Palladium-catalysed multicomponent aminocarbonylation of aryl or heteroaryl halides with Mo(CO)6i and aryl- or heteroarylamines using conventional heating

Article abstract of DOI:10.1002/ejoc.200900167

Di(hetero)arylamides have been synthesized in short reaction times by palladium-catalysed multicomponent aminocarbonylation of either electron-deficient or electron-rich heteroaryl halides and p-iodoanisole with, several, arylamines bearing either electro

Full text of DOI:10.1002/ejoc.200900167

FULL PAPER
DOI: 10.1002/ejoc.200900167
Palladium-Catalysed Multicomponent Aminocarbonylation of Aryl or
Heteroaryl Halides with [Mo(CO)6] and Aryl- or Heteroarylamines Using
Conventional Heating
Agathe Begouin[a] and Maria-João R. P. Queiroz*[a]
Keywords: Aminocarbonylation / Multicomponent reactions / Halides / Amines / Palladium / Amides
Di(hetero)arylamides have been synthesized in short reaction
times by palladium-catalysed multicomponent aminocarbon-
ylation of either electron-deficient or electron-rich heteroaryl
halides and p-iodoanisole with several arylamines bearing
either electron-donating or -withdrawing groups and amino-
We have demonstrated that these reactions can be performed
under conventional heating (110–125 °C) to yield the corre-
sponding di(hetero)arylamides in moderate-to-high yields in
short reaction times (from 1–3 h) with no need for MW irradi-
ation. A N-substituted isoindoline-1,3-dione from 2-iodo-
pyridines using [Mo(CO)6] as a solid CO source and conven- benzoic acid or methyl 2-iodobenzoate and p-anisidine
tional heating. Starting from heteroaryl bromides, a pallada-
cycle with tBu3PHBF4 as ligand is required together with
DBU as a base in dioxane and a temperature of 125 °C. From
(hetero)aryl iodides, Pd(OAc)2 without a ligand and DBU
were used in dioxane at 110 °C. Under the latter conditions
we were able to apply this reaction to deactivated amino-
pyridines to obtain the corresponding di(hetero)arylamides.
through a one-step carbonylative cyclization reaction was
also obtained. Thus, we have extended the scope of this
palladium-catalysed aminocarbonylation reaction with
[Mo(CO)6] to several (hetero)aryl substrates using conven-
tional heating.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Other operational advances in the conversion of aryl ha-
lides into diarylamides have included the use of solid
[Mo(CO)6] as the carbon monoxide source and microwave
reactors to facilitate these transformations.[5–7] Wannberg
and Larhed[6] improved the CO release from a tandem
[Mo(CO)6]/amidation methodology by using DBU (1,8-di-
azabicyclo[5.4.0]undec-7-ene) as a base and THF as solvent
in microwave protocols. With this more general method
they were able to accomplish aminocarbonylations using
aniline, benzylamine, the sterically hindered tert-butylamine
and amino acids. The same authors performed two experi-
ments starting with aryl iodides, [Mo(CO)6] and amines
using conventional heating with no significant change in
the product yield but the general procedure reported was
performed under MW irradiation. This reaction has already
been described with heteroaryl halides such as bromopyr-
idines, bromopyrimidines and bromoquinolines among
others reacting with alkylamines.[7] However, electron-rich
heterocycles, like halothiophenes, have been less used.
Some carbonylation reactions using [Mo(CO)6] have also
been described without the assistance of microwave heating.
Yamazaki and Kondo performed a solid-phase palladium-
catalysed aminocarbonylation of aryl halides using CO gen-
erated in situ from [Mo(CO)6] by ligand exchange with
CH3CN at 80 °C. They used Pd(OAc)2 as the catalyst, BI-
NAP [2,2Ј-bis(diphenylphosphanyl)-1,1Ј-binaphthyl] as the
ligand and Cs2CO3 as the base.[8] The same research group
has described a palladium-catalysed double carbonylation
Introduction
Palladium-catalysed carbonylation of aryl halides is a
highly efficient method for the synthesis of carbonyl com-
pounds.[1,2] Particularly important is the aminocarbon-
ylation reaction, which is a selective and useful method for
the direct synthesis of amides through the coupling of ha-
lides with primary/secondary amines. However, in compari-
son with other transition-metal-mediated reactions, such as
cross-couplings and Heck and Sonogashira reactions, tran-
sition-metal-mediated carbonylation and aminocarbon-
ylation reactions for the functionalization of aryl or hetero-
aryl halides have seldom been explored.
Most of the aminocarbonylation reactions that have been
reported use carbon monoxide gas as the CO source.[2–4]
The scope of this reaction is broad and the tolerance for
different functional groups is high. However, although this
type of reaction has been extensively used in large-scale
production, its true potential has not been fully exploited
in laboratory-scale syntheses. In particular, the cumbersome
handling of CO gas and the long reactions times (ranging
from hours to days) severely limit the usefulness of this car-
bonylative transformation in drug discovery and other
small-scale applications.
[a] Centro de Química, Universidade do Minho, Campus de
Gualtar,
4710-057 Braga, Portugal
Fax: +351-253604382
E-mail: mjrpq@quimica.uminho.pt
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Multicomponent Aminocarbonylation of Aryl or Heteroaryl Halides
of aryl iodides with alkylamines using tBu3P as the ligand,
[Mo(CO)6] and DBU at room temperature.[9] They also
used tBu3P in the palladium-catalysed [Pd(tBu3P)2]-alkynyl-
carbonylation of aryl iodides with phenylacetylene and
[Mo(CO)6] in the presence of CH3CN and Et3N at room
temperature.[10]
Herein we report the use of [Mo(CO)6] in the multicom-
ponent palladium-assisted aminocarbonylation of electron-
deficient and -rich heteroaryl halides and iodoanisole with
several (hetero)arylamines to give the corresponding di-
(hetero)arylamides using conventional heating for 1–3 h,
thus extending the scope of this reaction. Palladium acetate
was used as the palladium source with the (hetero)aryl
iodides and trans-di-µ-acetatobis[2-(di-o-tolylphosphanyl)-
benzyl]dipalladium(II), also known as “Herrmann’s pallad-
acycle”,[11,12] was used with the (hetero)aryl bromides. With
the latter, tBu3PHBF4 was used as the ligand and, in both
cases, DBU was used as the base.[6,7]
Scheme 2. Formation of the active Pd0 ionic complex from Herr-
mann’s palladacycle.
