Microwave-assisted, palladium-catalyzed carbonylative cyclization - Rapid synthesis of 2-quinolones from unprotected 2-iodoanilines and terminal alkynes

Article abstract of DOI:10.1139/V10-002

Palladium-catalyzed cyclocarbonylations of 2-iodoanilines with various terminal alkynes have been carried out by the use of commercially available molybdenum hexacarbonyl as a convenient and solid carbon monoxide source. The reactions were conducted at 160 °C for 30 min under microwave irradiation and in the presence of Et₃N in THF, affording the corresponding 2-quinolone derivatives in good regioselectivities and yields.

Full text of DOI:10.1139/V10-002

331
Microwave-assisted, palladium-catalyzed
carbonylative cyclization — Rapid synthesis of
2-quinolones from unprotected 2-iodoanilines and
terminal alkynes
Jia-Rong Chen, Jie Liao, and Wen-Jing Xiao
Abstract: Palladium-catalyzed cyclocarbonylations of 2-iodoanilines with various terminal alkynes have been carried out
by the use of commercially available molybdenum hexacarbonyl as a convenient and solid carbon monoxide source. The
reactions were conducted at 160 8C for 30 min under microwave irradiation and in the presence of Et3N in THF, affording
the corresponding 2-quinolone derivatives in good regioselectivities and yields.
Key words: microwave, palladium, carbonylation, 2-iodoaniline, 2-quinolone.
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Resume : Faisant appel a des catalyseurs de palladium et de l’hexacarbonyle de molybdene disponible commercialement
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comme source commode et solide de monoxyde de carbone, on a effectue des cyclocarbonylations de 2-iodoanilines avec
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divers alcynes en position terminale. Les reactions ont ete effectuees a 160 8C, pendant 30 minutes, sous irradiations de
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micro-ondes et en presence de Et3N dans le THF et elles conduisent a la formation des 2-quinoleones correspondantes
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avec de bons rendements et de bonnes regioselectivites.
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Mots-cles : micro-onde, palladium, carbonylation, 2-iodoaniline, 2-quinoleone.
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[Traduit par la Redaction]
cently, Kadnikov and Larock reported an elegant approach
to 2-quinolones, which was based on palladium-catalyzed
carbonylative annulation of terminal or internal alkynes with
2-iodoanilines.10 However, relatively long reaction time and
an additive (e.g., n-Bu4NCl) are usually required. Moreover,
the amino group of 2-iodoanilines has to be protected in the
reaction process. Therefore, the development of more rapid
and flexible strategy for the synthesis of 2-quinolones is still
highly desirable.
Microwave activation as a potential energy source has
proven to be a very popular and useful technology in syn-
thetic organic chemistry, especially in the synthesis of heter-
ocyclic compounds.11 Compared to the traditional heating,
the microwave-accelerated reaction has the major advan-
tages of shorter reaction times, cleaner product profiles, and
minimal quantities of solvent. As part of our ongoing en-
deavors on carbo- and hetero-cycle-oriented organometallic
catalysis,12 we recently reported a rapid synthesis of chro-
men-2-one by microwave-accelerated, palladium-catalyzed
carbonylative cyclization of 2-iodophenol with alkynes.13
This method features the use of commercially available mo-
lybdenum hexacarbonyl as a convenient and solid carbon
monoxide source.14 Herein, we extend this carbonylative
cyclization strategy as a practical and convenient synthesis
Introduction
Undoubtedly, the transition-metal-catalyzed carbonylation
has become one of the most important carbonyl-formation
reactions in organic synthesis.1 Particularly, palladium-cata-
lyzed cyclocarbonylation of unsaturated substrates provides
a unique, concise, and efficient approach toward carbo- and
hetero-cycles bearing a carbonyl moiety.2 For example, the
insertion of CO into aryl–palladium bond leading to the for-
mation of acylpalladium complex, which could react with
various nucleophiles, is a ubiquitous process for the synthe-
sis of aryl carbonyl compounds.3 Representative examples
include palladium-catalyzed carbonylative cyclizations of
2-iodophenols or 2-iodoanilines with unsaturated substrates,
such as terminal alkynes, 1,2- and 1,3- dienes, and allenes
by the use of gaseous CO.4
2-Quinolones are widely distributed in nature and in many
biologically important alkaloids, which showed remarkable
activities, such as anticancer,5 antitumor, and antihyperten-
sive properties.6 In addition, they are useful intermediates in
organic synthesis.7 Conventional methods for the synthesis
¨
of 2-quinolones are usually based on the Friedlander synthe-
sis via Schiff base condensation8 and the Knorr synthesis
through acid-catalyzed cyclization of b-ketoanilides.9 Re-
Received 6 August 2009. Accepted 26 November 2009. Published on the NRC Research Press Web site at canjchem.nrc.ca on 8 March
2010.
J.-R. Chen, J. Liao, and W. Xiao.1 The Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China.
1Corresponding author (e-mail: wxiao@mail.ccnu.edu.cn).
Can. J. Chem. 88: 331–337 (2010)
doi:10.1139/V10-002
Published by NRC Research Press

332
Can. J. Chem. Vol. 88, 2010
Scheme 1.
Table 1. Effects of the base on the carbonylative annulations of
2-iodoaniline with 1-octyne.
of 3- and 4-substituted 2-quinolones from 2-iodoanilines and
terminal alkynes (Scheme 1).
