Phosphine-mediated cascade reaction of azides with MBH-acetates of acetylenic aldehydes to substituted pyrroles: A facile access to N-fused pyrrolo-heterocycles

Article abstract of DOI:10.1039/c2ob25272d

One-pot synthesis of substituted pyrroles by a cascade reaction of azides with Morita-Baylis-Hillman acetates of acetylenic aldehydes is described and the reaction is efficiently mediated by triphenyl phosphine at room temperature. Sodium azide is successfully used to provide N-unsubstituted pyrroles, while alkyl azides afforded the corresponding N-alkylated pyrroles through a sequence of allylic substitution/azide reduction/cycloisomerization reactions. The obtained products have provided a new entry to indolizino indoles, pyrrolo isoquinolines and 8-oxo-5,6,7,8-tetrahydroindolizine.

Full text of DOI:10.1039/c2ob25272d

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PAPER
Phosphine-mediated cascade reaction of azides with MBH-acetates of
acetylenic aldehydes to substituted pyrroles: a facile access to N-fused
pyrrolo-heterocycles†
Chada Raji Reddy,* Motatipally Damoder Reddy and Boinapally Srikanth
Received 6th February 2012, Accepted 23rd March 2012
DOI: 10.1039/c2ob25272d
One-pot synthesis of substituted pyrroles by a cascade reaction of azides with Morita–Baylis–Hillman
acetates of acetylenic aldehydes is described and the reaction is efficiently mediated by triphenyl
phosphine at room temperature. Sodium azide is successfully used to provide N-unsubstituted pyrroles,
while alkyl azides afforded the corresponding N-alkylated pyrroles through a sequence of allylic
substitution/azide reduction/cycloisomerization reactions. The obtained products have provided a new
entry to indolizino indoles, pyrrolo isoquinolines and 8-oxo-5,6,7,8-tetrahydroindolizine.
handy substrates for heterocyclic compounds.11 It is worth men-
tioning that the majority of the Morita–Baylis–Hillman adducts
Introduction
Pyrrole is one of the important heterocyclic motifs present in
number of bio-active natural products as well as pharmaceuticals
and has attracted lot of interest for its synthesis.1 Traditional
methods such as Hantzsch,2 Knorr3 and Paal–Knorr4 synthesis
rely on precursors which often need multi-step reactions and
some times harsh conditions.5 Recently, a range of new
approaches have been developed.6–8 Among these, cycloisomeri-
zation of alkynyl- and allenyl-compounds are prominent and the
majority of them involve metal-catalyzed reactions.8 Therefore,
it remains a challenge to have an efficient method for the syn-
thesis of substituted pyrroles under metal-free conditions from
easily accessible starting materials. Recently, we have reported a
mild and metal-free access to 1,2,4-tri- as well as 1,2,4,5-tetra-
substituted pyrroles via a one-pot reaction of Morita–Baylis–
Hillman (MBH)-acetates of acetylenic aldehydes with amines
and sulphonamides.9
studied were derived either from aromatic aldehydes or aliphatic
aldehydes and the MBH-chemistry of acetylenic aldehydes is
much less investigated.12
Herein, we wish to report the reaction of azides with MBH-
acetates of acetylenic aldehydes affording substituted pyrroles
under mild reaction conditions.
We hypothesized that sodium azide would participate in
allylic substitution with MBH-acetate (1) to obtain allylic azide
A, which would be reduced to amine B and subsequently would
undergo cycloisomerization to afford the desired pyrrole (3,
Scheme 1) in a one-pot operation. Further, we anticipated that
Ph3P in THF–H2O (Staudinger reaction conditions) would be
the reagent system of choice.
Results and discussion
To verify the aforementioned hypothesis, MBH-acetate 1a was
treated with sodium azide in presence of triphenyl phosphine in
However, the direct formation of N-unsubstituted pyrroles was
the limitation of the method and to overcome this, we became
interested in exploring the possibility of using azide as a N-atom
transfer agent. Azides have drawn much attention for use as
potential N-atom precursors for the construction of C–N bonds
due to their ease of accessibility and because they produce envir-
onmentally benign N2 gas as a by-product.10 Further, the pro-
ducts obtained from Morita–Baylis–Hillman (MBH) reaction
and their acetate derivatives have already been established as
Division of Natural Products Chemistry, CSIR-Indian Institute of
Chemical Technology, Hyderabad 500 007, India.
E-mail: rajireddy@iict.res.in; Fax: +91-40-27160512
†Electronic supplementary information (ESI) available: Copies of 1H
NMR and 13C NMR spectra of all the new compounds. See DOI:
10.1039/c2ob25272d
Scheme 1 Proposed route for the synthesis of N-unsubstituted
pyrroles.
4280 | Org. Biomol. Chem., 2012, 10, 4280–4288
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Table 1 Synthesis of N-unsubstituted pyrrolesa
Entry
MBH-Acetate (1)
Time (h)
18
Pyrrole (3)b
Yieldc (%)
1
91
2
3
4
5
R = 2-Thiophenyl, 1b
R = nPropyl, 1c
R = 4-MeO-Ph, 1d
R = 4-NO2-Ph, 1e
20
22
08
06
R = 2-Thiophenyl, 3b
R = n-Propyl, 3c
R = 4-MeO-Ph, 3d
R = 4-NO2-Ph, 3e
95
79
72
63
6
16
65
a Reaction conditions: MBH-acetate (1 mmol), NaN3 (1.2 mmol), Ph3P (1.25 mmol), THF–H2O (8 : 2, 5 mL), rt. b All the products were characterized
by 1H, 13C NMR, IR and MS spectra. c Isolated yield.
Table 2 Synthesis of N-benzyl pyrrolesa
THF–H2O as a solvent system. To our delight, the reaction pro-
ceeded efficiently to completion in 18 h at room temperature fur-
Entry MBH-Acetate (1) Time (h) Product (3)b
Yieldc (%)
nishing the pyrrole 3a in 91% yield (entry 1, Table 1).13 With
this success, the scope of the reaction was studied using a set of
MBH-acetates 1b to 1e as presented in Table 1. MBH-Acetates
derived from various substituted acetylenic aldehydes (1b–1e)
were reacted with sodium azide to provide the corresponding N-
unsubstituted pyrroles 3b–3e in good yields. The reactions
demonstrate the tolerance of aliphatic (entry 3) and aromatic
groups with electron-donating (entry 4) as well as electron-with-
drawing groups (entry 5) on the alkyne functionality. In addition,
the reaction of MBH-acetate 1f, obtained from cyclohexenone,
with NaN3 also gave the desired 2-benzyl-6,7-dihydro-1H-indol-
4(5H)-one (3f) in 65% yield (entry 6).
1
1a
10
94
2
3
4
5
1b
1c
1d
1e
08
10
05
04
R = 2-Thiophenyl, 3h 88
R = n-Propyl, 3i
R = 4-MeO-Ph, 3j
R = 4-NO2-Ph, 3k
77
81
72
Next, we focused our attention on finding out the reactivity of
alkyl azide with MBH-acetate (1) to provide the corresponding
N-alkyl pyrrole under similar reaction conditions via the
reduction of azide to amine/allylic substitution/cycloisomeriza-
tion sequence (Scheme 2). Thus, MBH-acetate 1a was treated
with benzyl azide (2b) under Ph3P in THF–H2O at room temp-
erature. Interestingly, as expected, the domino process ensued
well in 10 h to furnish 2,4-disubstituted N-benzyl pyrrole 3g in
94% yield (entry 1, Table 2). Encouraged by this result, other
MBH-acetates 1b to 1f were also examined for the reaction with
6
1f
24
85
a Reaction conditions: MBH-Acetate (1 mmol), BnN3 (1.2 mmol), Ph3P
(1.25 mmol), THF–H2O (8 : 2, 6 mL), rt. b All the products were
characterized by 1H, 13C NMR, IR and MS spectra. c Isolated yield.
benzyl azide (2b) and the results are summarized in Table 2. All
the substrates 1b to 1f participated smoothly to afford the corre-
sponding N-benzyl pyrroles 3h–3l in good yields (entries 2–6,
Table 2).
To compare the newly developed reaction conditions with the
earlier method,9 the reaction of benzyl amine with 1a was
carried out. Interestingly, the reaction proceeded cleanly in the
presence of Ph3P in THF–H2O to provide the pyrrole 3g in 95%
yield and in the absence of Ph3P it gave only 61% (entries 1 and
2, Table 3). This result represents a distinct improvement, when
compared to the reaction of benzyl amine with 1a under K2CO3/
DMF/45 °C (entry 2, Table 3).
Later, we extended the scope of various azides as nitrogen pre-
cursors for the synthesis of N-substituted pyrroles under the
Scheme 2 Hypothesis for the reaction of alkyl azide with MBH-
acetate of acetylenic aldehyde.
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conditions described by treating them with MBH-acetates of
acetylenic aldehydes and the results are compiled in Table 4.
Initially, the reaction of cinnamyl azide (2c) with 1a was per-
formed using Ph3P in THF–H2O at room temperature, which
provided the corresponding N-cinnamyl pyrrole 3m in 79% yield
(entry 1, Table 4). Likewise, MBH-acetate 1b also reacted with
2c to furnish 3n in 81% yield (entry 2, Table 4). Ethyl azidoace-
tate 2d was reacted with 1a as well as 1b to obtain the corre-
sponding trisubstituted pyrroles 3o and 3p in 86 and 88% yields,
respectively. Azides obtained from furano-sugars 2e and 2f were
effectively employed in the reaction with 1a and 1b to offer the
corresponding pyrroles 3q to 3t in good yields (entries 5 to 8,
Table 4). The observed result clearly demonstrates that the
method developed is useful for the conversion of azides to the
corresponding N-substituted pyrroles in one pot under mild reac-
tion conditions14 which accordingly may find a wide range of
applications.
Table 3 Reaction of MBH-acetate 1a with benzyl amine
Further, our interest in investigating the applicability of the
pyrrole obtained resulted in a novel access to 6,11-dihydro-5H-
indolizino[6,7-b]indoles and 5,10-dihydropyrrolo[1,2-b]isoqui-
nolines via an acid-catalyzed tandem carbon–carbon bond
forming reaction. These are attractive frameworks for drug dis-
covery.15 Thus, the MBH-acetate 1a was treated with azide 2g to
obtain the corresponding pyrrole 3u in 72% yield. This pyrrole
3u can be used as a versatile scaffold for the preparation of 6,11-
dihydro-5H-indolizino[6,7-b]indoles, by reacting with alde-
hydes. Accordingly, 3u was treated with 4-nitrobenzaldehyde in
presence of pTSA (5 mol%) in CH2Cl2 at room temperature and
Entry
Reagent
Solvent
T (°C)
Time (h)
Yielda [%]
1
Ph3P
—
K2CO3
THF–H2O
THF–H2O
DMF
rt
rt
45
14
20
12
95
61
86
2
39
a Isolated yield.
Table 4 Synthesis of pyrroles from alkyl azidesa
Entry
1
Azide (2)
MBH-Acetate/time (h)
Product (3)b/yieldc (%)
1a/8
2
3
2c
1b/11
1a/8
R = 2-Thiophenyl, 3n/81
4
5
2d
1b/9
R = 2-Thiophenyl, 3p/88
1a/30
6
7
2e
1b/36
1a/33
R = 2-Thiophenyl, 3r/66
8
2f
1b/34
R = 2-Thiophenyl, 3t/78
a Reaction conditions: MBH-acetate (1 mmol), RN3 (1.2 mmol), Ph3P (1.25 mmol), THF–H2O (8 : 2, 6 mL), rt. b All the products were characterized
by 1H, 13C NMR, IR and MS spectra. c Isolated yield.
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MBH-acetates of acetylenic aldehydes under metal-free reaction
conditions. The use of sodium azide in the reaction provided N-
unsubstituted pyrroles and alkyl azide afforded N-alkylated pyr-
roles. The mild reaction conditions and use of easily accessible
azides as well as MBH-acetate of acetylenic aldehydes give the
present method potential in pyrrole synthesis. Further, this
approach led us to develop a facile and novel entry to indolizino
indoles, pyrrolo isoquinolines and 8-oxo-5,6,7,8-tetrahydroindo-
lizine, which are useful for generating libraries of new molecular
entities.
Experimental
General
Reactions were monitored by thin-layer chromatography carried
out on silica plates (silica gel 60 F254, Merck) using UV-light
and anisaldehyde or potassium permanganate or β-naphthol for
visualization. Column chromatography was performed on silica
gel (60–120 mesh) using n-hexane and ethyl acetate as eluent.
Evaporation of solvents was conducted under reduced pressure
at temperatures less than 45 °C. IR spectra were recorded on
Perkin-Elmer 683 or Nicolet Nexus 670 spectrometers. 1H NMR
and 13C NMR spectra were recorded in CDCl3, DMSO-d6 sol-
vents on a 300 MHz or 500 MHz NMR spectrometer. Chemical
shifts δ and coupling constants J are given in ppm (parts per
million) and Hz (hertz) respectively. Chemical shifts are reported
Scheme 3 Synthesis of indolizino[6,7-b]indoles and pyrrolo[1,2-b]
isoquinolines.
to our satisfaction the desired indolizino[6,7-b]indole 4a was
obtained in 93% yield. Similarly, the reaction of 3u with
4-cyanobenzaldehyde gave the indole derivative 4b in 86%
yield. Another interesting scaffold 3v, obtained from the reaction
of 1a with azide 2h, was also successfully examined for the syn-
thesis of 5,10-dihydropyrrolo[1,2-b]isoquinoline derivatives 5a
and 5b but after longer reaction times (Scheme 3). To the best of
our knowledge, this is the first demonstration of one-step syn-
thesis of indolizino[6,7-b]indoles and pyrrolo[1,2-b]isoquino-
lines from N-benzylated pyrroles.
relative to residual solvent as an internal standard for 1H and 13
C
(CDCl3: δ 7.26 ppm for 1H and 77.0 ppm for 13C). Mass spectra
were obtained on Finnigan MAT1020B, Micromass VG 70–70H
or LC/MSD trapSL spectrometer operating at 70 eV using direct
inlet system.
Morita–Baylis–Hillman acetate adducts have been prepared
using the literature procedure9,12a to obtain 1a to 1h. Alkyl
azides and other starting materials have been prepared using the
literature procedure.18
Additionally, the synthesis of 8-oxo-5,6,7,8-tetrahydroindoli-
zine, a useful bio-active framework and precursor for indolizi-
dine alkaloids,16 has also been accomplished using the described
methodology. The treatment of azido carboxylic acid 2i with 1a
afforded the corresponding pyrrole 3w (70% yield), which was
subsequently treated with polyphosphoric acid at 80 °C for 3 h
to afford indolizidone 6 in 69% yield (Scheme 4).17
Methyl
3-acetoxy-5-(4-methoxyphenyl)-2-methylenepent-4-
1
ynoate (1d). Pale yellow oil; H NMR (300 MHz, CDCl3): δ
7.40 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 6.52 (s, 1H),
6.51 (s, 1H), 6.33 (s, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 2.11 (s,
3H); 13C NMR (75 MHz, CDCl3): δ 169.2, 164.8, 159.9, 136.6,
133.3, 128.9, 113.8, 113.7, 87.1, 82.3, 62.1, 55.1, 52.1, 20.7; IR
(KBr): 2942, 2851, 2447, 1955, 1735, 1515, 1343, 1223, 980,
854, 691 cm−1; MS (ESI): m/z 311 (M + Na)+; HRMS (ESI): m/
z calcd for C16H16NaO5 (M + Na)+: 311.0890, found: 311.0893.
Methyl 3-acetoxy-2-methylene-5-(4-nitrophenyl)pent-4-ynoate
(1e). Yellow solid; mp: 92–93 °C; 1H NMR: (300 MHz,
CDCl3): δ 8.20 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H),
6.51 (s, 1H), 6.47 (s, 1H), 6.26 (s, 1H), 3.84 (s, 3H), 2.14 (s,
3H); 13C NMR (75 MHz, CDCl3): δ 169.2, 164.6, 147.5, 136.0,
132.7, 129.4, 129.3, 123.5, 89.0, 84.8, 61.8, 52.4, 20.8; IR
(KBr): 2929, 2358, 1734, 1515, 1222, 1157, 980, 854,
689 cm−1; MS (ESI): m/z 326 (M + Na)+; HRMS (ESI): m/z
calcd for C15H13NaNO6 (M + Na)+: 326.0635, found: 326.0608.
Scheme 4 Synthesis of indolizidone 6.
Conclusions
Procedure for the preparation of 2-(azidomethyl)-1-methyl-
1H-indole (2g). To a solution of (1-methyl-1H-indol-2-yl)metha-
nol (1 g, 6.21 mmol) in THF (12 mL) at room temperature was
In summary, we have developed a new cascade reaction for the
synthesis of substituted pyrroles from the reaction of azides with
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added sequentially triphenylphosphine (2.44 g, 9.32 mmol),
diisopropyl azodicarboxylate (1.5 mL, 9.32 mmol), and diphe-
nylphosphonic azide (2.7 mL, 12.42 mmol). The reaction was
stirred for 5 hours before the volatiles were concentrated in
vacuo. The residue was purified by column chromatography over
silica gel (hexanes–ethyl acetate: 98 : 2) to afford azide 2g
(0.75 g, 65%) as a brown oil.
δ 8.09 (br, 1H), 7.27 (s, 1H), 7.09 (d, J = 8.9 Hz, 2H), 6.84 (d, J
= 8.9 Hz, 2H), 6.37 (s, 1H), 3.87 (s, 2H), 3.78 (s, 6H); 13C
NMR (75 MHz, CDCl3): δ 165.5, 158.4, 132.3, 130.8, 130.4,
129.7, 122.9, 114.2, 107.4, 55.3, 51.0, 32.9; IR (KBr): 3251,
2926, 2860, 1724, 1688, 1511, 1214, 1032, 757 cm−1; MS
(ESI): m/z 268 (M + Na); HRMS (ESI): m/z calcd for
C14H16NO3 (M + H)+: 246.1125, found: 246.1124.
2-(Azidomethyl)-1-methyl-1H-indole
(2g). 1H
NMR
Methyl 5-(4-nitrobenzyl)-1H-pyrrole-3-carboxylate (3e).
White solid; mp: 148–150 °C; H NMR (300 MHz, CDCl3 +
1
(300 MHz, CDCl3): δ 7.60 (d, J = 7.7 Hz, 1H), 7.35–7.22 (m,
2H), 7.12 (t, J = 7.5 Hz, 1H), 6.54 (s, 1H), 4.46 (s, 2H), 3.75 (s,
3H); 13C NMR (75 MHz, CDCl3): δ 138.1, 132.8, 126.9, 122.3,
120.8, 119.7, 109.2, 103.2, 46.8, 29.6; IR (KBr): 2930, 2171,
2100, 1476, 1205, 965, 743 cm−1; MS (EI): m/z 186.
DMSO-d6): δ 8.38 (d, J = 8.5 Hz, 2H), 8.08–8.04 (m, 3H), 7.71
(s, 1H), 7.13 (s, 1H), 3.78 (s, 3H), 3.35 (s, 2H); 13C NMR
(75 MHz, CDCl3 + DMSO-d6): δ 163.2, 149.0, 142.7, 130.0,
129.3, 128.1, 123.2, 119.7, 117.0, 50.6, 28.8; IR (KBr): 3349,
2924, 2854, 1689, 1513, 1248, 1121, 1034, 764 cm−1; MS
(ESI): m/z 261 (M + H); HRMS (ESI): m/z calcd for
C13H13N2O4 (M + H)+: 261.0870, found: 261.0867.
General procedure for the preparation of N-unsubstituted
pyrroles. To a solution of MBH-acetate (1.0 mmol) and sodium
azide (1.2 mmol) in 5 mL of THF–H2O (8 : 2) was added tri-
phenyl phosphine (1.25 mmol) at room temperature. The reac-
tion mixture was stirred at the same temperature for 6 to 22 h.
After the completion of the reaction, the reaction mixture was
diluted with water (10 mL) and extracted with ethyl acetate
(3 × 10 mL). The combined organic extracts were washed with
brine (20 mL), dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography on silica
gel (EtOAc–hexanes) to afford the corresponding product.
2-Benzyl-6,7-dihydro-1H-indol-4(5H)-one (3f). Pale yellow
1
oil; H NMR (300 MHz, CDCl3): δ 7.29–7.14 (m, 4H), 7.11 (d,
J = 6.7 Hz, 2H), 6.29 (s, 1H), 3.91 (s, 2H), 2.69 (t, J = 6.6 Hz,
2H), 2.42 (t, J = 6.0 Hz, 2H), 2.15 (m, 2H); 13C NMR (75 MHz,
CDCl3): δ 200.0, 144.3, 133.3, 128.5, 128.4, 128.3, 128.1,
126.4, 104.5, 32.8, 30.6, 23.4, 21.8; IR (KBr): 3440, 2925,
2849, 1646, 1481, 1036, 750 cm−1; MS (ESI): m/z 226 (M + H);
HRMS (ESI): m/z calcd for C15H16NO (M + H)+: 226.1226,
found: 226.1221.
Spectral data for all new compounds
General procedure for the preparation of N-substituted pyr-
roles. To a solution of alkyl azide (1.2 mmol) in 5 mL of THF–
H2O (8 : 2) was added triphenyl phosphine (1.25 mmol) at room
temperature. The reaction mixture was stirred at the same temp-
erature for 3 h. A solution of MBH-acetate (1.0 mmol) in 1 mL
of THF was added to it, and stirred for 1–32 h. After the com-
pletion of the reaction, the reaction mixture was diluted with
water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The
combined organic extracts were washed with brine (20 mL),
dried over Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (EtOAc–
hexanes) to afford the corresponding product.
Methyl 5-benzyl-1H-pyrrole-3-carboxylate (3a).9 White solid;
mp: 125–127 °C; 1H NMR (300 MHz, CDCl3): δ 8.06 (brs, 1H),
7.31–7.13 (m, 6H), 6.37 (s, 1H), 3.93 (s, 2H), 3.77 (s, 3H); 13C
NMR (75 MHz, CDCl3): δ 165.6, 138.5, 131.9, 128.7, 128.6,
126.6, 123.1, 116.1, 107.6, 50.9, 33.8; IR (KBr): 3238, 2919,
1686, 1517, 1451, 1218, 1026, 994, 747, 707 cm−1; MS (ESI):
m/z 216.0 (M + H)+. HRMS (ESI): m/z calcd for C13H14NO2 (M
+ H)+: 216.1019, found: 216.1020.
Methyl 5-(thiophen-2-ylmethyl)-1H-pyrrole-3-carboxylate (3b).
1
White solid; mp: 104–106 °C; H NMR (300 MHz, CDCl3): δ
8.33 (br, 1H), 7.31 (dd, J = 1.5, 2.6 Hz, 1H), 7.18 (d, J = 5.1
Hz, 1H), 6.94 (dd, J = 5.1, 3.5, 1H), 6.84 (d, J = 3.5 Hz, 1H),
6.45 (s, 1H), 4.14 (s, 2H), 3.79 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 165.3, 141.1, 130.9, 127.0, 125.5, 124.5, 123.1,
116.3, 107.5, 51.0, 28.1; IR (KBr): 3460, 2922, 1640, 1516,
1205, 997, 699 cm−1; MS (ESI): m/z 222 (M + H); HRMS
(ESI): m/z calcd for C11H12NO2S (M + H)+: 222.0583, found:
222.0588.
Methyl 1,5-dibenzyl-1H-pyrrole-3-carboxylate (3g).9 White
solid; mp: 99–101 °C; 1H NMR (300 MHz, CDCl3): δ
7.32–7.14 (m, 7H), 7.05 (d, J = 7.1 Hz, 2H), 6.91 (d, J = 7.3
Hz, 2H), 6.37 (s, 1H), 4.84 (s, 2H), 3.76 (s, 3H), 3.75 (s, 2H);
13C NMR (75 MHz, CDCl3): δ 165.3, 138.2, 136.6, 132.7,
128.8, 128.5, 128.3, 127.7, 127.1, 126.5, 126.4, 114.5, 109.9,
50.99, 50.93, 32.6; IR (KBr): 2925, 1706, 1518, 1445, 1217,
1090, 714, 617 cm−1; MS (ESI): m/z 306 (M + H); HRMS
(ESI): m/z calcd for C20H20NO2 (M + H)+: 306.1489, found:
306.1493.
Methyl 5-butyl-1H-pyrrole-3-carboxylate (3c). Pale yellow
1
oil; H NMR (300 MHz, CDCl3): δ 8.65 (br, 1H), 7.29 (s, 1H),
6.31, (s, 1H), 3.80 (s, 3H), 2.56 (t, J = 7.3 Hz, 2H), 1.63–1.55
(m, 2H), 1.40–1.30 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3): δ 166.0, 134.0, 122.4, 115.7, 106.0, 51.0,
31.3, 27.0, 22.1, 13.7; IR (KBr): 3449, 2929, 1635, 1517, 1207,
1129, 726, 562 cm−1; MS (ESI): m/z 204 (M + Na); HRMS
(ESI): m/z calcd for C10H15NNaO2 (M + Na)+: 204.0995, found:
204.0992.
Methyl
1-benzyl-5-(thiophen-2-ylmethyl)-1H-pyrrole-3-car-
boxylate (3h).9 White solid; mp: 104–106 °C; 1H NMR
(300 MHz, CDCl3): δ 7.34–7.23 (m, 4H), 7.13 (dd, J = 1.3, 5.1
Hz, 1H), 7.0–6.92 (m, 2H), 6.88 (dd, J = 3.6, 5.1, 1H),
6.72–6.67 (m, 1H), 6.47 (s, 1H), 4.93 (s, 2H), 3.94 (s, 2H), 3.78
(s, 3H); 13C NMR (75 MHz, CDCl3): δ 165.2, 141.5, 136.5,
132.1, 128.9, 127.8, 127.3, 126.8, 126.6, 125.1, 124.1, 114.7,
109.7, 51.0, 50.9, 27.1; IR (KBr): 2925, 2853, 1703, 1518,
1444, 1362, 1212, 1179, 1001, 762, 712 cm−1; MS (ESI): m/z
Methyl 5-(4-methoxybenzyl)-1H-pyrrole-3-carboxylate (3d).
White solid; mp: 95–97 °C; 1H NMR (300 MHz, CDCl3):
4284 | Org. Biomol. Chem., 2012, 10, 4280–4288
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312 (M + H)+; HRMS (ESI): m/z calcd for C18H18NO2S (M +
2H), 4.12 (s, 2H), 3.80 (s, 3H); 13C NMR (75 MHz, CDCl3): δ
165.2, 141.6, 135.8, 132.7, 131.8, 128.5, 128.0, 126.8, 126.6,
126.4, 125.1, 124.1, 124.0, 114.6, 109.5, 50.9, 49.2, 27.0; IR
(KBr): 2924, 2885, 1706, 1519, 1443, 1215, 1097, 1004, 759,
698 cm−1; MS (ESI): m/z 338 (M + H)+; HRMS (ESI): m/z
calcd for C20H20NO2S (M + H)+: 338.1209, found: 338.1230.
H)+: 312.1053, found: 312.1056.
Methyl 1-benzyl-5-butyl-1H-pyrrole-3-carboxylate (3i). Pale
1
yellow oil; H NMR (300 MHz, CDCl3): δ 7.26–7.16 (m, 4H),
6.93–6.84 (m, 2H), 6.30 (s, 1H), 4.94 (s, 2H), 3.70 (s, 3H), 2.33
(t, J = 7.3 Hz, 2H), 1.52–1.41 (m, 2H), 1.31–1.21 (m, 2H), 0.79
(t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 165.5, 136.9,
134.9, 128.8, 127.7, 126.5, 126.3, 114.5, 107.4, 50.9, 50.7, 30.4,
25.6, 22.3, 13.7; IR (KBr): 2952, 2864, 1707, 1640, 1215, 761,
611 cm−1; MS (ESI): m/z 272 (M + H); HRMS (ESI): m/z calcd
for C17H22NO2 (M + H)+: 272.1645, found: 272.1626.
Methyl 5-benzyl-1-(2-ethoxy-2-oxoethyl)-1H-pyrrole-3-car-
boxylate (3o). Yellow solid; mp: 94–96 °C; 1H NMR (300 MHz,
CDCl3): δ 7.29–7.09 (m, 6H), 6.36 (s, 1H), 4.37 (s, 2H), 4.08
(q, J = 7.5 Hz, 2H), 3.87 (s, 2H), 3.77 (s, 3H), 1.22 (t, J = 7.5
Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 167.6, 165.0, 137.8,
132.7, 128.6, 128.4, 127.6, 126.6, 115.3, 109.9, 61.8, 50.9, 48.7,
32.5, 14.0; IR (KBr): 2921, 2851, 1734, 1715, 1528, 1216,
721 cm−1; MS (ESI): m/z 302 (M + H)+; HRMS (ESI): m/z
calcd for C17H20NO4 (M + H)+: 302.1387, found: 302.1378.
Methyl 1-benzyl-5-(4-methoxybenzyl)-1H-pyrrole-3-carboxy-
late (3j). Pale yellow oil; 1H NMR (300 MHz, CDCl3): δ
7.30–7.21 (m, 4H), 6.96–6.89 (m, 4H), 6.74 (d, J = 8.9 Hz, 2H),
6.32 (s, 1H), 4.84 (s, 2H), 3.75 (s, 6H), 3.68 (s, 2H); 13C NMR:
(75 MHz, CDCl3): δ 165.0, 146.7, 145.9, 136.2, 130.9, 129.2,
128.9, 127.9, 127.6, 126.4, 123.7, 115.0, 110.6, 51.4, 51.2, 51.0,
Methyl 1-(2-ethoxy-2-oxoethyl)-5-(thiophen-2-ylmethyl)-1H-
pyrrole-3-carboxylate (3p). White solid; mp: 99–101 °C; 1H
NMR (300 MHz, CDCl3): δ 7.26 (d, J = 1.5 Hz, 1H), 7.16 (d, J
= 5.1 Hz, 1H), 6.91 (dd, J = 1.5, 3.6 Hz, 1H), 6.75 (d, J = 3.6
Hz, 1H), 6.47 (s, 1H), 4.48 (s, 2H), 4.15 (q, J = 7.2 Hz, 2H),
4.06 (s, 2H), 3.78 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3): δ 167.7, 164.9, 140.9, 132.1, 127.8, 126.8,
125.3, 124.4, 115.3, 109.6, 61.8, 50.9, 48.7, 27.0, 14.0; IR
(KBr): 2922, 1706, 1685, 1194, 1119, 998, 721, 541 cm−1; MS
(ESI): m/z 308 (M + H); HRMS (ESI): m/z calcd for
C15H18NO4S (M + H)+: 308.0951, found: 308.0969.
32.5; IR (KBr): 2946, 1705, 1518, 1345, 1219, 1101, 761 cm−1
;
MS (ESI): m/z 358 (M + Na)+; HRMS (ESI): m/z calcd for
C21H21NNaO3 (M + Na)+: 358.1414, found 358.1417.
Methyl 1-benzyl-5-(4-nitrobenzyl)-1H-pyrrole-3-carboxylate
1
(3k). Pale yellow oil; H NMR (300 MHz, CDCl3): δ 8.08 (d, J
= 9.1 Hz, 2H), 7.32–7.23 (m, 4H), 7.19 (d, J = 9.1 Hz, 2H),
6.93–6.86 (m, 2H), 6.36 (s, 1H), 4.88 (s, 2H), 3.85 (s, 2H), 3.78
(s, 3H); 13C NMR: (75 MHz, CDCl3): 165.3, 158.3, 136.7,
133.3, 130.3, 129.4, 128.8, 127.8, 127.1, 126.6, 114.6, 114.0,
109.8, 55.2, 51.0, 31.8; IR (neat): 2924, 2851, 1707, 1514,
1449, 1218, 1004, 822, 760 cm−1; MS (ESI): m/z 373 (M +
Na)+; HRMS (ESI) m/z calcd for C20H18N2NaO4 (M + Na)+:
373.1159, found: 373.1165.
Methyl 5-benzyl-1-((3aR,5S,6R,6aR)-5-(methoxycarbonyl)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl)-1H-pyrrole-3-car-
boxylate (3q). White solid; mp: 165–166 °C; [α]2D0 = −24.0 (c
1
0.42, CHCl3); H NMR (300 MHz, CDCl3): δ 7.36–7.12 (m,
6H), 6.26 (s, 1H), 6.20 (d, J = 3.6 Hz, 1H), 5.03 (d, J = 4.7 Hz,
1H), 4.81 (d, J = 4.7 Hz, 1H), 4.47 (d, J = 3.6 Hz, 1H), 3.97 (q,
J = 11.7 Hz, 2H), 3.75 (s, 3H), 3.53 (s, 3H), 1.51 (s, 3H), 1.26
(s, 3H); 13C NMR (75 MHz, CDCl3): δ 167.1, 164.8, 137.7,
133.4, 128.7, 128.5, 126.7, 123.8, 116.4, 112.7, 109.6, 105.3,
84.7, 78.5, 62.5, 52.4, 51.0, 32.5, 26.6, 25.9; IR (neat): 2948,
1710, 1515, 1437, 1242, 1195, 759, 697 cm−1; MS (ESI): m/z
416 (M + H)+; HRMS (ESI): m/z calcd for C22H26NO7 (M +
H)+: 416.1704, Found: 416.1714.
1,2-Dibenzyl-6,7-dihydro-1H-indol-4(5H)-one (3l).Pale yellow
oil; 1H NMR (300 MHz, CDCl3): δ 7.36–7.15 (m, 6H),
7.13–7.07 (m, 2H), 6.93–6.82 (m, 2H), 6.37 (s, 1H), 4.92 (s,
2H), 3.77 (s, 2H), 2.61 (t, J = 6.0 Hz, 2H), 2.47 (t, J = 6.4 Hz,
2H), 2.15–2.04 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 194.3,
144.7, 138.0, 136.5, 133.7, 128.9, 128.5, 128.4, 127.5, 126.5,
125.5, 120.0, 105.3, 47.2, 37.6, 32.7, 23.6, 21.9; IR (KBr):
2933, 2864, 1711, 1654, 1474, 1170, 697 cm−1; MS (ESI): m/z
316 (M + H); HRMS (ESI): m/z calcd for C22H22NO (M + H)+:
316.1696, found: 316.1683.
Methyl 1-((3aR,5S,6R,6aR)-5-(methoxycarbonyl)-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3]dioxol-6-yl)-5-(thiophen-2-ylmethyl)-
1H-pyrrole-3-carboxylate (3r). White solid; mp: 130–131 °C;
Methyl 5-benzyl-1-cinnamyl-1H-pyrrole-3-carboxylate (3m).
1
1
[α]2D0 = −20.2 (c 0.36, CHCl3); H NMR (300 MHz, CDCl3): δ
Pale yellow oil; H NMR (300 MHz, CDCl3): δ 7.29–7.09 (m,
11H), 6.37 (d, J = 1.5 Hz, 1H), 6.30 (dt, J = 15.8, 1.5 Hz, 1H),
6.05 (dt, J = 15.8, 5.3 Hz, 1H), 4.42 (dd, J = 1.5, 5.3 Hz, 2H),
3.93 (s, 2H), 3.77 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 165.2,
138.3, 135.8, 132.6, 132.4, 128.5, 128.3, 128.0, 126.7, 126.6,
126.5, 126.4, 124.1, 114.5, 109.7, 50.9, 49.1, 32.5; IR (KBr):
2925, 1705, 1520, 1444, 1214, 1095, 1003, 757, 699 cm−1; MS
(ESI): m/z 332 (M + H)+, HRMS (ESI): m/z calcd for
C22H22NO2 (M + H)+: 332.1645, found: 332.1660.
7.19–7.14 (m, 2H), 6.93 (t, J = 5.3 Hz, 1H), 6.80 (d, J = 3.0 Hz,
1H), 6.37 (s, 1H), 6.19 (d, J = 3.0 Hz, 1H), 4.99 (d, J = 4.5 Hz,
1H), 4.80 (d, J = 4.5 Hz, 1H), 4.49 (d, J = 3.8 Hz, 1H), 4.15 (s,
2H), 3.78 (s, 3H), 3.56 (s, 3H), 1.52 (s, 3H), 1.28 (s, 3H); 13C
NMR (75 MHz, CDCl3): δ 167.0, 164.7, 140.8, 132.6, 127.0,
125.4, 124.5, 123.9, 116.5, 112.7, 109.4, 105.3, 84.8, 78.5, 62.6,
52.5, 51.0, 27.0, 26.6, 26.0; IR (neat): 2955, 1699, 1523, 1216,
1081, 1030, 764 cm−1; MS (ESI): m/z 444 (M + Na)+; HRMS
(ESI): m/z calcd for C20H24NO7S (M + H)+: 422.1268, found:
422.1253.
Methyl 1-cinnamyl-5-(thiophen-2-ylmethyl)-1H-pyrrole-3-car-
1
boxylate (3n). Pale yellow oil; H NMR (300 MHz, CDCl3): δ
7.35–7.24 (m, 6H), 7.16 (d, J = 4.2 Hz, 1H), 6.93 (t, J = 4.2 Hz,
1H), 6.79 (d, J = 15.6 Hz, 1H), 6.50 (s, 1H), 6.31 (d, J = 15.6
Hz, 1H), 6.13 (dt, J = 15.6, 6.2 Hz, 1H), 4.51 (d, J = 6.2 Hz,
Methyl 5-benzyl-1-((3aR,5S,6R,6aR)-5-(((3aR,5S,6R,6aR)-5-
(methoxycarbonyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]
dioxol-6-yl)carbamoyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]
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dioxol-6-yl)-1H-pyrrole-3-carboxylate (3s). White solid; mp:
149–150 °C; [α]2D0 = +37.2 (c 0.5, CHCl3); 1H NMR (300 MHz,
CDCl3): δ 7.55 (s, 2H), 7.38–7.29 (m, 3H), 6.24 (s, 1H), 6.98 (s,
1H), 6.89 (d, J = 9.0 Hz, 1H), 5.95 (d, J = 3.3 Hz, 1H), 5.86 (d,
J = 3.2 Hz, 1H), 4.83–4.72 (m, 2H), 4.68 (d, J = 4.3 Hz, 1H),
4.60 (d, J = 3.2 Hz, 1H), 4.48 (d, J = 3.4 Hz, 1H), 3.83 (s, 3H),
3.78–3.72 (m, 5H), 1.51 (s, 3H), 1.42 (s, 3H), 1.29 (s, 3H), 1.25
(s, 3H); 13C NMR (75 MHz, CDCl3): δ 168.2, 168.1, 166.4,
138.7, 131.8, 129.3, 128.4, 122.6, 122.1, 112.7, 112.2, 105.4,
104.9, 102.3, 84.9, 83.8, 83.0, 80.9, 62.4, 55.9, 52.6, 52.2,
44.8, 29.6, 26.9, 26.6, 26.1, 26.0; IR (KBr): 3122, 2944, 1695,
1525, 1229, 769 cm−1; MS (ESI): m/z 601 (M + H)+; HRMS
(ESI): m/z calcd for C30H37N2O11 (M + H)+: 601.2392, found:
601.2438.
109.5, 51.0, 45.9, 32.5, 30.5, 25.7; IR (KBr): 3450, 2950, 1706,
1442, 1219, 1003, 761, 722 cm−1; MS (ESI): m/z 324 (M +
Na)+; HRMS (ESI): m/z calcd for C17H19NNaO4 (M + Na)+:
324.1206, found: 324.1203.
1-tert-Butyl 3-methyl 5-benzyl-1H-pyrrole-1,3-dicarboxylate
(3a′). Pale yellow oil; 1H NMR (300 MHz, CDCl3): δ 7.70 (d, J
= 2.2 Hz, 1H), 7.23–7.03 (m, 5H), 6.04 (s, 1H), 4.10 (s, 2H),
3.71 (s, 3H), 1.46 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 164.5,
148.6, 138.7, 135.5, 128.8, 128.3, 126.4, 126.3, 117.0, 112.5,
84.8, 51.3, 34.8, 27.8; IR (KBr): 2961, 1752, 1720, 1634, 1526,
1269, 1205, 1155, 1086, 760, 708 cm−1; MS (ESI): m/z 338 (M
+ Na). HRMS (ESI): m/z calcd for C18H21 Na NO4 (M + Na)+:
338.1363, found: 338.1376.
General procedure for the preparation of compounds 4 and
5. To a solution of N-substituted pyrrole (1.0 mmol) and alde-
hyde (1.1 mmol) in 5 mL dichloromethane was added pTSA
(5 mol%) at room temperature. The reaction mixture was stirred
at the same temperature for 1 to 24 h. After the completion of
reaction, the reaction mixture was diluted with water (5 mL) and
extracted with dichloromethane (3 × 10 mL). The combined
organic extracts were washed with brine (10 mL), dried over
Na2SO4 and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (EtOAc–hexanes) to afford
the corresponding product.
Methyl 1-((3aR,5S,6R,6aR)-5-(((3aR,5S,6R,6aR)-5-(methoxy-
carbonyl)-2,2 dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl)car-
bamoyl)-2,2-dimethyltetrahydrofuro[2,3d][1,3]dioxol-6-yl)-5-
(thiophen-2-ylmethyl)-1H-pyrrole-3-carboxylate
(3t). White
1
solid; mp: 98–99 °C; [α]2D0 = −49.2 (c 0.64, CHCl3); H NMR
(300 MHz, CDCl3): δ 7.14 (d, J = 4.9 Hz, 1H), 6.94–6.87 (m,
2H), 6.86–6.78 (m, 2H), 6.25 (s, 1H), 6.22 (d, J = 3.2 Hz, 1H),
5.87 (d, J = 3.2 Hz, 1H), 4.84–4.78 (m, 2H), 4.63–4.57 (m, 2H),
4.48 (d, J = 3.0 Hz, 1H), 4.18 (dd, J = 17.5, 4.15 Hz, 2H), 3.75
(s, 3H), 3.68 (s, 3H), 1.51 (s, 3H), 1.46 (s, 3H), 1.28 (s, 3H),
1.27 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 167.6, 166.5,
164.6, 141.0, 133.9, 126.9, 125.3, 124.2, 122.9, 116.5, 112.8,
108.9, 105.1, 104.7, 84.9, 83.4, 79.6, 75.7, 61.7, 56.8, 52.5,
50.9, 31.5, 29.5, 26.8, 26.4, 26.3, 26.0; IR (KBr): 2920, 1713,
1214, 1082, 1033, 764 cm−1; MS (ESI): m/z 629 (M + Na)+;
HRMS (ESI): m/z calcd for C28H34 Na N2O11S (M + Na)+:
629.1776, found: 629.1726.
Methyl
3-benzyl-6-methyl-11-(4-nitrophenyl)-6,11-dihydro-
5H-indolizino[6,7-b]indole-1-carboxylate (4a). Pale yellow solid;
1
mp: 236–237 °C; H NMR (300 MHz, CDCl3): δ 8.01 (d, J =
8.7 Hz, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.39–7.15 (m, 9H), 7.06
(t, J = 7.4 Hz, 1H), 6.50 (s, 1H), 6.16 (s, 1H), 5.08 (td, J = 16.4,
2.5 Hz, 2H), 4.14 (s, 2H), 3.71 (s, 3H), 3.62 (s, 3H); 13C NMR
(75 MHz, CDCl3): δ 164.7, 152.3, 146.0, 137.9, 136.7, 130.4,
128.9, 128.7, 128.3, 127.6, 127.5, 127.4, 126.9, 124.7, 123.5,
122.3, 119.9, 118.6, 110.8, 110.6, 109.0, 50.7, 41.0, 38.9, 32.9,
29.6; IR (KBr): 2924, 2853, 1745, 1685, 1515, 1442,
1343,1110, 1050, 743 cm−1; MS (ESI): m/z 492 (M + H)+;
HRMS (ESI): m/z calcd for C30H26N3O4 (M + H)+: 492.1918,
found: 492.1900.
Methyl 5-benzyl-1-((1-methyl-1H-indol-2-yl)methyl)-1H-pyr-
1
role-3-carboxylate (3u). Pale yellow solid; mp: 128–129 °C; H
NMR (300 MHz, CDCl3): δ 7.56 (d, J = 8.3 Hz, 1H), 7.33–7.04
(m, 9H), 6.46 (d, J = 1.5 Hz, 1H), 6.33 (s, 1H), 4.93 (s, 2H),
3.96 (s, 2H), 3.72 (s, 3H), 3.28 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 165.2, 138.2, 138.1, 133.2, 132.5, 128.8, 128.5,
127.2, 126.8, 126.2, 122.2, 120.8, 119.9, 114.8, 110.2, 109.2,
103.3, 51.0, 43.7, 32.9, 29.4; IR (KBr): 2925, 1706, 1520, 1214,
1004, 770 cm−1; MS (ESI): m/z 359 (M + H)+; HRMS (ESI): m/
z calcd for C23H23N2O2 (M + H)+: 359.1754, found: 359.1749.
Methyl 3-benzyl-11-(4-cyanophenyl)-6-methyl-6,11-dihydro-
5H-indolizino[6,7-b]indole-1-carboxylate (4b). Pale yellow solid;
mp: 245–246 °C; 1H NMR (300 MHz, CDCl3): δ 7.61–7.04 (m,
13H), 6.49 (s, 1H), 6.12 (s, 1H), 5.07 (td, J = 14.2, 2.6 Hz, 2H),
4.13 (s, 2H), 3.71 (s, 3H), 3.61 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 164.7, 150.2, 137.9, 136.9, 132.0, 130.3, 128.8,
128.6, 128.3, 127.6, 127.5, 126.8, 124.7, 122.3, 119.8, 119.0,
118.6, 110.8, 110.5, 109.6, 109.2, 109.0, 50.7, 41.0, 39.0, 32.9,
29.6; IR (KBr): 2924, 2854, 2225, 1744, 1697, 1460, 1220,
1163, 1057, 741 cm−1; MS (ESI): m/z 472 (M + H)+; HRMS
(ESI): m/z calcd for C31H26N3O2 (M + H)+: 472.2020, found:
472.2037.
Methyl 5-benzyl-1-(3,5-dimethoxybenzyl)-1H-pyrrole-3-car-
1
boxylate (3v). Pale green oil; H NMR (300 MHz, CDCl3): δ
7.36–7.18 (m, 4H), 7.11 (s, 1H), 7.10 (s, 1H), 6.39 (s, 1H), 6.36
(t, J = 1.9 Hz, 1H), 6.08 (d, J = 1.9 Hz, 2H), 4.81 (s, 2H), 3.80
(s, 2H), 3.78 (s, 3H), 3.72 (s, 6H); 13C NMR (75 MHz, CDCl3):
δ 161.1, 139.0, 138.2, 131.6, 128.5, 128.3,127.1, 126.5, 121.8,
109.8, 106.6, 104.5, 99.3, 55.2, 50.9, 50.8, 32.5; IR (KBr):
2944, 2842, 1708, 1602, 1459, 1347, 1063, 757 cm−1; MS
(ESI): m/z 366 (M + H)+; HRMS (ESI): m/z calcd for
C22H24NO4 (M + H)+: 366.1700, found: 366.1710.
Methyl 3-benzyl-7,9-dimethoxy-10-(4-nitrophenyl)-5,10-dihy-
dropyrrolo[1,2-b]isoquinoline-1-carboxylate (5a). White solid;
1
4-(2-Benzyl-4-(methoxycarbonyl)-1H-pyrrol-1-yl)butanoic acid
mp: 120–122 °C; H NMR (300 MHz, CDCl3): δ 8.01 (d, J =
1
(3w).Pale yellow oil; H NMR (300 MHz, CDCl3): δ 7.26–7.08
8.9 Hz, 2H), 7.36–7.15 (m, 7H), 6.41 (s, 2H), 6.40 (s, 1H), 6.28
(s, 1H), 4.89 (d, J = 16.1 Hz, 1H), 4.73 (d, J = 16.1 Hz, 1H),
4.06 (dd, J = 16.1, 8.1 Hz, 2H), 3.82 (s, 3H), 3.78 (s, 6H); 13C
NMR (75 MHz, CDCl3): δ 165.2, 159.8, 157.6, 151.0, 146.1,
(m, 6H), 6.30 (s, 1H), 3.90 (s, 2H), 3.80–3.72 (m, 5H), 2.23 (t, J
= 7.0 Hz, 2H), 1.88 (m, 2H); 13C NMR (75 MHz, CDCl3): δ
177.0, 165.5, 138.3, 132.5, 132.0, 128.5, 128.3, 126.7, 114.4,
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5 For selected examples, see: (a) B. M. Trost and G. A. Doherty, J. Am.
Chem. Soc., 2000, 122, 3801–3810; (b) F. Palacios, D. Aparico,
J. M. D. Santos and J. Vicario, Tetrahedron, 2001, 57, 1961–1972.
6 For selected multi-component methods, see: (a) X. Lin, Z. Mao, X. Dai,
P. Lu and Y. Wang, Chem. Commun., 2011, 47, 6620–6622; (b) L.
V. Frolova, N. M. Evdokimov, K. Hayden, I. Malik, S. Rogelj,
A. Kornienko and I. V. Magedov, Org. Lett., 2011, 13, 1118–1121; (c) O.
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7 For selected recent methods, see: (a) S. Ngwerume and J. E. Camp,
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138.0, 136.6, 132.8, 129.9, 128.7, 128.5, 128.3, 126.6, 123.4,
116.7, 109.9, 109.6, 102.2, 97.8, 55.5, 55.4, 50.7, 45.9, 37.3,
32.6; IR (KBr): 2937, 1697, 16.4, 1520, 1345, 1211, 1057, 827,
697 cm−1; MS (ESI): m/z 499 (M + H)+; HRMS (ESI): m/z
calcd for C29H27N2O6 (M + H)+: 499.1864, found: 499.1883.
Methyl 3-benzyl-10-(4-cyanophenyl)-7,9-dimethoxy-5,10-dihy-
dropyrrolo[1,2-b]isoquinoline-1-carboxylate (5b). White solid;
1
mp: 190–191 °C; H NMR (300 MHz, CDCl3): δ 7.44 (d, J =
8.3 Hz, 2H), 7.35–7.14 (m, 7H), 6.39 (s, 2H), 6.37 (s, 1H), 6.16
(d, J = 1.5 Hz, 1H), 4.86 (d, J = 16.6 Hz, 1H), 4.69 (d, J = 16.6
Hz, 1H), 4.04 (dd, J = 16.6, 2.7 Hz, 2H), 3.82–3.75 (m, 9H);
13C NMR (75 MHz, CDCl3): δ 165.2, 159.8, 157.7, 148.8,
138.1, 136.8, 133.0, 131.9, 129.8, 128.7, 128.5, 128.3, 126.6,
119.0, 117.0, 109.9, 109.8, 109.6, 102.3, 97.9, 55.5, 55.4, 50.7,
46.0, 37.5, 32.7; IR (KBr): 2924, 2845, 2226, 1699, 1609, 1496,
1211, 1142, 1056, 775, 553 cm−1; MS (ESI): m/z 479 (M + H)+;
HRMS (ESI): m/z calcd for C30H27N2O4 (M + H)+: 479.1965,
found: 479.1955.
8 For cycloisomerization methods, see: (a) Y. Wang, X. Bi, D. Li, P. Liao,
Y. Wang, J. Yang, Q. Zhang and Q. Liu, Chem. Commun., 2011, 47, 809–
811; (b) D. M. Barber, H. Sanganee and D. J. Dixon, Chem. Commun.,
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Procedure for the preparation of compound 6. 4-(2-Benzyl-4-
(methoxycarbonyl)-1H-pyrrol-1-yl)butanoic acid (301 mg,
1 mmol) was stirred in polyphosphoric acid (>84% phosphate as
P2O5) (1 mL) at 75 °C for 3 h. The reaction mixture was
quenched with water (5 mL), and the resulting solution was
extracted with dichloromethane (3 × 5 mL). The organic phases
were combined, dried over Na2SO4, filtered and concentrated.
The residue was purified by column chromatography on silica
gel (EtOAc–hexanes) to afford the corresponding product 6
(195 mg, 69%) as a colorless oil.
11 For reviews, see: (a) D. Basavaiah and D. V. Lenin, Eur. J. Org. Chem.,
2010, 5650–5658; (b) D. Basavaiah, B. S. Reddy and S. S. Badsara,
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3498; (b) V. K. Aggarwal, I. Emme and S. Y. Fulford, J. Org. Chem.,
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Methyl 3-benzyl-8-oxo-5,6,7,8-tetrahydroindolizine-1-carboxy-
late (6). 1H NMR (500 MHz, CDCl3): δ 7.34–7.22 (m, 3H),
7.12 (d, J = 7.9 Hz, 2H), 6.43 (s, 1H), 3.97 (s, 2H), 3.88–3.81
(m, 5H), 2.58 (t, J = 5.9 Hz, 2H), 2.22–2.15 (m, 2H); 13C NMR
(75 MHz, CDCl3): δ 186.0, 165.1, 136.8, 135.5, 132.0, 128.9,
128.4, 126.9, 120.1, 113.3, 52.0, 43.1, 36.7, 32.7, 22.8; IR
(KBr): 2956, 2926, 1728, 1670, 1488, 1278, 1134, 773 cm−1
;
MS (ESI): m/z 306 (M + Na)+; HRMS (ESI): m/z calcd for
13 The addition of (Boc)2O into the same reaction was provided the Boc-
protected pyrrole in one pot.
C17H17NNaO3 (M + Na)+: 306.1101, found: 306.1097.
Acknowledgements
The authors thank Council of Scientific and Industrial Research
(CSIR)-New Delhi for the award of fellowships to MDR and
BS. CRR is thankful to DST, New Delhi, for funding (SR/SI/
OC-66/2011).
.
14 Methods are known for the synthesis of pyrroles using azides and
majority of them are transition metal-catalyzed reactions. See
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