Functionalized N-containing heterocyclic scaffolds derived from N-substituted pyrroles via inter- and intramolecular annulations

Article abstract of DOI:10.1016/j.tet.2018.08.022

Two series of N-containing heterocycles were synthesized by one-step intramolecular or intermolecular annulations of N-substituted pyrrole-2-carbaldehydes and pyrrole-2-carbonitriles. These facile and atom-economic synthetic routes involved the inherent three potential electrophilic and nucleophilic reactive sites of the synthons and the reaction solvent plays a crucial role leading to these different types of products. Additionally, plausible mechanisms are proposed.

Full text of DOI:10.1016/j.tet.2018.08.022

Tetrahedron xxx (2018) 1e7
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Tetrahedron
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Functionalized N-containing heterocyclic scaffolds derived from N-
substituted pyrroles via inter- and intramolecular annulations
,
,
,
, *
Nana Shao a 1, Jinbiao Li a 1, Huajian Zhu a b, Shuaizhong Zhang a, Hongbin Zou a
a College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
b Zhejiang University City College, Hangzhou, 310015, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Two series of N-containing heterocycles were synthesized by one-step intramolecular or intermolecular
annulations of N-substituted pyrrole-2-carbaldehydes and pyrrole-2-carbonitriles. These facile and
atom-economic synthetic routes involved the inherent three potential electrophilic and nucleophilic
reactive sites of the synthons and the reaction solvent plays a crucial role leading to these different types
of products. Additionally, plausible mechanisms are proposed.
Received 31 May 2018
Received in revised form
26 July 2018
Accepted 17 August 2018
Available online xxx
© 2018 Elsevier Ltd. All rights reserved.
Keywords:
N-containing heterocycles
N-substituted pyrroles
Annulation
Atom-efficient
Mumm-rearrangement
1. Introduction
sites [6]. Derivatives of another fused five- and seven-membered
pyrrolotriazepine were formed by hydrazinium and the five-atom
N-containing heterocycles are extensively prevalent in bioactive
natural products, as well as in pharmaceuticals, organic dyes and
many other compounds of industrial use [1]. During the past de-
cades, constructions of these heterocycles from substituted pyr-
roles have been gradually recognized [2]. N-substituted pyrroles 1
unit (
a, g) of substrates 1 [7]. Monoamination of the dicarbonyl
(a, g) of 1 provided dehydrated cyclization products of pyrrolo[1,2-
a]pyrazines by reacting with ammonium chloride [8].
These intermolecular reactions usually took place between the
b/
g
or
a/g
sites of 1 and other different kinds of reagents. However,
and posi-
(Fig. 1), containing at least two potential electrophilic
a
and
g
there is also an underrated two-atom unit between
a
b
(X ¼ CHO, CN, etc.) and one nucleophilic ( ) sites, are highly ver-
b
tions in substrates 1, which gives good opportunity to build six-
membered blocks with four-atom unit of other reactants, or even
themselves. Intrigued by this, we report herein the intramolecular
or intermolecular reactions of 1 (Fig. 1). Aldol cyclization of two
molecules of N-substituted pyrrole-2-carbaldehydes (1a) at corre-
satile synthons which provide potential two-, four- or five-atom
units to generate molecular diversity. Among these biologically
interesting scaffolds (Fig. 1) [3], the most frequently occurring
5,6,7-trisubstituted indolizines (Fig. 1) were synthesized by Knoe-
venagel condensation of 1 with various 1,3-dicarbonyl compounds
or malononitrile [4]. Alkynes, another two-atom unit, could also
afford indolizine derivatives by Michael addition of 1, while the
same strategy with alkenes provided the dihydroindolizines [5].
When chloro-substituted cyclopropyl derivatives were applied,
pyrrolo[1,2-a]azepin derivatives were obtained with a newly built
seven-membered ring through a [4 þ 3] annulation reaction, and
sponding
intramolecular cyclization of N-substituted pyrrole-2-carbonitriles
(1b) at and sites gave the products of pyrrolo[1,2-a]pyrazin-
b/g and a/b sites afforded indolizine derivatives while
a
g
1(2H)-ones. Furthermore, We also present an interesting example
showing the synthetic capacity of the indolizine product origi-
nating from 1a. Novel highly fused pyrrolo[10,20:1,6]pyrazino[2,3-g]
indolizines were synthesized by one-step reaction from 2a.
the four-atom unit (b, g) of substrates 1 served as donor-acceptor
2. Results and discussion
* Corresponding author.
Initially, we chose 1-(2-oxo-2-phenylethyl)-1H-pyrrole-2-
carbaldehyde 1a-1 as the substrate to optimize the reaction
E-mail address: zouhb@zju.edu.cn (H. Zou).
1
These authors contributed equally to this article.
https://doi.org/10.1016/j.tet.2018.08.022
0040-4020/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: N. Shao, et al., Functionalized N-containing heterocyclic scaffolds derived from N-substituted pyrroles via
inter- and intramolecular annulations, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.08.022

2
N. Shao et al. / Tetrahedron xxx (2018) 1e7
Fig. 1. Substrates 1 for N-containing heterocycles.
Scheme 1. Scope of intermolecular aldol cyclization of N-substituted pyrrole-2-
carbaldehydes. Reaction Conditions: 1a (0.2 mmol, 1.0 equiv.), t-BuOK (0.24 mmol, 1.2
conditions. We tested several kinds of solvents at 80 ꢀC in the
presence of K2CO3, and the results indicated that DMF was the most
favorable solvent to give product 2a (Table 1, entries 1e6). Next,
both organic and inorganic base were tested, revealing that the
yield increased with the enhancement of alkalinity, and t-BuOK was
identified as the most favorable base (Table 1, entries 6e10). A
notable increase of the reaction yield of 2a was observed when the
temperature was increased from 40 to 120 ꢀC (Table 1, 44e76%,
entries 8, 11 and 12).
