Optimization of the Suzuki coupling reaction in the synthesis of 2-[(2-substituted)phenyl]pyrrole derivatives

Article abstract of DOI:10.1002/jhet.792

A facile three-step synthesis of 2-(2-aminophenyl)pyrrole (1) and 2-[(2-aminomethyl)phenyl]pyrrole (2) is reported by use of Suzuki coupling of N-Boc-pyrrol-2-yl boronic acid (3) and o-substituted aryl halogenides, followed by hydrogenation. The Pd-catalyzed cross-coupling reaction is optimized to be applicable to a wide range of substitued aryl halogenides, with electron-donating and electron-withdrawing substituents, 5a-g. Moreover, Pd-catalyzed coupling of o-bromoaniline and 3 could be applied for the one-step preparation of pyrrolo[1,2-c]quinazolin-5(6H)-one (8). Copyright

Full text of DOI:10.1002/jhet.792

November 2011 Optimization of the Suzuki Coupling Reaction in the Synthesis of
2-[(2-Substituted)phenyl]pyrrole Derivatives
1329
ˇ ´ ´ ´
Marija Aleskovic, Nikola Basaric, and Kata Mlinaric-Majerski*
-
Department of Organic Chemistry and Biochemistry, Ruder Boskovic Institute, Bijenicka cesta 54,
ˇ
´
ˇ
10000 Zagreb, Croatia
*E-mail: majerski@irb.hr
Received September 27, 2010
DOI 10.1002/jhet.792
Published online 18 August 2011 in Wiley Online Library (wileyonlinelibrary.com).
A facile three-step synthesis of 2-(2-aminophenyl)pyrrole (1) and 2-[(2-aminomethyl)phenyl]pyrrole
(2) is reported by use of Suzuki coupling of N-Boc-pyrrol-2-yl boronic acid (3) and o-substituted aryl
halogenides, followed by hydrogenation. The Pd-catalyzed cross-coupling reaction is optimized to be
applicable to a wide range of substitued aryl halogenides, with electron-donating and electron-withdraw-
ing substituents, 5a–g. Moreover, Pd-catalyzed coupling of o-bromoaniline and 3 could be applied for
the one-step preparation of pyrrolo[1,2-c]quinazolin-5(6H)-one (8).
J. Heterocyclic Chem., 48, 1329 (2011).
INTRODUCTION
On the other hand, modern synthetic methods more
often rely on the versatile use of Pd-catalyzed CAC
bond formation [11–16]. Thus, arylpyrroles can be
prepared by Stille coupling of N-protected pyrrole
stanannes with arylhalogenides [17], Suzuki–Miyaura
coupling [18,19] of N-protected pyrrole boronic acid
with arylhalogenides [20] as well as from N-protected
pyrrole bromides with aryl boronic acids [21,22], or pal-
ladium-catalyzed direct arylation [23,24]. However, the
arylation by o-substituted aryl halogenides often fails or
proceeds with very low yield [20,25]. These reactions
with sterically hindered reagents are possible but often
employ modified Pd-catalyzed systems wherein structur-
ally modified ligands are used [26].
The on-going project in our laboratory on adamantane-
dipyrromethane anion receptors A and B [1,2] envisaged
new host molecules in which hydrogen at the position 2 of
the pyrrole ring is replaced by an aryl substituent bearing a
hydrogen donor site in the ortho position. In particular,
amino or methylamino groups, as in pyrrole derivatives 1
and 2, are potentially good H-bond donors (Fig. 1).
Synthesis of pyrrole derivatives having molecular
skeletons similar to 1 and 2 has been reported [3–8].
However, the synthetic strategy was mostly based on te-
dious multistep synthetic procedures involving a conden-
sation of the pyrrole ring [3–8]. Recently, the one-pot
synthesis of diverse 2-substituted, 2,3- and 2,5-disubsti-
tuted NH- and N-vinylpyrroles through the Trofimov
reaction of ketoximes with acetylenes was reported [9].
This simple and efficient route to pyrrole derivatives is
widely used [10].
Herein, we describe a facile three-step synthetic pro-
tocol for the preparation of pyrrole derivatives 1 and 2
that involves Suzuki coupling of the N-protected pyrrole
boronic acid and nitrophenyl or cyanophenyl derivative,
and subsequent hydrogenation to the amines. Also,
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M. Aleskovic, N. Basaric, and K. Mlinaric-Majerski
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nophenyl)pyrrole (1), first we performed the coupling
reaction between N-Boc-pyrrol-2-yl boronic acid (3) and
2-nitrobromobenzene (4a, Scheme 1). We applied the
protocol published by Burgess and co-workers [21,22]
that includes Pd(PPh3)4 as a catalyst and an aqueous so-
lution of Na2CO3 in a 5:1 mixture of toluene and metha-
nol. However, under these conditions we obtained less
than 2% of N-Boc-2-(o-nitrophenyl)pyrrole (5a) (Table
1, entry 1). The low yield prompted us to investigate the
reaction conditions in more detail. To optimize the reac-
tion conditions, various factors were investigated includ-
ing catalyst (type and amount), base, solvent, and reac-
tion time. The results are summarized in Table 1.
As the first reaction conditions did not work in our
case, we removed water from the reaction mixture.
Addition of solid Na2CO3 increased the yield, and the
product 5a was isolated in 26% yield (Table 1, entry 2).
Changing the base to Cs2CO3 increased the yield of the
product to 42%, but the product was isolated as the
unprotected form of 5a (Table 1, entry 3). Performing
the reaction with a smaller amount of methanol was a
disappointment even with prolonging the reaction time
(Table 1, entry 4). The yield was also poor when solely
toluene was used as a solvent (Table 1, entry 5). Simi-
larly poor yields were obtained when dimethoxyethane
(DME) was used as a solvent with either of the bases
Na2CO3 or Cs2CO3 (Table 1, entries 6 and 7).
