New vistas in quinoline synthesis

Article abstract of DOI:10.1016/j.tet.2007.01.050

The gold-catalyzed Friedlander reaction was applied to the condensation of 2-aminoarylketones with β-keto-esters, β-diketones, β-keto-amides, and β-keto-sulfones to afford a diverse range of 2,3,4-trisubstituted quinolines in 3-82% yield. The seven-membered rings 1,3-cycloheptadione and azepane-2,4-dione reacted smoothly in 75% yield. An alternative procedure for the synthesis of 3-(methanesulfonyl)quinolines was developed and provided an entry into late stage manipulation of the 4-position of these quinolines. The requisite 2-aminoarylketones for the Friedlander reaction were prepared in one pot by modified Sugasawa reaction using gallium(III) chloride and boron(III) chloride in 12-54% yield.

Full text of DOI:10.1016/j.tet.2007.01.050

Tetrahedron 63 (2007) 2811–2823
New vistas in quinoline synthesis
Sarkis Atechian, Nadine Nock, Roger D. Norcross, Hassen Ratni,
*
Andrew W. Thomas, Julien Verron and Raffaello Masciadri
F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Discovery Chemistry, CH-4070 Basel, Switzerland
Received 21 December 2006; revised 18 January 2007; accepted 25 January 2007
Available online 30 January 2007
Abstract—The gold-catalyzed Friedlander reaction was applied to the condensation of 2-aminoarylketones with b-keto-esters, b-diketones,
b-keto-amides, and b-keto-sulfones to afford a diverse range of 2,3,4-trisubstituted quinolines in 3–82% yield. The seven-membered rings
1,3-cycloheptadione and azepane-2,4-dione reacted smoothly in 75% yield. An alternative procedure for the synthesis of 3-(methane-
sulfonyl)quinolines was developed and provided an entry into late stage manipulation of the 4-position of these quinolines. The requisite
2-aminoarylketones for the Friedlander reaction were prepared in one pot by modified Sugasawa reaction using gallium(III) chloride and
boron(III) chloride in 12–54% yield.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
and robust and afforded the desired products in unoptimized
yields of 3–82% in unoptimized reaction time of 0.5 h to 4
days under reflux in ethanol or 2-propanol in the presence
of 2–3 mol % of sodium tetrachloroaurate.
In the course of a medicinal chemistry program directed at
the synthesis of novel GABAB enhancers,1 we were chal-
lenged with a number of synthetic strategies to address var-
ious substitution patterns on the quinoline nucleus. During
this endeavor, we capitalized on recent developments re-
garding the gold-catalyzed green Friedlander condensation
discovered by Arcadi.2 During the review of this paper,
Adapa3 published a much improved neodymium(III) nitrate
hexahydrate catalyzed Friedlander condensation.
Z
R
Y
X
Z
N
Z
Y
X
R
a
3
+
O
10 - 80%
+
O
NH2
1
2
R
X
Y
The Friedlander condensation4 has been previously per-
formed under neutral (150 ꢀC, neat),5 basic (NaOH, EtOH),
and acidic (H2SO4, AcOH)6 conditions. The Friedlander
condensation is a two-step process including enamine forma-
tion and cyclodehydration. In its gold-catalyzed version,
NaAuCl4 catalyzes the first step. The ratio of regioisomers
formed in the Friedlander condensation is stronglydependent
on the method and the substrates used in the process.
N
4
Scheme 1. Generalized gold-catalyzed green Friedlander reaction: (a)
i
3 mol % NaAuCl4$2H2O, EtOH or PrOH, 80 ꢀC, 0.5 h to 4 d; X, Y, Z,
and R as defined in Table 1.
The condensation of 2-aminobenzophenones 1 (Z¼Ph) and
unsymmetrical 1,3-diones 2 led to regioisomeric mixtures
of quinolines 3 and 4 if the two carbonyl groups present in
2 had similar reactivity with regard to enamine formation,
e.g., 3e, 4e and 3f, 4f (Table 1).
2. Gold-catalyzed Friedlander reaction
Starting from 2-aminoarylketones 1, we have applied the
protocol of Arcadi2 to a wide range of 1,3-diones 2 including
b-keto-esters, b-diketones, b-keto-amides, and b-keto-sul-
fones (Scheme 1, Table 1). The method proved to be general
1,1,1-Trifluoro-2,4-pentanedione2 (2h) and 1-cyclopropyl-
1,3-butanedione (2i) gave exclusively the regioisomers 3h
and 3i (Scheme 2).
This can be rationalized by the preferred hydrate formation
rather than imine/enamine formation of the carbonyl group
next to the CF3 group in 2h. The marked regioselectivity ob-
served with 2i came as a surprise but reflects the lower reactiv-
ity of the carbonyl group adjacent to the cyclopropyl residue.
Keywords: Sodium tetrachloroaurate; Gold-catalyzed Friedlander reaction;
Regioselectivity; 3-(Methanesulfonyl)quinolines; Sugasawa reaction;
Gallium chloride.
* Corresponding author. Tel.: +41 61 688 7504; fax: +41 61 688 6459;
e-mail: raffaello.masciadri@roche.com
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.050

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S. Atechian et al. / Tetrahedron 63 (2007) 2811–2823
Table 1. Quinolines 3 and 4 synthesized by the gold-catalyzed green Friedlander reaction depicted in Scheme 1
No
X
Y
Z
R
Time
Yield (%)
3a
3b
3c
3d
3e
4e
3f
Me
Me
CO2Et
COMe
COEt
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH2Cl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
OCF3
Br
Br
Br
Br
Br
Br
Br
2 d
1 d
1 d
4 d
1 d
1 d
1 d
1 d
1 d
14 h
1 d
2 d
2 d
1 d
0.5 h
1 d
3 d
4 d
3 d
4 d
1 d
1 d
4 d
52a
44b
37a
46a
9a
Et
iPr
COiPr
iBu
Me
COMe
COiBu
COMe
COCH2OMe
COPh
55a
15a
21a
61a
64c
75c
3a
CH2OMe
Me
Me
Me
Me
4f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
COCF3
COcPr
CO(CH2)2
CO(CH2)3
CO(CH2)4
17a
75a
75a
82a
66c
50c
40c
21c
50c
29c
33c
CONH(CH2)3
Me
Me
Me
Me
Me
Me
Me
Me
COMe
CONHPh-4-Cl
CONHPh
CONHMe
CONMe2
NH(CH2)2OH
CO morpholine
SO2Me
3u
a
NaAuCl4$2H2O (3 mol%), 1,3-dione (1.5 equiv), EtOH, 80 ꢀC.
NaAuCl4$2H2O (3 mol%), 1,3-dione (1.5 equiv), acetylacetone, 140 ꢀC.
NaAuCl4$2H2O (3 mol%), 1,3-dione (1.5 equiv), iPrOH, 80 ꢀC.
b
c
O
O
O
2j-m
Ph
(NH)n
(CH2)m
F3C
O
O
2h
64%
Br
Br
O
CF3
O
Ph
Br
Br
O
N
(NH)n
(CH2)m
Br
3h
O
O
O
a
NH2
N
O
NH2
1a
3j m = 2, n = 0, 3%
3k m = 3, n = 0, 17%
3l m = 4, n = 0, 75%
3m m = 3, n = 1, 75%
2i
75%
Ph
(NH)n
(CH2)m
1a
EtO
N
5j m = 2, n = 0
5k m = 3, n = 0
3i
Scheme 2. Exclusive regioisomer formation in the gold-catalyzed Fried-
lander reaction with special 1,3-diketones.
Scheme 3. Gold-catalyzed Friedlander reaction with cyclic 1,3-diones.
in 4% yield (Scheme 4). A previous synthesis of 3-(methane-
sulfonyl)quinolines using MeSO2Cl and KCN reported
yields of 3–36%.10
The cyclic five-, six-, and seven-membered 1,3-diones 2j–m
led to 2,3-annulated quinolines 3j–m in 3, 17, 75, and 75%
yield, respectively (Scheme 3). The five- and six-membered
1,3-diones 2j and 2k were predominantly transformed to
enol ethyl ethers 5j and 5k, respectively, by reaction
with the solvent. These by-products were very difficult to
separate from the products. The Friedlander reactions of
the seven-membered 1,3-diones 1,3-cycloheptadione (2l)
and b-keto-caprolactam (2m)7–9 proceeded both in excellent
75% yield. This demonstrates that the seven-membered
rings have the optimal ring size for the Friedlander con-
densation.
Ph
Br
SO2Me
O
SO2Me
Ph
N
2u
Br
3u 33%
+
a
O
Ph
NH2
Br
1a
SO2Me
N
6
4%
Scheme 4. Gold-catalyzed Friedlander reaction with b-keto-sulfones: (a)
3 mol % NaAuCl4$2H2O, 1,3-dione (1.5 equiv), iPrOH, 80 ꢀC, 4 days.
Secondary and tertiary b-keto-amides led to exclusive for-
mation of the 3-(carboxamido)quinolines 3o–t (Table 1).
Even b-keto-sulfones, like methanesulfonylacetone (2u),
underwent gold-catalyzed Friedlander reaction, although
very sluggishly: after 4 days under reflux we obtained
3-(methanesulfonyl)quinoline 3u in 33% isolated yield.
A regioisomer 6 could be isolated from the reaction mixture
3. Synthesis of 3-(methanesulfonyl)quinolines
We have also developed an alternative synthesis of 3-
(methanesulfonyl)quinolines (Scheme 5), starting from

S. Atechian et al. / Tetrahedron 63 (2007) 2811–2823
2813
2-methyl-4H-3,1-benzoxazin-4-ones (8a,b), which are read-
ily available on large scale from anthranilic acids 7a,b.
Practically, these proposals worked out as planned. The po-
tassium salt of methanesulfonylacetone (2u) was readily
formed by treating cold DMF solution with BuOK. The
t
benzoxazinone 10 was added and the ring opening was
allowed to proceed for 4 h at 20 ꢀC to afford 14. After cool-
ing, a second equivalent of the base was added, which led to
the formation of a red transient dianion 15, which rapidly cy-
clized sequentially to 16 and 17 while warming up to 20 ꢀC
within 15 min. Finally, the mixture was heated at 100 ꢀC
for 30 min to induce aromatization accompanied by loss of
potassium acetate to afford 18. After cooling, 18 was neutral-
ized with 4 N HCl and all solvents were removed under high
vacuum. The solid 9 was mixed vigorously with water, which
led to the formation of a filterable precipitate that could be
further purified by digestion with hot MeOH, which mainly
dissolved further impurities. This one-pot protocol afforded
the 4-hydroxy-3-(methanesulfonyl)quinolines 9a,b in 45%
yield without chromatographic purification.
O
O
R
R
b
45%
a
85%
O
OH
NH2
7a R = Br
7b R = I
N
8a R = Br
8b R = I
Cl
OH
R
SO2Me
SO2Me
R
c
d
80%
80%
N
10a R = Br
10b R = I
N
9a R = Br
9b R = I
O
N
O
N
O
e
78%
R
SO2Me
N
SO2Me
N
N
12
4. Late stage modifications of quinolines
11a R = Br
11b R = I
O
N
This opened up the avenue for introducing new substituents
in the 4-position of quinolines 9a,b. The 4-hydroxyl groups
of 9a,b were readily transformed to chloro-leaving groups
by treatment with POCl3 and N,N-dimethyl-p-toluidine in
toluene under reflux for 7 h. These 4-chloro intermediates
10a,b were crystalline, shelf-stable materials. They could
be readily derivatized by treatment with secondary amines,
MeO
SO2Me
f
56%
N
13
t
Scheme 5. (a) Ac2O, neat, 100 ꢀC, 1 h; (b) MeCOCH2SO2Me, BuOK
(2 equiv), DMF, 100 ꢀC, 0.5 h; (c) POCl3 (1.1 equiv), Me2NTol (2 equiv),
toluene, 110 ꢀC, 7 h; (d) morpholine (1.2 equiv), DIPEA (1.2 equiv),
DMF, 100 ꢀC, 30 min; (e) morpholine (1.2 equiv), Pd2(dba)3+X-PHOS (1+
ꢀ
€
like morpholine in DMF at 100 C in the presence of Hunig’s
base to afford 11a,b in 80% yield (Scheme 5).
t
2 mol %), BuOH, Cs2CO3 (1.5 equiv), 110 ꢀC, 2 h; (f) 4-MeO-PhB(OH)2
Moreover, we found that the 6-bromo and 6-iodo quinolines
11a,b readily underwent Buchwald amination14–16 with a va-
riety of secondary amines. Optimal conditions employed
1 mol % of Pd2(dba)3, 2 mol % of X-PHOS ligand, and
1.5 equiv of Cs2CO3 in tert-butanol at 110 ꢀC for 2 h in
a sealed tube (Scheme 5).
(1.5 equiv), K3PO4 (3 equiv), Pd(PPh3)4 (3 mol %), dioxane, reflux, 7 h.
Following literature precedent11–13 for analogous transfor-
mations, we speculated that treating benzoxazinone with
only 1 equiv of the potassium salt of methanesulfonylace-
tone in DMF would lead to ring opening. Adding a second
t
equivalent of BuOK would induce ring closure and finally
potassium acetate would be eliminated under forcing condi-
tions. This proposed mechanism is depicted in Scheme 6.
Suzuki–Miyaura17,18 couplings of 11a were performed in
the presence of catalytic amounts of Pd(PPh3)4 with aryl-
boronic acids and K3PO4 in dioxane under reflux for 8 h.
4-Methoxyphenylboronic acid afforded 6-aryl-quinoline 13
in 56% yield (Scheme 5).
O
2u
SO2Me
OK
SO2Me
O
O
N
t-BuOK
DMF
t-BuOK
DMF
0-20 °C
R
R
R
The 4-chloromethylquinoline 3n was subjected to further
derivatization with morpholine to afford the 4-(morpholino-
methyl)quinoline 3v in 89% yield (Scheme 7).
O
0-20 °C
NH
8
14
O
KO
O
SO2Me
OK
OK
O
Cl
R
SO2Me R
SO2Me
N
O
O
O
CF3O
CF3O
a
N
N
O
NK
OK
N
89%
O
N
OK
15
16
17
3n
3v
Scheme 7. (a) Morpholine (2 equiv), K2CO3, EtOH, 20 ꢀC, 24 h.
OH
OK
-KOAc
100 °C
R
SO2Me
R
SO2Me
HCl
N
9
N
5. 2-Aminoarylketones via Sugasawa reaction
18
2-Aminobenzophenones 1 (Z¼Ar) were first prepared by
Scheme 6. Proposed mechanism for the transformation of benzoxazine 8 to
3-(methanesulfonyl)quinoline 9.
Sternbach,19,20 as the first step of his famous benzodiazepine

