Synthesis of ortho-alkoxy-aryl carboxamides via alladium-catalyzed aminocarbonylation

Article abstract of DOI:10.1080/00397910802542028

Various aryl carboxamides with alkoxy substituents at the ortho-position, applicable as direct intermediates toward novel ligands, were synthesised via aminocarbonylation of aryl-iodides (2-iodoanisole, 5-chloro-7-iodo-8-methoxy- quinoline, and 5-chloro-7-iodo-8-benzyloxy-quinoline) in the presence of in situ generated palladium(0) catalysts. Simple primary and secondary amines as well as aminoacid esters were used as N-nucleophiles. The optimization of the reaction conditions allowed the preferential formation of carboxamides or ketocarboxamides by simple or double carbon monoxide insertion, respectively. A strong dependence of the chemoselectivity on carbon monoxide pressure was observed. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802542028

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Synthesis of Ortho-alkoxy-aryl
Carboxamides via Palladium-
Catalyzed Aminocarbonylation
Attila Takács a , Artur R. Abreu b , Andreia F. Peixoto
b , Mariette Pereira b & László Kollár a
a Department of Inorganic Chemistry, University of
Pécs, Pécs, Hungary
b Departamento de Quimica, Universidade de
Coimbra, Coimbra, Portugal
Published online: 02 Apr 2009.
To cite this article: Attila Takcs , Artur R. Abreu , Andreia F. Peixoto , Mariette
Pereira & Lszl Kollr (2009) Synthesis of Ortho-alkoxy-aryl Carboxamides via Palladium-
Catalyzed Aminocarbonylation, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:9, 1534-1548, DOI:
10.1080/00397910802542028
To link to this article: http://dx.doi.org/10.1080/00397910802542028
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Synthetic Communications1, 39: 1534–1548, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802542028
Synthesis of Ortho-alkoxy-aryl Carboxamides
via Palladium-Catalyzed Aminocarbonylation
1
Attila Takacs, Artur R. Abreu, Andreia F. Peixoto,
2
2
ꢀ
Mariette Pereira, and Laszlo Kollar
2
1
ꢀ
Department of Inorganic Chemistry, University of Pecs, Pecs, Hungary
ꢀ
ꢀ
1
´
´
2Departamento de Quimica, Universidade de Coimbra, Coimbra, Portugal
Abstract: Various aryl carboxamides with alkoxy substituents at the ortho-
position, applicable as direct intermediates toward novel ligands, were synthesised
via aminocarbonylation of aryl-iodides (2-iodoanisole, 5-chloro-7-iodo-8-methoxy-
quinoline, and 5-chloro-7-iodo-8-benzyloxy-quinoline) in the presence of in situ
generated palladium(0) catalysts. Simple primary and secondary amines as well
as aminoacid esters were used as N-nucleophiles. The optimization of the reaction
conditions allowed the preferential formation of carboxamides or ketocarboxa-
mides by simple or double carbon monoxide insertion, respectively. A strong
dependence of the chemoselectivity on carbon monoxide pressure was observed.
Keywords: Aminocarbonylation, carbon monoxide, carbonylation, iodo-
aromatics, palladium, quinoline
INTRODUCTION
Palladium-catalyzed carbonylation reactions including aminocarbonyla-
tions are widely used in synthetic chemistry.[1] There are a number of
applications concerning the synthesis of simple building blocks and
the functionalization of biologically important skeletons.[2] Aminocarbo-
nylation of iodoarenes and iodoalkenes (and that of the corresponding
aryl- and enol-triflates) plays a special role among these reactions. Even
Received August 8, 2008.
Address correspondence to Laszlo Kollar, Department of Inorganic
ꢀ
ꢀ
ꢀ
Chemistry, University of Pecs and MTA-PTE Research Group for Chemical
´
Sensors, H-7624 Pecs, Ifjusag u. 6., Hungary. E-mail: kollar@ttk.pte.hu
´ ꢀ
´
1534