Figure 1. Structure of adamantane-dipyrromethanes A and B and pyr-
role derivatives 1 and 2.
keeping in mind the easy availability of the reagents
used in the synthesis, particularly inexpensive commer-
cial catalysts and ligands, the conditions for the Suzuki
coupling were optimized.
RESULTS AND DISCUSSION
It is known that Pd-catalyzed reactions with o-bro-
moaniline are quite difficult as the amino group elec-
tronically deactivates the CABr bond in the oxidative
addition to the Pd catalyst [27,28]. Nevertheless, there
are examples of direct Suzuki coupling for preparation
of biaryls and heteroaryls involving an unprotected NH2
group [29–35]. However, to the best of our knowledge,
an attempt to couple a pyrrole moiety to o-substituted
anilines in a Pd-catalyzed reaction has not been
reported.
In all of the coupling reactions that proceeded with
moderate yield of the product 5a, the by-products 6a
and 7 [20] were also formed. Compound 6a is the result
of deprotection of 5a in basic reaction conditions, and
compound 7 is the product of a competitive homocou-
pling reaction that uses up the starting boronic acid 3.
To minimize the formation of by-product 7, we exam-
ined the influence of the addition time of 3 to the reac-
tion mixture.
To avoid additional protection and deprotection steps
of the amino group, we turned our attention to the Pd-
catalyzed coupling reaction between N-Boc-pyrrol-2-yl
boronic acid [36] and the aryl halogenide bearing ortho
substituents that could be subsequently transformed to
the amino group. Hence, for the synthesis of 2-(o-ami-
Surprisingly, when the reaction was carried out in a
10:1 mixture of toluene:methanol and starting compound
3 was added to the reaction mixture dropwise, the yield
of the coupling products was dramatically increased to
81% and the by-product 7 was formed in 2% yield (Ta-
ble 1, entry 11). A similar result was obtained when the
Scheme 1
Journal of Heterocyclic Chemistry
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November 2011
Optimization of the Suzuki Coupling Reaction in the Synthesis of
2-[(2-Substituted)phenyl]pyrrole Derivatives
1331
Table 1
Optimization of coupling reaction between pyrrole derivative 3 and o-nitroaryl halogenides 4a and 4a0.
Yield of coupling
reaction (%)c (5a þ 6a)d
Entry
Aryl
Catalyst (mol %)
Solventa
Base
Time (h)b
Yield, 7 (%)c
1
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a0
4a0
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (2.5)
Pd(PPh3)4 (7.5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
T:M (5:1)
T:M (5:1)
T:M (5:1)
T:M (10:1)
T
DME
DME
DME
DME
Na2CO3 (aq)
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
Cs2CO3
Na2CO3
Cs2CO3
Na2CO3
Cs2CO3
Na2CO3
Cs2CO3
Na2CO3
Cs2CO3
K3PO4
0/48
0/48
0/24
0/32
0/24
0/24
0/24
7/24
7/24
7/24
7/24
7/24
7/24
7/24
7/24
7/24
7/24
7/24
7/24
7/24
7/24
2 (2 þ 0)
26 (26 þ 0)
42 (0 þ 42)
24 (16 þ 8)
11 (9þ2)
–
11
57
30
30
5
2
3
4
5
6
36 (32þ4)
7
8
11 (9 þ 2)
<2 (2 þ 0)
69 (64 þ 5)
18 (15 þ 3)
81 (78 þ 3)
<2 (2 þ0)
7 (7 þ 0)
38
1
9
1
–
10
11
12
13
14
15
16
17
18
19
20
21
T:M (10:1)
T:M (10:1)
DME
2
–
2
DME
T:M (10:1)
T:M (10:1)
T:M (10:1)
T:M (10:1)
T:M (10:1)
T:M (10:1)
T:M (10:1)
DME
61 (56 þ 5)
28 (28 þ 0)
54 (52 þ 5)
<2 (2 þ 0)
67 (59 þ 8)
64 (45 þ 19)
74 (68 þ 6)
69 (67 þ 2)
3
3
1
–
Ba(OH)2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
1
1
1
–
a T:M ¼ toluene:MeOH; DME ¼ dimethoxyethane.
b Time of the addition of 3/overall reaction time.
c Isolated yield after chromatography.
d Ratio between 5a and 6a varies from run to run.
reaction was carried out in DME and by prolonging the
addition time of 3, formation of 7 can be kept below
5%.
compared with the experiment done with Cs2CO3 (entry
11). The use of Ba(OH)2 afforded 5a in less than 2%
yield (entry 17). The poor yield with Ba(OH)2 could be
explained by the problems that occurred during the
work-up of the reaction. Fine colloidal particles of the
base precipitated and caused a troublesome extraction of
the product. Interestingly, in the presence of Pd(PPh3)4
as a catalyst, Cs2CO3 acted as a more efficient base than
Na2CO3, yielding product 5a in better yields in both
sets of solvents. One of the reasons for a more pro-
nounced effectiveness of Cs2CO3 over other bases could
be due to an increased solubility of cesium carbonate in
organic solvent such as methanol [37].
