Divergent synthesis of 2,3-dihydro-1H-pyrroles, 3-alkyl-1H-pyrroles and 3-alkenyl-1H-pyrroles from 2,4-pentadienenitriles and isocyanides

Article abstract of DOI:10.1039/c4ob00912f

An efficient and divergent one-pot synthesis of 2,3-dihydro-1H-pyrroles, 3-alkyl-1H-pyrroles and 3-alkenyl-1H-pyrroles from readily accessible 2,4-pentadienenitriles with isocyanide based on reaction condition selection has been described. The reaction of 2,4-pentadienenitriles with ethyl isocyanoacetate undergoes a formal [2 + 3] annulation either to generate 2,3-dihydro-1H-pyrroles in the presence of DBU (0.3 equiv.) in EtOH at room temperature or to give 3-alkyl-1H-pyrroles in the presence of DBU (2.0 equiv.) in EtOH under reflux. Moreover, the 2,3-dihydro-1H-pyrroles could be converted to 3-alkenyl-1H-pyrroles with DDQ as an oxidant. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00912f

Organic &
Biomolecular Chemistry
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PAPER
Divergent synthesis of 2,3-dihydro-1H-pyrroles,
3-alkyl-1H-pyrroles and 3-alkenyl-1H-pyrroles
from 2,4-pentadienenitriles and isocyanides†
Cite this: Org. Biomol. Chem., 2014,
12, 5477
Xiaoqing Xin,a Xu Liu,a Dingyuan Zhang,a Rui Zhang,a Yongjiu Liang,*a Fushe Hana
and Dewen Dong*a,b
An efficient and divergent one-pot synthesis of 2,3-dihydro-1H-pyrroles, 3-alkyl-1H-pyrroles and
3-alkenyl-1H-pyrroles from readily accessible 2,4-pentadienenitriles with isocyanide based on reaction
condition selection has been described. The reaction of 2,4-pentadienenitriles with ethyl isocyanoacetate
undergoes a formal [2 + 3] annulation either to generate 2,3-dihydro-1H-pyrroles in the presence of DBU
(0.3 equiv.) in EtOH at room temperature or to give 3-alkyl-1H-pyrroles in the presence of DBU
(2.0 equiv.) in EtOH under reflux. Moreover, the 2,3-dihydro-1H-pyrroles could be converted to
3-alkenyl-1H-pyrroles with DDQ as an oxidant.
Received 3rd May 2014,
Accepted 3rd June 2014
DOI: 10.1039/c4ob00912f
www.rsc.org/obc
alkenes or alkynes.9 The van Leusen pyrrole synthesis is such a
representative organic transformation, in which p-toluene-
Introduction
Pyrroles constitute the core structure of many natural products sulfonyl methyl isocyanide (TosMIC) was used as a substrate
and synthetic compounds along with a broad range of bio- (Scheme 1, Path A).10 Barton and Zard also achieved the
and pharmacological activities, such as antibiotic, antitumor, pyrrole synthesis via the reaction of isocyanides with nitro-
antitubercular, multi-drug resistance inhibition and lowering alkenes (Scheme 1, Path B).11 Later on, other alkenes activated
cholesterol.1 Also, functionalized pyrroles are widely used by SO2Ar, CN, and SMe were employed in such pyrrole
as versatile building blocks in the synthesis of a wide range of syntheses.12
heterocycles, including indoles, indolizidine alkaloids and
In the course of our studies on the synthetic utilization of
indolizines.2 Additionally, pyrroles have found application in malononitrile and its derivatives, we developed a facile
functional materials, for instance in glucose sensors, organic synthesis of highly substituted benzenes13 from malononitrile
semiconductors and BODIPY dyes.3 Their utilization in
organic chemistry, biochemistry, medicinal chemistry and
material chemistry has intrigued researchers in search of
efficient synthetic approaches for the construction of the
skeleton of this type of heterocycle. The classical synthetic
methods for pyrroles, including Knorr synthesis,4 Paal–Knorr
synthesis5 and Hantzsch synthesis,6 have been established.
Recently, transition metal-catalyzed cyclization7 and multi-
component reactions (MCRs)8 have emerged as attractive and
important transformations to the synthesis of pyrroles owing
to their high efficiency and selectivity.
On the other hand, isocyanides are recognized as versatile
synthons in pyrrole synthesis by reacting with activated
aChangchun Institute of Applied Chemistry, Chinese Academy of Sciences,
Changchun, 130022, P. R. China. E-mail: yjliang@ciac.ac.cn, dwdong@ciac.ac.cn
bChangzhou Institute of Energy Storage Materials & Devices, Changzhou, 213000,
P. R. China
†Electronic supplementary information (ESI) available: Copies of NMR spectra
for compounds 2–4. CCDC 968815 and 968816. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c4ob00912f
Scheme 1 The reaction of electron-efficient alkenes and isocyanides.