Aminocarbonylation of Iodoquinoline
1535
carboxamides with bulky N-substituents are available via this methodol-
ogy from easily available starting materials. The synthesis of aryl carbox-
amides and 2-oxo-carboxamides with various structures by using aryl
triflates or aryl halides as model substrates was already published.[3]
Many aspects of carbonylation reactions including aminocarbonylations
have been published recently.[4] The potential of the aminocarbonylation
of ortho-alkoxy-aryl-halides has been shown by several examples to result
in compounds of biological importance. Various large-ring macrocycles[5]
and O-, N-, or S-containing heterocycles[6] are available via intramolecu-
lar aminocarbonylations. The intermolecular version of this reaction
allows the facile synthesis of tetracycline derivatives[7] C-11-labeled
amides,[8] and Weinreb amides,[9] which are of high synthetic importance.
Efforts were made to carbonylate amides on a polymer support.[10]
Although the N-acylation of amino acids is widely used in synthetic chem-
istry, there are just a few examples using homogeneous aminocarbonylation
of aryl halides as a tool for the introduction of a carboxamide moiety.[11–13]
To the best of our knowledge, only sporadic results are available on
catalytic coupling reactions using 2-iodoanisole or iodoquinolines.
Palladium–Tol-BINAP systems were used in asymmetric amination
of 2-iodoanisole with racemic amines.[14] Copper-catalyzed coupling of
2-iodoanisole with imidazole followed by methoxycarbonylation was car-
ried out to synthesize an active site model compound of cytochrome-c
oxidase.[15] However, the para-substituted analog, 4-iodoanisole, has
been investigated in more detail. Its oxidative addition to palladium(0)
species, formed via electroreduction, was found to be very efficient.[16]
The Sonogashiracouplings of 4-iodoanisole with phenylacetylene[17] and
with a diethynyl-benzothiadiazole derivative[18] were catalyzed by a cata-
lyst formed from PdCl2(PPh3)2, copper(I)-iodide, and aqueous ammonia
and by a pincer-palladacycle catalyst, respectively. The kinetic investiga-
tion of the Heck reaction between 4-iodoanisole and styrene in the
presence of a phosphorus-carbon-phosphorus (PCP)–pincer-palladium
catalyst was carried out.[19] The double Suzuki reaction between pyridine-
diboronic acid and 4-iodoanisole resulted in 2,6-bis(4-methoxyphenyl)
pyridines, which can be used as synthetic building blocks.[20] Aminocar-
bonylation of 4-iodo-anisole[21] and, quite recently, its structural analog,
2,6-dimethoxy-iodobenzene,[8] was also carried out with in situ formed
and ‘‘preformed’’ Pd(0) catalytic systems, respectively. Palladium-cata-
lyzed cross-coupling reactions of iodoquinoline derivatives with alkynes
were carried out to synthesise tri-substituted pyrroloquinolines[22] and
4-substituted quinolines.[23]
As a main goal of our present reseach, encouraged by the increasing
importance of the systematic investigation of ligand synthesis, we decided
to extend the scope of aminocarbonylation to ortho-substituted iodoaryl

ꢀ
A. Takacs et al.
1536
substrates, 2-iodoanisole and 7-iodo-8-alkoxy-quinoline derivatives.
After deprotection of the methoxy moiety, the carboxamides=
ketocarboxamides, available via aminocarbonylation of these types of
substituted iodoarenes, could serve as challenging ligands in coordination
chemistry of aluminum,[24] titanium,[25] molybdenum complexes.[26]
Furthermore, the improvement of alternative synthetic methods for
alkoxy-quinoline derivatives is of great interest because of their potential
biological activity as PDE4 inhibitors[27] as well as for the preparation of
electroluminescent materials for organic LEDs.[24]
Accordingly, the facile, high-yielding, palladium-catalyzed aminocar-
bonylation of 2-iodoanisole, 5-chloro-7-iodo-8-methoxy-quinoline, and
5-chloro-7-iodo-8-benzyloxy-quinoline with various N-nucleophiles is
published in the present article. The ortho-carboxamido- or ketocarbox-
amido phenols, available by the convential organic transformation of the
ether functionality to the corresponding phenol, could serve as novel
sterically and electronically tuned ligands both in main-group metal
and transition-metal coordination chemistry.
RESULTS AND DISCUSSION
Aminocarbonylation of 2-Iodo-anisole (1)
2-Iodo-anisole (1) was reacted with carbon monoxide and various
primary or secondary amines such as N-nucleophiles [tert-butylamine
(a), piperidine (b), morpholine (c), methyl glycinate (d), or benzyl
prolinate (e)] in dimethylformamide (DMF) in the presence of
palladium–phosphine catalysts (Fig. 1). The in situ formation of
highly reactive, coordinatively unsaturated palladium(0) species from
palladium(II) acetate has been investigated in details.[28,29]
Depending on the carbon monoxide pressure, the prevailing forma-
tion of carboxamides (2a–e) or ketocarboxamides (3a–e) can be achieved.
In general, the simple or double carbon monoxide insertion is favored
(vide infra) under atmospheric pressure or 40 bar, respectively (e.g., entry
1 and 2, Table 1). Both the corresponding carboxamido derivatives
(2a–d) and ketocarboxamides (3a–d) were synthesized in moderate to
good isolated yields, depending on the structure of the amine, under
appropriate reaction conditions (Table 1). However, by using proline
benzyl ester, the dicarbonylated derivative 3e was formed as prevailing
product and could be isolated preferentially (entry 10).
The aminocarbonylation reaction can be carried out even under
atmospheric carbon monoxide. High reactivities were observed in all
cases, and conversions higher than 95% have been obtained. As for the

