Palladium-catalysed regioselective sequential C-5 and C-2 direct arylations of 3-acetylpyrroles with aryl bromides

Article abstract of DOI:10.1002/adsc.201300123

The PdCl(C₃H₅)(dppb)/KOAc system was found to be effective for the direct regioselective C-5 arylation of 3-acetylpyrroles with ortho-substituted aryl bromides. This procedure has been found to be tolerant to a variety of functional groups at C-2 of the aryl bromide such as methyl, formyl, nitrile, nitro, hydroxymethyl, chloro, fluoro or trifluoromethyl. The sequential direct C-5 arylation followed by C-2 arylation of such 3-substituted pyrroles allows the synthesis of 2,5-diaryl-3-acetylpyrroles in high yields. Copyright

Full text of DOI:10.1002/adsc.201300123

UPDATE
DOI: 10.1002/adsc.201300123
Palladium-Catalysed Regioselective Sequential C-5 and C-2
Direct Arylations of 3-Acetylpyrroles with Aryl Bromides
Yijing Xu,a,b Liqin Zhao,a Yiqun Li,b,* and Henri Douceta,*
a
Institut Sciences Chimiques de Rennes, UMR 6226 CNRS – Universitꢀ de Rennes “Organomꢀtalliques matꢀriaux et
Catalyse”, Campus de Beaulieu, 35042 Rennes, France
Fax : (+33)-(0)2-2323-6939; phone: (+33)-(0)2-2323-6384; e-mail: henri.doucet@univ-rennes1.fr
Department of Chemistry, Jinan University, Guangzhou 510632, Peopleꢁs Republic of China
b
E-mail: tlyq@jnu.edu.cn
Received: February 6, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300123.
Abstract: The PdCl
(C3H5)
E
procedure for the preparation of arylated heteroar-
enes.[1–4] Such couplings are very attractive compared
to classical palladium-catalysed reactions such as
Stille, Suzuki or Negishi couplings as they do not re-
quire the preliminary synthesis of organometallic de-
rivatives.[5] The regioselectivity of the palladium-cata-
lysed direct arylation of 3-substituted furans or thio-
phenes has been largely studied in recent years.[6,7]
When using 3-formyl, 3-cyano, 3-methyl, 3-hydroxy-
methyl or 3-bromothiophenes, the 2-arylated thio-
phenes were obtained in 76–95% regioselectivity. On
the other hand, the arylation of 3-acetylthiophene
gave the 5-arylated thiophenes in 52–90% regioselec-
tivities. With this thiophene derivative, the use of con-
gested aryl bromides was found to favour the aryla-
tion at C-5 (Scheme 1).[7]
found to be effective for the direct regioselective C-
5 arylation of 3-acetylpyrroles with ortho-substitut-
ed aryl bromides. This procedure has been found to
be tolerant to a variety of functional groups at C-2
of the aryl bromide such as methyl, formyl, nitrile,
nitro, hydroxymethyl, chloro, fluoro or trifluoro-
methyl. The sequential direct C-5 arylation followed
by C-2 arylation of such 3-substituted pyrroles
allows the synthesis of 2,5-diaryl-3-acetylpyrroles in
high yields.
Keywords: aryl halides; atom economy; C H bond
functionalisation; palladium; pyrroles
The palladium-catalysed direct arylation of 3-substi-
tuted pyrroles has attracted much less attention.[8–10]
Among heterocycles, some 2-aryl-4-carbonylpyrrole In 2006, Sames and co-workers reported a single ex-
derivatives display important biological properties. ample of the direct arylation of a 3-acetylpyrrole
For example, Atorvastatin is used for lowering choles- using iodobenzene as the coupling partner. For this
terol and Isoprazone is an analgesic antipyretic agent coupling, 5 mol% of palladium associated to a carbene
(Figure 1). Therefore, the discovery of general and ligand were used as the catalyst, and a mixture of re-
simple routes to a variety of 2-aryl-4-carbonylpyrroles gioisomers was formed (Scheme 2).[10] 5-Phenyl-3-ace-
has potential for medicinal chemistry.
tylpyrrole was obtained in 29% yield; whereas, 2-
The direct coupling of heteroarenes with aryl hal-
À
ides via a C H bond activation/functionalisation pro-
vides a cost-effective and environmentally attractive
Scheme 1. Most reactive positions for Pd-catalysed direct ar-
ylation of 3-substituted thiophenes.
Figure 1. Examples of bioactive arylpyrroles.
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Here, we wish to report (i) on the influence of
some parameters on the regioselectivity of the reac-
tion of 3-acetylpyrrole derivatives with aryl halides;
(ii) the scope of the reaction using a set of electroni-
cally and sterically diverse aryl bromides; (iii) the fur-
ther reactivity of these formed 5-aryl-3-acetylpyrroles
À
for palladium-catalysed C H bond functionalization
at C-2 of the pyrrole ring to produce 2,5-diarylpyrrole
derivatives.
We decided to employ commercially available 1-
methyl-3-acetylpyrrole as the test substrate for our
study (Scheme 3, Table 1). We initially examined the
influence of the nature of the halide on the selectivity
of this reaction using DMA as the solvent and
Scheme 2. Reported direct arylation of 1-methyl-3-acetylpyr-
role.[10]
1 mol% PdClACTHNUTRGNEN(UG C3H5)ACHTUGNTREN(NUGN dppb) as the catalyst, as such
phenyl-3-acetylpyrrole and 2,5-diphenyl-3-acetylpyr- conditions were previously found operative for some
role were produced in 7% and 14% yields, respective- direct arylations of heteroaromatics.[3a] In the pres-
ly. Therefore, the influence of the reaction parameters ence of iodobenzene, a complete conversion was ob-
on the regioselectivity of the palladium-catalysed served, and the C-5 arylated pyrrole 1a was obtained
direct arylation of 3-substituted pyrroles needed to be as the major isomer in 50% selectivity (Table 1, en-
investigated.
tries 1 and 2). However, the C-2 arylated product 1b
was also obtained in 26% selectivity, and 24% of the
2,5-diarylated pyrrole 1c were also produced. A
slightly higher selectivity in favour of the formation
of 1a was observed in the presence of bromobenzene,
as 1a was obtained in 51–55% selectivity (Table 1, en-
tries 3 and 4). The ratio of the reactant also appears
to have a minor influence on the selectivity. Then,
a few other catalyst precursors were employed. How-
ever, the use of phosphine-free Pd
ACHTUNGRTEN(NUNG OAc)2, or
Pd(OAc)2 associated to PPh3 or dppb led to 1a–c in
AHCTUNGTRENNUNG
similar regioselectivities (Table 1, entries 5–7). More-
over, a moderate conversion of 62% of bromoben-
Scheme 3. Influence of the reaction conditions for the palla-
dium-catalysed direct arylations of 1-methyl-3-acetylpyrrole
with aryl halides.
zene was observed with phosphine-free Pd
ACHTUNGRTENN(UNG OAc)2 cat-
alyst leading to 1a in only 21%. Changing the base to
Table 1. Influence of the reaction conditions for the palladium-catalysed direct arylations of 1-methyl-3-acetylpyrrole with
aryl halides (Scheme 3).[a]
Entry
X
R
Ratio ArBr:3-acetyl- Catalyst (mol%)
pyrrole
Base
Solvent Ratio of products a:b:c Yield in a [%]
1
2
3
4
5
6
7
8
I
I
H
H
H
H
H
H
H
H
H
H
H
H
1:2
1:1.5
1:2
1:1.5
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
PdCl
PdCl
PdCl
PdCl
N
G
42
–
37
–
21
–
–
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Pd
Pd
Pd
N
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
–
9
–
[b]
10
11
12
13
14
15
–
–
–
[b]
Br 4-CN 1:2
Br 3-CN 1:2
Br 2-CN 1:2
41
40
80
[a]
Reaction conditions: base (3 equiv.), 20 h, 1508C.