Results and discussion
The reaction conditions previously used for the carbonyla-
tive cyclization reactions of 2-iodophenol with alkynes13a
were initially applied to the reaction of 2-iodoaniline with
1-octyne (Table 1, entry 1). To our delight, the desired
2-quinolone was obtained in a 59% yield as a mixture of
two regioisomers. The structure of 2-quinolone (1a) was
proposed by NMR and unambiguously confirmed by X-ray
crystallographic analysis (Figure 1) (see Supplementary
data). Fortunately, these two isomers can easily be separated
by flash column chromatography. To optimize the reaction
conditions, the effects of the bases, catalysts, ligands, and
solvents on the model reaction were further examined.
As can be seen from the results summarized in Table 1,
both organic and inorganic bases were effective in this reac-
tion. Among the organic bases screened, trialkylamine gave
better results than secondary alkyl amines did (Table 1, en-
tries 2 and 4 vs. entry 3). The use of unhindered pyridines or
DMAP as the base resulted in decreased yields but with bet-
ter regioselectivity (Table 1, entries 5 and 7). A similar ef-
fect was also observed in the case of DBU (Table 1, entry
6). The employment of inorganic bases led to low yields
and moderate regioselectivity for this reaction. As a result,
Et3N proved to be the best base, and the desired products
were obtained in overall 60% yield with 3.5:1 regioselective
ratio. Thereafter, different palladium catalysts, ligands, and
solvents were also carefully examined to further improve
the yields and regioselectivity with Et3N as the base.
Among the three palladium–PPh3 systems examined,
Pd(OAc)2 exhibited good catalytic activity (Table 2, entry 2).
Thus, other common phosphine ligands, such as DPPB,
DPPP, DPPE, and DPPF were then examined. It was found
that DPPE was the best choice in terms of regioselectivity
and yield (1a:2a = 4:1, 60%) (Table 2, entry 6). The profile
of solvent via reaction efficiency revealed that the reaction in
THF gave higher yield and regioselectivity than in other sol-
vents (Table 2, entries 8–12). Thus, the optimized reaction
conditions for the microwave-accelerated carbonylative cycli-
zation of 2-iodoaniline and alkynes with Mo(CO)6 as the CO
source have been determined to be 1 mmol of 2-iodoaniline, 2
equiv. of alkyne, 0.5 equiv. of Mo(CO)6, 5 mol% Pd(OAc)2,
and 20 mol% DPPE in the presence of 2 equiv. of Et3N in
1 mL of THF under microwave irradiation at 160 8C for
30 min (1a:2a = 3.9:1, 62% yield) (Table 2, entry 8).
Entry
1c
2
3
4
5
6
7
8
Base
DMAP–DIPEA
Et3N
Yield (%)a
Ratio of 1a:2ab
1.2:1
3.5:1
3:1
1.5:1
3:1
3.5:1
>10:1
4:1
59
60
38
62
39
23
28
35
44
29
Et2NH
DIPEA
Pyridine
DBU
DMAP
Imidazole
K2CO3
9
10
4.6:1
1.5:1
Cs2CO3
Note: Representative experimental procedure: 2-iodoaniline (1 mmol),
1-octyne (2 mmol), base (2 mmol), Pd(OAc)2 (5 mol%, 0.05 mmol), PPh3
(20 mol%, 0.2 mmol), and Mo(CO)6 (0.5 mmol); carried in THF (1 mL)
under microwave irradiation at 60 8C for 10 min and then at 160 8C for
30 min.
aIsolated yield.
bThe ratios were determined by GC.
cDMAP (1 mmol) and DIPEA (1 mmol) were used.
ylative cyclization proceeded smoothly with good yields. For
example, 1-octyne, 1-heptyne, and 1-hexyne were suitable
for this protocol (Table 2, entries 16 and 17), affording the
2-quinolones 1 and 2 in 60%, 69%, and 70% overall yields,
respectively (Table 3, entries 1–3). Aryl-substituted alkynes
can also be employed in this transformation. Importantly,
only one regioisomer was isolated in these cases, although
the yield was moderate (Table 3, entries 4, 6, 8, and 10–12).
Structural variation in the iodoanilines component is also
possible. For example, methyl, Cl, and Br can be introduced
on the benzene ring at the C(4) position without significant
loss in reaction yield or efficiency (Table 3, entries 5–12).
As shown in Table 3 (entries 5, 6, and 9–15), we have suc-
cessfully utilized halogenated 2-iodoaniline substrates in this
reaction. Moreover, these products should be valuable for
further chemical transformations.15 Note that the reaction
has some limitations. Neither internal alkynes or N-protected
2-iodoanilines can be used in this carbonylative annulation.
Conclusions
With the standard conditions in hand, we next investigated
the scope and limitation of this process. A series of alkyl/aryl
alkynes and differently substituted 2-iodoanilines were
subjected to the optimized conditions. Generally, the carbon-
In summary, we have established a rapid and efficient
synthesis of 3- or 4-substituted 2-quinolones starting from
readily available unprotected 2-iodoanilines and alkynes
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Chen et al.
333
Fig. 1. Crystal structure of 1a.
Table 2. Optimization of reaction conditions for the carbonylative annulations.