Aminocarbonylation of Iodoquinoline
1537
Figure 1. Aminocarbonylation of 2-iodoanisole.
chemoselectivity of aminocarbonylation, the carboxamides (2) formed
via monocarbonylation prevail over ketocarboxamides (3), especially in
case of methyl glycinate (d) where 2d was exclusively formed.
Table 1. Aminocarbonylation of 2-iodo-anisole (1) with primary and secondary
aminesa
Ratio of the carbonylated
b
products to isolated
c
yields (%)
R time p(CO) Conv.
(h)
Entry
Amine
(bar)
(%) Carboxamide Ketocarboxamide
1
2
3
4
5
6
7
8
9
10
tBuNH2 (a)
tBuNH2 (a)
piperidine (b)
piperidine (b)
morpholine (c)
morpholine (c)
GlyOMe (d)
GlyOMe (d)
GlyOMe (d)
ProOBn (e)
91
24
23
23
24
24
70
70
24
24
1
40
1
40
1
40
1
40
60
40
>98
93
>98
>98
>98
>98
78 (2a): 60
38 (2a): 57
92 (2b): 80
20 (2b): n.d.
83 (2c): 71
15 (2c): n.d.
22 (3a): n.d.
62 (3a): 51
8 (3b): n.d.
80 (3b): 67
17 (3c): n.d.
85 (3c): 73
0 (3d): 0
24 (3d): 10
83 (3d): 70
95 (3e): 74d
95 100 (2d): 80
96
95
95
76 (2d): 60
17 (2d): n.d.
5 (2e): n.d.d
aReaction conditions: 0.025 mmol Pd(OAc)2; 0.05 mmol PPh3, 1 mmol 1;
3 mmol unfunctionalized amine (or 1.1 mmol amino acid methylester hydrochlor-
ide), 0.5 ml triethylamine; 10 ml DMF, 50ꢀC.
bDetermined by GC-MS.
cIsolated yields are based on the amount of the starting material 1.
dThe ketocarboxamide derivative (3e) was isolated and characterized only.

ꢀ
A. Takacs et al.
1538
The application of high carbon monoxide pressure (40 bar) resulted
in the opposite chemoselectivity towards carboxamides except for d. In
this specific case, the chemoselectivity toward double carbonylation
could be shifted by using an increased carbon monoxide pressure
(60 bar) (entry 9).
Aminocarbonylation of 7-Iodo-Quinoline Derivatives (4, 5, and 8)
5-Chloro-7-iodo-8-hydroxy-quinoline (4) was reacted with various
amines and carbon monoxide in the presence of the palladium(0)
catalysts described previously (Fig. 2, Table 2). The carbon monoxide
pressure was varied from 1 to 60 bar. The expected amides (5-chloro-7-
carboxamido-8-hydroxy-quinoline derivatives) could not be detected
even in traces by gas chromatography–mass spectrometry (GC-MS).
However, selective dehydroiodination of the 7-iodo-aryl moiety resulted
in known compound 5-chloro-8-hydroxy-quinoline (40)[30,31] with wide
application. It was isolated in nearly quantitative yields both in the
presence of tert-butylamine and piperidine (entries 1–4). It has to be
added that an oxidative addition—reductive elimination reaction
sequence, including the formation of a palladium-hydride intermediate,
might be operative. The same dehydroiodination was observed when
attempts to protect the 8-hydroxyl group with iodomethane in the
presence of NaH were carried out.
5-Chloro-7-iodo-8-methoxy-quinoline (5), prepared from 5-chloro-7-
iodo-8-hydroxy-quinoline (4) with methyl iodide and sodium methy-
late,[25] was reacted with primary and secondary amines [tert-butyl-amine
(a) and piperidine (b)] and carbon monoxide in the presence of the
catalyst described previously (Fig. 3, Table 2). Monocarbonylation was
observed as the prevailing reaction, resulting in the corresponding car-
boxamides (6a, 6b) in all cases. Double carbonylation took place only
to a small extent. Less than 15% yields of ketocarboxamides (7a, 7b) have
Figure 2. Dehydroiodination of 5-chloro-7-iodo-8-hydroxy-quinoline under
carbonylation conditions.