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and chalcones in ionic liquids and an efficient synthesis of
multi-substituted pyridines14 via a MCR of malonitrile, β-oxo
amides and aromatic aldehydes in alcohols. Very recently, we
achieved the synthesis of aminopyridines via a MCR of
2-[(amino)methylene]malononitriles, sulfonyl azides and
alkynes,15 and a formal [5C + 1N] annulation of 2,4-penta-
dienenitriles with hydroxyl amine, respectively.16 In connection
with these research studies and the aim to establish novel syn-
thetic approaches for heterocycles, we explored the reaction of
2,4-pentadienenitriles 1 with isocyanides under different con-
ditions. As a result of these studies, we achieved divergent
synthesis of 2,3-dihydro-1H-pyrroles, 3-alkyl-1H-pyrroles and
3-alkenyl-1H-pyrroles via [2 + 3] cycloaddition of readily acces-
sible 2,4-pentadienenitriles with ethyl isocyanoacetate under
different conditions (Scheme 1, Path C). Herein, we report our
experimental results and propose a mechanism involved in
these reactions.
Table 2 Reaction of 2,4-pentadienenitriles
acetate to 2,3-dihydro-1H-pyrroles 2a
1 with ethyl isocyano-
Entry
1
Ar
R1
X
2
Yieldb (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
4-ClC6H4
4-MeC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
C6H5
C6H5
4-ClC6H4
4-ClC6H4
H
H
H
H
H
H
Me
H
H
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CONH2
CSNH2
2a
2b
2c
2d
2e
2f
2g
2a
2a
85
79
82
77
80
74
81
76
78
a Reagents and conditions:
1 (1.0 mmol), ethyl isocyanoacetate
(1.0 mmol), DBU (0.3 mmol), EtOH (10.0 mL), rt, 0.5–1.0 h. b Isolated
yields.
Results and discussion
ethanol at room temperature and furnished a product, which
was characterized as (E)-ethyl 3-(4-chlorostyryl)-4-cyano-2,3-
dihydro-1H-pyrrole-2-carboxylate 2a on the basis of its spectra
and analytical data (Table 1, entry 4). Other bases, such as
piperidine, triethylamine and K2CO3, were also tested but
proved to be less active than DBU (Table 1, entries 5–7). Sub-
sequent experiments revealed that 0.3 equivalent of DBU was
effective for the reaction of 1a with ethyl isocyanoacetate to
form 2a (Table 1, entries 8–10).
The substrates, 2,4-pentadienenitriles 1, were prepared by the
Knoevenagel condensation of commercially available nitriles
with cinnamaldehydes in the presence of piperidine in
ethanol in excellent yields according to our previous reported
procedure.16 Then, we selected ethyl 5-(4-chlorophenyl)-2-cyano-
penta-2,4-dienoate 1a as the model compound to examine
its reaction behavior. The reaction of 1a with ethyl isocyano-
acetate was initially attempted in the presence of 1,8-diazabi-
cyclo[5.4.0] undec-7-ene (DBU, 2.0 equiv.) in N,N-dimethyl-
formamide at room temperature for 12.0 h, and a complex
mixture was formed (Table 1, entry 1). A similar phenomenon
was observed when 1a, ethyl isocyanoacetate and DBU were
subjected to acetonitrile or tetrahydrofuran (Table 1, entries 2
and 3). To our delight, the reaction proceeded smoothly in
Under the same reaction conditions as for 2a in entry 9
(Table 1), a range of reactions of substrates 1 with ethyl iso-
cyanoacetate was carried out to determine the scope and limit-
ation of the 2,3-dihydro-1H-pyrrole synthesis, and some of the
results are summarized in Table 2. The efficiency of the cycli-
zation proved to be suitable for 2,4-pentadienenitriles 1b–g
bearing varied substituents Ar and R1 on their double bond to
afford the corresponding trisubstituted dihydropyrroles 2b–g
in good yields (Table 2, entries 2–7). When 2-carbamoyl-2,4-
pentadienenitriles 1h and 1i were employed under identical
conditions, dihydropyrrole 2a was obtained in good yield
(Table 2, entries 8 and 9). In the 1H NMR spectra of 2a, a
triplet peak at δ 3.88 and a doublet peak at 4.33 were assigned
to the 3-H and the 2-H of the dihydropyrrole. The correlation
between 3-H and 2-CO2CH2 as well as that between 2-H and
3-CH indicated a trans configuration of 2a (see ESI†). Actually,
2,3-dihydro-1H-pyrroles constitute the core structure of many
natural products and synthetic compounds along with a broad
range of bioactivities, and serve as versatile building blocks for
the synthesis of functionalized pyrrolidines and pyrroles.17 In
the present work, we provided a facile and efficient synthesis
of 2,3-dihydro-1H-pyrroles of type 2 in a diastereoselective
manner.
Table 1 Reactions of 1a with ethyl isocyanoacetate under different
conditionsa
Entry
Base (equiv.)