Entry
1
2
3
4
5
6
7
8
Catalyst
PdCl2
Ligand
PPh3
PPh3
Solvent
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
THF
Yield (%)a
Ratio of 1a:2ab
2.5:1
3.5:1
2.2:1
2.4:1
3.0:1
4.0:1
1.1:1
58
60
54
59
49
60
17
62
25
15
28
NDc
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
DPPB
DPPP
DPPE
DPPF
DPPE
DPPE
DPPE
DPPE
DPPE
3.9:1
9
DMF
>10:1
>10:1
2.4:1
NDc
10
11
12
CH3CN
CH2Cl2
ClCH2CH2Cl
Note: Representative experimental procedure: iodoaniline (1 mmol), alkyne (2 mmol), Et3N
(2 mmol), palladium catalyst (5 mol%, 0.05 mmol), ligand (20 mol%, 0.2 mmol), and Mo(CO)6
(0.5 mmol); carried out in solvent (1 mL) under microwave irradiation at 60 8C for 10 min and
then at 160 8C for 30 min.
aIsolated yield.
bThe ratios were determined by GC.
cND: no products were detected.
under microwave-irradiation conditions. The current meth-
odology is attractive because of the short reaction time, the
operational simplicity, and the absence of toxic gaseous car-
bon monoxide.
Compounds 1b, 1c, 1d, 1f, 1j, 2a, 2b, and 2c are known
compounds; and the data of these compounds have been
found to be identical with those reported.10a,17
All experiments were performed in a Smith Synthesizer
producing controlled irradiation at 2450 MHz with a power
of 0–300 W.
Experimental section
General methods
Representative procedure for the synthesis of
2-quinolones from unprotected 2-iodoanilines and
terminal alkynes
Unless otherwise noted, materials were purchased from
commercial suppliers and used without further purification.
Solvents and liquid organic bases were freshly distilled ac-
cording to the known procedures.16 Column chromatography
was performed using 200–300 mesh silica gel. All melting
To a 2.0–5.0 mL process vial were added 2-iodoaniline
(1 mmol) and Pd(OAc)2 (0.05 mmol), DPPE (0.2 mmol),
Et3N (2 mmol), alkyne (2 mmol), Mo(CO)6 (0.5 mmol), and
anhydrous THF (1 mL). The vial was immediately capped
with a Teflon septum under N2 and irradiated with micro-
wave at 60 8C for 10 min, then at 160 8C for another
30 min. After cooling to room temperature, the contents of
the vessel were filtered through a short Celite pad, washed
with acetone, and then concentrated under reduced pressure.
The residue was purified by silica-gel chromatography to af-
ford the desired products.
1
points are uncorrected. H NMR spectra were recorded on
Varian Mercury 400 (400 MHz) spectrometers. Chemical
shifts are reported in ppm from TMS with the solvent reso-
nance as the internal standard (CDCl3: d 7.24, DMSO: d
2.50). Data are reported as follows: chemical shift, multi-
plicity (singlet (s), doublet (d), triplet (t), quartet (q), broad
(br), or multiplet (m)), coupling constants (Hz). 13C NMR
spectra were recorded on Varian Mercury 400 (100 MHz)
with complete proton decoupling spectrophotometers
(CDCl3: d 77.7, DMSO: d 39.5). Elemental analysis was per-
formed on a Vario EL III elemental analysis instrument.
3-n-Hexyl-2-1H-quinoline (1a)
White solid (recrystallized from petroleum ether/acetone).
Published by NRC Research Press

334
Can. J. Chem. Vol. 88, 2010
Table 3. Scope of the carbonylative annulations.
Entry
1
2
R1
H
H
H
R2
Product(s)
Yield (%)a
Ratio of 1:2b
3.9:1
4.0:1
6.7:1
n-Hex
n-Pen
n-Bu
Ph
n-Bu
Ph
n-Bu
Ph
n-Bu
Ph
1a
2a
2b
2c
60
69
70
39
67
29
68
73
66
29
46
47
1b
1c
1d
1e
1f
1g
1h
1i
3
4c
5
H
Cl
Cl
Me
Me
Br
Br
Br
Br
2e
2g
2i
4.3:1
7.2:1
10.7:1
6c
7
8c
9
10c
11c
12c
1j
1k
1l
4-MeC6H4
3-FC6H4
Note: Representative experimental procedure: iodoaniline (1 mmol), alkyne (2 mmol), Et3N (2 mmol),
Pd(OAc)2 (5 mol%, 0.05 mmol), DPPE (10 mol%, 0.10 mmol), and Mo(CO)6 (0.5 mmol); carried out in
THF (1 mL) under microwave irradiation at 60 8C for 10 min and then at 160 8C for 30 min.
aIsolated yield.
bThe ratios were determined by GC.
cOnly the major isomers were detected.
1
Mp 113–116 8C. H NMR (CDCl3, 400 MHz) d: 11.04 (s,
1H), 7.60 (s, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.29 (t, J =
10.6 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 2.67 (t, J = 7.6 Hz,
2H), 1.69 (t, J = 7.6 Hz, 1H), 1.64 (s, 2H), 1.43 (s, 2H),
1.35 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H). 13C NMR (CDCl3,
100 MHz) d: 164.5, 137.4, 136.5, 134.3, 129.2, 127.0,
122.3, 120.3, 115.6, 31.7, 30.2, 29.1, 28.3, 22.6, 14.1. MS
m/z: 229 [M+]. Anal. calcd. for C15H19NO: C, 78.56; H,
8.35; N, 6.11. Found: C, 78.60; H, 8.30; N, 6.14.