We also explored the use of two palladium catalysts,
Pd(PPh3)4 and Pd(PPh3)2Cl2, in various solvents and
with different bases. Experiments in DME (entries 12
and 13, Table 1), carried out with Pd(PPh3)2Cl2 and
bases Na2CO3 or Cs2CO3, gave 5a in very low yields
compared to reactions performed in a 10:1 mixture of
toluene:methanol, which gave 5a in moderate yields of
56% and 28% (entries 14 and 15). It is obvious that
Pd(PPh3)4 acts as
a more efficient catalyst than
Pd(PPh3)2Cl2 yielding products 5a and 6a in up to 81%
yield. By varying the amount of Pd catalyst (entries 18
and 19), we found that both decrease or increase of the
amount of catalyst gives rise to a decrease in the yield
of 5a and an increase in the yield of the unprotected
derivative 6a. Thus, the best yield of 5a (78%) was
achieved by the use of 5 mol % of Pd(PPh3)4, a 10:1
mixture of toluene and methanol and Cs2CO3 as a base
(entry 11).
The change to a different halogen atom did not
appear to have any significant effect on the course of
the reaction. When o-nitroaryl iodide (4a0) was used
under the same conditions, coupling products were
obtained in a fairly analogous yield of 74% (Table 1,
entry 20). Likewise, the change of the solvent to DME
furnished 5a in a similar yield (Table 1, entry 21).
After the examination of these various reaction pa-
rameters (catalyst, base, solvent, and reaction time), the
optimal conditions were identified for the cross-coupling
reaction of 3 and o-nitroaryl halogenides. These condi-
tions were then applied to several o-substituted aryl
To probe for the influence of the base on the course
of the reaction, we used K3PO4 and Ba(OH)2 in addition
to Na2CO3 and Cs2CO3. When K3PO4 was applied as a
base (entry 16), the yield of the 5a slightly decreased
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M. Aleskovic, N. Basaric, and K. Mlinaric-Majerski
1332
Vol 48
Table 2
CABr bond toward the oxidative addition to the Pd cat-
alyst, and thus, a competitive reaction of homocoupling
takes place to a greater extent.
Coupling reaction of 3 and arylhalogenides 4a–4g in the presence of
Cs2CO3 and Pd(PPh3)4.
The coupling reaction with the substrate 4d bearing
an electron-donating methoxy group at the ortho posi-
tion furnished 5d [22] in moderate yields (Table 2,
entries 7 and 8). The reaction with 2-bromobenzonitrile
(4e) was more successful when carried out in a 10:1
mixture of toluene and methanol than in DME (Table 2,
entries 9 and 10). Reactions carried out with meta- and
para-substituted nitriles 4f and 4g gave coupling prod-
ucts similar to the reaction with ortho-nitrile.
As shown in Tables 1 and 2, the coupling reaction is
efficient with aryl bromides substituted by electron-with-
drawing groups such as nitro and cyano. The best result
was achieved with the o-nitrobromobenzene and this is
in accordance with the proposition of Widdowson and
Wilhelm [38] that a nitro group in the 2-position may
coordinate an incoming Pd atom, and thus, help in the
insertion step of the catalytic cycle.
Yield of coupling
reaction (%)b
Yield,
7 (%)b
Entry
Aryl
Solventa
(5a–5g þ 6a–6g)c
1
4a
4a
4b
4c
4c
4c
4d
4d
4e
4e
4f
T:M (10:1)
DME
T:M (10:1)
T:M (10:1)
T:M (10:1)
DME
81 (78 þ 3)
69 (64 þ 5)
93 (86 þ 7)
– (–)
2.5
1d
–
2
3
4
–
5e
6
10 (10 þ 0)
48
21
<1d
1d
–
5 (5 þ 0)
7
8
T:M (10:1)
DME
39 (39 þ 0)
41 (41 þ 0)
61 (50 þ 11)
32 (32 þ 0)
32 (32 þ 0)
51 (51þ 0)
9
T:M (10:1)
DME
10
11
12
8
T:M (10:1)
T:M (10:1)
–
–
4g
a T:M ¼ toluene:MeOH; DME ¼ dimethoxyethane.
b Isolated yield after chromatography.
c Ratio between 5a–5g and 6a–6g varies from run to run.
d 1H-NMR yield of the crude mixture, done by internal standard.
e Na2CO3 was used as a base.
Good results for Suzuki coupling reactions between
pyrrole boronic acid derivative 3 and ortho-substituted
arylhalogenides prompted us to test if o-bromoaniline as a
substrate would undergo the desired coupling reactions.
Indeed, using the above optimized reaction conditions, we
obtained the coupling product in 23% yield, but in addi-
tion some secondary cyclization took place. Namely, after
the first Pd-catalyzed coupling step, ring closure occurs
due to a nucleophilic attack of the aniline amino-group on
the carbonyl of the Boc-protecting group (Scheme 2).
Obtained derivative 8 has a quinazoline skeleton which
is in focus of interest in medicinal chemistry because of its
very pronounced biological activities such as antiviral,
antimalarial, antibacterial, and antihypertensive [39].
Therefore, this type of reaction could be of great impor-
tance for obtaining quinazoline derivatives in contrast to
multistep synthesis employed to date in the literature [40].
Preparation of the title compounds, amino-derivatives
1 and 2, was straightforward from nitro- and cyanoaryl-
pyrroles 5a and 5e, respectively, as shown in Scheme 3.
Removal of the Boc-protecting group was performed by
sodium methoxide in methanol. The proceeding catalytic
reduction of the nitro- and cyano-derivatives 6a and 6e
was accomplished by hydrogenation in methanol over
the inexpensive catalyst 10% Pd-C, giving amino deriv-
atives 1 [41] and 2 in 63% and 58% yield, respectively.
halogenides 4a–4g to investigate the scope of the reac-
tion. The results of the cross-coupling reaction between
3 and various aryl halogenides are presented in Table 2.