With the optimized conditions in hand, various substrates of 1a
were employed for the preparation of 2 under the optimized con-
ditions (Scheme 1). The result demonstrated that substrates with
electron-donating groups on the phenyl ring had lower yields (2b,
equiv.), 2.0 ml of DMF, 120 ꢀC, 12 h.
2c and 2g, 53e60%) than electron-withdrawing groups (2de2f,
65e75%). But the electron-rich five-membered substrates with
furanyl and thiophenyl gave the most impressive transformation
(70% and 78% for 2h and 2i). Complex mixture were observed when
methyl-, t-butyl-, cyclo-propyl- and o-mehthoxyl-phenyl were
used as the substituents.
After the reactive activities of 1a were fully studied, we tested 1-
(2-oxo-2-phenylethyl)-1H-pyrrole-2-carbonitriles (1b-1) at the
same condition. Interestingly, 3a was found as the product which
was completely different from 2. To find the optimal condition for
the intramolecular preparation of 3a, different reaction conditions
were examined based on 1b-1. Initially, t-BuOK was chosen as the
base to optimize the reaction solvents, and the results showed that
toluene was the best solvent to afford an impressive 98% yield of 4a
(Table 2, entries 1e6). Various bases were tested next, and t-BuOK
was still found to be the most favorable one (Table 2, entries 1 and
7e10). Significant improvement in the reaction yield was observed
when the temperature was increased from 20 to 80 ꢀC (Table 2,
45e98%, entries 1, 11 and 12). However, further increase of tem-
perature resulted in a slight decrease in the yield (Table 2, entry 13).
As in the transformation of 1a to 2 (Scheme 1), solvent selection is
also crucial in a successful conversion of 1b to 3. Non-polar solvents
are preferable in this reaction, while polar solvents, such as DMF,
barely gave any of the desired product 3, in contrast to the con-
version of 1a to 2. It was shown that the best isolated yield of 3a
(98%) from 1b-1 was obtained in toluene at 80 ꢀC in the presence of
t-BuOK.
Under the above optimized conditions, different substitutions of
1b were tested for the scope of this cyclization. In general, a wide
variety of groups was tolerated with impressive isolated yields
(Scheme 3, 82e98%). Electron-withdrawing groups (such as eF, eCl
and eBr) on a phenyl ring delivered the annulated products (3de3f,
92e95%) in better yields than electron-donating groups (3be3c,
89e91%). The cyclization also accepted substrates that contained
methoxyl at ortho-, meta- and para-positions on the phenyl ring
with similar yields (3c and 3ge3h, 87e90%). Electron-rich alkyl,
furanyl and thiophenyl groups gave relatively lower yields (3ie3m,
Table 1
Optimization of intermolecular aldol cyclization conditions.a
entry
base
solvent
temp (ꢀC)
yieldb (%)
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaHCO3
t-BuOK
Et3N
toluene
CH3CN
EtOH
CH2Cl2
THF
DMF
DMF
DMF
DMF
80
80
80
80
80
80
80
80
80
80
40
120
0
0
59
0
0
62
15
64
0
26
44
76
9
10
11
12
DBU
t-BuOK
t-BuOK
DMF
DMF
DMF
It’s the most optimized reaction condition which is also used in the reaction for
compounds preparation.
a
Reaction Conditions: 1-(2-oxo-2-phenylethyl)-1H-pyrrole-2-carbaldehyde
(0.2 mmol, 1.0 equiv.), base (0.24 mmol, 1.2 equiv.), 2.0 ml of solvent, 12 h.
b
Isolated yield.
Please cite this article in press as: N. Shao, et al., Functionalized N-containing heterocyclic scaffolds derived from N-substituted pyrroles via
inter- and intramolecular annulations, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.08.022

N. Shao et al. / Tetrahedron xxx (2018) 1e7
3
Table 2
Optimization of intramolecular cyclization conditions.a
entry
base
solvent
temp (ꢀC)
yieldb (%)
1
2
3
4
5
6
7
8
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
NaHCO3
K2CO3
Et3N
DBU
t-BuOK
t-BuOK
t-BuOK
toluene
CH3CN
EtOH
CH2Cl2
THF
80
80
80
80
80
80
80
80
80
80
20
40
120
98
32
44
83
24
0
0
0
0
0
Scheme 3. Further functionalization of 2a.
DMF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
9
10
11
12
13
45
67
86
It’s the most optimized reaction condition which is also used in the reaction for
compounds preparation.
a
Reaction
Conditions:
1-(2-oxo-2-phenylethyl)-1H-pyrrole-2-carbonitrile
(0.2 mmol, 1.0 equiv.), base (0.24 mmol, 1.2 equiv.), 2.0 ml of solvent, 12 h.
b
Isolated yield.
Scheme 4. Possible mechanism for the reactions.
82e90%). The structure of compound 3 was confirmed by single
crystal X-ray diffraction using 3e (Scheme 2) as an example. In
comparison with previously reported methods [9], we have
developed a one-step, facile and efficient approach to provide 3-
substituted pyrrolo[1,2-a]pyrazin-1(2H)-ones 3 with extraordi-
narily high yields.
Meanwhile, product 2 from 1a, possessing a free reactive alde-
hyde group and an interesting indolizine structure [10], can be
readily harnessed for further synthetic manipulation to 4 (Scheme
3). The O-acetyl oxime from aldehyde group was used as a directing
group and the following acidic cleavage of NeO bond and forma-
tion of CeN bond spontaneously afforded the conjugate product 4.