Aminocarbonylation of Iodoquinoline
1539
Table 2. Aminocarbonylation of 5-chloro-7-iodo-8-hydroxyquinoline (4), 5-
chloro-7-iodo-8-methoxyquinoline (5), and 5-chloro-7-iodo-8-benzyloxyquinoline
(8) with tert-butylamine (a) and piperidine (b)a
Ratio of carbonylated productsb
to isolated yieldsc (%)
R time p(CO) Conv.
Entry Substrate Amine [h]
(bar) (%) Carboxamide Ketocarboxamide
1
2
3
4
5
6
7
8
9
4
4
4
4
5
5
5
5
5
5
8
a
a
b
b
a
a
a
a
a
b
a
24
24
24
24
24
24
27
72
24
24
24
1
60
1
60
1
20
40
60
60
60
60
>98d
>98d
>98d
>98d
0
5
85
>98
97
0
0
0
0
0
0
0
0
0
0
>98 (6a): n.d
94 (6a): 67
92 (6a): 76
85 (6a): 72
<2 (7a): n.d.
6 (7a): n.d.
8 (7a): n.d.
15 (7a): 9
<2 (7b): n.d.
<2 (10a): n.d.
10
11
50 >98 (6b): 41
70 >98 (9a): 62
aReaction conditions: 0.025 mmol Pd(OAc2); 0.05 mmol PPh3; 0.5 mmol sub-
strate; 15 ml DMF; 0.5 ml Et3N; and 1.5 mmol tBuNH2 (or piperidine).
bDetermined by GC-MS.
cIsolated yields (in brackets) are based on the amount of the starting material
(5 or 8).
dThe substrate (4) has been converted to 5-chloro-8-hydroxyquinoline (40).
been obtained. Similarly, the tert-butylaminocarbonylation of 5-chloro-
7-iodo-8-benzyloxy-quinoline (8) resulted mainly in the formation of
the corresponding monocarboxamide, 9a (Fig. 4, Table 2). It is worth
noting that the reaction of simple iodoarenes such as iodobenzene
and 2-iodo-naphthalene with carbon monoxide and amines provides
Figure 3. Aminocarbonylation of 5-chloro-7-iodo-8-methoxy-quinoline.

ꢀ
A. Takacs et al.
1540
Figure 4. Aminocarbonylation of 5-chloro-7-iodo-8-benzyloxy-quinoline.
the mixture of the corresponding carboxamides and 2-ketocarboxamides
with the prevailing formation of the latter product under similar reaction
conditions.[11,12]
Furthermore, the reaction with 5 goes much more slowly than with
simple monofunctionalized iodo-arenes. As a result of that, nearly com-
plete conversion to carbonylated products has been observed only with
tert-butylamine (entry 8 and 9). Using piperidine as nucleophile, we
obtained 50% conversion of carboxamide 6b (entry 10). The yield of
the aminocarbonylation was influenced substantially by the carbon
monoxide pressure. Nearly complete conversion to 6a and 7a could be
obtained under more severe conditions [60 bar carbon monoxide pressure
and elevated reaction time (entry 8 only)]. The low reactivity of this
substrate can be also illustrated by the fact that no reaction occurs at
atmospheric carbon monoxide pressure (entry 5). It has to be noted
that the aminocarbonylation at high carbon monoxide pressure is accom-
panied by the formation of some 2-ketocarboxamides (up to 15% and 2%
for tert-butyl-amine and piperidine, respectively) (entries 7–10).
CONCLUSION
The palladium-catalyzed aminocarbonylation of ortho-alkoxy-iodoarenes
can be carried out, and the corresponding carboxamides and 2-ketocar-
boxamides were isolated in moderate to high isolated yields. The chemos-
electivity is dependent on the carbon monoxide pressure; that is, at low
pressure the formation of monocarboxamides is observed. However,
at high pressure the formation of ketocarboxamides is favored. The pro-
ducts are potential intermediates of ligands (e.g., the quinoline derivatives
may form oxine-type ligands after deprotection) or are of direct practical
importance (e.g. the acylated amino acid derivatives).
The high yields related to those obtained with conventional proce-
dures and the high functional group tolerance of homogeneous catalytic
aminocarbonylation make these reactions of great synthetic relevance.