4-n-Pentyl-2-1H-quinoline (2b)
White solid (recrystallized from petroleum ether/acetone).
1
Mp 142–145 8C. H NMR (CDCl3, 600 MHz) d: 12.75 (s,
1H), 7.71 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 13.2 Hz, 2H),
7.25–7.21 (m, 1H), 6.59 (s, 1H), 2.84 (t, J = 7.6 Hz, 2H),
1.74–1.68 (2H, m), 1.50–1.44 (2H, m), 0.98 (t, J = 4.8 Hz,
3H). 13C NMR (CDCl3, 100 MHz) d: 164.6, 153.4, 138.5,
130.3, 124.1, 122.4, 119.8, 119.2, 116.8, 32.2, 31.6, 28.0,
22.5, 14.0. MS m/z: 215 [M+]. Anal. calcd. for C14H17NO:
C, 78.10; H, 7.96; N, 6.51. Found: C, 78.13; H, 7.98; N,
6.50.
4-n-Hexyl-2-1H-quinoline (2a)
White solid (recrystallized from petroleum ether/acetone).
Mp 155–157 8C. H NMR (CDCl3, 400 MHz) d: 12.33 (s,
1
3-n-Butyl-2-1H-quinoline (1c)
1H), 7.73 (d, J = 8.0 Hz, 1H), 7.52–7.46 (m, 2H), 7.27–
7.22 (m, 1H), 76.60 (s, 1H), 2.86 (t, J = 7.8 Hz, 2H), 1.83–
1.69 (2H, m), 1.45 (t, J = 10.4 Hz, 2H), 1.83–1.69 (m, 2H),
1.36–1.33 (m, 4H), 0.95–0.88 (m, 3H). 13C NMR (CDCl3,
100 MHz) d: 164.7, 153.3, 138.7,130.2, 124.0, 122.3, 119.8,
119.2, 116.9, 32.2, 31.5, 29.1, 28.7, 22.5, 14.0. MS m/z: 229
[M+]. Anal. calcd. for C15H19NO: C, 78.56; H, 8.35; N, 6.11.
Found: C, 78.59; H, 8.34; N, 6.14.
Brown solid (recrystallized from petroleum ether/ace-
tone). Mp 151–154 8C. 1H NMR (CDCl3, 400 MHz) d:
12.20 (s, 1H), 7.62 (s, 1H), 7.53–7.40 (m, 2H), 7.21–7.17
(m, 1H), 2.70 (t, J = 7.4 Hz, 2H), 1.74–1.66 (m, 2H), 1.49–
1.44 (m, 2H), 0.99 (t, 7.4 Hz, 3H). 13C NMR(CDCl3,
100 MHz) d: 164.6, 137.5, 136.4, 134.2, 126.9, 122.2,
120.3, 115.7, 30.5, 29.9, 22.5, 14.0. MS m/z: 201 [M+].
Anal. calcd. for C13H15NO: C, 77.58; H, 7.51; N, 6.96.
Found: C, 77.60; H, 7.49; N, 6.99.
3-n-Pentyl-2-1H-quinoline (1b)
4-n-Butyl-2-1H-quinoline (2c)
Brown solid (recrystallized from petroleum ether/ace-
tone). Mp 133–136 8C. 1H NMR (CDCl3, 400 MHz) d:
11.83 (s, 1H), 7.62 (s, 1H), 7.53–7.18 (m, 4H), 2.69 (t, J =
7.6 Hz, 2H), 1.71 (t, J = 1.6 Hz, 2H), 1.43–1.40 (m, 4H),
0.93 (t, J = 7.0 Hz, 3H). 13C NMR (CDCl3, 100 MHz) d:
164.6, 137.4, 136.4, 134.2, 129.2, 126.9, 122.2, 120.3,
115.7, 31.6, 30.2, 28.0, 22.6, 14.0. MS m/z: 215 [M+]. Anal.
calcd. for C14H17NO: C, 78.10; H, 7.96; N, 6.51. Found: C,
78.14; H, 7.92; N, 6.53.
Brown solid (recrystallized from petroleum ether/ace-
tone). Mp 112–115 8C. 1H NMR (CDCl3, 400 MHz) d:
12.77 (s, 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.48 (d, J = 2.4 Hz,
2H), 7.24–7.21 (m, 1H), 6.60 (s, 1H), 2.85 (t, J = 5.2 Hz,
2H), 1.73–1.68 (m, 1H), 1.50–1.44 (m, 2H), 0.98 (t, J =
4.8 Hz, 3H). 13C NMR (CDCl3, 100 MHz) d: 164.6, 153.4,
138.5, 130.3, 124.1, 122.4, 119.8, 119.2, 116.9, 31.9, 30.9,
22.6, 14.0. MS m/z: 201 [M+]. Anal. calcd. for C13H15NO:
Published by NRC Research Press

Chen et al.
335
C, 77.58; H, 7.51; N, 6.96. Found: C, 77.56; H, 7.53; N,
6.94.
