Reactivity of 3-(pyrrol-1-yl)thiophenes in Pd-catalysed direct arylations

Article abstract of DOI:10.1016/j.tet.2015.03.022

Abstract The regioselectivity of the Pd-catalysed direct arylation of 3-(pyrrol-1-yl)thiophene derivatives was investigated. Conditions allowing either the regioselective arylation at C2 or at C5 of the thiophene ring are reported. From methyl 3-(pyrrol-1

Full text of DOI:10.1016/j.tet.2015.03.022

Tetrahedron xxx (2015) 1e8
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Tetrahedron
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Reactivity of 3-(pyrrol-1-yl)thiophenes in Pd-catalysed direct
arylations
Imen Smari a , Chiraz Youssef , Hamed Ben Ammar *, Bechir Ben Hassine b,
,
b
b
b,
a
a,
*
Jean-Fran c¸ ois Soul eꢀ , Henri Doucet
Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Universit ꢀe de Rennes, Organom ꢀe talliques: Mat ꢀe riaux et Catalyse, Campus de Beaulieu,
a
3
5042 Rennes, France
b
Laboratoire de Synth ꢁe se Organique Asym ꢀe trique et Catalyse Homog ꢁe ne, (UR 11ES56) Universit ꢀe de Monastir, Facult ꢀe des Sciences de Monastir,
Avenue de l’environnement, Monastir 5000, Tunisia
a r t i c l e i n f o
a b s t r a c t
Article history:
The regioselectivity of the Pd-catalysed direct arylation of 3-(pyrrol-1-yl)thiophene derivatives was in-
vestigated. Conditions allowing either the regioselective arylation at C2 or at C5 of the thiophene ring are
reported. From methyl 3-(pyrrol-1-yl)thiophene-2-carboxylate using KOAc as the base, DMA as the
solvent and only 1 mol % Pd(OAc) catalyst, the target 5-arylated thiophenes were obtained in moderate
2
to good yields with a wide variety of aryl halides; whereas the use of 1-(4-methylthiophen-3-yl)-pyrrole
affords the C2-arylated thiophenes. The sequential palladium catalysed 2,5-diheteroarylation of such 3-
Received 26 January 2015
Received in revised form 26 February 2015
Accepted 5 March 2015
Available online xxx
Keywords:
Palladium
Catalysis
CeH bond activation
Thiophenes pyrroles
Direct arylation
Aryl halides
(
pyrrol-1-yl)thiophene is also reported allowing the access to thiophenes bearing two different aryl units
at C2 and C5. A pyrazole bearing an ester substituent at C4 and a pyrrole substituent at C5 was only
arylated at C2 on the pyrrole ring.
Ó 2015 Published by Elsevier Ltd.
1. Introduction
properties, the discovery of simple accesses to a variety of thio-
phene or pyrrole derivatives remains an important challenge for
Both thiophene and pyrrole derivatives represent important
structures due to their biological and/or physical properties. For
organic chemists.
As early as in 1985e1992, Ohta et al. reported the direct aryla-
tion of heteroaromatics with aryl halides via a CeH bond activation
1a
example, Motapizone is used against platelet aggregation, Savi-
prazole1b is a gastric proton pump inhibitor and Tiflucarbine
displays antidepressant properties (Fig. 1). Due to these
1c
2
using Pd(PPh
3
)
4
catalyst. Since these results, the Pd-catalysed di-
rect arylation of several heteroaryls using aryl halides as the cou-
pling partners has proved to be a very powerful method for
a simpler and greener access to a wide variety of arylated hetero-
3
,4
cycles. This method is very attractive as it avoids the preparation
of an organometallic derivative and as the major by-products of the
5
reaction are a base associated to HX, instead of metallic salts.
The direct arylation of a variety of thiophene and pyrrole de-
6
,7
rivatives has been reported in recent years.
However, to our
knowledge, the reactivity of a thiophene substituted by a pyrrole
unit at C3 and also of a 5-pyrrolylpyrazole for Pd-catalysed direct
arylations has not been described. Therefore, the reactivity for di-
rect arylation of such substrates needed to be investigated.
Here, we wish to report (i) conditions allowing a regioselective
arylation of a 3-(pyrrol-1-yl)thiophene derivative, (ii) a one pot
procedure with arylation at C5 of the thiophene derivative followed
by decarboxylation at C2 and (iii) the sequential arylation to pre-
pare 2,5-diarylated thiophenes with two different aryl units.
Fig. 1. Examples of bioactive thiophene derivatives.
*
Corresponding authors. Tel.: þ33 2 23 23 63 84; fax: þ33 2 23 23 69 39 (H.D.);
tel.: þ216 73 500 275; fax: þ216 73 500 278 (H.B.); e-mail address: henri.doucet@
univ-rennes1.fr (H. Doucet).
http://dx.doi.org/10.1016/j.tet.2015.03.022
0
040-4020/Ó 2015 Published by Elsevier Ltd.
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2
I. Smari et al. / Tetrahedron xxx (2015) 1e8
2
. Results and discussion
Based on previous results, for this study DMA was initially
8
chosen as the solvent and KOAc as the base. The reactions were
performed at 130e150 C under argon in the presence of Pd(OAc)
ꢀ
2
3 5 2
or PdCl(C H )(dppb) catalysts. First, using only 1 mol % Pd(OAc) ,
the reaction of 1 equiv of 3-bromonitrobenzene with 1.5 equiv of
methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate as the
ꢀ
coupling partners at 150 C during 17 h affords selectively the in
situ decarboxylated C5-arylation product 1b in 78% yield (Table 1,
entry 1). On the other hand, the reaction performed under the same
reaction conditions, but after only 2 h affords a mixture of 1a and 1b
in a 83:17 ratio (Table 1, entry 2).
Table 1
Influence of the reaction conditions for the palladium catalysed direct arylation
using
methyl
4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
and
3-
bromonitrobenzene as the coupling partners (Scheme 1)
Entry Catalyst (mol %) Base
Time Temp Ratio 1a:1b:1c Yield in
ꢀ
(h)
( C)
1a or 1b (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
2
2
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
KOAc
KOAc
KOAc
CsOAc 17
CsOAc
NaOAc 17
17
2
2
150
150
130
150
130
150
130
150
150
0:100:0
83:17:0
93:7:0
49:51:0
94:6:0
23:77:0
69:31:0
0:100:0
14:86:0
76 of 1b
d
78 of 1a
d
2
78 of 1a
d
NaOAc
Cs CO
KOAc
2
17
17
d
2
3
77 of 1b
70 of 1b
3 5
PdCl(C H )
(
dppb) (2)
Conditions: 3-bromonitrobenzene (1 equiv), 4-methyl-3-(pyrrol-1-yl)thiophene-2-
carboxylate (1.5 equiv), base (2 equiv), DMA, isolated yields, complete conversion of
3-bromonitrobenzene was observed in all cases.
