40
12b (78)
12b (22)
120b (—)
120b (12)
p-(t-Bu)–C6H4–
p-CF3–C6H4–
16
40
140
12c (84)
12c (22)
12c (—)
120c (—)
120c (29)
120c (63)
16
48
12d (66)
12d (6)
120d (2)
120d (53)
derivatives 13a–m and 14a–m, thus providing, respectively,
AQ (9a–m) and ApQ (10a–m) analogues with good yields.
(60F-254) using UV light as a visualizing agent and by
HPLC. Thick-layer chromatography (TLC) was performed
using silica gel from Merck, from which the compounds
were extracted using the following solvent system: DCM/
Figure 4 compares the global yields by the two synthetic
pathways according to Scheme 3 or 4. In most of the cases,
global yields of the desired products are better if the cross-
coupling reaction is conducted on the bromo para-nitro
substituted intermediate 4 (Scheme 4), instead of the quino-
line bromo derivative 2 (Scheme 3).
MeOH/NH4OH, 8/2/0.2. All melting points were determined
1
€
on a Buchi melting point apparatus and are uncorrected. H
and 13C NMR spectra were obtained using a Bruker
300 MHz spectrometer and chemical shifts (d) were ex-
pressed in parts per million relative to TMS used as an inter-
nal standard. Mass spectra were recorded on a MALDI-TOF
Voyager-DE-STR spectrometer. The purity of final com-
pounds was verified by two types of high-pressure liquid
chromatographic (HPLC) columns: C18 Deltapak (C18N)
and C4 Interchrom UP5WC4-25QS (C4). Analytical HPLC
was performed on a Shimadzu system equipped with an
UV detector set at 254 nm. Compounds were dissolved in
CH3CN/H2O/TFA, 80/20/0.05 and injected through a
50 mL loop. The following eluent systems were used: A
(H2O/TFA, 100/0.05) and B (CH3CN/H2O/TFA, 80/20/
0.05). HPLC retention times (HPLC tR) were obtained, at
flow rates of 1 mL/min, using the following conditions: for
the 10 min method: a gradient run from 100% eluent A
for 30 s, then to 100% eluent B over the next 8 min and for
the 40 min method: a gradient run from 100% eluent A for
1 min, then to 100% eluent B over the next 30 min. Reagents
were obtained from Acros, Aldrich, Lancaster, Novabiochem
and Avocado.
70
scheme 3
scheme 4
60
50
40
30
20
10
0
R' substituant
Figure 4. Global yields for the synthesis of target compounds starting from
bromonitro derivative 4.
3. Conclusion
The following abbreviations were used: EP (petroleum
ether), AcOEt (ethyl acetate), Hex (n-hexane), Cyh (cyclo-
hexane), DCM (dichloromethane), Quin (quinoline), Thio
(2-thiophene), Fur (2-furane), and Phthal (phthaloyl).
This study presents the synthesis of some new 40-substituted
aryl and alkyl AQ and ApQ analogues following a general
protocol, which allowed the introduction of the convenient
diversity using Suzuki–Miyaura cross-coupling reactions
between bromine activated intermediates and commercially
available boronic acids. These compounds will be further
evaluated for their antimalarial properties, cytotoxicity,
and ability to inhibit b-hematine formation.
4.2. 2-(2-Bromo-5-nitro-benzyl)-isoindole-1,3-dione 5
To a suspension of N-hydroxymethylphthalimide (2.0 g,
0.5 equiv) in trifluoromethanesulfonic acid (20 mL) at 0 ꢀC
was added 1-bromo-4-nitrobenzene (4.57 g, 22.6 mmol).
After stirring the mixture at room temperature overnight,
the reaction medium was added dropwise to cold water
(150 mL). A white solid precipitated. The aqueous layer
was extracted with DCM (3ꢁ100 mL). The organic layers
were then combined, dried over MgSO4, and the solvent
was evaporated. The residue was purified from excess 1-bro-
mo-4-nitrobenzene by flash chromatography (DCM) to yield
compound 5 as a white solid (3.43 g, 84% yield); Rf 0.7
4. Experimental
4.1. General
All the reactions were monitored by thin-layer chromato-
graphy carried out on 0.2 mm E. Merck silica gel plates

12796
E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
(DCM); mp¼158–159 ꢀC; HPLC (C18—10 min) PHPLC
73% yield); Rf 0.6 (Cyh/AcOEt/NH4OH, 8/2/0.2); mp¼43–
1
99%, tR 6.07 min; 1H NMR (CDCl3) d 8.01 (1H, dd,
44 ꢀC; HPLC (C18—10 min) PHPLC 99%, tR 3.13 min; H
3
4
4
Ar–H4, J4,3¼8.4 Hz, J4,6¼2.7 Hz), 7.98 (1H, d, Ar–H6,
4J6,4¼2.7 Hz), 7.92–7.95 (2H, m, Phthal–H), 7.77–7.82
(3H, m, Ar–H3, Phthal–H), 5.02 (2H, s, CH2); 13C NMR
(CDCl3) d 134.5 (2C, Phthal), 133.9 (Ar–C3), 123.8 (2C,
Phthal), 123.6 (Ar–C4), 122.9 (Ar–C6), 41.5 (CH2).
NMR (CDCl3) d 8.38 (1H, d, Ar–H6, J6,4¼2.8 Hz), 7.95
3
4
(1H, dd, Ar–H4, J4,3¼8.7 Hz, J4,6¼2.8 Hz), 7.70 (1H, d,
3
Ar–H3, J3,4¼8.7 Hz), 3.78 (2H, s, CH2), 2.61–2.65 (4H,
m, N–CH2), 1.83–1.88 (4H, m, CH2); 13C NMR (CDCl3)
d 133.5 (Ar–C3), 125.0 (Ar–C6), 122.8 (Ar–C4), 59.3
(CH2), 54.3 (2C, N–CH2), 23.8 (2C, CH2); m/z 285.0–
287.0 [M+H]+.
4.3. 2-Bromo-5-nitro-benzylamine 6
To a suspension of compound 5 (1.68 g, 4.65 mmol) in
CH3CN (150 mL) was added hydrazine hydrate (1.14 mL,
5 equiv) and the mixture was stirred at reflux for 22 h. A
white solid precipitated. The reaction medium was cooled
to 0 ꢀC, filtered, and the filtrate was evaporated. The residue
was purified by TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to
yield the expected compound 6 as a yellow solid (0.83 g,
78% yield); Rf 0.9 (DCM/MeOH/NH4OH, 9.5/0.5/0.2); mp¼
63–64 ꢀC;HPLC(C18—10 min)PHPLC 99%, tR 2.80 min;1H
NMR (CDCl3) d 8.36(1H, d, Ar–H6, 4J6,4¼2.7 Hz), 7.98 (1H,
dd, Ar–H4, 3J4,3¼8.7 Hz, 4J4,6¼2.7 Hz), 7.66 (1H, d, Ar–H3,
3J3,4¼8.7 Hz), 4.02 (2H, s, CH2), 1.58 (2H, s large, NH2);
13C NMR (CDCl3) d 133.6 (Ar–C3), 123.4 (Ar–C6), 122.9
(Ar–C4), 46.3 (CH2); m/z 231.0–233.0 [M+H]+.
4.6. Reduction of nitro group: general procedure A
To a solution of nitro compound (1 equiv) in THF was added
a solution of tin chloride (4 equiv) in THF with 1 M HCl
(3 equiv). After stirring at reflux, the mixture was concen-
trated, alkalinized with NaHCO3 (pH 8), and the aqueous
layer was extracted with DCM (5ꢁ50 mL). The organic
layers were then combined, dried over MgSO4, the solvent
was evaporated, and the residue was purified by TLC.
4.7. Aromatic substitution of 4-Cl group: general
procedure B
To a solution of amine (1 equiv) in CH3CN was added
a solution of 4,7-dichloroquinoline (4,7-diClQuin) (1 equiv)
in CH3CN and 1 M HCl (1 equiv). After stirring at reflux, the
mixture was concentrated and purified by TLC to yield the
target compound.
4.4. (2-Bromo-5-nitro-benzyl)-diethyl-amine 3
To a solution of 2-bromo-5-nitro-benzylamine 6 (0.65 g,
2.82 mmol) in CH3CN (20 mL) was added NaOH (0.68 g,
6 equiv). After stirring the mixture at room temperature
for 20 min, ethyl bromide (10 mL) was added and stirring
was continued for 48 h at 40 ꢀC. At room temperature, inor-
ganic salts were filtered and the filtrate was evaporated. Sat-
urated aqueous solution of NaHCO3 (50 mL) was added and
the aqueous layer was extracted with DCM (5ꢁ50 mL). The
organic layers were then combined, dried over MgSO4, and
the solvent was evaporated. The residue was purified by
TLC (Hex/AcOEt/NH4OH, 9/1/0.2) to yield the expected
compound 3 as a yellow powder (0.57 g, 84% yield); Rf
0.7 (AcOEt/Cyh/NH4OH, 3/7/0.2); mp¼39–40 ꢀC; HPLC
(C18—10 min) PHPLC 99%, tR 3.35 min; 1H NMR
4.8. Suzuki coupling: general procedure C
To a suspension of bromide (1 equiv), boronic acid (2 equiv),
Pd(OAc)2 (7.5%), P(o-tol)3 (15%), and TBAB (20%) in tol-
uene (3 mL) was added 2 M aqueous solution of Na2CO3
(1 mL) and EtOH (2 mL) under inert atmosphere. The reac-
tion medium was heated to 65 ꢀC and the evolution of the
reaction was followed by TLC. The medium was evaporated,
solubilized with aq satd NaHCO3 (50 mL), and extracted
with DCM (5ꢁ50 mL). Combined organic layers were dried
over MgSO4, filtered, and concentrated. The residue was
purified by TLC to yield the expected compound.
4
(CDCl3) d 8.49 (1H, d, Ar–H6, J6,4¼2.7 Hz), 7.94 (1H,
3
4
dd, Ar–H4, J4,3¼8.7 Hz, J4,6¼2.7 Hz), 7.68 (1H, d, Ar–
4.9. Synthesis according to Scheme 3
3
H3, J3,4¼8.7 Hz), 3.67 (2H, s, CH2), 2.61 (4H, q, N–CH2,
3J¼7.1 Hz), 1.07 (6H, t, CH3, 3J¼7.1 Hz); 13C NMR
(CDCl3) d 133.2 (Ar–C3), 125.0 (Ar–C6), 122.5 (Ar–C4),
57.1 (CH2), 47.6 (2C, N–CH2), 12.1 (2C, CH3); m/z
287.1–289.1 [M+H]+.
4.9.1. 4-Bromo-3-diethylaminomethyl-phenylamine 7.
Synthesized from compound 3 (408 mg, 1.42 mmol) and
SnCl2 (1.077 g) in HCl (4.26 mL) and THF (25 mL) accord-
ing to general procedure A (reflux for 15 h). The residue was
purified by TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to
yield compound 7 as a yellow oil (254 mg, 69% yield); Rf
0.6 (DCM/MeOH/NH4OH, 9.5/0.5/0.2); HPLC (C18—10 min)
4.5. 1-(2-Bromo-5-nitro-benzyl)-pyrrolidine 4
1
To a solution of 2-bromo-5-nitro-benzylamine 6 (0.673 g,
2.91 mmol) in CH3CN (125 mL) was added K2CO3
(2.01 g, 5 equiv). After stirring the mixture at room temper-
ature for 20 min, 1,4-dibromobutane (0.52 mL, 1.5 equiv)
was added and stirring was continued for 48 h at reflux. At
room temperature, inorganic salts were filtered and the fil-
trate was evaporated. Saturated aqueous solution of NaHCO3
(50 mL) was added and the aqueous layer was extracted with
DCM (5ꢁ50 mL). The organic layers were then combined,
dried over MgSO4, and the solvent was evaporated. The res-
idue was purified by TLC (Hex/AcOEt/NH3, 8/2/0.2) to yield
the expected compound 4 as a yellow-orange powder (0.61 g,
PHPLC 98%, tR 2.80 min; H NMR (CDCl3) d 7.25 (1H, d,
Ar–H3, 3J3,4¼8.5 Hz), 6.97 (1H, d, Ar–H6, 4J6,4¼2.9 Hz), 6.44
(1H, dd, Ar–H0, 3J4,3¼8.5 Hz, 4J4,6¼2.9 Hz), 3.67 (2H, s large,
3
NH2), 3.60 (2H, s, CH2), 2.59 (4H, q, N–CH2, J¼7.1 Hz),
3
1.07 (6H, t, CH3, J¼7.1 Hz); 13C NMR (CDCl3) d 132.8
(Ar–C3), 116.9 (Ar–C6), 115.1 (Ar–C4), 56.8 (CH2), 47.1 (2C,
N–CH2), 11.7 (2C, CH3); m/z 257.2–259.2 [M+H]+.
4.9.2. 4-Bromo-3-pyrrolidin-1-ylmethyl-phenylamine 8.
Synthesized from compound 4 (503 mg, 1.76 mmol) and
SnCl2 (1.338 g) in HCl (5.29 mL) and THF (80 mL) accord-
ing to general procedure A (reflux for 6 h). The residue was

E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
12797
purified by TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to
yield compound 8 as a yellow solid (339 mg, 75% yield);
Rf 0.6 (DCM/MeOH/NH4OH, 9.5/0.5/0.2); mp¼57–58 ꢀC;
(16 mg), and TBAB (23 mg) according to general procedure
C (reflux for 40 h). The residue was purified by TLC (Cyh/
AcOEt/NH4OH, 9/1/0.2) to yield the expected compound
11a as a yellow oil (43 mg, 43% yield); Rf 0.5 (Cyh/
AcOEt/NH4OH, 9/1/0.2); HPLC (C18—10 min) PHPLC
95%, tR 4.29 min; 1H NMR (CDCl3) d 8.59 (1H, d, Ar–H6,
1
HPLC (C18—10 min) PHPLC 97%, tR 3.02 min; H NMR
3
(CDCl3) d 7.19 (1H, d, Ar–H3, J3,4¼8.5 Hz), 6.82 (1H, d,
4
3
Ar–H6, J6,4¼2.9 Hz), 6.38 (1H, dd, Ar–H4, J4,3¼8.5 Hz,
4J4,6¼2.9 Hz), 3.63 (2H, s, CH2), 2.58–2.64 (4H, m,
N–CH2), 1.70–1.82 (4H, m, CH2); 13C NMR (CDCl3)
d 133.1 (Ar–C3), 117.1 (Ar–C6), 115.4 (Ar–C4), 59.5 (CH2),
54.4 (2C, N–CH2), 23.7 (2C, CH2); m/z 255.1–257.1 [M+H]+.
3
4J6,4¼2.4 Hz), 8.10 (1H, dd, Ar–H4, J4,3¼8.4 Hz,
4J4,6¼2.4 Hz), 7.42–7.48 (3H, m, Ph), 7.35 (1H, d, Ar–H3,
3J3,4¼8.4 Hz), 7.29–7.33 (2H, m, Ph), 3.52 (2H, s, CH2),
2.44 (4H, q, N–CH2, 3J¼7.1 Hz), 0.93 (6H, t, CH3,
3J¼7.1 Hz); 13C NMR (CDCl3) d 130.6 (Ar–C3), 128.8
(2C, Ph), 128.2 (2C, Ph), 127.9 (Ph), 124.5 (Ar–C6), 121.1
(Ar–C4), 54.3 (CH2), 46.9 (2C, N–CH2), 11.8 (2C, CH3);
m/z 285.2 [M+H]+.
4.9.3. (4-Bromo-3-diethylaminomethyl-phenyl)-(7-chlo-
ro-quinolin-4-yl)-amine 1. Synthesized from compound 7
(242 mg, 0.94 mmol) and 4,7-diClQuin (186 mg) in HCl
(0.94 mL) and CH3CN (50 mL) according to general proce-
dure B (reflux for 7 h). The residue was purified by TLC
(DCM/MeOH/NH4OH, 9.5/0.5/0.2) to yield the expected
compound 1 as a white solid (344 mg, 88% yield); Rf 0.6
(DCM/MeOH/NH4OH, 9.5/0.5/0.2); mp¼176–177 ꢀC;
HPLC (C18—10 min) PHPLC 96%, tR 3.49 min; HPLC
(C18—40 min) PHPLC 94%, tR 14.91 min; HPLC (C4—
40 min) PHPLC >99%, tR 13.93 min; 1H NMR (CDCl3)
4.10.2. Diethyl-(40-methyl-4-nitro-biphenyl-2-ylmethyl)-
amine 11b. Synthesized from compound 3 (200 mg,
0.696 mmol), 4-methylphenylboronic acid (189 mg),
Pd(OAc)2 (12 mg), P(o-tol)3 (32 mg), and TBAB (45 mg)
according to general procedure C (reflux for 16 h). The
residue was purified by TLC (Cyh/AcOEt/NH4OH, 9/1/
0.2) to yield the expected compound 11b as a yellow solid
(161 mg, 78% yield); Rf 0.6 (Cyh/AcOEt/NH4OH, 9/1/
0.2); mp¼36–37 ꢀC; HPLC (C18—10 min) PHPLC 99%, tR
4.70 min; 1H NMR (CDCl3) d 8.60 (1H, d, Ar–H6,
3
d 8.53 (1H, d, Quin–H2, J2,3¼5.4 Hz), 8.00 (1H, d, Quin–
4
3
H8, J8,6¼2.1 Hz), 7.92 (1H, d, Quin–H5, J5,6¼9.0 Hz),
4
7.55 (1H, d, Ar–H6, J6,4¼2.7 Hz), 7.51 (1H, d, Ar–H3,
3J3,4¼8.4 Hz), 7.41 (1H, dd, Quin–H6, J6,5¼9.0 Hz,
4J6,4¼2.5 Hz), 8.06 (1H, dd, Ar–H4, J4,3¼8.4 Hz,
3
3
4J6,8¼2.1 Hz), 7.00–7.20 (1H, s large, NH), 7.05 (1H, dd,
Ar–H4, 3J4,3¼8.4 Hz, 4J4,6¼2.7 Hz), 6.95 (1H, d, Quin–H3,
3J3,2¼5.4 Hz), 3.64 (2H, s, CH2), 2.58 (4H, q, N–CH2,
3J¼7.2 Hz), 1.03 (6H, t, CH3, 3J¼7.2 Hz); 13C NMR
(CDCl3) d 152.0 (Quin–C2), 133.5 (Ar–C3), 129.0 (Quin–
C8), 126.3 (Quin–C6), 124.4 (Ar–C6), 122.1 (Ar–C4),
121.7 (Quin–C5), 102.8 (Quin–C3), 57.2 (CH2), 47.5 (2C,
N–CH2), 12.2 (2C, CH3); m/z 418.1–420.1 [M+H]+.
4J4,6¼2.5 Hz), 7.33 (1H, d, Ar–H3, J3,4¼8.4 Hz), 7.26
3
(2H, m, Ph), 7.19 (2H, m, Ph), 3.55 (2H, s, CH2), 2.45
(4H, q, N–CH2, J¼7.1 Hz), 2.42 (3H, s, N–CH3), 0.94
3
3
(6H, t, CH3, J¼7.1 Hz); 13C NMR (CDCl3) d 130.9 (Ar–
C3), 129.2 (2C, Ph), 129.0 (2C, Ph), 124.6 (Ar–C6), 121.4
(Ar–C4), 54.6 (CH2), 47.2 (2C, N–CH2), 21.4 (N–CH3),
12.1 (2C, CH3); m/z 299.2 [M+H]+.
4.10.3. (40-tert-Butyl-4-nitro-biphenyl-2-ylmethyl)-
diethyl-amine 11c. Synthesized from compound 3 (200 mg,
0.696 mmol), 4-tert-butylphenylboronic acid (248 mg),
Pd(OAc)2 (12 mg), P(o-tol)3 (32 mg), and TBAB (45 mg) ac-
cording to general procedure C (reflux for 40 h). The residue
was purified by TLC (Cyh/AcOEt/NH4OH, 9/1/0.2) to yield
the expected compound 11c as a white solid (129 mg, 54%
yield); Rf 0.7 (Cyh/AcOEt/NH4OH, 9/1/0.2); mp¼91–
4.9.4. (4-Bromo-3-pyrrolidin-1-ylmethyl-phenyl)-(7-
chloro-quinolin-4-yl)-amine 2. Synthesized from com-
pound 8 (429 mg, 1.29 mmol) and 4,7-diClQuin (256 mg)
in HCl (1.3 mL) and CH3CN (100 mL) according to general
procedure B (reflux overnight). The residue was purified by
TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to yield the ex-
pected compound 2 as a white solid (511 mg, 95% yield);
Rf 0.9 (DCM/MeOH/NH4OH, 9.5/0.5/0.2); mp¼155–
156 ꢀC; HPLC (C18—10 min) PHPLC 98%, tR 3.50 min;
HPLC (C18—40 min) PHPLC 98%, tR 14.80 min; HPLC
(C4—40 min) PHPLC 98%, tR 13.75 min; 1H NMR (MeOD)
1
92 ꢀC; HPLC (C18—10 min) PHPLC 99%, tR 5.68 min; H
4
NMR (CDCl3) d 8.59 (1H, d, Ar–H6, J6,4¼2.5 Hz), 8.09
3
4
(1H, dd, Ar–H4, J4,3¼8.4 Hz, J4,6¼2.5 Hz), 7.46 (2H, m,
3
3
Ph, J¼8.0 Hz), 7.35 (1H, d, Ar–H3, J3,4¼8.4 Hz), 7.23
(2H, m, Ph, 3J¼8.0 Hz), 3.55 (2H, s, CH2), 2.45 (4H, q, N–
CH2, 3J¼7.1 Hz), 1.38 (9H, s, t-Bu), 0.94 (6H, t, CH3,
3J¼7.1 Hz); 13C NMR (CDCl3) d 130.7 (Ar–C3), 128.5
(2C, Ph), 125.1 (2C, Ph), 124.4 (Ar–C6), 121.1 (Ar–C4),
54.3 (CH2), 47.0 (2C, N–CH2), 31.3 (3C, t-Bu), 11.9 (2C,
CH3); m/z 341.2 [M+H]+.
3
d 8.35 (1H, d, Quin–H2, J2,3¼5.5 Hz), 8.21 (1H, d, Quin–
3
4
H5, J5,6¼9.1 Hz), 7.81 (1H, d, Quin–H8, J8,6¼2.1 Hz),
3
7.56 (1H, d, Ar–H3, J3,4¼8.5 Hz), 7.45 (1H, dd, Quin–H6,
3J6,5¼9.1 Hz, J6,8¼2.2 Hz), 7.43 (1H, d, Ar–H6, J6,4
¼
4
4
3
4
2.7 Hz), 7.15 (1H, dd, Ar–H4, J4,3¼8.5 Hz, J4,6¼2.7 Hz),
3
6.92 (1H, d, Quin–H3, J3,2¼5.5 Hz), 3.74 (2H, s, CH2),
2.58–2.62 (4H, m, N–CH2), 1.74–1.79 (4H, m, CH2); 13C
NMR (MeOD) d 151.3 (Quin–C2), 133.5 (Ar–C3), 126.6
(Quin–C8), 125.7 (Quin–C6), 125.1 (Ar–C6), 123.5 (Quin–
C5), 123.2 (Ar–C4), 102.0 (Quin–C3), 59.3 (CH2), 53.9 (2C,
N–CH2), 23.0 (2C, CH2); m/z 416.2–418.2 [M+H]+.
4.10.4. Diethyl-(4-nitro-40-trifluoromethyl-biphenyl-2-yl-
methyl)-amine 11d. Synthesized from compound
3
(200 mg, 0.696 mmol), 4-(trifluoromethyl)-benzeneboronic
acid (265 mg), Pd(OAc)2 (12 mg), P(o-tol)3 (32 mg), and
TBAB (45 mg) according to general procedure C (reflux
for 40 h). The residue was purified by TLC (Cyh/AcOEt/
NH4OH, 9/1/0.2) to yield the expected compound 11d as
a white solid (148 mg, 60% yield); Rf 0.5 (Cyh/AcOEt/
NH4OH, 9/1/0.2); mp¼36–37 ꢀC; HPLC (C18—10 min)
4.10. Synthesis according to Scheme 4
4.10.1. Diethyl-(4-nitro-biphenyl-2-ylmethyl)-amine 11a.
Synthesized from compound 3 (100 mg, 0.348 mmol),
phenylboronic acid (85 mg), Pd(OAc)2 (6 mg), P(o-tol)3
1
PHPLC 98%, tR 5.09 min; H NMR (CDCl3) d 8.59 (1H, d,