2H), 2.47–2.42 (t, J = 10.0 Hz, 3H), 1.77–1.70 (m, 2H),
1.68–1.43 (m, 2H), 1.03–0.94 (m, 3H). 13C NMR (CDCl3,
100 MHz) d: 164.5, 153.0, 136.5, 131.8, 131.6, 123.6,
119.7, 119.1, 116.8, 31.8, 30.8, 22.5, 21.2, 13.9. MS m/z:
215 [M+]. Anal. calcd. for C14H17NO: C, 78.10; H, 7.96; N,
6.51. Found: C, 78.14; H, 7.97; N, 6.48.
3-n-Phenyl-2-1H-quinoline (1d)
White solid (recrystallized from petroleum ether/acetone).
1
Mp 229–232 8C. H NMR (DMSO, 400 MHz) d: 11.98 (s,
1H), 8.11 (s, 1H), 7.78–7.73 (m, 3H), 7.51–7.20 (m, 6H).
13C NMR (DMSO, 100 MHz) d: 161.1, 138.4, 136.3, 131.6,
130.2, 128.7, 128.1, 128.0, 121.9, 119.6, 114.7. MS m/z: 221
[M+]. Anal. calcd. for C15H11NO: C, 81.43; H, 5.01; N, 6.33.
Found: C, 81.46; H, 5.04; N, 6.30.
3-Phenyl-6-methyl-2-1H-quinoline (1h)
White solid (recrystallized from petroleum ether/acetone).
1
Mp 220–223 8C. H NMR (DMSO, 400 MHz) d: 11.90 (s,
1H), 8.02 (t, J = 10.0 Hz, 1H), 7.78–7.72 (m, 2H), 7.53 (d,
J = 10.0 Hz, 1H), 7.46–7.22 (m, 5H), 2.36 (t, J = 9.8 Hz,
3H). 13C NMR (DMSO, 100 MHz) d: 161.0, 137.4, 136.4,
131.5, 130.9, 128.8, 128.0, 127.8, 127.6, 119.6, 114.7, 20.5.
MS m/z: 235 [M+]. Anal. calcd. for C16H13NO: C, 81.68; H,
5.57; N, 5.95. Found: C, 81.70; H, 5.60; N, 5.92.
3-n-Butyl-6-chloro-2-1H-quinoline (1e)
White solid (recrystallized from petroleum ether/acetone).
1
Mp 169–172 8C. H NMR (CDCl3, 400 MHz) d: 12.76 (s,
1H), 7.48 (d, J = 12.8 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H),
2.67 (t, J = 3.6 Hz, 2H), 1.69–1.63 (m, 2H), 1.50–1.40 (m,
2H), 0.98 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz)
d: 164.4, 135.9, 135.5, 135.2, 129.4, 127.5, 126.0, 121.2,
117.2, 30.4, 29.9, 22.5, 14.0. MS m/z: 238 [M+]. Anal. calcd.
for C13H14ClNO: C, 66.24; H, 5.99; N, 5.94. Found: C,
66.26; H, 5.96; N, 5.92.
3-Butyl-6-bromo-2-1H-quinoline (1i)
White solid (recrystallized from petroleum ether/acetone).
1
Mp 172–174 8C. H NMR (DMSO, 400 MHz) d: 12.36 (s,
1H), 7.65 (d, J = 2.4 Hz, 1H), 7.53 (d, J = 4.6 Hz, 2H),
7.28 (t, J = 8.2 Hz, 1H), 2.68 (t, J = 7.8 Hz, 2H), 1.71–1.63
(m, 2H), 1.48–1.42 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H). 13C
NMR (DMSO, 100 MHz) d: 164.3, 136.2, 135.6, 135.2,
132.0, 129.2, 121.7, 117.4, 114.9, 30.4, 29.9, 22.5, 14.0.
MS m/z: 281 [M+]. Anal. calcd. for C13H14BrNO: C, 55.73;
H, 5.04; N, 5.00. Found: C, 55.70; H, 5.08; N, 5.02.
4-n-Butyl-6-chloro-2-1H-quinoline (2e)
White solid (recrystallized from petroleum ether/acetone).
1
Mp 163–165 8C. H NMR (DMSO, 400 MHz) d: 11.75 (s,
1H), 7.76 (d, J = 2.0 Hz, 1H), 7.53 (1H, dd, J = 2.0,
2.0 Hz), 7.33 (d, J = 8.8 Hz, 1H), 6.60 (s, 1H), 2.79 (t, J =
7.6 Hz, 2H), 1.58 (t, J = 7.6 Hz, 2H), 1.42–1.37 (m, 2H),
0.93 (t, J = 7.2 Hz, 3H). 13C NMR (DMSO, 100 MHz) d:
161.4, 150.8, 137.6, 130.0, 125.8, 123.6, 120.9, 120.0,
117.5, 30.7, 30.4, 21.9, 13.7. MS m/z: 238 [M+]. Anal. calcd.
for C13H14ClNO: C, 66.24; H, 5.99; N, 5.94. Found: C,
66.27; H, 5.97; N, 5.95.
4-Butyl-6-bromo-2-1H-quinoline (2i)
White solid (recrystallized from petroleum ether/acetone).
1
Mp181–184 8C. H NMR (DMSO, 400 MHz) d: 11.78 (1s,
H), 7.89 (s, 1H), 7.66 (t, J = 4.4 Hz,1H), 7.28 (d, J =
8.8 Hz, 1H), 6.4 (s, 1H), 2.79 (t, J = 7.4 Hz, 2H), 1.61–
1.54(m, 2H), 1.43–1.36 (m, 2H), 0.93 (t, J = 7.4 Hz). 13C
NMR (DMSO, 100 MHz) d: 164.3, 136.2, 135.6, 135.2,
132.0, 129.2, 121.7, 117.4, 114.9, 30.4, 29.9, 22.5, 14.0.