As bromo derivatives are more easily available than their
iodo counterparts, they were initially used in these amino-
carbonylation reactions. On the basis of the catalytic cycle,
the presence of electron-donating groups in the amines
should favour attack on the acylpalladium complex as they
increase the electron density on the amine group, thus en-
hancing its nucleophilicity. Thus, we first studied the reac-
tivity of 3-bromothiophene with the activated p-anisidine to
determine the most effective conditions (Table 1).
Table 1. Aminocarbonylation of 3-bromothiophene.[a]
Results and Discussion
The general mechanism for the aminocarbonylation reac-
tion using gaseous carbon monoxide is illustrated in
Scheme 1.[13] The active catalytic species is a Pd0 complex.
The oxidative addition of the aryl halide to the metal centre
is followed by the insertion of CO into the intermediate aryl
complex. In contrast to coupling reactions, the final step in
the aminocarbonylation is the nucleophilic attack of the
amine on the acylpalladium complex rather than reductive
elimination.
Entry
Hermann’s
catalyst [mol-%]
tBu3PHBF4
[mol-%]
Temp. [°C] Time [h] % Yield
1
2
3
4
4
2.4
8
8
5
110
125
125
6
1
1
10
72
68
[a] Reagents and conditions: p-anisidine (1.4 equiv.), Herrmann’s
palladacycle (2.4–4.0 mol-%), tBu3PHBF4 (5.0–8.0 mol-%), DBU
(0.7 equiv.) and [Mo(CO)6] (0.5 equiv.).
Analysis of Table 1 shows that whereas decreasing the
amounts of the catalytic components from 4 mol-% of Pd
catalyst and 8 mol-% of ligand (entry 2) to 2.4 mol-% of Pd
catalyst and 5 mol-% of ligand (entry 3) did not seem to
influence significantly the yield, the reaction temperature
is of great importance, as heating at 110 °C provided the
carboxamide 1 in only 10% yield on heating for 6 h (en-
try 1). By heating at 125 °C, compound 1 was obtained in
high yields (entries 2 and 3) in only 1 h.
More experiments were performed with p-anisidine and
several electron-rich and -deficient heteroaryl bromides
using the conditions of entry 2 or 3 of Table 1. The results
are presented in Table 2.
In all cases presented in Table 2, the use of the highest
amounts of the catalytic components provided the best
Scheme 1. General catalytical cycle for the aminocarbonylation of
aryl halides.
With (hetero)aryl bromides, a palladacycle, Herrmann’s yields, and in the reaction involving 3-bromothiophene the
catalyst {trans-di-µ-acetatobis[2-(di-o-tolylphosphanyl)ben- reaction time was also significantly reduced (Table 2, com-
zyl]dipalladium(II)}, was used as the catalyst, the active pound 2). Concerning the reaction with 2-bromopyridine,
catalytic species being the Pd0 ionic complex resulting from the use of higher amounts of the catalytic components was
the reduction of the initial PdII complex without rupture of also required to obtain the best yield, but in this case, 2-
the carbon–palladium bond (Scheme 2).[11,12]
bromopyridine had to be used in excess as well (Table 2).
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A. Begouin, M.-J. R. P. Queiroz
FULL PAPER
Table 2. Carbonylation of p-anisidine with several heteroaryl bro- Table 3. Aminoarbonylation of 3-bromothiophene with various
mides.
arylamines.[a]
[a] 1.4 equiv. of 2-bromopyridine and 1.0 equiv. of p-anisidine.
As the best result was obtained with 3-bromothiophene
(Table 1, entry 2; compound 1 was obtained in 72% yield),
it was decided to study its reactivity in aminocarbonylation
reactions with various arylamines bearing either electron-
donating (EDG) or -withdrawing (EWG) groups (Table 3).
The reaction involving 2,4-dimethoxyaniline gave product 5
in an excellent yield (86%), which shows that the presence
of two EDGs in the ortho and para positions is important.
The reaction with 2-chloro-N-methylaniline, a secondary
arylamine, gave compound 6 in only 30% yield. This mod-
erate yield could be due to the presence of an EWG in the
ortho position.
[a] Reagents and conditions: 3-bromothiophene (1.0 equiv.), aryl-
amine (1.4 equiv.), PdII (4.0 mol-%), tBu3PHBF4 (8.0 mol-%),
DBU (0.7 equiv.) and [Mo(CO)6] (0.5 equiv.) at 125 °C in dry diox-
ane. [b] 2-chloro-N-methylaniline (1.0 equiv.) and 3-bromothio-
phene (1.4 equiv.).
hydrochloride; (hetero)arylamide 11 was obtained in only
30% yield on heating for 5 h (Scheme 3), which confirms
the effect of an o-chlorine atom in the aniline already ob-
served for amide 6 (Table 2).
Reactions with anilines bearing EWGs also successfully
afforded the expected (hetero)arylamides. Thus, compound
7, which results from the reaction with 4-fluoroaniline, was
obtained in high yield (70%) and reactions with deactivated
amines bearing a nitrile group, 4- and 3-aminobenzonitrile,
also afforded the expected amides 8 and 9 in moderate-to-
good yields. In the latter case, the presence of the cyano
group in the meta position led to a decrease in the yield of
Scheme 3. Reaction of 3-bromobenzo[b]thiophene and 2-chloro-5-
the corresponding product. With deactivated aminopyr- methoxyaniline hydrochloride.
idines the results were more disappointing: reaction with 3-
aminopyridine gave heteroarylamide 10 in only 15% yield,
With these results in hand, we then studied the reactivity
whereas no reaction occurred using 2-aminopyridine on of some iodo derivatives in these aminocarbonylation reac-
heating for 6 h (Table 3) and the starting materials were re- tions to see if better results could be obtained. The catalytic
covered.