12798
E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
4
3
3
Ar–H6, J6,4¼2.4 Hz), 8.14 (1H, dd, Ar–H4, J4,3¼8.3 Hz,
d, Ph, JCH,F¼21.3 Hz), 55.8 (CH2), 48.3 (2C, N–CH2),
4J4,6¼2.4 Hz), 7.71 (2H, d, Ph, J¼8.0 Hz), 7.45 (2H, d,
12.9 (2C, CH3); m/z 303.2 [M+H]+.
3
3
3
Ph, J¼8.0 Hz), 7.35 (1H, d, Ar–H3, J3,4¼8.3 Hz), 3.51
3
(2H, s, CH2), 2.45 (4H, q, N–CH2, J¼7.1 Hz), 0.93 (6H,
4.10.8. Diethyl-(4-nitro-40-thiophen-2-yl-biphenyl-2-yl-
methyl)-amine 11h. Synthesized from compound 3
3
t, CH3, J¼7.1 Hz); 13C NMR (CDCl3) d 130.8 (Ar–C3),
3
129.5 (2C, Ph), 125.5 (2C, d, Ph, JCH,F¼3.9 Hz), 125.0
(200 mg, 0.696 mmol), 2-thiopheneboronic acid (267 mg),
Pd(OAc)2 (18 mg), P(o-tol)3 (48 mg), and TBAB (45 mg)
according to general procedure C (reflux for 5 days). The
residue was purified by TLC (Cyh/AcOEt/NH4OH, 9/1/
0.2) to yield the expected compound 11h as an orange solid
(31 mg, 15% yield); Rf 0.5 (Cyh/AcOEt/NH4OH, 9/1/0.2);
mp¼40–41 ꢀC; HPLC (C18—10 min) PHPLC 96%, tR
4.27 min; 1H NMR (CDCl3) d 8.60 (1H, d, Ar–H6,
(Ar–C6), 121.8 (Ar–C4), 54.7 (CH2), 47.0 (2C, N–CH2),
11.8 (2C, CH3); m/z 353.1 [M+H]+.
4.10.5. Diethyl-(40-methoxy-4-nitro-biphenyl-2-yl-
methyl)-amine 11e. Synthesized from compound
3
(200 mg, 0.696 mmol), 4-methoxyphenylboronic acid
(318 mg), Pd(OAc)2 (18 mg), P(o-tol)3 (48 mg), and
TBAB (45 mg) according to general procedure C (reflux
for 5 days). The residue was purified by TLC (Cyh/AcOEt/
NH4OH, 9/1/0.2) to yield the expected compound 11e as
a white solid (98 mg, 45% yield); Rf 0.5 (Cyh/AcOEt/
NH4OH, 9/1/0.2); mp¼59–60 ꢀC; HPLC (C18—10 min)
4J6,4¼2.5 Hz), 8.09 (1H, dd, Ar–H4, J4,3¼8.5 Hz,
3
4J4,6¼2.5 Hz), 7.53 (1H, d, Ar–H3, J3,4¼8.5 Hz), 7.45
4
3
4
(1H, dd, Thio–H5, J5,4¼5.1 Hz, J5,3¼1.2 Hz), 7.21 (1H,
3
4
dd, Thio–H3, J3,4¼3.6 Hz, J3,5¼1.2 Hz), 7.14 (1H, dd,
3
3
Thio–H4, J4,3¼3.6 Hz, J4,5¼5.1 Hz), 3.74 (2H, s, CH2),
2.54 (4H, q, N–CH2, 3J¼7.1 Hz), 1.00 (6H, t, CH3,
3J¼7.1 Hz); 13C NMR (CDCl3) d 131.2 (Ar–C3), 128.3
(Thio–C3), 127.3 (Thio–C4), 127.0 (Thio–C5), 124.8 (Ar–
C6), 121.3 (Ar–C4), 54.7 (CH2), 46.7 (2C, N–CH2), 11.5
(2C, CH3); m/z 291.2 [M+H]+.
1
PHPLC 99%, tR 4.52 min; H NMR (CDCl3) d 8.59 (1H, d,
4
3
Ar–H6, J6,4¼2.5 Hz), 8.08 (1H, dd, Ar–H4, J4,3¼8.4 Hz,
4J4,6¼2.5 Hz), 7.35 (1H, d, Ar–H3, J3,4¼8.4 Hz), 7.25
3
(2H, m, Ph), 6.98 (2H, m, Ph), 3.87 (3H, s, O–CH3), 3.59
(2H, s, CH2), 2.48 (4H, q, N–CH2, J¼7.1 Hz), 0.96 (6H,
3
3
t, CH3, J¼7.1 Hz); 13C NMR (CDCl3) d 131.7 (Ar–C3),
131.1 (2C, Ph), 125.6 (Ar–C6), 122.3 (Ar–C4), 114.7 (2C,
Ph), 56.2 (O–CH3), 55.3 (CH2), 47.9 (2C, N–CH2), 12.6
(2C, CH3); m/z 315.3 [M+H]+.
4.10.9. Diethyl-(40-furan-2-yl-4-nitro-biphenyl-2-yl-
methyl)-amine 11i. Synthesized from compound
3
(200 mg, 0.696 mmol), 2-furaneboronic acid (195 mg),
Pd(OAc)2 (12 mg), P(o-tol)3 (32 mg), and TBAB (45 mg)
according to general procedure C (reflux for 5 days). The
residue was purified by TLC (Cyh/AcOEt/NH4OH, 9/1/
0.2) to yield the expected compound 11i as an yellow oil
(35 mg, 16% yield); Rf 0.4 (Cyh/AcOEt/NH4OH, 9/1/0.2);
4.10.6. 1-(20-Diethylaminomethyl-40-nitro-biphenyl-
4-yl)-ethanone 11f. Synthesized from compound
3
(200 mg, 0.696 mmol), 4-acetylphenylboronic acid (228 mg),
Pd(OAc)2 (12 mg), P(o-tol)3 (32 mg), and TBAB (45 mg)
according to general procedure C (reflux for 40 h). The resi-
due was purified by TLC (Cyh/AcOEt/NH4OH, 7/3/0.2) to
yield the expected compound 11f as a white solid (89 mg,
39% yield); Rf 0.5 (Cyh/AcOEt/NH4OH, 7/3/0.2); mp¼
96–97 ꢀC; HPLC (C18—10 min) PHPLC 98%, tR 4.16 min;
1
HPLC (C18—10 min) PHPLC 99%, tR 4.45 min; H NMR
(CDCl3) d 8.61 (1H, d, Ar–H6, J6,4¼2.5 Hz), 8.12 (1H,
4
dd, Ar–H4, 3J4,3¼8.4 Hz, 4J4,6¼2,5 Hz), 7.39–7.46 (1H, m,
3
40-CH), 7.35 (1H, d, 3-CH, J3,4¼8.4 Hz), 7.23–7.28 (2H,
m, 50-CH, 60-CH), 7.13–7.24 (1H, m, 30-CH), 3.47 (2H, s,
1H NMR (CDCl3) d 8.58 (1H, d, Ar–H6, J6,4¼2.4 Hz),
7-CH2), 2.42 (4H, qv, 2ꢁ9-CH2, J9,10¼7.1 Hz), 0.91
4
3
3
4
3
8.12 (1H, dd, Ar–H4, J4,3¼8.4 Hz, J4,6¼2.4 Hz), 8.06
(2H, m, Ph), 7.44 (2H, m, Ph), 7.37 (1H, d, Ar–H3,
4J3,4¼8.4 Hz), 3.51 (2H, s, CH2), 2.68 (3H, s, CO–CH3),
2.44 (4H, q, N–CH2, 3J¼7.2 Hz), 0.93 (4H, t, CH3,
3J¼7.2 Hz); 13C NMR (CDCl3) d 130.5 (Ar–C3), 129.3
(2C, Ph), 128.4 (2C, Ph), 124.7 (Ar–C6), 121.5 (Ar–C4),
54.7 (CH2), 46.9 (2C, N–CH2), 26.8 (CO–CH3), 11.9 (2C,
CH3); m/z 327.2 [M+H]+.
(6H, t, 2ꢁ10-CH3, J10,9¼7.1 Hz). 8.64 (1H, d, Ar–H6,
4J6,4¼2.5 Hz), 8.12 (1H, dd, Ar–H4, J4,3¼8.7 Hz, J4,6
¼
3
4
4
2.5 Hz), 7.81 (1H, d, Ar–H3, J3,4¼8.7 Hz), 7.60 (1H, dd,
3
4
Fur–H5, J5,4¼1.8 Hz, J5,3¼0.5 Hz), 6.84 (1H, dd, Fur–
3
4
H3, J3,4¼3.4 Hz, J3,5¼0.5 Hz), 6.57 (1H, dd, Fur–H4,
3J4,3¼3.4 Hz, J4,5¼1.8 Hz), 3.86 (2H, s, CH2), 2.63 (4H,
3
q, N–CH2, J¼7.1 Hz), 1.07 (6H, t, CH3, J¼7.1 Hz); 13C
NMR (CDCl3) d 143.8 (Fur–C5), 128.1 (Ar–C3), 125.4
(Ar–C6), 122.05 (Ar–C4), 112.6 (Fur–C3), 112.3 (Fur–C4),
55.7 (CH2), 47.4 (2C, N–CH2), 11.9 (2C, CH3); m/z 275.1
[M+H]+.
3
3
4.10.7. Diethyl-(40-fluoro-4-nitro-biphenyl-2-ylmethyl)-
amine 11g. Synthesized from compound 3 (200 mg,
0.696 mmol), 4-fluorophenylboronic acid (195 mg),
Pd(OAc)2 (12 mg), P(o-tol)3 (32 mg), and TBAB (45 mg)
according to general procedure C (reflux for 48 h). The resi-
due was purified by TLC (Cyh/AcOEt/NH4OH, 9/1/0.2) to
yield the expected compound 11g as a white solid (71 mg,
34% yield); Rf 0.5 (Cyh/AcOEt/NH4OH, 9/1/0.2);
mp¼42–43 ꢀC; HPLC (C18—10 min) PHPLC 97%, tR
4.48 min; 1H NMR (CDCl3) d 8.57 (1H, d, Ar–H6,
4.10.10. Diethyl-(20-fluoro-4-nitro-biphenyl-2-ylmethyl)-
amine 11j. Synthesized from compound 3 (200 mg,
0.696 mmol), 2-fluorophenylboronic acid (195 mg),
Pd(OAc)2 (12 mg), P(o-tol)3 (32 mg), and TBAB (45 mg) ac-
cording to general procedure C (reflux for 54 h). The residue
was purified by TLC (Cyh/AcOEt/NH4OH, 9/1/0.2) to yield
the expected compound 11g as a white solid (35 mg, 16%
yield); Rf 0.5 (Cyh/AcOEt/NH4OH, 9/1/0.2); mp¼42–
4J6,4¼2.7 Hz), 8.12 (1H, dd, Ar–H4, J4,3¼8.4 Hz,
3
4J4,6¼2.7 Hz), 7.35 (1H, d, Ar–H3, J3,4¼8.4 Hz), 7.30
43 ꢀC; HPLC (C18—10 min) PHPLC 97%, tR 4.48 min; H
3
1
4
(2H, m, Ph), 7.13 (2H, m, Ph), 3.56 (2H, s, CH2), 2.48
(4H, q, N–CH2, 3J¼6.9 Hz), 0.95 (6H, t, CH3, 3J¼6.9 Hz);
13C NMR (CDCl3) d 132.3 (Ar–C3), 132.1 (2C, Ph,
4JCH,F¼8.4 Hz), 126.3 (Ar–C6), 123.0 (Ar–C4), 116.8 (2C,
NMR (CDCl3) d 8.61 (1H, d, Ar–H6, J6,4¼2.5 Hz), 8.12
3
4
(1H, dd, Ar–H4, J4,3¼8.4 Hz, J4,6¼2,5 Hz), 7.39–7.46
3
(1H, m, Ph), 7.35 (1H, d, Ar–H3, J3,4¼8.4 Hz), 7.23–7.28
(2H, m, Ph), 7.13–7.24 (1H, m, Ph), 3.47 (2H, s, 7-CH2),

E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
12799
2.42 (4H, qv, 2ꢁ9-CH2, 3J9,10¼7.1 Hz), 0.91 (6H, t, 2ꢁ10-
3J3,4¼8.4 Hz), 3.60 (2H, s, CH2), 2.81 (2H, q, Ar–CH2,
3
3
3
CH3, J10,9¼7.1 Hz); 13C NMR (CDCl3) d 131.3 (Ar–C3),
J1 ,2 ¼7.5 Hz), 2.53 (4H, q, N–CH2, J¼7.5 Hz), 1.25 (3H,
0
0
4
131.1 (d, Ph–C6, J6,F¼2.6 Hz), 130.5 (d, Ph–C4,
t, CH3, 3J¼7.5 Hz), 1.05 (6H, t, CH3, 3J¼7.5 Hz); 13C
NMR (CDCl3) d 129.2 (Ar–C3), 124.4 (Ar–C6), 121.9
(Ar–C4), 57.9 (CH2), 47.2 (2C, N–CH2), 25.7 (Ar–CH2),
14.7 (N–CH3), 12.0 (2C, CH3); m/z 237.3 [M+H]+, 221.3
[M+H–O]+.
4J4,F¼8.1 Hz), 124.5 (Ph–C5), 124.4 (Ar–C6), 121.5 (Ar–
3
0
C4), 115.9 (d, Ph–C3, J3 ,F¼21.9 Hz), 54.5 (CH2), 47.3
(2C, N–CH2), 12.0 (2C, CH3); m/z 303.2 [M+H]+.
4.10.11. (40-Chloro-4-nitro-biphenyl-2-ylmethyl)-di-
ethyl-amine 11k. Synthesized from compound 3 (200 mg,
0.696 mmol), 4-chlorophenylboronic acid (218 mg),
Pd(OAc)2 (12 mg), P(o-tol)3 (32 mg), and TBAB (45 mg)
according to general procedure C (reflux for 16 h). The
residue was purified by TLC (Cyh/AcOEt/NH4OH, 9/1/
0.2) to yield the expected compound 11k as a yellow oil
(143 mg, 64% yield); Rf 0.7 (Cyh/AcOEt/NH4OH, 9/1/
4.10.14. 1-(4-Nitro-biphenyl-2-ylmethyl)-pyrrolidine
12a. Synthesized from compound 4 (150 mg, 0.526 mmol),
phenylboronic acid (128 mg), Pd(OAc)2 (9 mg), P(o-tol)3
(24 mg), and TBAB (34 mg) according to general procedure
C (reflux for 40 h). The residue was purified by TLC (Cyh/
AcOEt/NH4OH, 8/2/0.2) to yield the expected compound
12a as a white solid (111 mg, 75% yield); Rf 0.6 (Cyh/
AcOEt/NH4OH, 8/2/0.2); mp¼77 ꢀC; HPLC (C18—
1
0.2); HPLC (C18—10 min) PHPLC 98%, tR 4.68 min; H
NMR (CDCl3) d 8.56 (1H, d, Ar–H6, J6,4¼2.5 Hz), 8.09
4
1
10 min) PHPLC 94%, tR 4.49 min; H NMR (CDCl3) d 8.48
3
4
4
(1H, dd, Ar–H4, J4,3¼8.4 Hz, J4,6¼2.5 Hz), 7.43 (2H, m,
(1H, d, Ar–H6, J6,4¼2.4 Hz), 8.10 (1H, dd, Ar–H4,
3
4
Ph), 7.34 (1H, d, Ar–H3, J3,4¼8.4 Hz), 7.28 (2H, m, Ph),
3J4,3¼8.4 Hz, J4,6¼2.4 Hz), 7.35–7.48 (6H, m, Ar–H3,
3
3.53 (2H, s, CH2), 2.46 (4H, q, N–CH2, J¼7.1 Hz), 0.94
Ph), 3.61 (2H, s, CH2), 2.44–2.49 (4H, m, N–CH2), 1.70–
1.80 (4H, m, CH2); 13C NMR (CDCl3) d 130.8 (Ar–C3),
129.0 (2C, Ph), 128.3 (2C, Ph), 128.0 (Ph), 124.5 (Ar–C6),
121.4 (Ar–C4), 56.9 (CH2), 53.8 (2C, N–CH2), 23.6 (2C,
CH2); m/z 283.2 [M+H]+.
(6H, t, CH3, 3J¼7.1 Hz); 13C NMR (CDCl3) d 131.5
(Ar–C3), 131.1 (2C, Ph), 129.3 (2C, Ph), 125.5 (Ar–C6),
122.2 (Ar–C4), 55.3 (CH2), 47.7 (2C, N–CH2), 12.5 (2C,
CH3); m/z 319.2–321.2 [M+H]+.
4.10.12. Diethyl-(2-methyl-5-nitro-benzyl)-amine 11l. To
a suspension of compound 3 (200 mg, 0.697 mmol), methyl-
boronic acid (84 mg, 1.5 equiv), Pd(OAc)2 (24 mg,
0.15 equiv), P(o-tol)3 (63 mg, 0.3 equiv), and K2CO3
(289 mg, 3 equiv) in THF (5 mL) was added water
(0.5 mL) under inert atmosphere. The reaction medium
was heated to 75 ꢀC for 13 days. The medium was evapo-
rated, solubilized with aq satd NaHCO3 (50 mL), and ex-
tracted with DCM (5ꢁ50 mL). Combined organic layers
were dried over MgSO4, filtered, and concentrated. The res-
idue was purified by TLC (Cyh/AcOEt/NH4OH, 9/1/0.2) to
yield the expected compound 11l as a yellow oil (105 mg,
68% yield); Rf 0.5 (AcOEt/Cyh/NH4OH, 1/9/0.2); HPLC
(C18—10 min) PHPLC 98%, tR 3.34 min; 1H NMR (CDCl3)
4.10.15. 1-(40-Methyl-4-nitro-biphenyl-2-ylmethyl)-pyr-
rolidine 12b. Synthesized from compound 4 (200 mg,
0.701 mmol), 4-methylphenylboronic acid (191 mg),
Pd(OAc)2 (12 mg), P(o-tol)3 (32 mg), and TBAB (45 mg)
according to general procedure C (reflux for 16 h). The res-
idue was purified by TLC (Cyh/AcOEt/NH4OH, 9/1/0.2) to
yield the expected compound 12b as a white solid (149 mg,
71% yield); Rf 0.4 (Hex/AcOEt/NH4OH, 9/1/0.2); mp¼66–
1
67 ꢀC; HPLC (C18—10 min) PHPLC 97%, tR 4.84 min; H
4
NMR (CDCl3) d 8.47 (1H, d, Ar–H6, J6,4¼2.5 Hz), 8.11
3
4
(1H, dd, Ar–H4, J4,3¼8.4 Hz, J4,6¼2.5 Hz), 7.38 (1H, d,
3
Ar–H3, J3,4¼8.4 Hz), 7.23–7.29 (4H, m, Ph), 3.61 (2H, s,
CH2), 2.45–2.49 (4H, m, N–CH2), 2.39 (3H, s, CH3),
1.73–1.82 (4H, m, CH2); 13C NMR (CDCl3) d 130.9
(Ar–C3), 129.0 (4C, Ph), 124.6 (Ar–C6), 121.5 (Ar–C4),
57.0 (CH2), 53.9 (2C, N–CH2), 23.6 (2C, CH2), 21.3
(CH3); m/z 297.1 [M+H]+.
4
d 8.26 (1H, d, Ar–H6, J6,4¼2.7 Hz), 7.97 (1H, dd, Ar–H4,
4
3J4,3¼8.4 Hz, J4,6¼2.7 Hz), 7.26 (1H, d, Ar–H3,
3J3,4¼8.4 Hz), 3.56 (2H, s, CH2), 2.53 (4H, q, N–CH2,
3J¼7.2 Hz), 2.44 (3H, s, CH3), 1.04 (6H, t, CH3,
3J¼7.2 Hz); 13C NMR (CDCl3) d 130.9 (Ar–C3), 124.1
(Ar–C6), 121.7 (Ar–C4), 55.5 (CH2), 47.2 (2C, CH2), 19.6
(CH3), 12.0 (2C, CH3); m/z 223.2 [M+H]+, 207.2 [M+H–O]+.
4.10.16. 1-(40-Methyl-4-nitro-biphenyl-2-ylmethyl)-pyr-
role 120b. Isolated as a by-product (white solid, 12%); Rf
0.5 (Cyh/AcOEt/NH4OH, 9/1/0.2); mp¼98 ꢀC; HPLC
(C18—10 min) PHPLC 96%, tR 7.93 min; 1H NMR (CDCl3)
3
4
4.10.13. Diethyl-(2-ethyl-5-nitro-benzyl)-amine 11m. To
a suspension of compound 3 (200 mg, 0.697 mmol), ethyl-
boronic acid (99 mg, 1.5 equiv), Pd(OAc)2 (24 mg,
0.15 equiv), P(o-tol)3 (63 mg, 0.3 equiv), and K2CO3
(289 mg, 3 equiv) in THF (5 mL) was added water
(0.5 mL) under inert atmosphere. The reaction medium
was heated to 75 ꢀC for 13 days. The medium was evapo-
rated, solubilized with aq satd NaHCO3 (50 mL), and
extracted with DCM (5ꢁ50 mL). Combined organic layers
were dried over MgSO4, filtered, and concentrated. The resi-
due was purified by TLC (Cyh/AcOEt/NH4OH, 9/1/0.2) to
yield the expected compound 11m as a yellow oil (112 mg,
68% yield); Rf 0.6 (Cyh/AcOEt/NH4OH, 9/1/0.2);
d 8.15 (1H, dd, Ar–H4, J4,3¼8.4 Hz, J4,6¼2.3 Hz), 7.80
4
(1H, d, Ar–H6, J6,4¼2.3 Hz), 7.42 (1H, d, Ar–H3,
3
3J3,4¼8.4 Hz), 7.29 (2H, d, Ph, J¼8.0 Hz), 7.15 (2H, d,
3
Ph, J¼8.0 Hz), 6.53 (2H, m, Pyr–H2), 6.18 (2H, m, Pyr–
H3), 5.05 (2H, s, N–CH2), 2.44 (3H, s, CH3); 13C NMR
(CDCl3) d 131.1 (Ar–C3), 129.4 (2C, Ph), 128.4 (2C, Ph),
123.0 (Ar–C6), 122.4 (Ar–C4), 120.8 (2C, Pyr–C2), 109.1
(2C, Pyr–C2), 50.8 (CH2), 21.1 (CH3); m/z 293.2 [M+H]+.
4.10.17. 1-(40-tert-Butyl-4-nitro-biphenyl-2-ylmethyl)-
pyrrolidine 12c. Synthesized from compound 4 (200 mg,
0.701 mmol), 4-tert-butylphenylboronic acid (250 mg),
Pd(OAc)2 (12 mg), P(o-tol)3 (32 mg), and TBAB (45 mg)
according to general procedure C (reflux for 16 h). The resi-
due was purified by TLC (Hex/AcOEt/NH4OH, 9/1/0.2) to
yield the expected compound 12c as a white solid
1
HPLC (C18—10 min) PHPLC 93%, tR 3.82 min; H NMR
(CDCl3) d 8.31 (1H, d, Ar–H6, 4J6,4¼2.4 Hz), 8.01 (1H, dd,
3
4
Ar–H4, J4,3¼8.4 Hz, J4,6¼2.4 Hz), 7.30 (1H, d, Ar–H3,