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
DBU (2.0)
DBU (2.0)
DBU (2.0)
DBU (2.0)
Piperidine (2.0)
Et3N (2.0)
K2CO3 (2.0)
DBU (1.0)
DBU (0.3)
DBU (0.1)
DMF
CH3CN
THF
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
12.0
12.0
12.0
0.5
0.5
6.0
0.5
0.5
0.5
2.0
Mixture
Mixture
Mixture
83
57
20(15)
69
84
85
10
72(18)c
Next, we investigated the reaction of 2,4-penta-dienenitriles
1 and ethyl isocyanoacetate in EtOH under reflux. It was found
that the reaction of 1a and ethyl isocyanoacetate (1.0 equiv.) in
a Reagents and conditions: 1a (1.0 mmol), ethyl isocyanoacetate
(1.0 mmol), solvent (10.0 mL), rt. b Isolated yields. c Recovery of 1a in
parentheses.
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It should be mentioned that the richness of the functional-
ity of the 2,3-dihydropyrroles 2 may render them versatile pre-
cursors in further synthetic transformations. Encouraged by
this, we successfully synthesized multi-substituted pyrroles 4
in good yields by a one-pot, two-step procedure: the reactions
of 1 and ethyl isocyanoacetate (1.0 equiv.) were performed in
EtOH in the presence of DBU (0.3 equiv.) at room temperature
for 0.5–1.0 h, and then stirred under reflux for 1.0–2.0 h after
the addition of DDQ (1.0 equiv.) (Table 4, entries 1–7). The
structure of 4d was elucidated by means of the X-ray single
crystal analysis (Fig. 2) and supported by its spectral and
analytical data. Indeed, 3-alkenylpyrrole was first synthesized
from pyrroles in five steps by Salvadori and coworkers.18 There-
fore, we provided an alternative and straight route to 3-alkenyl
pyrrole of type 4 from open chain precursors.
Scheme 2 Reaction of 1a with ethyl isocyanoacetate under reflux.
Table 3 Reaction of 2,4-pentadienenitriles
acetate to 3-alkylpyrroles 3a
1 with ethyl isocyano-
On the basis of the results obtained together with the
reported literature,11,12,19 a mechanism for the divergent
synthesis of 2,3-dihydro-1H-pyrroles 2, 3-alkylpyrroles 3 and
3-alkenylpyrrole 4 is proposed as depicted in Scheme 3. The
overall transformation is triggered by the deprotonation of
ethyl isocyanoacetate in the presence of DBU at room tempera-
ture, and followed by a formal [2 + 3] cycloaddition with 2,4-
pentadienenitrile 1 to form a 3,4-dihydro-2H-pyrrole inter-
Entry
1
Ar
R1
3
Yieldb (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
4-ClC6H4
4-MeC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
C6H5
H
H
H
H
H
H
Me
3a
3b
3c
3d
3e
3f
67
65
58
60
63
61
72
1g
C6H5
3g
Table 4 Reaction of 2,4-pentadienenitriles
acetate to 3-alkenylpyrroles 4a
1 with ethyl isocyano-
a Reagents and conditions:
(1.0 mmol), DBU (2.0 mmol), EtOH (10.0 mL), reflux, 5.0–6.0 h.
b Isolated yields.
1 (1.0 mmol), ethyl isocyanoacetate
the presence of DBU (0.3 equiv.) could be completed within
20 min and 2a was obtained in 81% yield (Scheme 2). It was
interesting to note that when 1a, ethyl isocyanoacetate
(1.0 equiv.) and DBU (2.0 equiv.) were subjected to EtOH
under reflux for 5.0 h, the reaction furnished a main product,
which was characterized as ethyl 3-(4-chlorophenethyl)-
4-cyano-1H-pyrrole-2-carboxylate 3a (Scheme 2).
In the same fashion, the reactions of 1b–g with ethyl iso-
cyanoacetate (1.0 equiv.) and DBU (2.0 equiv.) were carried out
in EtOH under reflux. All the reactions proceeded smoothly to
afford the corresponding 3-alkyl-1H-pyrroles 3b–g in moderate
yields (Table 3, entries 2–7). The structure of 3a was estab-
lished by its X-ray single crystal analysis (Fig. 1).
Entry
1
Ar
R1
4
Yieldb (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
4-ClC6H4
4-MeC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
C6H5
H
H
H
H
H
H
Me
4a
4b
4c
4d
4e
4f
81
76
73
75
77
72
78
1g
C6H5
4g
a Reagents and conditions: (i) 1 (1.0 mmol), ethyl isocyanoacetate
(1.0 mmol), DBU (0.3 mmol), EtOH (10.0 mL), rt, 0.5–1.0 h; (ii)
reflux, 1.0–2.0 h. b Isolated yields.
Fig. 1 ORTEP drawing of 3a.
Fig. 2 ORTEP drawing of 4d.