system was changed: phosphane- or ligand-free Pd catalysts
The aminocarbonylation reaction was also performed on are active in the coupling of aryl iodides (but not of aryl
3-bromobenzo[b]thiophene with 2-chloro-5-methoxyaniline bromides).[12] Thus, “Herrmann’s palladacycle” was re-
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Multicomponent Aminocarbonylation of Aryl or Heteroaryl Halides
placed by Pd(OAc)2 and no ligand was used. Several reac-
Reactions with 2- and 3-iodothiophene were also per-
tion conditions were tested using 4-iodoanisole and 2-bro- formed with various (hetero)arylamines. Compound 2,
moaniline (Table 4).
which results from the reaction of 2-halothiophene and p-
anisidine, was obtained in the same yield (≈65%) using
either 2-iodothiophene (Table 5) or 2-bromothiophene
(Table 2). With 4-aminobenzonitrile, the yield of amide 8
obtained with 3-iodothiophene (Table 5, 70%) was only
slightly higher than that obtained with 3-bromothiophene
(Table 3, 63%). Nevertheless, with aminopyridines, a wider
range of yields was noted: reaction of 3-iodothiophene with
3-aminopyridine afforded the heteroarylamide 10 in 55%
yield, which was obtained in only 15% with 3-bromothio-
phene (Table 3). The heteroarylamine 15, which results
from the reaction of 3-iodothiophene and 2-aminopyridine,
was obtained in good yield (Table 5, 44%), but no reaction
occurred with 3-bromothiophene (Table 3). These results
show that iodo derivatives are more reactive than the corre-
sponding bromo compounds when deactivated amines are
used.
Table 4. Aminocarbonylation of 4-iodoanisole with 2-bromoani-
line.[a]
2-Bromoaniline
(equiv.)
DBU
(equiv.)
[Mo(CO)6] Time [h] % Yield
(equiv.)
1
2
1.4
2.5
1.5
3.0
0.5
1.0
1
1
54
72
[a] Reagents and conditions: Pd(OAc)2 (10 mol-%), DBU and
[Mo(CO)6] at 110 °C in dry dioxane.
We also performed the aminocarbonylations of 2-iodo-
benzoic acid and methyl 2-iodobenzoate with p-anisidine
and obtained the isoindoline-1,3-dione 16 after intramo-
lecular cyclization in a one-pot procedure (Table 6). This
reaction has already been described by Worlikar and
Larock,[14] who showed that the reactions of o-iodo-
benzoates with primary amines in the presence of gaseous
carbon monoxide, Pd(OAc)2 as catalyst and Cs2CO3 as base
successfully afforded isoindoline-1,3-diones. Unfortunately,
in our case, the yields were very poor; compound 16 was
synthesized in yields of 10% with the acid in dioxane
(Table 6, entry 1) and 35% when the ester was used in tolu-
ene (Table 6, entry 3).
The conditions used in entry 2 (Table 4) gave the best
yield of the amide 12. Performing the reaction at 125 °C did
not lead to an increase in the yield. Thus, it was decided to
use these conditions with other aryl and heteroaryl iodides
in the aminocarbonylation reactions with (hetero)aryl-
amines at 110 °C (Table 5).
Table 5. Aminocarbonylation of aryl and heteroaryl iodides with
aryl or heteroarylamines.
Table 6. Aminocarbonylation of 2-iodobenzoic acid and the methyl
ester.
Entry
Solvent
R
% Yield
1
2
3
dioxane
dioxane
toluene
H
OMe
OMe
10
20
35
[a] Reagents and conditions: Pd(OAc)2 (10 mol-%), DBU
(3.0 equiv.) and [Mo(CO)6] (1.0 equiv.) at 110 °C in dry solvents.
Conclusions
Reactions with 4-iodoanisole and 2-aminopyridine gave
amide 13 in an unexpectedly high yield (76%), which shows
We have demonstrated that [Mo(CO)6] can be success-
that even deactivated amines can be used under these condi- fully used as a CO source in aminocarbonylation reactions
tions. However, the use of the more cumbersome 2-amino- without requiring microwave irradiation. All the reactions
3-bromo-5-methylpyridine provided the debrominated were performed using conventional heating in short reac-
amide 14 in a rather poor yield (only 25%).
tion times (1–3 h), thus extending the scope of the reaction.
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A. Begouin, M.-J. R. P. Queiroz
FULL PAPER
chromatography using a solvent gradient from neat petroleum ether
to 50% diethyl ether/petroleum ether, compound 1 was obtained as
an off-white solid (103 mg, 72%). Recrystallization from diethyl
Di(hetero)arylamides resulting from halothiophenes and
arylamines bearing either electron-withdrawing or -donat-
ing groups were successfully synthesized, with no significant
improvement in yields noted when iodothiophenes were
used in place of bromothiophenes. However, with deacti-
vated heteroarylamines, iodo derivatives were significantly
more reactive than the corresponding bromo compounds.
In this work we have also increased the range of (hetero)-
aryl substrates, either halides or amines, that can be used in
the aminocarbonylation reaction.
1
ether/petroleum ether gave off-white crystals, m.p. 163–165 °C. H
NMR (300 MHz, CDCl3): δ = 3.81 (s, 3 H, OCH3), 6.89 (d, J =
9.3 Hz, 2 H, 3Ј-, 5Ј-H), 7.38 (dd, J = 4.8, 3.0 Hz, 1 H, 5-H), 7.47–
7.53 (m, 3 H, 2Ј-, 6Ј-, 4-H), 7.76 (br. s, 1 H, NH), 7.96 (br. s, 1 H,
2-H) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 55.47 (OCH3),
114.19 (2 CH, 3Ј-, -5Ј-CH), 122.23 (2 CH, 2Ј-, 6Ј-CH), 126.12 (4-
CH), 126.72 (5-CH), 128.49 (2-CH), 130.74 (C-1’), 137.79 (C-3),
156.60 (C-4’), 161.17 (C=O) ppm. IR (Nujol): ν = 3328 (NH), 3111
˜
(NH), 1644 (C=O) cm–1. MS (EI): m/z (%) = 234 (5) [M + 1]+, 233
(35) [M]+, 111 (100) [M – 122]+. HRMS: calcd. for C12H11NO2S
[M]+ 233.0511; found 233.0514.