12800
E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
(200 mg, 84% yield); Rf 0.4 (Hex/AcOEt/NH4OH, 9/1/0.2);
mp¼45–47 ꢀC; HPLC (C18—10 min) PHPLC 98%, tR
5.82 min; 1H NMR (CDCl3) d 8.48 (1H, d, Ar–H6,
residue was purified by TLC (Cyh/AcOEt/NH4OH, 9/1/
0.2) to yield the expected compound 12e as a yellow oil
(129 mg, 59% yield); Rf 0.4 (Cyh/AcOEt/NH4OH, 9/1/
3
1
4J6,4¼2.4 Hz), 8.11 (1H, dd, Ar–H4, J4,3¼8.5 Hz,
0.2); HPLC (C18—10 min) PHPLC 98%, tR 4.54 min; H
NMR (CDCl3) d 8.45 (1H, d, Ar–H6, J6,4¼2.5 Hz), 8.08
4J4,6¼2.4 Hz), 7.46 (2H, m, Ph), 7.39 (1H, d, Ar–H3,
3J3,4¼8.5 Hz), 7.31 (2H, m, Ph), 3.64 (2H, s, CH2), 2.47–
2.51 (4H, m, N–CH2), 1.74–1.82 (4H, m, CH2), 1.38 (9H,
s, t-Bu); 13C NMR (CDCl3) d 130.7 (Ar–C3), 128.6 (2C,
Ph), 125.0 (2C, Ph), 124.4 (Ar–C6), 121.3 (Ar–C4), 56.8
(CH2), 53.7 (2C, N–CH2), 31.2 (3C, t-Bu), 23.4 (2C,
CH2); m/z 339.2 [M+H]+.
4
3
4
(1H, dd, Ar–H4, J4,3¼8.4 Hz, J4,6¼2.5 Hz), 7.37 (1H, d,
3
Ar–H3, J3,4¼8.4 Hz), 7.34 (2H, m, Ph), 6.98 (2H, m, Ph),
3.86 (3H, s, O–CH3), 3.63 (2H, s, CH2), 2.47–2.51 (4H, m,
N–CH2), 1.71–1.81 (4H, m, CH2); 13C NMR (CDCl3)
d 130.9 (Ar–C3), 130.4 (2C, Ph), 124.7 (Ar–C6), 121.5
(Ar–C4), 113.7 (2C, Ph), 57.0 (CH2), 55.3 (O–CH3), 53.8
(2C, N–CH2), 23.6 (2C, CH2); m/z 313.3 [M+H]+.
4.10.18. 1-(40-tert-Butyl-4-nitro-biphenyl-2-ylmethyl)-
pyrrole 120c. Isolated as a by-product (yellow solid, 63%);
Rf 0.5 (Cyh/AcOEt/NH4OH, 9/1/0.2); mp¼137 ꢀC; HPLC
(C18—10 min) PHPLC 99%, tR 9.15 min; 1H NMR (CDCl3)
4.10.22. 1-(40-Nitro-20-pyrrolidin-1-ylmethyl-biphenyl-4-
yl)-ethanone 12f. Synthesized from compound 4 (200 mg,
0.701 mmol), 4-acetylphenylboronic acid (230 mg),
Pd(OAc)2 (12 mg), P(o-tol)3 (32 mg), and TBAB (45 mg)
according to general procedure C (reflux for 40 h). The res-
idue was purified twice by TLC (Cyh/AcOEt/NH4OH, 8/2/
0.2 and then Cyh/AcOEt/NH4OH, 7/3/0.2) to yield the
expected compound 12f as a yellow solid (158 mg, 70%
yield); Rf 0.3 (Cyh/AcOEt/NH4OH, 8/2/0.2); mp¼104–
105 ꢀC; HPLC (C18—10 min) PHPLC 97%, tR 4.27 min;
3
4
d 8.10 (1H, dd, Ar–H4, J4,3¼8.4 Hz, J4,6¼2.3 Hz), 7.75
4
(1H, d, Ar–H6, J6,4¼2.3 Hz), 7.49 (2H, m, Ph), 7.40 (1H,
3
d, Ar–H3, J3,4¼8.4 Hz), 7.21 (2H, m, Ph), 6.51 (2H, m,
Pyr–H2), 6.15 (2H, m, Pyr–H3), 5.05 (2H, s, N–CH2), 1.38
(9H, s, CH3); 13C NMR (CDCl3) d 131.4 (Ar–C3), 128.6
(2C, Ph), 125.9 (2C, Ph), 123.2 (Ar–C6), 122.7 (Ar–C4),
121.2 (2C, Pyr–C2), 109.4 (2C, Pyr–C3), 50.9 (CH2), 31.6
(CH3); m/z 335.4 [M+H]+.
4
1H NMR (CDCl3) d 8.46 (1H, d, Ar–H6, J6,4¼2.4 Hz),
3
4
8.14 (1H, dd, Ar–H4, J4,3¼8.4 Hz, J4,6¼2.4 Hz), 8.06
4.10.19. 1-(4-Nitro-40-trifluoromethyl-biphenyl-2-yl-
methyl)-pyrrolidine 12d. Synthesized from compound 4
(200 mg, 0.701 mmol), 4-trifluoromethylphenylboronic
acid (266 mg), Pd(OAc)2 (12 mg), P(o-tol)3 (32 mg), and
TBAB (45 mg) according to general procedure C (reflux
for 16 h). The residue was purified twice by TLC (Hex/
AcOEt/NH4OH, 8/2/0.2 and then Cyh/DCM/NH4OH, 3/7/
0.2) to yield the expected compound 12d as a yellow solid
(162 mg, 66% yield); Rf 0.7 (Hex/AcOEt/NH4OH, 8/2/
0.2); mp¼83–85 ꢀC; HPLC (C18—10 min) PHPLC 98%,
tR 5.18 min; 1H NMR (CDCl3) d 8.47 (1H, d, Ar–H6,
(2H, dd, Ph, 3J¼6.9 Hz, 4J¼1.5 Hz), 7.54 (2H, dd,
4
Ph, 3J¼6.9 Hz, 4J¼1.8 Hz), 7.42 (1H, d, Ar–H3, J3,4
¼
8.4 Hz), 3.59 (2H, s, CH2), 2.68 (3H, s, CO–CH3), 2.45–
2.47 (4H, m, N–CH2), 1.74–1.77 (4H, m, CH2); 13C NMR
(CDCl3) d 130.8 (Ar–C3), 129.6 (2C, Ph), 128.4 (2C, Ph),
124.9 (Ar–C6), 121.8 (Ar–C4), 57.2 (CH2), 54.0 (2C, N–
CH2), 26.8 (CO-CH3), 23.8 (2C, CH); m/z 325.2 [M+H]+.
4.10.23. 1-(40-Fluoro-4-nitro-biphenyl-2-ylmethyl)-pyr-
rolidine 12g. Synthesized from compound 4 (200 mg,
0.701 mmol), 4-fluorophenylboronic acid (196 mg),
Pd(OAc)2 (12 mg), P(o-tol)3 (32 mg), and TBAB (45 mg)
according to general procedure C (reflux for 48 h). The resi-
due was purified twice by TLC (Cyh/AcOEt/NH4OH, 9/1/
0.2 and then Cyh/AcOEt/NH4OH, 8/2/0.2) to yield the ex-
pected compound 12g as a white solid (81 mg, 38% yield);
Rf 0.8 (Cyh/AcOEt/NH4OH, 8/2/0.2); mp¼78–79 ꢀC;
3
4J6,4¼2.4 Hz), 8.17 (1H, dd, Ar–H4, J4,3¼8.4 Hz,
3
4J4,6¼2.4 Hz), 7.72 (2H, d, Ph, J¼8.5 Hz), 7.54 (2H, d,
3
3
Ph, J¼8.5 Hz), 7.40 (1H, d, Ar–H3, J3,4¼8.4 Hz), 3.56
(2H, s, CH2), 2.44–2.49 (4H, m, N–CH2), 1.71–1.83 (4H,
m, CH2); 13C NMR (CDCl3) d 130.7 (Ar–C3), 129.4 (2C,
3
Ph), 125.2 (2C, d, Ph, JCH,F¼3.1 Hz), 124.8 (Ar–C6),
1
121.7 (Ar–C4), 56.9 (CH2), 53.7 (2C, N–CH2), 23.5 (2C,
HPLC (C18—10 min) PHPLC 99%, tR 4.46 min; H NMR
CH2); m/z 351.2 [M+H]+.
(CDCl3) d 8.53 (1H, d, Ar–H6, J6,4¼2.4 Hz), 8.15 (1H,
4
3
4
dd, Ar–H4, J4,3¼8.5 Hz, J4,6¼2.4 Hz), 7.39 (1H, d,
3
4.10.20. 1-(4-Nitro-40-trifluoromethyl-biphenyl-2-yl-
methyl)-pyrrole 120d. Isolated as a by-product (white solid,
53%); Rf 0.8 (DCM/Cyh/NH4OH, 7/3/0.2); mp¼120 ꢀC;
Ar–H3, J3,4¼8.5 Hz), 7.37 (2H, m, Ph), 7.17 (2H, m, Ph),
3.71 (2H, s, CH2), 2.57 (4H, m, N–CH2), 1.78–1.83 (4H,
m, CH2); 13C NMR (CDCl3) d 131.1 (Ar–C3), 130.9 (2C,
1
3
HPLC (C18—10 min) PHPLC 96%, tR 7.97 min; H NMR
Ph, JCH,F¼8.3 Hz), 125.1 (Ar–C6), 122.1 (Ar–C4), 115.5
3
4
2
(CDCl3) d 8.22 (1H, dd, Ar–H4, J4,3¼8.4 Hz, J4,6
¼
(2C, Ph, JCH,F¼21.3 Hz), 56.6 (CH2), 53.9 (2C, N–CH2),
4
2.4 Hz), 7.88 (1H, d, Ar–H6, J6,4¼2.4 Hz), 7.74 (2H, d,
23.5 (2C, CH2); m/z 301.3 [M+H]+.
3
3
Ph, J¼8.0 Hz), 7.43 (1H, d, Ar–H3, J3,4¼8.4 Hz), 7.36
(2H, d, Ph, 3J¼8.0 Hz), 6.47 (2H, m, Pyr–H2), 6.17 (2H, m,
Pyr–H3), 5.01 (2H, s, N–CH2); 13C NMR (CDCl3) d 131.1
4.10.24. 1-(4-Nitro-40-thiophen-2-yl-biphenyl-2-yl-
methyl)-pyrrolidine 12h. Synthesized from compound 4
(200 mg, 0.701 mmol), 2-thiopheneboronic acid (270 mg),
Pd(OAc)2 (18 mg), P(o-tol)3 (48 mg), and TBAB (45 mg)
according to general procedure C (reflux for 140 h). The
residue was purified by TLC (Cyh/AcOEt/NH4OH, 8/2/
0.2) to yield the expected compound 12h as a yellow oil
(86 mg, 43% yield); Rf 0.7 (Cyh/AcOEt/NH4OH, 8/2/0.2);
3
(Ar–C3), 129.0 (2C, Ph), 125.7 (2C, Ph, JH,F¼3.2 Hz),
123.4 (Ar–C6), 122.8 (Ar–C4), 120.8 (2C, Pyr–C2), 109.4
(2C, Pyr–C3), 50.7 (CH2); m/z 347.1 [M+H]+.
4.10.21. 1-(40-Methoxy-4-nitro-biphenyl-2-ylmethyl)-
pyrrolidine 12e. Synthesized from compound 4 (200 mg,
0.701 mmol), 4-methoxyphenylboronic acid (320 mg),
Pd(OAc)2 (18 mg), P(o-tol)3 (48 mg), and TBAB (45 mg)
according to general procedure C (reflux for 5 days). The
1
HPLC (C18—10 min) PHPLC 97%, tR 4.23 min; H NMR
(CDCl3) d 8.42 (1H, d, Ar–H6, J6,4¼2.5 Hz), 8.10 (1H,
4
3
4
dd, Ar–H4, J4,3¼8.5 Hz, J4,6¼2.5 Hz), 7.58 (1H, d,