Aminocarbonylation of Iodoquinoline
1541
EXPERIMENTAL
General Procedures
1H and 13C NMR spectra were recorded in CDCl3 on a Varian Inova 400
spectrometer at 400.13 MHz and 100.62 MHz, respectively. Chemical
shifts d are reported in parts per million (ppm) relative to CHCl3 (7.26
1
and 77.00 ppm for H and 13C, respectively). Elemental analyses were
measured on a 1108 Carlo Erba apparatus. Samples of the catalytic reac-
tions were analyzed with a Hewlett Packard 5830A gas chromatograph
fitted with a capillary column coated with OV-1.
5-Chloro-7-iodo-8-methoxy-quinoline and 5-chloro-7-iodo-8-benzyloxy-
quinoline were synthesized as described previously.[32] 2-Iodo-anisole and
5-chloro-7-iodo-8-hydroxy-quinoline, as well as the amines, were pur-
chased from Aldrich and were used without any further purification.
Solvents were dried and purified by generally used procedures.
Aminocarbonylation Reaction at High Pressure
In a typical reaction, 5.6 mg (0.025 mmol) of Pd(OAc)2 and 13.0 mg
(0.05 mmol) of PPh3 together with 1 mmol of substrate (1, 4, 5, or 6) were
placed into a 100-ml autoclave equipped with a magnetic stirring bar. The
atmosphere was changed to argon, and all the solid substances were
dissolved in 15 ml dimethylformamide (DMF), and then 0.5 ml triethyla-
mine and 1.5 mmol of the appropriate amine were added. The atmo-
sphere was changed to carbon monoxide, the autoclave was pressurized
by carbon monoxide to the given pressure, and the reaction mixture
was kept at 50ꢀC for 24 h. After cooling and venting the autoclave, the
reaction mixture was analyzed immediately by GC-MS.
The solvent was evaporated to dryness, and the residue was dissolved
in chloroform. It was washed three times with water and brine. The
organic phase was dried over Na2SO4 and evaporated. The carboxamides
were isolated by column chromatography (silica gel, EtOAc=CH2Cl2, or
EtOAc=CHCl3 eluent mixtures; exact composition and physical state of
compounds vide infra).
Analytical and Spectroscopic Data of Compounds
(2-Methoxyphenyl)-tert-butylamino-methanone (2a)
dH (400 MHz, CDCl3) 8.06 (ddt, 7.7 Hz, 1.8 Hz, 0.7 Hz, 1H, Ar); 7.72 (br
s, 1H, NH); 7.28 (dtt, 8.3 Hz, 1.9 Hz, 0.8 Hz, 1H, Ar); 6.95 (dt, 7.7 Hz,

ꢀ
A. Takacs et al.
1542
0.7 Hz, 1H, Ar); 6.82 (d, 8.3 Hz, 1H, Ar); 3.80 (s, 3H, OCH3); 1.35 (s, 9H,
tBu). dC (100.6 MHz, CDCl3) 164.1, 157.2, 132.3, 131.7, 122.7, 121.1,
111.4, 55.8, 50.9, 28.9. IR (KBr, cmꢁ1): 3397 (NH); 1660 (CON). MS
m=z (rel. int., %): 207 (11), 192 (12), 135 (100), 105 (8), 77 (15). Analysis
calculated for C12H17NO2 (207.27): C, 69.54; H, 8.27; N, 6.76. Found: C,
69.45; H, 8.42; N, 6.60, Rf (5% EtOAc=CH2Cl2) 0.65; Rf (20%
EtOAc=petroleum ether) 0.81; highly viscous material.
(2-Methoxyphenyl)-tert-butylamino-ethandione (3a)
dH (400 MHz, CDCl3) 7.61 (d, 7.6 Hz, 1H, Ar); 7.47 (t, 8.5 Hz, 1H, Ar);
7.01 (t, 7.6 Hz, 1H, Ar); 6.96 (d, 8.5 Hz, 1H, Ar); 6.45 (br s, 1H, NH); 3.83
(s, 3H, OCH3); 1.46 (s, 9H, tBu). dC (100.6 MHz, CDCl3) 192.4, 162.5,
159.5, 134.3, 131.0, 124.8, 120.7, 112.0, 56.0, 51.5, 28.4. IR (KBr, cmꢁ
1): 3268 (NH); 1668 (CO); 1638 (CON). MS m=z (rel. int., %): 235 (5),
135 (100), 92 (8), 77 (15). Analysis calculated for C13H17NO3 (235.28):
C, 66.36; H, 7.28; N, 5.95. Found: C, 66.17; H, 7.52; N, 5.69. Rf (3%
EtOAc=CH2Cl2) 0.54; mp 87–90ꢀC; white crystalline material.
(2-Methoxyphenyl)piperidin-1-yl-methanone (2b)
dH (400 MHz, CDCl3) 7.28 (dt, 7.7 Hz, 1.6 Hz, 1H, Ar); 7.17 (d, 8.3 Hz,
1H, Ar); 6.92 (dt, 7.7 Hz, 1.6 Hz, 1H, Ar); 6.83 (d, 8.3 Hz, 1H, Ar);
3.76 (s, 3H, OCH3); 3.60–3.80 (m, 2H, NCH2); 3.12 (br s, 2H, NCH2);
1.35–1.63 (m, 6H, 3 ꢂ CH2). dC (100.6 MHz, CDCl3) 167.6, 155.3,
130.0, 127.6, 126.5, 120.8, 110.9, 55.5, 47.9, 42.5, 26.3, 25.6, 24.6. IR
(KBr, cmꢁ1): 1635 (CON). MS m=z (rel. int., %): 219 (23), 218 (84),
135 (100), 77 (22). Analysis calculated for C13H17NO2 (219.28): C,
71.21; H, 7.81; N, 6.39. Found: C, 71.05; H, 8.02; N, 6.20; Rf (20%
EtOAc=CH2Cl2) 0.51; highly viscous material.
(2-Methoxyphenyl)piperidin-1-yl-ethandione (3b)
d
H (400 MHz, CDCl3) 7.87 (dd, 7.6 Hz, 1.7 Hz, 1H, Ar); 7.49 (dt, 8.4 Hz,
1.7 Hz, 1H, Ar); 7.01 (t, 7.6 Hz, 1H, Ar); 6.93 (d, 8.4 Hz, 1H, Ar); 3.82 (s,
3H, OCH3); 3.6 (m, 2H, NCH2); 3.26 (m, 2H, NCH2); 1.48–1.50 (m, 6H,
3 ꢂ CH2). dC (100.6 MHz, CDCl3) 190.7, 167.1, 160.2, 135.9, 131.0, 123.6,
121.2, 112.3, 56.1, 46.6, 41.9, 25.5, 25.3, 24.5. IR (KBr, cmꢁ1): 1668 (CO);
1647 (CON). MS m=z (rel. int., %): 247 (4), 135 (100), 77 (12). Analysis
calculated for C14H17NO3 (247.29): C, 68.00; H, 6.93; N, 5.66. Found: C,
67.85, H, 7.12; N, 5.60. Rf (10% EtOAc=CH2Cl2) 0.54; highly viscous
material.