Again, in addition to the N-Boc-2-arylpyrroles 5a–5g,
unprotected arylpyrroles 6a–6g and by-product 7 were
formed. In all the reactions, performed in either 10:1
toluene:methanol mixture or DME, the highest yields
were obtained when Pd(PPh3)4 was used as a catalyst,
Cs2CO3 as a base, and the N-Boc-pyrrole boronic acid
was added to the reaction mixture in small portions dur-
ing 7h and with subsequent heating for 17 h. It is note-
worthy to mention that the crucial parameter for a suc-
cessful reaction is the portionwise addition of 3 to the
reaction mixture. As can be seen from Table 2, the best
yield of 5 was obtained with iodobenzene, which gave
more than 93% of coupled 2-phenylpyrrole (5b þ 6b).
When aryl halogenide with a tosyl-protected amino
group was subjected to the reaction, the results were dis-
appointing because there was no isolable product (Table
2, entry 4). However, the reaction with Na2CO3 as a
base gave 10% of 5c and 48% of the by-product 7 (Ta-
ble 2, entry 5). It is possible that the p-toluenesulfonyl
group which is sterically congested, deactivates the
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2011
Optimization of the Suzuki Coupling Reaction in the Synthesis of
2-[(2-Substituted)phenyl]pyrrole Derivatives
1333
Scheme 3
300 MHz) d: 1.33 (s, 9H), 6.19 (dd, 1H, J ¼ 3.3, 1.8 Hz),
6.27 (t, 1H, J ¼ 3.3 Hz), 7.41 (dd, 1H, J ¼ 3.3, 1.8 Hz),
7.43ꢁ7.54 (m, 2H), 7.62 (dt, 1H, J ¼ 7.5, 1.3 Hz), 8.10 ppm
(dd, 1H, J ¼ 8.2, 1.1 Hz); 13C-NMR (CDCl3, 75 MHz) d: 27.4
(3C, q), 83.9 (1C, s), 110.7 (1C, d), 114.7 (1C, d), 122.5 (1C,
d), 124.2 (1C, d), 128.5 (1C, d), 129.4 (1C, s), 129.9 (1C, s),
132.6 (1C, d), 132.7 (1C, d), 148.4 (1C, s), 148.7 ppm (1C, s).
IR (KBr): 3453 (w), 2974 (w), 1747 (s), 1522 (s), 1351 (s),
1324 (s), 1147 (s), 976 (m), 722 cmꢁ1 (m); HRMS: m/z [M þ
H]þ calcd for C15H17N2O4: 289.1183; found: 289.1172.
In the catalytic reduction of 6e, besides the amino prod-
uct 2, a small amount of 2-(o-methylphenyl)pyrrole (9)
[42] was also formed.
CONCLUSIONS
We have found a good synthetic protocol for the
preparation of 2-(2-aminophenyl)pyrrole (1) and 2-[(2-
aminomethyl)phenyl]pyrrole (2) involving Suzuki cou-
pling and hydrogenation. The reaction conditions for the
Suzuki coupling reaction of pyrrole with aryl halogen-
ides bearing the substituent in the ortho-position were
optimized. The reaction employs commercially available
Pd catalyst and is applicable for different substituents,
those with electron withdrawing as well as electron
donating groups. Moreover, the unprotected amino-aryl-
halogenides could be used, and reaction could be
employed for the construction of the quinazoline skele-
ton. The latter is under current investigation.
N-Boc-2-[(2-tosylamino)phenyl]pyrrole (5c). This com-
1
pound was obtained as pale pink powder; mp 174ꢁ177ꢂC; H-
NMR (CDCl3, 300 MHz) d: 1.22 (s, 9H), 2.38 (s, 3H), 5.55
(dd, 1H, J ¼ 3.2, 1.7 Hz), 6.17 (t, 1H, J ¼ 3.3 Hz), 6.57 (br.
s, 1H), 7.05 (d, 2H, J ¼ 4.5 Hz), 7.20 (d, 2H, J ¼ 8.1 Hz),
7.26ꢁ7.33 (m, 1H), 7.39 (dd, 1H, J ¼ 3.2, 1.7 Hz), 7.56 (d,
2H, J ¼ 8.1 Hz), 7.63 ppm (d, 1H, J ¼ 8.1 Hz); 13C-NMR
(CDCl3, 75 MHz) d: 21.4 (1C, q), 27.2 (3C, q), 84.1 (1C, s),
110.7 (1C, d), 115.4 (1C, d), 119.7 (1C, d), 122.8 (1C, d),
123.6 (1C, d), 125.9 (1C, s), 127.1 (2C, d), 127.6 (1C, s),
128.9 (1C, d), 129.4 (2C, d), 131.3 (1C, d), 135.6 (1C, s),
136.2 (1C, s), 143.7 (1C, s), 118.6 ppm (1C, s); IR (KBr):
3252 (s), 2984 (w), 2928 (w), 1732 (s), 1397 (s), 1335 (s),
1310 (s), 1171 (s), 1145 (s), 738 cmꢁ1 (m); HRMS: m/z [M þ
K]þ calcd for C22H24KN2O4S: 451.1088; found: 451.1066.
N-Boc-2-(2-cyanophenyl)pyrrole (5e). This compound was
EXPERIMENTAL SECTION
1
1
General. H- and 13C-NMR spectra were recorded on a
obtained as brown oil; H-NMR (CDCl3, 300 MHz) d: 1.39 (s,
Brucker Spectrometer at 300 or 600 MHz. All NMR spectra
were measured in CDCl3 using tetramethylsilane as a refer-
ence. High-resolution mass spectra (HRMS) were measured on
an Applied Biosystems 4800 Plus MALDI TOF/TOF instru-
ment. Melting points were obtained using an Original Kofler
apparatus and are uncorrected. IR spectra were recorded on a
Perkin Elmer M-297 and ABB Bomem M-102 spectrophotom-
eters. Silica gel (0.05–0.2 mm) was used for chromatographic
purifications. Solvents were purified by distillation.