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Typical procedure for the synthesis of 2,3-dihydro-1H-pyrroles
2 (2a as an example)
A mixture of ethyl 5-(4-chlorophenyl)-2-cyanopenta-2,4-dieno-
ate 1a (1.0 mmol, 262 mg), ethyl isocyanoacetate (1.0 mmol,
113 mg) and DBU (0.3 mmol, 45.6 mg) in ethanol (10.0 mL)
was stirred under room temperature for 0.5 h, and then
poured into saturated aqueous NaCl (50 mL), which was
extracted with dichloromethane (3 × 20 mL). The combined
organic phase was washed with water (3 × 20 mL), dried over
MgSO4, filtered and concentrated in vacuo. The crude product
was purified by flash chromatography (silica gel, petroleum
ether–ethyl acetate = 2 : 1) to give 2a as a colorless oil (257 mg,
85%); 1H NMR (400 MHz, DMSO): δ 1.22 (t, J = 7.2 Hz, 3H),
3.88 (q, J = 7.2 Hz, 1H), 4.13–4.21 (m, 2H), 4.33 (d, J = 6.4 Hz,
1H), 6.31 (dd, J1 = 16.0 Hz, J2 = 8.4 Hz, 1H), 6.54 (d, J =
16.0 Hz, 1H), 7.31 (s, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.42 (d, J =
2.0 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz,
DMSO): δ 14.1, 49.4, 61.1, 65.2, 77.7, 119.1, 128.2, 128.7, 129.7,
130.1, 132.1, 135.3, 151.8, 171.3; Anal. Calcd for
C16H15ClN2O2: C, 63.47; H, 4.99; N, 9.25. Found: C, 63.73;
H, 4.98; N, 9.20.
Scheme 3 Plausible mechanism for the synthesis of 2,3-dihydro-1H-
pyrroles 2, 3-alkylpyrroles 3 and 3-alkenylpyrroles 4.
mediate A. By the attack of the ethoxide ion, A is converted
into intermediate B, which might shed diethyl carbonate in
ethanol to give 2,3-dihydro-1H-pyrrole 2. The process is
different from the Barton–Zard reaction in which a pyrrole
would be formed directly. Further treated by DBU at higher
temperature, 2,3-dihydro-1H-pyrrole 2 undergoes double [1,3]-
H shifts to afford 3-alkylpyrrole 3. In another way, 2 could be
oxidized to 3-alkenylpyrrole 4 by DDQ.
Typical procedure for the synthesis of 3-alkyl-1H-pyrroles 3
(3a as an example)
A mixture of ethyl 5-(4-chlorophenyl)-2-cyanopenta-2,4-dieno-
ate 1a (1.0 mmol, 262 mg), ethyl isocyanoacetate (1.0 mmol,
113 mg) and DBU (2.0 mmol, 304 mg) in ethanol (10.0 mL)
was stirred under reflux for 5.0 h, and then poured into satu-
rated aqueous NaCl (50 mL), which was extracted with dichloro-
methane (3 × 20 mL). The combined organic phase was
washed with water (3 × 20 mL), dried over MgSO4, filtered and
concentrated in vacuo. The crude product was purified by flash
chromatography (silica gel, petroleum ether–ethyl acetate =
2 : 1) to give 3a as a white solid (204 mg, 67%); mp 157–158 °C;
1H NMR (400 MHz, DMSO): δ 1.28 (t, J = 7.2 Hz, 3H), 2.81 (q,
J = 8.4 Hz, 2H), 3.04 (q, J = 8.4 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H),
7.14 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.70 (d, J =
3.6 Hz, 1H), 12.51 (s, 1H); 13C NMR (100 MHz, DMSO): δ 14.2,
27.2, 35.4, 60.2, 94.6, 115.3, 119.8, 128.2, 129.6, 130.1, 130.6,
133.0, 139.8, 159.8; IR (KBr): ν = 3273, 3128, 2226, 1676, 1418,
1283, 1153, 1014, 783 cm−1; Anal. Calcd for C16H15ClN2O2:
C, 63.47; H, 4.99; N, 9.25. Found: C, 63.22; H, 5.01; N, 9.28.
Crystal data for 3a: C16H15ClN2O2, white crystal, M = 302.76,
monoclinic, P21/c, a = 13.476(5) Å, b = 6.865(3) Å, c = 17.826(7)
Å, α = 90.00°, β = 104.27(1)°, γ = 90.00°, V = 1598.23(306) Å3,
Z = 4, T = 298 K, F000 = 624.0, F000′ = 624.29, R = 0.0834(1482),
wR2 = 0.2409(3163). CCDC deposition number: 968815.
Conclusions
In summary, a facile and divergent synthesis of 2,3-dihydro-
1H-pyrroles, 3-alkyl-1H-pyrroles and 3-alkenyl-1H-pyrroles has
been developed via a formal [2 + 3] annulation of 2,4-penta-
dienenitriles and ethyl isocyanoacetate by variation of reaction
conditions. The protocol is associated with readily available
starting materials, very mild conditions, moderate to good
yields and structural diversity of products. The potential utiliz-
ation and extension of the scope of the methodology and
the evaluation of biological activity of the novel products are
currently under investigation in our laboratory.
Experimental
General
All reagents were purchased from commercial sources and
used without further treatment, unless otherwise indicated.