The isolated yield increased from 52% to 74% when Fe(III) partici-
pated in this transformation by enhancing deacetylation.
As shown in Scheme 4, possible mechanisms of these reactions
were proposed. Formation of II can be visualized as an intermo-
lecular aldol condensation of two molecules of intermediate I in the
presence of base. One molecule of I provides a two-carbon unit of
methylene and carbonyl groups and the other provides methylene
and aldehyde groups as a four-atom unit. Subsequent dehydration
of the intermediate II affords product 2. The oxygen anion from
enol intermediates of 1b attacked cyano to give O-alkyl imidate III
which could rearrange in a type of Mumm-rearrangement to
compounds 3.
3. Conclusions
In summary, we have developed facile and atom-efficient routes
to prepare two types of N-containing heterocycles by intra-
molecular or intermolecular annulations of N-substituted pyrrole-
2-carbaldehydes and pyrrole-2-carbonitriles. These two substrates,
having very similar potential electrophilic and nucleophilic sites,
provided two-atom or four-atom units as structural elements for
these syntheses. Aldol cyclization plays the key role in the inter-
molecular reaction of pyrrole-2-carbaldehydes to indolizines, while
intramolecular reaction to pyrrolo[1,2-a]pyrazin-1(2H)-one de-
rivatives was facilitated by Mumm-rearrangement. Due to the
remaining reactive aldehyde group originating from pyrrole-2-
carbaldehydes, we also had a chance to further functionalize the
indolizine product. The results described herein give further in-
sights to the property of the highly versatile synthons N-
substituted pyrroles 1 providing an excellent opportunity to
construct diversified heterocycles.
Scheme 2. Scope of intramolecular cyclization by N-substituted pyrrole-2-
carbonitriles. Reaction Conditions: 1b (0.2 mmol, 1.0 equiv.), t-BuOK (0.24 mmol, 1.2
equiv.), 2.0 ml of toluene, 80 ꢀC, 12 h.
Please cite this article in press as: N. Shao, et al., Functionalized N-containing heterocyclic scaffolds derived from N-substituted pyrroles via
inter- and intramolecular annulations, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.08.022

4
N. Shao et al. / Tetrahedron xxx (2018) 1e7
4. Experimental section
4.2.3. 1-(5-(4-Methoxybenzoyl)-6-(4-methoxyphenyl)indolizin-7-
yl)-1H-pyrrole-2-carbaldehyde (2c)
4.1. General
Following the general procedure, 1-(2-(4-methoxyphenyl)-2-
oxoethyl)-1H-pyrrole-2-carbaldehyde 1a-3 (48.6 mg, 0.2 mmol)
was used. Purification via column chromatography on silica gel
(hexane:EtOAc ¼ 15:1, Rf ¼ 0.5) afforded 2c as yellow solid
(23.1 mg, 54% yield). Mp: 118e120 ꢀC. 1H NMR (500 MHz, CDCl3):
Unless otherwise noted, materials were purchased from com-
mercial suppliers and used without further purification. All the
solvents were treated according to general methods. Analytical thin
layer chromatography (TLC) was performed on Merck precoated
silica gel 60 F254. Visualization on TLC was achieved by the use of UV
light (254 nm). Solvents mixtures were understood as volume/
volume. Purifications of reaction products were carried out by
chromatography using silica gel (200e300 mesh). Melting points
were determined with a SGW X-4 digital melting point apparatus,
and the thermometer was uncorrected. NMR spectra were mostly
recorded for 1H NMR at 500 MHz and for 13C NMR at 125 MHz. For
d
9.39 (1H, s), 7.76 (2H, d, J ¼ 9.0 Hz), 7.51 (1H, s), 7.13 (1H, d,
J ¼ 2.0 Hz), 6.88 (1H, m), 6.83 (5H, m), 6.80 (1H, s), 6.64 (1H, d,
J ¼ 4.0 Hz), 6.49 (2H, d, J ¼ 8.5 Hz), 6.20 (1H, dd, J ¼ 3.5, 2.5 Hz), 3.81
(3H, s), 3.63 (3H, s); 13C NMR (125 MHz, CDCl3):
d 190.0,178.7,164.6,
159.0, 133.5, 132.1, 132.0, 131.9, 131.5, 131.0, 129.2, 128.7, 125.1, 121.8,
117.8, 115.6, 114.2, 113.3, 110.4, 101.9, 55.5, 54.9; HRMS Calcd. for
C
28H22N2O4 þ Hþ: 451.1658, found: 451.1653.
1H NMR, tetramethylsilane (TMS) served as internal standard (
d).
4.2.4. 1-(5-(4-Fluorobenzoyl)-6-(4-fluorophenyl)indolizin-7-yl)-
1H-pyrrole-2-carbaldehyde (2d)
The spectra data presented here are reported as follows: chemical
shift, integration, multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet,
q ¼ quartet, m ¼ multiplet), and coupling constant (s) in Hertz. For
Following the general procedure, 1-(2-(4-fluorophenyl)-2-
oxoethyl)-1H-pyrrole-2-carbaldehyde 1a-4 (46.2 mg, 0.2 mmol)
was used. Purification via column chromatography on silica gel
(hexane:EtOAc ¼ 15:1, Rf ¼ 0.5) afforded 2d as yellow solid
(28.9 mg, 65% yield). Mp: 120e122 ꢀC. 1H NMR (500 MHz, CDCl3):
13C NMR TMS (
d
¼ 0), CDCl3 (
d
¼ 77.05) or DMSO‑d6 ( ¼ 39.99) was
d
used as internal standard and spectra were obtained with complete
proton decoupling. HRMS were obtained using ESI ionization.
