New synthesis of methyl 5-aryl or heteroaryl pyrrole-2-carboxylates by a tandem Sonogashira coupling/5-endo-dig-cyclization from β-iododehydroamino acid methyl esters and terminal alkynes

Article abstract of DOI:10.1016/j.tet.2008.08.105

A new and versatile 'Pd'/CuI catalyzed protocol was developed for the synthesis in good to high yields of substituted pyrroles from N-Boc-β-iododehydroamino acid methyl esters and several terminal alkynes. This one-pot, two-step procedure occurs by a Sonogashira coupling followed by a 5-endo-dig-cyclization, which involves the nitrogen atom of the dehydroamino acid. After several experiments using different Pd(0) and Pd(II) species it was possible to establish the more general reaction conditions, which are: the use of a Pd(II) catalyst, CuI and Cs₂CO₃ as base in dry DMF at 70 °C. The best yields were obtained with arylacetylenes bearing electron-donating groups and with electron-rich heteroarylacetylenes.

Full text of DOI:10.1016/j.tet.2008.08.105

Tetrahedron 64 (2008) 10714–10720
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New synthesis of methyl 5-aryl or heteroaryl pyrrole-2-carboxylates
by a tandem Sonogashira coupling/5-endo-dig-cyclization from
b-iododehydroamino acid methyl esters and terminal alkynes
*
Maria-Joa˜o R.P. Queiroz , Agathe Begouin, Goreti Pereira, Paula M.T. Ferreira
Centro de Qu´ımica, Univ. do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2008
Received in revised form 28 August 2008
Accepted 29 August 2008
Available online 17 September 2008
A new and versatile ‘Pd’/CuI catalyzed protocol was developed for the synthesis in good to high yields of
substituted pyrroles from N-Boc-b-iododehydroamino acid methyl esters and several terminal alkynes.
This one-pot, two-step procedure occurs by a Sonogashira coupling followed by a 5-endo-dig-cyclization,
which involves the nitrogen atom of the dehydroamino acid. After several experiments using different
Pd(0) and Pd(II) species it was possible to establish the more general reaction conditions, which are: the
use of a Pd(II) catalyst, CuI and Cs2CO3 as base in dry DMF at 70 ꢀC. The best yields were obtained with
arylacetylenes bearing electron-donating groups and with electron-rich heteroarylacetylenes.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Dehydroamino acids
Sonogashira coupling
Intramolecular cyclization
Pyrroles
1. Introduction
o-iodo-N-mesylanilide afforded indole products in a single step
through a domino process.11
Pyrrole rings are of great interest in organic chemistry as they
can be found in several natural products,1 organic materials2 and
bioactive molecules.3 Especially substituted pyrroles present anti-
bacterial,4a–d antiviral,5a,b anti-inflammatory and antioxidant ac-
tivities.6 The development of practical methods for the preparation
of pyrroles bearing various substituents has become a critical goal
in organic synthesis.7,8a–d The most recent methods are based on
metal-catalyzed reactions.9a–g
For some years now, our research group has been interested in
the linkage of heterocycles to dehydroamino acid derivatives by
palladium-catalyzed Suzuki cross-couplings using either
b-bromo
or -dibromo dehydroamino acids as starting materials. The
b,b
coupling products gave fused heterocycles like indoles, tri- and
tetracyclic heteroaromatic compounds using a new metal-assisted
C–N intramolecular cyclization involving the nitrogen atom of the
dehydroamino acid derivative.12a–e
Crawley et al. synthesized substituted methyl pyrrole-2-carboxyl-
ates from N-acetyl or N-benzyloxycarbonyl-(Z)-b-iododehydroamino
Herein we describe a new approach for the synthesis of
N-(tert-butoxycarbonyl)-2,3,5-substituted pyrroles by a one-pot
two-step reaction: Sonogashira coupling of the methyl ester of
acid derivatives and internal alkynes by a palladium-catalyzed
cyclization.9g
N-Boc-(Z)-
or of N-Boc-(Z)-
-I)-OMe)13 1b with several terminal aryl- and hetero-
b
-iododehydrophenylalanine (Boc-Z-
DPhe(
b-I)-OMe) 1a
Buchwald et al. have developed a domino Cu-catalyzed C–N
coupling/hydroamidation reaction for the synthesis of pyrroles
via an intramolecular cyclization of enyne intermediates obtained
from haloenynes and tert-butylcarbamate by a Cu-catalyzed
amidation. Only the combination of the catalyst with the base
was effective, suggesting that the intramolecular hydroamidation
is both a copper-catalyzed and a base-assisted process.9f
The synthesis of indoles using a Sonogashira coupling10 can
also be performed following one-pot methodologies, since Saka-
moto et al. observed that the treatment of terminal alkynes with
b
-iododehydroaminobutyric acid (Boc-Z-
DAbu-
(b
arylacetylenes, followed by a 5-endo-dig-cyclization (Scheme 1).
To our knowledge this is the first time that dehydroamino acids
and terminal alkynes were used to synthesize substituted pyrroles.
2. Results and discussion
The dehydroamino acid 1a was prepared stereoselectively from
the corresponding (Z)-dehydrophenylalanine, Boc-Z-D
Phe-OMe,14
with N-iodosuccinimide followed by treatment with NEt3.
We studied the Sonogashira coupling of 1a with phenyl-
acetylene to determine the most effective conditions that allowed
* Corresponding author.
E-mail address: mjrpq@quimica.uminho.pt (M.-J.R.P. Queiroz).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.105

M.-J.R.P. Queiroz et al. / Tetrahedron 64 (2008) 10714–10720
10715
Boc
N
intermediate alkyne 2. Heating at 70 ꢀC did not increase the pyrrole
yield (Table 1, entry 6). As the yield for pyrrole 3 was not very high,
it was decided to use Pd(II) catalysts: PdCl2(PPh3)2 (Table 1, entry 7)
and PdCl2(dppf)$CH2Cl2 1:1 (Table 1, entry 8) and both afforded the
corresponding pyrrole in good yields. The best conditions proved to
be those using PdCl2(PPh3)2 (Table 1, entry 7) but Pd(0) proved also
to be efficient at 50 ꢀC or at 70 ꢀC in the tandem reaction, despite
giving the pyrrole 3 in a lower yield (Table 1, entries 5 and 6).
Having these results in hands, it was decided to use both
Pd2(dba)3 (conditions A) and PdCl2(PPh3)2 (conditions B) as the
catalytic species in the reaction of compound 1a with several aryl-
and heteroarylacetylenes in order to compare the results (Table 2).
The best yields were obtained with arylacetylenes bearing
electron-donating groups in the phenyl ring. Thus, pyrroles 4–6
(Table 2, entries 1–3), resulting from the reaction of amino-
phenylacetylenes, were obtained in the highest yields. The
amino groups of pyrroles 5 and 6 may allow further function-
alization. The reaction involving 4-ethynylanisole required the
use of higher temperature (Table 2, entry 4). Using conditions A
at 50 ꢀC both Sonogashira coupling product 7 and pyrrole 8
were obtained whereas increasing the temperature up to 70 ꢀC
provided the sole pyrrole 8 in 50% yield. Almost the same result
was obtained with conditions B. With 2-ethynylanisole (Table 2,
entry 5) using conditions A at 70 ꢀC also afforded the two
H
N
CO2Me
5-endo-dig
cyclization
(Het)Ar
CO2Me
Boc
(Het)Ar
Sonogashira
coupling
R
R
R = Ph or Me
(Het)Ar
H
N
CO2Me
Boc
1a R = Ph
1b R = Me
I
R
Scheme 1. Retrosynthetic analysis of our pyrrole synthesis.
the intramolecular cyclization to occur (Table 1). In all reactions an
excess of phenylacetylene was used, as it is well known that an
important side reaction, namely the Glaser-type oxidative di-
merization of the alkyne, usually occurs in the presence of Cu(I).15
We first chose Pd(0) instead of Pd(II) as we have previously noticed
that the use of the latter sometimes favours the isomerization of
the dehydroamino acid double bond.12e When the triphenylphos-
phine ligand was used (Table 1, entries 1–3) only by-products,
resulting from the hydrodehalogenation of the amino acid de-
rivative and from the oxidative dimerization of the phenyl-
acetylene, were isolated and no starting materials were recovered
at the end of the reaction. In the latter cases we used NEt3
(18 equiv) as base as in the classical Sonogashira coupling condi-
tions.16 We then tried to perform this reaction under amine- and
phosphine-free conditions using Pd2dba3 and Cs2CO3 as base, at rt
(Table 1, entry 4). Thus it was possible to isolate the Sonogashira
coupling product 2 in 30% yield together with the side products
referred above. To promote the formation of pyrrole 3, the mixture
was heated at 50 ꢀC and the pyrrole was obtained in 35% yield
(Table 1, entry 5), resulting from a 5-endo-dig-cyclization of the
products, the intermediate
9 in poor yield (8%) and the
corresponding pyrrole 10 in good yield. In this case however
conditions B were much more efficient as they afforded pyrrole
10 in 65% yield and the intermediate in only 6% yield. Using
3-ethynylanisole and conditions B, pyrrole 11 was obtained as
the only product in good yield (Table 2, entry 6).
The reactions with 4-fluoro and 4-bromophenylacetylenes
afforded the corresponding pyrroles 12 and 13 in moderate yields
using conditions A and B (Table 2, entries 7 and 8). These pyrroles
are also interesting as they may be further functionalized by nu-
cleophilic substitution or cross-coupling reactions.
With heteroarylalkynes it was found that the reaction with the
electron-rich 3-ethynylthiophene afforded the expected pyrrole 14
in good yield, using both conditions (Table 2, entry 9). Electron-
poor ethynylpyridines however were much less reactive: the re-
action with 3-ethynylpyridine (Table 2, entry 10) gave pyrrole 15 in
moderate yields (30–35%) using both conditions, whereas 2-ethy-
nylpyridine did not react, starting materials being isolated.
The Boc group of the synthesized pyrroles can be easily removed
with TFA at rt, thus pyrrole 16 was obtained in quantitative yield
from the corresponding N-protected pyrrole 8 (Scheme 2).
We have also applied conditions B, as they seem to be more
Table 1
Optimization of the reaction conditions
H
N
CO2Me
Ph
Boc
H
N
Catalyst
Base
CO2Me
2
Boc
Ph
+
or
H
Ph
dry DMF
I
Ph
Boc
N
1a
1.5 equiv.
CO2Me
Ph
Ph
1.0 equiv.
general, to the reaction of Boc-Z-DAbu(b
-I)-OMe 1b13 with aryl or
3
heteroarylacetylenes (Scheme 3). In this case the pyrroles obtained
bear a methyl group in position 3 instead of the phenyl group.
Reactions of 1b with 4-ethynyl-N,N-dimethylaniline and 4-
ethynylanisole gave pyrroles 17 and 18 in good to high yields
comparable with those obtained from compound 1a in the syn-
thesis of pyrroles 4 and 8 (Table 2, entries 1 and 4). Reaction of 1b
with 3-ethynylthiophene gave pyrrole 19 in a lower yield (33%)
comparing with the one for pyrrole 14 (55%) obtained from the
dehydrophenylalanine derivative 1a (Table 2, entry 9).
Entry
Catalytic
system
Base
T (ꢀC)/t (h)
Yields (%)
for 2 or 3
da
1
2
3
Pd(PPh3)4 4 mol %
CuI 8 mol %
Pd(PPh3)4 4 mol %
CuI 8 mol %
Pd/C 6 mol %
PPh3 24 mol %
CuI 12 mol %
Pd2dba3 10 mol %
CuI 20 mol %
Pd2dba3 10 mol %
CuI 20 mol %
Pd2dba3 10 mol %
CuI 20 mol %
PdCl2(PPh3)2 5 mol %
CuI 10 mol %
Et3N 18 equiv
Et3N 18 equiv
Et3N 18 equiv
rt/21
70/3
70/3
da
da
4
5
6
7
8
Cs2CO3 2 equiv
Cs2CO3 2 equiv
Cs2CO3 2 equiv
Cs2CO3 2 equiv
Cs2CO3 2 equiv
rt/24
50/4
70/4
70/4
70/4
2, 30
3, 35
3, 33
3, 60
3, 54
In summary, we have developed a new convenient regiose-
lective method for the synthesis of methyl N-Boc-3,5-substituted
pyrrole-2-carboxylates using a tandem Sonogashira coupling/5-
endo-dig-cyclization by reacting N-Boc-b-iododehydroamino acid
methyl esters with terminal aryl or heteroarylalkynes, under ‘Pd’
and Cu(I) catalysis and using Cs2CO3 as base. Both Pd(0) (conditions
A) and Pd(II) species (conditions B) are efficient, although the use of
Pd(II) provides higher yields in some cases. The pyrroles obtained
present an aryl or a heteroaryl substituent in position 5. Some of
them may be further functionalized due to the presence of different
PdCl2(dppf)$CH2Cl2 5 mol %
CuI 10 mol %
a
Only by-products were isolated like phenylacetylene dimers and dehalogenated
dehydrophenylalanine.

10716
M.-J.R.P. Queiroz et al. / Tetrahedron 64 (2008) 10714–10720
Table 2
One-pot two-step pyrrole synthesis from the methyl ester of N-Boc-(Z)-
b-iododehydrophenylalanine (1a) and several aryl and heteroarylacetylenes
Boc
N
H
N
CO2Me
Ph
Ar or
HetAr
"Pd" / CuI
Boc
CO2Me
Ar or
+
HetAr
Cs2CO3 (2 equiv.)
dry DMF, Δ
4-6h, Argon
I
Ph
1.5 equiv.
1a
Entry
1
Phenylacetylenes
Conditions
Time
Product
Yield (%)
Boc
N
(Me)2N
CO2Me
Ph
A
B
5 h
5 h
70
70
N(Me)2
4
Boc
H2N
H2N
N
CO2Me
A
B
5 h
5 h
60
62
2
3
NH2
5
Ph
NH2
Boc
N
A
B
4 h
4 h
61
63
CO2Me
Ph
6
A
A
B
4 h
7: 15, 8: 30
7: 0, 8: 50
7: 0, 8: 48
H
N
70 ꢀC/5 h
CO2Me
Boc
5 h
Boc
N
MeO
Ph
CO2Me
Ph
4
+
OMe
7
8
MeO
MeO
H
N
CO2Me
Ph
Boc
MeO
A
A
B
5 h
9: 14, 10: 25
9: 8, 10: 49
9: 6, 10: 65
Boc
70 ꢀC/6 h
6 h
N
5
6
CO2Me
+
OMe
9
Ph
10
MeO
OMe
Boc
N
B
6 h
55
CO2Me
Ph
11
Boc
F
N
CO2Me
A
B
6 h
6 h
40
43
7
8
9
F
12
Ph
Boc
Br
N
CO2Me
A
B
6 h
6 h
36
41
Br
13
Ph
Boc
S
N
CO2Me
A
B
6 h
6 h
53
55
S
14
Ph
A
B
70 ꢀC/6 h
3 h
30
35
N
Boc
N
CO2Me
10
N
Ph
15
A: amino acid (1.0 equiv), Pd2dba3 (10 mol %), CuI (20 mol %), terminal alkyne (1.5 equiv), Cs2CO3 (2 equiv), dry DMF, under argon, at 50 ꢀC or at 70 ꢀC when specified.
B: PdCl2(PPh3)2 (5 mol %) and CuI (10 mol %) were used as the catalytic system heating at 70 ꢀC.

M.-J.R.P. Queiroz et al. / Tetrahedron 64 (2008) 10714–10720
10717
Boc
N
H
N
ArH) ppm. 13C NMR (75.4 MHz, CDCl3):
d
28.06 (CH3 Boc), 52.36
MeO
MeO
(OCH3), 82.14 (CO2C(CH3)3), 91.78 (C), 128.14 (2ꢁCH), 128.69
(2ꢁCH), 128.81 (CH), 129.49 (C), 140.66 (C), 152.08 (C]O Boc),
162.27(CO2CH3) ppm. Anal. Calcd for C15H18INO4 (403.21): C 44.68;
H 4.50; N 3.47. Found: C 44.70; H 4.64; N 3.78.
CO2Me
TFA, CH2Cl2
r.t.
CO2Me
Ph
Ph
quantitative yield
8
16
Scheme 2. Removal of the N-protecting group using TFA.
3.3. General procedures for the synthesis of pyrroles
Conditions A. In a Schlenk tube, Pd2dba3 (10 mol %) was added
under argon to a solution of N-Boc-(Z)-b-iododehydroamino acid
Boc
Me2N
N
CO2Me
methyl ester in dry DMF (1–2 mL) and the reaction was left stirring
for about 5 min at rt. Then the aryl or heteroarylacetylene
(1.5 equiv), CuI (20 mol %) and Cs2CO3 (2.0 equiv) were successively
added and the solution was stirred at 50 ꢀC for several hours. The
reaction was monitored by TLC, following the disappearance of the
dehydroamino acid. After cooling, the reaction mixture was diluted
with ether and washed three times with water. Then the organic
layer was collected, dried over MgSO4, filtered and concentrated
under reduced vacuum. The resulting oil was purified by column
chromatography.
NMe2
i
17, 76%
H
N
CO2Me
Boc
N
Boc
MeO
i
CO2Me
I
1b
OMe
18, 48%
i
Boc
N
S
S
CO2Me
Conditions B. The same as conditions A but using PdCl2(PPh3)2
(5 mol %) and CuI (10 mol %) as catalytic system and heating at
70 ꢀC.
19, 33%
Scheme 3. (i) Amino acid (1.0 equiv), PdCl2(PPh3)2 (5 mol %), CuI (10 mol %), terminal
alkyne (1.5 equiv), Cs2CO3 (2 equiv), dry DMF, under argon, at 70 ꢀC.
3.3.1. Methyl ester of N-Boc-(Z)-b-(phenylethynyl)-a,b-
dehydrophenylalanine (2)
From compound 1a (80.0 mg, 0.244 mmol) and phenylacetylene
(61.0 mg, 0.367 mmol) following conditions A, but stirring at rt
for 24 h, and after purification by column chromatography using
a solvent gradient from neat petroleum ether to 25% ether/petro-
leumether, compound 2 was obtained as ayellowsolid (28 mg, 30%).
Recrystallization from ether/petroleum ether gave yellow crystals,
substituents in the aryl moiety. The Boc group is easily removed to
give the N-unprotected pyrroles.
3. Experimental
3.1. General
mp 68–69 ꢀC.1H NMR (300 MHz, CDCl3):
d 1.51 (s, 9H, CH3 Boc), 3.62
(s, 3H, OCH3), 6.93 (br s,1H, NH), 7.32–7.41 (m, 8H, 8ꢁArH), 7.48–7.51
(m, 2H, 2ꢁArH) ppm. m/z EI (%) 377.16 (Mþ, 2), 277.11 (MþꢂBoc, 78),
217.09 (82), 216.08 (88), 190.08 (75), 189.07 (100). HRMS: Calcd for
C23H23NO4 [Mþ] 377.1627. Found [Mþ] 377.1628.
Melting points were determined on a Stuart SMP3 apparatus and
are uncorrected. The 1H NMR spectra were measured on a Varian
Unity Plus 300 or on an Avance III 400 Bruker. The 13C NMR spectra
were measured on the same instruments at 75.4 MHz or 100.6 MHz,
respectively. 1H–1H spin–spin decoupling technique was used to
attribute some signals. Heteronuclear correlations 1H, 13C, HMQC
and HMBC were also performed. Mass spectra (EI or ESI) and HRMS
were performed by the mass spectrometry service of University of
Vigo, Spain (CACTI). Elemental analysis was performed in a LECO
CHNS 932 instrument. Column chromatography was performed on
Macherey–Nagel silica gel 230–400 mesh. Petroleum ether refers to
the boiling range 40–60 ꢀC. Ether refers to diethyl ether. When
solvent gradient was used the increase of polarity was done grad-
ually from neat petroleum ether to mixtures of ether/petroleum
ether increasing 5% of ether until the isolation of the product.
3.3.2. Methyl N-Boc-3,5-diphenyl-1H-pyrrole-2-carboxylate (3)
From compound 1a (150 mg, 0.456 mmol) and phenylacetylene
(69.0 mg, 0.688 mmol) and after purification by column chroma-
tography using a solvent gradient from neat petroleum ether to 15%
ether/petroleum ether, pyrrole 3 was obtained as a beige solid
(conditions A: 61.0 mg, 35%; conditions B: 105.0 mg, 60%). Re-
crystallization from ether/petroleum ether gave beige pale crystals,
mp 71–73 ꢀC. 1H NMR (400 MHz, CDCl3):
3.77 (s, 3H, OCH3), 6.30 (s, 1H, 4-H), 7.33–7.47 (m, 8H, ArH), 7.51–
7.55 (m, 2H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3):
27.24 (CH3
d 1.39 (s, 9H, CH3 Boc),
d
Boc), 51.82 (OCH3), 85.16 (CO2C(CH3)3), 113.14 (4-CH), 120.81 (C),
127.41 (CH), 127.97 (4ꢁCH), 128.27 (CH), 129.07 (2ꢁCH), 129.16
(2ꢁCH), 132.16 (C), 132.23 (C), 134.09 (C), 137.65 (C), 149.19 (C]O
Boc), 162.12 (CO2CH3) ppm. m/z EI (%) 377.16 (Mþ, 1), 277.11
(MþꢂBoc, 100), 245.08 (95), 217.09 (96). HRMS: Calcd for
C23H23NO4 [Mþ] 377.1627. Found [Mþ] 377.1629.
3.2. Synthesis of Boc-Z-DPhe(b-I)-OMe (1a)
Boc-Z-
D
Phe-OMe14 (1.39 g, 5.00 mmol) was dissolved in
dichloromethane (0.1 M) and 2.5 equiv of N-iodosuccinimide was
added with vigorous stirring. After reacting for 16 h, triethylamine
(1.5 equiv) was added and stirring continued for 30 min. The sol-
vent was then evaporated at reduced pressure and the residue
partitioned between 100 mL of dichloromethane and 50 mL of
KHSO4 (1 M). The organic phase was washed with KHSO4 (1 M),
NaHCO3 (1 M) and brine (3ꢁ30 mL). After drying over MgSO4 the
extract was taken to dryness at reduced pressure and the residue
was submitted to column chromatography in diethyl ether/petro-
3.3.3. Methyl N-Boc-5-[4-(N,N-dimethylamino)phenyl]-3-phenyl-
1H-pyrrole-2-carboxylate (4)
From compound 1a (80.0 mg, 0.244 mmol) and 4-ethynyl-N,N-
dimethylaniline (53.0 mg, 0.367 mmol) and after purification by
column chromatography using a solvent gradient from neat pe-
troleum ether to 40% ether/petroleum ether, compound 4 was
obtained as a beige solid (conditions A or B: 71.0 mg, 70%). Re-
crystallization from ether/petroleum ether gave beige crystals, mp
leum ether (1:4) to afford Boc-Z-
a yellow solid. Recrystallization from ether/n-hexane gave yellow
crystals, mp 126–127 ꢀC. 1H NMR (300 MHz, CDCl3):
1.49 (s, 9H,
CH3 Boc), 3.48 (s, 3H, OCH3), 6.39 (s, 1H, NH), 7.26–7.31 (br s, 5H,
DPhe(b-I)-OMe (1.75 g, 87%) as
138–140 ꢀC. 1H NMR (300 MHz, CDCl3):
d 1.46 (s, 9H, CH3 Boc), 3.01
(s, 6H, N(CH3)2), 3.75 (s, 3H, OCH3), 6.23 (s, 1H, 4-H), 6.74 (d,
J¼8.7 Hz, 2H, 30-H and 50-H), 7.33–7.42 (m, 5H, ArH), 7.52–7.56 (m,
d

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M.-J.R.P. Queiroz et al. / Tetrahedron 64 (2008) 10714–10720
2H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3):
d
27.35 (CH3 Boc), 40.38
m/z EI (%) 407.17 (Mþ, 3), 307.12 (MþꢂBoc, 72), 275.09 (40), 247.10
(N(CH3)2), 51.57 (OCH3), 84.86 (CO2C(CH3)3), 111.54 (30-CH and 50-
CH), 112.34 (4-CH), 119.47 (C), 119.85 (C), 127.26 (CH), 127.82
(2ꢁCH), 129.23 (2ꢁCH), 130.04 (2ꢁCH), 132.92 (C), 134.50 (C),
138.92 (C),149.69 (C]O Boc),150.4 (40-C),161.92 (CO2CH3) ppm. m/z
EI (%) 420.21 (Mþ, 2), 320.15 (MþꢂBoc, 76), 288.12 (100), 260.13
(76), 259.12 (54), 216.08 (22). HRMS: Calcd for C24H25NO5 [Mþ]
420.2049. Found [Mþ] 420.2045.
(65), 246.09 (100), 220.09 (42), 203.07 (42), 176.06 (43). HRMS:
Calcd for C24H25NO5 [Mþ] 407.1733. Found [Mþ] 407.1730.
As the less polar, compound 8 was isolated as a yellow solid
(38.0 mg, 30%) (Table 2) described below.
3.3.7. Methyl N-Boc-5-(4-methoxyphenyl)-3-phenyl-1H-pyrrole-2-
carboxylate (8)
From compound 1a (150 mg, 0.456 mmol) and 4-ethynylanisole
(91.0 mg, 0.688 mmol) and after purification by column chroma-
tography using a solvent gradient from neat petroleum ether to 25%
ether/petroleum ether, compound 8 was obtained as a yellow solid
(conditions A heating at 70 ꢀC: 94.0 mg, 50%; conditions B: 90.0 mg,
48%). Recrystallization from ether/petroleum ether gave yellow
3.3.4. Methyl N-Boc-5-(4-aminophenyl)-3-phenyl-1H-pyrrole-2-
carboxylate (5)
From compound 1a (80.0 mg, 0.244 mmol) and 4-ethynylaniline
(43.0 mg, 0.367 mmol), and after purification by column chroma-
tography using a solvent gradient from neat petroleum ether to 40%
ether/petroleum ether, compound 5 was obtained as a beige solid
(conditions A: 57.0 mg, 60%; conditions B: 59.0 mg, 62%). Re-
crystallization from ether/petroleum ether gave beige crystals, mp
pale crystals, mp 94–96 ꢀC. 1H NMR (400 MHz, CDCl3):
d 1.42 (s, 9H,
CH3 Boc), 3.76 (s, 3H, CO2CH3), 3.86 (s, 3H, OCH3), 6.25 (s, 1H, 4-H),
6.94 (d, J¼8.8 Hz, 2H, 30-H and 50-H), 7.33–7.41 (m, 5H, ArH), 7.52–
114–116 ꢀC. 1H NMR (400 MHz, CDCl3):
d
1.44 (s, 9H, CH3 Boc), 3.75
7.53 (m, 2H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3):
d 27.31 (CH3
(s, 3H, OCH3), 3.80 (br s, 2H, NH2), 6.22 (s, 1H, 4-H), 6.70 (d,
J¼8.4 Hz, 2H, 30-H and 50-H), 7.26 (d, J¼8.4 Hz, 2H, 20-H and 60-H),
7.32–7.41 (m, 3H, ArH), 7.52–7.54 (m, 2H, ArH) ppm. 13C NMR
Boc), 51.71 (CO2CH3), 55.30 (OCH3), 85.07 (CO2C(CH3)3), 112.89 (4-
CH), 113.39 (30-CH and 50-CH), 120.42 (C), 124.41 (C), 127.36 (CH),
127.91 (2ꢁCH), 129.12 (2ꢁCH), 130.53 (2ꢁCH), 132.45 (C), 134.21
(C), 137.77 (C), 149.38 (C]O Boc), 159.73 (40-C), 162.02 (CO2CH3)
ppm. m/z EI (%) 407.17 (Mþ, 1), 307.12 (MþꢂBoc, 88), 275.09 (100),
247.10 (38), 232.08 (36), 204.08 (32). HRMS: Calcd for C24H25NO5
[Mþ] 407.1733. Found [Mþ] 407.1729.
(100.6 MHz, CDCl3):
d 27.31 (CH3 Boc), 51.60 (OCH3), 84.95
(CO2C(CH3)3), 112.47 (4-CH), 114.30 (30-CH and 50-CH), 119.98 (C),
121.85 (C),127.28 (CH),127.83 (2ꢁCH),129.17 (2ꢁCH),130.33 (20-CH
and 60-CH), 132.69 (C), 134.37 (C), 138.48 (C), 146.69 (C), 149.58
(C]O Boc),162.92 (CO2CH3) ppm. m/z EI (%) 392.17 (Mþ, 12), 292.09
(MþꢂBoc, 92), 260.06 (98), 232.07 (100), 231.07 (84). HRMS: Calcd
for C23H24N2O4 [Mþ] 392.1736. Found [Mþ] 392.1731.
3.3.8. Methyl ester of N-Boc-(Z)-b-(2-methoxyphenylethynyl)-a,b-
dehydrophenylalanine (9) and methyl N-Boc-5-(2-methoxyphenyl)-
3-phenyl-1H-pyrrole-2-carboxylate (10)
3.3.5. Methyl N-Boc-5-(3-aminophenyl)-3-phenyl-1H-pyrrole-2-
carboxylate (6)
From compound 1a (150 mg, 0.456 mmol) and 2-ethynylani-
sole (91.0 mg, 0.688 mmol) and after purification by column
chromatography using a solvent gradient from neat petroleum
ether to 30% ether/petroleum ether compounds 9 and 10 were
obtained, the most polar product isolated as a yellow solid was
shown to be compound 9 (conditions A: 26.0 mg, 14%; condi-
tions A heating at 70 ꢀC: 15.0 mg, 8%; conditions B: 11.0 mg, 6%).
Recrystallization from ether/petroleum ether gave yellow crys-
From compound 1a (80.0 mg, 0.244 mmol) and 3-ethynylaniline
(43.0 mg, 0.367 mmol), and after purification by column chroma-
tography using a solvent gradient from neat petroleum ether to 40%
ether/petroleum ether, compound 6 was obtained as a brown oil
(conditions A: 58.0 mg, 61%; conditions B: 60.0 mg, 63%). Re-
crystallization from ether/petroleum ether gave brown crystals, mp
83–86 ꢀC. 1H NMR (300 MHz, CDCl3):
d
1.42 (s, 9H, CH3 Boc), 3.76
tals, mp 68–70 ꢀC. 1H NMR (300 MHz, CDCl3):
d 1.45 (s, 9H, CH3
(s, 3H, OCH3), 6.27 (s, 1H, 4-H), 6.70–6.77 (m, 2H, ArH), 6.82–6.86
(m, 1H, ArH), 7.16–7.21 (dd, J¼8.1 and 8.1 Hz, 1H, Ar-H), 7.34–7.42
(m, 3H, ArH), 7.51–7.54 (m, 2H, ArH) ppm. 13C NMR (100.6 MHz,
Boc), 3.87 (s, 3H, OCH3), 3.96 (s, 3H, CO2CH3), 6.25 (br s, 1H,
NH), 6.85–6.92 (m, 2H, 2ꢁArH), 7.26–7.47 (m, 5H, 5ꢁArH), 7.57
(d, J¼7.2 Hz, 2H, 2ꢁArH) ppm. 13C NMR (75.4 MHz, CDCl3):
CDCl3):
d
27.31 (CH3 Boc), 51.84 (OCH3), 85.31 (CO2C(CH3)3), 113.26
d 28.07 (CH3 Boc), 52.43 (CO2CH3), 55.73 (OCH3), 81.87
(4-CH), 117.50 (CH), 118.25 (CH), 120.91 (C), 122.83 (CH), 127.43
(CH), 127.98 (2ꢁCH), 129.07 (2ꢁCH), 129.15 (CH), 132.12 (C), 133.56
(C), 134.01 (C), 137.03 (C), 140.85 (C), 149.13 (C]O Boc), 162.08
(CO2CH3) ppm. m/z ESI (%) 393.18 (MþþH, 56), 337.12 (58), 293.13
(MþþH-Boc, 100). HRMS: Calcd for C23H24N2O4 [MþþH] 393.1809.
Found [MþþH] 393.1818.
(CO2C(CH3)3), 92.05 (C), 110.33 (C), 110.71 (CH), 120.39 (CH),
128.20 (C), 128.25 (CH), 128.56 (CH), 128.80 (2ꢁCH), 128.91
(2ꢁCH), 129.96 (CH), 130.23 (C), 133.41 (50-CH), 135.45 (C), 151.79
(C]O Boc), 160.08 (20-C), 164.90 (CO2CH3) ppm. m/z EI (%) 407.17
(Mþ, 3), 333.10 (Mþꢂ74, 21), 307.12 (Mþꢂ100, 100), 247.09
(Mþꢂ160, 39), 246.09 (Mþꢂ161, 92), 232.08 (Mþꢂ175, 34),
191.09 (Mþꢂ216, 39), 176.06 (Mþꢂ231, 36). HRMS: Calcd for
C24H25NO5 [Mþ] 407.1733. Found [Mþ] 407.1724.
3.3.6. Methyl ester of N-Boc-(Z)-
-dehydrophenylalanine (7)
Following conditions A, from compound 1a (100 mg,
b-(4-methoxyphenylethynyl)-
a,
b
As the less polar, compound 10 was obtained as a yellow
solid (conditions A: 47.0 mg, 25%; conditions A heating at 70 ꢀC:
92.0 mg, 49%; conditions B: 122.0 mg, 65%). Recrystallization
from ether/petroleum ether gave yellow crystals, mp 127–129 ꢀC.
0.306 mmol) and 4-ethynylanisole (61.0 mg, 0.459 mmol), heating
at 50 ꢀC for 4 h and after purification by column chromatography
using a solvent gradient from neat petroleum ether to 10% ether/
petroleum ether, the most polar product isolated as a yellow solid
was shown to be compound 7 (19.0 mg, 15%). Recrystallization from
ether/petroleum ether gave yellow crystals, mp 119–121 ꢀC. 1H
1H NMR (400 MHz, CDCl3):
d 1.35 (s, 9H, CH3 Boc), 3.78 (s, 3H,
OCH3), 3.78 (s, 3H, OCH3), 6.26 (s, 1H, 4-H), 6.91 (dd, J¼8.0 and
0.8 Hz, 1H, 30-H), 7.02 (ddd, J¼7.4, 7.4 and 0.8 Hz, 1H, 50-H),
7.32–7.41 (m, 5H, 5ꢁArH), 7.55 (d, J¼7.4 Hz, 2H, 2ꢁArH) ppm.
NMR (400 MHz, CDCl3):
d
1.44 (s, 9H, CH3 Boc), 3.81 (s, 3H, OCH3),
13C NMR (100.6 MHz, CDCl3):
d 27.21 (CH3 Boc), 51.93 (OCH3),
3.95 (s, 3H, CO2CH3), 6.22 (br s, 1H, NH), 6.84 (d, J¼8.8 Hz, 2H, 30-H
55.24 (OCH3), 84.09 (CO2C(CH3)3), 110.01 (30-CH), 113.33 (4-CH),
120.39 (50-CH), 121.13 (C), 122.36 (C), 127.25 (CH), 128.02 (2ꢁCH),
128.83 (2ꢁCH), 129.75 (CH), 130.77 (CH), 131.14 (C), 134.03 (C),
148.66 (C]O Boc), 156.99 (20-C), 162.78 (CO2CH3) ppm. m/z EI
(%) 407.17 (Mþ, 2), 307.12 (100), 247.10 (35), 246.09 (75), 176.06
(12), 118.05 (14). HRMS: Calcd for C24H25NO5 [Mþ] 407.1733.
Found [Mþ] 407.1739.
and 50-H), 7.34–7.39 (m, 3H, Ar-H), 7.42–7.46 (m, 2H, ArH), 7.50–
7.53 (m, 2H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3):
d 28.05 (CH3
Boc), 52.39 (OCH3), 55.28 (CO2CH3), 81.84 (CO2C(CH3)3), 86.19 (C),
95.60 (C), 113.95 (30-CH and 50-CH), 115.18 (C), 128.48 (C), 128.58
(CH), 128.62 (2ꢁCH), 128.97 (2ꢁCH), 131.77 (C), 133.10 (2ꢁCH),
135.63 (C), 151.83 (C]O Boc), 159.84 (40-C), 164.97 (CO2CH3) ppm.

M.-J.R.P. Queiroz et al. / Tetrahedron 64 (2008) 10714–10720
10719
3.3.9. Methyl N-Boc-5-(3-methoxyphenyl)-3-phenyl-1H-pyrrole-2-
carboxylate (11)
55%). Recrystallization from ether/petroleum ether gave yellow
crystals, mp 69–71 ꢀC. 1H NMR (300 MHz, CDCl3):
1.47 (s, 9H, CH3
d
From compound 1a (80.0 mg, 0.244 mmol) and 3-ethynylani-
sole (49.0 mg, 0.367 mmol) and after purification by column
chromatography using a solvent gradient from neat petroleum
ether to 25% ether/petroleum ether, compound 11 was obtained as
a yellow oil (conditions B: 55.0 mg, 55%). Recrystallization from
ether/petroleum ether gave yellow crystals, mp 99–101 ꢀC. 1H NMR
Boc), 3.76 (s, 3H, OCH3), 6.33 (s, 1H, 4-H), 7.23 (dd, J¼5.0 and 1.2 Hz,
1H, ArH), 7.33–7.45 (m, 5H, ArH), 7.50–7.53 (m, 2H, ArH) ppm. 13C
NMR (75.4 MHz, CDCl3):
d 27.33 (CH3 Boc), 51.77 (OCH3), 85.31
(CO2C(CH3)3), 113.31 (4-CH), 120.60 (C), 124.51 (CH), 124.95 (CH),
127.44 (CH), 127.94 (2ꢁCH), 128.87 (CH), 129.10 (2ꢁCH), 131.90 (C),
132.42 (C), 132.77 (C), 134.06 (C), 149.38 (C]O Boc), 161.93
(CO2CH3) ppm. m/z EI (%) 383.12 (Mþ, 5), 341.32 (32), 327.26 (25),
283.06 (MþꢂBoc, 30), 251.04 (35), 81.07 (84), 69.07 (100). HRMS:
Calcd for C21H21NO4S [Mþ] 383.1191. Found [Mþ] 383.1202.
(300 MHz, CDCl3): d 1.41 (s, 9H, CH3 Boc), 3.77 (s, 3H, CO2CH3), 3.84
(s, 3H, OCH3), 6.31 (s, 1H, 4-H), 6.92–7.05 (m, 3H, ArH), 7.27–7.43
(m, 4H, ArH), 7.52–7.55 (m, 2H, ArH) ppm. 13C NMR (75.4 MHz,
CDCl3):
d 27.25 (CH3 Boc), 51.81 (CO2CH3), 55.20 (OCH3), 85.17
(CO2C(CH3)3), 113.05 (4-CH), 114.04 (CH), 114.61 (CH), 120.71 (C),
121.53 (CH), 127.41 (CH), 127.95 (2ꢁCH), 129.01 (2ꢁCH), 129.07
(CH), 132.14 (C), 133.40 (C), 134.07 (C), 137.42 (C), 149.17 (Cþ]O Boc),
159.15 (40-C), 162.05 (CO2CH3) ppm. m/z ESI (%) 408.18 (M þH, 46),
384.11 (3), 352.11 (18), 320.18 (13), 255.16 (71), 233.18 (100). HRMS:
Calcd for C24H25NO5 [MþþH] 408.1806. Found [MþþH] 408.1799.
3.3.13. Methyl N-Boc-5-(pyridin-3-yl)-3-phenyl-1H-pyrrole-2-
carboxylate (15)
From compound 1a (100 mg, 0.306 mmol) and 3-ethynylpyr-
idine (48.0 mg, 0.459 mmol) and after purification by column
chromatography using a solvent gradient from neat petroleum
ether to 40% ether/petroleum ether, compound 15 was obtained as
a yellow solid (conditions A: 34.0 mg, 30%; conditions B: 40.0 mg,
35%). Recrystallization from ether/petroleum ether gave yellow
3.3.10. Methyl N-Boc-5-(4-fluorophenyl)-3-phenyl-1H-pyrrole-2-
carboxylate (12)
pale crystals, mp 89–91 ꢀC. 1H NMR (400 MHz, CDCl3):
d 1.40 (s, 9H,
From compound 1a (100 mg, 0.306 mmol) and 1-fluoro-4-
ethynylbenzene (55.0 mg, 0.459 mmol) and after purification by
column chromatography using a solvent gradient from neat pe-
troleum ether to 20% ether/petroleum ether, compound 12 was
obtained as a yellow solid (conditions A: 49.0 mg, 40%; conditions
B: 53.0 mg, 43%). Recrystallization from ether/petroleum ether
gave yellow pale crystals, mp 89–91 ꢀC. 1H NMR (400 MHz, CDCl3):
CH3 Boc), 3.79 (s, 3H, OCH3), 6.37 (s, 1H, 4-H), 7.32–7.42 (m, 4H,
ArH), 7.50–7.53 (m, 2H, ArH), 7.80 (br d, J¼8.1 Hz, 1H, ArH), 8.63–
8.71 (m, 2H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3):
d 27.35 (CH3
Boc), 52.10 (OCH3), 85.78 (CO2C(CH3)3), 114.48 (4-CH), 122.30 (C),
122.95 (CH), 127.66 (CH), 128.16 (2ꢁCH), 128.80 (2ꢁCH), 131.70 (C),
133.48 (C), 133.83 (C), 136.92 (CH), 148.66 (C]O Boc), 148.90 (CH),
149.55 (CH), 162.33 (CO2CH3) ppm. m/z EI (%) 378.16 (Mþ, 8), 278.10
(MþꢂBoc, 100), 246.07 (78), 218.08 (59). HRMS: Calcd for
C24H25NO5 [Mþ] 378.1580. Found [Mþ] 378.1567.
d
1.41 (s, 9H, CH3 Boc), 3.78 (s, 3H, OCH3), 6.28 (s, 1H, 4-H), 7.11 (m,
2H, 30-H and 50-H), 7.32–7.46 (m, 5H, ArH), 7.51–7.54 (m, 2H, ArH)
ppm. 13C NMR (100.6 MHz, CDCl3):
27.30 (CH3 Boc), 51.86 (OCH3),
d
85.33 (CO2C(CH3)3), 113.39 (4-CH), 114.98 (d, J¼22 Hz, 30-CH and 50-
CH), 121.01 (C), 127.49 (CH), 128.01 (2ꢁCH), 129.00 (2ꢁCH), 131.07
(d, J¼8 Hz, 20-CH and 60-CH), 131.15 (C), 132.07 (C), 133.91 (C),
136.59 (C), 149.08 (C]O Boc), 162.11 (CO2CH3), 162.79 (d,
J¼248.5 Hz, CF) ppm. m/z EI (%) 395.15 (Mþ, 1), 295.10 (MþꢂBoc,
100), 263.07 (100), 235.08 (98). HRMS: Calcd for C23H23NO4 [Mþ]
395.1533. Found [Mþ] 395.1535.
3.3.14. Methyl N-Boc-5-[4-(N,N-dimethylamino)phenyl]-3-methyl-
1H-pyrrole-2-carboxylate (17)
From compound 1b (80.0 mg, 0.235 mmol) and 4-ethynyl-N,N-
dimethylaniline (51.0 mg, 0.352 mmol) and after purification by
column chromatography using a solvent gradient from neat pe-
troleum ether to 25% ether/petroleum ether, compound 17 was
obtained as a yellow pale solid (conditions B: 64.0 mg, 76%). Re-
crystallization from ether/petroleum ether gave white crystals, mp
3.3.11. Methyl N-Boc-5-(4-bromophenyl)-3-phenyl-1H-pyrrole-2-
carboxylate (13)
114–115 ꢀC. 1H NMR (400 MHz, CDCl3):
d 1.44 (s, 9H, CH3 Boc), 2.32
(s, 3H, 3-CH3), 2.99 (s, 6H, N(CH3)2), 3.86 (s, 3H, OCH3), 5.99 (s, 1H,
From compound 1a (100 mg, 0.306 mmol) and 1-bromo-4-
ethynylbenzene (86.0 mg, 0.459 mmol) and after purification by
column chromatography using a solvent gradient from neat pe-
troleum ether to 20% ether/petroleum ether, compound 13 was
obtained as a yellow solid (conditions A: 50.0 mg, 36%; conditions
B: 57.0 mg, 41%). Recrystallization from ether/petroleum ether gave
4-H), 6.71 (d, J¼8.8 Hz, 2H, ArH), 7.31 (d, J¼8.8 Hz, 2H, ArH) ppm.
13C NMR (100.6 MHz, CDCl3):
d 12.86 (3-CH3), 27.33 (CH3 Boc),
40.39 (N(CH3)2), 51.20 (OCH3), 84.46 (CO2C(CH3)3), 111.60 (2ꢁCH),
112.79 (4-CH), 119.47 (C), 120.59 (C), 129.93 (2ꢁCH), 133.60 (C),
139.41 (C), 150.21 (C), 150.34 (C]O Boc), 161.65 (CO2CH3) ppm. m/z
ESI (%) 381.18 (MþþNa, 4), 359.20 (MþþH, 100), 303.13 (16), 259.14
(MþþH-Boc, 14). HRMS: Calcd for C20H26N2O4 [MþþH] 359.1965.
Found [MþþH] 359.1976.
off-white crystals, mp 89–91 ꢀC. 1H NMR (400 MHz, CDCl3):
d 1.43
(s, 9H, CH3 Boc), 3.77 (s, 3H, OCH3), 6.30 (s, 1H, 4-H), 7.32–7.41 (m,
5H, ArH), 7.50–7.56 (m, 4H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3):
d
27.32 (CH3 Boc), 51.92 (OCH3), 85.51 (CO2C(CH3)3), 113.53 (4-CH),
3.3.15. Methyl N-Boc-5-(4-methoxyphenyl)-3-methyl-1H-pyrrole-
2-carboxylate (18)
121.37 (C), 122.55 (C), 127.53 (CH), 128.03 (2ꢁCH), 128.96 (2ꢁCH),
130.76 (2ꢁCH), 131.14 (2ꢁCH), 132.01 (C), 133.80 (C), 136.36 (C),
148.96 (C]O Boc),162.13 (CO2CH3) ppm. m/z EI (%) 457.07 (Mþ 81Br,
11), 455.05 (Mþ 79Br,10), 357.01 (Mþ 81Br-Boc, 65), 355.01 (Mþ 79Br-
Boc, 71), 324.98 (Mþ 81Br-132, 73), 322.99 (Mþ 79Br-132, 80), 216.08
(100). HRMS: Calcd for C23H22BrNO4 [Mþ 81Br] 457.0712, [Mþ 79Br]
455.0732. Found [Mþ 81Br] 457.0690, [Mþ 79Br] 455.0723.
From compound 1b (80.0 mg, 0.235 mmol) and 4-ethynylanisole
(47.0 mg, 0.352 mmol) and after purification by column chroma-
tography using a solvent gradient from neat petroleum ether to 15%
ether/petroleum ether, compound 18 was obtained as a yellow pale
solid (conditions B: 27.0 mg, 33%). Recrystallization from ether/pe-
troleum ether gave white crystals, mp 110–111 ꢀC. 1H NMR
(300 MHz, CDCl3): d 1.41 (s, 9H, CH3 Boc), 2.32 (s, 3H, 3-CH3), 3.84 (s,
3.3.12. Methyl N-Boc-5-(thien-3-yl)-3-phenyl-1H-pyrrole-2-
carboxylate (14)
3H, OCH3), 3.86 (s, 3H, OCH3), 6.00 (s,1H, 4-H), 6.91 (d, J¼9.0 Hz, 2H,
ArH), 7.35 (d, J¼9.0 Hz, 2H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3):
From compound 1a (100 mg, 0.306 mmol) and 3-ethynylth-
iophene (50.0 mg, 0.459 mmol) and after purification by column
chromatography using a solvent gradient from neat petroleum
ether to 10% ether/petroleum ether, compound 14 was obtained as
a yellow solid (conditions A: 63.0 mg, 53%; conditions B: 65.0 mg,
d 12.77 (3-CH3), 27.28 (CH3 Boc), 51.33 (OCH3), 55.28 (OCH3), 84.68
(CO2C(CH3)3), 113.34 (4-CH), 113.37 (2ꢁCH), 121.02 (C), 124.23 (C),
130.40 (2ꢁCH), 130.41 (C), 138.34 (C), 149.91 (C), 159.68 (C]O),
161.64 (C]O) ppm. Anal. Calcd for C19H23NO5: C, 66.07; H, 6.71; N,
4.06. Found: C, 66.11; H, 6.75; N, 4.04.

10720
M.-J.R.P. Queiroz et al. / Tetrahedron 64 (2008) 10714–10720
3.3.16. Methyl N-Boc-5-(thien-3-yl)-3-methyl-1H-pyrrole-2-
carboxylate (19)
References and notes
1. Lindel, T.; Breckle, G.; Hochgu¨ rtel, M.; Volk, C.; Grube, A.; Ko¨ck, M. Tetrahedron
Lett. 2004, 45, 8149.
2. (a) Nova´k, P.; Mu¨ller, K.; Santhanam, K. S. V.; Haas, O. Chem. Rev. 1997, 97, 207;
(b) Higgins, S. J. Chem. Soc. Rev. 1997, 26, 247.
3. Snyder, L. B.; Meng, Z.; Mate, R.; D’Andrea, S. V.; Marinier, A.; Quesnelle, C. A.;
Gill, P.; DenBleyker, K. L.; Fung-Tomc, J. C.; Frosco, M. B.; Martel, A.; Barrett, J. F.;
Bronson, J. J. Bioorg. Med. Chem. Lett. 2004, 14, 4735.
From compound 1b (80.0 mg, 0.235 mmol) and 3-ethynylth-
iophene (38.0 mg, 0.352 mmol) and after purification by column
chromatography using a solvent gradient from neat petroleum
ether to 25% ether/petroleum ether, compound 19 was obtained as
a yellow oil (conditions B: 36.0 mg, 48%). 1H NMR (400 MHz,
CDCl3):
d 1.46 (s, 9H, CH3 Boc), 2.31 (s, 3H, 3-CH3), 3.86 (s, 3H,
4. (a) Silvestri, R.; Artico, M.; La Regina, G.; De Martino, G.; La Colla, M.; Loddo, R.;
La Colla, P. Farmaco 2004, 59, 201; (b) Dannhardt, G.; Kiefer, W.; Kra¨mer, G.;
Maehrlein, S.; Nowe, U.; Fiebich, B. Eur. J. Med. Chem. 2000, 35, 499; (c) Ragno,
R.; Marshall, G. R.; Santo, R. D.; Costi, R.; Massa, S.; Rompei, R.; Artico, M. Bioorg.
Med. Chem. 2000, 8, 1423; (d) Unverferth, K.; Engel, J.; Ho¨fgen, N.; Rostock, A.;
Gu¨ nther, R.; Lankau, H. J.; Menzer, M.; Rolfs, A.; Liebscher, J.; Mu¨ller, B.; Hof-
mann, H. J. J. Med. Chem. 1998, 41, 63.
5. (a) Biava, M.; Porretta, G. C.; Poce, G.; Supino, S.; Forli, S.; Rovini, M.; Cappelli,
A.; Manetti, F.; Botta, M.; Sautebin, L.; Rossi, A.; Pergola, C.; Ghelardini, C.;
Vivoli, E.; Makovec, F.; Anzellotti, P.; Patrignani, P.; Anzini, M. J. Med. Chem.
2007, 50, 5403; (b) Harrak, Y.; Rosell, G.; Daidone, G.; Plescia, S.; Schillaci, D.;
Pujol, M. D. Bioorg. Med. Chem. 2007, 15, 4876.
OCH3), 6.09 (s, 1H, 4-H), 7.19 (dd, J¼5.2 and 1.2 Hz, 2H, ArH), 7.32
(dd, J¼5.2 and 3.2 Hz, 2H, ArH), 7.41 (dd, J¼3.2 and 1.2 Hz, 2H, ArH)
ppm. 13C NMR (100.6 MHz, CDCl3):
d 12.74 (3-CH3), 27.31 (CH3 Boc),
51.37 (OCH3), 84.93 (CO2C(CH3)3), 113.62 (4-CH), 121.19 (C), 124.20
(CH), 124.95 (CH), 128.66 (CH), 130.28 (C), 131.17 (C), 133.29 (C),
149.99 (C]O Boc), 161.56 (CO2CH3) ppm. m/z ESI (%) 344.09
(MþþNa, 18), 318.08 (26), 279.09 (15), 238.05 (49), 222.06 (MþþH-
Boc, 83), 190.04 (100). HRMS: Calcd for C16H19NO4S [MþþNa]
344.0927. Found [MþþNa] 344.0929.
6. Lehue´de´, J.; Fauconneau, B.; Barrier, L.; Ourakow, M.; Piriou, A.; Vierfonf, J.-M.
Eur. J. Med. Chem. 1999, 34, 991.
7. For recent reviews: (a) Patil, N. T.; Yamamoto, Y. Arkivoc 2007, 10, 121; (b)
Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213.
3.4. Synthesis of methyl 5-(4-methoxyphenyl)-3-phenyl-1H-
pyrrole-2-carboxylate (16)
8. (a) Kassaee, M. Z.; Masrouri, H.; Movahedi, F.; Partovi, T. Helv. Chim. Acta 2008,
91, 227; (b) Bhatt, U.; Duffy, B. C.; Guzzo, P. R. Synth. Commun. 2007, 37, 2793; (c)
Aydogan, F.; Basarir, M.; Yolacan, C.; Demir, A. S. Tetrahedron 2007, 63, 9746; (d)
Vizer, S. A.; Dedeshko, E. H.; Yerzhanov, K. B.; Dembitsky, V. M. Heteroat. Chem.
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9. (a) Chiba, S.; Wang, Y.-F.; Lapointe, G.; Narasaka, K. Org. Lett. 2008, 10, 313; (b)
Prior, A. M.; Robinson, R. S. Tetrahedron Lett. 2008, 49, 411; (c) Cadierno, V.;
Gimeno, J.; Nebra, N. Chem.dEur. J. 2007, 13, 9973; (d) Martin, R.; Larsen, C. H.;
Cuanca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 3379; (e) Dong, H.; Shen, M.;
Redford, J. E.; Stokes, B. J.; Pumphrey, A. L.; Driver, T. G. Org. Lett. 2007, 9, 5191;
(f) Martin, R.; Rivero, M. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45,
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To a solution of N-protected pyrrole 8 (40.0 mg, 0.0980 mmol) in
CH2Cl2 (3 mL), TFA (1 mL) was added and the reaction mixture was
then stirred at rt for about 2 h. Then, the solution was diluted with
more CH2Cl2, washed with NaHCO3 1 M (3ꢁ10 mL) and brine, dried
over MgSO4, filtered and concentrated under vacuum. Pyrrole 16
was obtained as a beige solid (30.0 mg, quantitative yield). Re-
crystallization from ether/petroleum ether gave beige crystals, mp
134–136 ꢀC. 1H NMR (400 MHz, CDCl3):
d 3.81 (s, 3H, CO2CH3), 3.86
(s, 3H, OCH3), 6.54 (d, J¼3.2 Hz, 1H, 4-H), 6.98 (d, J¼8.8 Hz, 2H, 30-H
and 50-H), 7.31–7.43 (m, 3H, ArH), 7.54 (d, J¼8.8 Hz, 2H, 20-H and 60-
H), 7.59–7.62 (m, 2H, ArH), 9.21 (br s, 1H, NH) ppm. 13C NMR
10. For a recent review on the Sonogashira reaction, see: Chinchilla, R.; Na´jera, C.
Chem. Rev. 2007, 107, 874.
11. Sakamoto, T.; Kondo, Y.; Iwashita, S.; Nagano, T.; Yamanaka, H. Chem. Pharm.
Bull. 1988, 36, 1305.
(100.6 MHz, CDCl3):
d 51.30 (CO2CH3), 55.38 (OCH3), 109.15 (4-CH),
12. (a) Queiroz, M.-J. R. P.; Castanheira, E. M. S.; Carvalho, M. S. D.; Abreu, A. S.;
Ferreira, P. M. T.; Karadeniz, H.; Erdem, A. Tetrahedron 2008, 64, 382; (b)
Queiroz, M.-J. R. P.; Abreu, A. S.; Castanheira, E. M. S.; Ferreira, P. M. T. Tetra-
hedron 2007, 63, 2215; (c) Abreu, A. S.; Ferreira, P. M. T.; Monteiro, L. S.; Queiroz,
M.-J. R. P.; Ferreira, I. C. F. R.; Calhelha, R. C.; Estevinho, L. M. Tetrahedron 2004,
60, 11821; (d) Abreu, A. S.; Silva, N. O.; Ferreira, P. M. T.; Queiroz, M.-J. R. P.
Tetrahedron Lett. 2003, 44, 3377; (e) Abreu, A. S.; Ferreira, P. M. T.; Queiroz, M.-J.
R. P.; Ferreira, I. C. F. R.; Calhelha, R. C.; Estevinho, L. M. Eur. J. Org. Chem. 2005,
2951.
114.54 (30 and 50-CH), 117.59 (C), 123.82 (C), 126.14 (20 and 60-CH),
127.12 (CH), 127.77 (2ꢁCH), 129.38 (2ꢁCH), 133.73 (C), 135.07 (C),
135.56 (C), 159.56 (40-C), 161.53 (CO2CH3) ppm. m/z EI (%) 307.12
(Mþ, 1), 81.07 (73), 69.06 (100). HRMS: Calcd for C19H17NO3 [Mþ]
307.1208. Found [Mþ] 307.1209.
Acknowledgements
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17489.
Foundation for the Science and Technology (Portugal) for finan-
cial support through: CQ-Univ. Minho, research project POCI/59407/
QUI/2004, A. Begouin post-doctoral grant (SFRH/BPD/36753/2007).