Low conversion of bromobenzene.
[b]
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Palladium-Catalysed Regioselective Sequential C-5 and C-2 Direct Arylations of 3-Acetylpyrroles
regioselectivity in 1a–c as DMA (Table 1, entries 11
and 12).
The influence of the bromobenzene substituents on
the reactivity and regioselectivity of the coupling with
1-methyl-3-acetylpyrrole was then examined. In the
presence of the electron-deficient aryl bromides, 3- or
4-bromobenzonitriles, the selectivity in isomers 2a–
c and 3a–c was very similar as with bromobenzene
(Scheme 3, Table 1, entries 13 and 14).
Scheme 4. Direct 5-arylations of 1-methyl-3-acetylpyrrole
with various aryl bromides.
On the other hand, a very regioselective reaction in
favour of the formation of 4a was observed in the
CsOAc or NaOAc also gave very similar results; presence of a congested aryl bromide, 2-bromobenzo-
whereas, K2CO3 gave 1a–c in low yield due to a poor nitrile (Table 1, entry 15). With this reactant, no for-
conversion of bromobenzene (Table 1, entries 8–10). mation of 2-arylated or 2,5-diarylated pyrroles 4b and
DMF was found to be quite ineffective as solvent for 4c was detected by GC/MS analysis and in the crude
this reaction. On the other hand, NMP gave a similar NMR spectrum, and 4a was isolated in 80% yield.
Table 2. Direct 5-arylations of 1-methyl-3-acetylpyrrole with various aryl bromides (Scheme 4).[a]
[a]
Reaction conditions: PdClACTHNURGTENN(UG C3H5)ACHTUTGNREN(NUGN dppb) (0.01 equiv.), aryl bromide (1 equiv.), 1-methyl-3-acetylpyrrole
(2 equiv.), KOAc (3 equiv.), DMA, 20 h, 1508C.
Other arylation products observed by GC/MS analysis.
[b]
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Then, we examined the scope of this procedure
using other meta- or ortho-substituted aryl bromides
and also heteroaryl bromides (Scheme 4, Table 2).
The use of 2-bromonitrobenzene gave selectively the
5-arylated pyrrole 5 in 86% yield (Table 2, entry 1).
From a protected 2-bromobenzaldehyde, 6 was isolat-
ed in 66% yield. Again, the reaction was completely
regioselective, but a partial decomposition of the
product was observed (Table 2, entry 2). The coupling
with 2,4-difluorobromobenzene, 2-chlorobromoben-
zene and 1-bromonaphthalene gave 7–9 in 78–80%
yields (Table 2, entries 3–5). It should be noted that
Scheme 5. Direct 5-arylations of 1-ethyl-3-acetylpyrrole with
various aryl bromides.
À
no cleavage of the C Cl bond of 2-chlorobromoben-
zene was observed in the course of this coupling al-
lowing further transformations. Even the slightly elec-
tron-rich aryl bromide, 2-bromotoluene was reactive
under these conditions to give selectively 10 in 73%
yield (Table 2, entry 6). On the other hand, no reac-
tion was observed in the presence of the more elec-
tron-rich 2-bromoanisole. The direct coupling of un-
protected (2-bromophenyl)methanol with 1-methyl-3-
acetylpyrrole could be very practical since it would
avoid a protection/deprotection sequence, and there-
fore would provide a more environmentally and eco-
nomically attractive access to such arylated pyrroles.
We were glad to observe that coupling of this reactant
proceeds nicely to give 11 in 69% yield (Table 2,
entry 7). Again, the reaction was regioselective at the
C-5 position. Then, a heteroarene was employed suc-
cessfully. From 4-bromoisoquinoline, 12 was isolated
in 81% yield (Table 1, entry 8). Two di-ortho-substi-
tuted aryl bromides were also reacted with 1-methyl-
3-acetylpyrrole. Both 9-bromoanthracene and 1-
bromo-2-methylnaphthalene led to the target prod-
ucts 13 and 14 in good yields (Table 2, entries 9 and
10). On the other hand, from the less congested 3-
bromoquinoline, 13 was only obtained in 58% yield
due to some formation of the 2-arylated pyrrole
(Table 2, entry 11). We also examined the reactivity of
3-bromonitrobenzene. Again, a poor regioselectivity
was observed, and 14a was only isolated in 33% yield
(Table 2, entry 12).
Table 3. Direct 5-arylations of 1-ethyl-3-acetylpyrrole with
various aryl bromides (Scheme 5).[a]
As expected, the reactivity of 1-methyl-3-acetylpyr-
role and 1-ethyl-3-acetylpyrrole was found to be very
similar. The reaction of 2-bromobenzonitrile, 1-bro-
monaphthalene or 4-bromoisoquinoline also gave re-
gioselectively the C-5 arylated pyrroles 17, 21 and 22
(Scheme 5, Table 3, entries 1, % and 6). With this pyr-
role derivative, we also employed 2-bromobenzalde-
hyde, 2-bromobenzotrifluoride or 2-fluorobromoben-
zene as the coupling partners. In all cases, the desired
C-5 arylation products 18–20 were obtained in high
yields with complete regioselectivity (Table 3, en-
tries 2–4).
Then, we studied the C-2 arylation with different
aryl groups of two of the previously obtained 5-aryl-
pyrroles to prepare 2,5-diarylpyrroles (Scheme 6 and
[a]
Reaction conditions: PdClACTHNUTRGENN(UG C3H5)ACHTUTGNREN(NUGN dppb) (0.01 equiv.), aryl
bromide (1 equiv.), 1-ethyl-3-acetylpyrrole (2 equiv.),
KOAc (3 equiv.), DMA, 20 h, 1508C.