d
9.37 (1H, s), 7.78 (2H, ddd, J ¼ 9.0, 5.5,1.5 Hz), 7.54 (1H, s), 7.18 (1H,
4.2. General procedure for systhesis of 2
m), 7.00 (2H, td, J ¼ 9.0, 2.0 Hz), 6.86 (4H, m), 6.83 (1H, dd, J ¼ 4.0,
1.5 Hz), 6.68 (1H, dd, J ¼ 4.0, 0.5 Hz), 6.66 (2H, t, J ¼ 9.0 Hz), 6.21
A
mixture of N-substituted pyrrole-2-carbaldehyde 1a
(1H, dd, J ¼ 4.0, 2.5 Hz); 13C NMR (125 MHz, CDCl3):
d 190.0, 178.7,
(0.2 mmol, 1.0 equiv.), t-BuOK (0.24 mmol, 1.2 equiv.) was stirred in
2.0 mL DMF at 120 ꢀC under N2. After being stirred for 12 h, the
reaction was quenched by 2.0 mL water. The mixture was extracted
with EtOAc (3 ꢁ 4.0 mL) and the organic layer was dried over
anhydrous Na2SO4. The concentrated residue was purified by col-
umn chromatography on silica gel to provide the desired product 2.
164.4 (d, J ¼ 256.6 Hz), 162.2 (d, J ¼ 256.6 Hz), 133.5, 132.3 (d,
J ¼ 9.6 Hz), 132.2 (d, J ¼ 2.9 Hz), 132.0, 131.6, 131.4, 128.9, 128.7(d,
J ¼ 3.3 Hz), 121.9, 118.3, 116.3, 116.1, 116.0, 115.0, 114.8, 113.5, 110.6,
102.5; HRMS Calcd. for C26H16F2N2O2 þ Hþ: 427.1258, found:
427.1254.
4.2.1. 1-(5-Benzoyl-6-phenylindolizin-7-yl)-1H-pyrrole-2-
carbaldehyde (2a)
4.2.5. 1-(5-(4-Chlorobenzoyl)-6-(4-chlorophenyl)indolizin-7-yl)-
1H-pyrrole-2-carbaldehyde (2e)
Following the general procedure, 1-(2-oxo-2-phenylethyl)-1H-
pyrrole-2-carbaldehyde 1a-1 (42.6 mg, 0.2 mmol) was used. Puri-
fication via column chromatography on silica gel (hex-
ane:EtOAc ¼ 15:1, Rf ¼ 0.5) afforded 2a as yellow solid (31.1 mg, 76%
Following the general procedure, 1-(2-(4-chlorophenyl)-2-
oxoethyl)-1H-pyrrole-2-carbaldehyde 1a-5 (55.4 mg, 0.2 mmol)
was used. Purification via column chromatography on silica gel
(hexane:EtOAc ¼ 15:1, Rf ¼ 0.5) afforded 2e as yellow solid
(38.0 mg, 71% yield). Mp: 132e134 ꢀC. 1H NMR (500 MHz, CDCl3):
yield). Mp: 112e114 ꢀC. 1H NMR (500 MHz, CDCl3):
d 9.38 (1H, s),
7.74 (2H, dd, J ¼ 8.0, 1.0 Hz), 7.56 (1H, s), 7.47 (1H, tt, J ¼ 7.0, 1.0 Hz),
7.31 (2H, t, J ¼ 8.0 Hz), 7.20 (1H, d, J ¼ 2.5 Hz), 7.00 (1H, tt, J ¼ 7.0,
1.5 Hz), 6.93 (2H, t, J ¼ 7.5 Hz), 6.89 (2H, dd, J ¼ 8.0, 1.0 Hz), 6.87 (1H,
dd, J ¼ 4.0, 1.5 Hz), 6.86 (1H, dd, J ¼ 4.0, 3.0 Hz), 6.81 (1H, dd, J ¼ 4.0,
d
9.36 (1H, s), 7.69 (2H, dd, J ¼ 7.0, 2.0 Hz), 7.53 (1H, s), 7.32 (2H, t,
J ¼ 8.5 Hz), 7.14 (1H, m), 6.94 (2H, d, J ¼ 8.5 Hz), 6.89 (1H, m), 6.86
(1H, d, J ¼ 4.0, 2.5 Hz), 6.83 (1H, dd, J ¼ 3.5, 2.0 Hz), 6.82 (2H, d,
J ¼ 7.0 Hz), 6.68 (1H, dd, J ¼ 4.0,1.0 Hz), 6.22 (1H, dd, J ¼ 4.0, 2.5 Hz);
1.5 Hz), 6.67 (1H, dd, J ¼ 4.0, 1.0 Hz), 6.18 (1H, dd, J ¼ 4.0, 2.5 Hz); 13
C
13C NMR (125 MHz, CDCl3):
d 190.2, 178.6, 141.1, 134.2, 134.1, 133.5,
NMR (125 MHz, CDCl3):
d 191.8, 178.8, 135.8, 134.3, 133.5, 132.8,
132.0, 131.6, 131.3, 131.2, 130.8, 129.4, 128.8, 128.0, 123.1, 121.9, 118.4,
116.1, 113.5, 110.7, 102.6; HRMS Calcd. for C26H16Cl2N2O2 þ Hþ:
459.0667, found: 459.0665.
132.0, 131.6, 130.0,129.5,128.8,127.8, 127.7, 122.9,118.3,115.8, 113.5,
110.5, 102.2; HRMS Calcd. for C26H18N2O2 þ Hþ: 391.1447, found:
391.1448.