Experimental Section
N-(4-Methoxyphenyl)thiophene-2-carboxamide (2): From 2-bromo-
thiophene (100 mg, 0.610 mmol) and p-anisidine (106 mg,
0.860 mmol) using conditions A and after purification by column
chromatography using a solvent gradient from neat petroleum ether
to 40% diethyl ether/petroleum ether, or from 2-iodothiophene
(100 mg, 0.480 mmol) and p-anisidine (143 mg, 1.19 mmol) using
conditions B and after purification by column chromatography
using a solvent gradient from neat petroleum ether to 35% diethyl
ether/petroleum ether, compound 2 was obtained as an off-white
solid (95.0 mg, 66%; 94.0 mg, 65%, respectively). Recrystallization
from diethyl ether/petroleum ether gave off-white crystals, m.p.
143–144 °C. 1H NMR (300 MHz, CDCl3): δ = 3.81 (s, 3 H, OCH3),
6.89 (d, J = 9.3 Hz, 2 H, 3Ј-, 5Ј-H), 7.11 (dd, J = 4.8, 3.6 Hz, 1 H,
4-H), 7.49–7.54 (m, 3 H, 2Ј-, 6Ј-, 5-H), 7.62 (dd, J = 3.6, 0.9 Hz, 1
H, 3-H), 7.75 (br. s, 1 H, NH) ppm. 13C NMR (75.4 MHz, CDCl3):
δ = 55.47 (OCH3), 114.21 (2 CH, 3Ј-, 5Ј-CH), 122.22 (2 CH, 2Ј-,
6Ј-CH), 127.75 (4-CH), 128.32 (3-CH), 130.48 (5-CH), 130.56 (C-
General Methods: Melting points were determined with a Gallen-
kamp apparatus and are uncorrected. 1H and 13C NMR spectra
were recorded with a Varian Unity Plus spectrometer at 300 and
75.4 MHz, respectively, or with a Bruker Avance II+ spectrometer
at 400 and 100.6 MHz, respectively. Two-dimensional 1H–1H and
1H–13C correlations were performed to assign some of the signals.
EI-MS and HRMS spectra were recorded by the Mass Spectrome-
try Service of the University of Vigo, Spain. The ESI mass spectra
were recorded with a Thermo Finnigan LXQ LC-MS spectrometer
by direct injection using MeOH as solvent. The IR spectra were
recorded as Nujol mulls using NaCl cells with a Bomem FTLA-
2000-104 spectrometer. Elemental analysis was performed on a
LECO CHNS 932 elemental analyser.
The reactions were monitored by thin-layer chromatography
(TLC). Column chromatography was performed with Macherey–
Nagel silica gel (230–400 mesh). Petroleum ether refers to the boil-
ing range 40–60 °C. When a solvent gradient was used, unless
stated otherwise, the polarity was increased from neat petroleum
ether to mixtures of diethyl ether/petroleum ether, increasing in
steps of 10% diethyl ether until the product was isolated.
1’), 139.26 (C-2), 156.67 (C-4’), 159.94 (C=O) ppm. IR (Nujol): ν
˜
= 3282 (NH), 3081 (NH), 1627 (C=O) cm–1. C12H11NO2S (233.29):
calcd. C 61.78, H 4.75, N 6.00, S 13.74%; found C 61.73, H 4.80,
N 6.01, S 13.95.
Typical Experimental Conditions for the Aminocarbonylation Reac-
tions
N-(4-Methoxyphenyl)benzo[b]thiophene-3-carboxamide (3): From 3-
bromobenzo[b]thiophene (100 mg, 0.470 mmol) and p-anisidine
(81.0 mg, 0.660 mmol) using conditions A and after purification by
column chromatography using a solvent gradient from neat petro-
leum ether to 50% diethyl ether/petroleum ether, compound 3 was
obtained as an off-white solid (80.0 mg, 60%). Recrystallization
from diethyl ether/petroleum ether gave off-white crystals, m.p.
207–209 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 3.74 (s, 3 H,
OCH3), 6.93 (d, J = 9.2 Hz, 2 H, 3Ј-, 5Ј-H), 7.41–7.49 (m, 2 H),
7.66 (d, J = 9.2 Hz, 2 H, 2’-, 6Ј-H), 8.05–8.07 (m, 1 H, 7-H), 8.39–
8.41 (m, 1 H, 4 H), 8.49 (s, 1 H, 2-H), 10.20 (br. s, 1 H, NH) ppm.
13C NMR (100.6 MHz, [D6]DMSO): δ = 55.21 (OCH3), 113.83 (2
CH, 3’-, 5Ј-CH), 121.81 (2 CH, 2Ј-, 6Ј-CH), 122.85 (7-CH), 124.33
(4-CH), 124.93 (CH), 125.00 (CH), 131.27 (C-3, 2-CH), 132.11 (C-
1’), 137.19 (C), 139.43 (C), 155.54 (C-4’), 161.58 (C=O) ppm. IR
Conditions A: The heteroaryl bromide was added to a Schlenk tube
containing dry dioxane (1–2 mL per 0.5 mmol of bromide). Then
the (hetero)arylamine (1.4 equiv.), DBU (1,8-diazabicyclo[5.4.0]-
undec-7-ene; 0.7 equiv.), trans-di-µ-acetatobis[2-(di-o-tolyphos-
phanyl)benzyl]dipalladium(II) (4 mol-%), tri-tert-butylphoshonium
tetrafluoroborate (8 mol-%) and molybdenum hexacarbonyl
(0.5 equiv.) were successively added and the solution was heated at
125 °C in a silicone bath for 1–5 h, unless stated otherwise (see
Tables 1, 2 and Scheme 3).
Conditions B: The (hetero)aryl iodide was added to a Schlenk tube
containing dry dioxane (1–2 mL per 0.5 mmol of iodide). Then the
(hetero)arylamine (2.5 equiv.), DBU (3.0 equiv.), palladium ace-
tate(II) (10 mol-%) and molybdenum hexacarbonyl (1.0 equiv.)
were successively added and the solution was heated at 110 °C in
a silicone bath for 1–3 h (see Tables 4 and 5).