The products were purified by column chromatography over
Typical procedure for the synthesis of 3-alkenyl-1H-pyrroles 4a
(4a as an example)
silica gel. 1H NMR and 13C NMR spectra were recorded at A mixture of ethyl 5-(4-chlorophenyl)-2-cyanopenta-2,4-dieno-
300 MHz, 400 MHz and 100 MHz, respectively, with TMS as an ate 1a (1.0 mmol, 262 mg), ethyl isocyanoacetate (1.0 mmol,
internal standard. IR spectra (KBr) were recorded on a FTIR 113 mg) and DBU (0.3 mmol, 45.6 mg) in ethanol (10.0 mL)
spectrophotometer in the range of 400–4000 cm−1. Petroleum was stirred at room temperature for 0.5 h, followed by the
ether (PE) used was the fraction boiling in the range 60–90 °C.
addition of DDQ (1.0 mmol, 227 mg) under reflux for 1.0 h.
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After completion of the reaction as indicated by TLC, the reac- 7.28–7.42 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 14.2, 49.5,
tion mixture was poured into saturated aqueous NaCl (50 mL), 62.2, 66.0, 84.1, 117.6, 126.7, 127.5, 128.0, 128.7, 132.7, 136.4,
which was extracted with dichloromethane (3 × 20 mL). The 149.5, 171.7; Anal. Calcd for C16H16N2O2: C, 71.62; H, 6.01; N,
combined organic phase was washed with water (3 × 20 mL), 10.44. Found: C, 71.89; H, 6.04; N, 10.41.
dried over MgSO4, filtered and concentrated in vacuo. The
2g: colorless oil; 1H NMR (300 MHz, CDCl3): δ 1.34 (t, J =
crude product was purified by flash chromatography (silica 7.2 Hz, 3H), 1.84 (s, 3H), 4.26–4.33 (m, 2H), 4.52 (dd, J1 = 7.8
gel, petroleum ether–ethyl acetate = 2 : 1) to give 4a as a yellow Hz, J2 = 2.1 Hz, 1H), 5.23 (d, J = 7.5 Hz, 1H), 6.61 (s, 1H), 7.06
solid (244 mg, 81%); mp 222–223 °C; 1H NMR (300 MHz, (d, J = 1.5 Hz 1H), 7.28–7.39 (m, 5H); 13C NMR (100 MHz,
DMSO): δ 1.34 (t, J = 7.2, 3H), 4.33 (q, J = 7.2 Hz, 2H), 7.36 (d, J = CDCl3): δ 11.9, 13.6, 61.4, 71.4, 85.7, 126.7, 127.7, 128.2, 128.5,
16.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 133.0, 135.9, 156.1, 170.1; Anal. Calcd for C17H18N2O2: C,
7.72 (d, J = 16.8 Hz, 1H), 7.89 (d, J = 3.3 Hz, 1H), 12.81 (s, 1H); 72.32; H, 6.43; N, 9.92. Found: C, 72.13; H, 6.41; N, 9.97.
13C NMR (100 MHz, DMSO): δ 14.2, 60.6, 90.7, 116.4, 120.1,
120.4, 127.9, 128.9, 129.5, 131.9, 132.5, 135.6, 159.7; IR (KBr): DMSO): δ 1.30 (t, J = 7.2 Hz, 3H), 2.26 (s, 3H), 2.74–2.79 (m,
ν = 3263, 3136, 2216, 1670, 1420, 1271, 962, 808, 608 cm−1
2H), 3.00–3.06 (m, 2H), 4.26 (q, J = 7.2 Hz, 2H), 7.04 (d, J = 8.1
Anal. Calcd for C16H13ClN2O2: C, 63.90; H, 4.36; N, 9.31. Hz, 2H), 7.09 (d, J = 8.1 Hz, 2H), 7.72 (d, J = 3.3 Hz, 1H), 12.52
Found: C, 63.67; H, 4.37; N, 9.27.
(s, 1H); 13C NMR (100 MHz, DMSO): δ 14.0, 20.4, 27.4, 35.7,
3b: yellow solid: mp 132–134 °C; 1H NMR (300 MHz,
;
1
2b: colorless oil; H NMR (300 MHz, CDCl3): δ 1.32 (t, J = 60.0, 94.4, 115.2, 119.7, 127.9, 128.7, 129.3, 133.3, 134.7, 137.7,
7.2 Hz, 3H), 2.34 (s, 3H), 4.02 (dd, J1 = 8.1 Hz, J2 = 5.1 Hz, 1H), 159.7; IR (KBr): ν = 3269, 3128, 2224, 1682, 1420, 1283, 1155,
4.18 (d, J = 5.1 Hz, 1H), 4.23–4.31 (m, 2H), 4.68 (s, 1H), 6.12 1018, 787 cm−1; Anal. Calcd for C17H18N2O2: C, 72.32; H, 6.43;
(dd, J1 = 15.6 Hz, J2 = 5.1 Hz, 1H), 6.59 (d, J = 15.6 Hz, 1H), N, 9.92. Found: C, 72.16; H, 6.40; N, 9.98.