Aminocarbonylation of Iodoquinoline
1543
(2-Methoxyphenyl)morpholin-4-yl-methanone (2c)
dH (400 MHz, CDCl3) 7.33 (dt, 7.6 Hz, 1.7 Hz, 1H, Ar); 7.20 (d, 8.4 Hz,
1H, Ar); 6.95 (dt, 7.6 Hz, 1.7 Hz, 1H, Ar); 6.87 (d, 8.4 Hz, 1H, Ar);
3.80 (s, 3H, OCH3); 3.70–3.80 (m, 4H, 2 ꢂ CH2); 3.50–3.65 (m, 2H,
CH2); 3.15–3.30 (m, 2H, CH2). dC (100.6 MHz, CDCl3) 167.9, 155.3,
130.6, 128.1, 125.4, 121.0, 111.0, 67.0, 66.8, 55.5, 47.3, 42.1. IR (KBr,
cmꢁ1): 1638 (CON). MS m=z (rel. int., %): 221 (7), 220 (18), 135 (100),
77 (15). Analysis calculated for C12H15NO3 (221.26): C, 65.14; H, 6.83;
N, 6.33. Found: C, 65.01, H, 6.89; N, 6.10. Rf (35% EtOAc=CH2Cl2)
0.40; highly viscous material.
(2-Methoxyphenyl)morpholin-4-yndione (3c)
dH (400 MHz, CDCl3) 7.87 (d, 7.8 Hz, 1H, Ar); 7.52 (dt, 8.2 Hz, 1.6 Hz,
1H, Ar); 7.04 (t, 7.8 Hz, 1H, Ar); 6.95 (d, 8.2 Hz, 1H, Ar); 3.86(s, 3H,
OCH3); 3.60–3.74 (m, 6H, 3 ꢂ CH2); 3.35 (t, 5 Hz, 2H, CH2). dC
(100.6 MHz, CDCl3) 190.2, 167.3, 160.2, 136.2, 131.0, 123.6, 121.4,
112.3, 66.5, 66.3, 56.2, 45.9, 41.4. IR (KBr, cmꢁ1): 1667 (CO); 1635
(CON). MS m=z (rel. int., %): 249 (3), 135 (100), 77 (15). Analysis calcu-
lated for C13H15NO4 (249.27): C, 62.64; H, 6.07; N, 5.62. Found: C,
62.44; H, 6.26; N, 5.39. Rf (35% EtOAc=CH2Cl2) 0.54; mp 142–145ꢀC,
white crystalline material.
(2-Methoxyphenyl)(methoxycarbonyl-methylamino)-methanone (2d)
dH (400 MHz, CDCl3) 8.42 (br s, 1H, NH); 8.16 (dt, 7.7 Hz, 1.6 Hz, 1H,
Ar); 7.41 (dt, 8.2 Hz, 1.8 Hz, 1H, Ar); 7.02 (dt, 7.7 Hz, 1.8 Hz, 1H, Ar);
6.93 (d, 8.2 Hz, 1H, Ar); 4.23 (d, 6.8 Hz, 2H, CH2); 3.94 (s, 3H,
OCH3); 3.76 (s, 3H, OCH3). dC (100.6 MHz, CDCl3) 170.7, 165.3,
157.8, 133.1, 132.3, 121.2, 120.8, 111.4, 56.0, 52.2, 41.8. IR (KBr, cmꢁ
1): 3383 (NH); 1744 (COO); 1659 (CON). MS m=z (rel. int., %): 223
(3), 164 (5), 135 (100), 105 (4), 77 (20). Analysis calculated for
C11H13NO4 (223.23): C, 59.19; H, 5.87; N, 6.27. Found: C, 59.03; H,
5.98; N, 6.01. Rf (20% EtOAc=CH2Cl2) 0.64; highly viscous material.
(2-Methoxyphenyl)(methoxycarbonyl-methylamino)-ethandione (3d)
dH (400 MHz, CDCl3) 7.65 (dd, 7.6 Hz, 1.8 Hz, 1H, Ar); 7.48 (dt, 8.4 Hz,
1.8 Hz, 1H, Ar); 7.15 (br s, 1H, NH); 7.00 (t, 7.6 Hz, 1H, Ar); 6.88