4.2.2. 1-(5-(4-Methylbenzoyl)-6-(p-tolyl)indolizin-7-yl)-1H-
pyrrole-2-carbaldehyde (2b)
4.2.6. 1-(5-(4-Bromobenzoyl)-6-(4-bromophenyl)indolizin-7-yl)-
1H-pyrrole-2-carbaldehyde (2f)
Following the general procedure, 1-(2-oxo-2-(p-tolyl)ethyl)-1H-
pyrrole-2-carbaldehyde 1a-2 (45.4 mg, 0.2 mmol) was used. Puri-
fication via column chromatography on silica gel (hex-
ane:EtOAc ¼ 15:1, Rf ¼ 0.5) afforded 2b as yellow solid (23.1 mg,
Following the general procedure, 1-(2-(4-bromophenyl)-2-
oxoethyl)-1H-pyrrole-2-carbaldehyde 1a-6 (58.0 mg, 0.2 mmol)
was used. Purification via column chromatography on silica gel
(hexane:EtOAc ¼ 15:1, Rf ¼ 0.5) afforded 2f as yellow solid (42.2 mg,
53% yield). Mp: 108e110 ꢀC. 1H NMR (500 MHz, CDCl3):
d
9.39 (1H,
75% yield). Mp: 138e140 ꢀC. 1H NMR (500 MHz, CDCl3):
d 9.36 (1H,
s), 7.67 (2H, d, J ¼ 8.5 Hz), 7.53 (1H, s), 7.14 (2H, d, J ¼ 8.0 Hz), 7.10
(1H, m), 6.88 (1H, m), 6.83 (1H, dd, J ¼ 4.5, 2.0 Hz), 6.82 (1H, d,
J ¼ 4.0, 3.0 Hz), 6.78 (2H, d, J ¼ 8.5 Hz), 6.74 (2H, d, J ¼ 8.0 Hz), 6.64
(1H, dd, J ¼ 4.0,1.5 Hz), 6.19 (1H, dd, J ¼ 4.0, 2.5 Hz), 2.35 (3H, s), 2.12
s), 7.61 (2H, d, J ¼ 8.5 Hz), 7.53 (1H, s), 7.50 (2H, d, J ¼ 8.5 Hz), 7.12
(1H, d, J ¼ 2.5 Hz), 7.10 (2H, d, J ¼ 8.5 Hz), 6.89 (1H, m), 6.87 (1H, dd,
J ¼ 4.0, 3.0 Hz), 6.83 (1H, dd, J ¼ 4.5, 1.5 Hz), 6.75 (2H, d, J ¼ 8.5 Hz),
6.68 (1H, d, J ¼ 3.5 Hz), 6.23 (1H, dd, J ¼ 4.0, 2.5 Hz); 13C NMR
(3H, s); 13C NMR (125 MHz, CDCl3):
d
191.1, 178.7, 145.5, 137.4, 133.4,
(125 MHz, CDCl3): d 190.4, 178.7, 134.4, 133.4, 132.4, 132.0, 131.7,
133.2,131.9,131.8,131.5,129.7,129.6,129.6,129.0,128.4,122.3,117.9,
115.6, 113.3, 110.3, 101.9, 21.8, 21.1; HRMS Calcd. for
C
131.6, 131.5, 131.1, 131.0, 130.9, 130.2, 130.0, 128.8, 122.5, 122.0, 118.4,
116.1, 113.5, 110.7, 102.6; HRMS Calcd. for C26H16Br2N2O2 þ Hþ:
546.9657, found: 546.9653.
28H22N2O2 þ Hþ: 419.1760, found: 419.1753.
Please cite this article in press as: N. Shao, et al., Functionalized N-containing heterocyclic scaffolds derived from N-substituted pyrroles via
inter- and intramolecular annulations, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.08.022

N. Shao et al. / Tetrahedron xxx (2018) 1e7
5
4.2.7. 1-(5-(3-Methoxybenzoyl)-6-(3-methoxyphenyl)indolizin-7-
yl)-1H-pyrrole-2-carbaldehyde (2g)
s), 7.57 (2H, dt, J ¼ 8.5, 1.5 Hz), 7.48 (2H, tt, J ¼ 8.5, 1.0 Hz), 7.42 (1H,
tt, J ¼ 8.5, 1.5 Hz), 7.21 (1H, dd, J ¼ 2.5, 1.0 Hz), 7.16 (1H, ddd, J ¼ 4.0,
1.5, 1.0 Hz), 6.61 (1H, dd, J ¼ 4.0, 2.5 Hz); 13C NMR (125 MHz,
Following the general procedure, 1-(2-(3-methoxyphenyl)-2-
oxoethyl)-1H-pyrrole-2-carbaldehyde 1a-7 (48.6 mg, 0.2 mmol)
was used. Purification via column chromatography on silica gel
(hexate:EtOAc ¼ 15:1, Rf ¼ 0.5) afforded 2g as yellow solid (28.1 mg,
DMSO):
d 156.8, 138.6, 129.8, 127.0, 126.3, 123.3, 120.0, 112.6, 109.4,
105.6; HRMS Calcd. for C13H10N2O þ Hþ: 211.0871, found: 211.0873.