E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
12801
Ar–H3, 4J3,4¼8.5 Hz), 7.46 (1H, dd, Thio–H5, 3J5,4¼5.1 Hz,
(CDCl3) d 130.8 (Ar–C3), 123.8 (Ar–C6), 121.8 (Ar–C4),
57.7 (CH2), 54.4 (2C, N–CH2), 23.6 (2C, CH2), 24.3 (1C,
CH3); m/z 221.1 [M+H]+.
4J5,3¼1.2 Hz), 7.36 (1H, dd, Thio–H3, 3J3,4¼3.6 Hz, 4J3,5
¼
¼
3
3
1.2 Hz), 7.14 (1H, dd, Thio–H4, J4,3¼3.6 Hz, J4,5
5.1 Hz), 3.79 (2H, s, CH2), 2.57–2.61 (4H, m, N–CH2),
1.76–1.85 (4H, m, CH2); 13C NMR (CDCl3) d 131.4 (Ar–
C3), 129.0 (Thio–C3), 127.7 (Thio–C4), 127.7 (Thio–C5),
125.3 (Ar–C6), 122.0 (Ar–C4), 57.5 (CH2), 53.7 (2C, N–
CH2), 23.6 (2C, CH2); m/z 289.2 [M+H]+.
4.10.28. 1-(2-Ethyl-5-nitro-benzyl)-pyrrolidine 12m. To
asuspensionofcompound4(200 mg, 0.701 mmol), ethylbor-
onic acid (77 mg, 1.5 equiv), Pd(OAc)2 (24 mg, 0.15 equiv),
P(o-tol)3 (63 mg, 0.3 equiv), and K2CO3 (291 mg, 3 equiv) in
THF (5 mL) was added water (0.5 mL) under inert atmo-
sphere. The reaction medium was heated to 75 ꢀC for 70 h.
The medium was evaporated, solubilized with aq satd
NaHCO3 (50 mL), and extracted with DCM (5ꢁ50 mL).
Combined organic layers were dried over MgSO4, filtered,
and concentrated. The residue was purified by TLC (pen-
tane/AcOEt/NH4OH, 9/1/0.2) to yield the expected com-
pound 12m as a yellow oil (79 mg, 48% yield); Rf 0.5
(pentane/AcOEt/NH4OH, 9/1/0.2); HPLC (C18—10 min)
4.10.25. 1-(40-Furan-2-yl-4-nitro-biphenyl-2-ylmethyl)-
pyrrolidine 12i. Synthesized from compound 4 (200 mg,
0.701 mmol), 2-furaneboronic acid (236 mg), Pd(OAc)2
(18 mg), P(o-tol)3 (48 mg), and TBAB (45 mg) according
to general procedure C (reflux for 140 h). The residue was
purified by TLC (Cyh/AcOEt/NH4OH, 8/2/0.2) to yield the
expected compound 12i as a yellow oil (76 mg, 40% yield);
Rf 0.5 (Cyh/AcOEt/NH4OH, 8/2/0.2); HPLC (C18—10 min)
1
1
PHPLC 96%, tR 3.85 min; H NMR (CDCl3) d 8.40 (1H, d,
Ar–H6, J6,4¼2.4 Hz), 8.13 (1H, dd, Ar–H4, J4,3¼8.7 Hz,
PHPLC 94%, tR 3.85 min; H NMR (CDCl3) d 8.16 (1H, d,
Ar–H6, J6,4¼2.4 Hz), 7.97 (1H, dd, Ar–H4, J4,3¼8.4 Hz,
4
3
4
3
4
4J4,6¼2.4 Hz), 7.85 (1H, d, Ar–H3, J3,4¼8.7 Hz), 7.60
4J4,6¼2.4 Hz), 7.25 (1H, d, Ar–H3, 3J3,4¼8.4 Hz), 3.61 (2H,
3
3
(1H, d, Fur–H5, J5,4¼1.7 Hz), 6.96 (1H, d, Fur–H3,
s, CH2), 2.75 (2H, q, Ar–CH2, J¼7.5 Hz), 2.43–2.51 (4H,
3
3
3J3,4¼3.4 Hz), 6.57 (1H, dd, Fur–H4, J4,3¼3.4 Hz, J4,5
¼
m, N–CH2), 1.67–1.78 (4H, m, CH2), 1.18 (3H, t, CH3,
3J¼7.5 Hz); 13C NMR (CDCl3) d 129.2 (Ar–C3), 124.3
(Ar–C6), 122.2 (Ar–C4), 57.3 (CH2), 54.5 (2C, N–CH2),
25.7 (Ar–CH2), 23.8 (2C, CH2), 14.8 (CH3); m/z 235.2
(M++1), 219.1 [M+H–O]+.
1.7 Hz), 3.85 (2H, s, CH2), 2.60–2.64 (4H, m, N–CH2),
1.78–1.87 (4H, m, CH2); 13C NMR (CDCl3) d 143.9 (Fur–
C5), 128.0 (Ar–C3), 125.6 (Ar–C6), 122.3 (Ar–C4), 113.1
(Fur–C3), 112.4 (Fur–C4), 58.4 (CH2), 54.2 (2C, N–CH2),
23.8 (2C, CH2); m/z 273.2 [M+H]+.
4.10.29. 2-Diethylaminomethyl-biphenyl-4-ylamine 13a.
Synthesized from compound 11a (43 mg, 0.150 mmol) and
SnCl2 (114 mg) in HCl (0.45 mL) and THF (15 mL) accord-
ing to general procedure A (reflux for 18 h). The residue was
purified by TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to
yield compound 13a as a yellow oil (29 mg, 76% yield);
Rf 0.4 (DCM/MeOH/NH4OH, 9.5/0.5/0.2); HPLC (C18—
4.10.26. 1-(40-Chloro-4-nitro-biphenyl-2-ylmethyl)-pyr-
rolidine 12k. Synthesized from compound 4 (200 mg,
0.701 mmol), 4-chlorophenylboronic acid (220 mg),
Pd(OAc)2 (12 mg), P(o-tol)3 (32 mg), and TBAB (45 mg)
according to general procedure C (reflux for 16 h). The resi-
due was purified by TLC (Cyh/AcOEt/NH4OH, 9/1/0.2) to
yield the expected compound 12k as a white solid
(129 mg, 58% yield); Rf 0.6 (Cyh/AcOEt/NH4OH, 9/1/
0.2); mp¼107–108 ꢀC; HPLC (C18—10 min) PHPLC 98%,
tR 4.17 min; 1H NMR (CDCl3) d 8.44 (1H, d, Ar–H6,
10 min) PHPLC 97%, tR 3.67 min; 1H NMR (CDCl3)
4
d 7.25–7.39 (5H, m, Ph), 7.05 (1H, d, Ar–H6, J6,4
2.7 Hz), 7.02 (1H, d, Ar–H3, J3,4¼8.1 Hz), 6.61 (1H, dd,
¼
3
3
4
Ar–H4, J4,3¼8.1 Hz, J4,6¼2.7 Hz), 3.77 (2H, s large,
NH2), 3.51 (2H, s, CH2), 2.47 (4H, q, N–CH2, 3J¼7.2 Hz),
3
4J6,4¼2.4 Hz), 8.12 (1H, dd, Ar–H4, J4,3¼8.4 Hz,
4J4,6¼2.4 Hz), 7.36–7,44 (5H, m, Ph, Ar–H3), 3.58 (2H, s,
CH2), 2.46–2.48 (4H, m, N–CH2), 1.72–1.81 (4H, m,
CH2); 13C NMR (CDCl3) d 131.0 (Ar–C3), 130.7 (2C, Ph),
128.7 (2C, Ph), 124.9 (Ar–C6), 121.9 (Ar–C4), 57.2 (CH2),
54.0 (2C, N–CH2), 23.8 (2C, CH2); m/z 317.2 [M+H]+.
0.92 (6H, t, CH3, J¼7.2 Hz); 13C NMR (CDCl3) d 130.8
3
(Ar–C3), 129.7 (2C, Ph), 127.8 (2C, Ph), 126.3 (Ph), 115.6
(Ar–C6), 113.5 (Ar–C4), 54.2 (CH2), 46.6 (2C, N–CH2),
11.2 (2C, CH3); m/z 255.3 [M+H]+.
4.10.30. 2-Diethylaminomethyl-40-methyl-biphenyl-4-yl-
amine 13b. Synthesized from compound 11b (161 mg,
0.540 mmol) and SnCl2 (408 mg) in HCl (1.62 mL) and
THF (10 mL) according to general procedure A (reflux for
16 h). The residue was purified by TLC (DCM/MeOH/
NH4OH, 9.5/0.5/0.2) to yield compound 13b as a yellow oil
(101 mg, 70% yield); Rf 0.5 (DCM/MeOH/NH4OH, 9.5/0.5/
4.10.27. 1-(2-Methyl-5-nitro-benzyl)-pyrrolidine 12l.
To a suspension of compound 4 (200 mg, 0.701 mmol),
methylboronic acid (63 mg, 1.5 equiv), Pd(OAc)2 (24 mg,
0.15 equiv), P(o-tol)3 (63 mg, 0.3 equiv), and K2CO3
(290 mg, 3 equiv) in THF (5 mL) was added water
(0.5 mL) under inert atmosphere. The reaction medium
was heated to 75 ꢀC for 70 h. The medium was evaporated,
solubilized with aq satd NaHCO3(50 mL), and extracted
with DCM (5ꢁ50 mL). Combined organic layers were dried
over MgSO4, filtered, and concentrated. The residue was pu-
rified by TLC (EP/AcOEt/NH4OH, 9/1/0.2) to yield the ex-
pected compound 12l as a yellow oil (106 mg, 73% yield);
Rf 0.5 (AcOEt/Cyh/NH4OH, 1/9/0.2); HPLC (C18—
10 min) PHPLC >99%, tR 3.28 min; 1H NMR (CDCl3)
1
0.2); HPLC (C18—10 min) PHPLC 98%, tR 3.97 min; H
NMR (CDCl3) d 7.16 (4H, m, Ph), 7.03 (1H, d, Ar–H6,
4J6,4¼2.5 Hz), 6.99 (1H, d, Ar–H3, 3J3,4¼8.1 Hz), 6.57 (1H,
3
4
dd, Ar–H4, J4,3¼8.1 Hz, J4,6¼2.5 Hz), 3.84 (2H, s large,
3
NH2), 3.48 (2H, s, CH2), 2.45 (4H, q, N–CH2, J¼7.1 Hz),
3
2.37 (3H, s, CH3), 0.92 (6H, t, CH3, J¼7.1 Hz); 13C NMR
(CDCl3) d 131.1 (Ar–C3), 129.8 (2C, Ph), 128.8 (2C, Ph),
115.9 (Ar–C6), 113.7 (Ar–C4), 54.6 (CH2), 47.0 (2C,
N–CH2), 21.4 (CH3), 11.7 (2C, CH3); m/z 269.3 [M+H]+.
4
d 8.14 (1H, d, Ar–H6, J6,4¼2.7 Hz), 7.94 (1H, dd, Ar–H4,
4
3
3J4,3¼8.7 Hz, J4,6¼2.7 Hz), 7.21 (1H, d, Ar–H3, J3,4
¼
8,7 Hz), 3.59 (2H, s, CH2), 2.45–2.52 (4H, m, N–CH2),
2.39 (3H, s, CH3), 1.70–1.81 (4H, m, CH2); 13C NMR
4.10.31. 40-tert-Butyl-2-diethylaminomethyl-biphenyl-4-
ylamine 13c. Synthesized from compound 11c (128 mg,

12802
E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
3
0.375 mmol) and SnCl2 (284 mg) in HCl (1.12 mL) and
THF (25 mL) according to general procedure A (reflux for
18 h). The residue was purified by TLC (DCM/MeOH/
NH4OH, 9.5/0.5/0.2) to yield compound 13c as a yellow
oil (74 mg, 63% yield); Rf 0.4 (DCM/MeOH/NH4OH, 9.5/
0.5/0.2); HPLC (C18—10 min) PHPLC 99%, tR 5.01 min;
1H NMR (CDCl3) d 7.37 (2H, m, Ph), 7.20 (2H, m, Ph),
m, Ar–H3, Ar–H6), 6.54 (1H, dd, Ar–H4, J4,3¼8.1 Hz,
4J4,6¼2.4 Hz), 3.80 (2H, s large, NH2), 3.37 (2H, s, CH2),
3
2.55 (3H, s, CO–CH3), 2.35 (4H, q, N–CH2, J¼6.9 Hz),
0.78 (6H, t, CH3, J¼6.9 Hz); 13C NMR (CDCl3) d 129.9
3
(Ar–C3), 129.1 (2C, Ph), 127.1 (2C, Ph), 115.0 (Ar–C6),
112.6 (Ar–C4), 53.8 (CH2), 45.8 (2C, N–CH2), 25.8 (CO-
CH2), 10.6 (2C, CH3); m/z 297.3 [M+H]+.
4
7.06 (1H, d, Ar–H6, J6,4¼2.5 Hz), 7.02 (1H, d, Ar–H3,
3
3J3,4¼8.1 Hz), 6.60 (1H, dd, Ar–H4, J4,3¼8.1 Hz,
4.10.35. 2-Diethylaminomethyl-40-fluoro-biphenyl-4-yl-
amine 13g. Synthesized from compound 11g (70 mg,
0.233 mmol) and SnCl2 (176 mg) in HCl (0.70 mL) and
THF (25 mL) according to general procedure A (reflux for
5 h). The residue was purified by TLC (DCM/MeOH/
NH4OH, 9.5/0.5/0.2) to yield compound 13g as a yellow
oil (42 mg, 66% yield); Rf 0.6 (DCM/MeOH/NH4OH, 9.5/
0.5/0.2); HPLC (C18—10 min) PHPLC 99%, tR 3.77 min;
1H NMR (CDCl3) d 7.21 (2H, m, Ph), 7.11 (1H, d, Ar–H6,
4J6,4¼2.4 Hz), 7.06 (2H, m, Ph), 6.99 (1H, d, Ar–H3,
4J4,6¼2.5 Hz), 3.92 (2H, s large, NH2), 3.55 (2H, s, CH2),
3
2.49 (4H, q, N–CH2, J¼7.1 Hz), 1.35 (9H, s, t-Bu), 0.92
3
(6H, t, CH3, J¼7.1 Hz); 13C NMR (CDCl3) d 131.9 (Ar–
C3), 130.2 (2C, Ph), 125.7 (2C, Ph), 116.6 (Ar–C6), 114.5
(Ar–C4), 55.1 (CH2), 47.6 (2C, N–CH2), 32.3 (3C, t-Bu),
11.9 (2C, CH3); m/z 311.3 [M+H]+.
4.10.32. 2-Diethylaminomethyl-40-trifluoromethyl-bi-
phenyl-4-ylamine 13d. Synthesized from compound 11d
(143 mg, 0.406 mmol) and SnCl2 (308 mg) in HCl
(1.22 mL) and THF (25 mL) according to general procedure
A (reflux for 18 h). The residue was purified by TLC (DCM/
MeOH/NH4OH, 9.5/0.5/0.2) to yield compound 13d as a yel-
low oil (86 mg, 66% yield); Rf 0.5 (DCM/MeOH/NH4OH,
9.5/0.5/0.2); HPLC (C18—10 min) PHPLC 98%, tR
3
3J3,4¼8.2 Hz), 6.64 (1H, dd, Ar–H4, J4,3¼8.2 Hz,
4J4,6¼2.4 Hz), 4.40 (2H, s large, NH2), 3.64 (2H, s, CH2),
2.59 (4H, q, N–CH2, 3J¼7.2 Hz), 0.96 (6H, t, CH3,
3J¼7.2 Hz); 13C NMR (CDCl3) d 131.3 (2C, d, Ph,
3JCH,F¼7.6 Hz), 131.2 (Ar–C3), 116.1 (Ar–C6), 115.0 (2C,
2
d, Ph, JCH,F¼21.0 Hz), 114.3 (Ar–C4), 53.9 (CH2), 46.4
4.68 min; 1H NMR (CDCl3) d 7.61 (2H, d, Ph, 3J3 ,2 ¼8 Hz),
(2C, N–CH2), 10.5 (2C, CH3); m/z 273.3 [M+H]+.
0
0
3
0
0
7.40 (2H, d, Ph, J2 ,3 ¼8 Hz), 7.06 (1H, d, Ar–H6,
3
4J6,4¼2,4 Hz), 6.99 (1H, d, Ar–H3, J3,4¼8,1 Hz), 6.63
4.10.36. 2-Diethylaminomethyl-40-thiophen-2-yl-biphe-
nyl-4-ylamine 13h. Synthesized from compound 11h
(77 mg, 0.264 mmol) and SnCl2 (200 mg) in HCl
(0.79 mL) and THF (25 mL) according to general procedure
A (reflux for 16 h). The residue was purified by TLC (DCM/
MeOH/NH4OH, 9.5/0.5/0.2) to yield compound 13h as a yel-
low oil (29 mg, 43% yield); Rf 0.4 (DCM/MeOH/NH4OH,
9.5/0.5/0.2); HPLC (C18—10 min) PHPLC 99%, tR
3.67 min; 1H NMR (CDCl3) d 7.27 (1H, dd, Thio–H5,
3
4
(1H, dd, Ar–H4, J4,3¼8,1 Hz, J4,6¼2,4 Hz), 4.13 (2H, s
large, NH2), 3.51 (2H, s, CH2), 2.49 (4H, q, N–CH2,
3J¼7,1 Hz), 0.92 (6H, t, CH3, 3J¼7,1 Hz); 13C NMR
(CDCl3) d 130.9 (Ar–C3), 130.0 (2C, Ph), 124.8 (2C, Ph,
3JCH,F¼3.0 Hz), 116.0 (Ar–C6), 113.7 (Ar–C4), 54.5 (1C,
CH2), 46.9 (2C, N–CH2), 11.1 (2C, CH3); m/z 323.2
[M+H]+.
4
4.10.33. 2-Diethylaminomethyl-40-methoxy-biphenyl-4-
ylamine 13e. Synthesized from compound 11e (98 mg,
0.312 mmol) and SnCl2 (237 mg) in HCl (0.94 mL) and
THF (10 mL) according to general procedure A (reflux for
16 h). The residue was purified by TLC (DCM/MeOH/
NH4OH, 9.5/0.5/0.2) to yield compound 13e as a yellow
oil (46 mg, 53% yield); Rf 0.4 (DCM/MeOH/NH4OH, 9/1/
3J5,4¼5.1 Hz, J5,3¼1.2 Hz), 7.16 (1H, d, Ar–H3,
4J3,4¼8.2 Hz), 7.05 (1H, d, Ar–H6, J6,4¼2.3 Hz), 7.04
4
3
3
(1H, dd, Thio–H4, J4,3¼3.5 Hz, J4,5¼5.1 Hz), 6.96 (1H,
3
4
dd, Thio–H3, J3,4¼3.5 Hz, J3,5¼1.2 Hz), 6.58 (1H, dd,
3
4
Ar–H4, J4,3¼8.2 Hz, J4,6¼2.5 Hz), 3.87 (2H, s large,
NH2), 3.65 (2H, s, CH2), 2.56 (4H, q, N–CH2, 3J¼7.1 Hz),
0.99 (6H, t, CH3, J¼7.1 Hz); 13C NMR (CDCl3) d 132.1
3
1
0.2); HPLC (C18—10 min) PHPLC 98%, tR 3.60 min; H
NMR (CDCl3) d 7.18 (2H, m, Ph), 7.03 (1H, d, Ar–H6,
(Ar–C3), 127.1 (1C, C-40), 126.7 (1C, C-30), 124.9 (1C, C-
50), 116.0 (Ar–C6), 113.7 (Ar–C4), 54.7 (CH2), 46.8 (2C,
N–CH2), 11.4 (2C, CH3); m/z 261.3 [M+H]+.
3
4J6,4¼2.4 Hz), 6.99 (1H, d, Ar–H3, J3,4¼8.1 Hz), 6.90
3
(2H, m, Ph), 6.60 (1H, dd, Ar–H4, J4,3¼8.1 Hz,
4J4,6¼2.4 Hz), 3.70–4.00 (2H, s large, NH2), 3.83 (3H, s,
O–CH3), 3.51 (2H, s, CH2), 2.48 (4H, q, N–CH2,
3J¼7.1 Hz), 0.93 (6H, t, CH3, 3J¼7.1 Hz); 13C NMR
(CDCl3) d 131.2 (Ar–C3), 130.9 (2C, Ph), 115.9 (Ar–C6),
113.8 (Ar–C4), 113.5 (2C, Ph), 55.4 (O–CH3), 54.5 (CH2),
46.9 (2C, N–CH2), 11.4 (2C, CH3); m/z 285.3 [M+H]+.
4.10.37. 2-Diethylaminomethyl-40-furan-2-yl-biphenyl-4-
ylamine 13i. Synthesized from compound 11i (68 mg,
0.249 mmol) and SnCl2 (189 mg) in HCl (0.75 mL) and
THF (25 mL) according to general procedure A (reflux for
16 h). The residue was purified by TLC (DCM/MeOH/
NH4OH, 9.5/0.5/0.2) to yield compound 13i as a yellow
oil (22 mg, 35% yield); Rf 0.2 (DCM/MeOH/NH4OH, 9.5/
0.5/0.2); HPLC (C18—10 min) PHPLC 98%, tR 3.24 min;
4.10.34. 1-(40-Amino-20-diethylaminomethyl-biphenyl-4-
yl)-ethanone 13f. Synthesized from compound 11f
(89 mg, 0.272 mmol) and SnCl2 (207 mg) in HCl
(0.82 mL) and THF (25 mL) according to general procedure
A (reflux for 18 h). The residue was purified by TLC (DCM/
MeOH/NH4OH, 9.5/0.5/0.2) to yield compound 13f as a yel-
low oil (54 mg, 67% yield); Rf 0.7 (DCM/MeOH/NH4OH,
9.5/0.5/0.2); HPLC (C18—10 min) PHPLC 96%, tR
3
1H NMR (CDCl3) d 7.44 (1H, dd, Fur–H5, J5,4¼1.8 Hz,
4J5,3¼0.7 Hz), 7.34 (1H, d, Ar–H3, J3,4¼8.3 Hz), 7.06
4
4
(1H, d, Ar–H6, J6,4¼2.5 Hz), 6.61 (1H, dd, Ar–H4,
3J4,3¼8.3 Hz, J4,6¼2.5 Hz), 6.45 (1H, dd, Fur–H4, J4,3
¼
4
3
3.2 Hz, 3J4,5¼1.8 Hz), 6.39 (1H, dd, Fur–H3, 3J3,4¼3.2 Hz,
4J3,5¼0.7 Hz), 3.60–4.10 (2H, s large, NH2), 3.79 (2H, s,
3
CH2), 2.64 (4H, q, N–CH2, J¼7.1 Hz), 1.05 (6H, t, CH3,
3.58 min; 1H NMR (CDCl3)
d
7.88 (2H, d, Ph,
3J¼7.1 Hz); 13C NMR (CDCl3) d 141.2 (Fur–C5), 129.8
3
3J¼8.1 Hz), 7.31 (2H, d, Ph, J¼8.1 Hz), 6.90–6.94 (2H,
(Ar–C3), 116.1 (Ar–C6), 113.9 (Ar–C4), 111.2 (Fur–C4),