It should be noted that in both cases no arylation at the pyrrole
ring to afford 1c was observed by GC/MS analysis of the crude
mixture. A lower temperature led to an increase in the selectivity
ꢀ
for 1a, as at 130 C ratio 1a:1b was 93:7 and 1a was isolated in 78%
yield (Table 1, entry 3). Then, we examined the influence of the
nature of the base for this reaction. The use of CsOAc instead of
ꢀ
KOAc at 150 C afforded lower amounts of decarboxylated product
1
Scheme 2. Scope of the C5-arylation of methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-
carboxylate.
ꢀ
b, and at 130 C a 94:6 ratio (1a:1b) was obtained, with 78% iso-
lated yield of 1a (Table 1, entries 4 and 5). NaOAc led to mixtures of
products 1a and 1b, whereas Cs CO afforded exclusively 1b (Table
2
3
8
b
1
, entries 6e8). The use of 2 mol % PdCl(C
3
H
5
) (dppb) catalyst
the non-decarboxylated products (Scheme 2). The reaction with the
para-substituted aryl bromides, 4-bromobenzonitrile, 4-
bromopropiophenone or 4-bromoanisole proceeds very smoothly
to afford the target products 2e5 in 75e83% yields. Meta-
substituted 3-bromoacetophenone and also 4-bromo-1-nitro-2-
(trifluoromethyl)benzene also react nicely to give 6 and 7 in 79%
instead of 1 mol % Pd(OAc)
lower yield (Table 1, entry 9).
2
, also affords 1b although in slightly
Then, using the most effective reaction conditions for coupling
ꢀ
with and without decarboxylation (DMA, KOAc, Pd(OAc)
2
, 130 C
ꢀ
2
h or 150 C 17 h), we explored the scope of this reaction using
a variety of aryl bromides as the coupling partner (Schemes 2
and 3).
and
60%
yields,
respectively.
3-Bromopyridine,
5-
bromonicotinonitrile and 5-bromopyrimidine were also success-
fully coupled with methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-
carboxylate, without decarboxylation, to afford 8e10 in 58e79%
yields.
First, we investigated the reaction of methyl 4-methyl-3-(pyr-
rol-1-yl)thiophene-2-carboxylate using 1 mol % Pd(OAc)
with a set of aryl bromides at 130 C during 2 h in order to obtain
2
catalyst
ꢀ
Scheme 1. Regioselectivity of the palladium catalysed direct arylation using methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate and 3-bromonitrobenzene as the coupling
partners.
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I. Smari et al. / Tetrahedron xxx (2015) 1e8
3
of the 5-arylated thiophene 20a and 2-arylated pyrrole 20b in
a 31:35 ratio was observed under the same reaction conditions
(Scheme 4).
Scheme 4. Regioselectivity of the arylation of methyl 3-(pyrrol-1-yl)thiophene-2-
carboxylate.
The regioselectivity of the arylation of 1-(4-methylthiophen-
3
4
-yl)-pyrrole was also investigated (Scheme 5). In the presence of
-bromobenzonitrile and 1 mol % Pd(OAc) catalyst, the regio-
2
specific formation of the C2-arylated product 21 was observed,
which indicates that the most reactive position of 3-
a
pyrrolylthiophene is the carbon C2 of the thienyl ring. There-
fore, this result confirms that an ester substituent at C2 on the
thienyl ring acts as a blocking group, allowing for selective ary-
lation at C5 position. A similar regioselectivity trend for direct
arylations
aminothiophene derivatives.
had
been
previously
observed
using
3-
9
Scheme 3. Scope of the C5-arylation of methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-
carboxylate with in-situ decarboxylation.
Scheme 5. Regioselectivity of the arylation of 1-(4-methylthiophen-3-yl)-pyrrole.
The scope of the C5-arylation with in situ decarboxylation was
also studied (Scheme 3). From 4-cyano-, 4-propionyl- and 4-
chlorobromobenzene, after 17 h at 150 C, the decarboxylated C5-
The reactivity of the arylated thiophene derivatives 12 and 17
for C5 arylation was then evaluated (Scheme 6). Such arylations
would allow the preparation of non-symmetrically 2,5-diarylated
thiophene derivatives. From 17 and bromobenzene the desired
product 22 was obtained in 56% yield. 12 reacted with 5-
bromopyridine also affords the desired 2,5-diarylated thiophene
ꢀ
arylated thiophenes 11e13 were obtained in good yields. On the
other hand, no formation of the desired decarboxylated product 14
was observed in the presence of the electron-rich 4-bromoanisole
as only product 5 was formed (68%). The decarboxylation step
appears to be favoured by the presence of electron-withdrawing
substituents on the arene. In the presence of 2-bromobenzonitrile
and 4-bromo-1-nitro-2-(trifluoromethyl)benzene, 15 and 16 were
obtained in 79% and 70% yields, respectively. Then, three hetero-
arenes were employed. 3-Bromopyridine, 5-bromonicotinonitrile
and 5-bromopyrimidine also afforded the desired decarboxylated
products 17e19 in good yields.
The selectivity of the arylation of 3-(pyrrol-1-yl)thiophene de-
rivatives appears to be very sensitive to the steric hindrance of the
pyrrolyl moiety. The presence of a substituent at C4 on the thienyl
ring seems to be crucial to control the selectivity. Indeed, in the
presence of methyl 3-(pyrrol-1-yl)thiophene-2-carboxylate and 4-
bromobenzonitrile as coupling partner, the formation of a mixture
23 in good yield.
The reactivity of 2-(pyrrol-1-yl)thiophene-3-carbonitrile in the
presence of 3-bromonitrobenzene was also investigated (Scheme
). A permutation of the electron-withdrawing (pyrrolyl) and
7
electron-donating (ester or cyano) substituents on the thiophene
was found to drastically modify the reactivity. In the presence of
1
2
2
2
mol % Pd(OAc) catalyst and KOAc as base, the expected product
4a was obtained in a very low yield and the C2-arylated pyrrole
4b was not observed.
We also explored the reactivity of a pyrazole bearing a pyrrole
substituent at C5 and an ester at C4 (Scheme 8). As the position C3
of pyrazoles derivatives generally exhibits a poor reactivity, the
formation of product 25b was expected. Indeed, 4-
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4
I. Smari et al. / Tetrahedron xxx (2015) 1e8
Scheme 6. C5-arylation of 2-aryl-3-methyl-4-(pyrrol-1-yl)thiophenes.
Scheme 8. Arylation of ethyl 1-methyl-5-(pyrrol-1-yl)-pyrazole-4-carboxylate.
4
4
. Experimental section
.1. General remarks
Scheme 7. Reactivity of 2-(pyrrol-1-yl)thiophene-3-carbonitrile.
All reactions were run under argon in Schlenk tubes using
bromobenzonitrile and this 5-(pyrrol-1-yl)-pyrazole in the pres-
vacuum lines. DMA analytical grade was not distilled before use.