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Palladium-Catalysed Regioselective Sequential C-5 and C-2 Direct Arylations of 3-Acetylpyrroles
Scheme 7. Direct 2-arylations of 1-(5-isoquinolin-4-yl-1-
methylpyrrol-3-yl)ethanone 12 with aryl halides.
allowing the C-5 catalytic arylation and a C-2 differ-
ent catalytic arylation leading to unsymmetrical 2,5-
diarylated 3-acetylpyrroles. The major by-products of
these reactions are AcOH/KBr instead of metallic
salts using more classical coupling procedures. More-
over, no prior preparation of an organometallic deriv-
Scheme 6. Direct 2-arylations of 1-(1-methyl-5-naphthalen-
1-ylpyrrol-3-yl)ethanone 9 with aryl halides.
Scheme 7). These reactions were performed using ative is required for these couplings, reducing the
also 1 mol% PdCl(C3H5)(dppb) as the catalyst and number of required steps to obtain these arylated pyr-
A
ACHTUNGTRENNUNG
KOAc as the base. The electron-deficient para- or roles. As it has already been demonstrated that sever-
meta-substituted aryl bromides, 4-bromobenzonitrile, al useful functional groups on the pyrrole nitrogen
4-bromonitrobenzene or 3-bromoacetophenone react- atom, such as aryl, benzyl or SEM [2-(trimethylsilyl)-
ed with 9 and gave very selectively the desired prod-
ethoxymethyl] are tolerated for such coupling,[6,11] this
ACHTUNGTRENNUNG
ucts 24, 25 and 27 in 75–80% yields. Even the elec- method should give access to several synthetically im-
tron-rich aryl bromide, 4-bromoanisole gave the ex- portant pyrroles derivatives.
pected product 26 in a high 78% yield. 3-Bromopyri-
dine was also successfully employed to give 28 in 80%
yield.
Similar results were obtained for the coupling of
Experimental Section
ethyl 4-bromobenzoate, 4-fluorobromobenzene or 3- General Remarks
bromobenzaldehyde with the 3-acetylpyrrole bearing
an isoquinoline at C-5 12 (Scheme 7). The desired
products 29–31 were obtained in 68–84% yields.
All reactions were performed in Schlenk tubes under argon.
DMA analytical grade was not distilled before use. Potassi-
um acetate 99+ was used. Commercial aryl bromides and
heteroaromatic derivatives were used without purification.
1H (300 and 400 MHz), 13C (75 and 100 MHz) spectra were
recorded in CDCl3 solutions. Chemical shifts are reported in
ppm relative to CDCl3 (1H: 7.26 and 13C: 77.0). Flash chro-
matography was performed on silica gel (230–400 mesh).
In summary, we report herein the first regioselec-
tive palladium-catalysed direct C-5 arylations of C-3
substituted pyrrole derivatives with aryl halides. The
influence of some reaction parameters on the regiose-
lectivity was studied. While the influence of the elec-
tronic properties of the substituents on the aryl bro-
mides appears to be relatively limited; on the other
hand, their steric properties are important. Aryl bro-
mides substituted at C-2 by a methyl, a cyano, a nitro,
a formyl, a hydroxymethyl, a fluoro, a trifluoromethyl
or a chloro gave regioselectively the 5-arylated pyr-
(dppb) Catalyst[11]
Preparation of the PdClACTHNUTGRENN(UG C3H5)ACHTUGNTRENNUGN
An oven-dried 40-mL Schlenk tube equipped with a magnet-
ic stirring bar under argon atmosphere, was charged with
[Pd
ACHTNUGRTNE(NGNU C3H5)Cl]2 (182 mg, 0.5 mmol) and dppb (426 mg,
1 mmol). 10 mL of anhydrous dichloromethane were added,
roles. We have also shown sequential transformations then the solution was stirred at room temperature for
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twenty minutes. The solvent was removed under vacuum.
The yellow powder was used without purification. 31P NMR
(81 MHz, CDCl3): d=19.3 (s).
d=7.64 (d, J=7.4 Hz, 1H), 7.57 (s, 1H), 7.52 (t, J=7.7 Hz,
1H), 7.49 (t, J=7.7 Hz, 1H), 6.61 (d, J=3.0 Hz, 1H), 6.58
(d, J=3.0 Hz, 1H), 3.37 (s, 3H), 2.20 (s, 3H).
The formation of 2,5-diarylated pyrrole 3c was also ob-
1
served (yellow solid; mp 140–1428C): H NMR (400 MHz,
CDCl3): d=7.70–7.50 (m, 8H), 6.68 (s, 1H), 3.31 (s, 3H),
2.23 (s, 3H).
General Procedure for the Synthesis of Compounds
1–31
2-(4-Acetyl-1-methylpyrrol-2-yl)benzonitrile (4a): From 2-
bromobenzonitrile (0.182 g, 1 mmol) and 1-methyl-3-acetyl-
pyrrole (0.247 g, 2 mmol), 4a was obtained as a yellow solid;
yield: 0.179 g (80%); mp 118–1208C. 1H NMR (400 MHz,
CDCl3): d=7.70 (d, J=8.0 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H),
7.43 (t, J=7.7 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 6.68 (s,
1H), 3.55 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=193.1, 135.6, 133.4, 132.7, 131.5, 131.3, 128.8,
128.6, 125.5, 117.8, 113.4, 111.5, 35.2, 27.0; elemental analy-
sis: calcd. (%) for C14H12N2O (224.26): C 74.98, H 5.39;
found: C 75.16, H 5.20.
As a typical experiment, the reaction of the aryl bromide
(1 mmol), pyrrole derivative (1.5 or 2 mmol, see Tables) and
KOAc (0.294 g, 3 mmol) at 1508C during 20 h in DMA
(4 mL) in the presence of PdClACTHNUTRGENNU(G C3H5)ACHTUNGTRENN(UGN dppb) (6.08 mg,
0.01 mmol) under argon afforded the coupling product after
evaporation of the solvent and purification on silica gel.
1-(1-Methyl-5-phenylpyrrol-3-yl)ethanone (1a): From bro-
mobenzene (0.157 g, 1 mmol) and 1-methyl-3-acetylpyrrole
(0.247 g, 2 mmol), 1a was obtained as a brown oil; yield:
0.084 g (42%). 1H NMR (400 MHz, CDCl3): d=7.40–7.22
(m, 6H), 6.56 (d, J=1.8 Hz, 1H), 3.60 (s, 3H), 2.35 (s, 3H);
13C NMR (75 MHz, CDCl3): d=193.4, 136.2, 132.0, 128.8,
128.6, 128.2, 127.7, 125.2, 109.0, 35.6, 27.0. elemental analy-
sis: calcd. (%) for C13H13NO (199.25): C 78.36, H 6.58;
found: C 78.46, H 6.50.
The formation of 2-arylated pyrrole 1b was also observed:
1H NMR (400 MHz, CDCl3): d=7.50–7.45 (m, 3H), 7.34 (d,
J=7.8 Hz, 2H), 6.68 (d, J=2.8 Hz, 1H), 6.63 (d, J=2.8 Hz,
1H), 3.39 (s, 3H), 2.06 (s, 3H).
