Synthesis of acyl pyrroles via palladium-catalyzed carbonylative amination of aryl and alkenyl iodides

Article abstract of DOI:10.1021/jo2022444

A palladium-catalyzed synthesis of acyl pyrroles from aryl and alkenyl iodides is reported. This carbonylative amination requires only atmospheric (balloon) pressure of carbon monoxide and proceeds with Pd(PPh₃) ₄ and Pd-NHC catalyst

Full text of DOI:10.1021/jo2022444

Note
pubs.acs.org/joc
Synthesis of Acyl Pyrroles via Palladium-Catalyzed Carbonylative
Amination of Aryl and Alkenyl Iodides
Stephanie Ho, Ganna Bondarenko, David Rosa, Bojan Dragisic, and Arturo Orellana*
Department of Chemistry, York University, 440 Chemistry Building 4700 Keele Street, Toronto, ON, Canada M3J 1P3
S
* Supporting Information
ABSTRACT: A palladium-catalyzed synthesis of acyl pyrroles from aryl and
alkenyl iodides is reported. This carbonylative amination requires only
atmospheric (balloon) pressure of carbon monoxide and proceeds with
Pd(PPh3)4 and Pd-NHC catalysts. Aryl and heteroaryl iodides give the
corresponding acyl pyrroles in good to excellent yields, while alkenyl iodides
provide the corresponding acyl pyrroles in low to moderate yields.
etones are perhaps the most versatile functional group, and their
preparation is a central issue in synthetic organic chemistry. The
reported by Buchwald. Our work was motivated in part by the lower
cost of pyrrole compared to that of N-methoxy-N-methylamine.24 At
the outset, we were aware that the nature of the nitrogen atom of
pyrrole is markedly different from that of an alkylamine and that this
would have implications on the mechanism of the proposed
carbonylative amination reaction and/or the efficiency of the
transformation.25,26 In this paper, we report that acyl pyrroles can
be efficiently prepared from aryl iodides and pyrrole using simple
catalytic systems and carbon monoxide at atmospheric pressure.
In our initial experiments we mimicked the conditions developed by
Buchwald for the synthesis of Weinreb amides. Surprisingly, we found
that subjecting bromobenzene to these reactions conditions provided
benzoyl pyrrole in only 21% yield.27 In contrast, the use of a simple
catalyst system consisting of Pd(OAc)2 and Ph3P provided benzoyl
pyrrole in 92% yield. Unfortunately, this reaction proved capricious
and resulted in highly variable yields. The use of freshly prepared
Pd(PPh3)4 and elevated carbon monoxide pressure28 did not
ameliorate the situation. During the course of this exploratory work
we also noted that the use of electron poor aryl bromides resulted in
diminished or no yield of the corresponding acyl pyrroles under these
conditions (Table 1).
K
addition of organometallic reagents to N-methoxy-N-methylamides,
commonly known as Weinreb amides,1−5 is a standard method for the
synthesis of ketones from carboxylic acid derivates. Morpholine
amides6−8 and acyl triazoles9 have also proven to be effective acylating
agents in the synthesis of ketones, but their use is much less frequent.
In general, these amides are prepared by condensation of carboxylic
acid derivatives with the corresponding amine. Recently, Buchwald10,11
reported a protocol for the synthesis of Weinreb amides from aryl
halides through a palladium-catalyzed carbonylative amination reaction
employing a xantphos/Pd2dba3 catalyst system.12 Other reports of
palladium-catalyzed carbonylative amidation leading to Weinreb
amides have also appeared.13,14 This method is attractive since it
incorporates a C1 unit in the form of carbon monoxide. It is worth
noting that morpholine amides can also be prepared using this
method.15
In 2002, Evans demonstrated that the reaction of acyl pyrroles with
organometallic reagents results in the formation of remarkably stable
aminals that could even survive purification by silica gel chromatog-
raphy.16 These intermediates could be induced to undergo elimination
of the pyrrole moiety to generate ketones in good yields. Thus, N-acyl
pyrroles can be viewed as alternative reagents to Weinreb amides. In
addition, N-acyl pyrroles have found use as monodentate electrophiles
in asymmetric conjugate addition reactions.17−19 N-Acyl pyrroles can
be synthesized by the reaction of an acyl chloride with pyrrole20,21 (eq
Table 1. Attempted Preparation of Acyl Pyrroles Using a
Range of Aryl Bromides
Since oxidative addition of electron-poor aryl bromides to
palladium(0) is expected to be facile, the results in Table 1 are
somewhat surprising and suggest that downstream intermediates (i.e.,
arylpalladium(II) or benzoylpalladium(II) intermediates) may be
subject to undesired decomposition. This unexpected trend prompted
1). An alternative protocol involves the synthesis of the pyrrole moiety
by condensation of an amide with 2,5-dimethoxytetrahydrofuran22 (eq
2).