2814
S. Atechian et al. / Tetrahedron 63 (2007) 2811–2823
Table 2. 2-Aminoarylketones 1 prepared via the Sugasawa reaction depicted
in Scheme 9
synthesis, from neat aniline and benzoyl chloride with ZnCl2
at 200 ꢀC. While many 2-aminobenzophenones are nowa-
days commercially available and many alternative protocols
have been reported,21–23 our method of choice to prepare
non-commercial items was via the Sugasawa reaction,24,25
which starts from an aniline and a (benzo)nitrile in the pres-
ence of stoichiometric amounts of AlCl3 and BCl3. The pro-
cess research groups of Merck and Novartis have improved
the yield of the Sugaswa reaction by replacing AlCl3 with
GaCl3,26 and by driving off efficiently the liberated HCl
gas.27 These observations led to a revised mechanism of
the Sugasawa reaction (Scheme 8).27
No.
R
Z
Yield (%)
1b
1c
1d
1e
1f
1g
1h
1i
OCF3
OCF3
OCF3
OCF3
OCF3
OCF3
OCF3
Br
CH2Cl
54
37
30
26
20
19
12
54
43
33
39
2,3-F2-Ph
3-CF3O-Ph
4-F-Ph
3-Cl-Ph
3-F,4-MeO-Ph
4-MeO-Ph
4-MeSO2-Ph
4-F-Ph
4-Cl-Ph
Ph
1j
1k
1l
Br
Br
tBu
CN
NH
a) BCl - GaCl
O
NH
2
3
3
2
DCE, reflux, 12 h
b) H O, 60 °C, 0.5 h
2
+
useful yields in the range of 20–50% were achieved with hal-
ogen, methanesulfonyl, trifluoromethoxy, and tert-butyl sub-
stituents. The Sugasawa reaction of chloroacetonitrile28
gave 54% yield with 4-(trifluoromethoxy)aniline but failed
to react with 4-(piperidino)aniline (Table 2).
a
b
+
Cl
B
Cl
Cl
-
B
+
+
+
80 °C
- HCl (g)
N
NH
HN
N
2
In summary, we have successfully used the gold-catalyzed
version of the Friedlander condensation to introduce avariety
of substituents in the 2-, 3-, and 4-position of the quinoline
nucleus. A new approach to 3-(methanesulfonyl)quinolines
was discovered, which allowed us to introduce secondary
amines in the 4-position of these quinolines. Further, late
stage transformations in the 6-position of these quinolines
via Buchwald aminations and Suzuki couplings worked
well. The scope of the Sugasawa reaction was explored in
the search for rapid access to 2-aminoarylketones, the start-
ing materials for the Friedlander condensation.
-H[GaCl ]
4
20
[GaCl ]-
19
4
Scheme 8. Mechanism of the Sugasawa reaction.
The two Lewis acids GaCl3 and BCl3 act synergistically
probably to form a highly reactive BCl2-species, which is
able to attack the delocalized lone pair of the aniline and
directs the Friedel–Crafts-type acylation selectively to the
ortho-position. The Merck process research group has found
NMR evidence for the positively charged complex 19, which
forms upon addition of the benzonitrile and which has
[GaCl4]ꢁ as counter ion. The intramolecular collapse of com-
plex 19 is accompanied by the expulsion of HCl gas and
affords the BCl-bis-imino-complex 20, which is then hydro-
lyzed by heating the acidic reaction mixture in the presence
of water.
6. Experimental
6.1. General experimental methods
All reactions were performed under a gentle stream of nitro-
gen in solvents of puriss quality. All extractions were per-
formed classically in separatory funnels with technical
grade solvents. All flash chromatographic separations were
run on a Biotage HorizonÔ or Jones Flashmaster IIÔ appa-
ratus with pre-packed cartridges: Isolute SPE Flash SiÔ
(IST), Isolute SPE Flash NH2Ô (IST), or Si-AmineÔ (Sili-
cycle). The former is referred to as silica gel and the latter
two are referred to as aminated silica gel in the procedures
below. Chromatography samples were absorbed on Bulk
Isolute SorbentÔ (IST) with AcOEt and thoroughly dried
at HV before starting chromatography. All solvents for chro-
matography and crystallization were of technical grade. All
final products were dried at HV (0.1 mbar) at ambient tem-
perature and for at least 5 h unless otherwise noted.
The Sugasawa reaction is a capricious protocol whose yields
are strongly substrate dependent. We obtained best results
when using fresh commercial granular anhydrous GaCl3,
which is soluble in 1,2-dichloroethane (DCE), in contrast
to AlCl3, which is insoluble, in combination with a fresh
commercial 1 M solution of BCl3 in DCM. We have
screened a range of substrates (Scheme 9, Table 2) and
have obtained yields in the range of 12–54%. The presence
of methoxy groups, dioxomethylene groups or nitrogen
heteroatoms either in the aniline 21 or in the benzonitrile
22 was deleterious and led to yields below 20%. Practically
NH2
6.1.1. (2-Amino-5-bromo-phenyl)phenyl-methanone29
(1a). 2-Aminobenzophenone (30 g, 152 mmol) was sus-
pended in acetic acid (300 mL). Potassium bromide (19.9 g,
167 mmol), sodium perborate tetrahydrate (28 g, 183 mmol),
and ammonium molybdate tetrahydrate (1.5 g) were added
and stirring continued for 3 h at 0 ꢀC. The resulting thick yel-
low precipitate was diluted with ice water (300 mL), filtered
off, washed with ice water, and dried at HV/50 ꢀC. One ob-
O
NH2
CN
Z
a, b
6 - 54 %
Z
+
R
21
R
22
1
Scheme 9. Substrate screening for the Sugasawa reaction: (a) GaCl3
(1.2 equiv), aniline 21 (1 equiv), 1 M BCl3 in DCM (1.1 equiv), nitrile 22
(1 equiv), DCE, ꢁ10 ꢀC to 80 ꢀC, 16 h; (b) DCM/H2O 2:1, 80 ꢀC, 0.5 h.
R and Z as defined in Table 2.
1
tained a yellow solid (40.3 g, 96%). H NMR (400 MHz,