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A. Takacs et al.
1544
(d, 8.4 Hz, 1H, Ar); 4.14 (d, 6.6 Hz, 2H, CH2); 3.83 (s, 3H, OCH3); 3.75
(s, 3H, OCH3). dC (100.6 MHz, CDCl3) 190.4, 169.5, 163.4, 159.7, 134.8,
131.1, 124.3, 120.7, 112.1, 56.1, 52.4, 41.0. IR (KBr, cmꢁ1): 3355 (NH);
1754 (COO); 1673 (vs, CO þ CON). MS m=z (rel. int., %): 251 (6), 135
(100), 92 (10), 77 (24). Analysis calculated for C12H13NO5 (251.24): C,
57.37; H, 5.22; N, 5.58. Found: C, 57.19, H, 5.03; N, 5.33. Rf (30%
EtOAc=CH2Cl2) 0.70; highly viscous material.
(2-Methoxyphenyl)(2-benzyloxycarbonyl-pyrrolidin-1-yl)-ethandione (3e)
dH (400MHz, CDCl3) (two conformational isomers due to C(O)-N hin-
dered rotation) 7.83=7.78 (dd, 7.5 Hz, 1.8 Hz, 1H, Ar); 7.50=7.46 (dt,
8.4 Hz, 1.8 Hz, 1H, Ar); 7.2–7.4 (m, 5H, Ph); 6.90–7.02 (m, 2H, Ar);
5.19=5.02 (AB-quartet=AB-quartet, 8.0 Hz, 11.0 Hz=8.0 Hz, 12.5 Hz, 2H,
CH2Ph); 4.58–4.63 (m, 1H, CHCOO); 3.82=3.78 (s, 3H, OCH3); 3.50–
3.80 (m, 2H, NCH2); 1.90–2.30 (m, 4H, 2 ꢂ CH2). dC (100.6 MHz, CDCl3)
(two conformational isomers due to C(O)-N hindered rotation) 190.6=
190.5, 171.5=171.4, 166.4=165.9, 160.4=160.1, 135.9=135.7, 135.5=135.4,
128.6, 128.5, 128.2, 128.0, 124.0=123.5, 121.1=121.0, 112.2=112.1,
66.9=66.8, 59.3=58.3, 56.3=56.1, 46.9=46.1, 31.1=29.3, 24.7=22.4. IR (KBr,
cmꢁ1): 1747 (COO); 1648 (vs, CO þ CON). Analysis calculated for
C21H21NO5 (367.40): C, 68.65; H, 5.76; N, 3.81. Found: C, 68.49; H,
5.52; N, 3.63. Rf (10% EtOAc=CH2Cl2) 0.75; highly viscous material.
5-Chloro-7-(N-tert-butylcarboxamido)-8-methoxy-quinoline (6a)
1H NMR(CDCl3) d: 8.95 (d, 2.8 Hz, 1H, H-2); 8.55 (d, 7 Hz, 1H, H-4);
8.30 (s, 1H, H-6); 8.16 (brs, 1H, N-H); 7.58 (dd, 2.8 Hz, 7 Hz, 1H,
H-3); 4.20 (s, 3H, OCH3); 1.51 [s, 9H, C(CH3)3]. 13C NMR (CDCl3) d:
162.7, 153.4, 150.4, 143.2, 133.3, 129.0, 127.3, 126.7, 126.5, 123.1, 63.2,
51.3, 28.8. IR (KBr, cmꢁ1): 3375 (NH); 1665 (CON). MS m=z (rel.
int., %): 292=294 (27=9) (Mþ), 235/233 (41=14), 220=222 (100=34),
205=207 (40=13), 191=193 (26=9), 179=181 (31=10). Analysis calculated
for C15H17N2O2Cl (292.77): C, 61.54; H, 5.85; N, 9.57. Found: C,
61.41; H, 5.59; N, 9.44. Rf (10% EtOAc=CH2Cl2) 0.44; highly viscous yel-
low material.
5-Chloro-7-(N-tert-butylglyoxylamido)-8-methoxy-quinoline (7a)
1H NMR(CDCl3) d: 8.93 (d, 2.8 Hz, 1H, H-2); 8.55 (d, 7 Hz, 1H, H-4);
7.75 (s, 1H, H-6); 7.57 (dd, 2.8 Hz, 7 Hz, 1H, H-3); 6.40 (brs, 1H, NH);