The formation of 2,5-diarylated pyrrole 1c was also ob-
served: 1H NMR (400 MHz, CDCl3): d=7.50–7.35 (m,
10H), 6.74 (s, 1H), 3.34 (s, 3H), 2.09 (s, 3H).
4-(4-Acetyl-1-methylpyrrol-2-yl)benzonitrile (2a): From 4-
bromobenzonitrile (0.182 g, 1 mmol) and 1-methyl-3-acetyl-
pyrrole (0.247 g, 2 mmol), 2a was obtained as a yellow solid;
yield: 0.092 g (41%); mp 152–1548C. 1H NMR (400 MHz,
CDCl3): d=7.69 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H),
7.36 (d, J=1.5 Hz, 1H), 6.72 (d, J=1.5 Hz, 1H), 3.71 (s,
3H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3): d=193.0,
136.5, 134.1, 132.4, 129.7, 128.8, 125.6, 118.6, 111.1, 110.7,
36.0, 27.1; elemental analysis: calcd. (%) for C14H12N2O
(224.26): C 74.98, H 5.39; found: C 75.04, H 5.49.
1-[1-Methyl-5-(2-nitrophenyl)pyrrol-3-yl]ethanone
(5):
From 1-bromo-2-nitrobenzene (0.202 g, 1 mmol) and 1-
methyl-3-acetylpyrrole (0.247 g, 2 mmol), 5 was obtained as
a brown oil; yield: 0.210 g (86%). 1H NMR (400 MHz,
CDCl3): d=7.97 (d, J=8.0 Hz, 1H), 7.61 (t, J=7.4 Hz, 1H),
7.53 (t, J=7.4 Hz, 1H), 7.38 (d, J=7.5 Hz, 1H), 7.30 (s,
1H), 6.48 (s, 1H), 3.39 (s, 3H), 2.34 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=193.2, 149.5, 133.7, 132.9, 130.3,
129.9, 128.0, 126.7, 125.4, 124.5, 109.7, 34.6, 27.0; elemental
analysis: calcd. (%) for C13H12N2O3 (244.25): C 63.93, H
4.95; found: C 63.99, H 4.81.
1-[5-(2-Diethoxymethylphenyl)-1-methylpyrrol-3-yl]etha-
none (6): From 1-bromo-2-diethoxymethylbenzene (0.259 g,
1 mmol) and 1-methyl-3-acetylpyrrole (0.247 g, 2 mmol), 6
1
was obtained as a brown oil; yield: 0.199 g (66%). H NMR
(400 MHz, CDCl3): d=7.67 (d, J=7.7 Hz, 1H), 7.39 (t, J=
7.4 Hz, 1H), 7.30 (t, J=7.4 Hz, 1H), 7.28 (s, 1H), 7.14 (d,
J=7.5 Hz, 1H), 6.46 (s, 1H), 3.50 (m, 2H), 3.33 (s, 3H),
3.27 (m, 2H), 2.35 (s, 3H), 1.06 (t, J=7.6 Hz, 6H);
13C NMR (100 MHz, CDCl3): d=193.7, 139.6, 133.2, 131.1,
130.9, 129.0, 128.1, 127.1, 126.4, 124.9, 109.4, 100.1, 62.8,
34.9, 26.9, 14.9; elemental analysis: calcd. (%) for
C18H23NO3 (301.38): C 71.73, H 7.69; found: C 71.50, H 7.59.
1-[5-(2,4-Difluorophenyl)-1-methylpyrrol-3-yl]ethanone
(7): From 1-bromo-2,4-difluorobenzene (0.193 g, 1 mmol)
and 1-methyl-3-acetylpyrrole (0.247 g, 2 mmol), 7 was ob-
tained as a yellow solid; yield: 0.183 g (78%); mp 112–
1148C. 1H NMR (400 MHz, CDCl3): d=7.30 (s, 1H), 7.24
(dd, J=15.0, 8.3 Hz, 1H), 6.92–6.80 (m, 2H), 6.54 (s, 1H),
3.49 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
193.2, 163.0 (dd, J=251.2, 11.9 Hz), 160.1 (dd, J=249.5,
11.7 Hz), 133.1 (dd, J=9.5, 4.0 Hz), 128.9, 128.1, 125.4, 116.0
(dd, J=15.1, 4.0 Hz), 111.6 (dd, J=20.7, 4.0 Hz), 110.5,
104.3 (t, J=26.2 Hz), 35.0, 26.9; elemental analysis: calcd.
(%) for C13H11F2NO (235.23): C 66.38, H 4.71; found: C
66.50, H 4.58.
The formation of 2-arylated pyrrole 2b was also observed
1
(yellow solid; mp 148–1508C): H NMR (400 MHz, CDCl3):
d=7.72 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 6.68 (d,
J=2.9 Hz, 1H), 6.64 (d, J=2.9 Hz, 1H), 3.43 (s, 3H), 2.26
(s, 3H).
The formation of 2,5-diarylated pyrrole 2c was also ob-
1
served (yellow solid; mp 188–1908C): H NMR (400 MHz,
CDCl3): d=7.77 (d, J=8.1 Hz, 2H), 7.74 (d, J=8.1 Hz, 2H),
7.55 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 6.79 (s,
1H), 3.39 (s, 3H), 2.29 (s, 3H).
3-(4-Acetyl-1-methylpyrrol-2-yl)benzonitrile (3a): From 3-
bromobenzonitrile (0.182 g, 1 mmol) and 1-methyl-3-acetyl-
pyrrole (0.247 g, 2 mmol), 3a was obtained as a yellow solid;
yield: 0.090 g (40%); mp 116–1188C. 1H NMR (400 MHz,
CDCl3): d=7.68 (s, 1H), 7.65–7.60 (m, 2H), 7.56 (t, J=
7.7 Hz, 1H), 7.38 (d, J=1.6 Hz, 1H), 6.70 (d, J=1.6 Hz,
1H), 3.70 (s, 3H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3):
d=193.1, 133.5, 133.3, 132.9, 131.9, 131.1, 129.6, 129.1, 125.5,
118.4, 113.0, 110.2, 35.7, 27.1; elemental analysis: calcd. (%)
for C14H12N2O (224.26): C 74.98, H 5.39; found: C 75.14, H
5.40.
1-[5-(2-Chlorophenyl)-1-methylpyrrol-3-yl]ethanone (8):
From 1-bromo-2-chlorobenzene (0.191 g, 1 mmol) and 1-
methyl-3-acetylpyrrole (0.247 g, 2 mmol), 8 was obtained as
a yellow oil; yield: 0.186 g (80%). 1H NMR (400 MHz,
CDCl3): d=7.41 (d, J=7.6 Hz, 1H), 7.32–7.23 (m, 4H), 6.51
(s, 1H), 3.42 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=193.3, 135.0, 132.9, 132.8, 131.2, 130.1, 129.7,
127.4, 126.8, 125.2, 110.0, 34.9, 27.0; elemental analysis:
The formation of 2-arylated pyrrole 3b was also observed
1
(yellow solid; mp 105–1068C): H NMR (400 MHz, CDCl3):
6
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Palladium-Catalysed Regioselective Sequential C-5 and C-2 Direct Arylations of 3-Acetylpyrroles
calcd. (%) for C13H12ClNO (233.69): C 66.81, H 5.18; found:
C 66.59, H 5.40.