MS m/z: 281 [M+]. Anal. calcd. for C13H14BrNO: C, 55.73;
H, 5.04; N, 5.00. Found: C, 55.70; H, 5.06; N, 5.01.
3-Phenyl-6-chloro-2-2H-quinoline (1f)
Brown solid (recrystallized from petroleum ether/ace-
tone). Mp 244–247 8C. 1H NMR (DMSO, 400 MHz) d:
12.11 (s, 1H), 8.09 (s, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.76
(t, J = 4.2 Hz, 1H), 7.56–7.34 (m, 5H). 13C NMR (DMSO,
100 MHz) d: 162.8, 137.3, 136.3, 135.6, 133.7, 130.5, 128.9,
128.4, 127.9, 127.0, 121.2, 116.9. MS m/z: 256 [M+]. Anal.
calcd. for C15H10ClNO: C, 70.46; H, 3.94; N, 5.48. Found:
C, 70.48; H, 3.96; N, 5.45.
3-Phenyl-6-bromo-2-1H-quinoline (1j)
White solid (recrystallized from petroleum ether/acetone).
1
Mp 256–259 8C. H NMR (DMSO, 400 MHz) d: 12.10 (s,
1H), 7.98 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H),
7.66 (dd, J = 2.0, 1.6 Hz, 1H), 7.47–7.40 (m, 3H), 7.28 (d,
J = 8.8 Hz, 1H). 13C NMR (DMSO, 100 MHz) d: 160.8,
137.4, 136.4, 135.9, 132.7, 130.0, 128.7, 128.1, 128.0,
121.3, 116.8, 113.4. MS m/z: 300 [M+]. Anal. calcd. for
C15H10BrNO: C, 60.02; H, 3.36; N, 4.67. Found: C, 60.04;
H, 3.38; N, 4.65.
3-Butyl-6-methyl-2-2H-quinoline (1g)
White solid (recrystallized from petroleum ether/acetone).
Mp 144–147 8C. 1H NMR (CDCl3, 400 MHz) d: 11.67
(brs,1H), 7.54 (s, 1H), 7.27 (m, 3H), 2.68 (t, J = 7.8 Hz,
2H), 2.43–2.38 (m, 3H), 1.72–1.65 (m, 2H), 1.50–1.41 (m,
2H), 1.02–0.96 (m, 3H). 13C NMR (CDCl3, 100 MHz) d:
164.4, 136.2, 135.4, 134.0, 131.7, 130.5, 126.5, 120.2,
115.6, 30.5, 29.9, 22.5, 20.9, 14.0. MS m/z: 215 [M+]. Anal.
calcd. for C14H17NO: C, 78.10; H, 7.96; N, 6.51. Found: C,
78.14; H, 7.97; N, 6.49.
3-(p-Tolyl)-6-bromo-2-1H-quinoline (1k)
Yellow solid (recrystallized from petroleum ether/ace-
tone). Mp 255–257 8C. 1H NMR (DMSO, 400 MHz) d:
12.07 (s, 1H), 8.06 (s, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.64
(dd, J = 8.0, 1.6 Hz, 3H), 7.29–7.24(m, 3H), 2.23 (m, 3H).
13C NMR (DMSO, 100 MHz) d: 160.9, 137.5, 137.2, 135.8,
133.0, 132.3, 129.9, 128.7, 128.5, 121.4, 116.9, 116.7, 113.4,
21.0. MS m/z: 314 [M+]. Anal. calcd. for C16H12BrNO: C,
61.17; H, 3.85; N, 4.46. Found: C, 61.20; H, 3.83; N, 4.49.
4-Butyl-6-methyl-2-1H-quinoline (2g)
Yellow solid (recrystallized from petroleum ether/ace-
tone). Mp 171–174 8C. 1H NMR (CDCl3, 400 MHz) d:
12.52 (s, 1H), 7.56–7.49 (m, 1H), 7.38–7.26 (m, 2H), 7.24–
7.21 (m, 1H), 6.59 (d, J = 9.6 Hz, 1H), 2.85 (t, J = 7.6 Hz,
Published by NRC Research Press

336
Can. J. Chem. Vol. 88, 2010
(6) Afonso, A.; Weinstein, J.; Gentles, M. J. (Schering Corp.).
PCT Int. Appl. WO 9,203,327, 1992.
(7) (a) Anzini, M.; Cappelli, A.; Vomero, S. J. Heterocycl.
Chem. 1991, 28 (7), 1809. doi:10.1002/jhet.5570280727.;
(b) Godard, A.; Fourquez, J. M.; Tamion, R.; Marsais, F.;
3-(3-Fluorophenyl)-6-bromo-2-1H-quinoline (1l)
White solid (recrystallized from petroleum ether/acetone).