7.04 (d, J = 2.4 Hz, 1H), 7.13 (d, J = 8.1 Hz, 2H), 7.29 (d, J =
3c: yellow solid: mp 121–123 °C; 1H NMR (300 MHz,
8.1 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 14.1, 21.1, 49.5, DMSO): δ 1.30 (t, J = 7.2 Hz, 3H), 2.72–2.77 (m, 2H), 2.99–3.04
62.1, 65.9, 84.1, 117.5, 126.4, 129.2, 132.4, 137.7, 149.3, 171.6; (m, 2H), 3.71 (s, 3H), 4.26 (q, J = 7.2 Hz, 2H), 6.84 (d, J = 8.7
Anal. Calcd for C17H18N2O2: C, 72.32; H, 6.43; N, 9.92. Found: Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 3.3 Hz, 1H), 12.51
C, 72.02; H, 6.45; N, 9.96.
(s, 1H); 13C NMR (100 MHz, DMSO): δ 14.1, 27.5, 35.3, 54.9,
2c: colorless oil; 1H NMR (300 MHz, CDCl3): δ 1.32 (t, J = 7.2 60.0, 94.5, 113.6, 115.2, 119.7, 129.0, 129.3, 132.8, 133.3, 157.5,
Hz, 3H), 3.81 (s, 3H), 4.00 (dd, J1 = 7.8 Hz, J2 = 5.7 Hz, 1H), 159.8; IR (KBr): ν = 3269, 3126, 2224, 1678, 1417, 1285, 1155,
4.18 (d, J = 5.1 Hz, 1H), 4.22–4.29 (m, 2H), 4.71 (s, 1H), 6.04 1041, 789 cm−1; Anal. Calcd for C17H18N2O3: C, 68.44; H, 6.08;
(dd, J1 = 15.6 Hz, J2 = 8.4 Hz, 1H), 6.56 (d, J = 15.6 Hz, 1H), N, 9.39. Found: C, 68.11; H, 6.09; N, 9.34.
6.86 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 2.1 Hz, 1H), 7.33 (d, J = 8.4
3d: yellow solid: mp 100–101 °C; 1H NMR (300 MHz,
Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 13.6, 49.0, 54.8, 61.6, DMSO): δ 1.30 (t, J = 7.2 Hz, 3H), 2.76–2.81 (m, 2H), 3.03–3.08
65.6, 83.5, 113.5, 117.1, 124.9, 127.3, 128.6, 131.5, 148.9, 159.0, (m, 2H), 3.72 (s, 3H), 4.26 (q, J = 7.2 Hz, 2H), 6.71–6.77 (m,
171.1; Anal. Calcd for C17H18N2O3: C, 68.44; H, 6.08; N, 9.39. 3H), 7.19 (t, J = 7.8 Hz, 1H), 7.72 (d, J = 3.3 Hz, 1H), 12.53 (s,
Found: C, 68.64; H, 6.09; N, 9.32.
1H); 13C NMR (100 MHz, DMSO): δ 14.1, 27.3, 36.2, 54.8, 60.2,
1
2d: orange oil; H NMR (400 MHz, CDCl3): δ 1.32 (t, J = 7.2 94.5, 111.4, 113.7, 115.4, 119.8, 120.4, 129.3, 129.5, 133.3,
Hz, 3H), 3.82 (s, 3H), 4.01–4.04 (m, 1H), 4.19 (d, J = 4.8 Hz, 142.4, 159.2, 159.9; IR (KBr): ν = 3273, 3126, 2224, 1678, 1418,
1H), 4.25–4.28 (m, 2H), 4.70 (s, 1H), 6.17 (dd, J1 = 16.0 Hz, J2 = 1285, 1155, 1032, 783 cm−1; Anal. Calcd for C17H18N2O3: C,
8.0 Hz, 1H), 6.59 (d, J = 16.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 68.44; H, 6.08; N, 9.39. Found: C, 68.76; H, 6.06; N, 9.37.
6.92 (s, 1H), 6.99 (d, J = 7.2 Hz, 1H), 7.04 (s, 1H), 7.21–7.25 (m,
3e: white solid: mp 141–143 °C; 1H NMR (300 MHz, DMSO):
1H); 13C NMR (100 MHz, CDCl3): δ 14.1, 49.4, 55.2, 62.1, 65.9, δ 1.29 (t, J = 7.2 Hz, 3H), 2.76–2.82 (m, 2H), 3.00–3.05 (m, 2H),
84.0, 111.9, 113.7, 117.4, 119.2, 127.8, 129.5, 132.5, 137.7, 3.77 (s, 3H), 4.25 (q, J = 7.2 Hz, 2H), 6.82 (t, J = 7.2 Hz, 1H),
149.4, 159.8, 171.5; Anal. Calcd for C17H18N2O3: C, 68.44; H, 6.91–7.00 (m, 2H), 7.17 (t, J = 7.2 Hz, 1H), 7.68 (d, J = 3.3 Hz,
6.08; N, 9.39. Found: C, 68.26; H, 6.10; N, 9.35.
1H), 12.48 (s, 1H); 13C NMR (100 MHz, DMSO): δ 14.1, 25.6,
1
2e: yellow oil; H NMR (400 MHz, CDCl3): δ 1.32 (t, J = 7.2 30.9, 55.0, 60.1, 94.7, 110.5, 115.3, 119.8, 120.0, 127.4, 128.7,
Hz, 3H), 3.85 (s, 3H), 4.04 (dd, J1 = 7.6 Hz, J2 = 5.6 Hz, 1H), 129.4, 133.7, 157.2, 159.9; IR (KBr): ν = 3302, 3128, 2226, 1686,
4.20 (d, J = 5.2 Hz, 1H), 4.23–4.31 (m, 2H), 6.21 (dd, J1 = 16.0 1418, 1285, 1036, 764 cm−1; Anal. Calcd for C17H18N2O3: C,
Hz, J2 = 8.0 Hz, 1H), 6.86–6.96 (m, 3H), 7.03 (d, J = 2.4 Hz, 1H), 68.44; H, 6.08; N, 9.39. Found: C, 68.15; H, 6.10; N, 9.33.
7.23 (t, J = 7.6 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H); 13C NMR
3f: white solid: mp 118–120 °C; 1H NMR (400 MHz, DMSO):
(100 MHz, CDCl3): δ 14.1, 49.4, 55.2, 62.1, 65.9, 84.0, 111.9, δ 1.30 (t, J = 7.2 Hz, 3H), 2.79–2.83 (m, 2H), 3.04–3.08 (m, 2H),
113.7, 117.4, 119.2, 127.8, 129.5, 132.5, 137.7, 149.4, 159.8, 4.26 (q, J = 7.2 Hz, 2H), 7.15–7.20 (m, 3H), 7.26–7.29 (m, 2H),
171.5; Anal. Calcd for C17H18N2O3: C, 68.44; H, 6.08; N, 9.39. 7.71 (d, J = 3.2 Hz, 1H), 12.50 (s, 1H); 13C NMR (100 MHz,
Found: C, 68.19; H, 6.05; N, 9.45.
DMSO): δ 14.2, 27.4, 36.3, 60.2, 94.5, 115.3, 119.8, 126.0, 128.1,
1
2f: yellow oil; H NMR (300 MHz, CDCl3): δ 1.33 (t, J = 7.2 128.2, 129.5, 133.3, 140.9, 159.9; IR (KBr): ν = 3279, 3126, 2224,
Hz, 3H), 4.04 (dd, J1 = 8.1 Hz, J2 = 5.1 Hz, 1H), 4.20 (d, J = 5.1 1682, 1420, 1285, 1157, 1028, 781 cm−1; Anal. Calcd for
Hz, 1H), 4.23–4.32 (m, 2H), 4.67 (s, 1H), 6.18 (dd, J1 = 15.9 Hz, C16H16N2O2: C, 71.62; H, 6.01; N, 10.44. Found: C, 71.34; H,
J2 = 8.1 Hz, 1H), 6.63 (d, J = 15.9 Hz, 1H), 7.05–7.06 (m, 1H), 6.02; N, 10.36.
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3g: colorless oil; 1H NMR (300 MHz, CDCl3): δ 1.34–1.42 (m,
4g: white solid: mp 77–79 °C; H NMR (300 MHz, CDCl3): δ
6H), 2.96–3.12 (m, 2H), 3.94–4.02 (m, 1H), 4.30 (t, J = 7.2 Hz, 1.25 (t, J = 7.2 Hz, 3H), 2.19 (s, 3H), 4.25 (q, J = 7.2 Hz, 2H),
2H), 7.12–7.23 (m, 5H), 7.29 (d, J = 3.6 Hz, 1H), 9.53 (s, 1H); 6.52 (s, 1H), 7.27–7.45 (m, 5H), 7.82 (s, 1H), 12.73 (s, 1H); 13C
13C NMR (100 MHz, CDCl3): δ 14.3, 19.7, 32.7, 42.6, 60.9, 94.3, NMR (100 MHz, DMSO): δ 14.1, 19.5, 60.3, 94.2, 115.6, 119.3,
115.9, 119.8, 125.9, 128.0, 128.7, 128.9, 138.8, 140.3, 160.5; 126.9, 128.3, 128.8, 129.4, 129.7, 130.8, 136.9, 136.9, 159.4; IR
Anal. Calcd for C17H18N2O2: C, 72.32; H, 6.43; N, 9.92. Found: (KBr): ν = 3279, 3126, 2220, 1674, 1418, 1271, 1175, 1018,
C, 72.56; H, 6.46; N, 9.97.
689 cm−1; Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N,
4b: yellow solid: mp 218–220 °C; 1H NMR (400 MHz, 9.99. Found: C, 72.56; H, 5.74; N, 9.97.