CDCl3): d=193.6, 137.0, 134.1, 132.2, 131.9, 128.9, 128.3,
127.9, 127.6, 126.9, 126.7, 125.4, 125.3, 125.2, 110.2, 34.5,
27.1, 20.5; elemental analysis: calcd. (%) for C18H17NO
(263.33): C 82.10, H 6.51; found: C 82.19, H 6.40.
1-(1-Methyl-5-naphthalen-1-ylpyrrol-3-yl)ethanone
(9):
From 1-bromonaphthalene (0.207 g, 1 mmol) and 1-methyl-
3-acetylpyrrole (0.247 g, 2 mmol), 9 was obtained as a brown
oil; yield: 0.197 g (79%). H NMR (300 MHz, CDCl3): d=
1-(1-Methyl-5-quinolin-3-ylpyrrol-3-yl)ethanone
From 3-bromoquinoline (0.208 g, 1 mmol) and 1-methyl-3-
(15):
1
7.93 (d, J=8.0 Hz, 2H), 7.65 (d, J=8.5 Hz, 1H), 7.60–7.40
(m, 5H), 6.71 (d, J=1.5 Hz, 1H), 3.41 (s, 3H), 2.49 (s, 3H);
13C NMR (75 MHz, CDCl3): d=193.5, 133.8, 133.6, 133.0,
129.6, 129.1, 129.0, 128.4, 127.4, 126.7, 126.2, 125.6, 125.3,
125.2, 110.2, 34.9, 27.1; elemental analysis: calcd. (%) for
C17H15NO (249.31): C 81.90, H 6.06; found: C 81.99, H 6.14.
1-(1-Methyl-5-o-tolylpyrrol-3-yl)ethanone (10): From 1-
bromo-2-methylbenzene (0.171 g, 1 mmol) and 1-methyl-3-
acetylpyrrole (0.247 g, 2 mmol ol), 10 was obtained as
a brown oil; yield: 0.156 g (73%). 1H NMR (400 MHz,
CDCl3): d=7.30–7.10 (m, 5H), 6.42 (s, 1H), 3.33 (s, 3H),
2.35 (s, 3H), 2.10 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
193.6, 138.2, 134.9, 131.6, 131.1, 130.2, 128.6, 126.9, 125.7,
125.1, 108.8, 34.6, 26.9, 19.8; elemental analysis: calcd. (%)
for C14H15NO (213.28): C 78.84, H 7.09; found: C 79.08, H
7.17.
acetylpyrrole (0.247 g, 2 mmol), 15 was obtained as a yellow
oil; yield: 0.145 g (58%). H NMR (400 MHz, CDCl3): d=
1
78.92 (s, 1H), 8.11–8.07 (m, 2H), 7.79 (d, J=8.1 Hz, 1H),
7.69 (t, J=7.4 Hz, 1H), 7.54 (t, J=7.4 Hz, 1H), 7.36 (d, J=
1.4 Hz, 1H), 6.74 (d, J=1.4 Hz, 1H), 3.69 (s, 3H), 2.39 (s,
3H); 13C NMR (100 MHz, CDCl3): d=193.2, 150.3, 147.0,
134.9, 132.5, 129.9, 129.3, 129.1, 127.9, 127.4, 125.7, 125.3,
110.5, 35.8, 27.1; elemental analysis: calcd. (%) for
C16H14N2O (250.30): C 76.78, H 5.64; found: C 76.62, H 5.40.
1-[1-Methyl-5-(3-nitrophenyl)pyrrol-3-yl]ethanone (16a):
From 1-bromo-3-nitrobenzene (0.202 g, 1 mmol) and 1-
methyl-3-acetylpyrrole (0.247 g, 2 mmol), 16a was obtained
as a yellow solid; yield: 0.081 g (33%); mp 208–2108C.
1H NMR (400 MHz, CDCl3): d=8.19 (s, 1H), 8.14 (d, J=
9.0 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.54 (t, J=7.9 Hz,
1H), 7.32 (d, J=1.2 Hz, 1H), 6.67 (d, J=1.2 Hz, 1H), 3.66
(s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
193.1, 148.4, 134.4, 133.6, 133.4, 129.7, 129.3, 125.5, 123.1,
122.4, 110.4, 35.8, 27.1; elemental analysis: calcd (%) for
C13H12N2O3 (244.25): C 63.93, H 4.95; found: C 63.68, H
4.99.
1-[5-(2-Hydroxymethylphenyl)-1-methylpyrrol-3-yl]etha-
none (11): From (2-bromophenyl)-methanol (0.187 g,
1 mmol) and 1-methyl-3-acetylpyrrole (0.247 g, 2 mmol), 11
1
was obtained as a yellow oil; yield: 0.158 g (69%). H NMR
(400 MHz, CDCl3): d=7.51 (d, J=7.6 Hz, 1H), 7.37 (t, J=
7.5 Hz, 1H), 7.31–7.24 (m, 2H), 7.15 (d, J=7.4 Hz, 1H),
6.46 (d, J=1.7 Hz, 1H), 4.46 (s, 2H), 3.35 (s, 3H), 2.33 (s,
3H); 13C NMR (100 MHz, CDCl3): d=193.5, 140.9, 133.4,
131.2, 130.4, 129.2, 128.3, 127.5, 127.4, 125.1, 109.4, 63.0,
34.9, 27.0; elemental analysis: calcd. (%) for C14H15NO2
(229.27): C 73.34, H 6.59; found: C 73.45, H 6.69.
1-(5-Isoquinolin-4-yl-1-methylpyrrol-3-yl)ethanone (12):
From 4-bromoisoquinoline (0.208 g, 1 mmol) and 1-methyl-
3-acetylpyrrole (0.247 g, 2 mmol), 12 was obtained as
a brown oil; yield: 0.202 g (81%). 1H NMR (400 MHz,
CDCl3): d=9.23 (bs, 1H), 8.42 (bs, 1H), 7.98 (d, J=8.0 Hz,
1H), 7.70–7.50 (m, 3H), 7.41 (s, 1H), 6.67 (s, 1H), 3.37 (s,
3H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3): d=193.2,
153.0, 144.3, 135.3, 131.1, 130.1, 128.1 (m), 127.9, 127.5,
125.4, 124.5, 123.2, 111.4, 35.1, 27.0; elemental analysis:
calcd. (%) for C16H14N2O (250.30): C 76.78, H 5.64; found:
C 76.89, H 5.51.
Compound 14b was also isolated: 1H NMR (400 MHz,
CDCl3): d=8.21 (d, J=9.0 Hz, 1H), 8.15 (s, 1H), 7.64 (d,
J=7.7 Hz, 1H), 7.55 (t, J=7.9 Hz, 1H), 6.63 (d, J=2.8 Hz,
1H), 6.59 (d, J=2.8 Hz, 1H), 3.40 (s, 3H), 2.23 (s, 3H).