Suzuki reaction—general procedure. To a stirred solution
of aryl halogenide (4, 0.95 mmol), cesium carbonate (1.89
mmol) and tetrakis(triphenylphosphine)palladium(0) (5 mol %)
in toluene (20 mL) at reflux under nitrogen atmosphere, a solu-
tion of N-Boc-pyrrol-2-yl boronic acid (3, 0.95 mmol) in the
mixture of toluene (10 mL) and methanol (3 mL) was added
during 7 h. The mixture was stirred at reflux for 17 h, cooled
and methanol was removed under reduced pressure. To a tolu-
ene suspension, water (30 mL) was added and the layers were
separated. The water layer was extracted with CH2Cl2 (3ꢀ 25
mL). Combined organic extracts were washed with water (30
mL), dried over MgSO4, and solvent was evaporated under
reduced pressure. The resulting crude product was purified by
chromatography on silica eluting with the mixture of (0 !
50%) diethyl ether in hexane to yield desired 2-phenylpyrrole.
N-Boc-2-(2-nitrophenyl)pyrrole (5a). This compound was
obtained as yellow crystals, mp 78ꢁ79ꢂC; 1H-NMR (CDCl3,
9H), 6.26ꢁ6.33 (m, 2H), 7.39ꢁ7.45 (m, 3H), 7.54ꢁ7.61 (m,
1H), 7.65ꢁ7.69 ppm (m, 1H); 13C-NMR (CDCl3, 75 MHz) d:
27.5 (3C, q), 84.0 (1C, s), 110.8 (1C, d), 113.4 (1C, s), 116.2
(1C, d), 118.1 (1C, s), 123.2 (1C, d), 127.5 (1C, d), 129.9 (1C,
s), 130.4 (1C, d), 131.9 (1C, d), 132.2 (1C, d), 138.3 (1C, s),
148.6 ppm (1C, s); IR (KBr): 3454 (m), 2983 (w), 2926 (w),
2367 (w), 2343 (w), 1748 (s), 1401 (m), 1340 (m), 1315 (s),
1150 (s), 975 (m), 842 (m), 765 cmꢁ1 (m); HRMS: m/z [M þ
Na]þ calcd for C16H16N2NaO2: 291.1104; found: 291.1110.
N-Boc-2-(3-cyanophenyl)pyrrole (5f). This compound was
obtained as white solid; mp 74ꢁ76ꢂC; 1H-NMR (CDCl3, 300
MHz) d: 1.40 (br.s, 9H), 6.21ꢁ6.27 (m, 2H), 7.38 (dd, 1H, J ¼
3.1, 2.0 Hz), 7.42ꢁ7.49 (m, 1H), 7.55ꢁ7.62 (m, 2H),
7.63ꢁ7.67 ppm (m, 1H); 13C-NMR (CDCl3, 75 MHz) d: 27.6
(3C, q), 84.1 (1C, s), 110.7 (1C, d), 111.7 (1C, s), 115.6 (1C,
d), 118.6 (1C, s), 123.4 (1C, d), 128.3 (1C, d), 130.4 (1C, d),
132.3 (1C, s), 132.6 (1C, d), 133.4 (1C, d), 135.4 (1C, s), 148.9
ppm (1C, s); IR (KBr): 3450 (w), 2231 (m), 1732 (s), 1473 (m),
1394 (m), 1374 (m), 1341 (m), 1323 (s), 1148 (m), 846 (m),
791 (m), 738 (m), 693 cmꢁ1 (m); HRMS: m/z [MþNa]þ calcd
for C16H16N2NaO2: 291.1104; found: 299.1115.
Pyrrolo[1,2-c]quinazolin-5(6H)-one (8). This compound
was obtained as white crystallinic solid; mp 263ꢁ265ꢂC; 1H-
NMR (DMSO-d6, 600 MHz) d: 6.67 (t, 1H, J ¼ 3.3 Hz), 7.00
(dd, 1H, J ¼ 3.5, 1.4 Hz), 7.18ꢁ7.21 (m, 1H), 7.25 (dd, 1H, J
¼ 8.1, 0.5 Hz), 7.30ꢁ7.34 (m, 1H), 7.59 (dd, 1H, J ¼ 3.0, 1.4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

ˇ ´ ´ ´
M. Aleskovic, N. Basaric, and K. Mlinaric-Majerski
1334
Vol 48
Hz), 7.89ꢁ7.92 (m, 1H), 11.46 ppm (br.s, 1H); 13C-NMR
(DMSO-d6, 150 MHz) d: 104.4 (1C, d), 113.7 (1C, d), 114.3
(1C, s), 115.4 (1C, d), 115.5 (1C, d), 122.1 (1C, d), 122.9 (1C,
d), 127.5 (1C, d), 129.1 (1C, s), 132.4 (1C, s), 145.4 ppm (1C,
s); IR (KBr): 3448 (m), 1707 (s), 1596 (m), 1493 (m), 1408
(m), 1341 (w), 718 cmꢁ1 (m); HRMS: m/z [M þ H]þ calcd
for C11H9N2O: 158.0709; found 185.0712.