S. Atechian et al. / Tetrahedron 63 (2007) 2811–2823
2815
CDCl3): d¼6.06 (br s, 2H, NH2), 6.64 (d, J¼9 Hz, 1H, ArH),
7.35 (dd, J1¼9 Hz, J2¼2 Hz, 1H, ArH), 7.48 (m, 2H,
ArH+Ph), 7.55 (m, 2H, Ph), 7.63 (m, 2H, Ph); LRMS (EI)
m/z¼275/277 (M), 274 (MꢁH).
HRMS (FT-ICR) m/z calcd for C14H8F5NO2 (MH+):
318.05480; found: 318.05467.
6.2.3. (2-Amino-5-trifluoromethoxy-phenyl)-(3-trifluoro-
methoxy-phenyl)methanone (1d). From 4-(trifluorometh-
oxy)aniline and 3-(trifluoromethoxy)benzonitrile according
to method A. Chromatography on silica gel with a gradient
6.2. General method A (Sugasawa reaction)
1
2-Aminoarylketones 1: a 5-necked glass flask fitted with stir-
rer, Hickmann condenser, thermometer, septum, nitrogen in-
let and outlet connected to a washing bottle containing 30%
NaOH, was flushed with nitrogen and then charged with the
content of a fresh ampoule of gallium(III) chloride (5 g,
29 mmol). 1,2-Dichloroethane (80 mL) was added and the
resulting solution was cooled at ꢁ10 ꢀC in a ice/MeOH mix-
ture. Aniline 21 (24 mmol) was added slowly while keeping
the temperature below 0 ꢀC. A fresh commercial 1 M solu-
tion of boron trichloride in DCM (27 mL) was added at
ꢁ10 ꢀC via a syringe fitted with a Teflon stop-cock while
keeping the temperature below 0 ꢀC. Finally, the nitrile 22
was added (24 mmol) and the mixture was allowed to
warm to 20 ꢀC and then heated in an oil bath at 90 ꢀC over
1–2 h. During this operation, DCM was distilled off (50 mL)
and a reflux temperature of 80 ꢀC was achieved. At this
point, the Hickmann condenser was replaced by a normal
reflux condenser and the reaction mixture was heated under
reflux for 14 h. The reaction mixture was cooled in ice
and hydrolyzed slowly with water (40 mL) and then heated
at 80 ꢀC for 30 min in order to hydrolyze the imine. The
reaction mixture was cooled again and then extracted
with DCM and water. The crude product was purified
by chromatography on silica gel in the indicated solvent
mixture.
of AcOEt (0–20%) in heptane. Yellow oil, 30% yield. H
NMR (400 MHz, CDCl3): d¼6.17 (br s, 2H, NH2), 6.74 (d,
J¼9 Hz, 1H, 3-H), 7.21 (dd, J1¼9 Hz, J2¼2 Hz, 1H, 4-H),
7.27 (d, J¼2 Hz, 1H, 6-H), 7.24 (m, 1H, PhOCF3), 7.55
(m, 3H, PhOCF3); 13C NMR (400 MHz, DMSO-d6): d¼
194.77, 151.08, 148.00, 147.98, 141.09, 135.96, 135.94,
130.68, 128.48, 127.56, 125.35, 123.82, 120.255 (d, JCF
¼
1012 Hz), 120.015 (d, JCF¼1020 Hz), 118.50, 114.78; IR:
nmax¼3471, 3360, 1635, 1585, 1553, 1482, 1437, 1244,
1203, 1146, 863, 810, 773 cmꢁ1; LRMS (EI) m/z¼365 (M,
100), 364 (MꢁH, 80), 280 (30); HRMS (FT-ICR) m/z calcd
for C15H9F6NO3 (MH+): 366.05594; found: 366.05588.
6.2.4. (2-Amino-5-trifluoromethoxy-phenyl)-(4-fluoro-
phenyl)methanone (1e). From 4-(trifluoromethoxy)aniline
and 4-fluorobenzonitrile according to method A. Chromato-
graphy on silica gel with a gradient of AcOEt (0–20%) in
heptane. Yellow oil, 26% yield. 1H NMR (400 MHz,
CDCl3): d¼6.03 (br s, 2H, NH2), 6.73 (d, J¼9 Hz, 1H,
3-H), 7.15 (m, 2H, 6-H+PhF2), 7.28 (dd, J1¼9 Hz, J2¼
2 Hz, 1H, 4-H), 7.15 (m, 2H, PhF2), 7.68 (m, 2H, PhF2);
13C NMR (400 MHz, DMSO-d6): d¼195.28, 163.905
(d, JCF¼996 Hz), 150.71, 136.02, 135.45, 131.46, 127.96,
125.35, 120.305 (d, JCF¼1012 Hz), 118.30, 115.56; IR:
nmax¼3446, 3330, 1631, 1599, 1557, 1490, 1241, 1210,
1156, 1100, 985, 919, 902, 852, 783 cmꢁ1; LRMS (ESI)
m/z¼298 (MꢁH); HRMS (FT-ICR) m/z calcd for
C14H9F4NO2 (MH+): 300.06422; found: 300.06417.
6.2.1. 1-(2-Amino-5-trifluoromethoxy-phenyl)-2-chloro-
ethanone (1b). From 4-(trifluoromethoxy)aniline and chloro-
acetonitrile according to method A. No chromatography
needed. Brown-yellow solid, 54% yield, HPLC purity 95%.
1H NMR (400 MHz, CDCl3): d¼4.62 (s, 2H, CH2Cl), 6.37
(br s, 2H, NH2), 6.69 (d, J¼9 Hz, 1H, 3-H), 7.20 (dd, J1¼
9 Hz, J2¼2 Hz, 1H, 4-H), 7.48 (d, J¼2 Hz, 1H, 6-H); 13C
NMR (400 MHz, DMSO-d6): d¼192.07, 150.68, 136.32,
128.65, 123.65, 120.355 (d, JCF¼1012 Hz), 118.50, 113.14,
47.43; IR: nmax¼3453, 3343, 1663, 1636, 1599, 1551, 1487,
1247, 1203, 1178, 1148, 1001, 864, 825, 811 cmꢁ1; LRMS
(EI) m/z¼253 (M, 55), 204 (MꢁCH2Cl, 25); HRMS (FT-
ICR) m/z calcd for C9H7ClF3NO2 (MH+): 254.01902; found:
254.01897.
6.2.5. (2-Amino-5-trifluoromethoxy-phenyl)-(3-chloro-
phenyl)methanone (1f). From 4-(trifluoromethoxy)aniline
and 3-chlorobenzonitrile according to method A. Chromato-
graphy on silica gel with a gradient of AcOEt (0–20%) in
heptane. Yellow oil, 20% yield. 1H NMR (400 MHz,
CDCl3): d¼6.14 (br s, 2H, NH2), 6.73 (d, J¼9 Hz, 1H, 3-
H), 7.21 (dd, J1¼9 Hz, J2¼2 Hz, 1H, 4-H), 7.27 (m, 1H,
PhCl), 7.42 (m, 2H, PhCl), 7.50 (m, 1H, PhCl), 7.63 (d,
J¼2 Hz, 1H, 6-H); 13C NMR (400 MHz, DMSO-d6):
d¼195.03, 151.03, 141.01, 135.95, 133.27, 131.13, 130.32,
128.43, 128.17, 127.13, 125.49, 120.30 (q, JCF¼1012 Hz),
118.46, 114.94; IR: nmax¼3455, 3349, 2924, 2854, 1645,
1602, 1562, 1488, 1467, 1299, 1262, 1211, 1152, 985, 922,
884, 817, 765, 714, 684, 669, 652 cmꢁ1; LRMS (EI)
m/z¼315 (M, 100), 314 (MꢁH, 95), 280 (MꢁCl, 45);
HRMS (FT-ICR) m/z calcd for C14H9ClF3NO2 (MH+):
316.03467; found: 316.03458.
6.2.2. (2-Amino-5-trifluoromethoxy-phenyl)-(3,4-di-
fluoro-phenyl)methanone (1c). From 4-(trifluoromethoxy)-
aniline and 3,4-difluorobenzonitrile according to method A.
Chromatography on silica gel with a gradient of AcOEt
(0–20%) in heptane. Yellow oil, 37% yield. 1H NMR
(400 MHz, CDCl3): d¼6.05 (br s, 2H, NH2), 6.74 (d,
J¼9 Hz, 1H, 3-H), 7.22 (dd, J1¼9 Hz, J2¼2 Hz, 1H, 4-H),
7.19 (d, J¼2 Hz, 1H, 6-H), 7.28 (m, 2H, 6-H+PhF2), 7.40
(m, 1H, PhF2), 7.50 (m, 1H, PhF2); 13C NMR (400 MHz,
6.2.6. (2-Amino-5-trifluoromethoxy-phenyl)-(3-fluoro-
4-methoxy-phenyl)methanone (1g). From4-(trifluorometh-
oxy)aniline and 3-fluoro-4-methoxybenzonitrile according
to method A. Chromatography on silica gel with a gradient
of AcOEt (0–20%) in heptane. Yellow oil, 19% yield.
1H NMR (400 MHz, CDCl3): d¼3.98 (s, 3H, OMe), 5.90
(br s, 2H, NH2), 6.73 (d, J¼9 Hz, 1H, 3-H), 7.02 (t,
J¼8 Hz, 1H, 5-H0), 7.18 (dd, J1¼9 Hz, J2¼2 Hz, 1H, 4-H),
7.32 (d, J¼2 Hz, 1H, 6-H), 7.45 (d, J¼8 Hz, 1H, 5-H0),
DMSO-d6): d¼194.03, 151.41 (dd, J1CF¼1000 Hz, J2CF
48 Hz), 150.93, 149.27 (dd, J1CF¼988 Hz, J2CF¼48 Hz),
136.39, 136.03, 128.33, 126.15, 125.47, 120.3 (d, JCF
¼
¼
1016 Hz), 118.40, 118.01, 117.62, 115.02; IR: nmax¼3470,
3355, 1585, 1545, 1513, 1248, 1214, 1180, 1148, 816, 786,
781 cmꢁ1; LRMS (EI) m/z¼317 (M, 100), 316 (MꢁH, 95);

2816
S. Atechian et al. / Tetrahedron 63 (2007) 2811–2823
7.48 (dd, J1¼12 Hz, J2¼2 Hz, 1H, 1-H0); 13C NMR
(400 MHz, DMSO-d6): d¼194.10, 150.94 (d, JCF¼967 Hz),
150.38, 136.09, 131.29, 127.62, 126.70, 125.15, 120.335 (d,
JCF¼1012 Hz), 118.15, 116.42 (d, JCF¼72 Hz), 116.00,
113.15, 56.27; IR: nmax¼3455, 3346, 1633, 1605, 1572,
1552, 1516, 1483, 1286, 1252, 1203, 1151, 1136, 1105, 1021,
887, 819, 778, 763 cmꢁ1; LRMS (EI) m/z¼329 (M, 100), 328
(MꢁH, 95), 314 (MꢁMe, 25); HRMS (FT-ICR) m/z calcd for
C15H11F4NO3 (MH+): 330.07478; found: 330.07479.
according to method A. Chromatography on silica gel with
a gradient of AcOEt (0–50%) in heptane. Yellow solid,
33% yield. 1H NMR (400 MHz, CDCl3): d¼6.05 (br s, 2H,
NH2), 6.64 (d, J¼9 Hz, 1H, 3-H), 7.36 (dd, J1¼9 Hz,
J2¼2 Hz, 1H, 4-H), 7.47 (m, 2H, PhCl), 7.49 (d, J¼2 Hz,
1H, 6-H), 7.58 (m, 2H, PhCl); 13C NMR (400 MHz,
DMSO-d6): d¼195.42, 150.80, 137.84, 136.71, 136.15,
134.84, 130.47, 128.51, 119.32, 117.47, 104.11; IR:
nmax¼3489, 3371, 1630, 1603, 1579, 1543, 1468, 1292,
1233, 1161, 1084, 939, 815, 777, 677 cmꢁ1; LRMS (EI)
m/z¼308/310 (M, 100), 309/311 (MꢁH, 80), 229 (MꢁHBr,
25); HRMS (FT-ICR) m/z calcd for C13H9BrClNO (MH+):
309.96288; found: 309.96283.
6.2.7. (2-Amino-5-trifluoromethoxy-phenyl)-(4-meth-
oxy-phenyl)methanone (1h). From 4-(trifluoromethoxy)-
aniline and 4-methoxybenzonitrile according to method A.
Chromatography on silica gel with a gradient of AcOEt
(0–20%) in heptane. Yellow oil, 12% yield. 1H NMR
(400 MHz, CDCl3): d¼3.89 (s, 3H, OMe), 5.86 (br s, 2H,
NH2), 6.71 (d, J¼8 Hz, 1H, 3-H), 6.97 (d, J¼7 Hz, 2H,
PhOMe), 7.17 (dd, J1¼8 Hz, J2¼2 Hz, 1H, 4-H), 6.33 (d,
J¼2 Hz, 1H, 6-H), 7.68 (d, J¼7 Hz, 2H, PhOMe); 13C
NMR (400 MHz, DMSO-d6): d¼195.16, 162.17, 150.14,
136.01, 135.99, 131.25, 130.95, 127.22, 125.04, 120.20
(q, JCF¼1000 Hz), 117.95, 116.56, 113.96, 55.42; IR:
nmax¼3462, 3355, 1638, 1587, 1557, 1485, 1266, 1241,
1169, 1142, 1027, 980, 847, 826, 778, 666 cmꢁ1; LRMS
(ESI) m/z¼312 (MH+); HRMS (FT-ICR) m/z calcd for
C15H12F3NO3 (MH+): 312.08420; found: 312.08405.
6.2.11. (2-Amino-5-tert-butyl-phenyl)phenyl-methanone
(1l). From 4-bromoaniline and 4-tert-butylaniline according
to method A. Chromatography on silica gel with a gradient
of AcOEt (0–20%) in heptane. Yellow solid, 39% yield.
1H NMR (400 MHz, CDCl3): d¼1.20 (s, 9H, tBu), 5.90 (br
s, 2H, NH2), 6.70 (d, J¼9 Hz, 1H, 3-H), 7.35 (dd,
J1¼9 Hz, J2¼2 Hz, 1H, 4-H), 7.45 (m, 3H, Ph+3-H), 7.50
(m, 1H, Ph), 7.65 (m, 2H, Ph); 13C NMR (400 MHz,
DMSO-d6): d¼197.80, 149.77, 140.01, 135.92, 132.01,
130.91, 129.30, 128.62, 128.11, 116.86, 115.58, 33.31,
30.90; IR: nmax¼3433, 3318, 2950, 1619, 1577, 1550, 1485,
1304, 1240, 1174, 956, 827, 710, 654 cmꢁ1; LRMS (ESI)
m/z¼254 (MH+); HRMS (FT-ICR) m/z calcd for
C17H19NO (MH+): 254.15394; found: 254.15382.
6.2.8. (2-Amino-5-bromo-phenyl)-(4-methanesulfonyl-
phenyl)methanone (1i). From 4-bromoaniline and 4-(meth-
ylsulfonyl)benzonitrile according to method A. Chromato-
graphy on silica gel with a gradient of AcOEt (0–50%) in
heptane. Yellow solid, 54% yield. 1H NMR (400 MHz,
CDCl3): d¼3.13 (s, 3H, Me), 6.27 (br s, 2H, NH2), 6.67
(d, J¼9 Hz, 1H, 3-H), 7.40 (dd, J1¼9 Hz, J2¼2 Hz, 1H,
4-H), 7.41 (d, J¼2 Hz, 1H, 6-H), 7.77 (dd, J1¼7 Hz, J2¼
2 Hz, 2H, Ph), 8.07 (dd, J1¼7 Hz, J2¼2 Hz, 2H, Ph); 13C
NMR (400 MHz, DMSO-d6): d¼195.51, 151.23, 143.76,
142.59, 137.22, 135.02, 129.12, 127.14, 119.52, 116.88,
104.17, 43.28; IR: nmax¼3472, 3365, 2924, 2824, 1640,
1611, 1588, 1548, 1466, 1398, 1377, 1314, 1302, 1240,
1154, 1138, 1086, 940, 769, 674 cmꢁ1; LRMS (ESI) m/z¼
354 (MH+); HRMS (FT-ICR) m/z calcd for C11H10BrNO3S
(MH+): 315.96375; found: 315.96370.
6.3. General method B (Friedlander reaction)
Quinolines: 2-aminoarylketone 1 (0.1–1 g scale) and 1,3-
dione 2 (1.5 equiv) and sodium tetrachloroaurate(III) di-
hydrate (0.025 equiv) were heated under nitrogen in the
EtOH or iPrOH (10% w/w solution) and reacted for the indi-
cated time at 80 ꢀC (see Table 2). The reaction mixture was
evaporated to dryness and the residue purified as described
below.
6.3.1. 6-Bromo-2-methyl-4-phenyl-quinoline-3-carboxy-
lic acid ethyl ester (3a). Compound 1a (3 g, 11 mmol),
ethylacetoacetate (21) (2.1 mL, 16 mmol), and sodium tetra-
chloroaurate(III) dihydrate (0.13 g) in ethanol (30 mL) were
refluxed at 95 ꢀC for 2 days. The solvent was evaporated.
The product was purified by flash chromatography on ami-
nated silica gel with heptane/AcOEt 85:15. One obtained
2.09 g (52%) of yellow solid. 1H NMR (400 MHz,
CDCl3): d¼0.96 (t, J¼7 Hz, 3H, CO2Et), 4.06 (q, J¼7 Hz,
2H, CO2Et), 2.76 (s, 3H, CH3), 7.34 (m, 2H, Ph), 7.50 (m,
3H, Ph), 7.70 (d, J¼2 Hz, 1H, 5-H), 7.78 (dd, J1¼9 Hz,
J2¼2 Hz, 1H, 7-H), 7.94 (d, J¼9 Hz, 1H, 8-H); 13C NMR
(400 MHz, DMSO-d6): d¼167.09, 154.69, 145.70, 144.63,
134.18, 133.59, 130.97, 129.07, 128.96, 128.53, 127.72,
127.69, 125.78, 119.99, 61.21, 23.30, 13.36; IR: nmax¼2978,
1716, 1566, 1556, 1477, 1377, 1308, 1220, 1064, 1013, 837,
711 cmꢁ1; LRMS (EI) m/z¼369/371 (M, 100), 324/326
(MꢁEt, 50); HRMS (FT-ICR) m/z calcd for C19H16BrNO2
(MH+): 370.04372; found: 370.04373.
6.2.9. (2-Amino-5-bromo-phenyl)-(4-fluoro-phenyl)-
methanone (1j). From 4-bromoaniline and 4-fluorobenzo-
nitrile according to method A. Chromatography on silica
gel with a gradient of AcOEt (0–50%) in heptane. Yellow
1
solid, 43% yield. H NMR (400 MHz, CDCl3): d¼5.99 (br
s, 2H, NH2), 6.67 (d, J¼9 Hz, 1H, 3-H), 7.17 (m, 2H, PhF),
7.36 (dd, J1¼9 Hz, J2¼2 Hz, 1H, 4-H), 7.50 (d, J¼2 Hz,
1H, 6-H), 7.67 (m, 2H, PhF); 13C NMR (400 MHz, DMSO-
d6): d¼195.30, 163.83 (d, JCF¼992 Hz), 150.68, 136.54,
135.63, 135.60, 134.83, 131.425 (d, JCF¼36 Hz), 119.28,
117.81, 115.455 (d, JCF¼84 Hz), 104.13; IR: nmax¼3436,
3330, 1629, 1595, 1575, 1538, 1502, 1467, 1403, 1292,
1235, 1222, 1155, 938, 852, 816, 803, 779 cmꢁ1; LRMS
(EI) m/z¼294 (M, 100), 293 (MꢁH, 80), 213 (MꢁHBr,
25); HRMS (FT-ICR) m/z calcd for C13H9BrFNO (MH+):
293.99243; found: 293.99240.
6.3.2. 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)etha-
none (3b). Compound 1a (0.3 g, 1 mmol) and sodium tetra-
chloroaurate(III) dihydrate (13 mg) in acetylacetone (3 mL)
were refluxed for 24 h. The solvent was evaporated. The
6.2.10. (2-Amino-5-bromo-phenyl)-(4-chloro-phenyl)meth-
anone (1k). From 4-bromoaniline and 4-chlorobenzonitrile

S. Atechian et al. / Tetrahedron 63 (2007) 2811–2823
2817
product was purified by flash chromatography on aminated
silica gel with heptane/AcOEt 67:33. One obtained 161 mg
(44%) of orange solid. 1H NMR (400 MHz, CDCl3): d¼1.99
(s, 3H, COMe), 2.67 (s, 3H, Me), 7.34 (m, 2H, Ph), 7.53 (m,
3H, Ph), 7.74 (d, J¼2 Hz, 1H, 5-H), 7.79 (dd, J1¼9 Hz,
J2¼2 Hz, 1H, 7-H), 7.94 (d, J¼9 Hz, 1H, 8-H); 13C NMR
(400 MHz, DMSO-d6): d¼204.70, 154.01, 145.44, 142.36,
135.29, 133.90, 133.25, 130.92, 129.69, 129.28, 128.90,
127.47, 125.96, 119.90, 31.73, 23.46; IR: nmax¼1701, 1567,
1554, 1476, 1353, 1193, 1158, 1064, 961, 830, 790, 764,
705 cmꢁ1; LRMS (EI) m/z¼339/341 (M, 60), 324/326
(MꢁMe, 100); HRMS (FT-ICR) m/z calcd for C18H14BrNO
(MH+): 340.03315; found: 340.03294.
for 24 h. The brown reaction mixture was evaporated to dry-
ness and purified by chromatography on silica gel in hep-
tane/AcOEt 20:1. One obtained two products, first eluted
was the minor component 3e (120 mg, 9%), then the major
component 4e (730 mg, 55%) both as white soft crystals.
1
Compound 3e. H NMR (400 MHz, CDCl3): d¼0.98 (d,
J¼7 Hz, 6H, CH2CHMe2), 1.98 (s, 3H, COMe), 2.35 (sept,
J¼7 Hz, 1H, CH2CHMe2), 2.78 (d, J¼7 Hz, 2H,
CH2CHMe2), 7.33 (m, 2H, Ph), 7.53 (m, 3H, Ph), 7.73 (d,
J¼2 Hz, 1H, 5-H), 7.78 (dd, J1¼9 Hz, J2¼2 Hz, 1H, 7-H),
7.96 (d, J¼9 Hz, 1H, 8-H); 13C NMR (400 MHz, DMSO-
d6): d¼204.67, 156.73, 145.44, 142.53, 135.68, 133.98,
133.25, 131.16, 129.79, 129.25, 128.85, 127.46, 125.98,
119.97, 44.59, 32.25, 27.81, 22.42; IR: nmax¼2951, 2924,
2854, 1701, 1601, 1562, 1551, 1464, 1353, 1197, 1156,
1065, 828, 703 cmꢁ1; LRMS (EI) m/z¼381/383 (M, 15),
366/368 (MꢁMe, 30), 338/340 (MꢁCOMe, 100); HRMS
(FT-ICR) m/z calcd for C21H20BrNO (MH+): 382.08010;
found: 382.08003.
6.3.3. 1-(6-Bromo-2-ethyl-4-phenyl-quinolin-3-yl)pro-
pan-1-one (3c). Compound 1a (1 g, 3.6 mmol) and 3,5-hep-
tanedione (0.736 mL, 5.4 mmol) were refluxed in EtOH
(15 mL) in the presence of sodium tetrachloroaurate di-
hydrate (43 mg, 0.1 mmol) for 24 h. The brown reaction
mixture was evaporated to dryness and purified by chromato-
graphy on silica gel in heptane/AcOEt 20:1. One obtained
500 mg (37%) of white crystals. 1H NMR (400 MHz,
CDCl3): d¼0.82 (t, J¼7 Hz, 3H, Me), 1.40 (t, J¼7 Hz, 3H,
Me), 2.22 (q, J¼7 Hz, 2H, CH2CO), 2.87 (q, J¼7 Hz, 2H,
CH2Me), 7.32 (m, 2H, Ph), 7.51 (m, 3H, Ph), 7.73 (d,
J¼2 Hz, 1H, 5-H), 7.77 (dd, J1¼9 Hz, J2¼2 Hz, 1H, 7-H),
7.97 (d, J¼9 Hz, 1H, 8-H); 13C NMR (400 MHz, DMSO-
d6): d¼207.57, 158.54, 145.57, 142.48, 135.19, 133.94,
133.17, 131.13, 129.82, 129.20, 128.82, 127.42, 125.94,
119.90, 37.47, 29.19, 12.92, 7.39; IR: nmax¼2977, 2937,
1699, 1570, 1475, 1433, 1374, 958, 831, 706 cmꢁ1; LRMS
(EI) m/z¼369/371 (M, 20), 338/340 (MꢁEt, 100), 312
(MꢁEtꢁCO, 20), 230 (MꢁEtꢁCOꢁHBr, 20), 230 (25);
HRMS (FT-ICR) m/z calcd for C20H18BrNO (MH+):
368.06445; found: 368.06437.
1
Compound 4e. H NMR (400 MHz, CDCl3): d¼0.65 (d,
J¼7 Hz, 6H, COCH2CHMe2), 2.00 (sept, J¼7 Hz, 1H,
COCH2CHMe2), 2.10 (d, J¼7 Hz, 2H, CH2CHMe2), 2.65
(s, 1H, ArMe), 2.78 (d, J¼7 Hz, 2H, CH2CHMe2), 7.32 (m,
2H, Ph), 7.52 (m, 3H, Ph), 7.72 (d, J¼2 Hz, 1H, 5-H), 7.77
(dd, J1¼9 Hz, J2¼2 Hz, 1H, 7-H), 7.93 (d, J¼9 Hz, 1H, 8-
H); 13C NMR (400 MHz, DMSO-d6): d¼206.09, 154.11,
145.39, 142.43, 135.11, 133.66, 133.18, 130.91, 129.97,
129.18, 128.78, 127.37, 126.01, 119.86, 52.54, 23.25, 22.60,
21.76; IR: nmax¼2956, 1693, 1571, 1366, 1156, 1001, 827,
697 cmꢁ1; LRMS (EI) m/z¼381/383 (M, 15), 324/326
i
(Mꢁ Pr, 100), 217 (50); HRMS (FT-ICR) m/z calcd for
C21H20BrNO (MH+): 382.08010; found: 382.07997.
6.3.6. 1-(6-Bromo-2-methoxymethyl-4-phenyl-quinolin-
3-yl)ethanone (3f) and 1-(6-bromo-2-methyl-4-phenyl-
quinolin-3-yl)-2-methoxy-ethanone (4f). Compound 1a
(1 g, 3.6 mmol) and 1-methoxy-pentane-2,4-dione (706 mg,
5.4 mmol) were stirred under nitrogen in EtOH (15 mL) in
the presence of sodium tetrachloroaurate dihydrate (43 mg,
0.1 mmol) for 30 h. One of the products precipitated sponta-
neously from the reaction mixture. The suspension was
stirred in ice for 10 min, and the crystals were filtered off
and washed with cold EtOH. One obtained 195 mg (14%)
of 3f as beige crystals. The mother liquor was evaporated
and subjected to silica gel chromatography with a heptane/
AcOEt gradient from 100:0 to 67:33. The first eluted com-
pound (80 mg, 6%) corresponded to the crystalline material
3f and the second was its regioisomer 4f obtained as brown
crystals (278 mg, 20%).
6.3.4. 1-(6-Bromo-2-isopropyl-4-phenyl-quinolin-3-yl)-2-
methyl-propan-1-one (3d). Compound 1a (0.5 g, 2 mmol),
2,6-dimethyl-3,5-heptanedione (0.424 g, 3 mmol), and so-
dium tetrachloroaurate(III) dihydrate (0.022 g) in EtOH
(5 mL) were refluxed at for 4 days. The solvent was evapo-
rated. The product was purified by flash chromatography
on aminated silica gel with heptane/AcOEt 85:15 gradient.
1
One obtained 328 mg (46%) of a yellow solid. H NMR
(400 MHz, CDCl3): d¼0.82 (d, J¼7 Hz, 6H, COiPr), 1.41
(d, J¼7 Hz, 6H, AriPr), 2.22 (sept, J¼7 Hz, 1H, COiPr),
2.95 (sept, J¼7 Hz, 1H, AriPr), 7.33 (m, 2H, Ph), 7.51 (m,
3H, Ph), 7.74 (d, J¼2 Hz, 1H, 5-H), 7.76 (dd, J1¼9 Hz,
J2¼2 Hz, 1H, 7-H), 7.97 (d, J¼9 Hz, 1H, 8-H); 13C NMR
(400 MHz, DMSO-d6): d¼210.71, 162.92, 145.79, 142.90,
134.17, 134.15, 133.21, 131.18, 130.07, 129.23, 128.83,
127.38, 125.97, 119.91, 41.72, 33.89, 22.63, 17.40; IR:
nmax¼2969, 2954, 1691, 1555, 1442, 1082, 975, 832,
705 cmꢁ1; LRMS (EI) m/z¼395/397 (M, 10), 352/355
Compound 3f. 1H NMR (400 MHz, CDCl3): d¼1.95 (s, 3H,
COMe), 3.38 (s, 3H, OMe), 4.75 (s, 2H, CH2OMe), 7.34 (m,
2H, Ph), 7.54 (m, 3H, Ph), 7.76 (d, J¼2 Hz, 1H, 5-H), 7.80
(dd, J1¼9 Hz, J2¼2 Hz, 1H, 7-H), 7.98 (d, J¼9 Hz, 1H, 8-H);
13C NMR (400 MHz, DMSO-d6): d¼202.80, 155.03, 144.72,
143.13, 134.48, 133.69, 133.48, 131.31, 129.64, 129.29,
128.87, 127.57, 126.98, 120.85, 74.46, 58.14, 31.21; IR:
nmax¼1696, 1559, 1479, 1202, 1109, 1066, 958, 840, 767,
709 cmꢁ1;LRMS(EI)m/z¼369/371(M, 10),341(MꢁOCH2,
80), 338/340 (MꢁOMe, 100); HRMS (FT-ICR) m/z calcd
for C19H16BrNO2 (MH+): 370.04372; found: 370.04359.
i
(Mꢁ Pr, 100); HRMS (FT-ICR) m/z calcd for C22H22BrNO
(MH+): 396.09575; found: 396.09566.
6.3.5. 1-(6-Bromo-2-isobutyl-4-phenyl-quinolin-3-yl)-
ethanone (3e) and 1-(6-bromo-2-methyl-4-phenyl-quino-
lin-3-yl)-3-methyl-butan-1-one (4e). Compound 1a (1 g,
3.6 mmol) and 6-methyl-2,4-heptanedione (696 mg,
5.4 mmol) were refluxed in EtOH (15 mL) in the presence
of sodium tetrachloroaurate dihydrate (43 mg, 0.1 mmol)

2818
S. Atechian et al. / Tetrahedron 63 (2007) 2811–2823
c
Compound 4f. 1H NMR (400 MHz, CDCl3): d¼2.67 (s, 3H,
ArMe), 3.07 (s, 3H, OMe), 3.74 (s, 2H, COCH2OMe), 7.35
(m, 2H, Ph), 7.53 (m, 3H, Ph), 7.75 (d, J¼2 Hz, 1H, 5-H),
7.80 (dd, J1¼9 Hz, J2¼2 Hz, 1H, 7-H), 7.95 (d, J¼9 Hz,
1H, 8-H); 13C NMR (400 MHz, DMSO-d6): d¼204.54,
154.43, 145.70, 143.67, 133.53, 133.46, 132.30, 130.96,
129.92, 129.34, 128.80, 127.45, 125.74, 120.00, 77.33,
58.06, 23.29; IR: nmax¼1699, 1579, 1572, 1554, 1476, 1367,
1195, 1110, 1040, 978, 827, 706 cmꢁ1; LRMS (EI)
m/z¼369/371 (M, 5), 324/326 (MꢁCH2OMe, 100); HRMS
(FT-ICR) m/z calcd for C19H16BrNO2 (MH+): 370.04372;
found: 370.04354.
NMR (400 MHz, CDCl3): d¼0.69 (m, 2H, Pr), 0.94 (m,
c
c
2H, Pr), 1.79 (m, 1H, Pr), 2.69 (s, 3H, ArMe), 7.34 (m,
2H, Ph), 7.50 (m, 3H, Ph), 7.76 (d, J¼2 Hz, 1H, 5-H), 7.77
(dd, J1¼9 Hz, J2¼2 Hz, 1H, 7-H), 7.94 (d, J¼9 Hz, 1H,
8-H); 13C NMR (400 MHz, DMSO-d6): d¼206.68, 154.08,
145.53, 143.02, 135.92, 134.14, 133.19, 130.95, 129.85,
128.99, 128.58, 127.52, 126.14, 119.83, 23.58, 23.40,
12.67; IR: nmax¼1681, 1566, 1479, 1443, 1394, 1366,
1030, 986, 828, 759, 700 cmꢁ1; LRMS (EI) m/z¼365/367
c
(M, 100), 324/326 (Mꢁ Pr, 95); HRMS (FT-ICR) m/z calcd
for C20H16BrNO (MH+): 366.04880; found: 366.04862.
6.3.10. 7-Bromo-9-phenyl-2,3-dihydro-cyclopenta[b]qui-
nolin-1-one (3j). Compound 1a (1 g, 3.6 mmol) and 1,3-cy-
clopentadione (533 mg, 5.4 mmol) were heated under reflux
in EtOH (15 mL) in the presence of sodium tetrachloro-
aurate dihydrate (43 mg, 0.1 mmol) for 24 h. The brown
reaction mixture was evaporated to dryness and purified
by chromatography on silica gel in heptane/AcOEt 3:1–1:1
(repeated once!). One obtained a 352 mg (29%) of brown
sticky crystals, which contained only 3% of 3j and consisted
mainly of 3-ethoxy-cyclopent-2-enone (5j).
6.3.7. (6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-
phenyl-methanone (3g). Compound 1a (1 g, 3.6 mmol)
and 1-phenyl-1,3-butanedione (881 mg, 5.4 mmol) were
refluxed in EtOH (15 mL) in the presence of sodium tetra-
chloroaurate dihydrate (43 mg, 0.1 mmol) for 24 h. Upon
evaporation, the product precipitated. The crystals were fil-
tered off and washed with EtOH. One obtained 900 mg
1
(61%) of beige crystals. H NMR (400 MHz, DMSO-d6):
d¼2.48 (s, 3H, Me), 7.22 (m, 2H, Ph), 7.34 (m, 3H, Ph),
7.40 (m, 2H, COPh), 7.55 (m, 2H, COPh+5-H), 7.61 (m,
2H, COPh), 7.79 (dd, J1¼8 Hz, J2¼2 Hz, 1H, 7-H), 8.06
(d, J¼8 Hz, 1H, 8-H); 13C NMR (400 MHz, DMSO-d6):
d¼196.60, 154.65, 145.84, 143.99, 136.11, 134.17, 133.67,
133.33, 132.82, 131.08, 129.72, 129.14, 128.92, 128.73,
128.25, 127.56, 126.25, 119.96, 23.56; IR: nmax¼1672,
1596, 1576, 1569, 1557, 1478, 1447, 1230, 961, 830,
695 cmꢁ1; LRMS (ESI) m/z¼402 (MH+); HRMS (FT-ICR)
m/z calcd for C23H16BrNO (MH+): 402.04880; found:
402.04867.
Compound 3j. 1H NMR (400 MHz, DMSO-d6): d¼2.78 (m,
2H, COCH2CH2), 3.33 (m, 2H, COCH2CH2), 7.38 (m, 2H,
Ph), 7.58 (m, 3H, Ph), 7.70 (m, 1H, 5-H), 8.04 (dd,
J1¼9 Hz, J2¼2 Hz, 1H, 7-H), 8.07 (d, J¼9 Hz, 1H, 8-H);
LRMS (EI) m/z¼336/338 (M, 100), 335/337 (MꢁH, 50),
322/324 (MꢁBr, 95).
Compound 5j. 1H NMR (400 MHz, DMSO-d6): d¼1.31
(t, J¼7 Hz, 3H, OCH2CH3), 2.29 (m, 2H, CH2CH2), 2.56
(m, 2H, CH2CH2), 4.07 (q, J¼7 Hz, 2H, OCH2CH3), 5.35
(s, 1H, ]CH).
6.3.8. 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-
2,2,2-trifluoro-ethanone (3h). Compound 1a (4 g,
14 mmol) was dissolved in PrOH (50 mL), 1,1,1-trifluoro-
i
6.3.11. 7-Bromo-9-phenyl-3,4-dihydro-2H-acridin-1-one
(3k). Compound 1a (1 g, 3.6 mmol) and 1,3-cyclohexane-
dione (609 mg, 5.4 mmol) were heated under reflux under
nitrogen in EtOH (15 mL) in the presence of sodium
tetrachloroaurate dihydrate (43 mg, 0.1 mmol) for 48 h.
The brown reaction mixture was evaporated to dryness and
purified by chromatography on silica gel in heptane/AcOEt
2:1–1:1. Despite poor separation, the product crystallized
upon evaporation, the crystals were triturated in heptane/
AcOEt 10:1, filtered, and washed with little heptane/AcOEt
2,4-pentanedione (2.68 g, 17 mmol) and sodium tetrachloro-
aurate(III) dihydrate (140 mg, 0.4 mmol) were added and
stirring under reflux continued over night. The reaction mix-
ture was evaporated to dryness and the residue purified by
flash chromatography on silica gel with heptane/AcOEt
1
20:1 to give a light yellow solid (3.7 g, 64%). H NMR
(400 MHz, CDCl3): d¼2.67 (s, 3H, ArMe), 7.31 (m, 2H,
Ph), 7.52 (m, 3H, Ph), 7.80 (d, J¼2 Hz, 1H, 5-H), 7.86
(dd, J1¼9 Hz, J2¼2 Hz, 1H, 7-H), 7.98 (d, J¼9 Hz, 1H, 8-
1
H); 13C NMR (400 MHz, DMSO-d6): d¼188.425 (q, JCF
¼
10:1. One obtained 215 mg (17%) of yellow crystals. H
148 Hz), 153.49, 146.50, 146.46, 134.94, 132.39, 131.10,
130.17, 130.07, 128.99, 127.72, 127.32, 125.08, 120.87,
114.465 (q, J¼1164 Hz), 23.42; IR: nmax¼1742, 1564,
1475, 1288, 1206, 1145, 1113, 1063, 961, 903, 834, 763,
708, 701, 670 cmꢁ1; LRMS (EI) m/z¼393/395 (M, 50),
324/326 (MꢁCF3, 100), 296/298 (MꢁCF3ꢁCO, 20), 217
(MꢁCF3ꢁCOꢁBr, 70); HRMS (FT-ICR) m/z calcd for
C18H11BrF3NO (MH+): 394.00489; found: 394.00475.
NMR (400 MHz, DMSO-d6): d¼2.17 (d, J¼7 Hz, 2H,
COCH2CH2CH2), 2.66 (d, J¼7 Hz, 2H, COCH2CH2CH2),
3.28 (d, J¼7 Hz, 2H, COCH2CH2CH2), 7.21 (m, 2H, Ph),
7.39 (m, 1H, 5-H), 7.49 (m, 3H, Ph), 7.97 (m, 2H, 7-H+8-
H); 13C NMR (400 MHz, DMSO-d6): d¼197.21, 163.12,
148.82, 146.51, 136.68, 134.55, 130.68, 128.96, 128.18,
128.07, 127.60, 124.42, 119.64, 33.79, 20.62; IR: nmax
¼
2955, 1687, 1546, 1474, 1426, 1211, 1134, 1015, 837,
695 cmꢁ1; LRMS (EI) m/z¼351/353 (M, 100), 350/352 (Mꢁ
H, 85), 322/324 (MꢁCHO, 45); HRMS (FT-ICR) m/z calcd
for C19H14BrNO (MH+): 352.03315; found: 352.03303.
6.3.9. (6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)cyclo-
propyl-methanone (3i). Compound 1a (1g, 3.62 mmol)
was dissolved in iPrOH (20 mL), 1-cyclopropyl-2,4-pentane-
dione (0.548 g, 4.32 mmol) and sodium tetrachloroaurate(III)
dihydrate (43 g, 0.1 mmol) were added and stirring under
reflux continued over night. Evaporated to dryness and puri-
fied by flash chromatography on silica gel with heptane/
AcOEt 1:2 to give a light yellow solid (1 g, 75%). 1H
6.3.12. 2-Bromo-11-phenyl-6,7,8,9-tetrahydro-cyclo-
hepta[b]quinolin-10-one (3l). Compound 1a (1 g, 3.6 mmol)
and 1,3-cycloheptanedione (0.623 mL, 5.4 mmol) were
heated under reflux under nitrogen in EtOH (15 mL) in the
presence of sodium tetrachloroaurate dihydrate (43 mg,

S. Atechian et al. / Tetrahedron 63 (2007) 2811–2823
2819
0.1 mmol) for 20 h. The product precipitated spontaneously
from the reaction mixture. The suspension was stirred in ice
for 10 min, and the crystals were filtered off and washed with
cold EtOH. One obtained 996 mg (75%) of beige crystals.
1H NMR (400 MHz, DMSO-d6): d¼1.87 (m, 2H,
COCH2CH2CH2CH2), 1.96 (m, 2H, COCH2CH2CH2CH2),
2.65 (t, J¼6 Hz, 2H, COCH2CH2CH2CH2), 3.07 (t, J¼
7 Hz, 2H, COCH2CH2CH2CH2), 7.33 (m, 2H, Ph), 7.50 (m,
3H, Ph), 7.55 (m, 1H, 5-H), 7.93 (dd, J1¼9 Hz, J2¼2 Hz,
1H, 7-H), 8.02 (d, J¼9 Hz, 1H, 8-H); 13C NMR (400 MHz,
DMSO-d6): d¼207.35, 157.39, 145.95, 144.21, 134.50,
134.47, 133.31, 131.11, 129.16, 128.47, 128.04, 126.94,
119.85, 42.66, 36.16, 24.26, 23.41; IR: nmax¼2945, 1691,
1583, 1570, 1556, 1477, 1376, 1122, 952, 827, 760, 707,
666 cmꢁ1; LRMS (EI) m/z¼365/367 (M, 80), 336/338
(MꢁEt, 100), 258 (MꢁCO–Br, 45); HRMS (FT-ICR) m/z
calcd for C20H16BrNO (MH+): 366.04880; found:
366.04867.
precipitated product was filtered off. One obtained 538 mg
(66%) of white solid. 1H NMR (400 MHz, CDCl3):
d¼2.84 (s, 3H, Me), 6.87 (s, 1H, NH), 7.07 (m, 2H, PhCl),
7.21 (m, 2H, PhCl), 7.42 (m, 2H, Ph), 7.50 (m, 3H, Ph),
7.75 (d, J¼2 Hz, 1H, 5-H), 7.80 (dd, J1¼9 Hz, J2¼2 Hz,
1H, 7-H), 7.95 (d, J¼9 Hz, 1H, 8-H); 13C NMR
(400 MHz, DMSO-d6): d¼165.36, 155.31, 145.56, 143.61,
137.20, 134.04, 133.21, 131.31, 130.97, 129.26, 128.78,
128.67, 128.34, 127.66, 127.64, 126.32, 121.10, 119.80,
23.11; IR: nmax¼3288, 1648, 1598, 1531, 1478, 1490,
1400, 1319, 1242, 828, 763, 703 cmꢁ1; LRMS (ESI)
m/z¼451 (MH+); HRMS (FT-ICR) m/z calcd for
C23H16BrClN2O (MH+): 451.02073; found: 451.02064.
6.3.16. 6-Bromo-2-methyl-4-phenyl-quinoline-3-carb-
oxylic acid phenylamide (3p). Compound 1a (0.5 g,
2 mmol) was dissolved in iPrOH (5 mL). Then acetoacetani-
lide (0.48 g, 3 mmol) and sodium tetrachloroaurate(III) di-
hydrate (22 mg) were added and the mixture was refluxed
for 4 days. After cooling, the precipitated product was fil-
6.3.13. 9-Bromo-11-phenyl-2,3,4,5-tetrahydro-aze-
pino[4,3-b]quinolin-1-one (3m). Compound 1a (2 g,
7.2 mmol), azepane-2,4-dione (1.01 g, 8 mmol), and sodium
tetrachloroaurate(III) (72 mg, 0.18 mmol) were heated un-
der nitrogen in EtOH (20 mL) for 30 min. The product pre-
cipitated spontaneously upon cooling in ice. One obtained
1
tered off. One obtained 374 mg (50%) of white solid. H
NMR (400 MHz, CDCl3): d¼2.86 (s, 3H, COMe), 6.90 (br
s, 1H, NH), 7.12 (m, 2H, Ph), 7.25 (m, 3H, Ph), 7.45 (m,
2H, Ph), 7.50 (m, 3H, Ph), 7.75 (d, J¼2 Hz, 1H, 5-H),
7.80 (dd, J1¼9 Hz, J2¼2 Hz, 1H, 7-H), 7.95 (d, J¼9 Hz,
1H, 8-H); 13C NMR (400 MHz, DMSO-d6): d¼165.23,
155.43, 145.49, 143.45, 138.29, 134.14, 133.10, 131.57,
130.95, 129.31, 128.73, 128.70, 128.31, 127.66, 126.40,
123.98, 119.70, 23.10; IR: nmax¼3384, 3221, 3035, 1657,
1599, 1558, 1498, 1481, 1444, 1381, 1333, 1259, 1074, 953,
828, 753, 688 cmꢁ1; LRMS (ESI) m/z¼417 (MH+); HRMS
(FT-ICR) m/z calcd for C23H17BrN2O (MH+): 417.05970;
found: 417.05952.
1
2 g (75%) of white crystals. H NMR (400 MHz, DMSO-
d6): d¼2.01 (br m, 2H, CONHCH2CH2CH2), 3.10 (m, 4H,
CONHCH2CH2CH2), 7.35 (m, 2H, Ph), 7.50 (m, 3H, Ph),
7.59 (m, 1H, 5-H), 7.92 (dd, J1¼9 Hz, J2¼2 Hz, 1H, 7-H),
8.02 (d, J¼9 Hz, 1H, 8-H), 8.20 (m, 1H, CONH); 13C
NMR (400 MHz, DMSO-d6): d¼168.45, 157.51, 146.15,
145.77, 135.24, 133.09, 131.17, 129.37, 129.15, 128.26,
127.97, 127.31, 119.67, 38.11, 33.46, 28.84; IR: nmax¼3179,
3064, 1655, 1640, 1582, 1570, 1476, 1344, 1327, 1146,
1065, 923, 830, 765, 709, 673 cmꢁ1; LRMS (ESI) m/z¼
367 (MH+); HRMS (FT-ICR) m/z calcd for C19H15BrN2O
(MH+): 367.04405; found: 367.04396.
6.3.17. 6-Bromo-2-methyl-4-phenyl-quinoline-3-carb-
oxylic acid methylamide (3q). Compound 1a (0.5 g,
2 mmol) was dissolved in iPrOH (5 mL). Then N-methylace-
toacetamide (0.42 mL, 3 mmol) and sodium tetrachloroaur-
ate(III) dihydrate (22 mg) were added and the mixture was
refluxed for 3 days. After cooling, the precipitated product
was filtered off and recrystallized from AcOEt. One obtained
257 mg (40%) of white solid. 1H NMR (400 MHz, CDCl3):
d¼2.63 (s, 3H, Me), 2.77 (s, 3H, CONHMe), 5.28 (br s, 1H,
NH), 7.37 (m, 2H, Ph), 7.51 (m, 3H, Ph), 7.71 (d, J¼2 Hz,
1H, 5-H), 7.77 (dd, J1¼9 Hz, J2¼2 Hz, 1H, 7-H), 7.92 (d, J¼
9 Hz, 1H, 8-H); 13C NMR (400 MHz, DMSO-d6): d¼
167.10, 155.70, 145.32, 143.14, 134.35, 132.79, 131.89,
130.90, 129.33, 128.58, 128.20, 127.59, 126.39, 119.50,
25.56, 23.04; IR: nmax¼3468, 3217, 3006, 1634, 1578, 1565,
1483, 1393, 1328, 1262, 1159, 1145, 1067, 848, 762, 708,
698 cmꢁ1; LRMS (ESI) m/z¼355 (MH+); HRMS (FT-
ICR) m/z calcd for C18H15BrN2O (MH+): 355.04405; found:
355.04390.
6.3.14. 1-(4-Chloromethyl-2-methyl-6-trifluoromethoxy-
quinolin-3-yl)ethanone (3n). Compound 1b (300 mg,
1.18 mmol), acetylacetone (0.121 mL, 1.18 mmol) and so-
dium tetrachloroaurate(III) dihydrate (8 mg, 0.02 mmol)
were refluxed in EtOH (4 mL) for 4 h. Evaporated to dryness
and purified by chromatography on silica gel in heptane/
AcOEt 80:20. One obtained 309 mg (82%) of white crystals.
1H NMR (400 MHz, CDCl3): d¼2.67 (s, 3H, ArMe), 2.70 (s,
3H, COMe), 4.79 (s, 2H, CH2Cl), 7.63 (dd, J1¼9 Hz,
J2¼2 Hz, 1H, 7-H), 7.89 (d, J¼2 Hz, 1H, 5-H), 8.10 (d,
J¼9 Hz, 1H, 8-H); 13C NMR (400 MHz, DMSO-d6): d¼
204.86, 154.28, 146.29, 145.51, 137.11, 136.06, 131.68,
124.17, 123.92, 120.125 (q, JCF¼1020 Hz), 116.00, 38.43,
32.43, 23.16; IR: nmax¼1698, 1588, 1500, 1256, 1206, 1162,
1064, 832 cmꢁ1; LRMS (EI) m/z¼317/319 (M, 50), 302/304
(MꢁMe, 100), 282 (MꢁMeꢁHF, 10), 272 (MꢁCOMe, 20);
HRMS (FT-ICR) m/z calcd for C14H11ClF3NO2 (MH+):
318.05032; found: 318.05014.
6.3.18. 6-Bromo-2-methyl-4-phenyl-quinoline-3-carb-
oxylic acid dimethylamide (3r). Compound 1a (0.5 g,
2 mmol) was dissolved in iPrOH (5 mL). Then N,N-
dimethylacetoacetamide (0.46 mL, 3 mmol) and sodium
tetrachloroaurate(III) dihydrate (22 mg) were added and the
mixture was refluxed for 4 days. The solvent was evaporated
and the residue was purified by flash chromatography on
aminated silica gel in heptane/AcOEt 2:1. One obtained
138 mg (21%) of an orange solid. 1H NMR (400 MHz,
6.3.15. 6-Bromo-2-methyl-4-phenyl-quinoline-3-carb-
oxylic acid (4-chloro-phenyl)amide (3o). Compound 1a
i
(0.5 g, 2 mmol) was dissolved in PrOH (5 mL). Then
40-chloroacetoacetanilide (0.575 g, 3 mmol) and sodium
tetrachloroaurate(III) dihydrate (22 mg) were added and
the mixture was refluxed for 3 days. After cooling, the

2820
S. Atechian et al. / Tetrahedron 63 (2007) 2811–2823
CDCl3): d¼2.59 (s, 3H, CONMe2), 2.70 (s, 3H, Me), 2.82 (s,
3H, CONMe2), 7.29 (m, 1H, Ph), 7.48 (m, 2H, Ph), 7.52 (m,
2H, Ph), 7.73 (d, J¼2 Hz, 1H, 5-H), 7.75 (dd, J1¼
9 Hz, J2¼2 Hz, 1H, 7-H), 7.93 (d, J¼9 Hz, 1H, 8-H); 13C
NMR (400 MHz, DMSO-d6): d¼167.02, 155.14, 145.51,
142.36, 133.97, 132.80, 130.96, 130.27, 129.43, 128.89,
128.86, 128.54, 128.18, 127.48, 126.23, 119.62, 37.21,
33.58, 22.94; IR: nmax¼1628, 1568, 1477, 1400, 1378,
1258, 1154, 1053, 830, 703 cmꢁ1; LRMS (EI) m/z¼368/
370 (M, 30), 353/355 (MꢁMe, 35), 324/326 (MꢁNMe2,
25), 217 (35); HRMS (FT-ICR) m/z calcd for C19H17BrN2O
(MH+): 369.05970; found: 369.05960.
DCM (100 mL) and all organic layers were washed with
50% NaCl solution. The crude product was purified twice
by chromatography on silica gel in DCM and then crystal-
lized from DCM/heptane by evaporation of DCM. One ob-
1
tained 4.6 g (33%) of beige crystals. H NMR (400 MHz,
CDCl3): d¼2.88 (s, 3H, SO2Me), 3.15 (s, 3H, COMe),
7.31 (m, 2H, Ph), 7.41 (d, J¼2 Hz, 1H, 5-H), 7.56 (m, 3H,
Ph), 7.85 (dd, J1¼9 Hz, J2¼2 Hz, 1H, 7-H), 7.94 (d,
J¼9 Hz, 1H, 8-H); 13C NMR (400 MHz, DMSO-d6):
d¼156.40, 149.80, 145.86, 135.29, 134.81, 132.73, 130.61,
128.99, 128.88, 128.40, 127.84, 127.81, 120.39, 45.39,
26.77; IR: nmax¼1596, 1556, 1539, 1469, 1441, 1302,
1142, 1065, 968, 835, 754, 702 cmꢁ1; LRMS (EI)
m/z¼375/377 (M, 100), 296/298 (MꢁSO2Me, 70), 217
(85); HRMS (FT-ICR) m/z calcd for C17H14BrNO2S
(MH+): 376.00014; found: 376.00002.
6.3.19. 6-Bromo-2-methyl-4-phenyl-quinoline-3-carb-
oxylic acid (2-hydroxy-ethyl)amide (3s). Compound 1a
(0.5 g, 2 mmol) was dissolved in iPrOH (5 mL). Then N-(2-
hydroxyethyl)acetoacetamide (0.4 g, 3 mmol) and sodium
tetrachloroaurate(III) dihydrate (22 mg) were added and
the mixture was refluxed for 1 day. After cooling, the precip-
itated product was filtered off. One obtained 346 mg (50%)
6.3.22. 6-Bromo-2-methanesulfonylmethyl-4-phenyl-
quinoline (6). Compound 1a (5 g, 18 mmol), methanesulfo-
nylacetone (4.9 g, 36 mmol) and sodium tetrachloro-
aurate(III) dihydrate (360 mg, 0.9 mmol) were heated
under reflux in 2-propanol (50 mL) for 4 days. The resulting
precipitate was filtered off and washed with 2-propanol and
then purified by chromatography on silica gel in DCM. Two
products were isolated and crystallized from heptane/DCM.
One obtained 4.1 g (57%) of 3v and 300 mg (4%) of 6. Com-
pound 3v was contaminated with methylsulfonylacetone,
thus further purified by extraction with DCM and 1 N
NaOH. 1H NMR (400 MHz, CDCl3): d¼3.01 (s, 3H,
SO2Me), 4.60 (s, 2H, CH2SO2Me), 7.31 (m, 2H, Ph), 7.54
(m, 6H, Ph+3-H), 7.83 (dd, J1¼9 Hz, J2¼2 Hz, 1H, 7-H),
7.99 (d, J¼9 Hz, 1H, 8-H), 8.10 (d, J¼2 Hz, 1H, 5-H); 13C
NMR (400 MHz, DMSO-d6): d¼151.23, 147.43, 146.45,
136.27, 133.09, 131.65, 129.31, 129.09, 129.02, 127.14,
126.40, 124.29, 120.63, 61.79, 40.79; IR: nmax¼1589, 1481,
1287, 1131, 956, 827, 774, 700 cmꢁ1; LRMS (EI) m/z¼375/
377 (M, 20), 296/298 (MꢁSO2Me, 100), 217 (70); HRMS
(FT-ICR) m/z calcd for C17H14BrNO2S (MH+): 376.00014;
found: 376.00015.
1
of white solid. H NMR (400 MHz, CDCl3): d¼1.33 (br s,
1H, OH), 2.78 (s, 3H, Me), 3.28 (m, 4H, NHCH2CH2OH),
5.75 (br s, 1H, NH), 7.42 (m, 2H, Ph), 7.55 (m, 3H, Ph),
7.69 (d, J¼2 Hz, 1H, 5-H), 7.77 (dd, J1¼9 Hz, J2¼2 Hz,
1H, 7-H), 7.93 (d, J¼9 Hz, 1H, 8-H); 13C NMR (400 MHz,
DMSO-d6): d¼166.62, 155.66, 145.29, 143.08, 134.31,
132.71, 131.86, 130.88, 129.42, 128.54, 128.12, 127.56,
126.39, 119.42, 59.17, 41.19, 23.02; IR: nmax¼3318, 3249,
1657, 1633, 1560, 1537, 1480, 1073, 831, 762, 710 cmꢁ1
;
LRMS (ESI) m/z¼384 (MH+); HRMS (FT-ICR) m/z calcd
for C19H17BrN2O2 (MH+): 385.5462; found: 385.5450.
6.3.20. (6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)mor-
pholin-4-yl-methanone (3t). Compound 1a (0.5 g,
2 mmol) was dissolved in iPrOH (5 mL). Then N-acetoace-
tylmorpholine (0.47 g, 3 mmol) and sodium tetrachloroaur-
ate(III) dihydrate (22 mg) were added and the mixture was
refluxed for 1 day. The solvent was evaporated and the resi-
due was purified by flash chromatography on aminated silica
gel in heptane/AcOEt 2:1. One obtained 215 mg (29%) of
1
white solid. H NMR (400 MHz, CDCl3): d¼2.71 (s, 3H,
6.4. New 3-(methanesulfonyl)quinoline synthesis
Me), 2.98 (m, 2H, NCH2CH2O), 3.07 (m, 1H, NCH2CH2O),
3.20 (m, 1H, NCH2CH2O), 3.40 (m, 1H, NCH2CH2O), 3.52
(m, 2H, NCH2CH2O), 3.60 (m, 1H, NCH2CH2O), 7.30 (m,
1H, Ph), 7.53 (m, 4H, Ph), 7.77 (m, 2H, 5-H+7-H), 7.93
(d, J¼9 Hz, 1H, 8-H); 13C NMR (400 MHz, DMSO-d6):
d¼165.72, 155.23, 145.65, 142.45, 133.79, 132.93, 130.97,
129.57, 129.47, 129.35, 129.04, 128.73, 128.19, 127.52,
126.05, 119.68, 65.83, 65.65, 45.88, 23.06; IR: nmax¼2977,
2855, 1616, 1580, 1463, 1435, 1269, 1231, 1110, 1018,
1006, 833, 704 cmꢁ1; LRMS (ESI) m/z¼411 (MH+);
HRMS (FT-ICR) m/z calcd for C21H19BrN2O2 (MH+):
411.07027; found: 411.07011.
6.4.1. 6-Bromo-2-methyl-4H-3,1-benzoxazin-4-one (8a).
2-Amino-5-bromobenzoic acid (25 g, 116 mmol) was added
in portions to acetic anhydride (150 mL) giving a slightly
exothermic reaction to 30 ꢀC. The suspension was heated
under reflux for 2 h. The product crystallized spontaneously
upon cooling. After stirring in ice for 30 min, the crystals
were filtered off and washed twice with heptane. The crystals
were thoroughly dried at 0.1 mbar/50 ꢀC. One obtained
22.4 g (85%) of beige crystals. 1H NMR (400 MHz,
CDCl3): d¼2.46 (s, 3H, Me), 7.42 (d, J¼8 Hz, 1H, 1-H),
7.87 (dd, J1¼8 Hz, J2¼2 Hz, 1H, 3-H), 8.31 (d, J¼2 Hz,
1H, 4-H); 13C NMR (400 MHz, DMSO-d6): d¼160.68,
158.07, 145.14, 139.35, 129.71, 128.37, 120.11, 118.34,
20.99; IR: nmax¼1755, 1640, 1596, 1466, 1250, 1181, 1053,
968, 902, 836, 781, 697, 676 cmꢁ1; LRMS (EI) m/z¼239/
241 (M, 100), 224/226 (MꢁMe, 40), 195/197 (MꢁCH2CO,
75); HRMS (FT-ICR) m/z calcd for C9H6BrNO2 (MH+):
239.96547; found: 239.96545.
6.3.21. 6-Bromo-3-methanesulfonyl-2-methyl-4-phenyl-
quinoline (3u). Compound 1a (10 g, 36 mmol), methanesul-
fonylacetone (7.4 g, 54 mmol), and sodium tetrachloro-
aurate(III) dihydrate (720 mg, 1.8 mmol) were heated under
reflux in 2-propanol (100 mL) for 4 days. The resulting
suspension was evaporated to dryness. The residue was
dissolved in DCM (100 mL) and excess methanesulfonyl-
acetone was removed by extraction with 1 N NaOH
(2ꢂ100 mL). The aqueous layers were back-extracted with
6.4.2. 6-Iodo-2-methyl-4H-3,1-benzoxazin-4-one (8b). 2-
Amino-5-iodobenzoic acid (25.4 g, 96.6 mmol) was added

S. Atechian et al. / Tetrahedron 63 (2007) 2811–2823
2821
in portions to cold acetic anhydride (100 mL). The suspen-
sion was first stirred without cooling then the resulting thick
precipitate was heated under reflux for 1 h (red solution).
The product crystallized spontaneously upon cooling. After
stirring in ice for 30 min, the crystals were filtered off and
washed twice with heptane. The crystals were thoroughly
dried at 0.1 mbar/50 ꢀC. One obtained 25.1 g (90%) of beige
crystals. 1H NMR (400 MHz, CDCl3): d¼2.45 (s, 3H, Me),
7.26 (d, J¼8 Hz, 1H, 1-H), 8.06 (dd, J1¼8 Hz, J2¼2 Hz, 1H,
3-H), 8.51 (d, J¼2 Hz, 1H, 4-H); 13C NMR (400 MHz,
DMSO-d6): d¼160.74, 157.90, 145.45, 144.99, 135.68,
128.15, 118.41, 92.87, 21.06; IR: nmax¼1752, 1627, 1593,
1465, 1375, 1259, 1040, 962, 834, 697 cmꢁ1; LRMS (EI)
m/z¼287 (M, 100), 272 (MꢁMe, 15), 243 (15); HRMS
(FT-ICR) m/z calcd for C9H6INO2 (MH+): 287.95160;
found: 287.95159.
DMSO-d6): d¼2.73 (s, 3H, ArMe), 3.29 (s, 3H, SO2Me),
7.41 (d, J¼9 Hz, 1H, 8-H), 8.03 (dd, J1¼9 Hz, J2¼2 Hz,
1H, 7-H), 8.38 (d, J¼2 Hz, 1H, 5-H), 12.3 (s, 1H, OH);
13C NMR (400 MHz, DMSO-d6): d¼171.84, 153.84,
141.15, 137.84, 133.43, 126.83, 120.59, 118.92, 89.71,
43.56, 19.59; IR: nmax¼3269, 1616, 1585, 1565, 1382,
1286, 1272, 1126, 1111, 961, 824 cmꢁ1; LRMS (EI)
m/z¼363 (M, 100), 284 (15); HRMS (FT-ICR) m/z calcd
for C11H10INO3S (MH+): 393.94988; found: 393.949883.
6.4.5. 6-Bromo-4-chloro-3-methanesulfonyl-2-methyl-
quinoline (10a). Compound 9a (6 g, 19 mmol) and N,N-
dimethyl-p-toluidine (5.5 mL, 38 mmol) were dissolved in
toluene (60 mL) and heated under argon to reflux. Then
phosphorous oxychloride (1.9 mL, 20.9 mL) was added
and heating under reflux continued for 6.5 h. The product
precipitated spontaneously upon cooling to 20 ꢀC, the crys-
tals were filtered off and washed with little toluene. One ob-
tained 4.19 g (66%) of light brown crystals. Since the
product is somewhat soluble in toluene, the mother liquor
was extracted with 3 N HCl (2ꢂ) and satd NaCl (2ꢂ). The
residue was purified by chromatography on silica gel in
DCM. One obtained 1.17 g (18%) of additional material.
1H NMR (400 MHz, CDCl3): d¼3.10 (s, 3H, ArMe), 3.38
(s, 3H, SO2Me), 7.93 (m, 2H, 7-H+8-H), 8.54 (d, J¼2 Hz,
1H, 5-H); 13C NMR (400 MHz, DMSO-d6): d¼171.98,
153.85, 137.49, 135.69, 127.14, 126.68, 120.86, 118.78,
117.52, 43.57, 19.33; IR: nmax¼3002, 1545, 1468, 1312,
1145, 1130, 966, 930, 822, 757 cmꢁ1; LRMS (EI)
m/z¼333/335 (M, 100), 254/256 (MꢁSO2Me, 35), 242/
244 (30); HRMS (FT-ICR) m/z calcd for C11H9BrClNO2S
(MH+): 333.92987; found: 333.92981.
6.4.3. 6-Bromo-3-methanesulfonyl-2-methyl-quinolin-4-
ol (9a). Methanesulfonylacetone (12.6 g, 92.9 mmol) was
dissolved in DMF (200 mL) and cooled in ice under nitro-
t
gen. Then BuOK (11.7 g, 102 mmol) was added (exother-
mic, 20 ꢀC) and stirring without cooling continued for
15 min. Cooled in ice again, then 8a (22.3 g, 92.9 mmol)
was added and then stirred without cooling for 4 h. Cooled
t
in ice again, then BuOK (11.7 g, 102 mmol) was added
and the resulting red solution was stirred at 20 ꢀC for
15 min and then heated at 100 ꢀC for 30 min. After cooling,
4 M HCl (30 mL) was added and the mixture was evaporated
thoroughly at 0.1 mbar/50 ꢀC. The residue was suspended in
water (200 mL) and stirred vigorously for 30 min, which led
to the formation of a filterable precipitate. This solid was
filtered off and washed with water (50 mL). One obtained
14.25 g (48.5%) of white crystals. 1H NMR (400 MHz,
DMSO-d6): d¼2.74 (s, 3H, ArMe), 3.29 (s, 3H, SO2Me),
7.56 (d, J¼9 Hz, 1H, 8-H), 7.90 (dd, J1¼9 Hz, J2¼2 Hz,
1H, 7-H), 8.19 (d, J¼2 Hz, 1H, 5-H), 12.3 (s, 1H, OH);
13C NMR (400 MHz, DMSO-d6): d¼172.00, 153.92,
137.54, 135.79, 127.20, 126.65, 120.86, 118.90, 117.52,
43.60, 19.58; IR: nmax¼3267, 3223, 3168, 1615, 1587,
1567, 1501, 1474, 1384, 1282, 1271, 1126, 1109, 961,
814 cmꢁ1; LRMS (ESI) m/z¼315/317 (MH+); HRMS (FT-
ICR) m/z calcd for C11H10BrNO3S (MH+): 315.96375;
found: 315.96375.
6.4.6. 4-Chloro-6-iodo-3-methanesulfonyl-2-methyl-
quinoline (10b). Compound 9b (14.7 g, 40.5 mmol) and
N,N-dimethyl-p-toluidine (11.7 mL, 81 mmol) were dis-
solved in toluene (150 mL) and heated under argon to reflux.
Then phosphorous oxychloride (4.1 mL, 44.5 mmol) was
added and heating under reflux continued for 9.5 h. The
thick suspension became gradually a dark solution. The re-
action mixture was allowed to cool and then extracted with
DCM (not soluble in toluene), cold 1 N HCl (2ꢂ), and
satd NaCl (2ꢂ). The product was crystallized from hep-
1
tane/DCM. One obtained 12 g (78%) of white crystals. H
6.4.4. 6-Iodo-3-methanesulfonyl-2-methyl-quinolin-4-ol
(9b). Methanesulfonylacetone (13 g, 95 mmol) was dis-
solved in DMF (200 mL) and cooled in ice under nitrogen.
NMR (400 MHz, CDCl3): d¼309 (s, 3H, ArMe), 3.37 (s,
3H, SO2Me), 7.75 (d, J¼9 Hz, 1H, 8-H), 8.10 (dd,
J1¼9 Hz, J2¼2 Hz, 1H, 7-H), 8.74 (d, J¼2 Hz, 1H, 5-H);
13C NMR (400 MHz, DMSO-d6): d¼171.83, 153.74,
141.10, 137.74, 133.40, 126.82, 120.54, 118.85, 89.72,
43.54, 19.42; IR: nmax¼1541, 1466, 1461, 1335, 1311,
t
Then BuOK (11.2 g, 100 mmol) was added (exothermic,
20 ꢀC) and stirring without cooling continued for 15 min.
Cooled in ice again, then 8b (27.4 g, 95.4 mmol) was added
and then stirred without cooling for 4 h. Cooled in ice again,
then tBuOK (11.2 g, 100 mmol) was added and the resulting
red solution was stirred at 20 ꢀC for 15 min and then heated
at 100 ꢀC for 30 min. After cooling, 4 M HCl (30 mL)
was added and the mixture was evaporated thoroughly at
0.1 mbar/50 ꢀC. The residue was suspended in water
(200 mL) and stirred vigorously for 30 min, which led to
the formation of a filterable precipitate. This solid was
filtered off and washed with water (50 mL). The crude prod-
uct was heated to reflux in MeOH (60 mL) in order to dis-
solve mainly impurities. The suspension was allowed to
cool to 20 ꢀC again and the solid was filtered off. One ob-
1143, 1132, 1042, 968, 924, 825, 816, 759, 657 cmꢁ1
;
LRMS (EI) m/z¼380 (M, 100), 302 (MꢁSO2Me, 25), 290
(25); HRMS (FT-ICR) m/z calcd for C11H9ClINO2S
(MH+): 381.91600; found: 381.91594.
6.4.7. 6-Bromo-3-methanesulfonyl-2-methyl-4-morpho-
lin-4-yl-quinoline (11a). Compound 10a (11.5 g,
34.4 mmol), morpholine (3.3 mL, 37.8 mmol), and N,N-
diisopropyl ethyl amine (6.5 mL, 37.8 mmol) were heated
at 100 ꢀC in dry DMF (10 mL) for 30 min. The reaction
mixture was evaporated to dryness and the residue was ex-
tracted with DCM, 10% Na2CO3, and satd NaCl. The crude
product was stirred and heated at 80 ꢀC in AcOEt (80 mL)
1
tained 15.1 g (43%) of a white solid. H NMR (400 MHz,

2822
S. Atechian et al. / Tetrahedron 63 (2007) 2811–2823
for 10 min, the resulting suspension was cooled in ice, the
crystals were filtered off and washed with little cold AcOEt.
One obtained 10.8 g (81%) of white crystals. 1H NMR
(400 MHz, CDCl3): d¼3.02 (s, 3H, ArMe), 3.41 (s, 3H,
SO2Me), 3.53 (m, 4H, NCH2), 3.98 (m, 4H, OCH2), 7.84
(dd, J1¼9 Hz, J2¼2 Hz, 1H, 7-H), 7.91 (d, J¼9 Hz, 1H,
8-H), 8.40 (d, J¼2 Hz, 1H, 5-H); 13C NMR (400 MHz,
DMSO-d6): d¼158.33, 156.68, 147.45, 134.93, 131.56,
131.45, 126.92, 126.82, 119.71, 66.47, 51.78, 44.41, 26.52;
IR: nmax¼3006, 2962, 2854, 1544, 1478, 1365, 1298, 1286,
1141, 1127, 1111, 994, 978, 851, 830, 761, 663 cmꢁ1; LRMS
(ESI) m/z¼385/387 (MH+); HRMS (FT-ICR) m/z calcd for
C15H17BrN2O3S (MH+): 385.02160; found: 385.02142.
reflux under argon for 7 h. Chromatography on silica gel
DCM/AcOEt gradient 100:0–80:20. One obtained 120 mg
(56%) of white crystals. 1H NMR (400 MHz, CDCl3):
d¼2.90 (s, 3H, ArMe), 3.50 (m, 4H, NCH2), 3.54 (s, 3H,
SO2Me), 3.84 (s, 3H, OMe), 3.88 (m, 4H, OCH2), 7.13 (m,
2H, PhOMe), 7.77 (m, 2H, PhOMe), 8.02 (d, J¼9 Hz, 1H,
8-H), 8.14 (dd, J1¼9 Hz, J2¼2 Hz, 1H, 7-H), 8.35 (d, J¼
2 Hz, 1H, 5-H); 13C NMR (400 MHz, DMSO-d6): d¼
159.50, 157.56, 157.08, 147.97, 137.80, 131.47, 131.27,
130.88, 129.89, 128.29, 125.90, 121.16, 114.79, 66.56,
55.28, 51.85, 44.58, 26.54; IR: nmax¼2858, 1610, 1548,
1519, 1486, 1295, 1181, 1139, 1109, 994, 826, 759 cmꢁ1
;
LRMS (ESI) m/z¼413 (MH+); HRMS (FT-ICR) m/z calcd
for C22H24N2O4S (MH+): 413.15295; found: 413.15274.
6.4.8. 6-Iodo-3-methanesulfonyl-2-methyl-4-morpholin-
4-yl-quinoline (11b). Compound 10b (1 g, 2.62 mmol),
morpholine (274 mg, 3.1 mmol) and N-ethyldiisopropyl-
amine (406 mg, 3.1 mmol) were heated at 100 ꢀC in dry
DMF (10 mL) for 30 min. The reaction mixture was evapo-
rated to dryness and the residue extracted with DCM, 10%
Na2CO3, and satd NaCl. Chromatography on silica gel
DCM/AcOEt 5:1. One obtained 913 mg (80%) of yellow
foam. 1H NMR (400 MHz, CDCl3): d¼2.86 (s, 3H,
ArMe), 3.42 (m, 4H, NCH2), 3.52 (s, 3H, SO2Me), 3.85 (m,
4H, OCH2), 7.74 (d, J¼9 Hz, 1H, 8-H), 8.10 (dd, J1¼9 Hz,
J2¼2 Hz, 1H, 7-H), 8.56 (d, J¼2 Hz, 1H, 5-H); 13C NMR
(400 MHz, DMSO-d6): d¼158.16, 156.30, 147.61, 140.11,
133.14, 131.28, 130.99, 127.17, 92.79, 66.37, 51.71, 44.35,
26.46; IR: nmax¼2961, 2850, 1546, 1475, 1363, 1298, 1286,
1260, 1135, 1126, 1111, 993, 977, 831, 760 cmꢁ1; LRMS
(ESI) m/z¼433 (MH+); HRMS (FT-ICR) m/z calcd for
C15H17IN2O3S (MH+): 433.00773; found: 433.00733.
Acknowledgements
We thank the Roche Basel NMR/MS/IR spectroscopy group
with Markus Buerkler, Cristian Bartelmus, Siegfried Stolz,
Marie-Claire Grunfelder and Monique Rossmeier for mea-
suring and interpreting all spectra.
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yl-quinoline (12). A tube placed under argon was charged
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26.29; IR: nmax¼2957, 1610, 1539, 1496, 1434, 1369,
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