We became intrigued by the possibility of preparing acyl pyrroles by
palladium-catalyzed carbonylative coupling of aryl halides with
pyrrole23 in a manner analogous to the synthesis of Weinreb amides
Received: November 1, 2011
Published: January 11, 2012
© 2012 American Chemical Society
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Note
us to explore a range of ligands for this reaction with the aim of finding
a general catalyst. As can be gleaned from Table 2, while a range of
structurally distinct phosphine-based ligands can be utilized, the yields
are uniformly poor (i.e., less than 50% isolated yield) for these
reactions. Notably, the use of an NHC-ligated precatalyst resulted in a
marked improvement in the yield, and the use of toluene at higher
temperature provided the acyl pyrrole in a satisfactory 80% yield.
Table 3. Scope of the Synthesis of Acyl Pyrroles from Aryl
Iodides via Carbonylative Amination
Table 2. Evaluation of Ligands for the Synthesis of Acyl
Pyrroles Using an Activated Aryl Bromide
a
Reactions conducted with 10 mol % of Pd(OAc)2 and 10 mol % of
b
ligand. Reactions conducted with 10 mol % of Pd(OAc)2 and 20 mol
% of ligand. Reactions conducted with 10 mol % of precatalyst.
c
Having determined that a Pd-NHC precatalyst system was suitable
for the synthesis of acyl pyrroles using electron-poor substrates, we
proceeded to evaluate other aryl bromides. We were dismayed to find
that this catalyst provided generally poor yields with a variety of aryl
bromides (not shown). In view of these results, we shifted our
attention to the use of aryl iodides for the preparation of acyl pyrroles
general, the reactions conducted at elevated pressure of CO were
significantly lower yielding than those conducted at atmospheric
pressure using a balloon of CO (entries 1−8). This method tolerates a
range of electron-donating (entries 1−6) and electron-withdrawing
(entries 7−11) substituents on the aryl ring. Heterocyclic iodides
provide the desired acyl pyrroles in excellent yield (entries 12 and 13).
In contrast, alkenyl iodides provide the desired product in low to
moderate yields (entries 14−16). Sterically demanding aryl iodides
work well (entries 2, 5, and 6), and the resulting di-ortho-substituted
acyl pyrroles (entries 2 and 6) display restricted rotation of the amide
function at room temperature as determined by NMR. Interestingly,
neither catalyst system (Pd(PPh3)4 or Pd-NHC) was superior across
all substrates. In general, however, good to excellent yields of the acyl
pyrroles could be obtained with both catalysts, with the exception of
alkenyl halides. In a couple of instances, a significant difference in yield
could be observed between the two catalysts (entries 4, 6, 10, and 11),
and thus, they appear to be somewhat complementary.
Figure 1. Reaction conditions for the synthesis of acyl pyrroles from
aryl iodides via carbonylative amination.
and evaluated the reaction conditions shown in Figure 1 based on our
experience with aryl bromides. Although the carbonylative amination
of aryl bromides proceeds with a catalyst system consisting of a 1:4
molar ratio of Pd(OAc)2 and PPh3, we elected to use freshly prepared
Pd(PPh3)4 for this study for consistency across all reactions and also
explored this catalyst system under elevated CO pressure.28 In
addition, we also evaluated the Pd-NHC precatalyst given its success in
the synthesis of acyl pyrroles from activated aryl bromides.
In conclusion, we have shown that acyl pyrroles can be prepared
readily from aryl, heteroaryl and alkenyl iodides using simple catalyst
systems and carbon monoxide at atmospheric pressure. This reaction
tolerates a range of functional groups on the aryl ring and provides the
acyl pyrroles in good to excellent yields in most cases.
As can be gleaned from Table 3, the synthesis of acyl pyrroles via
carbonylative amination proceeds with a range of aryl iodides. In
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Note
= 1708, 1595 cm−1; HRMS (ESI) m/z calcd for C13H14NO
([M + H]+) 200.1075, found 200.1070.
EXPERIMENTAL SECTION
■
General Procedure for the Synthesis of Acyl Pyrroles
via Carbonylative Amination. Conditions A. A 50 mL test
tube equipped with a stir bar and sealed with a rubber septum
was purged with argon and charged with potassium phosphate
(0.741 g, 3.49 mmol, 4.0 equiv), (IPr)Pd(allyl)Cl (0.050 g, 0.10
equiv, 0.087 mmol), and 3 mL of toluene. The aryl iodide (1.0
equiv, 0.873 mmol), pyrrole (0.181 mL, 3.0 equiv, 2.61 mmol),
and an additional 3 mL of toluene were added. The mixture was
then purged with CO for 30 s. The vessel was placed in an oil
bath heated to 90 °C for 19 h, and an atmosphere of CO was
maintained using a balloon. Upon completion, the reaction was
allowed to cool to room temperature, diluted with EtOAc,
filtered through a plug of Celite, and concentrated. The crude
product was purified by flash column chromatography, eluting
with the indicated solvent mixture to afford the desired acyl
pyrrole.
Conditions B. A 50 mL test tube equipped with a stir bar and
sealed with a rubber septum was purged with argon and
charged with potassium phosphate (0.741 g, 4.0 equiv, 3.49
mmol) and 3 mL of toluene. The aryl iodide (1.0 equiv, 0.873
mmol) and pyrrole (0.181 mL, 3.0 equiv, 2.61 mmol) were
then added to the mixture. Pd(PPh3)4 (0.100 g, 0.10 equiv,
0.087 mmol) was added to the reaction mixture, and the vessel
was then purged with CO for 30 s. The reaction vessel was
placed in an oil bath heated to 90 °C for 19 h and a CO
atmosphere was maintained using a balloon. Upon completion,
the reaction was allowed to cool to room temperature, diluted
with EtOAc, filtered through a plug of Celite, and concentrated.
The crude product was purified by flash column chromatog-
raphy, eluting with the indicated solvent mixture to afford the
desired acyl pyrrole.
(3-((tert-Butyldimethylsilyloxy)methyl)phenyl)(1H-pyrrol-
1-yl)methanone (Table 3, Entry 3). Isolated as a clear oil using
a 4% solution of ethyl acetate in hexanes (method A 79%,
method B 68%, method C 20%): 1H NMR (400 MHz, CDCl3)
δ 7.73 (s, 1H), 7.64 (d, J = 7.7 Hz, H), 7.59 (d, J = 7.7 Hz) 7.49
(dd, J = 7.7, 7,7 Hz, 1H), 7.31 (m, 2H), 6.36 (m, 2H), 4.82 (s,
2H), 0.97 (s, 9H), 0.14 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ 167.7, 142.0, 133.0, 129.7, 128.3, 128.0, 126.9, 121.2, 64.2,
25.8, 25.8, 18.3, −5.4; IR ν = 1699, 1558, 1507, 1466, 1330,
1303, 1157, 1086, 837, 778, 737 cm−1; HRMS (ESI) m/z calcd
for C18H25NO2Si ([M + H]+) 316.1733, found 316.1725.
1-(4-Methoxybenzoyl)pyrrole (Table 3, Entry 4). Isolated as
an oil using a 7% solution of ethyl acetate in hexanes (method
A 43%, method B 83%, method C 43%): 1H NMR (400 MHz,
CDCl3) δ 7.79 (d, J = 8.9 Hz, 2H), 7.32 (t, J = 1.7 Hz, 2H),
7.01 (d, J = 8.9 Hz, 2H), 6.36 (t, J = 2.0 Hz, 2H), 3.91 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 167.1, 162.9, 131.9, 125.1,
121.3, 113.7, 112.6, 76.6, 55.4; IR ν = 1687, 1603, 1511, 1465,
1328, 1299, 1257, 1172, 1089, 1074, 882, 741 cm−1; HRMS
(ESI) m/z calcd for C12H12NO2 ([M + H]+) 202.0868, found
202.0871.
1-(2-Methoxybenzoyl)-1H-pyrrole (Table 3, Entry 5).
Isolated as an oil using 15% solution of ethyl acetate in
1
hexanes (method A 85%, method B 89%, method C 73%): H
NMR (400 MHz, CDCl3) δ 7.51 (ddd, J = 1.6, 7.6, 8.4 Hz,
1H), 7.41 (d, J = 1.6, 8.4 Hz, 1H), 7.18 (br s, 2H), 7.07 (t, J =
7.6 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.31 (br s, 2H), 3.83 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 166.2, 156.6, 132.2,
129.1, 123.5, 120.5, 120.3, 112.9, 111.3, 55.6; IR ν = 1705,
1600, 1335 cm−1; HRMS (ESI) m/z calcd for C12H11NNaO2
([M + Na]+) 224.0687, found 224.0885.
Conditions C. A 150 mL pressure tube28 equipped with a stir
bar and sealed with a rubber septum was purged with argon and
charged with potassium phosphate (0.741 g, 4.0 equiv, 3.49
mmol) and 3 mL of toluene. The aryl iodide (1.0 equiv, 0.873
mmol) and pyrrole (0.181 mL, 3.0 equiv, 2.61 mmol) were
added to the mixture. Pd(PPh3)4 (0.100 g, 0.1 equiv, 0.087
mmol) was added, and the reaction vessel was further purged
with argon. The pressure reactor was assembled, pressurized
with CO to 50 psi, vented thrice, and finally pressurized to 50
psi. The vessel was placed in an oil bath heated to 65 °C for 19
h. Upon completion, the reaction was allowed to cool to room
temperature, diluted with EtOAc, filtered through a plug of
Celite, and concentrated. The crude product was purified by
flash column chromatography, eluting with the indicated
solvent mixture to afford the desired acyl pyrrole.
4-Toluylpyrrole (Table 3, Entry 1). Isolated as an oil using a
10% solution of ethyl acetate in hexanes (method A 81%,
method B 86%, method C 34%): 1H NMR (300 MHz, CDCl3)
δ 7.68 (d, J = 8.1 Hz, 2H), 7.33 (m, 4H), 6.36 (t, J = 2.4 Hz,
2H) 2.47 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 167.7, 143.0,
130.3, 129.7, 129.1, 121.3, 112.9, 21.6; IR ν = 1695, 1610, 1466,
1401, 1327, 1303, 1088, 882, 739 cm−1; HRMS (ESI) m/z
calcd for C12H12NO ([M + H]+) 186.0919, found 186.0921.
1-(2,6-Dimethylbenzoyl)pyrrole (Table 3, Entry 2). Isolated
as pink needle crystals using a 5% solution of EtOAc in hexanes
(method A 93%, method B 88%, method C 60%): mp 59 °C;
1H NMR (400 MHz, CDCl3) δ 7.69 (br s, 1H), 7.29 (m, 1H),
7.12 (d, J = 7.2 Hz, 2H), 6.51 (br s, 1H), 6.41 (br s, 1H), 6.24
(br s, 1H), 2.23 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 168.6,
134.6, 134.5, 129.6, 127.4, 120.9, 118.3, 113.8, 113.6, 18.9; IR ν
1-(4-Methoxy-2,6-dimethylbenzoyl)-1H-pyrrole (Table 3,
Entry 6). Isolated as a clear oil using 5% solution of ethyl
acetate in hexanes (method A 70%, method B 42%, method C
1
29%): H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 6.64 (s,
2H), 6.54 (s, 1H), 6.39 (s, 1H), 6.23 (s, 1H), 3.84 (s, 1H), 2.20
(s, 1H); 13C NMR (400 MHz, CDCl3) δ 168.7, 160.2, 136.7,
127.2, 121.1, 118.3, 113.7, 113.3, 112.8, 55.1, 19.3; IR ν = 1733,
1698, 1602, 1466, 1325, 1302, 1148, 1087, 884, 742 cm−1;
HRMS (ESI) m/z calcd for C14H15NO2 ([M + H]+) 230.1181,
found 230.1185.
1-(4-Fluorobenzoyl)-1H-pyrrole (Table 3, Entry 7). Isolated
as a solid using a 2% solution of ethyl acetate in hexanes
(method A 70%, method B 85%, method C 33%): mp 43 °C;
1H NMR (300 MHz, CDCl3) δ 7.77 (d, J = 8.6 Hz, 2H), 7.23
(m, 4H), 6.35 (t, J = 2.2 Hz, 2H); 13C NMR (75 MHz, CDCl3)
δ 166.6 (d, JC−F = 0.34 Hz), 163.4, 132.1 (d, JC−F = 0.12 Hz),
121.2 Hz, 115.6 (d, JC−F = 0.30 Hz), 113.1; 19F NMR (282
MHz, CDCl3) δ −104.4; IR ν = 1683, 1601, 1507, 1467, 1402,
1325, 1226, 1159, 1090, 1072, 882, 741 cm−1; HRMS (ESI) m/
z calcd for C11H8FNO (M+) 189.0590, found 189.0586.
1-(3,4-Dichlorobenzoyl)-1H-pyrrole (Table 3, Entry 8).
Isolated as a white solid using a 2% solution of ethyl acetate
in hexanes (method A 62%, method B 61%, method C 21%):
1
mp 64 °C; H NMR (300 MHz, CDCl3) δ 7.88 (s, 1H), 7.61
(d, J = 1.8 Hz, 2H), 7.27 (m, 2H), 6.40 (t, J = 2.4 Hz, 2H); 13
C
NMR (100 MHz, CDCl3) δ 165.3, 137.0, 133.2, 132.9, 131.4,
130.6, 128.5, 121.1, 113.8; IR ν = 1675, 1469, 1410, 1339,
1100, 1040, 907, 773, 732 cm−1; HRMS (EI) m/z calcd for
C11H7Cl2NO ([M + H]+) 239.9983, found 239.9983.
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The Journal of Organic Chemistry
Note
1-(3-Methoxybenzoyl)-1H-pyrrole (Table 3, Entry 9).
1643, 1662, 1351, 1125, 736 cm−1; HRMS (ESI) m/z calcd for
C11H15NO (M+) 177.1154, found 177.1158.
Isolated as a clear oil using a 4% solution of ethyl acetate in
1
hexanes (method A 68%, method B 75%): H NMR (400
Cyclohexenyl (1H-Pyrrol-1-yl)methanone (Table 1, Entry
16). Isolated as an oil using a 5% solution of ethyl acetate in
hexanes (method A 57%, method B 61%): H NMR (400
MHz, CDCl3) δ 7.43 (t, J = 7.8 Hz, 1H), 7.32 (m, 3H), 7.29
(m, 1H), 7.16 (m, 1H), 3.88 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 167.4, 159.4, 134.3, 129.4, 121.6, 121.2, 118.4, 114.2,
113.1, 55.4; IR ν = 1682, 1601, 1507, 1467, 1326, 1227, 1159,
1090, 1072, 882, 741 cm−1; HRMS (ESI) m/z calcd for
C12H12NO2 ([M + H]+) 202.0868, found 202.0870.
1
MHz, CDCl3) δ 7.28 (t, J = 3.2 Hz, 2H), 6.42 (m, 1H), 6.31 (t,
J = 3.2 Hz, 2H) 2.42 (m, 2H); 2.28 (m, 2H), 1.79−1.69 (m,
4H); 13C NMR (75 MHz, CDCl3) δ 168.8, 138.3, 132.9, 120.7,
112.5, 25.4, 25.3, 21.9, 21.4; IR ν = 2952, 1693, 1618, 1461,
1401, 1353, 1314, 1078, 791 cm−1; HRMS (ESI) m/z calcd for
C11H13NO (M+) 175.0997, found 175.0992.
1-(4-Cyanobenzoyl)pyrrole (Table 3, Entry 10). Isolated as a
solid using 15% solution of ethyl acetate in hexanes (method A
50%, method B 36%): mp 87 °C; 1H NMR (300 MHz, CDCl3)
δ 7.86 (m, 4H), 7.23 (m, 2H), 6.41 (dd, 2H); 13C NMR (100
MHz, CDCl3) δ 165.9, 137.2, 132.3, 129.8, 120.9, 117.6, 115.8,
114.1; IR ν = 2233, 1679, 1610 cm−1; HRMS (ESI) m/z calcd
for C12H8N2O ([M + Na]+) 219.0534, found 219.0531.
Ethyl 3-(1H-Pyrrole-1-carbonyl)benzoate (Table 3, Entry
11). Isolated as a oil using 15% solution of ethyl acetate in
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds. This material
is free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: aorellan@yorku.ca.
■
1
hexanes (method A 82%, method B 66%): H NMR (400
MHz, CDCl3) δ 8.43 (s, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.95 (d,
J = 6.8 Hz, 1H), 7.63 (dd, J = 8.0, 6.8 Hz, 1H), 7.29 (br s, 2H),
6.40 (br s, 2H), 4.44 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 166.7, 165.3, 133.5,
133.3, 132.9, 130.9, 130.2, 128.6, 121.1, 113.5, 61.4, 14.2; IR ν
= 1726, 1701, 1606 cm−1; HRMS (ESI) m/z calcd for
C14H14NO3 ([M + H]+) 244.0974, found 244.0972.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the support of this work from York
University and the Natural Sciences and Engineering Research
Council of Canada. We thank Dr. Howard N. Hunter (York
University) for assistance in conducting NMR spectroscopy
experiments and Professor Michael Organ (York University)
for generous sharing of resources.
(1H-Pyrrol-1-yl)(thiophene-2-yl)methanone (Table 3, Entry
12). Isolated as an oil using a 5% solution of ethyl acetate in
1
hexanes (method A 87%, method B 92%): H NMR (300
MHz, CDCl3) δ 7.77 (d, J = 3.6 Hz, 1H), 7.72 (d, J = 4.5 Hz,
1H), 7.48 (t, J = 1.8 Hz, 2H), 7.20 (t, J = 4.5 Hz, 1H), 6.40 (t, J
= 1.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 160.6, 135.8,
134.1, 133.4, 127.7, 121.0, 113.2; IR ν = 1672, 1459, 1419,
1357, 1321, 1063, 813 cm−1; HRMS (ESI) m/z calcd for
C9H7NOS ([M + H]+) 177.0248, found 177.0241.
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tert-butyl 3-(1H-Pyrrole-1-carbonyl)-1H-indole-1-carboxy-
late (Table 3, Entry 13). Isolated as a white crystalline solid
using a 5% solution of ethyl acetate in hexanes (method A 82%,
method B 85%): mp 83−85 °C; 1H NMR (400 MHz, CDCl3)
δ 8.23 (d, J = 8.0 Hz, 1H), 8.19 (s, 1H), 8.07 (d, J = 8.0 Hz,
1H), 7.51 (bs, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.39 (t, J = 8.0 Hz,
1H), 6.42 (bs, 2H), 1.75 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 162.2, 148.9, 135.1, 131.2, 128.2, 125.7, 124.1, 121.5,
120.6, 115.2, 113.6, 112.9, 85.5, 28.0; IR ν = 1743, 1677, 1459,
1366, 1285, 1232, 1152, 1116, 832, 756 cm−1; HRMS (ESI) m/
z calcd for C18H18N2O3 (M+) 310.1317, found 310.1311.
2-Phenyl-1-(1H-pyrrol-1-yl)prop-2-en-1-one (Table 3,
Entry 14). Isolated as a yellow oil using a 5% solution of
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1
ethyl acetate in hexanes (method A 35%, method B 28%): H
NMR (400 MHz, CDCl3) δ 7.46 (m, 2H), 7.40 (m, 3H), 7.30
(bs, 2H), 6.30 (m, 2 H), 6.08 (s, 1H), 5.71 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 167.4, 143.2, 135.3, 128.9, 128.8, 126.1,
120.4, 119.5, 113.4; IR ν = 1683, 1625, 1466, 1357, 1254, 1168,
829, 763 cm−1; HRMS (ESI) m/z calcd for C13H11NO (M+)
197.0841, found 197.0845.
́ ́
(13) Takacs, A.; Petz, A.; Kollar, L. Tetrahedron 2010, 66, 4479.
(14) Deagostino, A.; Larini, P.; Occhiato, E. G.; Pizzuto, L.; Prandi,
C.; Venturello, P. J. Org. Chem. 2008, 73, 1941.
(15) Martinelli, J. R.; Clark, T. P.; Watson, D. A.; Munday, R. H.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 8460.
(16) Evans, D. A.; Borg, G.; Scheidt, K. A. Angew. Chem., Int. Ed.
2002, 41, 3188.
(E)-1-(1H-Pyrrol-1-yl)hept-2-en-1-one (Table 3, Entry 15).
Isolated as a yellow oil using a 5% solution of ethyl acetate in
(17) Tanaka, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2010,
132, 8862.
(18) Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada, S.; Shibasaki,
M. J. Am. Chem. Soc. 2004, 126, 7559.
(19) Zhao, D.; Mao, L.; Wang, Y.; Yang, D.; Zhang, Q.; Wang, R.
Org. Lett. 2010, 12, 1880.
1
hexanes (method 24%, method B 30%): H NMR (400 MHz,
CDCl3) δ 7.40 (bs, 2H), 7.29 (dt, J = 15.2 Hz, 7.2 Hz, 1H),
6.57 (d, J = 15.2, 1H), 6.34 (bs, 2H), 2.36 (q, J = 7.2 Hz, 2H),
1.54 (quintet, J = 7.2 Hz, 2H), 1.40 (sextet, J = 7.2 Hz, 2H),
0.96 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.8,
152.9, 119.2, 119.1, 113.0, 32.4, 30.0, 22.2, 13.7; IR ν = 1697,
(20) D’Silva, C.; Iqbal, R. Synthesis 1996, 457.
2011
dx.doi.org/10.1021/jo2022444 | J. Org. Chem. 2012, 77, 2008−2012

The Journal of Organic Chemistry
Note
(21) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 595.
(22) Menger, F. M.; Donohue, J. A. J. Am. Chem. Soc. 1973, 95, 432.
(23) One example of this transformation has been reported in 64%
(GC) yield using Pd(OAc)2 and di-1-adamantybutylphosphine
(cataCXium A), 5 bar of CO, 30 bar of N2, and a large excess of
pyrrole. Neumann, H.; Brennfurer, A.; Groß, Riermeier, T.; Almena, J.;
̈
Beller, M. Adv. Synth. Catal. 2006, 348, 1255.
(24) Sigma-Aldrich pricing: N,O-dimethylhydroxylamine·HCl costs
$237/mol, while pyrrole costs only $35/mol (based on the cost of 100
g bottles).
(25) For a discussion on the mechanism of carbonylative amination
leading to amides, see: Hartwig, J. Organotransition Metal Chemistry:
From Bonding to Catalysis; University Science Books: Sausalito, CA,
2009; Chapter 17, pp 795−798.
(26) Since the pyrrole nitrogen is part of the aromatic system, it is
expected to be less nucleophilic than an aliphatic amine unless it is
deprotonated.
(27) The use of other common bases (i.e., Cs2CO3, K2CO3, Na2CO3,
Et3N) provided benzoyl pyrrole in lower yields.
(28) Reactions at increased CO pressure were conducted using an
apparatus similar to that described by Coates; see: Kramer, J. W.;
Treiler, D. S.; Coates, G. W.; Denmark, S. E.; Hoover, A. J. Org. Synth.
2009, 86, 287.
2012
dx.doi.org/10.1021/jo2022444 | J. Org. Chem. 2012, 77, 2008−2012