General procedure for removal of Boc. A suspension of
sodium methoxyde (freshly prepared by reacting 3.0 mmol of
sodium with 10 mL of methanol) was added to a stirred solution
of N-tert-butoxycarbonyl compound 5 (1.0 mmol) in methanol
(20 mL) and stirred at reflux for 3 h, and at 25ꢂC for additional
15 h. The solvent was evaporated, and the residue was parti-
tioned between dichloromethane and water. Water layer was
extracted with dichloromethane (2 ꢀ 25 mL), and the combined
organic extracts were washed with brine (30 mL). Organic
extracts were dried over MgSO4, solvent was evaporated to give
the products quantitatively, which were submitted to further pu-
rification by column chromatography on silica gel.
30% and 28% yield, respectively. It should be noted that this
is not surprising as many of the unprotected pyrrole derivatives
are generally known to be unstable, especially those substi-
tuted with electron donating groups.
2-(2-Aminophenyl)pyrrole (1). This compound was obtained
as white solid; mp 103ꢁ106ꢂC; 1H-NMR (CDCl3, 300 MHz)
d: 3.94 (br.s, 2H), 6.31 (dd, 1H, J ¼ 6.0, 2.7 Hz), 6.40ꢁ6.44
(m, 1H), 6.76 (dd, 1H, J ¼ 7.8, 0.9 Hz), 6.81 (dt, 1H, J ¼ 7.5,
1.2 Hz), 6.86 (dd, 1H, J ¼ 2.7, 1.5 Hz), 7.08 (dt, 1H, J ¼ 7.8,
1.6 Hz), 7.24 (dd, 1H, J ¼ 7.6, 1.4 Hz), 8.59 ppm (br.s, 1H);
13C-NMR (CDCl3, 75 MHz) d: 107.2 (1C, d), 109.3 (1C, d),
116.4 (1C, d), 117.9 (1C, d), 119.0 (1C, d), 119.6 (1C, s),
127.7 (1C, d), 128.3 (1C, d), 129.5 (1C, s), 143.3 ppm (1C, s);
IR (KBr): 3373 (s), 3300 (m), 3204 (m), 1614 (m), 1563 (m),
1497 (m), 1468 (m), 1302 (m), 1137 (m), 1116 (m), 755 (s),
714 cmꢁ1 (s); HRMS: m/z [M]þ calcd for C10H10N2:
158.0838; found: 158.0831 [41].
2-[(2-Aminomethyl)phenyl]pyrrole (2). This compound was
obtained as yellow oil; 1H-NMR (CDCl3, 300 MHz) d: 1.72
(br.s, 2H), 3.91 (s, 2H), 6.27ꢁ6.32 (m, 1H), 6.43ꢁ6.47 (m,
1H), 6.87ꢁ6.91 (m, 1H), 7.16 (dt, 1H, J ¼ 7.4, 1.3 Hz),
7.22ꢁ7.24 (m, 1H), 7.31 (dt, 1H, J ¼ 7.6, 1.5 Hz), 7.61 (dd,
1H, J ¼ 7.7, 1.2 Hz), 12.60 ppm (br. s, 1H); 13C-NMR
(CDCl3, 75 MHz) d: 46.2 (1C, t), 106.8 (1C, d), 108.7 (1C, d),
118.4 (1C, d), 125.9 (1C, d), 128.1 (1C, d), 128.8 (1C, d),
130.9 (1C, d), 132.7 (1C, s), 134.6 (1C, s), 135.3 ppm (1C, s);
IR (KBr): 3434 (s), 2922 (w), 2598 (w), 1486 (m), 1103 (m),
761 (s), 717 cmꢁ1 (s); HRMS: m/z [MþH]þ calcd for
C11H13N2: 173.1073; found: 173.1069.
2-(2-Tolyl)pyrrole (9). This compound was obtained as col-
orless oil; 1H-NMR (CDCl3, 300 MHz) d: 2.45 (s, 3H),
6.30ꢁ6.33 (m, 1H), 6.33ꢁ6.36 (m, 1H), 6.85ꢁ6.87 (m, 1H),
7.16ꢁ7.26 (m, 3H), 7.33ꢁ7.35 (m, 1H), 8.24 ppm (br. s, 1H);
13C-NMR (CDCl3, 75 MHz) d: 21.1 (1C, q), 108.7 (1C, d),
109.1 (1C, d), 117.8 (1C, d), 125.9 (1C, d), 126.7 (1C, d), 127.8
(1C, d), 130.9 (1C, d), 131.2 (1C, s), 132.8 (1C, s), 135.0 ppm
(1C, s); IR (KBr): 3423 (s), 2922 (w), 1489 (m), 1466 (m),
1099 (m), 1035 (m), 757 (s), 718 cmꢁ1 (s); HRMS: m/z
[MþH]þ calcd for C11H12N: 158.0964; found: 158.0967 [42].
2-(2-Nitrophenyl)pyrrole (6a). This compound was obtained
1
as orange oil; H-NMR (CDCl3, 300 MHz) d: 6.31 (dd, 1H, J
¼ 5.8, 2.7 Hz), 6.46ꢁ6.51 (m, 1H), 6.91ꢁ6.94 (m, 1H),
7.31ꢁ7.38 (m, 1H), 7.55 (dt, 1H, J ¼ 7.8, 1.2 Hz), 7.61 (dd,
1H, J ¼ 7.8, 1.2 Hz), 7.69ꢁ7.75 (m, 1H), 8.91 ppm (br.s, 1H);
13C-NMR (CDCl3, 75 MHz) d: 109.1 (1C, d), 110.9 (1C, d),
120.3 (1C, d), 124.3 (1C, d), 126.2 (1C, s), 126.8 (1C, s),
126.9 (1C, d), 130.6 (1C, d), 132.2 (1C, d), 148.0 ppm (1C, s);
IR (KBr): 3343 (s), 1609 (w), 1523 (s), 1482 (m), 1360 (m),
1116 (m), 1036 (m), 851 (w), 827 (w), 745 (s), 679 (w), 591
cmꢁ1 (w); HRMS: m/z [MþH]þ calcd for C10H9N2O2:
189.0659; found: 189.0661.