(Nujol): ν = 3292 (NH), 3089 (NH), 1641 (C=O) cm–1. MS (EI):
˜
m/z (%) = 284 (6) [M + 1]+, 283 (32) [M]+, 161 (100) [M – 122]+.
HRMS: calcd. for C16H13NO2S [M]+ 283.0667; found 283.0663.
General Work-up: The reactions were monitored by TLC, following
the disappearance of the halo derivative. After cooling, dichloro-
methane was added, the mixture was transferred to a round-bot-
tomed flask and the solvents were removed under reduced pressure.
The resulting oils were submitted to column chromatography to
give the products as solids.
N-(4-Methoxyphenyl)picolinamide (4): From 2-bromopyridine
(88.0 mg, 0.560 mmol) and p-anisidine (49.0 mg, 0.400 mmol) using
modified conditions A (Table 2) and after purification by column
chromatography using a solvent gradient from neat petroleum ether
to 40% diethyl ether/petroleum ether, compound 4 was obtained as
a yellow solid (55.0 mg, 60%). Recrystallization from diethyl ether/
petroleum ether gave yellow crystals, m.p. 96–98 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.83 (s, 3 H, OCH3), 6.94 (d, J = 9.2 Hz,
2 H, 3Ј-, 5Ј-H), 7.47–7.50 (m, 1 H, 5-H), 7.71 (d, J = 9.2 Hz, 2 H,
N-(4-Methoxyphenyl)thiophene-3-carboxamide (1): From 3-bromo-
thiophene (100 mg, 0.610 mmol) and p-anisidine (106 mg,
0.860 mmol) using conditions A and after purification by column
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Multicomponent Aminocarbonylation of Aryl or Heteroaryl Halides
2Ј-, 6Ј-H), 7.92 (dt, J = 7.6, 1.6 Hz, 1 H, 4-H), 8.31 (br. d, J =
7.6 Hz, 1 H, 3-H), 8.62 (br. d, J = 3.6 Hz, 1 H, 6-H), 9.35 (br. s, 1
H, NH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 55.48 (OCH3),
1.40 mmol) using conditions A and after purification by column
chromatography using a solvent gradient from neat petroleum ether
to 70% diethyl ether/petroleum ether, or from 3-iodothiophene
114.23 (2 CH, 3Ј-, 5Ј-CH), 121.24 (2 CH, 2Ј-, 6Ј-CH), 122.38 (3- (100 mg, 0.480 mmol) and 4-aminobenzonitrile (141 mg,
CH), 126.30 (5-CH), 131.00 (C-1’), 137.73 (CH), 147.80 (6-CH),
1.19 mmol) using conditions B and after purification by column
chromatography using a solvent gradient from neat petroleum ether
to 60% diethyl ether/petroleum ether, compound 8 was obtained as
149.90 (C-2), 156.39 (C-4’), 161.61 (C=O) ppm. IR (Nujol): ν =
˜
3355 (NH), 1682 (C=O) cm–1. MS (EI): m/z (%) = 229 (9) [M +
1]+, 228 (100) [M]+, 79 (53) [M – 149]+, 78 (56) [M – 150]+. HRMS:
calcd. for C13H12N2O2 [M]+ 228.0899; found 228.0896.
a
yellow solid (143 mg, 63%; 159 mg, 70%, respectively).
Recrystallization from diethyl ether/petroleum ether gave yellow
crystals, m.p. 157–159 °C. 1H NMR (400 MHz, [D6]DMSO): δ =
7.63 (dd, J = 5.2, 1.2 Hz, 2 H, 4-H), 7.67 (dd, J = 5.2, 2.8 Hz, 1
H, 5-H), 7.80 (d, J = 8.8 Hz, 2 H, 3Ј-, 5Ј-H), 7.95 (d, J = 8.8 Hz,
2 H, 2Ј-, 6Ј-H), 8.40 (dd, J = 2.8, 1.0 Hz, 1 H, 2-H), 10.41 (br. s, 1
H, NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 105.19
(CϵN), 119.04 (C), 120.04 (2 CH, 2Ј-, 6Ј-CH), 127.16 (4- or 5-
CH), 127.20 (5- or 4-CH), 130.61 (2-CH), 133.10 (2 CH, 3Ј-, 5Ј-
N-(2,4-Dimethoxyphenyl)thiophene-3-carboxamide (5): From 3-bro-
mothiophene (65.0 mg, 0.400 mmol) and 2,4-dimethoxyaniline
(86.0 mg, 0.560 mmol) using conditions A and after purification by
column chromatography using a solvent gradient from neat petro-
leum ether to 40% diethyl ether/petroleum ether, compound 5 was
obtained as an off-white solid (89.0 mg, 86%). Recrystallization
from diethyl ether/petroleum ether gave off-white crystals, m.p.
151–153 °C. 1H NMR (300 MHz, CDCl3): δ = 3.82 (s, 3 H, OCH3),
3.90 (s, 3 H, OCH3), 6.51–6.55 (m, 2 H, 3’-, 5Ј-H), 7.38–7.40 (m, 1
H, 5-H), 7.48–7.50 (m, 1 H, 2-H), 7.96–7.97 (m, 1 H, 4-H), 8.17
(br. s, 1 H, NH), 8.36 (d, J = 9.6 Hz, 1 H, 6Ј-H) ppm. 13C NMR
(75.4 MHz, CDCl3): δ = 55.40 (OCH3), 55.81 (OCH3), 98.63 (CH),
103.82 (CH), 120.68 (6Ј-CH), 121.16 (C-1’), 126.05 (2-CH), 126.63
(5-CH), 128.27 (4-CH), 138.30 (C-3), 149.31 (C-2’), 156.46 (C-4’),
CH), 137.09 (C-3), 143.36 (C), 161.29 (C=O) ppm. IR (Nujol): ν =
˜
3330 (NH), 3095 (NH), 2231 (CϵN), 1647 (C=O) cm–1. MS (EI):
m/z (%) = 229.04 (2) [M + 1]+, 228 (10) [M]+, 111 (100) [M –
117]+. HRMS: calcd. for C12H8N2OS [M]+ 228.0357; found
228.0361.
N-(3-Cyanophenyl)thiophene-3-carboxamide (9): From 3-bromo-
thiophene (163.0 mg, 1.00 mmol) and 3-aminobenzonitrile
(1.40 mmol, 165.0 mg) using conditions A and after purification by
column chromatography using a solvent gradient from neat petro-
leum ether to 50% diethyl ether/petroleum ether, compound 9 was
obtained as a yellow solid (103 mg, 45%). Recrystallization from
diethyl ether/petroleum ether gave yellow crystals, m.p. 166–168 °C.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.49 (m, 3 H), 7.52 (dd, J
= 5.2, 1.2 Hz, 1 H, 4-H), 7.87–7.89 (m, 1 H), 7.96 (br. s, 1 H,
NH), 8.02–8.04 (m, 2 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ
= 113.02 (C), 118.50 (C), 123.28 (CH), 124.36 (CH), 126.05 (4-
CH), 127.23 (CH), 127.85 (CH), 129.43 (CH), 129.97 (CH), 136.92
160.54 (C=O) ppm. IR (Nujol): ν = 3261 (NH), 3091 (NH), 1644
˜
(C=O) cm–1. MS (EI): m/z (%) = 264 (5) [M + 1]+, 263 (54) [M]+,
111 (100) [M – 152]+. HRMS: calcd. for C13H13NO3S [M]+
263.0616; found 263.0616.
N-(2-Chlorophenyl)-N-methylthiophene-3-carboxamide (6): From 3-
bromothiophene (1.40 equiv., 91.0 mg, 0.560 mmol) and 2-chloro-
N-methylaniline (1.00 equiv., 57.0 mg, 0.400 mmol) using modified
conditions
A (Table 3) and after purification by column
chromatography using a solvent gradient from neat petroleum ether
to 40% diethyl ether/petroleum ether, compound 6 was obtained as
a yellow solid (30.0 mg, 30%). Recrystallization from diethyl ether/
petroleum ether gave yellow crystals, m.p. 165–167 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.38 (s, 3 H, NCH3), 6.96–6.99 (m, 1 H),
7.03–7.07 (m, 1 H), 7.19–7.29 (m, 4 H), 7.44–7.46 (m, 1 H) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 37.05 (NCH3), 124.56 (CH),
128.02 (CH), 128.06 (CH), 128.95 (CH), 129.23 (CH), 130.18 (CH),
130.66 (CH), 132.70 (C), 136.45 (C), 142.10 (C), 162.24
(C), 138.70 (C), 161.25 (C=O) ppm. IR (Nujol): ν = 3357 (NH),
˜
3090 (NH), 2229 (CϵN), 1661 (C=O) cm–1. MS (EI): m/z (%) =
229 (4) [M + 1]+, 228 (39) [M]+, 111 (100) [M – 117]+. HRMS:
calcd. for C12H8N2OS [M]+ 228.0357; found 228.0354.
N-(Pyridin-3-yl)thiophene-3-carboxamide (10): From 3-bromothio-
phene (168 mg, 1.00 mmol) and 3-aminopyridine (132 mg,
1.40 mmol) using conditions A and after purification by column
chromatography using a solvent gradient from 50% diethyl ether/
petroleum ether to 50% ethyl acetate/diethyl ether, or from 3-iodo-
thiophene (0.48 mmol, 100.0 mg) and 3-aminopyridine (1.19 mmol,
112.0 mg) using conditions B and after purification by column
chromatography using a solvent gradient from 80% diethyl ether/
petroleum ether to 10% ethyl acetate/diethyl ether, compound 10
was obtained as an off-white solid (30.0 mg, 15%; 60.0 mg, 55%,
respectively). Recrystallization from diethyl ether/petroleum ether
gave off-white crystals, m.p. 166–168 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.32 (dd, J = 8.4, 4.8 Hz, 1 H, 5Ј-H), 7.39 (dd, J =
5.2, 3.2 Hz, 1 H, 5-H), 7.55 (dd, J = 5.2, 1.4 Hz, 1 H, 4-H), 8.08
(dd, J = 3.2, 1.2 Hz, 1 H, 2-H), 8.29–8.36 (m, 2 H), 8.38 (br. s, 1 H,
NH), 8.70 (d, J = 2.4 Hz, 1 H, 2Ј-H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 123.87 (5Ј-CH), 126.25 (4-CH), 127.02 (5-CH), 128.03
(CH), 129.45 (2-CH), 135.04 (C-3Ј), 137.00 (C-3), 141.28 (2Ј-CH),
(C=O) ppm. IR (Nujol): ν = 1647 (C=O) cm–1. MS (EI): m/z (%)
˜
= 253.02 (0.4) [M, 37Cl]+, 251.02 (1) [M, 35Cl]+, 216 (100) [M –
Cl]+, 110.97 (100) [M – 140]+. HRMS: calcd. for C12H10ClNOS
[M, 37Cl] 253.0142, [M, 35Cl] 251.0172; found 253.0138, 251.0182.
N-(4-Fluorophenyl)thiophene-3-carboxamide (7): From 3-bromo-
thiophene (100 mg, 0.610 mmol) and p-fluoroaniline (95.0 mg,
0.860 mmol) using conditions A and after purification by column
chromatography using a solvent gradient from neat petroleum ether
to 40% diethyl ether/petroleum ether, compound 7 was obtained as
an off-white solid (95.0 mg, 70%). Recrystallization from diethyl
1
ether/petroleum ether gave off-white crystals, m.p. 165–167 °C. H
NMR (300 MHz, CDCl3): δ = 7.03–7.08 (m, 2 H, 3’-, 5Ј-H), 7.39–
7.41 (m, 1 H, 5-H), 7.48–7.50 (m, 1 H, 4-H), 7.55–7.60 (m, 2 H,
2Ј-, 6Ј-H), 7.75 (br. s, 1 H, NH), 7.97–7.99 (m, 1 H, 2-H) ppm. 13
C
NMR (75.4 MHz, CDCl3): δ = 115.73 (d, J = 22.4 Hz, 2 CH, 3Ј-,
5Ј-CH), 122.15 (d, J = 8.1 Hz, 2 CH, 2Ј-, 6Ј-CH), 126.04 (4-CH),
126.96 (5-CH), 128.77 (2-CH), 133.66 (d, J = 3.2 Hz, C-1Ј), 137.50
(C-3), 159.72 (d, J = 244 Hz, CF), 161.15 (C=O) ppm. IR (Nujol):
145.00 (CH), 161.64 (C=O) ppm. IR (Nujol): ν = 3215 (NH), 3097
˜
(NH), 1661 (C=O) cm–1. MS (ESI): m/z (%) = 227.1667 (35) [M +
Na]+, 205.1667 (100) [M + H]+.
ν = 3326 (NH), 1647 (C=O) cm–1. C H FNOS (221.25): C 59.71,
˜
11
8
N-(2-Chloro-5-methoxyphenyl)benzo[b]thiophene-3-carboxamide
(11): From 3-bromobenzo[b]thiophene (100 mg, 0.470 mmol) and
2-chloro-5-methoxyaniline hydrochloride (127 mg, 0.660 mmol)
using conditions A and after purification by column chromatog-
H 3.64, N 6.33, S 14.49; found C 59.59, H 3.70, N 6.32, S 14.65.
N-(4-Cyanophenyl)thiophene-3-carboxamide (8): From 3-bromo-
thiophene (163 mg, 1.00 mmol) and 4-aminobenzonitrile (165 mg,
Eur. J. Org. Chem. 2009, 2820–2827
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2825

A. Begouin, M.-J. R. P. Queiroz
FULL PAPER
raphy using a solvent gradient from neat petroleum ether to 10%
diethyl ether/petroleum ether, compound 11 was obtained as a yel-
low solid (44.0 mg, 30%). Recrystallization from diethyl ether/pe-
troleum ether gave yellow crystals, m.p. 116–118 °C. 1H NMR
1
crystals, m.p. 112–114 °C. H NMR (400 MHz, CDCl3): δ = 2.32
(s, 3 H, CH3), 3.87 (s, 3 H, OCH3), 6.98 (d, J = 8.8 Hz, 2 H, 3-, 5-
H), 7.60–7.63 (m, 1 H, 4Ј-H), 7.94 (d, J = 8.8 Hz, 2 H, 2-, 6-H),
8.07 (m, 1 H, 6Ј-H), 8.35 (d, J = 8.8 Hz, 1 H, 3Ј-H), 9.03 (br. s, 1
(300 MHz, CDCl3): δ = 3.88 (s, 3 H, OCH3), 6.68 (dd, J = 9.0, H, NH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 17.78 (CH3),
3.0 Hz, 1 H, 4Ј-H), 7.31 (d, J = 9.0 Hz, 1 H, 3Ј-H), 7.43–7.55 (m, 55.45 (OCH3), 114.00 (3 CH, 3-, 5-, 3Ј-CH), 126.19 (C-1), 129.10
2 H, 5-, 6-H), 7.93 (d, J = 8.1 Hz, 1 H, 4- or 7-H), 8.09 (s, 1 H, 2-
H), 8.30 (d, J = 3.0 Hz, 1 H, 6Ј-H), 8.34 (br. s, 1 H, NH), 8.51 (d,
J = 8.1 Hz, 1 H, 4- or 7 H) ppm. 13C NMR (75.4 MHz, CDCl3): δ
(5Ј-C), 129.29 (2 CH, 2-, 6-CH), 139.95 (4Ј-CH), 146.18 (6Ј-CH),
149.37 (C-2’), 162.85 (C-4), 165.11 (C=O) ppm. IR (Nujol): ν =
˜
3236 (NH), 1674 (C=O) cm–1. MS (EI): m/z (%) = 243.11 (2) [M +
= 55.68 (OCH3), 106.33 (6Ј-CH), 111.37 (4Ј-CH), 113.94 (C), H]+, 242.11 (15) [M]+, 214.11 (31) [M – 28]+, 135.03 (100) [M –
122.68 (4- or 7-CH), 124.18 (7- or 4-CH), 125.42 (6- or 5-CH),
C6H7N2]+. HRMS: calcd. for C14H14N2O2 [M]+ 242.1055; found
125.47 (5- or 6-CH), 129.23 (C-3Ј), 130.46 (2-CH), 132.00 (C), 242.1063.
135.30 (C), 136.44 (C), 140.35 (C), 159.06 (5Ј-C), 161.58
N-(Pyridin-2-yl)thiophene-3-carboxamide (15): From 3-iodothio-
(C=O) ppm. IR (Nujol): ν = 3291 (NH), 3078 (NH), 1650
˜
phene (100 mg, 0.480 mmol) and 2-aminopyridine (112 mg,
1.19 mmol) using conditions B and after purification by column
chromatography using a solvent gradient from 80% diethyl ether/
petroleum ether to 10% ethyl acetate/diethyl ether, compound 15
was obtained as a beige solid (45.0 mg, 44%). Recrystallization
from diethyl ether/petroleum ether gave off-white crystals, m.p.
180–182 °C. 1H NMR (400 MHz, CDCl3): δ = 7.02–7.06 (m, 1 H),
7.37 (dd, J = 5.2, 3.0 Hz, 1 H, 5-H), 7.56 (dd, J = 5.2, 1.2 Hz, 1
H, 4-H), 7.72–7.76 (m, 1 H), 8.07–8.08 (m, 1 H), 8.19–8.21 (m, 1
H), 8.36–8.38 (m, 1 H, 3Ј-H), 9.06 (br. s, 1 H, NH) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 114.44 (3Ј-CH), 119.76 (CH), 126.34 (4-
CH), 126.81 (5-CH), 129.50 (2-CH), 137.24 (C-3), 138.58 (CH),
(C=O) cm–1. MS (EI): m/z (%)
=
319.03 (2) [M,
37Cl]+, 317.03 (5) [M, 35Cl]+, 282.06 (48) [M – Cl]+, 161.00 (100)
[M – 156]+. HRMS: calcd. for C16H12ClNO2S [M, 37Cl] 319.0248,
[M, 35Cl] 317.0277; found 319.0262, 317.0273.
N-(2-Bromophenyl)-4-methoxybenzamide (12): From 4-iodoanisole
(100 mg, 0.430 mmol) and 2-bromoaniline (184 mg, 1.07 mmol)
using conditions B and after purification by column chromatog-
raphy using a solvent gradient from neat petroleum ether to 100%
diethyl ether, compound 12 was obtained as a yellow solid
(94.0 mg, 72%). Recrystallization from diethyl ether/petroleum
ether gave pale-yellow crystals, m.p. 141–143 °C. 1H NMR
(300 MHz, CDCl3): δ = 3.89 (s, 3 H, OCH3), 6.98–7.04 (m, 3 H, 3-
, 5-, 5Ј-H), 7.37 (m, 1 H, 4Ј-H), 7.58 (dd, J = 8.0, 1.5 Hz, 1 H, 6Ј-
H), 7.92 (d, J = 8.7 Hz, 2 H, 2-, 6-H), 8.41 (br. s, 1 H, NH), 8.55
(dd, J = 8.3, 1.8 Hz, 1 H, 3Ј-H) ppm. 13C NMR (75.4 MHz,
CDCl3): δ = 55.48 (OCH3), 113.59 (C-1’), 114.12 (2 CH, 3-, 5-CH),
121.61 (3Ј-CH), 124.97 (5Ј-CH), 126.76 (C-1), 128.51 (4Ј-CH),
128.99 (2 CH, 2-, 6-CH), 132.18 (6Ј-CH), 135.97 (C-Br), 162.75 (C-
147.50 (CH), 151.52 (C-2’), 161.16 (C=O) ppm. IR (Nujol): ν =
˜
3232 (NH), 3108 (NH), 1674 (C=O) cm–1. MS (ESI): m/z (%) =
227.1667 (100) [M + Na]+, 205.1667 (31) [M + H]+.
2-(4-Methoxyphenyl)isoindoline-1,3-dione (16): From methyl 2-
iodobenzoate (157 mg, 0.600 mmol) and p-anisidine (185 mg,
1.50 mmol) using modified conditions B (Table 6) in dry toluene
and after purification by column chromatography using a solvent
gradient from neat petroleum ether to 50% diethyl ether/petroleum
ether, compound 16 was obtained as a beige solid (53.0 mg, 35%).
Recrystallization from diethyl ether/petroleum ether gave off-white
4), 164.75 (C=O) ppm. IR (Nujol):
ν = 3273 (NH), 1649
˜
(C=O) cm–1. MS (EI): m/z (%) = 307.01 (2) [M, 81Br]+, 305.01
(2) [M, 79Br]+, 226.09 (20) [M – Br]+, 135.04 (100) [M –
C6H5BrN]+. HRMS: calcd. for C14H12BrNO2 [M, 81Br] 307.0031,
[M, 79Br] 305.0051; found 307.0034, 305.0045.
1
crystals, m.p. 157–159 °C. H NMR (400 MHz, CDCl3): δ = 3.86
(s, 3 H, OCH3), 7.03 (d, J = 9.0 Hz, 2 H, 3Ј-, 5Ј-H), 7.35 (d, J =
9.0 Hz, 2 H, 2Ј-, 6Ј-H), 7.78–7.80 (m, 2 H), 7.95–7.97 (m, 2 H) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 55.50 (OCH3), 114.48 (2 CH,
3’-, 5Ј-CH), 123.66 (2 CH), 124.26 (C-1’), 127.93 (2 CH, 2’-, 6Ј-
CH), 131.84 (2 C), 134.29 (2 CH), 159.26 (C-4’), 167.56 (2
4-Methoxy-N-(pyridin-2-yl)benzamide (13): From 4-iodoanisole
(100 mg, 0.430 mmol) and 2-aminopyridine (101 mg, 1.07 mmol)
using conditions B and after purification by column chromatog-
raphy using a solvent gradient from neat petroleum ether to 80%
diethyl ether/petroleum ether, compound 13 was obtained as a yel-
low solid (74.0 mg, 76%). Recrystallization from diethyl ether/pe-
troleum ether gave yellow crystals, m.p. 106–107 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.88 (s, 3 H, OCH3), 6.99 (d, J = 8.8 Hz,
2 H, 3-, 5-H), 7.04–7.07 (m, 1 H), 7.73–7.77 (m, 1 H), 7.91 (d, J =
8.8 Hz, 2 H, 2-, 6-H), 8.27–8.28 (m, 1 H), 8.38 (m, 1 H, 3Ј-H), 8.63
(br. s, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 55.47
(OCH3), 114.02 (3 CH, 3-, 5-, 3Ј-CH), 119.69 (CH), 126.42 (C-1),
129.13 (2 CH, 2, 6-CH), 138.39 (CH), 147.85 (CH), 151.74 (C),
C=O) ppm. IR (Nujol): ν = 1709 (C=O) cm–1. MS (EI): m/z (%) =
˜
254 (15) [M + 1]+, 253 (100) [M]+, 238 (60) [M – 15]+, 210 (24)
[M – 43]+. HRMS: calcd. for C15H11NO3 [M]+ 253.0739; found
253.0744.
Acknowledgments
We thank the Fundação para a Ciência e Tecnologia (FCT) – Por-
tugal and FEDER (European fund) for financial support through
Centro de Química/UM, through NMR national network (Bruker
400) and through the post-Doctoral grant attributed to A. B.
(SFRH/BPD/36753/2007).
162.80 (C-4), 165.16 (C=O) ppm. IR (Nujol): ν = 3275 (NH), 1674
˜
(C=O) cm–1. MS (EI): m/z (%) = 229.09 (1) [M + 1]+, 228.09 (8)
[M]+, 200.09 (14) [M – 28]+, 199.09 (15) [M – 29]+, 135.04 (100)
[M – 170]+. HRMS: calcd. for C13H12N2O2 [M]+ 228.0899; found
228.0904.
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Recrystallization from diethyl ether/petroleum ether gave yellow
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2820–2827

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Received: February 17, 2009
Published Online: April 30, 2009
Eur. J. Org. Chem. 2009, 2820–2827
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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