E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
12803
107.4 (Fur–C3), 55.0 (CH2), 46.8 (2C, N–CH2), 11.0 (2C,
CH3); m/z 245.2 [M+H]+.
18 h). The residue was purified by TLC (DCM/MeOH/
NH4OH, 9/1/0.2) to yield compound 13m as a yellow oil
(68 mg, 69% yield); Rf 0.4 (DCM/MeOH/NH4OH, 9/1/
0.2); HPLC (C18—10 min) PHPLC 88%, tR 0.64–2.49 min;
4.10.38. 2-Diethylaminomethyl-20-fluoro-biphenyl-4-yl-
amine 13j. Synthesized from compound 11j (91 mg,
0.301 mmol) and SnCl2 (228 mg) in HCl (0.91 mL) and
THF (25 mL) according to general procedure A (reflux for
16 h). The residue was purified by TLC (DCM/MeOH/
NH4OH, 9.5/0.5/0.2) to yield compound 13j as a yellow
oil (53 mg, 65% yield); Rf 0.7 (DCM/MeOH/NH4OH, 9.5/
0.5/0.2); HPLC (C18—10 min) PHPLC 98%, tR 3.88 min;
1H NMR (CDCl3) d 7.27–7.32 (1H, m, Ph–H4), 7.18–7.26
3
1H NMR (CDCl3) d 6.94 (1H, d, Ar–H3, J3,4¼8.1 Hz),
4
6.80 (1H, d, Ar–H6, J6,4¼2.4 Hz), 6.52 (1H, dd, Ar–H4,
4
3J4,3¼8.0 Hz, J4,6¼2.4 Hz), 3.50 (2H, s large, NH2), 3.46
3
(2H, s, CH2), 2.60 (2H, q, Ar–CH2, J¼7.5 Hz), 2.51 (4H,
3
3
q, N–CH2, J¼7.2 Hz), 1.15 (3H, t, CH3, J¼7.5 Hz), 1.03
(3H, t, CH3, J¼7.2 Hz); 13C NMR (CDCl3) d 129.4 (Ar–
3
C3), 116.7 (Ar–C6), 114.0 (Ar–C4), 55.1 (CH2), 47.1 (2C,
N–CH2), 24.9 (Ar–CH2), 15.8 (CH3), 11.9 (2C, CH3); m/z
207.3 (M++1).
3
(1H, m, Ph–H5), 7.23–7.28 (1H, dd, Ph–H6, J6,5¼7.2 Hz,
4J6,4¼1.1 Hz), 7.04–7.14 (2H, m, Ph–H3, Ar–H6), 6.98
3
(1H, d, Ar–H3, J3,4¼8.1 Hz), 6.61 (1H, dd, Ar–H4,
4.10.42. 2-Pyrrolidin-1-ylmethyl-biphenyl-4-ylamine
14a. Synthesized from compound 12a (104 mg,
0.367 mmol) and SnCl2 (279 mg) in HCl (1.10 mL) and
THF (25 mL) according to general procedure A (reflux for
18 h). The residue was purified by TLC (DCM/MeOH/
NH4OH, 9.5/0.5/0.2) to yield compound 14a as a yellow
oil (70 mg, 75% yield); Rf 0.4 (DCM/MeOH/NH4OH, 9.5/
0.5/0.2); HPLC (C18—10 min) PHPLC 99%, tR 3.42 min;
1H NMR (CDCl3) d 7.13–7.27 (5H, m, Ph), 6.95 (1H, d,
4
3J4,3¼8.1 Hz, J4,6¼2.4 Hz), 3.93 (2H, s large, NH2), 3.39
3
(2H, s, CH2), 2.43 (4H, q, N–CH2, J¼7.1 Hz), 0.90 (6H,
3
t, CH3, J¼7.1 Hz); 13C NMR (CDCl3) d 133.1 (d, Ph–C5,
3J5,F¼2.9 Hz), 132.1 (Ar–C3), 129.6 (d, Ph–C4,
3
3J4,F¼7.5 Hz), 124.8 (d, Ph–C6, J6,F¼2.8 Hz), 116.6 (Ar–
2
C3), 116.2 (d, Ph–C3, J3,F¼22.6 Hz), 114.4 (Ar–C4), 55.4
(CH2), 47.8 (2C, N–CH2), 12.4 (2C, CH3); m/z 273.3
[M+H]+.
3
4
Ar–H3, J3,4¼8.1 Hz), 6.88 (1H, d, Ar–H6, J6,4¼2.4 Hz),
3
4
4.10.39. 40-Chloro-2-diethylaminomethyl-biphenyl-4-yl-
amine 13k. Synthesized from compound 11k (143 mg,
0.449 mmol) and SnCl2 (341 mg) in HCl (1.35 mL) and
THF (25 mL) according to general procedure A (reflux for
16 h). The residue was purified by TLC (DCM/MeOH/
NH4OH, 9.5/0.5/0.2) to yield compound 13k as a yellow
solid (78 mg, 60% yield); Rf 0.4 (DCM/MeOH/NH4OH,
9.5/0.5/0.2); mp¼37–38 ꢀC; HPLC (C18—10 min) PHPLC
6.52 (1H, dd, Ar–H4, J4,3¼8.1 Hz, J4,6¼2.4 Hz), 3.74
(2H, s large, NH2), 3.46 (2H, s, CH2), 2.35–2.39 (4H, m,
N–CH2), 1.61–1.66 (4H, m, CH2); 13C NMR (CDCl3)
d 130.0 (Ar–C3), 128.9 (2C, Ph), 126.9 (2C, Ph), 125.3
(Ph), 114.8 (Ar–C6), 112.6 (Ar–C4), 56.3 (CH2), 53.0 (2C,
N–CH2), 22.5 (2C, CH2); m/z 253.3 [M+H]+.
4.10.43. 40-Methyl-2-pyrrolidin-1-ylmethyl-biphenyl-4-
ylamine 14b. Synthesized from compound 12b (149 mg,
0.501 mmol) and SnCl2 (380 mg) in HCl (1.50 mL) and
THF (25 mL) according to general procedure A (reflux for
18 h). The residue was purified by TLC (DCM/MeOH/
NH4OH, 9.5/0.5/0.2) to yield compound 14b as a yellow
oil (95 mg, 71% yield); Rf 0.6 (DCM/MeOH/NH4OH, 9/1/
1
99%, tR 4.23 min; H NMR (CDCl3) d 7.32 (2H, m, Ph),
4
7.20 (2H, m, Ph), 7.01 (1H, d, Ar–H6, J6,4¼2.5 Hz), 6.97
3
(1H, d, Ar–H3, J3,4¼8.1 Hz), 6.60 (1H, dd, Ar–H4,
4
3J4,3¼8.1 Hz, J4,6¼2.5 Hz), 3.95 (2H, s large, NH2), 3.45
3
(2H, s, CH2), 2.46 (4H, q, N–CH2, J¼7.1 Hz), 0.92 (6H,
3
t, CH3, J¼7.1 Hz); 13C NMR (CDCl3) d 133.3 (2C, Ph),
1
131.3 (Ar–C3), 128.2 (2C, Ph), 116.1 (Ar–C6), 113.8 (Ar–
C4), 54.7 (CH2), 46.8 (2C, N–CH2), 11.5 (2C, CH3); m/z
289.3–291.3 [M+H]+.
0.2); HPLC (C18—10 min) PHPLC 99%, tR 3.94 min; H
NMR (CDCl3) d 7.21 (2H, m, Ph), 7.16 (2H, m, Ph), 7.02
3
(1H, d, Ar–H3, J3,4¼8.1 Hz), 6.94 (1H, d, Ar–H6,
3
4J6,4¼2.4 Hz), 6.58 (1H, dd, Ar–H4, J4,3¼8.1 Hz,
4.10.40. 3-Diethylaminomethyl-4-methyl-phenylamine
13l. Synthesized from compound 11l (105 mg,
0.473 mmol) and SnCl2 (359 mg) in HCl (1.42 mL) and
THF (25 mL) according to general procedure A (reflux for
18 h). The residue was purified by TLC (DCM/MeOH/
NH4OH, 9/1/0.2) to yield compound 13l as a yellow oil
(51 mg, 56% yield); Rf 0.4 (DCM/MeOH/NH4OH, 9/1/
0.2); HPLC (C18—10 min) PHPLC 87%, tR 0.64–2.31 min;
4J4,6¼2.4 Hz), 3.75 (2H, s large, NH2), 3.53 (2H, s, CH2),
2.43–2.47 (4H, m, N–CH2), 2.37 (3H, s, CH3), 1.69–1.76
(4H, m, CH2); 13C NMR (CDCl3) d 131.9 (Ar–C3), 130.7
(2C, Ph), 129.6 (2C, Ph), 116.7 (Ar–C6), 114.5 (Ar–C4),
58.3 (CH2), 54.9 (2C, N–CH2), 24.5 (2C, CH2); m/z 267.2
[M+H]+.
4.10.44. 40-tert-Butyl-2-pyrrolidin-1-ylmethyl-biphenyl-
4-ylamine 14c. Synthesized from compound 12c (200 mg,
0.591 mmol) and SnCl2 (448 mg) in HCl (1.78 mL) and
THF (25 mL) according to general procedure A (reflux for
16 h). The residue was purified by TLC (DCM/MeOH/
NH4OH, 9.5/0.5/0.2) to yield compound 14c as a yellow
oil (135 mg, 74% yield); Rf 0.6 (DCM/MeOH/NH4OH, 9/
1/0.2); HPLC (C18—10 min) PHPLC 99%, tR 4.96 min;
1H NMR (CDCl3) d 7.36 (2H, m, Ph), 7.26 (2H, m, Ph),
3
1H NMR (CDCl3) d 6.90 (1H, d, Ar–H3, J3,4¼8.1 Hz),
4
6.78 (1H, d, Ar–H6, J6,4¼2.4 Hz), 6.49 (1H, dd, Ar–H4,
4
3J4,3¼8.1 Hz, J4,6¼2.4 Hz), 3.55 (2H, s large, NH2), 3.44
3
(2H, s, CH2), 2.53 (4H, q, N–CH2, J¼7.2 Hz), 2.22 (3H,
3
s, CH3), 1.04 (4H, t, CH3, J¼7.2 Hz); 13C NMR (CDCl3)
d 130.9 (Ar–C3), 116.7 (Ar–C6), 113.7 (Ar–C4), 55.6
(CH2), 47.1 (2C, N–CH2), 18.6 (CH3), 11.8 (2C, CH3); m/z
193.2 [M+H]+.
3
7.03 (1H, d, Ar–H3, J3,4¼8.1 Hz), 6.95 (1H, d, Ar–H6,
3
4
4.10.41. 3-Diethylaminomethyl-4-ethyl-phenylamine
13m. Synthesized from compound 11m (112 mg,
0.475 mmol) and SnCl2 (360 mg) in HCl (1.43 mL) and
THF (25 mL) according to general procedure A (reflux for
4J6,4¼2.4 Hz), 6.56 (1H, dd, Ar–H4, J4,3¼8.1 Hz, J4,6
¼
2.4 Hz), 3.60–3.90 (2H, s large, NH2), 3.56 (2H, s, CH2),
2.44–2.47 (4H, m, N–CH2), 1.71–1.74 (4H, m, CH2), 1.35
(9H, s, t-Bu); 13C NMR (CDCl3) d 131.3 (Ar–C3), 129.6

12804
E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
(2C, Ph), 125.0 (2C, Ph), 115.9 (Ar–C6), 113.7 (Ar–C4), 57.6
(CH2), 54.2 (2C, N–CH2), 31.7 (3C, t-Bu), 23.7 (2C, CH2);
m/z 309.3 [M+H]+.
NH4OH, 9.5/0.5/0.2) to yield compound 14g as a yellow
oil (39 mg, 55% yield); Rf 0.4 (DCM/MeOH/NH4OH, 9.5/
0.5/0.2); HPLC (C18—10 min) PHPLC 97%, tR 3.72 min;
1H NMR (CDCl3) d 7.27 (2H, m, Ph), 7.06 (2H, m, Ph),
3
4.10.45. 2-Pyrrolidin-1-ylmethyl-40-trifluoromethyl-bi-
phenyl-4-ylamine 14d. Synthesized from compound 12d
(178 mg, 0.507 mmol) and SnCl2 (385 mg) in HCl
(1.52 mL) and THF (25 mL) according to general procedure
A (reflux for 16 h). The residue was purified by TLC (DCM/
MeOH/NH4OH, 9.5/0.5/0.2) to yield compound 14d as a yel-
low oil (116 mg, 71% yield); Rf 0.4 (DCM/MeOH/NH4OH,
9.5/0.5/0.2); HPLC (C18—10 min) PHPLC 99%, tR 4.57 min;
1H NMR (CDCl3) d 7.61 (2H, d, Ph, 3J¼8.0 Hz), 7.48 (2H, d,
7.01 (1H, d, Ar–H3, J3,4¼8.1 Hz), 6.97 (1H, d, Ar–H6,
3
4J6,4¼2.4 Hz), 6.63 (1H, dd, Ar–H4, J4,3¼8.1 Hz,
4J4,6¼2.4 Hz), 4.18 (2H, s large, NH2), 3.61 (2H, s, CH2),
2.49–2.58 (4H, m, N–CH2), 1.70–1.84 (4H, m, CH2); 13C
3
NMR (CDCl3) d 131.6 (2C, d, Ph, JCH,F¼7.4 Hz), 131.4
(Ar–C3), 116.2 (Ar–C6), 115.2 (2C, d, Ph, 2JCH,F¼20.9 Hz),
114.3 (Ar–C4), 57.3 (CH2), 54.2 (2C, N–CH2), 23.6 (2C,
CH2); m/z 271.3 [M+H]+.
3
3
Ph, J¼8.0 Hz), 7.02 (1H, d, Ar–H3, J3,4¼8.2 Hz), 6.93
4.10.49. 2-Pyrrolidin-1-ylmethyl-40-thiophen-2-ylbi-
phenyl-4-ylamine 14h. Synthesized from compound 12h
(86 mg, 0.299 mmol) and SnCl2 (277 mg) in HCl
(0.90 mL) and THF (25 mL) according to general procedure
A (reflux for 18 h). The residue was purified by TLC (DCM/
MeOH/NH4OH, 9.5/0.5/0.2) to yield compound 14h as
a yellow oil (50 mg, 65% yield); Rf 0.4 (DCM/MeOH/
NH4OH, 9.5/0.5/0.2); HPLC (C18—10 min) PHPLC 99%,
4
(1H, d, Ar–H6, J6,4¼2.4 Hz), 6.61 (1H, dd, Ar–H4,
3J4,3¼8.1 Hz, J4,6¼2.4 Hz), 3.70–3.90 (2H, s large, NH2),
4
3.48 (2H, s, CH2), 2.42–2.47 (4H, m, N–CH2), 1.67–1.77
(4H, m, CH2); 13C NMR (CDCl3) d 131.8 (Ar–C3), 130.9
(2C, Ph), 125.6 (2C, d, Ph, 3JCH,F¼3.8 Hz), 116.9 (Ar–C6),
114.5 (Ar–C4), 58.3 (CH2), 54.8 (2C, N–CH2), 24.3 (2C,
CH2); m/z 321.1 [M+H]+.
1
tR 3.56 min; H NMR (CDCl3) d 7.17 (1H, dd, Thio–H5,
¼
4
4
4.10.46. 40-Methoxy-2-pyrrolidin-1-ylmethyl-biphenyl-4-
ylamine 14e. Synthesized from compound 12e (129 mg,
0.412 mmol) and SnCl2 (313 mg) in HCl (1.24 mL) and
THF (25 mL) according to general procedure A (reflux for
16 h). The residue was purified by TLC (DCM/MeOH/
NH4OH, 9.5/0.5/0.2) to yield compound 14e as a yellow
oil (66 mg, 56% yield); Rf 0.4 (DCM/MeOH/NH4OH, 9.5/
0.5/0.2); HPLC (C18—10 min) PHPLC 99%, tR 3.57 min;
1H NMR (CDCl3) d 7.22 (2H, m, Ph), 7.02 (1H, d, Ar–H3,
3J5,4¼5.1 Hz, J5,3¼1.5 Hz), 7.11 (1H, d, Ar–H3, J3,4
3
4
8.1 Hz), 6.98 (1H, dd, Thio–H3, J3,4¼3.6 Hz, J3,5
¼
1.5 Hz), 6.96 (1H, dd, Thio–H4, 3J4,3¼3.6 Hz, 3J4,5¼5.1 Hz),
4
6.83 (1H, d, Ar–H6, J6,4¼2.4 Hz), 6.49 (1H, dd, Ar–H4,
4
3J4,3¼8.1 Hz, J4,6¼2.4 Hz), 3.73 (2H, s large, NH2), 3.55
(2H, s, CH2), 2.43–2.47 (4H, m, N–CH2), 1.63–1.76 (4H, m,
CH2); 13C NMR (CDCl3) d 132.1 (Ar–C3), 127.1 (Thio–C4),
126.7 (Thio–C3), 124.8 (Thio–C5), 116.2 (Ar–C6), 113.7 (Ar–
C4), 57.8 (CH2), 54.1 (2C, N–CH2), 23.7 (2C, CH2); m/z
259.2 [M+H]+.
4
3J3,4¼8.1 Hz), 6.96 (1H, d, Ar–H6, J6,4¼2.4 Hz), 6.90
3
4
(2H, m, Ph), 6.60 (1H, dd, Ar–H4, J4,3¼8.1 Hz, J4,6
¼
2.4 Hz), 4.06 (2H, s large, NH2), 3.83 (3H, s, O–CH3),
3.61 (2H, s, CH2), 2.51–2.54 (4H, m, N–CH2), 1.72–1.76
(4H, m, CH2); 13C NMR (CDCl3) d 131.2 (Ar–C3), 131.0
(2C, Ph), 116.0 (Ar–C6), 114.1 (Ar–C4), 113.6 (2C, Ph),
57.2 (CH2), 55.4 (O–CH3), 54.0 (2C, N–CH2), 23.5 (2C,
CH2); m/z 283.2 [M+H]+.
4.10.50. 40-Furan-2-yl-2-pyrrolidin-1-ylmethyl-biphenyl-
4-ylamine 14i. Synthesized from compound 12i (76 mg,
0.278 mmol) and SnCl2 (211 mg) in HCl (0.84 mL) and
THF (25 mL) according to general procedure A (reflux for
18 h). The residue was purified by TLC (DCM/MeOH/
NH4OH, 9.5/0.5/0.2) to yield compound 14i as a yellow
oil (30 mg, 44% yield); Rf 0.4 (DCM/MeOH/NH4OH, 9.5/
0.5/0.2); HPLC (C18—10 min) PHPLC 98%, tR 3.05 min;
4.10.47. 1-(40-Amino-20-pyrrolidin-1-ylmethyl-biphenyl-
4-yl)-ethanone 14f. Synthesized from compound 12f
(158 mg, 0.488 mmol) and SnCl2 (370 mg) in HCl
(1.47 mL) and THF (25 mL) according to general procedure
A (reflux for 4 h). The residue was purified by TLC (DCM/
MeOH/NH4OH, 9.5/0.5/0.2) to yield compound 14f as a yel-
low oil (102 mg, 71% yield); Rf 0.5 (DCM/MeOH/NH4OH,
9.5/0.5/0.2); HPLC (C18—10 min) PHPLC 99%, tR 3.46 min;
1H NMR (CDCl3) d 7.96 (2H, m, Ph), 7.46 (2H, m, Ph),
3
1H NMR (CDCl3) d 7.44 (1H, dd, Fur–H5, J5,4¼1.8 Hz,
4
4J5,3¼0.9 Hz), 7.41 (1H, d, Ar–H3, J3,4¼8.4 Hz), 6.90
4
(1H, d, Ar–H6, J6,4¼2.4 Hz), 6.61 (1H, dd, Ar–H4,
4
3
3J4,3¼8.4 Hz, J4,6¼2.4 Hz), 6.96 (1H, dd, Fur–H3, J3,4
¼
3.3 Hz, 4J3,5¼0.9 Hz), 6.57 (1H, dd, Fur–H4, 3J4,3¼3.3 Hz,
3J4,5¼1.8 Hz), 3.95 (2H, s large, NH2), 3.73 (2H, s, CH2),
2.57–2.62 (4H, m, N–CH2), 1.77–1.81 (4H, m, CH2); 13C
NMR (CDCl3) d 140.9 (Fur–C5), 129.3 (Ar–C3), 116.1
(Ar–C6), 113.6 (Ar–C4), 111.1 (Fur–C4), 107.3 (Fur–C3),
57.9 (CH2), 53.9 (2C, N–CH2), 23.4 (2C, CH2); m/z 243.2
[M+H]+.
4
7.05 (1H, d, Ar–H3, J3,4¼8.2 Hz), 6.95 (1H, d, Ar–H6,
3
4
4J6,4¼2.4 Hz), 6.63 (1H, dd, Ar–H4, J4,3¼8.2 Hz, J4,6
¼
2.4 Hz), 4.05 (2H, s large, NH2), 3.54 (2H, s, CH2), 2.63
(3H, s, CO–CH3), 2.45–2.50 (4H, m, N–CH2), 1.71–1.78
(4H, m, CH2); 13C NMR (CDCl3) d 130.8 (Ar–C3), 129.9
(2C, Ph), 128.0 (2C, Ph), 116.0 (Ar–C6), 113.7 (Ar–C4),
57.3 (CH2), 53.8 (2C, N–CH2), 26.6 (CO–CH2), 23.4 (2C,
CH2); m/z 295.3 [M+H]+.
4.10.51. 40-Chloro-2-pyrrolidin-1-ylmethyl-biphenyl-4-
ylamine 14k. Synthesized from compound 12k (129 mg,
0.407 mmol) and SnCl2 (309 mg) in HCl (1.23 mL) and
THF (10 mL) according to general procedure A (reflux for
16 h). The residue was purified by TLC (DCM/MeOH/
NH4OH, 9.5/0.5/0.2) to yield compound 14k as a yellow
oil (69 mg, 59% yield); Rf 0.5 (DCM/MeOH/NH4OH, 9.5/
0.5/0.2); HPLC (C18—10 min) PHPLC 98%, tR 4.17 min;
1H NMR (CDCl3) d 7.32 (2H, m, Ph), 7.26 (2H, m, Ph),
4.10.48. 40-Fluoro-2-pyrrolidin-1-ylmethyl-biphenyl-4-
ylamine 14g. Synthesized from compound 12g (78 mg,
0.258 mmol) and SnCl2 (196 mg) in HCl (0.84 mL) and
THF (25 mL) according to general procedure A (reflux for
2 h). The residue was purified by TLC (DCM/MeOH/
3
6.99 (1H, d, Ar–H3, J3,4¼8.1 Hz), 6.92 (1H, d, Ar–H6,