2-(2-Cyanophenyl)pyrrole (6e). This compound was
obtained as white solid; mp 84ꢁ86ꢂC; 1H-NMR (CDCl3, 300
MHz) d: 6.30ꢁ6.38 (m, 1H), 6.77ꢁ6.85 (m, 1H), 6.99ꢁ7.00
(m, 1H), 7.20ꢁ7.27 (m, 1H), 7.51ꢁ7.58 (m, 1H), 7.60ꢁ7.67
(m, 2H), 9.18 ppm (br. s, 1H); 13C-NMR (CDCl3, 75 MHz) d:
105.9 (1C, s), 110.2 (1C, d), 110.3 (1C, d), 120.0 (1C, s),
120.8 (1C, d), 125.8 (1C, d), 126.5 (1C, d), 128.1 (1C, s),
133.0 (1C, d), 133.9 (1C, d), 135.6 ppm (1C, s). IR (KBr):
3331 (m), 2228 (m), 1599 (w), 1486 (w), 1463 (w), 1135 (m),
1042 (m), 758 (s), 724 (s), 603 cmꢁ1 (w); HRMS: m/z
[MþH]þ calcd for C11H9N2: 169.0760; found: 169.0753.
2-(3-Cyanophenyl)pyrrole (6f). This compound was obtained
as white solid; mp 95ꢁ97ꢂC; 1H-NMR (CDCl3, 300 MHz) d:
6.33 (dd, 1H, J ¼ 6.0, 2.6 Hz), 6.56ꢁ6.63 (m, 1H), 6.88ꢁ6.96
(m, 1H), 7.40ꢁ7.50 (m, 2H), 7.66ꢁ7.70 (m, 1H), 7.74 (br. s,
1H), 8.55 ppm (br.s, 1H); 13C-NMR (CDCl3, 75 MHz) d: 107.5
(1C, d), 110.6 (1C, d), 112.9 (1C, s), 118.7 (1C, s), 120.2 (1C,
d), 126.9 (1C, d), 127.7 (1C, d), 129.1 (1C, d), 129.6 (1C, d),
133.8 ppm (1C, s), 1C is not seen; IR (KBr): 3372 (s), 3365 (s),
2234 (s), 1605 (m), 1468 (m), 1136 (w), 1042 (m), 884 (m),
795(s), 723 (s), 682 (s), 587 cmꢁ1 (m); HRMS: m/z [MþH]þ
calcd for C11H9N2: 169,0760; found: 169.0736.
Acknowledgments. This work was supported by the Croatian
Ministry of Science, Education and Sports, Grant no. 098-
0982933-2911. The authors thank Dr. T. Pace for critical reading
of the manuscript.
REFERENCES
´ ´ ´
[1] Renic, M.; Basaric, N.; Mlinaric-Majerski, K. Tetrahedron
Lett 2007, 48, 7873.
ˇ ´ ´ ´ ˇ
[2] Aleskovic, M.; Basaric, N.; Mlinaric-Majerski, K.; Molca-
´ ´
nov, K.; Kojic-Prodic, B.; Kesharwani, M. K.; Ganguly, B. Tetrahe-
dron 2010, 66, 1689.
[3] Aiello, E.; Dattolo, G.; Cirrincione, G.; Almerico, A. M.;
D’Asdia, I. J Heterocyclic Chem 1981, 18, 1153.
[4] Dattolo, G.; Cirrincione, G; Almerico, A. M.; D’Asdia, I.;
Aiello, E. Heterocycles 1982, 19, 681.
General procedure for hydrogenation. Compounds 6a or
6e (98 mg or 20 mg, respectively) were submitted to hydro-
genation on 10% Pd-C (30 mg or 10 mg, respectively) in abso-
lute methanol (50 mL or 20 mL, respectively) in a Paar appa-
ratus at 60 psi at room temperature for 8 or 2 h, respectively.
The catalyst was filtered off, and the solvent was evaporated
under reduced pressure to afford crude products of amino
derivatives 1 and 2 in 63% and 58% yield, respectively. After
column chromatography on silica gel, 1 and 2 were isolated in
[5] Aiello, E.; Dattolo, G.; Cirrincione, G.; Almerico, A. M.
J Heterocyclic Chem 1984, 21, 721.
[6] Dattolo, G.; Cirrincione, G.; Almerico, A. M.; Aiello, E.;
D’Asdia, I. J Heterocyclic Chem 1986, 23, 1371.
[7] Cirrincione, G.; Almerico, A. M.; Aiello, E.; Dattolo, G.
J Heterocyclic Chem 1990, 27, 983.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2011
Optimization of the Suzuki Coupling Reaction in the Synthesis of
2-[(2-Substituted)phenyl]pyrrole Derivatives
1335
[8] Testa, M. L.; Lamartina, L.; Mingoia, F. Tetrahedron 2004,
60, 5873.
[9] Schmidt, E. Y.; Mikhaleva, A. I.; Vasil’tsov, A. M., Zait-
[25] Alzarez, A.; Guzmen, A.; Ruiz, A.; Velardis, E.; Muchow-
ski, J. J Org Chem 1992, 57, 1653.
[26] Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L.
Angew Chem Int Ed 2006, 45, 3484.
sev, A. B.; Zorina, N. V. Arkivoc 2005, vii, 11.