KOAc (99%) was used. Commercial heteroarenes and aryl bro-
mides were used without purification. The reactions were fol-
ꢀ
ence of 1 mol % Pd(OAc)
2
and KOAc in DMA at 130 C, 2 or 17 h
affords the C2-arylated pyrrole 25b in 42% yield. No formation of
5a was observed. A similar regioselectivity was observed in the
presence of 4-bromonitrobenzene, 4-bromobenzaldehyde, 4-
bromo-1-nitro-2-(trifluoromethyl)benzene and 5-
1
13
2
lowed by GC and NMR. H and C spectra were recorded with
a Bruker 400 MHz spectrometer in CDCl solutions. Chemical
shifts are reported in ppm relative to CDCl
3
1
3
(7.25 for H NMR and
13
bromopyrimidine as the coupling partners, and products 26e29
were obtained in 40e58% yields, respectively. The formation of
diarylation products in trace amounts was also observed by GC/MS
analysis of the crude mixtures.
77.0 for C NMR). Flash chromatography was performed on silica
gel (230e400 mesh).
4.2. General procedure
3
. Conclusion
In a typical experiment, the thiophene derivative (1.5 mmol),
aryl bromide (1 mmol), KOAc (0.196 g, 2 mmol) and Pd(OAc)
(2.24 mg, 0.01 mmol) or PdCl(C )(dppb) (12.1 mg, 0.02 mmol),
2
In conclusion, thiophenes bearing a pyrrole unit at C3 and
3 5
H
a methyl at C4 were found to react exclusively at the thienyl ring. We
were dissolved in DMA (5 mL) under an argon atmosphere. The
ꢀ
established that 1 mol % of air stable palladium Pd(OAc)
2
catalyst and
reaction mixture was stirred at 130 or 150 C for 2 or 17 h (see
ꢀ
ꢀ
KOAc as base at 130 C promotes 5-arylation of methyl 3-(pyrrol-1-
schemes). Then, the reaction was stirred at 30e40 C in vacuum
yl)thiophene-2-carboxylate without decarboxylation; whereas, at
(0.4 mbar) to remove the solvent, and the product was purified by
silica gel column chromatography.
ꢀ
150 C a C5 arylation followed by an in situ decarboxylation was
observed. On the other hand, 1-(4-methylthiophen-3-yl)-pyrrole
was selectively arylated at carbon C2 of the thienyl ring. From the
decarboxylated 5-arylated thiophenes, the direct arylation at C2
position of thiophene was also found to be possible, and affords 2,5-
diheteroarylated thiophenes bearing two different aryl units. A
pyrazole bearing an ester substituent at C4 and a pyrrole substituent
at C5 was only arylated at C2 on the pyrrole ring.
4.2.1. Preparation of the PdCl(C3H5)(dppb) catalyst.10 An oven-
dried 40 mL Schlenk tube equipped with a magnetic stirring bar
under argon atmosphere, was charged with [Pd(C H )Cl] (182 mg,
3 5 2
0.5 mmol) and dppb (426 mg, 1 mmol). 10 mL of anhydrous
dichloromethane were added, then, the solution was stirred at
room temperature for twenty minutes. The solvent was removed in
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I. Smari et al. / Tetrahedron xxx (2015) 1e8
5
vacuum. The yellow powder was used without purification. 31P
NMR (81 MHz, CDCl
¼19.3 (s).
1 mmol) at 130 C during 2 h product 3 was obtained in 82%
(0.291 g) yield.
ꢀ
3
)
d
1H NMR (400 MHz, CDCl
)
d
8.13 (d, J¼8.0 Hz, 2H), 7.58 (d,
3
4
.3. Methyl 4-methyl-5-(3-nitrophenyl)-3-(pyrrol-1-yl)thio-
J¼8.0 Hz, 2H), 6.75 (t, J¼2.0 Hz, 2H), 6.36 (t, J¼2.0 Hz, 2H), 3.95 (s,
phene-2-carboxylate (1a)
3H), 3.77 (s, 3H), 2.06 (s, 3H).
13
C NMR (100 MHz, CDCl
133.7, 130.1, 128.9, 127.2, 122.0, 109.3, 109.2, 52.3, 52.1, 12.8.
S (355.41): calcd C 64.21, H 4.82; Found C 64.02, H
3
) d 166.4, 160.7, 143.9, 141.7, 137.9,
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
(
0.318 g, 1.5 mmol) and 3-bromonitrobenzene (0.202 g, 1 mmol)
19 4
C H17NO
4.99.
ꢀ
at 130 C during 2 h product 1a was obtained in 78% (0.267 g) yield.
1
H NMR (400 MHz, CDCl
.82 (d, J¼8.0 Hz, 1H), 7.67 (t, J¼7.8 Hz, 1H), 6.76 (t, J¼2.0 Hz, 2H),
.37 (t, J¼2.0 Hz, 2H), 3.78 (s, 3H), 2.07 (s, 3H).
3
)
d
8.37 (s, 1H), 8.29 (d, J¼8.0 Hz, 1H),
7
6
4.8. Methyl 5-(4-methoxyphenyl)-4-methyl-3-(pyrrol-1-yl)
thiophene-2-carboxylate (5)
13
3
C NMR (100 MHz, CDCl ) d 160.5, 148.5, 143.8, 139.8, 135.1,
1
4
4
34.7, 134.2, 130.0, 125.2, 123.7, 123.3, 121.9, 109.3, 52.3, 12.8.
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
(0.318 g, 1.5 mmol) and 4-bromoanisole (0.187 g, 1 mmol) at
130 C during 2 h product 5 was obtained in 78% (0.255 g) yield.
C
17 14 2 4
H N O S (342.37): calcd C 59.64, H 4.12; Found C 59.41, H
ꢀ
.27.
1
H NMR (400 MHz, CDCl
3
)
d
7.43 (d, J¼8.0 Hz, 2H), 6.99 (d,
.4. 1-(4-Methyl-5-(3-nitrophenyl)thiophen-3-yl)-pyrrole
J¼8.0 Hz, 2H), 6.75 (t, J¼2.0 Hz, 2H), 6.35 (t, J¼2.0 Hz, 2H), 3.96 (s,
(
1b)
3H), 3.76 (s, 3H), 2.02 (s, 3H).
13
C NMR (100 MHz, CDCl
130.4, 126.0, 123.2, 122.1, 114.5, 109.1, 55.5, 52.2, 12.9.
S (327.40): calcd C 66.03, H 5.23; Found C 65.89, H
3
) d 161.2, 160.2, 144.0, 143.5, 132.3,
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
(
0.318 g, 1.5 mmol) and 3-bromonitrobenzene (0.202 g, 1 mmol)
18 3
C H17NO
ꢀ
at 150 C during 17 h product 1b was obtained in 76% (0.216 g)
5.07.
yield.
1H NMR (400 MHz, CDCl
)
d
8.37 (s, 1H), 8.25 (d, J¼8.0 Hz, 1H),
.83 (d, J¼8.0 Hz, 1H), 7.65 (t, J¼7.8 Hz, 1H), 7.26 (s, 1H), 6.88 (t,
J¼2.0 Hz, 2H), 6.36 (t, J¼2.0 Hz, 2H), 2.22 (s, 3H).