DMSO): 1.34 (t, J = 7.2, 3H), 2.32 (s, 3H), 4.33 (q, J = 7.2 Hz,
2H), 7.22 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 16.8 Hz, 1H), 7.40 (d,
J = 8.0 Hz, 2H), 7.68 (d, J = 16.8 Hz, 1H), 7.87 (d, J = 3.2 Hz,
Acknowledgements
1H), 12.75 (s, 1H); 13C NMR (100 MHz, DMSO): δ 14.2, 20.8,
60.6, 90.5, 116.6, 118.3, 120.0, 126.2, 128.5, 129.6, 130.9, 131.9, Financial support of this research by the National Natural
133.9, 137.8, 159.8; IR (KBr): ν = 3267, 3134, 2216, 1672, 1420, Science Foundation of China (51073150 and 21172211)
1265, 1163, 962, 800 cm−1; Anal. Calcd for C17H16N2O2: C, and Department of Science and Technology of Jilin
72.84; H, 5.75; N, 9.99. Found: C, 72.48, H, 5.77; N, 10.04.
Province (20111802, 201105030 and 201205027) is greatly
4c: yellow solid: mp 207–208 °C; 1H NMR (400 MHz, acknowledged.
DMSO): 1.34 (t, J = 7.2, 3H), 3.79 (s, 3H), 4.32 (q, J = 7.2 Hz,
2H), 6.98 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 16.8 Hz, 1H), 7.45 (d,
J = 8.8 Hz, 2H), 7.58 (d, J = 16.8 Hz, 1H), 7.86 (s, 1H), 12.72 (s,
Notes and references
1H); 13C NMR (100 MHz, DMSO): δ 14.2, 55.2, 60.5, 90.4,
114.4, 116.6, 117.0, 119.8, 127.6, 128.8, 129.2, 130.6, 131.8,
159.4, 159.8; IR (KBr): ν = 3248, 3119, 2222, 1676, 1420, 1271,
1171, 1038, 779 cm−1; Anal. Calcd for C17H16N2O3: C, 68.91; H,
5.44; N, 9.45. Found: C, 69.26; H, 5.42; N, 9.42.
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4d: yellow solid: mp 188–189 °C; 1H NMR (400 MHz,
DMSO): 1.35 (t, J = 7.2 Hz, 3H), 3.81 (s, 3H), 4.33 (q, J = 7.2 Hz,
2H), 6.89–6.92 (m, 1H), 7.04 (s, 1H), 7.09 (d, J = 7.6 Hz, 1H),
7.31–7.38 (m, 2H), 7.72 (d, J = 16.8 Hz, 1H), 7.89 (s, 1H), 12.80
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111.1, 114.1, 116.5, 118.8, 119.7, 120.3, 128.1, 130.0, 130.8,
131.9, 138.1, 159.7, 159.8; IR (KBr): ν = 3244, 3119, 2218, 1680,
1421, 1271, 1169, 966, 777 cm−1; Anal. Calcd for C17H16N2O3:
C, 68.91; H, 5.44; N, 9.45. Found: C, 68.70; H, 5.43; N, 9.47.
Crystal data for 4d: C17H16N2O3, white crystal, M = 296.32,
monoclinic, P21/c, a = 8.8199(8) Å, b = 12.7684(12) Å, c =
13.8563(13) Å, α = 90.00°, β = 91.733(2)°, γ = 90.00°, V = 1559.7(3)
Å3, Z = 4, T = 298 K, F000 = 624.0, F000′ = 624.29, R = 0.0545-
(2132), wR2 = 0.1276(3070). CCDC deposition number: 968816.
4e: white solid: mp 197–199 °C; 1H NMR (400 MHz, DMSO):
1.34 (t, J = 7.2, 3H), 3.84 (s, 3H), 4.32 (q, J = 7.2 Hz, 2H),
6.98–7.07 (m, 2H), 7.29–7.33 (m, 1H), 7.52–7.54 (m, 1H), 7.72
(s, 2H), 7.86 (s, 1H), 12.73 (s, 1H); 13C NMR (100 MHz, DMSO):
δ 14.2, 55.7, 60.5, 90.5, 111.6, 116.5, 119.5, 120.0, 120.8, 125.3,
126.0, 129.0, 129.5, 131.9, 156.7, 159.8; IR (KBr): ν = 3250,
3128, 2226, 1676, 1420, 1277, 1026, 978, 743 cm−1; Anal. Calcd
for C17H16N2O3: C, 68.91; H, 5.44; N, 9.45. Found: C, 68.67; H,
5.45; N, 9.39.
4f: orange solid: mp 186–187 °C; 1H NMR (300 MHz,
DMSO): 1.35 (t, J = 7.2, 3H), 4.33 (q, J = 7.2 Hz, 2H), 7.30–7.53
(m, 6H), 7.74 (d, J = 16.8 Hz, 1H), 7.90 (d, J = 3.3 Hz, 1H), 12.81
(s, 1H); 13C NMR (100 MHz, DMSO): δ 14.2, 60.6, 90.6, 116.5,
119.3, 120.2, 126.2, 128.2, 128.9, 130.9, 131.9, 136.6, 159.8; IR
(KBr): ν = 3248, 3144, 2220, 1672, 1423, 1269, 1169, 964,
775 cm−1; Anal. Calcd for C16H14N2O2: C, 72.16; H, 5.30; N,
10.52. Found: C, 71.82; H, 5.32; N, 10.56.
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Org. Biomol. Chem., 2014, 12, 5477–5483 | 5483