1
Mp 279–282 8C. H NMR (DMSO, 400 MHz) d: 12.16 (s,
1H), 8.19 (s, 1H), 7. 98 (d, J = 1.6 Hz, 1H), 7.69–7.59 (m,
3H), 7.52–7.47 (m, 1H), 7.30–7.22 (m, 1H). 13C NMR
(DMSO, 100 MHz) d: 163.0, 160.6, 138.1, 137.5, 133.0,
131.0, 130.0, 124.7, 121.1, 117.0, 115.6, 115.0, 113.5. MS
m/z: 318 [M+]. Anal. calcd. for C15H9BrFNO: C, 56.63; H,
2.85; N, 4.40. Found: C, 56.67; H, 2.83; N, 4.43.
´
Queguiner, G. Synlett 1994, 1994 (04), 235. doi:10.1055/s-
1994-22807.
(8) (a) Quinolines; Jones, G., Ed.; John Wiley & Sons: London–
New York–Sydney–Toronto, 1977; p. 181; (b) Quinolines;
Jones, G., Ed.; John Wiley & Sons: London–New York–Syd-
ney–Toronto, 1977; p. 191.
Supplementary data
(9) Quinolines; Jones, G., Ed.; John Wiley & Sons: London–
New York–Sydney–Toronto, 1977; p. 151.
Supplementary data for this article are available on the
journal Web site (canjchem.nrc.ca) or may be purchased
from the Depository of Unpublished Data, Document Deliv-
ery, CISTI, National Research Council Canada, Ottawa, ON
K1A 0R6, Canada. DUD 5355. For more information on ob-
taining material, refer to cisti-icist.nrc-cnrc.gc.ca/cms/
unpub_e.shtml.
(10) (a) Kadnikov, D. V.; Larock, R. C. J. Organomet. Chem.
2003, 687 (2), 425. doi:10.1016/S0022-328X(03)00786-1.;
(b) Kadnikov, D. V.; Larock, R. C. J. Org. Chem. 2004, 69
(20), 6772. doi:10.1021/jo049149+. PMID:15387602.
(11) (a) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R.
¨
J. Chem. Res. 2002, 4, 95; (b) Lidstrom, P.; Tierney, J.;
Wathey, B.; Westman, J. Tetrahedron 2001, 57 (45), 9225.
doi:10.1016/S0040-4020(01)00906-1.; (c) Perreux, L.;
Loupy, A. Tetrahedron 2001, 57 (45), 9199. doi:10.1016/
Acknowledgement
¨
S0040-4020(01)00905-X.; (d) Mavandadi, F.; Lidstrom, P.
We are grateful to the Program for Academic Leader in
Wuhan Municipality (200851430486) and the National Sci-
ence Foundation of China (20672040 and 20872043) for
support of this research.
Curr. Top. Med. Chem. 2004, 4 (7), 773. doi:10.2174/
1568026043451078. PMID:15032686.
(12) (a) Yang, Q.; Alper, H.; Xiao, W.-J. Org. Lett. 2007, 9 (5),
769. doi:10.1021/ol062959i. PMID:17279763.; (b) Yang, Q.;
Xiao, W.-J.; Yu, Z.-K. Org. Lett. 2005, 7 (5), 871. doi:10.
1021/ol047356q. PMID:15727462.; (c) Yang, Q.; Li, X.-Y.;
Wu, H.; Xiao, W.-J. Tetrahedron Lett. 2006, 47 (23), 3893.
doi:10.1016/j.tetlet.2006.03.164.; (d) Chen, J.-R.; Li, C.-F.;
An, X.-L.; Zhang, J.-J.; Zhu, X.-Y.; Xiao, W.-J. Angew.
Chem. Int. Ed. 2008, 47 (13), 2489. doi:10.1002/anie.
200705194.
(13) (a) Cao, H.; Xiao, W.-J. Can. J. Chem. 2005, 83 (6-7), 826.
doi:10.1139/v05-094.; (b) For our other related palladium-
catalyzed reactions, see: Xiao, W.-J.; Alper, H. J. Org.
Chem. 1997, 62 (11), 3422. doi:10.1021/jo970126n.; (c)
Xiao, W.-J.; Vasapollo, G.; Alper, H. J. Org. Chem. 1998,
63 (8), 2609. doi:10.1021/jo972121w. PMID:11672126.; (d)
Xiao, W.-J.; Alper, H. J. Org. Chem. 1998, 63 (22), 7939.
doi:10.1021/jo9812328.; (e) Xiao, W.-J.; Vasapollo, G.; Al-
per, H. J. Org. Chem. 1999, 64 (6), 2080. doi:10.1021/
jo9824246. PMID:11674303.; (f) Xiao, W.-J.; Alper, H. J.
Org. Chem. 1999, 64 (26), 9646. doi:10.1021/jo9913098.;
(g) Xiao, W.-J.; Vasapollo, G.; Alper, H. J. Org. Chem.
2000, 65 (13), 4138. doi:10.1021/jo000231o. PMID:
10866632.; (h) Xiao, W.-J.; Alper, H. J. Org. Chem. 2001,
66 (19), 6229. doi:10.1021/jo0103773. PMID:11559167.; (i)
Xiao, W.-J.; Alper, H. J. Org. Chem. 2005, 70 (5), 1802.
doi:10.1021/jo047938l. PMID:15730305.; (j) Cao, H.; Xiao,
W.-J.; Alper, H. Adv. Synth. Catal. 2006, 348 (14), 1807.
doi:10.1002/adsc.200606213.; (k) Cao, Y.-J.; Lai, Y.-Y.;
Cao, H.; Xing, X.-N.; Wang, X.; Xiao, W.-J. Can. J. Chem.
2006, 84 (11), 1529. doi:10.1139/V06-151.
References
(1) (a) Colquhoun, H. M.; Thompson, D. J.; Twigg, M. V. In
Carbonylation: Direct Synthesis of Carbonyl Compounds;
Plenum Press: New York, 1991; (b) Falbe, J. In New Synth-
esis with Carbon Monoxide; Springer: New York, 1980; (c)
Khumtaveeporn, K.; Alper, H. Acc. Chem. Res. 1995, 28
(10), 414. doi:10.1021/ar00058a003.; (d) El Ali, B.; Alper,
H. In Transition Metals for Organic Synthesis: Building
Blocks and Fine Chemicals; Beller, M., Bolm, C., Eds.;. Wi-
ley-VCH: New York, 1998; Vol. 1, p. 49; (e) Stille, J. K. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming,
L., Eds.; Pergamon Press: New York, 1991; Vol. 4, p. 913.
(2) (a) For reviews, see: El Ali, B.; Alper, H. In Transition-Me-
tal-Catalyzed reactions; Murahashi, S.I., Davies, S.G., Eds.;
Blackwell Science: Malden, Mass, 1999. p. 261; (b) Larock,
R. C. J. Organomet. Chem. 1999, 576 (1-2), 111. doi:10.
1016/S0022-328X(98)01053-5.; (c) Tsuji, J. Palladium Re-
agents and Catalysts; Wiley: New York, 1995; (d) Khumta-
veeporn, K.; Alper, H. Acc. Chem. Res. 1995, 28 (10), 414.
doi:10.1021/ar00058a003.
(3) Tsuji, J. Palladium Reagents and Catalysts; Innovations in Or-
ganicSynthesis;JohnWiley&Sons,Ltd.:Chichester,U.K.,1995.
(4) (a) Moinet, C.; Fiaud, J. C. Synlett 1997, 1997 (1), 97.
doi:10.1055/s-1997-687.; (b) Grigg, R.; Khalil, H.; Levett,
P.; Virica, J.; Sridharan, V. Tetrahedron Lett. 1994, 35 (19),
3197. doi:10.1016/S0040-4039(00)76866-3.; (c) An, Z.-W.;
Catellani, M.; Chiusoli, G. P. J. Organomet. Chem. 1989,
371 (3), C51. doi:10.1016/0022-328X(89)85241-6.; (d) An,
Z.-W.; Catellani, M.; Chiusoli, G. P. Gazz. Chim. Ital. 1990,
120, 383; (e) Okuro, K.; Alper, H. J. Org. Chem. 1997, 62
(6), 1566. doi:10.1021/jo962283c.; (f) Grigg, R.; Liu, A.;
Shaw, D.; Suganthan, S.; Woodall, D.-E.; Yoganathan, G.
Tetrahedron Lett. 2000, 41 (36), 7125. doi:10.1016/S0040-
4039(00)01176-X.
(14) (a) Kaiser, N.-F. K.; Hallberg, A.; Larhed, M. J. Comb.
Chem. 2002, 4 (2), 109. doi:10.1021/cc010085f. PMID:
11886283.; (b) Georgsson, J.; Hallberg, A.; Larhed, M. J.
Comb. Chem. 2003, 5 (4), 350. doi:10.1021/cc0201086.
PMID:12857100.; (c) Wannberg, J.; Larhed, M. J. Org.
Chem. 2003, 68 (14), 5750. doi:10.1021/jo034382d. PMID:
12839476.; (d) Yamazaki, K.; Kondo, Y. J. Comb. Chem.
2004, 6 (1), 121. doi:10.1021/cc034029l. PMID:14714995.
(15) (a) Ma, J.-A.; Cahard, D. Chem. Rev. 2004, 104 (12), 6119.
¨
(5) Ferrer, P.; Avendan˜o, C.; Sollhuber, M. Liebigs Ann. 1995,
1995 (10), 1895. doi:10.1002/jlac.1995199510266.
Published by NRC Research Press

Chen et al.
doi:10.1021/cr030143e. PMID:15584697.; (b) Littke, A. F.;
Fu, G. C. Angew. Chem. Int. Ed. Engl. 1999, 38 (16), 2411.
doi:10.1002/(SICI)1521-3773(19990816)38:16<2411::AID-
ANIE2411>3.0.CO;2-T. PMID:10458805.; (c) Hartwig, J. F.
Acc. Chem. Res. 1998, 31 (12), 852. doi:10.1021/ar970282g.
(16) Armarego, W. L. F.; Perrin, D. D. Purifications of Labora-
tory Chemicals; Butterworth-Heinemann: Oxford, 1997.
337
(17) (a) Park, K. K.; Jung J. Y. Heterocycles 2005, 65, 2095; (b)
Li H. -B.; Yang H.; Petersen J. L.; Wang K. K. J. Org.
Chem. 2004, 69, 4500 doi:10.1021/ar970282g.; (a) Reisch, J.
Angew. Chem. 1963, 75, 1203 doi:10.1021/cc034029l.
PMID:14714995.; (b) Wolfe J. F.; Trimitsis G. B.; Morris D.
R. J. Org. Chem. 1969, 34, 3263. doi:10.1021/jo01263a009.
Published by NRC Research Press

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