E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
12805
3
4J6,4¼2.5 Hz), 6.60 (1H, dd, Ar–H4, J4,3¼8.1 Hz,
4J4,6¼2.5 Hz), 3.90 (2H, s large, NH2), 3.50 (2H, s, CH2),
2.44–2.49 (4H, m, N–CH2), 1.68–1.77 (4H, m, CH2); 13C
NMR (CDCl3) d 131.3 (2C, Ph), 131.1 (Ar–C3), 128.2
(2C, Ph), 116.2 (Ar–C6), 113.9 (Ar–C4), 57.5 (CH2), 54.1
(2C, N–CH2), 23.6 (2C, CH2); m/z 287.2–289.2 [M+H]+.
C3), 54.3 (CH2), 46.8 (2C, N–CH2), 11.6 (2C, CH3); m/z
416.3–418.3 [M+H]+.
4.10.55. (7-Chloro-quinolin-4-yl)-(2-diethylamino-
methyl-40-methyl-biphenyl-4-yl)-amine 9b. Synthesized
from compound 13b (101 mg, 0.376 mmol) and 4,7-
diClQuin (74 mg) in HCl (0.38 mL) and CH3CN (10 mL)
according to general procedure B (reflux for 5 h). The resi-
due was purified by TLC (DCM/MeOH/NH4OH, 9.5/0.5/
0.2) to yield the expected compound 9b as a yellow solid
(158 mg, 79% yield); Rf 0.6 (DCM/MeOH/NH4OH, 9.5/
0.5/0.2); mp¼174–175 ꢀC; HPLC (C18—10 min) PHPLC
99%, tR 4.44 min; HPLC (C18—40 min) PHPLC 99%, tR
18.81 min; HPLC (C4—40 min) PHPLC 99%, tR 18.26 min;
4.10.52. 4-Methyl-3-pyrrolidin-1-ylmethyl-phenylamine
14l. Synthesized from compound 12l (100 mg,
0.453 mmol) and SnCl2 (343 mg) in HCl (1.36 mL) and
THF (10 mL) according to general procedure A (reflux for
16 h). The residue was purified by TLC (DCM/MeOH/
NH4OH, 9.5/0.5/0.2) to yield compound 14l as a yellow
oil (69 mg, 44% yield); Rf 0.4 (DCM/MeOH/NH4OH, 9.5/
0.5/0.2); HPLC (C18—10 min) PHPLC 99%, tR 0.65–
2.26 min; 1H NMR (CDCl3) d 6.83 (1H, d, Ar–H3,
3
1H NMR (CDCl3) d 8.48 (1H, d, Quin–H2, J2,3¼5.5 Hz),
3
8.07 (1H, d, Quin–H5, J5,6¼9.0 Hz), 7.95 (1H, d, Quin–
3J3,4¼7.9 Hz), 6.64 (1H, d, Ar–H6, J6,4¼2.5 Hz), 6.40
H8, J8,6¼2.1 Hz), 7.65 (1H, d, Ar–H6, J6,4¼1.5 Hz), 7.33
4
4
4
3
4
3
4
(1H, dd, Ar–H4, J4,3¼7.9 Hz, J4,6¼2.5 Hz), 3.44 (2H, s,
CH2), 2.43–2.49 (4H, m, N–CH2), 2.14 (3H, s, Ar–CH3),
1.65–1.93 (4H, m, CH2); 13C NMR (CDCl3) d 130.9
(Ar–C3), 116.4 (Ar–C6), 113.8 (Ar–C4), 58.0 (CH2), 54.6
(2C, N–CH2), 23.7 (2C, CH2), 18.5 (Ar–CH3); m/z 191.2
[M+H]+.
(1H, dd, Quin–H6, J6,5¼8.9 Hz, J6,8¼2.1 Hz), 7.18–7.26
(6H, m, Ph, Ar–H3, Ar–H4), 7.03 (1H, d, Quin–H3,
3J3,2¼5.5 Hz), 3.56 (2H, s, CH2), 2.45 (4H, q, N–CH2,
3J¼7.1 Hz), 2.40 (3H, s, CH3), 0.90 (6H, t, CH3,
3J¼7.1 Hz); 13C NMR (CDCl3) d 151.5 (Quin–C2), 131.0
(Ar–C3), 129.3 (2C, Ph), 128.8 (2C, Ph), 128.1 (Quin–C8),
125.8 (Quin–C6), 123.5 (Ar–C6), 122.3 (Quin–C5), 20.7
(Ar–C4), 102.3 (Quin–C3), 54.3 (CH2), 46.8 (2C, N–CH2),
21.2 (CH3), 11.5 (2C, CH3); m/z 430.4–432.4 [M+H]+.
4.10.53. 4-Ethyl-3-pyrrolidin-1-ylmethyl-phenylamine
14m. Synthesized from compound 12m (64 mg,
0.271 mmol) and SnCl2 (206 mg) in HCl (0.82 mL) and
THF (20 mL) according to general procedure A (reflux for
6 h). The residue was purified by TLC (DCM/MeOH/
NH4OH, 9.5/0.5/0.2) to yield compound 14m as a yellow
oil (35 mg, 63% yield); Rf 0.5 (DCM/MeOH/NH4OH, 9.5/
0.5/0.2); HPLC (C18—10 min) PHPLC 91%, tR 0.65–
2.82 min; 1H NMR (CDCl3) d 6.95 (1H, d, Ar–H3,
4.10.56. (40-tert-Butyl-2-diethylaminomethyl-biphenyl-4-
yl)-(7-chloro-quinolin-4-yl)-amine 9c. Synthesized from
compound 13c (74 mg, 0.237 mmol) and 4,7-diClQuin
(45 mg) in HCl (0.24 mL) and CH3CN (15 mL) according
to general procedure B (reflux for 16 h). The residue was pu-
rified by TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to yield
the expected compound 9c as a white solid (93 mg, 83%
yield); Rf 0.6 (DCM/MeOH/NH4OH, 9.5/0.5/0.2);
mp¼213–214 ꢀC; HPLC (C18—10 min) PHPLC 98%, tR
5.01 min; HPLC (C18—40 min) PHPLC 99%, tR 21.62 min;
3J3,4¼8.0 Hz), 6.71 (1H, d, Ar–H6, J6,4¼2.5 Hz), 6.54
4
3
4
(1H, dd, Ar–H4, J4,3¼8.0 Hz, J4,6¼2.5 Hz), 3.57 (2H, s,
CH2), 3.35–3.55 (2H, large signal, NH2), 2.60 (2H, q,
3
Ar–CH2, J¼7.5 Hz), 2.52–2.57 (4H, m, N–CH2), 1.74–
1.83 (4H, m, CH2), 1.15 (3H, t, CH3, 3J¼7.5 Hz); 13C
NMR (CDCl3) d 129.3 (Ar–C3), 116.2 (Ar–C6), 113.7
(Ar–C4), 57.3 (CH2), 54.2 (2C, N–CH2), 24.9 (Ar–CH2),
23.3 (2C, CH2), 15.6 (CH3); m/z 205.1 [M+H]+.
HPLC (C4—40 min) PHPLC 99%, tR 21.07 min; H NMR
(CDCl3) d 8.56 (1H, d, Quin–H2, J2,3¼5.3 Hz), 8.03 (1H,
1
3
4
d, Quin–H8, J8,6¼2.1 Hz), 7.91 (1H, d, Quin–H5,
4
3J5,6¼9.0 Hz), 7.63 (1H, d, Ar–H6, J6,4¼2.1 Hz), 7.46
3
4
(1H, dd, Quin–H6, J6,5¼9.0 Hz, J6,8¼2.1 Hz), 7.42 (2H,
3
4.10.54. (7-Chloro-quinolin-4-yl)-(2-diethylamino-
methyl-biphenyl-4-yl)-amine 9a. Synthesized from com-
pound 13a (29 mg, 0.113 mmol) and 4,7-diClQuin (22 mg)
in HCl (0.11 mL) and CH3CN (10 mL) according to general
procedure B (reflux for 3 h). The residue was purified by
TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to yield the ex-
pected compound 9a as a white solid (32 mg, 68% yield);
Rf 0.6 (DCM/MeOH/NH4OH, 9.5/0.5/0.2); mp¼174–
175 ꢀC; HPLC (C18—10 min) PHPLC 98%, tR 4.25 min;
HPLC (C18—40 min) PHPLC 99%, tR 17.62 min; HPLC
(C4—40 min) PHPLC 97%, tR 17.20 min; 1H NMR
d, Ph, J¼6.6 Hz), 7.23–7.28 (4H, m, Ph, Ar–H3, Ar–H4),
3
7.07 (1H, d, Quin–H3, J3,2¼5.3 Hz), 6.83 (1H, s large,
3
NH), 3.55 (2H, s, CH2), 2.46 (4H, q, N–CH2, J¼7.1 Hz),
1.38 (9H, s, t-Bu), 0.93 (6H, t, CH3, 3J¼7.1 Hz); 13C
NMR (CDCl3) d 152.1 (Quin–C2), 131.2 (Ar–C3), 129.2
(2C, Ph), 129.1 (Quin–C8), 126.1 (Quin–C6), 125.1 (2C,
Ph), 123.3 (Ar–C6), 121.4 (Quin–C5), 120.3 (Ar–C4),
102.6 (Quin–C3), 54.5 (CH2), 47.1 (2C, N–CH2), 31.5 (3C,
t-Bu), 11.9 (2C, CH3); m/z 472.3–474.3 [M+H]+.
4.10.57. (7-Chloro-quinolin-4-yl)-(2-diethylamino-
methyl-40-trifluoromethyl-biphenyl-4-yl)-amine 9d. Syn-
thesized from compound 13d (86 mg, 0.267 mmol) and
4,7-diClQuin (53 mg) in HCl (0.27 mL) and CH3CN
(15 mL) according to general procedure B (reflux for
16 h). The residue was purified by TLC (DCM/MeOH/
NH4OH, 9.5/0.5/0.2) to yield the expected compound 9d
as a white solid (108 mg, 84% yield); Rf 0.7 (DCM/
MeOH/NH4OH, 9.5/0.5/0.2); mp¼214–215 ꢀC; HPLC
(C18—10 min) PHPLC 99%, tR 4.65 min; HPLC (C18—
40 min) PHPLC 99%, tR 19.67 min; HPLC (C4—40 min)
3
(CDCl3) d 8.56 (1H, d, Quin–H2, J2,3¼5.4 Hz), 8.02 (1H,
4
d, Quin–H8, J8,6¼2.1 Hz), 7.93 (1H, d, Quin–H5,
3J5,6¼9.0 Hz), 7.65 (1H, s, Ar–H6), 7.31–7.45 (6H, m,
Quin–H6, Ph), 7.24–7.26 (2H, m, Ar–H3, Ar–H4), 7.07
(1H, d, Quin–H3, J3,2¼5.4 Hz), 7.01 (1H, s large, NH),
3
3
3.52 (2H, s, CH2), 2.45 (4H, q, N–CH2, J¼7.2 Hz), 0.92
(4H, t, CH3, 3J¼7.2 Hz); 13C NMR (CDCl3) d 151.8
(Quin–C2), 130.9 (Ar–C3), 129.4 (2C, Ph), 128.8 (Quin–
C8), 128.0 (2C, Ph), 126.9 (Ph), 125.9 (Quin–C6), 123.1
(Ar–C6), 121.3 (Quin–C5), 120.2 (Ar–C4), 102.4 (Quin–

12806
E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
1
PHPLC 99%, tR 19.56 min; H NMR (CDCl3) d 8.58 (1H,
d, Quin–H2, J2,3¼5.3 Hz), 8.04 (1H, d, Quin–H8,
4.10.60. 7-Chloro-N-(2-((diethylamino)methyl)-40-fluo-
robiphenyl-4-yl)quinolin-4-amine 9g. Synthesized from
compound 13g (40 mg, 0.148 mmol) and 4,7-diClQuin
(29 mg) in HCl (0.15 mL) and CH3CN (15 mL) according
to general procedure B (reflux for 8 h). The residue was pu-
rified by TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to yield
the expected compound 9g as a white solid (42 mg, 66%
yield); Rf 0.7 (DCM/MeOH/NH4OH, 9.5/0.5/0.2);
mp¼167–168 ꢀC; HPLC (C18—10 min) PHPLC 98%, tR
4.08 min; HPLC (C18—40 min) PHPLC >99%, tR
17.92 min; HPLC (C4—40 min) PHPLC 98%, tR 17.50 min;
3
4J8,6¼2.1 Hz), 7.92 (1H, d, Quin–H5, J5,6¼9.0 Hz), 7.68
3
(2H, d, Ph, 3J¼7.9 Hz), 7.62 (1H, d, Ar–H6, 4J6,4¼1.7 Hz),
7.45–7.49 (3H, m, Quin–H6, Ph), 7.22–7.28 (2H, m, Ar–
3
H3, Ar–H4), 7.09 (1H, d, Quin–H3, J3,2¼5.3 Hz), 6.84
(1H, s large, NH), 3.49 (2H, s, CH2), 2.44 (4H, q, N–CH2,
3J¼7.1 Hz), 0.92 (6H, t, CH3, 3J¼7.1 Hz); 13C NMR
(CDCl3) d 151.9 (Quin–C2), 130.8 (Ar–C3), 129.7 (2C,
Ph), 128.9 (Quin–C8), 126.1 (Quin–C6), 124.9 (2C, Ph,
3JCH,F¼3.6 Hz), 123.1 (Ar–C6), 121.2 (Quin–C5), 120.1
(Ar–C4), 102.6 (Quin–C3), 54.6 (CH2), 46.7 (2C, N–CH2),
11.7 (2C, CH3); m/z 484.3–486.2 [M+H]+.
3
1H NMR (CDCl3) d 8.57 (1H, d, Quin–H2, J2,3¼5.4 Hz),
4
8.03 (1H, d, Quin–H8, J8,6¼2.1 Hz), 7.95 (1H, d, Quin–
3
4
H5, J5,6¼9.0 Hz), 7.63 (1H, d, Ar–H6, J6,4¼2.1 Hz), 7.47
3
4
4.10.58. (7-Chloro-quinolin-4-yl)-(2-diethylamino-
methyl-40-methoxy-biphenyl-4-yl)-amine 9e. Synthesized
from compound 13e (46 mg, 0.162 mmol) and 4,7-diClQuin
(32 mg) in HCl (0.17 mL) and CH3CN (10 mL) according
to general procedure B (reflux for 5 h). The residue was
purified by TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to
yield the expected compound 9e as a yellow solid (66 mg,
91% yield); Rf 0.5 (DCM/MeOH/NH4OH, 9.5/0.5/0.2);
mp¼155–156 ꢀC; HPLC (C18—10 min) PHPLC 99%, tR
4.30 min; HPLC (C18—40 min) PHPLC 98%, tR 18.08 min;
(1H, d, Quin–H6, J6,5¼9.0 Hz, J6,8¼2.1 Hz), 7.23–7.33
(4H, m, Ph, Ar–H3, Ar–H4), 7.14 (2H, m, Ph), 7.07 (1H, d,
Quin–H3, J3,2¼5.4 Hz), 3.60 (2H, s, CH2), 3.49 (1H, s,
3
3
NH), 2.54 (4H, q, N–CH2, J¼7.1 Hz), 0.96 (6H, t, CH3,
3J¼7.1 Hz); 13C NMR (CDCl3) d 151.7 (Quin–C2), 131.0
4
(Ar–C3), 130.9 (2C, d, Ph, JCH,F¼8.0 Hz), 128.7 (Quin–
C8), 126.0 (Quin–C6), 123.1 (Ar–C6), 121.3 (Quin–C5),
120.3 (Ar–C4), 115.0 (2C, d, Ph, JCH,F¼21.2 Hz), 102.4
3
(Quin–C3), 54.1 (CH2), 46.6 (2C, N–CH2), 11.0 (2C,
CH3); m/z 434.3–436.3 [M+H]+.
1
HPLC (C4—40 min) PHPLC 99%, tR 17.44 min; H NMR
(CDCl3) d 8.52 (1H, d, Quin–H2, J2,3¼5.4 Hz), 8.00 (1H,
3
4.10.61. (7-Chloro-quinolin-4-yl)-(2-diethylamino-
methyl-40-thiophen-2-ylbiphenyl-4-yl)-amine 9h. Synthe-
sized from compound 13h (29 mg, 0.113 mmol) and
4,7-diClQuin (22 mg) in HCl (0.11 mL) and CH3CN
(10 mL) according to general procedure B (reflux for 4 h).
The residue was purified by TLC (DCM/NH4OH, 10/0.2)
to yield the expected compound 9h as a orange solid
(41 mg, 87% yield); Rf 0.6 (DCM/NH4OH, 10/0.2);
mp¼154–155 ꢀC; HPLC (C18—10 min) PHPLC 98%, tR
3.92 min; HPLC (C18—40 min) PHPLC 99%, tR 17.36 min;
3
4
d, Quin–H5, J5,6¼8.9 Hz), 7.98 (1H, d, Quin–H8, J8,6
¼
4
2.2 Hz), 7.63 (1H, d, Ar–H6, J6,4¼1.4 Hz), 7.62 (1H, dd,
3
4
Quin–H6, J6,5¼8.9 Hz, J6,8¼2.2 Hz), 7.21–7.27 (4H, m,
3
Ph, Ar–H3, Ar–H4), 7.04 (1H, d, Quin–H3, J3,2¼5.4 Hz),
3
6.96 (2H, d, Ph, J3,4¼8.2 Hz), 3.86 (3H, s, O–CH3), 3.59
3
(2H, s, CH2), 2.50 (4H, q, N–CH2, J¼7.1 Hz), 0.93 (6H,
t, CH3, 3J¼7.1 Hz); 13C NMR (CDCl3) d 151.7 (Quin–C2),
131.2 (Ar–C3), 130.9 (2C, Ph), 128.5 (Quin–C8), 126.0
(Quin–C6), 123.5 (Ar–C6), 121.9 (Quin–C5), 120.7 (Ar–
C4), 113.6 (2C, Ph), 102.4 (Quin–C3), 55.3 (O–CH3), 54.3
(CH2), 46.8 (2C, N–CH2), 11.3 (2C, CH3); m/z 446.3–
448.3 [M+H]+.
1
HPLC (C4—40 min) PHPLC 97%, tR 10.79 min; H NMR
(CDCl3) d 8.53 (1H, d, Quin–H2, J2,3¼5.4 Hz), 8.03 (1H,
3
3
d, Quin–H5, J5,6¼9.0 Hz), 7.98 (1H, d, Quin–H8,
4
4J8,6¼2.1 Hz), 7.66 (1H, d, Ar–H6, J6,4¼2.4 Hz), 7.35–
4.10.59. 1-[40-(7-Chloro-quinolin-4-ylamino)-20-diethyl-
aminomethyl-biphenyl-4-yl]-ethanone 9f. Synthesized
from compound 13f (54 mg, 0.184 mmol) and 4,7-diClQuin
(36 mg) in HCl (0.19 mL) and CH3CN (10 mL) according to
general procedure B (reflux for 5 h). The residue was puri-
fied by TLC (DCM/NH4OH, 10/0.2) to yield the expected
compound 9f as a white solid (54 mg, 64% yield); Rf 0.4
(DCM/NH4OH, 10/0.2); mp¼141–142 ꢀC; HPLC (C18—
10 min) PHPLC 98%, tR 4.13 min; HPLC (C18—40 min)
PHPLC 98%, tR 17.09 min; HPLC (C4—40 min) PHPLC
98%, tR 16.42 min; 1H NMR (CDCl3) d 8.46 (1H, d, Quin–
7.41 (3H, m, Ar–H3, Quin–H6, Thio–H5), 7.25 (1H, dd,
Ar–H4, J4,3¼8.4 Hz, J4,6¼2.4 Hz), 7.05–7.13 (3H, m,
3
4
Thio–H3, Thio–H4, Quin–H3), 3.76 (2H, s, CH2), 2.58 (4H,
3
3
q, N–CH2, J¼7.2 Hz), 0.98 (6H, t, CH3, J¼7.2 Hz); 13C
NMR (CDCl3) d 151.5 (Quin–C2), 132.2 (Ar–C3), 128.5
(Quin–C8), 127.4 (2C, Thio–C3, Thio–C4), 126.3 (Thio–
C5), 125.8 (Quin–C6), 123.4 (Ar–C6), 122.1 (Quin–C5),
120.5 (Ar–C4), 102.8 (Quin–C3), 54.6 (CH2), 46.9 (2C,
N–CH2), 11.2 (2C, CH3); m/z 422.3–424.3 [M+H]+.
4.10.62. (7-Chloro-quinolin-4-yl)-(2-diethylamino-
methyl-40-furan-2-yl-biphenyl-4-yl)-amine 9i. Synthe-
sized from compound 13i (22 mg, 0.088 mmol) and
4,7-diClQuin (18 mg) in HCl (0.09 mL) and CH3CN
(10 mL) according to general procedure B (reflux for 4 h).
The residue was purified by TLC (DCM/MeOH/NH4OH,
9.5/0.5/0.2) to yield the expected compound 9i as a yellow
solid (26 mg, 73% yield); Rf 0.6 (DCM/MeOH/NH4OH,
9.5/0.5/0.2); mp¼146–147 ꢀC; HPLC (C18—10 min)
PHPLC 98%, tR 3.73 min; HPLC (C18—40 min) PHPLC
96%, tR 16.48 min; HPLC (C4—40 min) PHPLC 96%, tR
10.05 min; 1H NMR (CDCl3) d 8.53 (1H, d, Quin–H2,
3
3
H2, J2,3¼5.4 Hz), 8.01 (1H, d, Quin–H5, J5,6¼9.0 Hz),
4
7.90 (2H, m, Ph), 7.86 (1H, d, Quin–H8, J8,6¼2.1 Hz),
4
7.59 (1H, d, Ar–H6, J6,4¼2.1 Hz), 7.36 (2H, m, Ph), 7.31
3
4
(1H, dd, Quin–H6, J6,5¼9.0 Hz, J6,8¼2.1 Hz), 7.22 (1H,
3
4
dd, Ar–H4, J4,3¼8.2 Hz, J4,6¼2.3 Hz), 7.16 (1H, d, Ar–
3
3
H3, J3,4¼8.2 Hz), 6.98 (1H, d, Quin–H3, J3,2¼5.4 Hz),
3.49 (2H, s, CH2), 2.53 (3H, s, CO–CH2), 2.38 (4H, q, N–
CH2, J¼7.1 Hz), 0.80 (6H, t, CH3, J¼7.1 Hz); 13C NMR
(CDCl3) d 152.4 (Quin–C2), 131.8 (Ar–C3), 130.7 (2C, Ph),
129.1 (Quin–C8), 129.1 (2C, Ph), 126.8 (Quin–C6), 124.4
(Ar–C6), 123.3 (Quin–C5), 121.5 (Ar–C4), 103.5 (Quin–
C3), 55.5 (CH2), 47.6 (2C, N–CH2), 27.5 (1C, C-60), 12.0
(2C, CH3); m/z 458.3–460.3 [M+H]+.
3
3
4
3J2,3¼5.4 Hz), 7.99 (1H, d, Quin–H8, J8,6¼2.1 Hz), 7.98
3
(1H, d, Quin–H5, J5,6¼9.0 Hz), 7.66 (1H, d, Ar–H6,

E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
12807
4J6,4¼2.2 Hz), 7.60 (1H, d, Ar–H3, 3J3,4¼8.4 Hz), 7.52 (1H,
4.10.65. (7-Chloro-quinolin-4-yl)-(3-diethylamino-
methyl-4-methyl-phenyl)-amine 9l. Synthesized from
compound 13l (51 mg, 0.263 mmol) and 4,7-diClQuin
(52 mg) in HCl (0.27 mL) and CH3CN (25 mL) according
to general procedure B (reflux for 16 h). The residue was pu-
rified by TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to yield
the expected compound 9l as a white-yellow solid (92 mg,
98% yield); Rf 0.4 (DCM/MeOH/NH4OH, 9.5/0.5/0.2);
mp¼151–152 ꢀC; HPLC (C18—10 min) PHPLC 93%, tR
4.19 min; HPLC (C18—40 min) PHPLC 93%, tR 14.84 min;
HPLC (C4—40 min) PHPLC >99%, tR 13.92 min; 1H
3
3
d, Fur–H5, J5,4¼1.8 Hz), 7.40 (1H, dd, Quin–H6, J6,5
¼
4
3
9.0 Hz, J6,8¼2.1 Hz), 7.27 (1H, dd, Ar–H4, J4,3¼8.4 Hz,
4J4,6¼2.2 Hz), 7.05 (1H, d, Quin–H3, J3,2¼5.4 Hz), 6.56
3
3
(1H, d, Fur–H3, J3,4¼3.3 Hz), 6.51 (1H, dd, Fur–H4,
3J4,3¼3.3 Hz, J4,5¼1.8 Hz), 3.87 (2H, s, CH2), 2.65 (4H,
3
q, N–CH2, J¼7.1 Hz), 1.05 (6H, t, CH3, J¼7.1 Hz); 13C
NMR (CDCl3) d 151.6 (Quin–C2), 142.0 (Fur–C5), 129.4
(Ar–C3), 128.5 (Quin–C8), 126.2 (Quin–C6), 123.2 (Ar–
C6), 121.9 (Quin–C5), 120.4 (Ar–C4), 111.5 (Fur–C4),
109.0 (Fur–C3), 102.9 (Quin–C3), 55.1 (CH2), 47.0 (2C,
N–CH2), 11.2 (2C, CH3); m/z 406.3–408.3 [M+H]+.
3
3
3
NMR (CDCl3) d 8.45 (1H, d, Quin–H2, J2,3¼5.4 Hz),
3
7.97 (1H, d, Quin–H5, J5,6¼8.9 Hz), 7.95 (1H, d, Quin–
4
4.10.63. 7-Chloro-N-(2-((diethylamino)methyl)-20-fluo-
robiphenyl-4-yl)quinolin-4-amine 9j. Synthesized from
compound 13j (53 mg, 0.196 mmol) and 4,7-diClQuin
(39 mg) in HCl (0.20 mL) and CH3CN (10 mL) according
to general procedure B (reflux for 16 h). The residue was
purified by TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to
yield the expected compound 9g as a white solid (70 mg,
82% yield); Rf 0.6 (DCM/MeOH/NH4OH, 9.5/0.5/0.2);
mp¼180–181 ꢀC; HPLC (C18—10 min) PHPLC 95%, tR
4.12 min; HPLC (C18—40 min) PHPLC >99%, tR
17.87 min; HPLC (C4—40 min) PHPLC 96%, tR 17.37 min;
H8, J8 ,6 ¼2.0 Hz), 7.25–7.55 (1H, s large, NH), 7.34 (1H,
0
0
4
3
d, Ar–H6, J6,4¼2.2 Hz), 7.33 (1H, dd, Quin–H6, J6,5
¼
4
3
8.9 Hz, J6,8¼2.0 Hz), 7.14 (1H, d, Ar–H3, J3,4¼8.1 Hz),
3
4
7.08 (1H, dd, Ar–H4, J4,3¼8.1 Hz, J4,6¼2.2 Hz), 6.85
3
(1H, d, Quin–H3, J3,2¼5.4 Hz), 3.50 (2H, s, CH2), 2.51
3
(4H, q, N–CH2, J¼7.2 Hz), 2.34 (3H, s, Ar–CH3), 1.01
(6H, t, CH3, 3J¼7.2 Hz); 13C NMR (CDCl3) d 151.6
(Quin–C2), 131.1 (Ar–C3), 128.4 (Quin–C8), 125.7 (Quin–
C6), 124.2 (Ar–C6), 121.9 (Quin–C5), 121.5 (Ar–C4),
101.8 (Quin–C3), 55.3 (CH2), 47.0 (2C, N–CH2), 18.8
(Ar–CH3), 11.7 (2C, CH3); m/z 354.3–356.3 [M+H]+.
3
1H NMR (CDCl3) d 8.58 (1H, d, Quin–H2, J2,3¼5.3 Hz),
4
8.03 (1H, d, Quin–H8, J8,6¼2.1 Hz), 7.93 (1H, d, Quin–
4.10.66. (7-Chloro-quinolin-4-yl)-(3-diethylamino-
methyl-4-ethyl-phenyl)-amine 9m. Synthesized from com-
pound 13m (68 mg, 0.328 mmol) and 4,7-diClQuin (65 mg)
in HCl (0.33 mL) and CH3CN (25 mL) according to general
procedure B (reflux for 18 h). The residue was purified by
TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to yield the ex-
pected compound 9m as a white-yellow solid (117 mg,
97% yield); Rf 0.5 (DCM/MeOH/NH4OH, 9.5/0.5/0.2);
mp¼167–168 ꢀC; HPLC (C18—10 min) PHPLC 99%, tR
3.51 min; HPLC (C18—40 min) PHPLC 95%, tR 15.71 min;
4
H5, 3J5,6¼9.0 Hz), 7.66 (1H, d, Ar–H6, J6,4¼1.9 Hz), 7.46
3
4
00 00
(1H, dd, Quin–H6, J6,5¼9.0 Hz, J6 ,8 ¼2.1 Hz), 7.34–
7.42 (1H, m, Ph), 7.22–7.30 (4H, m, Ph, Ar–H3, Ar–H4),
7.15–7.09 (1H, m, Ph), 7.12 (1H, d, Quin–H3, J3,2
3
¼
5.3 Hz), 6.85–7.05 (1H, s large, NH), 3.49 (2H, s, CH2),
2.44 (4H, q, N–CH2, 3J¼7.1 Hz), 0.92 (6H, t, CH3,
3J¼7.1 Hz); 13C NMR (CDCl3) d 151.7 (Quin–C2), 131.4
3
(Ph–C5), 131.1 (Ar–C3), 129.1 (d, Ph–C4, J4,F¼7.4 Hz),
128.7 (Quin–C8), 126.9 (Quin–C6), 123.8 (d, Ph–C6,
3J6,F¼3.5 Hz), 122.4 (Ar–C6), 121.1 (Quin–C5), 119.7
HPLC (C4—40 min) PHPLC 99%, tR 14.88 min; H NMR
(CDCl3) d 8.45 (1H, d, Quin–H2, J2,3¼5.4 Hz), 7.99 (1H,
1
2
3
(Ar–C4), 115.2 (d, Ph–C3, J3,F¼22.2 Hz), 102.5 (Quin–
3
4
C3), 54.1 (CH2), 46.8 (2C, N–CH2), 11.4 (2C, CH3); m/z
d, Quin–H5, J5,6¼9.0 Hz), 7.95 (1H, d, Quin–H8, J8,6¼
434.0–436.0 [M+H]+.
2.1 Hz), 7.40–7.70 (1H, s large, NH), 7.39 (1H, d, Ar–H6,
4J6,4¼2.1 Hz), 7.32 (1H, dd, Quin–H6, J6,5¼9.0 Hz,
3
3
4.10.64. (40-Chloro-2-diethylaminomethyl-biphenyl-4-
yl)-(7-chloro-quinolin-4-yl)-amine 9k. Synthesized from
compound 13k (78 mg, 0.269 mmol) and 4,7-diClQuin
(53 mg) in HCl (0.27 mL) and CH3CN (10 mL) according
to general procedure B (reflux for 5 h). The residue was pu-
rified by TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to yield
the expected compound 9k as a white solid (109 mg, 90%
yield); Rf 0.5 (DCM/MeOH/NH4OH, 9.5/0.5/0.2); mp¼
179–180 ꢀC; HPLC (C18—10 min) PHPLC 97%, tR
4.51 min; HPLC (C18—40 min) PHPLC 99%, tR 19.07 min;
HPLC (C4—40 min) PHPLC >99%, tR 18.51 min; 1H
4J6,8¼2.1 Hz), 7.18 (1H, d, Ar–H3, J3,4¼7.5 Hz), 7.12
3
4
(1H, dd, Ar–H4, J4,3¼7.5 Hz, J4,6¼2.1 Hz), 6.88 (1H, d,
3
Quin–H3, J3,2¼5.4 Hz), 3.53 (2H, s, CH2), 2.71 (2H, q,
Ar–CH2, 3J¼7.5 Hz), 2.50 (4H, q, N–CH2, 3J¼7.1 Hz),
1.23 (3H, t, CH3, 3J¼7.5 Hz), 1.00 (6H, t, CH3,
3J¼7.1 Hz); 13C NMR (CDCl3) d 151.4 (Quin–C2), 129.4
(Ar–C3), 128.2 (Quin–C8), 125.6 (Quin–C6), 124.3 (Ar–
C6), 121.9 (Quin–C5), 121.6 (Ar–C4), 101.8 (Quin–C3),
54.7 (CH2), 46.9 (2C, N–CH2), 24.9 (Ar–CH2), 15.1
(CH3), 11.7 (2C, CH3); m/z 368.2–370.2 [M+H]+.
3
NMR (CDCl3) d 8.50 (1H, d, Quin–H2, J2,3¼5.4 Hz),
4.10.67. (7-Chloro-quinolin-4-yl)-(2-pyrrolidin-1-yl-
methyl-biphenyl-4-yl)-amine 10a. Synthesized from com-
pound 14a (70 mg, 0.277 mmol) and 4,7-diClQuin (55 mg)
in HCl (0.28 mL) and CH3CN (10 mL) according to general
procedure B (reflux for 18 h). The residue was purified by
TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to yield the ex-
pected compound 10a as a white solid (105 mg, 91% yield);
Rf 0.5 (DCM/MeOH/NH4OH, 9.5/0.5/0.2); mp¼183–
184 ꢀC; HPLC (C18—10 min) PHPLC 99%, tR 4.04 min;
HPLC (C18—40 min) PHPLC 98%, tR 17.58 min; HPLC
(C4—40 min) PHPLC >99%, tR 16.92 min; 1H NMR
3
8.05 (1H, d, Quin–H5, J5,6¼9.0 Hz), 7.96 (1H, d, Quin–
4
4
H8, J8,6¼2.1 Hz), 7.62 (1H, d, Ar–H6, J6,4¼2.2 Hz),
7.35–7.41 (3H, m, Ph, Quin–H6), 7.18–7.29 (3H, m, Ph,
Ar–H4), 7.20 (1H, d, Ar–H3, J3,4¼8.2 Hz), 7.04 (1H, d,
3
3
Quin–H3, J3,2¼5.4 Hz), 3.50 (2H, s, CH2), 3.49 (1H, s,
3
NH), 2.46 (4H, q, N–CH2, J¼7.1 Hz), 0.91 (6H, t, CH3,
3J¼7.1 Hz); 13C NMR (CDCl3) d 151.7 (Quin–C2), 131.2
(Ar–C3), 131.1 (2C, Ph), 128.5 (2C, Ph), 128.4 (Quin–C8),
126.2 (Quin–C6), 123.8 (Ar–C6), 122.4 (Quin–C5), 120.9
(Ar–C4), 102.7 (Quin–C3), 54.7 (CH2), 47.0 (2C, N–CH2),
11.7 (2C, CH3); m/z 450.2 [M+H]+.
3
(CDCl3) d 8.45 (1H, d, Quin–H2, J2,3¼5.4 Hz), 7.91 (1H,

12808
E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
3
d, Quin–H5, J5,6¼8.7 Hz), 7.89 (1H, d, Quin–H8,
and 4,7-diClQuin (72 mg) in HCl (0.36 mL) and CH3CN
(25 mL) according to general procedure B (reflux for
16 h). The residue was purified by TLC (DCM/NH4OH,
10/0.2) to yield the expected compound 10d as a white solid
(164 mg, 94% yield); Rf 0.3 (DCM/NH4OH, 10/0.2);
mp¼203–204 ꢀC; HPLC (C18—10 min) PHPLC 99%, tR
5.05 min; HPLC (C18—40 min) PHPLC 98%, tR 19.67 min;
HPLC (C4—40 min) PHPLC >99%, tR 19.46 min; 1H
4J8,6¼2.4 Hz), 7.45 (1H, d, Ar–H6, J6,4¼1.2 Hz), 7.19–
4
7.37 (8H, m, Quin–H6, Ar–H4, Ar–H3, Ph), 7.07 (1H, s large,
3
NH), 6.96 (1H, d, Quin–H3, J3,2¼5.4 Hz), 3.51 (2H, s,
CH2), 2.36–2.38 (4H, m, N–CH2), 1.60–1.64 (4H, m,
CH2); 13C NMR (CDCl3) d 151.3 (Quin–C2), 130.3 (Ar–
C3), 128.7 (2C, Ph), 128.0 (Quin–C8), 127.2 (2C, Ph),
126.3 (Ph), 125.2 (Quin–C6), 122.5 (Ar–C6), 121.0 (Quin–
C5), 119.9 (Ar–C4), 101.7 (Quin–C3), 56.2 (CH2), 53.1
(2C, N–CH2), 22.8 (2C, CH2); m/z 414.3–416.3 [M+H]+.
3
NMR (CDCl3) d 8.59 (1H, d, Quin–H2, J2,3¼5.3 Hz),
4
8.04 (1H, d, Quin–H8, J8,6¼2.1 Hz), 7.93 (1H, d, Quin–
3
3
H5, J5,6¼9.0 Hz), 7.69 (2H, d, Ph, J¼8.1 Hz), 7.53–7.57
3
4.10.68. (7-Chloro-quinolin-4-yl)-(40-methyl-2-pyrroli-
din-1-ylmethyl-biphenyl-4-yl)-amine 10b. Synthesized
from compound 14b (95 mg, 0.356 mmol) and 4,7-diClQuin
(71 mg) in HCl (0.36 mL) and CH3CN (25 mL) according to
general procedure B (reflux for 4 h). The residue was puri-
fied by TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to yield
the expected compound 10b as a white solid (143 mg,
94% yield); Rf 0.7 (DCM/MeOH/NH4OH, 9.5/0.5/0.2);
mp¼174–175 ꢀC; HPLC (C18—10 min) PHPLC 99%, tR
4.33 min; HPLC (C18—40 min) PHPLC 99%, tR 18.74 min;
HPLC (C4—40 min) PHPLC >99%, tR 18.10 min; 1H
(3H, m, Ph, Ar–H6), 7.47 (1H, dd, Quin–H6, J6,5¼9 Hz,
4J6,8¼2.1 Hz), 7.26–7.30 (2H, m, Ar–H3, Ar–H4), 7.08
3
(1H, d, Quin–H3, J3,2¼5.3 Hz), 6.93 (1H, s large, NH),
3.56 (2H, s, CH2), 2.47–2.55 (4H, m, N–CH2), 1.73–1.79
(4H, m, CH2); 13C NMR (CDCl3) d 152.1 (Quin–C2),
131.2 (Ar–C3), 130.1 (2C, Ph), 129.2 (Quin–C8), 126.4
(Quin–C6), 125.2 (2C, Ph), 123.5 (Ar–C6), 121.5 (Quin–
C5), 120.6 (Ar–C4), 103.0 (Quin–C3), 57.4 (CH2), 54.1
(2C, N–CH2), 23.7 (2C, CH2); m/z 482.0–484.0 [M+H]+.
4.10.71. (7-Chloro-quinolin-4-yl)-(40-methoxy-2-pyrroli-
din-1-ylmethyl-biphenyl-4-yl)-amine 10e. Synthesized
from compound 14e (66 mg, 0.232 mmol) and 4,7-diClQuin
(46 mg) in HCl (0.24 mL) and CH3CN (10 mL) according to
general procedure B (reflux for 16 h). The residue was puri-
fied by TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to yield the
expected compound 10e as a white solid (97 mg, 94% yield);
Rf 0.5 (DCM/MeOH/NH4OH, 9.5/0.5/0.2); mp¼160–
161 ꢀC; HPLC (C18—10 min) PHPLC 99%, tR 4.16 min;
HPLC (C18—40 min) PHPLC 98%, tR 18.03 min; HPLC
(C4—40 min) PHPLC 99%, tR 17.31 min; 1H NMR
3
NMR (CDCl3) d 8.56 (1H, d, Quin–H2, J2,3¼5.3 Hz),
4
8.02 (1H, d, Quin–H8, J8,6¼2.1 Hz), 7.91 (1H, d, Quin–
3
4
H5, J5,6¼9.0 Hz), 7.53 (1H, d, Ar–H6, J6,4¼1.5 Hz), 7.44
3
4
(1H, dd, Quin–H6, J6,5¼9.0 Hz, J6,8¼2.1 Hz), 7.22–7.30
(6H, m, Ar–H3, Ar–H3, Ph), 7.05 (1H, d, Quin–H3,
3J3,2¼5.3 Hz), 6.94 (1H, s large, NH), 3.62 (2H, s, CH2),
2.46–2.49 (4H, m, N–CH2), 2.42 (3H, s, CH3), 1.69–1.80
(4H, m, CH2); 13C NMR (CDCl3) d 152.1 (Quin–C2),
131.3 (Ar–C3), 129.6 (2C, Ph), 129.1 (Quin–C8), 128.9
(2C, Ph), 126.2 (Quin–C6), 123.5 (Ar–C6), 121.5 (Quin–
C5), 120.7 (Ar–C4), 102.6 (Quin–C3), 57.3 (CH2), 54.2
(2C, N–CH2), 23.6 (2C, CH2), 21.3 (CH3); m/z 428.1–
430.1 [M+H]+.
3
(CDCl3) d 8.52 (1H, d, Quin–H2, J2,3¼5.4 Hz), 7.98–8.01
(2H, m, Quin–H5, Quin–H8), 7.52 (1H, s, Ar–H6), 7.25–
7.32 (3H, m, Quin–H6, Ph), 7.25–7.27 (2H, m, Ar–H3, Ar–
3
H4), 7.02 (1H, d, Quin–H3, J3,2¼5.4 Hz), 6.95 (2H, d, Ph,
4.10.69. (40-tert-Butyl-2-pyrrolidin-1-ylmethyl-biphenyl-
4-yl)-(7-chloro-quinolin-4-yl)-amine 10c. Synthesized
from compound 14c (135 mg, 0.439 mmol) and 4,7-diCl-
Quin (87 mg) in HCl (0.44 mL) and CH3CN (25 mL)
according to general procedure B (reflux for 4 h). The resi-
due was purified by TLC (DCM/MeOH/NH4OH, 9.5/0.5/
0.2) to yield the expected compound 10c as a white solid
(200 mg, 97% yield); Rf 0.7 (DCM/MeOH/NH4OH, 9.5/
0.5/0.2); mp¼206–207 ꢀC; HPLC (C18—10 min) PHPLC
99%, tR 5.05 min; HPLC (C18—40 min) PHPLC 99%, tR
21.49 min; HPLC (C4—40 min) PHPLC >99%, tR
20.92 min; 1H NMR (CDCl3) d 8.57 (1H, d, Quin–H2,
3J¼8.7 Hz), 3.86 (3H, s, O–CH3), 3.63 (2H, s, CH2), 2.50
(4H, m, N–CH2), 1.72 (4H, m, CH2); 13C NMR (CDCl3)
d 151.6 (Quin–C2), 131.1 (Ar–C3), 130.5 (2C, Ph), 128.4
(Quin–C8), 125.8 (Quin–C6), 123.5 (Ar–C6), 121.8 (Quin–
C5), 120.8 (Ar–C4), 113.5 (2C, Ph), 102.3 (Quin–C3), 56.9
(CH2), 55.2 (CH3), 53.8 (2C, N–CH2), 23.3 (2C, CH2); m/z
444.3–446.3 [M+H]+.
4.10.72. 1-[40-(7-Chloro-quinolin-4-ylamino)-20-pyrroli-
din-1-ylmethyl-biphenyl-4-yl]-ethanone 10f. Synthesized
from compound 14f (102 mg, 0.345 mmol) and 4,7-diCl-
Quin (68 mg) in HCl (0.35 mL) and CH3CN (10 mL)
according to general procedure B (reflux for 18 h). The res-
idue was purified by TLC (DCM/MeOH/NH4OH, 9.5/0.5/
0.2) to yield the expected compound 10f as a yellow solid
(135 mg, 91% yield); Rf 0.5 (DCM/MeOH/NH4OH, 9.5/
0.5/0.2); mp¼207–208 ꢀC; HPLC (C18—10 min) PHPLC
99%, tR 3.87 min; HPLC (C18—40 min) PHPLC 93%, tR
17.12 min; HPLC (C4—40 min) PHPLC 99%, tR 16.33 min;
3J2,3¼5.4 Hz), 8.03 (1H, d, Quin–H8, J8,6¼2.1 Hz), 7.91
4
3
(1H, d, Quin–H5, J5,6¼9.0 Hz), 7.54 (1H, d, Ar–H6,
4J6,4¼2.0 Hz), 7.42–7.48 (3H, m, Ph, Quin–H6), 7.24–7.34
(4H, m, Ph, Ar–H3, Ar–H4), 7.06 (1H, d, Quin–H3,
3J3,2¼5.4 Hz), 6.89 (1H, s large, NH), 3.65 (2H, s, CH2),
2.49–2.54 (4H, m, N–CH2), 1.73–1.78 (4H, m, CH2), 1.39
(9H, s, t-Bu); 13C NMR (CDCl3) d 152.0 (Quin–C2), 131.2
(Ar–C3), 129.2 (2C, Ph), 129.0 (Quin–C8), 126.1 (Quin–
C6), 125.0 (2C, Ph), 123.3 (Ar–C6), 121.3 (Quin–C5), 120.5
(Ar–C4), 102.5 (Quin–C3), 57.1 (CH2), 54.0 (2C, N–CH2),
31.4 (3C, t-Bu), 23.5 (2C, CH2); m/z 470.2–472.2 [M+H]+.
3
1H NMR (CDCl3) d 8.43 (1H, d, Quin–H2, J2,3¼5.4 Hz),
3
8.04 (1H, d, Quin–H5, J5,6¼9.0 Hz), 7.92 (2H, d, Ph,
3
4
0
0
J3 ,2 ¼8.3 Hz), 7.87 (1H, d, Quin–H8, J8,6¼2.1 Hz), 7.54
(1H, d, Ar–H6, 4J6,4¼2.0 Hz), 7.41 (2H, d, Ph, 3J2 ,3 ¼8.3 Hz),
0
0
3
4
7.33 (1H, dd, Quin–H6, J6,5¼9.0 Hz, J6,8¼2.1 Hz), 7.29
3
4
4.10.70. (7-Chloro-quinolin-4-yl)-(2-pyrrolidin-1-yl-
methyl-40-trifluoromethyl-biphenyl-4-yl)-amine 10d.
Synthesized from compound 14d (116 mg, 0.361 mmol)
(1H, dd, Ar–H4, J4,3¼8.3 Hz, J4,6¼2.1 Hz), 7.22 (1H, d,
Ar–H3, 3J3,4¼8.3 Hz), 6.99 (1H, d, Quin–H3, 3J3,2¼5.4 Hz),
3.66 (2H, s, CH2), 2.54 (3H, s, CO–CH3), 2.51–2.54 (4H,

E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
12809
m, N–CH2), 1.66–1.69 (4H, m, CH2); 13C NMR (CDCl3)
d 150.6 (Quin–C2), 130.3 (Ar–C3), 129.0 (2C, Ph), 127.5
(2C, Ph), 127.3 (Quin–C8), 125.1 (Quin–C6), 122.6 (Ar–
C6), 121.7 (Quin–C5), 120.2 (Ar–C4), 101.9 (Quin–C3),
55.6 (CH2), 52.9 (2C, N–CH2), 25.7 (CO–CH3), 22.4 (2C,
CH2); m/z 456.4–458.4 [M+H]+.
0.5/0.2); mp¼135–136 ꢀC; HPLC (C18—10 min) PHPLC
99%, tR 3.88 min; HPLC (C18—40 min) PHPLC >99%, tR
12.97 min; HPLC (C4—40 min) PHPLC >99%, tR
10.48 min; 1H NMR (CDCl3) d 8.52 (1H, d, Quin–H2,
3
3J2,3¼5.1 Hz), 7.99 (1H, d, Quin–H5, J5,6¼11.1 Hz), 7.98
4
(1H, d, Quin–H8, J8,6¼2.1 Hz), 7.49 (1H, d, Ar–H6,
3
4J6,4¼2.1 Hz), 7.43 (1H, d, Ar–H3, J3,4¼8.1 Hz), 7.36
4.10.73. (40-Chloro-2-pyrrolidin-1-ylmethyl-biphenyl-4-
yl)-(7-chloro-quinolin-4-yl)-amine 10k. Synthesized from
compound 14k (69 mg, 0.239 mmol) and 4,7-diClQuin
(47 mg) in HCl (0.24 mL) and CH3CN (10 mL) according
to general procedure B (reflux for 5 h). The residue was pu-
rified by TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to yield
the expected compound 10k as a white solid (102 mg,
95% yield); Rf 0.6 (DCM/MeOH/NH4OH, 9.5/0.5/0.2);
mp¼194–195 ꢀC; HPLC (C18—10 min) PHPLC 98%, tR
4.51 min; HPLC (C18—40 min) PHPLC 94%, tR 19.14 min;
(1H, dd, Quin–H6, 3J6,5¼11.1 Hz, 4J6,8¼2.1 Hz), 7.35 (1H,
3
4
dd, Thio–H5, J5,4¼5.1 Hz, J5,3¼1.2 Hz), 7.24 (1H, dd,
3
4
Ar–H4, J4,3¼8.1 Hz, J4,6¼2.1 Hz), 7.18 (1H, dd, Thio–
3
4
H3, J3,4¼3.6 Hz, J3,5¼1.2 Hz), 7.09 (1H, dd, Thio–H4,
3
3J4,3¼3.6 Hz, J4,5¼5.1 Hz), 7.03 (1H, d, Quin–H3,
3J3,2¼5.1 Hz), 3.71 (2H, s, CH2), 2.54 (4H, m, N–CH2),
1.68–1.79 (4H, m, CH2); 13C NMR (CDCl3) d 151.5
(Quin–C2), 131.8 (Ar–C3), 128.3 (Quin–C8), 127.2 (Thio–
C3), 127.1 (Thio–C4), 125.8 (Quin–C6), 125.5 (Thio–C5),
123.4 (Ar–C6), 121.8 (Quin–C5), 120.4 (Ar–C4), 102.6
(Quin–C3), 57.3 (CH2), 53.7 (2C, N–CH2), 23.3 (2C, CH2);
m/z 420.2–422.2 [M+H]+.
1
HPLC (C4—40 min) PHPLC 98%, tR 18.36 min; H NMR
(CDCl3) d 8.55 (1H, d, Quin–H2, J2,3¼5.3 Hz), 8.01 (1H,
3
4
d, Quin–H8, J8,6¼2.1 Hz), 7.96 (1H, d, Quin–H5,
4
3J5,6¼9.0 Hz), 7.50 (1H, d, Ar–H6, J6,4¼1.6 Hz), 7.33–
4.10.76. (7-Chloro-quinolin-4-yl)-(40-furan-2-yl-2-pyrro-
lidin-1-ylmethyl-biphenyl-4-yl)-amine 10i. Synthesized
from compound 14i (30 mg, 0.122 mmol) and 4,7-diClQuin
(24 mg) in HCl (0.12 mL) and CH3CN (10 mL) according to
general procedure B (reflux for 16 h). The residue was puri-
fied by TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to yield the
expected compound 10i as an orange solid (47 mg,
94% yield); Rf 0.6 (DCM/MeOH/NH4OH, 9.5/0.5/0.2);
mp¼66–67 ꢀC; HPLC (C18—10 min) PHPLC 98%, tR
7.44 (5H, m, Quin–H6, Ph), 7.26–7.30 (2H, m, Ar–H3, Ar–
3
H4), 7.05 (1H, d, Quin–H3, J3,2¼5.3 Hz), 3.57 (2H, s,
CH2), 2.46–2.50 (4H, m, N–CH2), 1.72–1.76 (4H, m,
CH2); 13C NMR (CDCl3) d 151.5 (Quin–C2), 131.1 (Ar–
C3), 130.9 (2C, Ph), 128.4 (2C, Ph), 128.2 (Quin–C8),
126.0 (Quin–C6), 123.5 (Ar–C6), 122.2 (Quin–C5), 120.8
(Ar–C4), 102.5 (Quin–C3), 56.8 (CH2), 53.9 (2C, N–CH2),
23.3 (2C, CH2); m/z 448.2–450.2 [M+H]+.
3.64 min;
HPLC
(C18—40 min)
PHPLC
>99%,
4.10.74. (7-Chloro-quinolin-4-yl)-(40-fluoro-2-pyrrolidin-
1-ylmethyl-biphenyl-4-yl)-amine 10g. Synthesized from
compound 14g (39 mg, 0.142 mmol) and 4,7-diClQuin
(28 mg) in HCl (0.14 mL) and CH3CN (10 mL) according
to general procedure B (reflux for 16 h). The residue was pu-
rified by TLC (DCM/MeOH/NH4OH, 9.5/0.5/0.2) to yield
the expected compound 10g as a white solid (54 mg, 88%
yield); Rf 0.6 (DCM/MeOH/NH4OH, 9.5/0.5/0.2);
mp¼187–188 ꢀC; HPLC (C18—10 min) PHPLC 97%, tR
4.13 min; HPLC (C18—40 min) PHPLC 94%, tR 17.91 min;
tR 12.02 min; HPLC (C4—40 min) PHPLC >99%, tR
9.69 min; 1H NMR (CDCl3) d 8.44 (1H, d, Quin–H2,
4
3J2,3¼5.4 Hz), 7.91 (1H, d, Quin–H8, J8,6¼2.1 Hz), 7.89
3
(1H, d, Quin–H5, J5,6¼9.0 Hz), 7.57 (1H, d, Ar–H3,
3
3J3,4¼8.4 Hz), 7.43 (1H, dd, Fur–H5, J5,4¼1.8 Hz,
4
4J5,3¼0.7 Hz), 7.39 (1H, d, Ar–H6, J6,4¼2.2 Hz), 7.29
3
4
(1H, dd, Quin–H6, J6,5¼9.0 Hz, J6,8¼2.1 Hz), 7.19 (1H,
dd, Ar–H4, 3J4,3¼8.4 Hz, 4J4,6¼2.2 Hz), 6.93 (1H, d, Quin–
3
3
H3, J3,2¼5.4 Hz), 6.57 (1H, dd, Fur–H3, J3,4¼3.4 Hz,
4J3,5¼0.7 Hz), 6.43 (1H, dd, Fur–H4, J4,3¼3.4 Hz,
3
1
HPLC (C4—40 min) PHPLC 97%, tR 17.37 min; H NMR
(CDCl3) d 8.57 (1H, d, Quin–H2, J2,3¼5.3 Hz), 8.03 (1H,
3J4,5¼1.8 Hz), 3.75 (2H, s, CH2), 2.55 (4H, m, N–CH2),
1.70–1.73 (4H, m, CH2); 13C NMR (CDCl3) d 150.6
(Quin–C2), 140.9 (Fur–C5), 128.0 (Ar–C3), 127.5 (Quin–
C8), 125.0 (Quin–C6), 122. 6 (Ar–C6), 120.8 (Quin–C5),
119.6 (Ar–C4), 110.5 (Fur–C4), 108.1 (Fur–C3), 101.7
(Quin–C3), 56.8 (1C CH2), 52.9 (2C, N–CH2), 22.4 (2C,
CH2); m/z 404.2–406.2 [M+H]+.
3
4
d, Quin–H8, J8,6¼2.1 Hz), 7.90 (1H, d, Quin–H5,
3J5,6¼9.0 Hz), 7.63 (1H, m, Ar–H6), 7.46 (1H, dd, Quin–
3
4
H6, J6,5¼9.0 Hz, J6,8¼2.1 Hz), 7.35–7.41 (2H, m, Ph),
7.26–7.29 (2H, m, Ar–H3, Ar–H4), 7.08–7.15 (2H, m, Ph),
3
7.06 (1H, d, Quin–H3, J3,2¼5.3 Hz), 6.84 (1H, s large,
NH), 3.55 (2H, s, CH2), 2.46–2.48 (4H, m, N–CH2), 1.73–
1.81 (4H, m, CH2); 13C NMR (CDCl3) d 152.1 (Quin–C2),
131.3 (2C, Ph), 131.2 (Ar–C3), 129.2 (Quin–C8), 126.3
(Quin–C6), 123.6 (Ar–C6), 121.4 (Quin–C5), 120.7 (Ar–
4.10.77. (7-Chloro-quinolin-4-yl)-(4-methyl-3-pyrroli-
din-1-ylmethyl-phenyl)-amine 10l. Synthesized from com-
pound 14l (61 mg, 0.323 mmol) and 4,7-diClQuin (64 mg)
in HCl (0.33 mL) and CH3CN (10 mL) according to general
procedure B (reflux for 4 h). The residue was purified by
TLC (DCM/MeOH/NH4OH, 9/1/0.2) to yield the expected
compound 10l as a white solid (107 mg, 95% yield); Rf 0.4
(DCM/MeOH/NH4OH, 9.5/0.5/0.2); mp¼140–141 ꢀC;
HPLC (C18—10 min) PHPLC >99%, tR 3.56 min; HPLC
(C18—40 min) PHPLC 93%, tR 14.92 min; HPLC (C4—
40 min) PHPLC >99%, tR 13.77 min; 1H NMR (CDCl3)
2
C4), 115.1 (2C, d, Ph, JCH,F¼21.1 Hz), 102.7 (Quin–C3),
57.5 (CH2), 54.2 (2C, N–CH2), 23.7 (2C, CH2); m/z
432.0–434.0 [M+H]+.
4.10.75. (7-Chloro-quinolin-4-yl)-(2-pyrrolidin-1-
ylmethyl-40-thiophen-2-ylbiphenyl-4-yl)-amine 10h.
Synthesized from compound 14h (50 mg, 0.194 mmol)
and 4,7-diClQuin (38 mg) in HCl (0.20 mL) and CH3CN
(10 mL) according to general procedure B (reflux for 18 h).
The residue was purified by TLC (DCM/MeOH/NH4OH,
9.5/0.5/0.2) to yield the expected compound 10h as an orange
solid (73 mg, 90% yield); Rf 0.7 (DCM/MeOH/NH4OH, 9.5/
3
d 8.35 (1H, d, Quin–H2, J2,3¼5.4 Hz), 7.93 (1H, d, Quin–
3
4
H5, J5,6¼8.9 Hz), 7.87 (1H, d, Quin–H8, J8,6¼2.1 Hz),
7.70–7.40 (1H, s large, NH), 7.25 (1H, dd, Quin–H6,
3J6,5¼8.9 Hz, J6,8¼2.1 Hz), 7.20 (1H, d, Ar–H6,
4

12810
E. Paunescu et al. / Tetrahedron 63 (2007) 12791–12810
4J6,4¼2.1 Hz), 7.09 (1H, d, Ar–H3, 3J3,4¼8.1 Hz), 7.04 (1H,
dd, Ar–H4, 3J4,3¼8.1 Hz, 4J4,6¼2.1 Hz), 6.76 (1H, d, Quin–
H3, 3J3,2¼5.4 Hz), 3.51 (2H, s, CH2), 2.41–2.48 (4H, m, N–
CH2), 2.28 (3H, s, Ar–CH3), 1.67–1.74 (4H, m, CH2); 13C
NMR (CDCl3) d 151.7 (Quin–C2), 131.3 (Ar–C3), 128.3
(Quin–C8), 125.8 (Quin–C6), 124.4 (Ar–C6), 122.2 (Quin–
C5), 121.9 (Ar–C4), 101.9 (Quin–C3), 57.9 (CH2), 54.5
(2C, N–CH2), 23.7 (2C, CH2), 18.9 (Ar–CH3); m/z 352.3–
354.3 [M+H]+.
References and notes
1. World Health Organization. Malaria Fact sheet No. 94,
2006; http://www.who.int/mediacentre/factssheets/fs94/en/,
June 2007.
2. O’Neill, P. M.; Mukhtar, A.; Stocks, P. A.; Randle, L. E.;
Hindley, S.; Ward, S. A.; Storr, R. C.; Bickley, J. F.; O’Neil,
I. A.; Maggs, J. L.; Hughes, R. H.; Winstanley, P. A.; Bray,
P. G.; Park, B. K. J. Med. Chem. 2003, 46, 4933.
3. Dorn, A.; Stoffel, R.; Matile, H.; Bubendorf, A.; Ridley, R. G.
Nature 1995, 374, 269.
4. For reviews, see: (a) Bringmann, G.; Walter, R.; Weirich, R.
Angew. Chem., Int. Ed. Engl. 1990, 29, 977; (b) Hegedus,
L. S. Organometallics in Synthesis; Schlosser, M., Ed.;
Wiley: Chichester, UK, 2002; p 1123; (c) Handbook of
Organopalladium for Organic Synthesis; Negishi, E., Ed.;
Wiley-Interscience: New York, NY, 2002; (d) Miyaura, N.;
Suzuki, A. Chem. Rev. 1995, 95, 2457; (e) Herrmann, W. A.
Angew. Chem., Int. Ed. 2002, 41, 1290.
5. O’Neill, P. M.; Willock, D. J.; Hawley, S. R.; Bray, P. G.; Storr,
R. C.; Ward, S. A.; Park, B. K. J. Med. Chem. 1997, 40, 437.
6. Li, J.-H.; Zhu, Q.-M.; Xie, Y.-X. Tetrahedron 2006, 62, 10888
and Refs. 2–4 cited therein.
7. Molander, G. A.; Ham, J.; Seapy, D. G. Tetrahedron 2007, 63,
768.
8. Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2001, 40, 4544.
9. Sato, M.; Miyaura, N.; Suzuki, A. Chem. Lett. 1989, 18, 1405.
10. Botella, L.; Najera, C. J. Organomet. Chem. 2002, 663, 46.
11. Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org.
Chem. 2002, 67, 5553.
12. Kondolff, I.; Doucet, H.; Santelli, M. Tetrahedron 2004, 60,
3813.
4.10.78. (7-Chloro-quinolin-4-yl)-(4-ethyl-3-pyrrolidin-
1-ylmethyl-phenyl)-amine 10m. Synthesized from com-
pound 14m (35 mg, 0.170 mmol) and 4,7-diClQuin (34 mg)
in HCl (0.17 mL) and CH3CN (20 mL) according to general
procedure B (reflux for 3 h). The residue was purified by TLC
(DCM/MeOH/NH4OH, 9.5/0.5/0.2) to yield the expected
compound 10m as a white-yellow solid (57 mg, 91% yield);
Rf 0.7 (AcOEt/MeOH/NH4OH, 9.5/0.5/0.2); mp¼143–
144 ꢀC; HPLC (C18—10 min) PHPLC 98%, tR 3.79 min;
HPLC (C18—40 min) PHPLC 94%, tR 15.77 min; HPLC
(C4—40 min) PHPLC 99%, tR 14.75 min; 1H NMR (CDCl3)
3
d 8.36 (1H, d, Quin–H2, J2,3¼5.4 Hz), 7.87 (1H, d, Quin–
4
3
H8, J8,6¼2.1 Hz), 7.85 (1H, d, Quin–H5, J5,6¼9.0 Hz),
3
4
7.27 (1H, dd, Quin–H6, J6,5¼9.0 Hz, J6,8¼2.1 Hz), 7.21
4
(1H, d, Ar–H6, J6,4¼2.4 Hz), 7.11 (1H, d, Ar–H3,
3J3,4¼8.4 Hz), 7.06 (1H, dd, Ar–H4, J4,3¼8.4 Hz,
3
4J4,6¼2.4 Hz), 6.78 (1H, d, Quin–H3, J3,2¼5.4 Hz), 3.54
3
3
(2H, s, CH2), 2.63 (2H, q, Ar–CH2, J¼7.5 Hz), 2.38–2.47
(4H, m, N–CH2), 1.63–1.73 (4H, m, CH2), 1.14 (3H, t,
CH3, J¼7.5 Hz); 13C NMR (CDCl3) d 153.2 (Quin–C2),
3
131.0 (Ar–C3), 129.6 (Quin–C8), 127.2 (Quin–C6), 125.0
(Ar–C6), 123.0 (Ar–C4), 122.4 (Quin–C5), 103.2 (Quin–
C3), 57.9 (CH2), 55.6 (2C, N–CH2), 25.9 (Ar–CH2), 24.6
(2C, CH2), 16.7 (CH3); m/z 366.2–368.2 [M+H]+.
13. Andrus, M. B.; Song, C. Org. Lett. 2001, 3, 3761.
14. Molander, G. A.; Yun, C.-S. Tetrahedron 2002, 58, 1465.
15. Olah, G. A.; Wang, Q.; Sandford, G.; Oxyzoglou, A. B.;
Prakash, G. K. S. Synthesis 1993, 1077.
Acknowledgements
16. Nishiguchi, T.; Tachi, K.; Fukuzumi, K. J. Org. Chem. 1975,
40, 237–240.
17. Johnstone, R. A. W.; Wilby, A. H.; Entwistle, I. D. Chem. Rev.
1985, 85, 129–170.
ꢁ
We express our thanks to Gerard Montagne for the NMR ex-
periments and Herve Drobecq for the mass spectra. This
ꢁ
ꢁ
work was supported by CNRS, Universite de Lille II and
Agence Universitaire de la Francophonie (AUF). E.P. was
a recipient of fellowships from the French Government,
the Romanian Government, Erasmus/Socrates, AUF and
18. Imai, H.; Nishiguchi, T.; Fukuzumi, K. J. Org. Chem. 1977, 42,
431–434.
19. Zhang, X.; Fried, A.; Knapp, S.; Goldman, A. S. Chem.
Commun. 2003, 2060–2061.
ꢁ
Universite de Lille II.