60% yield). Mp: 115e117 ꢀC. 1H NMR (500 MHz, CDCl3):
d
9.40 (1H,
4.3.2. 3-(p-Tolyl)pyrrolo[1,2-a]pyrazin-1(2H)-one (3b)
s), 7.54 (1H, s), 7.33 (2H, dt, J ¼ 8.5, 0.5 Hz), 7.22 (2H, m), 7.03 (1H,
ddd, J ¼ 8.5, 3.0, 1.0 Hz), 6.86 (4H, m), 6.67 (1H, dd, J ¼ 4.0, 1.0 Hz),
6.56 (1H, ddd, J ¼ 8.5, 2.5, 0.5 Hz), 6.52 (1H, dt, J ¼ 7.5, 1.0 Hz), 6.42
(1H, t, J ¼ 0.5 Hz), 6.21 (1H, dd, J ¼ 4.0, 3.0 Hz), 3.78 (3H, s), 3.50 (3H,
Following the general procedure, 1-(2-oxo-2-(p-tolyl)ethyl)-1H-
pyrrole-2-carbonitrile 1b-2 (44.8 mg, 0.2 mmol) was used. Purifi-
cation
(CHCl3:CH3OH ¼ 20:1, Rf ¼ 0.7) afforded 3b as white solid (40.8 mg,
91% yield). Mp: 189e191 ꢀC. 1H NMR (500 MHz, DMSO):
10.74 (1H,
via
column
chromatography
on
silica
gel
s); 13C NMR (125 MHz, CDCl3):
d
191.0, 178.2, 170.7, 159.3, 158.2,
d
136.7, 133.6, 133.1, 131.6, 131.1, 131.1, 129.4, 128.3, 128.3, 122.2, 122.2,
122.1, 120.8, 117.8, 115.4, 114.1, 113.0, 112.3, 110.1, 101.7, 55.0, 54.5;
HRMS Calcd. for C28H22N2O4 þ Hþ: 451.1658, found: 451.1655.
s), 7.70 (1H, s), 7.56 (2H, d, J ¼ 8.0 Hz), 7.50 (1H, dd, J ¼ 2.5, 1.5 Hz),
7.26 (2H, d, J ¼ 8.0 Hz), 6.90 (1H, dd, J ¼ 4.0, 2.0 Hz), 6.56 (1H, dd,
J ¼ 3.5, 2.5 Hz), 2.34 (3H, s); 13C NMR (125 MHz, DMSO):
d 156.8,
138.6, 129.8, 127.0, 126.3, 123.3, 120.0, 112.6, 109.4, 105.6, 21.2;
4.2.8. 1-(5-(Furan-2-carbonyl)-6-(furan-2-yl)indolizin-7-yl)-1H-
pyrrole-2-carbaldehyde (2h)
HRMS Calcd. for C14H12N2O þ Hþ: 225.1028, found: 225.1036.
Following the general procedure, 1-(2-(furan-2-yl)-2-oxoethyl)-
1H-pyrrole-2-carbaldehyde 1a-8 (40.6 mg, 0.2 mmol) was used.
Purification via column chromatography on silica gel (hex-
ane:EtOAc ¼ 15:1, Rf ¼ 0.5) afforded 2h as yellow solid (27.2 mg,
4.3.3. 3-(4-Methoxyphenyl)pyrrolo[1,2-a]pyrazin-1(2H)-one (3c)
Following the general procedure, 1-(2-(4-methoxyphenyl)-2-
oxoethyl)-1H-pyrrole-2-carbonitrile 1b-3 (48.0 mg, 0.2 mmol) was
used. Purification via column chromatography on silica gel
(CHCl3:CH3OH ¼ 20:1, Rf ¼ 0.7) afforded 3c as white solid (42.7 mg,
70% yield). Mp: 114e116 ꢀC. 1H NMR (500 MHz, CDCl3):
d 9.50 (1H,
s), 7.57 (1H, d, J ¼ 1.0 Hz), 7.51 (1H, s), 7.50 (1H, dd, J ¼ 2.5, 1.0 Hz),
7.07 (2H, dd, J ¼ 3.0, 0.5 Hz), 7.03 (1H, dd, J ¼ 4.0, 1.5 Hz), 6.94 (1H,
m), 6.89 (1H, d, J ¼ 4.0, 2.0 Hz), 6.66 (1H, dd, J ¼ 4.0, 1.0 Hz), 6.39
(1H, dd, J ¼ 3.5, 1.5 Hz), 6.33 (1H, dd, J ¼ 4.0, 2.5 Hz), 6.06 (1H, dd,
J ¼ 4.0, 1.5 Hz), 5.72 (1H, d, J ¼ 3.5 Hz); 13C NMR (125 MHz, CDCl3):
89% yield). Mp: 200e202 ꢀC. 1H NMR (500 MHz, DMSO):
d 10.72
(1H, s), 7.64 (1H, s), 7.60 (2H, dd, J ¼ 6.5, 2.0 Hz), 7.43 (1H, dd, J ¼ 2.5,
1.5 Hz), 7.02 (2H, dd, J ¼ 7.0, 2.0 Hz), 6.89 (1H, dd, J ¼ 4.0, 1.0 Hz),
6.56 (1H, dd, J ¼ 4.0, 2.5 Hz), 3.34 (3H, s); 13C NMR (125 MHz,
DMSO):
d 160.1, 156.8, 127.8, 126.9, 124.9, 123.2, 119.9, 114.6, 112.5,
d
178.6, 177.8, 151.7, 148.6, 145.8, 143.3, 133.8, 131.6, 131.3, 130.3,
109.3, 105.1, 55.7; HRMS Calcd. for C14H12N2O2 þ Hþ: 241.0977,
127.1, 121.9, 121.5, 119.5, 116.2, 114.2, 114.1, 112.6, 111.5, 111.2, 110.7,
found: 241.0971.
103.1; HRMS Calcd. for
371.1048.