[10] (a) Trofimov, B. A. In Advanced Heterocyclic Chemistry;
Katritzky, A. R., Ed.; Academic Press: San Diego, 1990; Vol. 51, p
177; (b) Trofimov, B. A. In The Chemistry of Heterocyclic Com-
pounds. Part 2. Pyrroles; Jones, R. A., Ed.; Wiley: New York, 1992;
Vol. 48, p 131; (c) Mikhaleva, A. I.; Schmidt, E. Y. In Selected Meth-
ods for Synthesis and Modification of Heterocycles.; Kartsev, V. G.,
Ed.; IBS Press: Moscow, 2002; Vol. 1, p 334; (d) Trofimov, B. A.;
Mikhaleva, A. I.; Schmidt, E. Y.; Sobenina, L. N. In Advanced Heter-
ocyclic Chemistry; Pyrroles and N-Vinylpyrroles from Ketones and
Acetylenes: Recent Studies; Katritzky, A., Ed., Elsevier: New York,
2010, Vol. 99, Chapter 7, p 209.
[27] Caron, S.; Massett, S. S.; Bogle, D. E.; Castaldi, M. J.; Bra-
ish, T. F. Org Process Res Dev 2001, 5, 254.
´
[28] Dajka-Halasz, B.; Monsieurs, K.; Elias, O.; Karolyhazy, L.;
´
´
´
´
´ ´
Tapolcsanyi, P.; Maes, B. U. W.; Riedl, Z.; Hajos, G.; Dommisse, R.
` ˇ ´
A.; Lemiere, G. L. F.; Kosmrlj, J.; Matyus, P. Tetrahedron 2004, 60,
2283.
[29] Thompson, A. E.; Batsanov, A. S.; Bryce, M. R.; Saygili,
N.; Parryc, P. R.; Tarbit, B. Tetrahedron 2005, 61, 5131.
[30] Thompson, A. E.; Hughes, G.; Batsanov, A. S.; Bryce, M.
R.; Parry, P. R.; Tarbit, B. J. Org Chem 2005, 70, 388.
`
[31] Maes, B. U. W.; Lemiere, G. L. F.; Dommisse, R.; Augus-
[11] Schlosser, M. Organometallics in Synthesis, 2nd ed.; Wiley:
New York, 2002.
tyns, K.; Haemers, A. Tetrahedron 2000, 56, 1777.
[32] Itoh, T.; Mase, T. Tetrahedron Lett 2005, 46, 3573.
¨
[33] Schulz, T.; Torborg, C.; Enthaler, S.; Schaffner, B.; Dum-
[12] Banwell, M. G.; Goodwin, T. E.; Ng, S.; Smith, J. A.;
Wong, D. J. Eur J Org Chem 2006, 3043.
¨
rath, A.; Spannenberg, A.; Neumann, H.: Borner, A.; Beller M. Chem
[13] Collins, I. J Chem Soc, Perkin Trans 2002, 1, 1921.
¨
[14] Schroter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245.
Eur J 2009, 15, 4528.
[34] Vuoti, S.; Autio, J.; Laitila, M.; Haukka, M.; Pursiainen J.
Eur J Inorg Chem 2008, 397.
[15] Rohand, T.; Qin, W.; Boens, N.; Dehaen, W. Eur J Org
Chem 2006, 4658.
[35] Youn, S. W.; Bihn J. H. Tetrahedron Lett 2009, 50, 4598.
[36] Martina, S.; Enkelmann, V.; Wegner, G.; Schlu¨ter, A.-D.
Synthesis 1991, 613.
[16] Setsune, J.; Toda, M.; Watanabe, K.; Panda, P. K.; Yoshida,
T. Tetrahedron Lett 2006, 47, 7541.
[17] Stille, J. K. Pure Appl Chem 1985, 57, 1771.
[18] Miyaura, N.; Suzuki, A. Chem Rev 1995, 95, 2457.
´
[19] Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
[37] Lide, D. R., Ed., CRC Handbook of Chemistry and Physics,
90th ed.; Taylor & Francis Group: Boca Raton, 2009–2010.
[38] Widdowson, D. A.; Wilhelm, R. Chem Commun 2003, 57.
[39] Bandurco, V. T.; Wong, E. M.; Levine, S. D.; Hajos, Z. G.
J Med Chem 1981, 24, 1455.
M. Chem Rev 2002, 102, 1359.
[20] Johnson,C. N.; Stemp, G., Anand, N.; Stephen, S. C.; Gal-
lagher, T. Synlett 1998, 1025.
[40] Brown, D. J.; Quinazolines, Supplement I; The Chemistry
of Heterocyclic Compounds; Wiley: Chichester, 1996, Vol. 55.
[41] The synthesis of 1 has been recently reported. However, 1
was obtained in a very low yield as undesired by-product under condi-
tions of flash-vacuum pyrolysis. Cadogan, J. I. G.; Clark, B. A. J.;
Ford, D.; MacDonald, R. J.; MacPherson, A. D.; McNab, H.; Nicolson,
I. S.; Reed, D.; Sommerville, C. C. Org Biomol Chem 2009, 7, 5173.
[42] Maeda, H.; Haketa, Y.; Nakanishi, T. J Am Chem Soc
2007, 129, 13661.
[21] Thoresen, L. H.; Kim, H.; Welch, M. B.; Burghart, A.; Bur-
gess, K. Synlett 1998, 1276.
[22] Burghart, A.; Kim, H.; Welch, M. B.; Thoresen, L. H.; Rei-
benspies, J.; Burgess, K. J Org Chem 1999, 64, 7813.
[23] Alberico, D.; Scott, M. E.; Lautens, M. Chem Rev 2007,
107, 174.
[24] Gryko, D. T.; Vakuliuk, O.; Gryko, D.; Koszarna, B. J Org
Chem 2009, 74, 9517.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet