Morita-Baylis-Hillman acetates of acetylenic aldehydes: Versatile synthons for substituted pyrroles via a metal-free tandem reaction

Article abstract of DOI:10.1039/c1ob05402c

A mild and metal-free access to 1,2,4-tri or 1,2,4,5-tetrasubstituted pyrroles has been developed by the reaction of Morita-Baylis-Hillman acetates of acetylenic aldehydes with amines and sulfonamides. This new protocol is based on K₂CO₃

Full text of DOI:10.1039/c1ob05402c

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PAPER
Morita–Baylis–Hillman acetates of acetylenic aldehydes: versatile synthons
for substituted pyrroles via a metal-free tandem reaction†
Chada Raji Reddy,* Motatipally Damoder Reddy, Boinapally Srikanth and Kothakonda Rajendra Prasad
Received 14th March 2011, Accepted 23rd May 2011
DOI: 10.1039/c1ob05402c
A mild and metal-free access to 1,2,4-tri or 1,2,4,5-tetrasubstituted pyrroles has been developed by the
reaction of Morita–Baylis–Hillman acetates of acetylenic aldehydes with amines and sulfonamides. This
new protocol is based on K2CO3-promoted tandem allylic substitution/cycloisomerization reactions.
Introduction
The Morita–Baylis–Hillman (MBH) reaction,1 one of the most
atom economic reactions, has become a powerful tool in current
organic synthesis.2 The products obtained from this reaction
and their acetate derivatives serve as a versatile precursors for
numerous useful compounds, particularly heterocycles.2 In spite
of these vast efforts, applications of acetylenic aldehydes in
MBH reaction remains less investigated.3 In continuation of
our efforts towards the synthesis of bio-active natural prod-
ucts and heterocyclic compounds using alkyne chemistry,4 we
became interested in exploring the construction of substituted
pyrroles using Morita–Baylis–Hillman acetates of acetylenic
aldehydes. To the best of our knowledge, one-pot synthesis of
pyrroles starting from MBH acetate has not been reported so
far.5
Scheme 1 Proposed route for the synthesis of pyrroles.
Results and discussion
Over the years considerable efforts have been made towards the
We commenced our study with the use of Morita–Baylis–Hillman
acetate 1a, derived from the reaction of 3-phenylpropiolaldehyde
with methyl acrylate,3a as starting material. As shown in Table
1, the reaction between 1a and benzylamine (2a) was chosen
as a model to identify the optimal condition. To begin with,
the reaction was carried out using K2CO3 in DMF at room
temperature which afforded only 14% of the desired product 3a
after 24 h (entry 1, Table 1). Subsequently, variety of reaction
conditions were examined (Table 1) and we foun◦d, 3a was obtained
in excellent yield using K2CO3 in DMF at 45 C (entry 5, Table
1). Whereas, other conditions carried out with change of base to
Cs2CO3 and solvent to THF or CH3CN at room temperature were
not helpful in providing good yield for the desired product (entries
2 to 4, Table 1). As could be observed in the Table 1, increasing the
reaction temperature to 45 ◦C offered good to excellent yield of 3a
either under K2CO3/DMF or CH3CN conditions, (entries 5 and 6,
Table 1). Absence of base however did not show any progress in the
reaction (entry 7, Table 1). Now, having the optimized condition
in hand, scope and limitations of both the amines (2) and MBH
acetates (1) were investigated for this tandem reaction.
synthesis of substituted pyrroles due to their wide occurrence in
natural products and pharmaceuticals.6–10 Among which cycloiso-
merization of substrates having alkyne and allene-functionalities
are one of the useful approaches for forming pyrroles.10 However,
these cycloisomerization reactions, while offering some advantages
also suffer from disadvantages such as a) the use of metal catalyst
either in preparation of starting material or in cycloisomerization
reaction,10a,10c–10e b) limitations in using the amines10b or c) multi-
step reaction sequence.10c Hence, an efficient construction of
substituted pyrroles using easily accessible starting materials
and metal-free reagents is of high interest. Herein, we report
a metal-free synthetic approach to substituted pyrroles (3) via
K2CO3-mediated tandem allylic substitution/cycloisomerization
reaction of MBH acetates (1) with various amines (2)
(Scheme 1).
Organic Chemistry Division-I, Indian Institute of Chemical Technology,
Hyderabad, 500 607, 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 compounds. See DOI:
10.1039/c1ob05402c
Firstly, the reactions of various amines with MBH acetate 1a
have been studied (Table 2). Aniline (2b), furfurylamine (2c) and
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Table 1 Optimization of reaction condition
Entry
Base (1 equiv.)
Solvent
T (◦ C)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
—
DMF
DMF
THF
CH3CN
DMF
rt
rt
rt
rt
45
45
45
24
16
24
24
12
16
14
14
8
8
28
86
68
0
CH3CN
DMF
a Isolated yield.
Table 2 Synthesis of pyrroles from 1a using different amines
Entry
Amine (2)
PhNH2 2b
Time (h)
Product (3)a
Yield (%)b
1
2
6
R1 = Ph; 3b
R1 = furfuryl; 3c
77
82
4.5
3
4
5
MeNH2 2d
TsNH2 2e
PhSO2NH2 2f
15
28
22
R1 = Me; 3d
R1 = Ts; 3e
R1 = PhSO2, 3f
89
72
65
6
2g
28
3g
62
7
8
BocNH2 2h
CbzNh2 2i
48c
48c
No reaction
No reaction
—
—
a All the products were characterized by 1H, 13C NMR, IR and mass spectra. b Isolated yield. c reaction at 90 ◦C.
methylamine (2d) were successfully participated in the tandem
reaction to provide the corresponding pyrroles 3b, 3c and 3d
in 77%, 82% and 89% yields, respectively (entries 1 to 3, Table
2). Interestingly, the reactions of sulfonamides 2e and 2f led to
the formation of N-sulfonyl pyrroles 3e and 3f in good yield
(entry 4 and 5, Table 2), which is an added advantage for
the present method to access the N-unsubstituted pyrroles via
desulfonylation.11 In addition, a chiral amino acid-methyl ester 2g
was employed as well, to afford pyrrole 3g in 62% yield (entry 6,
Table 2). However, no reaction was observed in the case of tert-
butyl carbamate (2h) and benzyl carbamate (2i) even after 48 h at
90 ◦C, which may be due to their weak nucleophilic nature (entry
7 and 8, Table 2).
was treated with amines 2a, 2b and 2c, which provided the
corresponding 1,2,4-trisubstituted pyrroles 3h to 3j in 84–86%
yield (entries 1 to 3, Table 3). Then, heptyl-MBH acetate 1c in
the presence of amines 2a and 2b also showed the same tendency
to furnish the corresponding pyrroles 3k and 3l in 74% and 61%,
respectively (entry 4 and 5, Table 3). The reaction of silyl-MBH
acetate 1d with amines 2a and 2b afforded desilylated pyrroles 3m
and 3n in good yield (entry 6 and 7, Table 3).12 Importantly, MBH
acetate without substitution on alkyne terminal 1e successfully
participated in the tandem reaction with 2a and 2c to provide
pyrroles 3m and 3o in 81% and 72%, respectively (entry 8 and 9,
Table 3).
Further, we extended the scope of MBH acetates derived by
varying activated alkenes towards the tandem reaction (Table 4).
Hence, the substrate 1f, prepared from 3-phenylpropiolaldehyde
and cyclopentenone, was employed to react with amine 2a. To
our delight, the tandem reaction ensued well in 2 h to furnish a
After the successful study in utilizing various amines as
nucleophiles, we focused on the reactivity of MBH acetates
bearing heteroaromatic, aliphatic, silyl group and no substitution
on alkyne terminal (Table 3). Thus, thiophene-MBH acetate 1b
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Table 3 Synthesis of pyrroles from the reaction of MBH acetates with aminesa
Entry
1
MBH acetate
Amine
Time (h)
6
Productb
Yield (%)c
84
2a
3h
2
3
1b
1b
2b
2c
8
6
R1 = Ph, 3i
R1 = Furfuryl, 3j
86
85
4
5
2a
16
3k
74
5
6
1c
1d
1e
2b
2a
16
24
R1 = Ph, 3l
61
71
3m
7
8
2b
2a
18
20
R1 = Ph, 3n
66
81
3m
9
2c
16
R1 = Furfuryl, 3o
72
a Reaction conditions: MBH acetate (1 mmol), amine (1 mmol), K2CO3 (1 mmol), DMF (5 mL), 45 ◦C. b All the products were characterized by 1H, 13
C
NMR, IR and mass spectra. c Isolated yield.
Table 4 Reactions of MBH acetates 1f–1ha
Entry
1
MBH acetate
Amine
Time (h)
Productb
Yield (%)c
1f
2a
2
3p
61
2
3
1g
2d
2c
1
3q
78
64
1h
24
4a
a Reaction conditions: MBH acetate (1 mmol), amine (1 mmol), K2CO3 (1 mmol), DMF (5 mL), 45 ◦C. b All the products were characterized by 1H, 13
NMR, IR and mass spectra. c Isolated yield.
C
tetrasubstituted fused pyrrole 3p in 61% yield (entry 1, Table 4).
Then, 1g also accomplished the desired fused pyrrole 3q in 78%
yield when treated with methyl amine 2d (entry 2, Table 4). How-
ever, the MBH acetate 1h, obtained from 3-phenylpropiolaldehyde
and acrylonitrile, was unable to furnish the desired pyrrole
even at elevated temperature (90 ◦C) for longer reaction time.
Whereas, an allylic substituted product 4a was obtained (entry
3, Table 4) which did not undergo further cycloisomerization.
Extensive 2D NMR studies confirmed that the product 4a was
obtained, after initial allylic substitution, as Z-isomer,13 in which
the spatial arrangement of the substitutions on the double bond
are not favorable for cycloisomerization. This suggests, MBH
acetates 1a–1g may provide the allylic amine intermediate with
E-selectivity which was not isolated as they underwent immediate
cycloisomerization to the corresponding pyrroles.
To verify the formation of (E)-isomer, the reaction of substrate
1a with a secondary amine 2j was performed, which afforded the
product 4b in 72% yield as anticipated (Scheme 2). Extensive 2D
NMR studies established the stereochemistry of allylic amine 4b
as (E)-isomer.14
Scheme 2 Synthesis of 4b.
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1H), 3.79 (s, 3H), 2.09 (s, 3H), 0.93 (s, 9H), 0.13 (s, 6H); 13C NMR
(75 MHz, CDCl3): d 169.1, 164.9, 136.4, 129.1, 100.1, 91.2, 61.9,
52.1, 25.9, 20.8, 16.4, -4.8; IR (KBr): 2956, 2926, 2078, 1731, 1639,
1396, 1056, 682 cm-1; MS (ESI): m/z 297 (M+H)+; HRMS (ESI):
m/z calcd for C15H25NaO4Si (M+H)+: 297.1517, found: 297.1525.
Conclusions
In summary, we have developed a simple and novel method for the
synthesis of substituted pyrroles starting from MBH acetates of
acetylenic aldehydes with amine using a tandem reaction involving
allylic substitution/cycloisomerization. The easy accessibility of
the starting materials via an atom economic MBH-reaction
and metal-free reaction condition makes the present method
potentially useful in organic synthesis. Further development and
synthetic applications of the described tandem reaction are under
investigation.
Methyl 3-acetoxy-2-methylenepent-4-ynoate (1e). 1H NMR
(500 MHz, CDCl3): Pale yellow oil; d 6.45 (d, J = 1.8 Hz, 1H),
6.24 (d, J = 1.8 Hz, 1H), 6.23 (s, 1H) 3.79 (s, 3H), 2.51 (br, 1H),
2.08 (s, 3H); 13C NMR (75 MHz, CDCl3): d 169.1, 164.6, 135.8,
129.3, 75.5, 61.2, 52.2, 29.6, 20.7; IR (KBr): 3267, 2956, 2920,
2850, 2105, 1742, 1721, 1438, 1370, 1235, 1009 cm-1; MS (ESI):
m/z 205 (M+Na)+.
Experimental
2-Cyano-5-phenylpent-1-en-4-yn-3-yl acetate (1h). Pale yellow
oil; 1H NMR (300 MHz, CDCl3): d 7.48 (dd, J = 7.2, 7.1 Hz, 2H),
7.40–7.29 (m, 3H), 6.30 (d, J = 1.1 Hz, 1H), 6.19 (d, J = 1.1 Hz, 1H),
6.18 (s, 1H), 2.20 (s, 3H); 13C NMR (75 MHz, CDCl3): d 169.1,
133.7, 132.0, 129.4, 128.3, 120.9, 120.3, 115.6, 89.1, 81.1, 63.3, 20.7;
IR (KBr): 2923, 2232, 1750, 1214, 1020, 757, 606 cm-1; MS (ESI):
m/z 248 (M+Na)+; HRMS (ESI): m/z calcd for C14H11NNaO2
(M+Na)+: 248.0682, found: 248.0682.
General
Reactions were monitored by thin-layer chromatography carried
out on silica plates using UV-light and anisaldehyde or potassium
permanganate or b-naphthol for visualization. Column chro-
matography 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.
1
IR spectra were recorded on either KBr pellets or as neat. H
NMR and 13C NMR spectra were recorded in CDCl3 solvent on
a 300 MHz and 500 MHz NMR spectrometer. Chemical shifts
d and coupling constants J are given in ppm (parts per million)
and Hz (hertz) respectively. Chemical shifts are reported relative
to residual solvent as an internal standard for 1H and 13C (CDCl3:
d 7.26 ppm for 1H and 77.0 ppm for 13C).
Methyl 1, 5-dibenzyl-1H-pyrrole-3-carboxylate (3a). White
solid; M.P: 99–101 ◦C; 1H NMR (300 MHz, CDCl3): d 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): d 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.
Morita–Baylis–Hillman acetates have been prepared using the
literature procedure3a to obtain 1a to 1h.
General procedure for the synthesis of substituted pyrroles
Methyl 5-benzyl-1-phenyl-1H-pyrrole-3-carboxylate (3b). Pale
yellow oil; H NMR (300 MHz, CDCl3): d 7.40–7.32 (m, 4H),
To a solution of MBH acetate (1, 1.0 mmol) and amine (2,
1.0 mmol) in 5 mL of dimethylformamide was added potassium
carbonate (1.0 mmol) at room temperature. Then, the temperature
was raised to 45 ◦C. The reaction mixture was stirred at the same
temperature for 1 to 28 h (see Tables 1–3). After the completion of
reaction, the 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
(3).
1
7.21–7.08 (m, 5H), 6.96 (d, J = 6.7 Hz, 2H), 6.40 (s, 1H), 3.81
(s, 2H), 3.79 (s, 3H); 13C NMR (75 MHz, CDCl3): d 165.2, 138.9,
138.6, 133.7, 129.1, 128.5, 128.3, 128.1, 127.2, 126.3, 126.23, 115.5,
109.7, 51.0, 32.9; IR (neat): 2948, 1710, 1515, 1437, 1242, 1195,
759, 697 cm-1; MS (ESI): m/z 292 (M+H)+; HRMS (ESI): m/z
calcd for C19H18NO2 (M+H)+: 292.1332, Found: 292.1330.
Methyl 5-benzyl-1-(furan-2-ylmethyl)-1H-pyrrole-3-carboxylate
(3c). Pale yellow oil; 1H NMR (300 MHz, CDCl3): d 7.33 (s, 1H),
7.29–7.15 (m, 4H), 7.11 (d, J = 6.9 Hz, 2H), 6.32 (s, 1H), 6.26 (dd,
J = 2.1, 1.7 Hz, 1H), 6.01 (d, J = 2.1 Hz, 1H), 4.78 (s, 2H), 3.94
(s, 2H), 3.75 (s, 3H); 13C NMR (75 MHz, CDCl3): d 165.2, 149.3,
142.9, 138.2, 132.4, 128.6, 128.4, 126.6, 126.5, 114.7, 110.4, 109.7,
108.5, 50.9, 43.8, 32.5; IR (neat): 2921, 1705, 1519, 1212, 753, 601
cm-1; MS (ESI): m/z 296 (M+H)+; HRMS (ESI): m/z calcd for
C18H18NO3 (M+H)+: 296.1281, found: 296.1279.
Spectral data for all new compounds
Methyl 3-acetoxy-2-methyleneundec-4-ynoate (1c). Pale yel-
1
low oil; H NMR: (300 MHz, CDCl3): d 6.41 (d, J = 1.5 Hz,
1H), 6.21 (s, 1H), 6.20 (d, J = 1.5 Hz, 1H), 3.79 (s, 3H), 2.23 (td,
J = 6.7, 2.2 Hz, 2H), 2.08 (s, 3H), 1.59–1.46 (m, 2H), 1.45–1.22
(m, 6H), 0.90 (t, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): d
169.3, 164.9, 136.9, 128.7, 88.5, 74.7, 61.9, 52.0, 31.1, 28.3, 28.1,
22.4, 20.7, 18.6, 13.9; IR (neat): 2930, 2858, 2236, 1744, 1638,
1225, 683 cm-1; MS (ESI): m/z 289 (M+Na)+; HRMS (ESI): m/z
calcd for C15H22NaO4 (M+Na)+: 289.1410 found: 289.1398.
Methyl
5-benzyl-1-methyl-1H-pyrrole-3-carboxylate
(3d).
◦
1
White solid; M.P: 105–106 C; H NMR (300 MHz, CDCl3): d
7.29–7.14 (m, 4H), 7.09 (d, J = 6.9 Hz, 2H), 6.31 (s, 1H), 3.90 (s,
2H), 3.76 (s, 3H), 3.42 (s, 3H); 13C NMR (75 MHz, CDCl3): d
165.3, 138.2, 132.6, 128.5, 128.3, 127.3, 126.4, 114.0, 109.3, 50.8,
34.3, 32.6; IR (KBr): 3122, 2944, 1695, 1525, 1229, 769 cm-1; MS
(ESI): m/z 230 (M+H)+; HRMS (ESI): m/z calcd for C14H16NO2
(M+H)+: 230.1176, found: 230.1174.
Methyl 3-acetoxy-5-(tert-butyldimethylsilyl)-2-methylenepent-
1
4-ynoate (1d). Pale yellow oil; H NMR: (300 MHz, CDCl3):
d 6.44 (d, J = 1.5 Hz, 1H), 6.25 (br, 1H), 6.23 (d, J = 1.5 Hz,
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Methyl 5-benzyl-1-tosyl-1H-pyrrole-3-carboxylate (3e). White
solid;M.P: 112–114 ◦C; 1HNMR(300MHz, CDCl3): d 7.70(d, J =
7.5, 2H), 7.60 (d, J = 8.1, 2H), 7.36–7.16 (m, 5H), 6.73 (s, 1H), 6.31
(s, 1H), 4.54 (s, 2H), 3.69 (s, 3H), 2.41 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 162.8, 144.3, 141.7, 140.1, 135.2, 132.8, 130.7, 129.7,
129.4, 128.97, 128.2, 127.9, 123.4, 56.9, 51.8, 21.6; IR (KBr): 2920,
1709, 1595, 1443, 1356, 1164, 1089, 697, 591 cm-1; MS (ESI): m/z
370 (M+H)+; HRMS (ESI): m/z calcd for C20H20NO4S (M+H)+:
370.1108, found: 370.1111.
6.10 (d, J = 3.1 Hz, 1H), 4.85 (s, 2H), 4.12 (s, 2H), 3.76 (s, 3H);
13C NMR (75 MHz, CDCl3): d 165.1, 149.2, 142.9, 141.4, 131.7,
126.9, 126.7, 125.2, 124.2, 114.8, 110.5, 109.5, 108.5, 50.9, 43.9,
29.6; IR (KBr): 2924, 2854, 1703, 1438, 1385, 1211, 1011, 761, 708
cm-1; MS (ESI): m/z 302 (M+H); HRMS (ESI): m/z calcd for
C16H16NO3S (M+H)+: 302.0845, found: 302.0838.
Methyl
1-benzyl-5-heptyl-1H-pyrrole-3-carboxylate
(3k).
◦
1
White solid; M.P: 56–58 C; H NMR (300 MHz, CDCl3): d
7.36–7.18 (m, 4H), 6.97 (d, J = 7.1 Hz, 2H), 6.32 (s, 1H), 5.02 (s,
2H), 3.76 (s, 3H), 2.37 (t, J = 7.3 Hz, 2H), 1.60–1.49 (m, 2H),
1.36–1.18 (m, 8H), 0.87 (t, J = 6.4 Hz, 3H); 13C NMR: (75 MHz,
CDCl3): d 165.4, 136.9, 134.9, 128.7, 127.6, 126.4, 126.2, 122.8,
107.2, 50.8, 50.6, 31.6, 29.1, 28.9, 28.2, 25.9, 22.5, 13.9; IR (KBr):
2925, 2853, 2212, 1699, 1518, 1220, 702 cm-1; MS (ESI): m/z
314 (M+H)+; HRMS (ESI): m/z calcd for C20H28NO2 (M+H)+:
314.2115, found 314.2119.
Methyl 5-benzyl-1-(phenyls◦ulfonyl)-1H-pyrrole-3-carboxylate
(3f). White solid; M.P: 56–58 C; 1H NMR (300 MHz, CDCl3):
d 7.98–7.88 (m, 2H), 7.62 (d, J = 7.3 Hz, 2H), 7.59–7.45 (m, 2H),
7.44–7.36 (m, 1H), 7.21–7.12 (m, 2H), 7.02–6.96 (m, 2H), 6.14 (s,
1H), 4.04 (s, 2H), 3.78 (s, 3H); 13C NMR (75 MHz, CDCl3): d
164.1, 141.8, 138.3, 137.4, 135.4, 134.3, 133.4, 129.7, 129.5, 129.1,
127.9, 127.3, 126.8, 118.5, 113.9, 51.7, 33.5; IR (neat): 2952,
2850, 1719, 1448, 1374, 1178, 730, 590 cm-1; MS (ESI): m/z 356
(M+H)+; HRMS (ESI): m/z calcd for C19H17NNaO4S (M+Na)+:
378.0770, found: 378.0788.
Methyl 5-heptyl-1-phenyl-1H-pyrrole-3-carboxylate (3l). Pale
1
yellow oil; H NMR (300 MHz, CDCl3): d 7.55–7.25 (m, 6H),
6.46 (s, 1H), 3.81 (s, 3H), 2.45 (t, J = 7.7 Hz, 2H), 1.54–1.40 (m,
2H), 1.33–1.14 (m, 8H), 0.85 (t, 3H); 13C NMR: (75 MHz, CDCl3):
d 165.4, 139.3, 135.5, 129.2, 127.9, 126.6, 126.1, 115.4, 107.6, 51.0,
31.6, 29.1, 28.9, 28.6, 26.4, 22.5, 14.0; IR (neat): 2926, 2855, 1714,
1507, 1438, 1237, 1101, 756, 695 cm-1; MS (ESI): m/z 300 (M+H)+;
HRMS (ESI) m/z calcd for C19H26NO2 (M+H)+: 300.1958, found:
300.1951.
(S)-Methyl-5-benzyl-1-(1-methoxy-1-oxo-3-phenylpropan-2-yl)-
1H-pyrrole-3 carboxylate (3g). Pale yellow oil; [a]2D1 -13.9 (c 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3): d 7.58 (d, J = 1.5 Hz, 1H),
7.29 (m, 6H), 7.01 (d, J = 1.5 Hz, 1H), 6.99 (s, 1H), 6.82–6.78
(m, 2H), 6.25 (s, 1H), 4.68 (dd, J = 9.1, 6.8 Hz, 1H), 3.80 (s,
3H), 3.60 (s, 5H), 3.34 (dd, J = 6.8, 13.6 Hz, 1H), 3.00 (dd, J =
9.1, 13.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 169.8, 165.2,
135.6, 133.1, 130.9, 128.9, 128.7, 128.6, 128.5, 127.2, 126.6, 124.3,
115.7, 109.3, 68.1, 52.7, 51.1, 39.4, 32.4; IR (KBr): 2925, 1723,
1711, 1519, 1454, 1272, 1217, 1005, 757, 700 cm-1; MS (ESI): m/z
378.0 (M+H)+; HRMS (ESI): m/z calcd for C23H24NO4 (M+H)+:
378.1700, found: 378.1706.
Methyl 1-benzyl-5-methyl-1H-pyrrole-3-carboxylate (3m).
1
Colourless oil; H NMR (300 MHz, CDCl3): d 7.33–7.19 (m,
4H), 6.98 (d, J = 6.6 Hz, 2H), 6.30 (s, 1H), 5.01 (s, 2H), 3.76 (s,
3H), 2.11 (s, 3H); 13C NMR: (75 MHz, CDCl3): d 165.3, 136.8,
130.0, 128.8, 127.7, 126.5, 126.3, 114.5, 108.5, 67.9, 50.9, 25.5;
IR (KBr): 2921, 2851, 1704, 1526, 1443, 1218, 765, 725 cm-1; MS
(ESI): m/z 230 (M+H)+; HRMS (ESI) m/z calcd for C14H16NO2
(M+H)+: 230.1176, found: 230.1177.
Methyl 1-benzyl-5-(thiophen-2-ylmethyl)-1H-pyrrole-3-carbo-
xylate (3h). White solid; M.P: 104–106 ◦C; 1H NMR (300 MHz,
CDCl3): d 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): d 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 312 (M+H)+; HRMS (ESI): m/z calcd for C18H18NO2S
(M+H)+: 312.1053, found: 312.1056.
Methyl
5-methyl-1-phenyl-1H-pyrrole-3-carboxylate
(3n).
1
Colourless oil; H NMR (300 MHz, CDCl3): d 7.49–7.22 (m,
6H), 6.39 (s, 1H), 3.79 (s, 3H), 2.17 (s, 3H); 13C NMR: (75 MHz,
CDCl3): d 165.3, 139.2, 130.3, 129.2, 127.8, 126.5, 125.7, 112.8,
108.9, 51.0, 12.7; IR (KBr): 2947, 2852, 1703, 1443, 1218, 1003,
725 cm-1; MS (ESI): m/z 216 (M+H)+; HRMS (ESI): m/z calcd
for C13H14NO2 (M+H)+: 216.1019, found: 216.1021.
Methyl 1-(furan-2-ylmethyl)-5-methyl-1H-pyrrole-3-carboxy-
late (3o). Yellow oil; H NMR (500 MHz, CDCl3): d 7.36 (s,
Methyl 1-phenyl-5-(thiophen-2-ylme◦thyl)-1H-pyrrole-3-carbo-
1
1
xylate (3i). Yellow solid; M.P: 69–70 C; H NMR (300 MHz,
1H), 7.30 (s, 1H), 7.24 (s, 1H), 6.32 (s, 1H), 6.19 (s, 1H), 4.93 (s,
2H), 3.77 (s, 3H), 2.23 (s, 3H); 13C NMR: (75 MHz, CDCl3): d
165.2, 149.6, 142.8, 129.7, 125.8, 124.4, 114.6, 110.4, 108.3, 50.8,
43.8, 11.8; IR (KBr): 2947, 2852, 1703, 1443, 1218, 1003, 725
cm-1; MS (ESI): m/z 219 (M+H)+; HRMS (ESI): m/z calcd for
C12H14NO3 (M+H)+: 219.0968, found: 219.0953.
CDCl3): d 7.38 (dd, J = 1.3, 5.1 Hz, 1H), 7.31 (dd, J = 1.5, 3.6 Hz,
1H), 7.16–7.08 (m, 2H), 7.04 (dd, J = 3.7, 5.1 Hz, 1H), 6.93 (s,
1H), 6.74–6.58 (m, 4H), 4.25 (s, 2H), 3.79 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 166.5, 147.3, 138.8, 133.4, 129.2, 129.1, 127.4,
121.9, 121.4, 117.8, 113.5, 96.3, 89.4, 52.1, 42.4; IR (KBr): 2930,
1691, 1600, 1438, 1239, 1110, 753, 700, 599 cm-1; MS (ESI): m/z
298 (M+H)+; HRMS (ESI): m/z calcd for C17H16NO2S (M+H)+:
298.0896, found: 298.0903.
1, 2-Bibenzyl-5, 6-dihydrocyclopenta[b]pyrrol-4(1H)-one (3p).
1
Pale yellow oil; H NMR (300 MHz, CDCl3): d 7.34–7.17 (m,
Methyl 1-(furan-2-ylmethyl)-5-(thiophen-2-ylmethyl)-1H-pyrro-
le-3-carboxylate (3j). White solid; M.P: 63–65 ◦C; 1H NMR
(300 MHz, CDCl3): d 7.35 (d, J = 2.3 Hz, 1H), 7.25 (d, J = 2.6 Hz,
1H), 7.14 (dd, J = 5.1, 1.2 Hz, 1H), 6.89 (dd, J = 5.1, 3.6 Hz, 1H),
6.74 (d, J = 2.3 Hz, 1H), 6.41 (s, 1H), 6.29 (dd, J = 1.9, 3.0 Hz, 1H),
6H) 7.05 (d, J = 6.7 Hz, 2H), 6.90 (d, J = 6.2 Hz, 2H), 6.17 (s,
1H), 4.84 (s, 2H), 3.80 (s, 2H), 2.82 (t, J = 4.1 Hz, 2H), 2.71 (t, J =
4.1 Hz, 2H); 13C NMR (75 MHz, CDCl3): d 197.4, 139.7, 136.1,
129.3, 128.9, 128.8, 128.6, 128.3, 127.8, 126.6, 126.2, 125.8, 102.5,
48.3, 40.8, 29.6, 20.7; IR (KBr): 2922, 2854, 1647, 1484, 1219, 772,
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573 cm-1; MS (ESI): m/z 302 (M+H)+; HRMS (ESI): m/z calcd
3 (a) S. P. Park, S. H. Ahn and K. J. Lee, Tetrahedron, 2010, 66, 3490–
3498; (b) V. K. Aggarwal, I. Emme and S. Y. Fulford, J. Org. Chem.,
2003, 68, 692–700; (c) P. R. Krishna, E. R. Sekhar and V. Kannan,
Tetrahedron Lett., 2003, 44, 4973–4975.
4 (a) Ch. R. Reddy, J. Vijaykumar and R. Gree, Synthesis, 2010, 3715–
3723; (b) Ch. R. Reddy and B. Srikanth, Synlett, 2010, 1536–1538;
(c) Ch. R. Reddy and E. Jithender, Tetrahedron Lett., 2009, 50, 5633–
5635; (d) Ch. R. Reddy and N. N. Rao, Tetrahedron Lett., 2009, 50,
2478–2480; (e) Ch. R. Reddy, B. Srikanth, N. N. Rao and D. S. Shin,
Tetrahedron, 2008, 64, 11666–11672.
5 For multistep synthesis of pyrroles via MBH reaction, see: (a) E.
Colacino, C. Andre, J. Martinez and F. Lamaty, Tetrahedron Lett.,
2008, 49, 4953–4955; (b) V. Declerck, H. Allouchi, J. Martinez and F.
Lamaty, J. Org. Chem., 2007, 72, 1518–1521; (c) S. J. Kim, H. S. Kim,
T. H. Kim and J. N. Kim, Bull. Korean Chem. Soc., 2007, 28, 1605–
1608; (d) H. S. Lee, J. M. Kim and J. N. Kim, Tetrahedron Lett., 2007,
48, 4119–4122; (e) V. Singh, S. Kanojiya and S. Batra, Tetrahedron,
2006, 62, 10100–10110; (f) V. Declerck, P. Ribieire, J. Martinez and F.
Lamaty, J. Org. Chem., 2004, 69, 8372–8381; (g) J. M. Kim, K. Y. Lee,
S. Lee and J. N. Kim, Tetrahedron Lett., 2004, 45, 2805; (h) M. Shi and
Y. M . X u , Eur. J. Org. Chem., 2002, 696–701.
6 (a) H. Fan, J. Peng, M. T. Hamann and J. F. Hu, Chem. Rev., 2008, 108,
264–287; (b) A. H. Lipkus, Q. Yuan, K. A. Lucas, S. A. Funk, W. F.
Bartelt, R. J. Schenk and A. J. Trippe, J. Org. Chem., 2008, 73, 4443–
4451; (c) C. T. Walsh, S. Garneau-Tsodikova and A. R. Howard-Jones,
Nat. Prod. Rep., 2006, 23, 517–531; (d) A. Furstner, Angew. Chem., Int.
Ed., 2003, 42, 3582–3603.
for C21H20NO (M+H)+: 302.1539, found: 302.1552.
2-Benzyl-1-methyl-6,7-dihydro-1H-indol-4(5H)-one
(3q).
◦
1
Brown solid; M.P: 55–57 C; H NMR (300 MHz, CDCl3): d
7.29–7.14 (m, 3H), 7.11 (d, J = 6.8 Hz, 2H), 6.29 (s, 1H), 3.91 (s,
2H), 3.30 (s, 3H), 2.69 (t, J = 6.8 Hz, 2H), 2.42 (t, J = 6.0 Hz,
2H), 2.15 (m, 2H); 13C NMR (75 MHz, CDCl3): d 194.0, 144.3,
133.3, 128.5, 128.4, 128.3, 128.1, 126.4, 104.5, 37.5, 32.8, 30.6,
23.4, 21.8; IR (NEAT): 2925, 2845, 1649, 1489, 1396, 1041, 992,
758, 691 cm-1; MS (ESI): m/z 240 (M+H)+; HRMS (ESI): m/z
calcd for C16H18NO (M+H)+: 240.1383, found: 240.1381.
(Z)-2-((Furan-2-ylmethylamino) methyl)-5-phenylpent-2-en-4-
ynenitrile (4a). Pale yellow oil; 1H NMR (300 MHz, CDCl3): d
7.55–7.49 (m, 2H), 7.38–7.31 (m, 4H), 6.49 (t, J = 1.5 Hz, 1H),
6.29 (dd, J = 3.0, 2.2 Hz, 1H), 6.18 (d, J = 3.0 Hz, 1H), 3.80 (s,
2H), 3.48 (d, J = 1.5 Hz, 2H); 13C NMR (75 MHz, CDCl3): d
152.6, 142.1, 132.0, 129.5, 128.4, 124.8, 122.7, 121.7, 116.9, 110.1,
107.6, 100.3, 84.6, 50.1, 44.4; IR (KBr): 3448, 2920, 2850, 2196,
1642, 758, 598 cm-1; MS (ESI): m/z 263 (M+H)+; HRMS (ESI):
m/z calcd for C17H15N2O (M+H)+: 263.1179, found: 263.1169.
7 For classical methods, see: (a) L. Knorr, Ber. Dtsch. Chem. Ges., 1884,
17, 1635–1642; (b) C. Paal, Ber. Dtsch. Chem. Ges., 1885, 18, 367–371;
(c) A. Hantzsch, Ber. Dtsch. Chem. Ges., 1890, 23, 1474–1476.
8 Recent representative methods, see: (a) S. Ngwerume and J. E. Camp,
Chem. Commun., 2011, 47, 1857–1859; (b) B. M. Trost, J.-P. Lumb
and J. M. Azzarelli, J. Am. Chem. Soc., 2011, 133, 740–743; (c) A. S.
Demir, M. Emrullahoglu and K. Buran, Chem. Commun., 2010, 46,
8032–8034; (d) H. Y. Wang, D. S. Mueller, R. M. Sachwani, H. N.
Londino and L. L. Anderson, Org. Lett., 2010, 12, 2290–2293; (e) T. J.
Donohoe, N. J. Race, J. F. Bower and C. K. A. Callens, Org. Lett., 2010,
12, 4094–4097; (f) D. Chernyak, C. Skontos and V. Gevorgyan, Org.
Lett., 2010, 12, 3242–3245; (g) M. Yoshimatsu, H. Watanabe and E.
Koketsu, Org. Lett., 2010, 12, 4192–4194; (h) S. Rakshit, F. W. Patureau
and F. Glorius, J. Am. Chem. Soc., 2010, 132, 9585–9587; (i) R. L. Yan,
J. Luo, C. X. Wang, C. W. Ma, G. S. Huang and Y. M. Liang, J. Org.
Chem., 2010, 75, 5395–5397; (j) A. Herath and N. D. P. Cosford, Org.
Lett., 2010, 12, 5182–5185; (k) X. Fu, J. Chen, G. Li and Y. Liu, Angew.
Chem., Int. Ed., 2009, 48, 5500–5504.
9 Representative methods, see: (a) S. Maiti, S. Biswas and U. Jana, J. Org.
Chem., 2010, 75, 1674–1693; (b) W. Liu, H. Jiang and L. Huang, Org.
Lett., 2010, 12, 312–315; (c) E. Merkul, C. Boersch, W. Frank and T. J.
J. Muller, Org. Lett., 2009, 11, 2269–2272; (d) S. Dey, C. Pal, D. Nandi,
V. S. Giri, M. Zaidlewicz, M. Krzeminski, L. Smentek, B. A. Hess, J.
Gawronski, Jr., M. Kwit, N. J. Babu, A. Nangia and P. Jaisankar, Org.
Lett., 2008, 10, 1373–1376; (e) D. J. St. Cyr and B. A. Arndtsen, J.
Am. Chem. Soc., 2007, 129, 12366–12367; (f) C. V. Galliford and K.
A. Scheidt, J. Org. Chem., 2007, 72, 1811–1813; (g) G. Balme, Angew.
Chem., Int. Ed., 2004, 43, 6238–6241; (h) A. R. Bharadwaj and K. A.
Scheidt, Org. Lett., 2004, 6, 2465–2468.
(E)-Methyl 2-((4-methyl-N-phenylphenylsulfonamido) methyl)-
5-phenylpent-2-en-4-ynoate (4b). Colorless oil; 1H NMR
(300 MHz, CDCl3): d 7.56–7.49 (m, 3H), 7.46 (d, J = 7.3 Hz,
2H), 7.42–7.32 (m, 3H), 7.25–7.16 (m, 5H), 7.02 (d, J = 6.3 Hz,
2H), 6.86 (s, 1H), 4.71 (s, 2H), 3.69 (s, 3H), 2.42 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 166.1, 143.3, 138.9, 136.2, 134.8, 132.0, 129.4,
129.3, 129.0, 128.5, 128.4, 128.0, 127.9, 124.3, 122.1, 103.9, 85.1,
52.1, 48.0, 21.5; IR (KBr): 2924, 2853, 2192, 1715, 1488, 1444,
1344, 1162, 1087, 758, 692 cm-1; MS (ESI): m/z 446 (M+H)+;
HRMS (ESI): m/z calcd for C26H24NO4S (M+H)+: 446.1421,
found: 446.1426.
Methyl 5-benzyl-1H-pyrrole-3-carboxylate (3ea). White solid;
M.P: 125–127 ◦C; 1H NMR (300 MHz, CDCl3): d 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): d 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.
Acknowledgements
10 Selected methods, see: (a) Y. Lu, X. Fu, H. Chen, X. Du, X. Jia and Y.
Liu, Adv. Synth. Catal., 2009, 351, 129–134; (b) T. Ishikawa, T. Aikawa,
S. Watanabe and S. Saito, Org. Lett., 2006, 8, 3881–3884; (c) B. Gabriele,
G. Salerno and A. Fazio, J. Org. Chem., 2003, 68, 7853–7861; (d) E.
Benedetti, G. Lemiere, L. L. Chapellet, A. Penoni, G. Palmisano, M.
Malacria, J. P. Goddard and L. Fensterbank, Org. Lett., 2010, 12,
4396–4399; (e) L. V. Seregin, A. W. Schammel and V. Gevorgyan, Org.
Lett., 2007, 9, 3433–3436; (f) E. Jimenez-Nunez and A. M. Echavarren,
Chem. Rev., 2008, 108, 3326–3350.
The authors thank Council of Scientific and Industrial Research-
New Delhi for the award of fellowships to MDR and BS.
Notes and references
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11 (a) Z. Xu and X. Lu, J. Org. Chem., 1998, 63, 5031–5041; (b) Detosy-
lation of 3e was accomplished in the presence of NaOMe in MeOH.
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(b) D. Basavaiah, B. S. Reddy and S. S. Badsara, Chem. Rev., 2010, 110,
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(f) K. Y. Lee, S. Gowrisankar and J. N. Kim, Bull. Korean Chem. Soc.,
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12 However, it is unclear whether the desilylation take place before allylic
substitution, between substitution and cycloisomerization or after
cycloisomerization.
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13 The (Z)-stereochemistry of 4a was supported by NOE cross peaks
14 No NOE cross peaks were observed between Ha–Hb in compound 4b.
between Ha–Hb and Ha–Hc as shown below.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6027–6033 | 6033
©