C
22H14N2O4
þ
Hþ: 371.1032, found:
4.3.4. 3-(4-Fluorophenyl)pyrrolo[1,2-a]pyrazin-1(2H)-one (3d)
Following the general procedure, 1-(2-(4-fluorophenyl)-2-
oxoethyl)-1H-pyrrole-2-carbonitrile 1b-4 (45.6 mg, 0.2 mmol) was
used. Purification via column chromatography on silica gel
(CHCl3:CH3OH ¼ 20:1, Rf ¼ 0.7) afforded 3d as white solid (43.3 mg,
95% yield). Mp: 205e207 ꢀC. 1H NMR (500 MHz, DMSO):
4.2.9. 1-(6-(Thiophen-2-yl)-5-(thiophene-2-carbonyl)indolizin-7-
yl)-1H-pyrrole-2-carbaldehyde (2i)
Following the general procedure, 1-(2-oxo-2-(thiophen-2-yl)
ethyl)-1H-pyrrole-2-carbaldehyde 1a-9 (43.8 mg, 0.2 mmol) was
used. Purification via column chromatography on silica gel (hex-
ane:EtOAc ¼ 15:1, Rf ¼ 0.5) afforded 2i as yellow solid (32.8 mg, 78%
d
10.82(1H, s), 7.71 (3H, m), 7.45 (1H, dd, J ¼ 2.5, 1.5 Hz), 7.30 (2H, t,
J ¼ 9.0 Hz), 6.91 (1H, dd, J ¼ 3.0, 1.0 Hz), 6.57 (1H, dd, J ¼ 4.0, 2.5 Hz);
13C NMR (125 MHz, DMSO):
yield). Mp: 118e120 ꢀC. 1H NMR (500 MHz, CDCl3):
d
9.48 (1H, s),
d
162.7 (d, J ¼ 244.5 Hz), 156.8, 129.1 (d,
7.65 (1H, dd, J ¼ 5.0, 1.0 Hz), 7.55 (1H, d, J ¼ 2.0 Hz), 7.52 (1H, s), 7.34
(1H, m), 7.07 (1H, dd, J ¼ 5.5, 1.5 Hz), 6.97 (1H, dd, J ¼ 5.0, 4.0 Hz),
6.95 (1H, d, J ¼ 4.0, 1.5 Hz), 6.89 (2H, dd, J ¼ 4.0, 3.0 Hz), 6.78 (1H,
dd, J ¼ 3.5, 1.0 Hz), 6.68 (1H, dd, J ¼ 5.0, 3.5 Hz), 6.67 (1H, dd, J ¼ 4.0,
1.5 Hz), 6.27 (1H, d, J ¼ 4.0, 3.0 Hz); 13C NMR (125 MHz, CDCl3):
J ¼ 3.3 Hz), 128.7 (d, J ¼ 8.3 Hz), 126.2, 123.3, 120.2, 116.1 (d,
J ¼ 21.8 Hz), 112.7, 109.5, 106.2; HRMS Calcd. for C13H9FN2O þ Hþ:
229.0777, found: 229.0771.
4.3.5. 3-(4-Chlorophenyl)pyrrolo[1,2-a]pyrazin-1(2H)-one (3e)
Following the general procedure, 1-(2-(4-chlorophenyl)-2-
oxoethyl)-1H-pyrrole-2-carbonitrile 1b-5 (48.8 mg, 0.2 mmol) was
used. Purification via column chromatography on silica gel
(CHCl3:CH3OH ¼ 20:1, Rf ¼ 0.7) afforded 3e as white solid (45.9 mg,
d
183.4, 178.7, 142.7, 136.5, 136.0, 134.1, 133.6, 132.1, 132.0, 131.5,
130.4, 128.4, 128.3, 126.4, 118.6, 116.1, 115.9, 113.8, 110.7, 102.7;
HRMS Calcd. for C22H14N2O2S2 þ Hþ: 403.0575, found: 403.0572.
4.3. General procedure for systhesis of 3
94% yield). Mp: 226e227 ꢀC. 1H NMR (500 MHz, DMSO):
d 10.72
(1H, s), 7.78 (1H, s), 7.69 (2H, m), 7.52 (2H, d, J ¼ 9.0 Hz), 7.46 (1H,
A mixture of N-substituted pyrrole-2-carbonitrile 1b (0.2 mmol,
1.0 equiv.), t-BuOK (0.24 mmol, 1.2 equiv.) was stirred in 2.0 mL
toluene at 80 ꢀC. After being stirred for 12 h, CHCl3 (4.0 mL) was
added to the mixture and the filtrate was concentrated under
reduced pressure. The residue was purified by column chroma-
tography on silica gel (CHCl3:CH3OH ¼ 20:1) to provide the desired
product 3.
dd, J ¼ 2.5, 1.5 Hz), 6.92 (1H, dd, J ¼ 3.5, 0.5 Hz), 6.58 (1H, dd, J ¼ 4.0,
2.5 Hz); 13C NMR (125 MHz, DMSO):
d 156.7, 133.7, 131.5, 129.2,
128.2, 126.0, 123.3, 120.3, 112.8, 109.6, 106.6; HRMS Calcd. for
C
13H9ClN2O þ Hþ: 245.0482, found: 245.0473.