4.9. Methyl 5-(3-acetylphenyl)-4-methyl-3-(pyrrol-1-yl)thio-
phene-2-carboxylate (6)
3
7
13
C NMR (100 MHz, CDCl
3
)
d
148.5, 141.0, 136.3, 134.7, 135.7,
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
(0.318 g, 1.5 mmol) and 3-bromoacetophenone (0.199 g, 1 mmol)
1
4
4
30.8, 129.7, 123.7, 122.4, 121.9, 117.9, 109.3, 13.1.
ꢀ
C
15 12
H N
2
O
2
S (284.33): calcd C 63.36, H 4.25; Found C 63.50, H
at 130 C during 2 h product 6 was obtained in 79% (0.268 g) yield.
1
.37.
H NMR (400 MHz, CDCl
3
)
d
8.08 (s, 1H), 7.99 (d, J¼8.0 Hz, 1H),
7
.69 (d, J¼8.0 Hz, 1H), 7.58 (t, J¼7.6 Hz, 1H), 6.75 (t, J¼2.0 Hz, 2H),
.5. Methyl 5-(4-cyanophenyl)-4-methyl-3-(pyrrol-1-yl)thio-
phene-2-carboxylate (2)
6.35 (t, J¼2.0 Hz, 2H), 3.76 (s, 3H), 2.65 (s, 3H), 2.04 (s, 3H).
13
C NMR (100 MHz, CDCl
33.9, 133.4, 133.2, 129.2, 128.6, 128.4, 124.3, 121.9, 109.0, 52.1, 26.6,
12.6.
3
) d 197.2, 160.7, 143.7, 141.7, 137.6,
1
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
(
1
0.318 g, 1.5 mmol) and 4-bromobenzonitrile (0.182 g, 1 mmol) at
C
5.30.
19 3
H17NO S (339.41): calcd C 67.24, H 5.05; Found C 67.02, H
ꢀ
30 C during 2 h product 2 was obtained in 75% (0.241 g) yield.
1
H NMR (400 MHz, CDCl
J¼8.0 Hz, 2H), 6.74 (t, J¼2.0 Hz, 2H), 6.36 (t, J¼2.0 Hz, 2H), 3.78 (s,
H), 2.06 (s, 3H).
3
)
d
7.76 (d, J¼8.0 Hz, 2H), 7.61 (d,
4.10. Methyl 4-methyl-5-(4-nitro-3-(trifluoromethyl)phenyl)-
3-(pyrrol-1-yl)thiophene-2-carboxylate (7)
3
13
3
C NMR (100 MHz, CDCl ) d 141.1, 139.2, 136.4, 132.5, 130.8,
1
4
4
29.3, 121.9, 118.6, 118.2, 111.2, 109.3, 13.3.
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
C
18
H
14
N
2
O
2
S (322.38): calcd C 67.06, H 4.38; Found C 67.24, H
(0.318 g, 1.5 mmol) and 4-bromo-1-nitro-2-(trifluoromethyl)ben-
ꢀ
.27.
zene (0.270 g, 1 mmol) at 130 C during 2 h product 7 was obtained
in 60% (0.246 g) yield.
1
.6. Methyl 4-methyl-5-(4-propionylphenyl)-3-(pyrrol-1-yl)
H NMR (400 MHz, CDCl
3
)
d
8.03 (d, J¼8.0 Hz, 1H), 7.95 (s, 1H),
thiophene-2-carboxylate (3)
7.84 (d, J¼8.0 Hz, 1H), 6.75 (t, J¼2.0 Hz, 2H), 6.38 (t, J¼2.0 Hz, 2H),
.79 (s, 3H), 2.08 (s, 3H).
3
13
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
3
C NMR (100 MHz, CDCl ) d 160.3, 144.0, 138.5, 138.1, 135.2,
(
1
(
0.318 g, 1.5 mmol) and 4-bromopropiophenone (0.213 g,
mmol) at 130 C during 2 h product 3 was obtained in 83%
133.0, 128.2 (q, J¼5.3 Hz), 126.4, 125.9, 124.5 (q, J¼34.4 Hz), 121.8 (q,
ꢀ
J¼273.9 Hz), 121.9, 109.5, 52.4, 12.9.
0.293 g) yield.
18 13 3 2 4
C H F N O S (410.37): calcd C 52.68, H 3.19; Found C 52.74, H
3.04.
1H NMR (400 MHz, CDCl
)
d
8.06 (d, J¼8.0 Hz, 2H), 7.60 (d,
3
J¼8.0 Hz, 2H), 6.75 (t, J¼2.0 Hz, 2H), 6.36 (t, J¼2.0 Hz, 2H), 3.77 (s,
3
H), 3.04 (q, J¼7.6 Hz, 2H), 2.06 (s, 3H), 1.25 (t, J¼7.6 Hz, 3H).
4.11. Methyl 4-methyl-5-(pyridin-3-yl)-3-(pyrrol-1-yl)thio-
phene-2-carboxylate (8)
1
3
C NMR (100 MHz, CDCl
36.5, 133.6, 128.9, 128.3, 127.2, 121.8, 109.0, 52.0, 31.7, 12.7, 8.0.
S (353.43): calcd C 67.97, H 5.42; Found C 67.87, H
3
) d 199.8, 160.6, 143.7, 141.5, 137.7,
1
5
4
C
20
H19NO
3
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
(0.318 g, 1.5 mmol) and 3-bromopyridine (0.158 g, 1 mmol) at
.34.
ꢀ
1
30 C during 2 h product 8 was obtained in 79% (0.235 g) yield.
1
.7. Methyl 5-(4-(methoxycarbonyl)phenyl)-4-methyl-3-(pyr-
H NMR (400 MHz, CDCl
7.80 (d, J¼7.9 Hz, 1H), 7.41 (dd, J¼7.9, 4.2 Hz, 1H), 6.75 (s, 2H), 6.36
s, 2H), 3.77 (s, 3H), 2.05 (s, 3H).
3
)
d
8.77 (s, 1H), 8.66 (d, J¼4.2 Hz, 1H),
rol-1-yl)thiophene-2-carboxylate (4)
(
1
3
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
C NMR (100 MHz, CDCl
3
) d 160.7, 149.7, 149.5, 143.9, 138.9,
(
0.318 g, 1.5 mmol) and methyl 4-bromobenzoate (0.215 g,
136.2, 134.1, 129.7, 125.1, 123.6, 122.0, 109.2, 52.2, 12.7.
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6
I. Smari et al. / Tetrahedron xxx (2015) 1e8
C
.58.
16
H
14
N
2
O
2
S (298.36): calcd C 64.41, H 4.73; Found C 64.55, H
13C NMR (100 MHz, CDCl
129.5, 128.9, 121.9, 116.8, 109.1, 13.1.
12ClNS (273.78): calcd C 65.80, H 4.42; Found C 65.88, H
3
) d 140.7, 137.3, 133.8, 133.0, 130.2,
4
15
C H
4.28.
4
.12. Methyl 5-(5-cyanopyridin-3-yl)-4-methyl-3-(pyrrol-1-yl)
thiophene-2-carboxylate (9)
4.17. 2-(3-Methyl-4-(pyrrol-1-yl)thiophen-2-yl)benzonitrile
(15)
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
(
0.318 g, 1.5 mmol) and 5-bromonicotinonitrile (0.183 g, 1 mmol)
ꢀ
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
at 130 C during 2 h product 9 was obtained in 58% (0.187 g) yield.
1
(0.318 g, 1.5 mmol) and 2-bromobenzonitrile (0.182 g, 1 mmol) at
H NMR (400 MHz, CDCl
3
) d 9.26 (s, 1H), 8.89 (s, 2H), 6.74 (t,
ꢀ
1
50 C during 17 h product 15 was obtained in 79% (0.208 g) yield.
J¼2.0 Hz, 2H), 6.37 (t, J¼2.0 Hz, 2H), 3.79 (s, 3H), 2.07 (s, 3H).
1
13
H NMR (400 MHz, CDCl3)
d
7.82 (d, J¼8.2 Hz, 1H), 7.70 (t,
3
C NMR (100 MHz, CDCl ) d 160.4, 158.2, 156.2, 143.9, 135.2,
J¼7.8 Hz, 1H), 7.60e7.47 (m, 2H), 6.91 (t, J¼2.0 Hz, 2H), 6.35 (t,
J¼2.0 Hz, 2H), 2.12 (s, 3H).
1
4
34.5, 128.2, 126.2, 121.9, 109.4, 52.3, 12.7.
C H N O S (323.37): calcd C 63.14, H 4.05; Found C 63.00, H
17 13 3 2
.24.
1
3
3
C NMR (100 MHz, CDCl ) d 140.3, 138.0, 133.8, 133.4, 132.7,
1
32.3, 131.8, 128.6, 121.9, 118.3, 117.9, 113.6, 109.2, 13.2.
C
16
H
12
N
2
S (264.34): calcd C 72.70, H 4.58; Found C 72.54, H 4.33.
4
.13. Methyl 4-methyl-5-(pyrimidin-5-yl)-3-(pyrrol-1-yl)thio-
phene-2-carboxylate (10)
4.18. 1-(4-Methyl-5-(4-nitro-3-(trifluoromethyl)phenyl)thio-
phen-3-yl)-pyrrole (16)
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
(
1
0.318 g, 1.5 mmol) and 5-bromopyrimidine (0.159 g, 1 mmol) at
ꢀ
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
30 C during 2 h product 10 was obtained in 62% (0.185 g) yield.
1
(0.318 g, 1.5 mmol) and 4-bromo-1-nitro-2-(trifluoromethyl)ben-
3
H NMR (400 MHz, CDCl ) d 9.26 (s, 1H), 8.86 (s, 2H), 6.75 (t,
ꢀ
zene (0.270 g, 1 mmol) at 150 C during 17 h product 16 was ob-
J¼2.0 Hz, 2H), 6.37 (t, J¼2.0 Hz, 2H), 3.79 (s, 3H), 2.07 (s, 3H).
13
tained in 70% (0.246 g) yield.
3
C NMR (100 MHz, CDCl ) d 160.3, 158.2, 156.2, 143.9, 135.2,
1
H NMR (400 MHz, CDCl
3
)
d
8.01 (d, J¼8.0 Hz, 1H), 7.93 (s, 1H),
1
4
34.5, 128.2, 126.2, 121.9, 109.4, 52.4, 12.7.
C H N O S (299.35): calcd C 60.18, H 4.38; Found C 60.01, H
15 13 3 2
.24.
7
.81 (d, J¼8.0 Hz, 1H), 7.31 (s, 1H), 6.84 (t, J¼2.0 Hz, 2H), 6.34 (t,
J¼2.0 Hz, 2H), 2.21 (s, 3H).
13
C NMR (100 MHz, CDCl
31.9, 128.0 (q, J¼5.5 Hz), 125.8, 124.2 (q, J¼34.0 Hz), 121.7 (q,
J¼272.5 Hz), 121.9, 119.1, 109.5, 13.3.
S (352.33): calcd C 54.54, H 3.15; Found C 54.47, H
3
) d 146.6, 141.4, 139.7, 134.5, 132.6,
1
4
(
.14. 4-(3-Methyl-4-(pyrrol-1-yl)thiophen-2-yl)benzonitrile
11)
16 11 3 2 2
C H F N O
3.07.
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
(
1
0.318 g, 1.5 mmol) and 4-bromobenzonitrile (0.182 g, 1 mmol) at
4
.19. 3-(3-Methyl-4-(pyrrol-1-yl)thiophen-2-yl)quinoline (17)
ꢀ
50 C during 17 h product 11 was obtained in 90% (0.238 g) yield.
1
H NMR (400 MHz, CDCl
J¼8.0 Hz, 2H), 7.26 (s, 1H), 6.86 (t, J¼2.0 Hz, 2H), 6.34 (t, J¼2.0 Hz,
H), 2.20 (s, 3H).
3
)
d
7.75 (d, J¼8.0 Hz, 2H), 7.61 (d,
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
(0.318 g, 1.5 mmol) and 3-bromoquinoline (0.208 g, 1 mmol) at
2
ꢀ
150 C during 17 h product 17 was obtained in 61% (0.177 g) yield.
13
C NMR (100 MHz, CDCl
3
)
d
141.2, 139.2, 136.5, 132.5, 130.8,
1
3
H NMR (400 MHz, CDCl ) d 9.07 (s, 1H), 8.22 (s, 1H), 8.16 (d,
1
29.4, 121.9, 118.5, 118.2, 111.3, 109.3, 13.2.
J¼8.0 Hz, 1H), 7.88 (d, J¼8.0 Hz, 1H), 7.75 (t, J¼7.8 Hz, 1H), 7.60 (t,
C
16
H
12
N
2
S (264.34): calcd C 72.70, H 4.58; Found C 72.49, H 4.37.
J¼7.8 Hz, 1H), 6.89 (t, J¼2.0 Hz, 2H), 6.35 (t, J¼2.0 Hz, 2H), 2.24 (s,
3
H).
4
.15. 1-(4-(3-Methyl-4-(pyrrol-1-yl)thiophen-2-yl)phenyl)
13C NMR (100 MHz, CDCl
3
) d 150.5, 147.2, 141.0, 135.2, 134.7,
propan-1-one (12)
130.6, 129.8, 129.3, 127.9, 127.8, 127.6, 127.2, 121.8, 117.7, 109.2, 13.1.
C
18
14
H N
2
S (290.38): calcd C 74.45, H 4.86; Found C 74.67, H 5.01.
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
(
0.318 g, 1.5 mmol) and 4-bromopropiophenone (0.213 g, 1 mmol)
4
.20. 5-(3-Methyl-4-(pyrrol-1-yl)thiophen-2-yl)nicotinoni-
ꢀ
at 150 C during 17 h product 12 was obtained in 72% (0.212 g)
yield.
trile (18)
1H NMR (400 MHz, CDCl
)
d
8.09 (d, J¼8.7 Hz, 2H), 7.59 (d,
J¼8.7 Hz, 2H), 7.21 (s, 1H), 6.86 (t, J¼2.0 Hz, 2H), 6.33 (t, J¼2.0 Hz,
H), 3.04 (q, J¼7.6 Hz, 2H), 2.20 (s, 3H), 1.26 (t, J¼7.6 Hz, 3H).
3
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
0.318 g, 1.5 mmol) and 5-bromonicotinonitrile (0.183 g, 1 mmol)
(
2
ꢀ
at 150 C during 17 h product 18 was obtained in 76% (0.201 g)
yield.
13
C NMR (100 MHz, CDCl
3
) d 200.1, 141.0, 139.0, 137.4, 135.8,
1
5
30.2, 128.9, 128.4, 121.9, 117.6, 109.1, 31.8, 13.3, 8.2.
C H17NOS (295.40): calcd C 73.19, H 5.80; Found C 73.00, H
18
.89.
1H NMR (400 MHz, CDCl
3
) d 8.94 (s, 1H), 8.87 (s, 1H), 8.04 (s, 1H),
7.31 (s, 1H), 6.85 (t, J¼3.1 Hz, 2H), 6.34 (t, J¼3.1 Hz, 2H), 2.19 (s, 3H).
13
3
C NMR (100 MHz, CDCl ) d 152.6, 150.8, 141.2, 138.7, 131.9,
131.8, 131.2, 121.9, 119.0, 116.1, 109.5, 13.1.
4
.16. 1-(5-(4-Chlorophenyl)-4-methylthiophen-3-yl)-pyrrole
C
15
H
11
N
3
S (265.33): calcd C 67.90, H 4.18; Found C 68.06, H 4.29.
(
13)
4.21. 5-(3-Methyl-4-(pyrrol-1-yl)thiophen-2-yl)pyrimidine
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
(19)
(
0.318 g, 1.5 mmol) and 4-bromochlorobenzene (0.191 g, 1 mmol)
ꢀ
at 150 C during 17 h product 13 was obtained in 66% (0.180 g) yield.
From methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate
1
H NMR (400 MHz, CDCl
3
)
d
7.42 (s, 4H), 7.16 (s, 1H), 6.85 (t,
(0.318 g, 1.5 mmol) and 5-bromopyrimidine (0.159 g, 1 mmol) at
ꢀ
J¼2.0 Hz, 2H), 6.33 (t, J¼2.0 Hz, 2H), 2.15 (s, 3H).
150 C during 17 h product 19 was obtained in 74% (0.178 g) yield.
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I. Smari et al. / Tetrahedron xxx (2015) 1e8
7
1H NMR (400 MHz, CDCl
.85 (t, J¼3.1 Hz, 2H), 6.34 (t, J¼3.1 Hz, 2H), 2.19 (s, 3H).
)
d
9.20 (s, 1H), 8.87 (s, 2H), 7.30 (s, 1H),
13C NMR (100 MHz, CDCl
136.3, 133.5, 129.3, 128.8, 128.6, 126.8, 121.2, 110.9, 31.9, 12.9, 8.2.
d
200.0, 157.4, 154.2, 138.0, 137.1,
3
3
)
6
13
C NMR (100 MHz, CDCl
3
)
d
157.6, 156.3, 141.3, 131.9, 130.7,
22 19 3
C H N OS (373.47): calcd C 70.75, H 5.13; Found C 70.82, H
129.2, 122.0, 118.9, 109.6, 13.1.
5.01.
C
13 11
H N
3
S (241.31): calcd C 64.70, H 4.59; Found C 64.41, H 4.38.
4.26. 5-(3-Nitrophenyl)-2-(pyrrol-1-yl)thiophene-3-
4
.22. Methyl 5-(4-nitrophenyl)-3-(pyrrol-1-yl)thiophene-2-
carbonitrile (24a)
carboxylate (20a) and methyl 3-(2-(4-nitrophenyl)-pyrrol-1-
yl)thiophene-2-carboxylate (20b)
From
2-(pyrrol-1-yl)thiophene-3-carbonitrile
(0.261
g,
ꢀ
1
.5 mmol) and 3-bromonitrobenzene (0.202 g, 1 mmol) at 150 C
From methyl 3-(pyrrol-1-yl)thiophene-2-carboxylate (0.310 g,
.5 mmol) and 4-bromonitrobenzene (0.202 g, 1 mmol) at 130 C
during 2 h a mixture of 20a and 20b was obtained in a 31:35 ratio.
After column chromatography, roduct 20b was obtained in 35%
0.115 g) yield, and product 20a was isolated in low yield.
during 17 h product 24a was obtained in <10% (0.029 g) yield. This
ꢀ
1
compound was not isolated in pure form.
1
H NMR (400 MHz, CDCl
3
)
d
8.38 (s, 1H), 8.29 (d, J¼8.0 Hz, 1H),
7.84 (d, J¼8.0 Hz, 1H), 7.63 (t, J¼7.8 Hz, 1H), 7.27 (t, J¼2.0 Hz, 2H),
(
6.44 (t, J¼2.0 Hz, 2H).
1
2
0a: H NMR (400 MHz, CDCl
J¼8.0 Hz, 2H), 7.44 (s, 1H), 7.09e7.06 (m, 2H), 6.39e6.35 (m, 2H),
.89 (s, 3H).
3
)
d
8.35 (d, J¼8.0 Hz, 2H), 7.81 (d,
4.27. Ethyl 5-(2-(4-cyanophenyl)-pyrrol-1-yl)-1-
methylpyrazole-4-carboxylate (25b)
3
1
2
0b: H NMR (400 MHz, CDCl
3
)
d
8.06 (d, J¼8.0 Hz, 2H), 7.52 (d,
J¼5.2 Hz, 1H), 7.22 (d, J¼8.0 Hz, 2H), 6.97 (t, J¼1.3 Hz, 1H), 6.91 (d,
From ethyl 1-methyl-5-(pyrrol-1-yl)-pyrazole-4-carboxylate
(0.328 g, 1.5 mmol) and 4-bromobenzonitrile (0.182 g, 1 mmol) at
J¼5.2 Hz, 1H), 6.64 (dd, J¼3.6, 1.6 Hz, 1H), 6.43 (t, J¼3.3 Hz, 1H), 3.71
ꢀ
(
s, 3H).
130 C during 2 h product 25b was obtained in 42% (0.134 g) yield.
13C NMR (100 MHz, CDCl
30.6, 128.4, 127.1, 127.0, 125.0, 123.6, 112.5, 110.2, 52.2.
S (328.34): calcd C 58.53, H 3.68; Found C 59.01, H
)
d
160.4, 145.7, 142.1, 139.1, 132.9,
1
H NMR (400 MHz, CDCl
)
d
7.98 (s, 1H), 7.50 (d, J¼8.0 Hz, 2H),
3
3
1
3
4
7.14 (d, J¼8.0 Hz, 2H), 6.88e6.80 (m, 1H), 6.69e6.66 (m, 1H), 6.49 (t,
J¼3.1 Hz, 1H), 4.14 (q, J¼7.6 Hz, 2H), 3.40 (s, 3H), 1.17 (t, J¼7.6 Hz,
3H).
16 12 2 4
C H N O
.55.
13C NMR (100 MHz, CDCl
)
d
161.3, 141.1, 139.6, 136.1, 133.3,
132.5, 126.4, 126.2, 118.6, 112.4, 111.7, 110.2, 110,1, 60.4, 35.7, 14.1.
(320.35): calcd C 67.49, H 5.03; Found C 67.66, H
3
.23. 4-(4-Methyl-3-(pyrrol-1-yl)thiophen-2-yl)benzonitrile
21)
(
18 16 4 2
C H N O
4.78.
From 1-(4-methylthiophen-3-yl)-pyrrole (0.326 g, 2 mmol) and
ꢀ
4
-bromobenzonitrile (0.182 g, 1 mmol) at 130 C during 2 h product
4.28. Ethyl 1-methyl-5-(2-(4-nitrophenyl)-pyrrol-1-yl)-pyr-
azole-4-carboxylate (26)
21 was obtained in 46% (0.121 g) yield.
1
H NMR (400 MHz, CDCl
3
)
d
7.50 (d, J¼8.0 Hz, 2H), 7.07 (s, 1H),
7
.02 (d, J¼8.0 Hz, 2H), 6.59 (t, J¼2.0 Hz, 2H), 6.33 (t, J¼2.0 Hz, 2H),
From ethyl 1-methyl-5-(pyrrol-1-yl)-pyrazole-4-carboxylate
(0.328 g, 1.5 mmol) and 4-bromonitrobenzene (0.202 g, 1 mmol)
2
.08 (s, 3H).
13C NMR (100 MHz, CDCl
at 130 C during 2 h product 26 was obtained in 40% (0.136 g) yield.
ꢀ
3
) d 136.8, 136.7, 136.6, 134.8, 132.4,
1
127.2, 121.3, 120.8, 118.6, 111.0, 110.1, 13.6.
H NMR (400 MHz, CDCl
3
)
d
8.13 (d, J¼8.0 Hz, 2H), 8.02 (s, 1H),
C
16 12
H N
2
S (264.34): calcd C 72.70, H 4.58; Found C 72.78, H 4.79.
7.21 (d, J¼8.0 Hz, 2H), 6.87 (t, J¼3.1 Hz, 1H), 6.79e6.75 (m, 1H), 6.54
t, J¼3.1 Hz, 1H), 4.18 (q, J¼7.6 Hz, 2H), 3.46 (s, 3H), 1.20 (t, J¼7.6 Hz,
3H).
13C NMR (100 MHz, CDCl
26.3, 124.1, 113.0, 111.9, 110.2, 60.4, 35.7, 14.1.
(340.33): calcd C 59.99, H 4.74; Found C 60.11, H
(
4
.24. 3-(3-Methyl-5-phenyl-4-(pyrrol-1-yl)thiophen-2-yl)
quinoline (22)
3
) d 161.3,146.1,141.1,138.0,133.1,126.6,
1
From 3-(3-methyl-4-(pyrrol-1-yl)thiophen-2-yl)quinoline 17
0.435 g, 1.5 mmol) and bromobenzene (0.157 g, 1 mmol) at 150 C
17 16 4 4
C H N O
ꢀ
(
4.59.
during 17 h product 22 was obtained in 56% (0.205 g) yield.
1
H NMR (400 MHz, CDCl
3
)
d
9.11 (s, 1H), 8.27 (s, 1H), 8.15 (d,
4.29. Ethyl 5-(2-(4-formylphenyl)-pyrrol-1-yl)-1-
methylpyrazole-4-carboxylate (27)
J¼8.0 Hz, 1H), 7.89 (d, J¼8.0 Hz, 1H), 7.76 (t, J¼7.8 Hz, 1H), 7.61 (t,
J¼7.8 Hz, 1H), 7.30e7.24 (m, 3H), 7.07 (d, J¼8.0 Hz, 2H), 6.71 (t,
J¼2.0 Hz, 2H), 6.33 (t, J¼2.0 Hz, 2H), 2.17 (s, 3H).
From ethyl 1-methyl-5-(pyrrol-1-yl)-pyrazole-4-carboxylate
(0.328 g, 1.5 mmol) and 4-bromobenzaldehyde (0.185 g, 1 mmol)
13
3
C NMR (100 MHz, CDCl ) d 150.5, 137.5, 135.8, 135.0, 133.7,
ꢀ
1
1
31.8, 129.9, 129.4, 128.8, 128.1, 127.9, 127.7, 127.3, 127.1, 121.7, 109.7,
2.9.
at 130 C during 2 h product 27 was obtained in 50% (0.161 g) yield.
1
3
H NMR (400 MHz, CDCl ) d 9.98 (s, 1H), 7.99 (s, 1H), 7.74 (d,
C
24
H
18
N
2
S (366.48): calcd C 78.66, H 4.95; Found C 78.54, H 5.11.
J¼8.0 Hz, 2H), 7.21 (d, J¼8.0 Hz, 2H), 6.87 (t, J¼3.1 Hz, 1H),
.74e6.70 (m, 1H), 6.50 (t, J¼3.1 Hz, 1H), 4.16 (q, J¼7.6 Hz, 2H), 3.40
(s, 3H), 1.17 (t, J¼7.6 Hz, 3H).
6
4
.25. 1-(4-(3-Methyl-5-(pyrimidin-5-yl)-4-(pyrrol-1-yl)thio-
phen-2-yl)phenyl)propan-1-one (23)
13
C NMR (100 MHz, CDCl
34.5, 133.9, 130.2, 126.4, 126.2, 112.3, 111.6, 110.1, 60.3, 35.7, 14.1.
(323.34): calcd C 66.86, H 5.30; Found C 67.04, H
3
) d 191.4, 161.4, 141.1, 139.8, 137.5,
1
From methyl 4-methyl-5-(4-propionylphenyl)-3-(pyrrol-1-yl)
18 17 3 3
C H N O
thiophene-2-carboxylate 3 (0.529 g, 1.5 mmol) 5-bromopyrimidine
5.07.
ꢀ
(
0.159 g, 1 mmol) at 150 C during 17 h product 23 was obtained in
7
1% (0.264 g) yield.
4.30. Ethyl 1-methyl-5-(2-(4-nitro-3-(trifluoromethyl)phe-
nyl)-pyrrol-1-yl)-pyrazole-4-carboxylate (28)
1
H NMR (400 MHz, CDCl
3
)
d
9.05 (s, 1H), 8.26 (s, 2H), 8.08 (d,
J¼8.7 Hz, 2H), 7.63 (d, J¼8.7 Hz, 2H), 6.68 (t, J¼2.0 Hz, 2H), 6.39 (t,
J¼2.0 Hz, 2H), 3.05 (q, J¼7.6 Hz, 2H), 2.16 (s, 3H), 1.27 (t, J¼7.6 Hz,
From ethyl 1-methyl-5-(pyrrol-1-yl)-pyrazole-4-carboxylate
(0.328 g, 1.5 mmol) and 4-bromo-1-nitro-2-(trifluoromethyl)
3
H).