Compound 14c was also isolated: 1H NMR (400 MHz,
CDCl3): d=8.30–8.20 (m, 4H), 7.80–7.65 (m, 2H), 7.64–7.58
(m, 2H), 6.75 (s, 1H), 3.38 (s, 3H), 2.27 (s, 3H).
2-(4-Acetyl-1-ethylpyrrol-2-yl)-benzonitrile (17): From 2-
bromobenzonitrile (0.182 g, 1 mmol) and 1-ethyl-3-acetyl-
pyrrole (0.275 g, 2 mmol), 17 was obtained as a yellow oil;
1
yield: 0.197 g (83%). H NMR (400 MHz, CDCl3): d=7.70
(d, J=7.6 Hz, 1H), 7.59 (t, J=7.4 Hz, 1H), 7.50–7.30 (m,
3H), 6.64 (s, 1H), 3.82 (q, J=7.3 Hz, 2H), 2.36 (s, 3H), 1.24
(t, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=193.3,
135.9, 133.4, 132.7, 131.4, 130.8, 128.7, 126.5, 125.7, 117.8,
113.6, 111.6, 42.4, 26.9, 16.2; elemental analysis: calcd. (%)
for C15H14N2O (238.28): C 75.61, H 5.92; found: C 75.43, H
5.99.
1-(5-Anthracen-9-yl-1-methylpyrrol-3-yl)ethanone
(13):
From 9-bromoanthracene (0.257 g, 1 mmol) and 1-methyl-3-
acetylpyrrole (0.247 g, 2 mmol), 13 was obtained as a brown
solid; yield: 0.218 g (73%); mp 140–1428C. 1H NMR
(300 MHz, CDCl3): d=8.58 (s, 1H), 8.07 (d, J=9.5 Hz, 2H),
7.69 (d, J=9.5 Hz, 2H), 7.60 (s, 1H), 7.53 (t, J=7.2 Hz,
2H), 7.45 (t, J=7.2 Hz, 2H), 6.82 (s, 1H), 3.23 (s, 3H), 2.54
(s, 3H); 13C NMR (75 MHz, CDCl3): d=193.5, 132.1, 131.3,
131.1, 128.6, 128.4, 127.3, 126.4, 126.0, 125.9, 125.5, 125.4,
111.9, 34.7, 27.2; elemental analysis: calcd. (%) for
C21H17NO (299.37): C 84.25, H 5.72; found: C 84.35, H 5.60.
1-[1-Methyl-5-(2-methylnaphthalen-1-yl)-pyrrol-3-yl]etha-
none (14): From 1-bromo-2-methylnaphthalene (0.221 g,
1 mmol) and 1-methyl-3-acetylpyrrole (0.247 g, 2 mmol), 14
2-(4-Acetyl-1-ethylpyrrol-2-yl)benzaldehyde (18): From 2-
bromobenzaldehyde (0.185 g, 1 mmol) and 1-ethyl-3-acetyl-
pyrrole (0.275 g, 2 mmol), 18 was obtained as a brown oil;
yield: in 0.193 g (80%). 1H NMR (400 MHz, CDCl3): d=
9.88 (s, 1H), 8.01 (d, J=7.7 Hz, 1H), 7.65 (t, J=7.4 Hz,
1H), 7.54 (t, J=7.4 Hz, 1H), 7.46 (s, 1H), 7.39 (d, J=
7.5 Hz, 1H), 6.59 (s, 1H), 3.78 (q, J=7.3 Hz, 2H), 2.41 (s,
3H), 1.23 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=193.3, 191.6, 135.3, 135.1, 133.7, 131.8, 130.0, 129.1, 127.9,
126.1, 125.5, 112.2, 42.5, 27.1, 16.3; elemental analysis: calcd.
(%) for C15H15NO2 (241.29): C 74.67, H 6.27; found: C
74.49, H 6.20.
1-[1-Ethyl-5-(2-trifluoromethylphenyl)pyrrol-3-yl]etha-
none (19): From 1-bromo-2-trifluoromethylbenzene (0.225 g,
1 mmol) and 1-ethyl-3-acetylpyrrole (0.275 g, 2 mmol), 19
1
was obtained as a yellow oil; yield: 0.200 g (76%). H NMR
(400 MHz, CDCl3): d=7.76 (d, J=8.6 Hz, 2H), 7.39 (d, J=
1.7 Hz, 1H), 7.38–7.26 (m, 4H), 6.52 (d, J=1.7 Hz, 1H),
3.17 (s, 3H), 2.39 (s, 3H), 2.20 (s, 3H); 13C NMR (100 MHz,
1
was obtained as a brown oil; yield: 0.230 g (82%). H NMR
(400 MHz, CDCl3): d=7.72 (d, J=7.6 Hz, 1H), 7.53 (t, J=
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Yijing Xu et al.
UPDATE
7.6 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.34 (s, 1H), 7.29 (d,
J=7.6 Hz, 1H), 6.48 (s, 1H), 3.62 (q, J=7.3 Hz, 2H), 2.36
(s, 3H), 1.19 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=193.5, 133.3, 131.3, 130.8 (q, J=29.4 Hz), 130.7,
130.5, 128.9, 126.3 (q, J=5.6 Hz), 125.2, 124.9, 123.6 (q, J=
273.0 Hz), 110.6, 42.3, 26.7, 15.5; elemental analysis: calcd.
(%) for C15H14F3NO (281.27): C 64.05, H 5.02; found: C
64.18, H 5.00.
1H), 7.50 (d, J=8.2 Hz, 2H), 7.48–7.40 (m, 4H), 6.68 (s,
1H), 3.04 (s, 3H), 2.26 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=193.5, 137.3, 135.6, 133.8, 133.7, 133.0, 132.0,
131.7, 129.6, 129.4, 129.2, 128.6, 127.0, 126.3, 125.4, 125.3,
123.0, 118.6, 112.3, 112.0, 32.8, 28.7; elemental analysis:
calcd. (%) for C24H18N2O (350.41): C 82.26, H 5.18; found:
C 82.06, H 5.47.
1-[1-Methyl-5-naphthalen-1-yl-2-(4-nitrophenyl)pyrrol-3-
yl]ethanone (25): From 1-bromo-4-nitrobenzene (0.202 g,
1 mmol) and 1-(1-methyl-5-naphthalen-1-ylpyrrol-3-yl)-etha-
none 9 (0.373 g, 1.5 mmol), 25 was obtained as a yellow
solid; yield: 0.281 g (76%); mp 182–1848C. 1H NMR
(400 MHz, CDCl3): d=8.23 (d, J=8.8 Hz, 2H), 7.90–7.80
(m, 2H), 7.65–7.60 (m, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.50–
7.40 (m, 4H), 6.67 (s, 1H), 3.01 (s, 3H), 2.28 (s, 3H);
13C NMR (100 MHz, CDCl3): d=193.6, 147.7, 139.2, 135.2,
135.1, 134.0, 133.7, 133.0, 131.9, 129.4, 129.3, 128.6, 127.0,
126.3, 125.4, 125.3, 123.4, 123.1, 112.1, 32.7, 28.7; elemental
analysis: calcd. (%) for C23H18N2O3 (370.40): C 74.58, H
4.90; found: C 74.38, H 4.99.
1-[1-Ethyl-5-(2-fluorophenyl)pyrrol-3-yl]ethanone
(20):
From 1-bromo-2-fluorobenzene (0.175 g, 1 mmol) and 1-
ethyl-3-acetylpyrrole (0.275 g, 2 mmol), 20 was obtained as
a brown oil; yield: 0.171 g (74%). 1H NMR (400 MHz,
CDCl3): d=7.38 (d, J=1.1 Hz, 1H), 7.32 (dd, J=12.9,
5.8 Hz, 1H), 7.26 (t, J=7.4 Hz, 1H), 7.14 (t, J=7.5 Hz, 1H),
7.08 (t, J=7.5 Hz, 1H), 6.53 (s, 1H), 3.79 (q, J=7.3 Hz,
2H), 2.36 (s, 3H), 1.25 (t, J=7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=193.7, 160.4 (d, J=247.2 Hz), 132.7
(d, J=3.0 Hz), 130.6 (d, J=8.1 Hz), 129.5, 126.1, 125.9, 124.6
(d, J=3.7 Hz), 120.4 (d, J=5.4 Hz), 116.1 (d, J=22.0 Hz),
110.8, 42.9, 27.3, 16.4; elemental analysis: calcd (%) for
C14H14FNO (231.27): C 72.71, H 6.10; found: C 72.47, H
6.24.
1-[2-(4-Methoxyphenyl)-1-methyl-5-naphthalen-1-ylpyr-
rol-3-yl]ethanone (26): From 4-bromoanisole (0.187 g,
1 mmol) and 1-(1-methyl-5-naphthalen-1-ylpyrrol-3-yl)-etha-
none 9 (0.373 g, 1.5 mmol), 26 was obtained as a brown oil;
1-(1-Ethyl-5-naphthalen-1-ylpyrrol-3-yl)ethanone
(21):
From 1-bromonaphthalene (0.207 g, 1 mmol) and 1-ethyl-3-
1
acetylpyrrole (0.275 g, 2 mmol), 21 was obtained as a brown
yield: 0.277 g (78%). H NMR (400 MHz, CDCl3): d=7.98–
1
oil; yield: 0.200 g (76%). H NMR (400 MHz, CDCl3): d=
7.78 (m, 2H), 7.85–7.75 (m, 1H), 7.60–7.50 (m, 4H), 7.44 (d,
J=8.2 Hz, 2H), 7.06 (d, J=8.2 Hz, 2H), 6.84 (s, 1H), 3.90
(s, 3H), 3.13 (s, 3H), 2.20 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=194.1, 160.2, 138.6, 133.7, 133.1, 132.6, 132.0,
130.3, 129.1, 129.0, 128.4, 126.7, 126.1, 125.8, 125.3, 124.7,
123.4, 114.0, 111.0, 55.2, 32.5, 28.8; elemental analysis: calcd.
(%) for C24H21NO2 (355.43): C 81.10, H 5.96; found: C
81.19, H 6.08.
7.85–7.75 (m, 2H), 7.54 (d, J=8.5 Hz, 1H), 7.50–7.30 (m,
5H), 6.57 (d, J=1.5 Hz, 1H), 3.58 (bs, 2H), 3.41 (s, 3H),
1.08 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d
193.6, 133.6, 133.2, 133.1, 129.8, 129.1, 129.0, 128.3, 126.7,
126.2, 125.7, 125.5, 125.3, 125.2, 110.5, 42.6, 27.1, 16.5; ele-
mental analysis: calcd. (%) for C18H17NO (263.33): C 82.10,
H 6.51; found: C 82.07, H 6.68.
1-(1-Ethyl-5-isoquinolin-4-ylpyrrol-3-yl)ethanone
From 4-bromoisoquinoline (0.208 g, 1 mmol) and 1-ethyl-3-
(22):
1-[2-(3-Acetylphenyl)-1-methyl-5-naphthalen-1-ylpyrrol-3-
yl]ethanone (27): From 3-bromoacetophenone (0.199 g,
1 mmol) and 1-(1-methyl-5-naphthalen-1-ylpyrrol-3-yl)etha-
none 9 (0.373 g, 1.5 mmol), 27 was obtained as a yellow oil;
acetylpyrrole (0.275 g, 2 mmol), 22 was obtained as a brown
1
oil; yield: 0.209 g (79%). H NMR (400 MHz, CDCl3): d=
1
9.27 (bs, 1H), 8.46 (bs, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.70–
7.55 (m, 3H), 7.52 (s, 1H), 6.68 (s, 1H), 3.69 (q, J=7.3 Hz,
2H), 2.43 (s, 3H), 1.17 (t, J=7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=193.6, 153.4, 144.8, 135.9, 131.4,
129.6, 128.5, 128.2, 127.9, 126.3, 126.0, 124.8, 123.7, 111.8,
42.9, 27.3, 16.7; elemental analysis: calcd. (%) for
C17H16N2O (264.32): C 77.25, H 6.10; found: C 77.29, H 6.34.
yield: 0.275 g (75%). H NMR (400 MHz, CDCl3): d=8.08
(s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.95–7.90 (m, 2H), 7.76–
7.67 (m, 2H), 7.65–7.50 (m, 5H), 6.78 (s, 1H), 3.11 (s, 3H),
2.65 (s, 3H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
197.5, 193.7, 137.3, 136.9, 135.5, 133.7, 133.2, 133.1, 133.0,
130.5, 129.9, 129.2, 129.1, 128.7, 128.6, 128.5, 126.9, 126.2,
125.6, 125.3, 123.0, 111.5, 32.7, 28.8, 26.6; elemental analysis:
calcd. (%) for C25H21NO2 (367.44): C 81.72, H 5.76; found:
C 81.89, H 5.89.
1-(5-Anthracen-9-yl-1-ethylpyrrol-3-yl)ethanone
(23):
From 9-bromoanthracene (0.257 g, 1 mmol) and 1-ethyl-3-
acetylpyrrole (0.275 g, 2 mmol), 23 was obtained as a white
solid; yield: 0.216 g (69%); mp 116–1188C. 1H NMR
(400 MHz, CDCl3): d=8.48 (s, 1H), 7.98 (d, J=8.5 Hz, 2H),
7.64 (d, J=8.5 Hz, 2H), 7.60 (s, 1H), 7.41 (t, J=7.2 Hz,
2H), 7.35 (t, J=7.2 Hz, 2H), 6.68 (s, 1H), 3.41 (q, J=
7.3 Hz, 2H), 2.44 (s, 3H), 0.97 (t, J=7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=193.6, 132.2, 131.3, 130.5, 128.5,
128.4, 126.4, 126.1, 126.0, 125.7, 125.4, 125.3, 111.9, 42.1,
26.7, 16.4; elemental analysis: calcd. (%) for C22H19NO
(313.39): C 84.31, H 6.11; found: C 84.50, H 6.28.