Aminocarbonylation of Iodoquinoline
1545
4.36 (s, 3H, OCH3); 1.53 [s, 9H, C(CH3)3]. 13C NMR (CDCl3) d: 191.8,
162.0, 156.6, 149.8, 143.1, 133.4, 130.1, 127.4, 126.8, 125.8, 123.4, 64.0,
51.7, 28.5. IR (KBr, cmꢁ1): 3378 (NH); 1653 (shoulder at ca. 1665)
(CO þ CON). MS m=z (rel. int., %): 320=322 (9=3) (Mþ), 220=222
(100=33), 193 (18), 164 (17), 57 (20). Analysis calculated for
C16H17N2O3Cl (320.78): C, 59.91; H, 5.34; N, 8.73. Found: C, 59.80;
ꢀ
H, 5.49; N, 8.66. Rf (10% EtOAc=CH2Cl2) 0.55; mp 127–130 C, white
crystalline material.
5-Chloro-7-(N,N-(10,50-pentadiyl)carboxamido)-8-methoxy-quinoline (6b)
1HNMR(CDCl3) d: 8.98 (d, 2.8 Hz, 1H, H-2); 8.56 (d, 7 Hz, 1H, H-4);
7.58 (dd, 2.8 Hz, 7 Hz, 1H, H-3); 7.50 (s, 1H, H-6); 4.18 (s, 3H, OCH3);
3.7–3.9 (m, 2H, NCH2); 3.1–3.3 (m, 2H, NCH2); 1.58–1.75 [m, 6H,
(CH2)3]. 13C NMR (CDCl3) (two conformational isomers due to C(O)-N
hindered rotation) d: 165.9, 150.6, 143.0, 133.3, 132.1, 132.0, 128.5,
128.4, 125.3, 122.5, 63.2, 48.3=47.1, 42.8=41.7, 26.4=25.6, 25.3=24.7,
24.4. IR (KBr, cmꢁ1): 1639 (CON). MS m=z (rel. int., %): 304=306
(40=14) (Mþ), 220=222 (100=34), 191=193 (50=13), 128 (31). Analysis
calculated for C16H17N2O2Cl (304.78): C, 63.05; H, 5.62; N, 9.19. Found:
C, 63.15; H, 5.50; N, 8.97. Rf (50% EtOAc=CH2Cl2) 0.39; highly viscous
material.
5-Chloro-7-(N-tert-butylcarboxamido)-8-benzyloxy-quinoline (9a)
1HNMR(CDCl3) d: 9.03 (d, 2.6 Hz, 1H, H-2); 8.58 (d, 7.2 Hz, 1H, H-4);
8.33 (s, 1H, H-6); 8.08 (brs, 1H, N-H); 7.60 (dd, 2.6 Hz, 7.2 Hz, 1H, H-3);
7.30–7.42 (m, 5H, Ph); 5.55 (s, 2H, CH2Ph); 1.22 [s, 9H, C(CH3)3]. 13C
NMR (CDCl3) d: 162.8, 159.6, 152.6, 150.0, 143.3, 136.4, 133.3, 129.0,
128.9, 128.6, 128.5, 127.5, 126.5, 123.0, 78.8, 51.3, 28.5. IR (KBr, cmꢁ
1): 3376 (NH), 1663 (CON). Analysis calculated for C21H21N2O2Cl
(368.86): C, 68.38; H, 5.74; N, 7.59. Found: C, 68.29; H, 5.56; N, 7.43.
Rf (10% EtOAc=CHCl3) 0.83; mp 165–168ꢀC, yellow crystalline material.
ACKNOWLEDGMENT
The authors thank the Hungarian Research Fund (OTKA NI61591), the
Portuguese FCT project (PTDC=QUI=66015=2006), and the Joint Project
of the European Union–Hungarian National Development Program
(GVOP-3.2.1-2004-04-0168=3) for the financial support and Johnson
Matthey for the generous gift of palladium(II) acetate. A. F. Peixoto

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A. Takacs et al.
1546
(SFRH=BD=29681=2006) and A. R. Abreu (SFRH=BD=21314=2005) are
thankful for their PhD grants.
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