Please cite this article in press as: Smari, I.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.03.022

8
I. Smari et al. / Tetrahedron xxx (2015) 1e8
ꢀ
benzene (0.270 g, 1 mmol) at 130 C during 2 h product 28 was
3. For reviews on Pd-catalysed C-H functionalisations: (a) Alberico, D.; Scott, M.
E.; Lautens, M. Chem. Rev. 2007, 107, 174e238; (b) Satoh, T.; Miura, M. Chem. Lett.
obtained in 56% (0.228 g) yield.
2007, 36, 200e205; (c) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949e957; (d)
1
H NMR (400 MHz, CDCl
3
)
d
7.99 (s, 1H), 7.80 (d, J¼8.0 Hz, 1H),
Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269e10310; (e) Ackermann, L.;
Vincente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792e9826; (f) Roger,
J.; Gottumukkala, A. L.; Doucet, H. ChemCatChem 2010, 2, 20e40; (g) Wu, X.-F.;
Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2010, 49,
7
(
.59 (s, 1H), 7.25 (d, J¼8.0 Hz, 1H), 6.90 (t, J¼3.1 Hz, 1H), 6.80e6.75
m, 1H), 6.54 (t, J¼3.1 Hz,1H), 4.16 (q, J¼7.6 Hz, 2H), 3.48 (s, 3H),1.18
t, J¼7.6 Hz, 3H).
(
7316e7319; (h) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew.
13
C NMR (100 MHz, CDCl
3
)
d
161.1,141.1,139.0,136.6,131.9,129.0,
Chem., Int. Ed. 2012, 51, 10236e10254; (i) Yamaguchi, J.; Yamaguchi, A. D.; Itami,
K. Angew. Chem., Int. Ed. 2012, 51, 8960e9009; (j) Wencel-Delord, J.; Glorius, F.
Nat. Chem. 2013, 5, 369e375; (k) Kuzhushkov, S. I.; Potukuchi, H. K.; Acker-
mann, L. Catal. Sci. Technol. 2013, 3, 562e571; (l) Rossi, R.; Bellina, F.; Lessi, M.;
Manzini, C. Adv. Synth. Catal. 2014, 356, 17e117; (m) He, M.; Soul eꢀ , J.-F.; Doucet,
H. ChemCatChem 2014, 6, 1824e1859; (n) Yuan, K.; Soul eꢀ , J.-F.; Doucet, H. ACS
1
27.1, 126.0, 125.4 (q, J¼5.6 Hz), 124.5 (q, J¼34.0 Hz), 121.6 (q,
J¼273.7 Hz), 113.6, 112.2, 110.5, 60.5, 35.7, 14.0.
18 15 3 4 4
C H F N O (408.33): calcd C 52.95, H 3.70; Found C 52.79, H
3
.89.
Catal. 2015, 5, 978e991.
4
. For selected examples of Pd-catalysed direct arylations from our laboratory: (a)
Beydoun, K.; Zaarour, M.; Williams, J. A. G.; Doucet, H.; Guerchais, V. Chem.
Commun. 2012, 1260e1262; (b) Fu, H. Y.; Chen, L.; Doucet, H. J. Org. Chem. 2012,
4
.31. Ethyl 1-methyl-5-(2-(pyrimidin-5-yl)-pyrrol-1-yl)-pyr-
azole-4-carboxylate (29)
77, 4473e4478; (c) Zhao, L.; Bruneau, C.; Doucet, H. Chem. Commun. 2013,
5598e5600.
From ethyl 1-methyl-5-(pyrrol-1-yl)-pyrazole-4-carboxylate
5. (a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry; Pergamon: Am-
sterdam, Netherlands, 2000; (b) Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York, NY, 2002; Part
III, p 213; (c) Schnurch, M.; Flasik, R.; Khan, A. F.; Spina, M.; Mihovilovic, M. D.;
Stanetty, P. Eur. J. Org. Chem. 2006, 3283e3307; (d) Ackermann, L. Modern Ar-
ylation Methods; Wiley: Weinheim, 2009.
(
1
0.328 g, 1.5 mmol) and 5-bromopyrimidine (0.159 g, 1 mmol) at
ꢀ
30 C during 2 h product 29 was obtained in 58% (0.172 g) yield.
€
1
H NMR (400 MHz, CDCl
.87 (t, J¼3.1 Hz, 1H), 6.75e6.70 (m, 1H), 6.53 (t, J¼3.1 Hz, 1H), 4.13
q, J¼7.6 Hz, 2H), 3.48 (s, 3H), 1.18 (t, J¼7.6 Hz, 3H).
3
) d 9.02 (s, 1H), 8.45 (s, 2H), 7.96 (s, 1H),
6
(
6
. For selected examples of Pd-catalysed direct arylations of thiophene de-
rivatives: (a) Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc. 2004, 126,
5074e5075; (b) David, E.; Pellet-Rostaing, S.; Lemaire, M. Tetrahedron 2007, 63,
13
C NMR (100 MHz, CDCl
3
) d 160.8, 156.5, 153.7, 140.8, 138.7,
8999e9006; (c) Amaladass, P.; Clement, J. A.; Mohanakrishnan, A. K. Tetrahe-
1
5
28.3, 125.9, 125.7, 111.9, 111.7, 110.2, 60.1, 35.3, 13.7.
dron 2007, 63, 10363e10371; (d) Nakano, M.; Tsurugi, H.; Satoh, T.; Miura, M.
Org. Lett. 2008, 10, 1851e1854; (e) Li eꢀ gault, B.; Petrov, I.; Gorlesky, S. I.; Fagnou,
K. J. Org. Chem. 2010, 75, 1047e1060; (f) Chen, L.; Roger, J.; Bruneau, C.; Dixneuf,
P. H.; Doucet, H. Chem. Commun. 2011, 1872e1874; (g) Yuan, K.; Doucet, H.
Chem. Sci. 2014, 5, 392e396.
15 15 5 2
C H N O (297.31): calcd C 60.60, H 5.09; Found C 60.41, H
.27.
Acknowledgements
7. For selected examples of Pd-catalysed direct arylations of pyrrole derivatives:
a) Toure, B. B.; Lane, B. S.; Sames, D. Org. Lett. 2006, 8, 1979e1982; (b) Yang, S.-
D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47,
473e1476; (c) Li eꢀ gaut, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J. Org.
Chem. 2009, 74, 1826e1834; (d) Roger, J.; Doucet, H. Adv. Synth. Catal. 2009, 351,
977e1990; (e) Gryko, D. T.; Vakuliuk, O.; Gryko, D.; Koszarna, B. J. Org. Chem.
(
We thank the Centre National de la Recherche Scientifique,
1
‘Rennes Metropole’, ‘UTIQUE’ and Scientific Ministry of Higher
1
Education Research of Tunisia for providing financial support.
2009, 74, 9517e9520; (f) Nadres, E. T.; Lazareva, A.; Daugulis, O. J. Org. Chem.
011, 76, 471e483; (g) Vakuliuk, O.; Koszarna, B.; Gryko, D. T. Adv. Synth. Catal.
2
References and notes
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Please cite this article in press as: Smari, I.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.03.022