1-(1-Methyl-5-naphthalen-1-yl-2-pyridin-3-ylpyrrol-3-yl)e-
thanone (28): From 3-bromopyridine (0.158 g, 1 mmol) and
1-(1-methyl-5-naphthalen-1-ylpyrrol-3-yl)-ethanone
9
(0.373 g, 1.5 mmol), 28 was obtained as a yellow oil; yield:
0.261 g (80%). 1H NMR (400 MHz, CDCl3): d=8.80–8.60
(m, 2H), 7.93 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H),
7.85 (d, J=8.0 Hz, 1H), 7.74–7.68 (m, 1H), 7.58–7.50 (m,
4H), 7.45–7.40 (m, 1H), 6.78 (s, 1H), 3.13 (s, 3H), 2.30 (s,
3H); 13C NMR (100 MHz, CDCl3): d=193.6, 170.5, 150.9,
149.5, 138.4, 134.1, 133.5, 133.4, 132.9, 129.5, 129.1, 128.5,
128.4, 126.8, 126.1, 125.4, 125.2, 123.3, 123.0, 111.7, 32.8,
28.7; elemental analysis: calcd. (%) for C22H18N2O (326.39):
C 80.96, H 5.56; found: C 81.09, H 5.41.
4-(3-Acetyl-1-methyl-5-naphthalen-1-ylpyrrol-2-yl)benzo-
nitrile (24): From 4-bromobenzonitrile (0.182 g, 1 mmol)
and 1-(1-methyl-5-naphthalen-1-ylpyrrol-3-yl)-ethanone
9
(0.373 g, 1.5 mmol), 24 was obtained as a yellow solid; yield:
0.280 g (80%); mp 206–2088C. H NMR (400 MHz, CDCl3):
d=7.88–7.78 (m, 2H), 7.69 (d, J=8.2 Hz, 2H), 7.65–7.60 (m,
Ethyl 4-(3-acetyl-5-isoquinolin-4-yl-1-methylpyrrol-2-yl)-
benzoate (29): From ethyl 4-bromobenzoate (0.229 g,
1 mmol) and 1-(5-isoquinolin-4-yl-1-methylpyrrol-3-yl)etha-
1
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Palladium-Catalysed Regioselective Sequential C-5 and C-2 Direct Arylations of 3-Acetylpyrroles
none 12 (0.357 g, 1.5 mmol), 29 was obtained as a yellow
solid; yield: 0.270 g (68%); mp 90–928C. 1H NMR
(400 MHz, CDCl3): d=9.24 (bs, 1H), 8.50 (bs, 1H), 8.10 (d,
J=8.2 Hz, 2H), 7.99 (d, J=8.0 Hz, 1H), 7.75–7.55 (m, 3H),
7.49 (d, J=8.2 Hz, 2H), 6.77 (s, 1H), 4.33 (q, J=7.1 Hz,
2H), 3.08 (s, 3H), 2.15 (s, 3H), 1.33 (t, J=7.3 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=193.6, 166.0, 153.2, 144.6,
137.8, 136.8, 135.4, 131.4, 130.8, 129.6, 128.3, 128.1, 127.7,
124.6, 123.6, 123.5, 112.6, 61.2, 33.1, 28.9, 14.3; elemental
analysis: calcd. (%) for C25H22N2O3 (398.45): C 75.36, H
5.57; found: C 75.09, H 5.41.
1-[2-(4-Fluorophenyl)-5-isoquinolin-4-yl-1-methylpyrrol-3-
yl]ethanone (30): From 1-bromo-4-fluorobenzene (0.175 g,
1 mmol) and 1-(5-isoquinolin-4-yl-1-methylpyrrol-3-yl)-etha-
none 12 (0.357 g, 1.5 mmol), 30 was obtained as a yellow
solid; yield: 0.289 g (84%); mp 150–1528C. 1H NMR
(400 MHz, CDCl3): d=9.23 (bs, 1H), 8.48 (bs, 1H), 7.98 (d,
J=8.0 Hz, 1H), 7.75–7.50 (m, 3H), 7.45–7.35 (m, 2H), 7.25–
7.10 (m, 2H), 6.76 (s, 1H), 3.06 (s, 3H), 2.12 (s, 3H);
13C NMR (100 MHz, CDCl3): d=193.6, 162.9 (d, J=
248.8 Hz), 153.0, 144.5, 137.9, 135.4, 132.5 (d, J=8.0 Hz),
131.2, 129.1, 128.2, 128.1 (d, J=3.2 Hz), 128.0, 127.6, 124.5,
123.7, 123.4, 115.6 (d, J=22.3 Hz), 112.2, 32.8, 28.8; elemen-
tal analysis: calcd. (%) for C22H17FN2O (344.38): C 76.73, H
4.98; found: C 76.60, H 4.76.
3-(3-Acetyl-5-isoquinolin-4-yl-1-methylpyrrol-2-yl)benzal-
dehyde (31): From 3-bromobenzaldehyde (0.185 g, 1 mmol)
and 1-(5-isoquinolin-4-yl-1-methylpyrrol-3-yl)ethanone 12
(0.357 g, 1.5 mmol), 31 was obtained as a brown oil; yield:
0.258 g (73%). 1H NMR (400 MHz, CDCl3): d=10.09 (s,
1H), 9.37 (bs, 1H), 8.62 (bs, 1H), 8.10 (d, J=8.2 Hz, 1H),
8.00–7.95 (m, 2H), 7.85–7.65 (m, 5H), 6.84 (s, 1H), 3.16 (s,
3H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3): d=196,
191.8, 153.3, 144.7, 137.2, 136.8, 136.5, 135.6, 131.6, 131.4,
130.1, 129.6, 129.2, 128.4, 128.2, 127.8, 124.6, 123.7, 123.3,
112.7, 33.0, 28.8; elemental analysis: calcd. (%) for
C23H18N2O2 (354.40): C 77.95, H 5.12; found: C 77.78, H
5.31.
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Acknowledgements
We are grateful to the “Chinese Scholarship Council” for
a grant to Z. L. and to the “Jinan University short-term over-
seas research program” for a grant to X. Y. We thank CNRS
and “Rennes Metropole” for providing financial support.
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UPDATE
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Palladium-Catalysed Regioselective Sequential C-5 and C-2
Direct Arylations of 3-Acetylpyrroles with Aryl Bromides
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Adv. Synth. Catal. 2013, 355, 1 – 11
Yijing Xu, Liqin Zhao, Yiqun Li,* Henri Doucet*
Adv. Synth. Catal. 0000, 000, 0 – 0
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