4.3.6. 3-(4-Bromophenyl)pyrrolo[1,2-a]pyrazin-1(2H)-one (3f)
Following the general procedure, 1-(2-(4-bromophenyl)-2-
oxoethyl)-1H-pyrrole-2-carbonitrile 1b-6 (57.6 mg, 0.2 mmol) was
used. Purification via column chromatography on silica gel
(CHCl3:CH3OH ¼ 20:1, Rf ¼ 0.7) afforded 3f as white solid (53.0 mg,
4.3.1. 3-Phenylpyrrolo[1,2-a]pyrazin-1(2H)-one (3a)
Following the general procedure, 1-(2-oxo-2-(p-tolyl)ethyl)-1H-
pyrrole-2-carbonitrile 1b-1 (42.0 mg, 0.2 mmol) was used. Purifi-
92% yield). Mp: 235e236 ꢀC. 1H NMR (500 MHz, DMSO):
d 10.84
cation
(CHCl3:CH3OH ¼ 20:1, Rf ¼ 0.7) afforded 3a as white solid (41.2 mg,
98% yield). Mp: 151e153 ꢀC. 1H NMR (500 MHz, DMSO):
9.05 (1H,
via
column
chromatography
on
silica
gel
(1H, s), 7.79 (1H, s), 7.64 (4H, m), 7.46 (1H, dd, J ¼ 2.5, 1.5 Hz), 6.92
(1H, dd, J ¼ 4.0, 1.0 Hz), 6.59 (1H, dd, J ¼ 4.0, 2.5 Hz); 13C NMR
d
(125 MHz, DMSO): d 156.7, 132.1, 131.9, 128.5, 126.0, 123.3, 122.2,
Please cite this article in press as: N. Shao, et al., Functionalized N-containing heterocyclic scaffolds derived from N-substituted pyrroles via
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6
N. Shao et al. / Tetrahedron xxx (2018) 1e7
120.3, 112.9, 109.7, 106.5; HRMS Calcd. for C13H9BrN2O þ Hþ:
4.3.12. 3-(Thiophen-2-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one (3l)
Following the general procedure, 1-(2-oxo-2-(thiophen-2-yl)
ethyl)-1H-pyrrole-2-carbonitrile 1b-12 (33.2 mg, 0.2 mmol) was
used. Purification via column chromatography on silica gel
(CHCl3:CH3OH ¼ 20:1, Rf ¼ 0.7) afforded 3l as white solid (27.2 mg,
288.9977, found: 288.9974.
4.3.7. 3-(3-Methoxyphenyl)pyrrolo[1,2-a]pyrazin-1(2H)-one (3g)
Following the general procedure, 1-(2-(3-methoxyphenyl)-2-
oxoethyl)-1H-pyrrole-2-carbonitrile 1b-7 (48.0 mg, 0.2 mmol) was
used. Purification via column chromatography on silica gel
(CHCl3:CH3OH ¼ 20:1, Rf ¼ 0.7) afforded 3g as white solid (41.8 mg,
82% yield). Mp: 240e242 ꢀC. 1H NMR (500 MHz, DMSO):
d 10.87
(1H, s), 7.77 (1H, d, J ¼ 1.0 Hz), 7.62 (1H, dd, J ¼ 3.5, 1.0 Hz), 7.56 (1H,
dd, J ¼ 5.0, 1.0 Hz), 7.50 (1H, dd, J ¼ 2.5, 1.5 Hz), 7.13 (1H, dd, J ¼ 5.0,
3.5), 6.91 (1H, m), 6.56 (1H, dd, J ¼ 4.0, 2.5 Hz); 13C NMR (125 MHz,
87% yield). Mp: 207e209 ꢀC. 1H NMR (500 MHz, DMSO):
d 10.78
DMSO):
d 156.4, 134.7, 128.5, 126.3, 126.1, 123.2, 121.9, 120.5, 112.8,
(1H, s), 7.79 (1H, s), 7.46 (1H, dd, J ¼ 2.5, 1.5 Hz), 7.36 (1H, t,
J ¼ 8.0 Hz), 7.25 (2H, m), 6.95 (1H, ddd, J ¼ 8.5, 3.0, 0.5 Hz), 6.92 (1H,
m), 6.58 (1H, dd, J ¼ 4.0, 2.5 Hz), 3.83 (3H, s); 13C NMR (125 MHz,
110.0, 105.3; HRMS Calcd. for C11H8N2OS þ Hþ: 217.0436, found:
217.0433.
DMSO):
d 160.0, 156.8, 133.9, 130.3, 126.8, 123.4, 120.2, 118.5, 115.1,
112.8, 111.5109.5, 106.3, 55.7; HRMS Calcd. for C14H12N2O2 þ Hþ:
4.3.13. 3-(tert-Butyl)pyrrolo[1,2-a]pyrazin-1(2H)-one (3m)
241.0977, found: 241.0973.
Following the general procedure, 1-(3,3-dimethyl-2-oxobutyl)-
1H-pyrrole-2-carbonitrile 1b-13 (38.0 mg, 0.2 mmol) was used.
Purification via column chromatography on silica gel
(CHCl3:CH3OH ¼ 20:1, Rf ¼ 0.7) afforded 3m as white solid
(32.3 mg, 85% yield). Mp: 211e213 ꢀC. 1H NMR (500 MHz, DMSO):
4.3.8. 3-(2-Methoxyphenyl)pyrrolo[1,2-a]pyrazin-1(2H)-one (3h)
Following the general procedure, 1-(2-(2-methoxyphenyl)-2-
oxoethyl)-1H-pyrrole-2-carbonitrile 1b-8 (48.0 mg, 0.2 mmol) was
used. Purification via column chromatography on silica gel
(CHCl3:CH3OH ¼ 20:1, Rf ¼ 0.7) afforded 3h as white solid (43.2 mg,
d
10.25 (1H, s), 7.39 (1H, t, J ¼ 2.0 Hz), 7.14 (1H, s), 6.80 (1H, dd,
J ¼ 3.5, 2.5 Hz), 6.49 (1H, dd, J ¼ 3.5, 2.5 Hz), 1.25 (9H, s); 13C NMR
90% yield). Mp: 204e206 ꢀC. 1H NMR (500 MHz, DMSO):
d 10.49
(125 MHz, DMSO):
d 157.0, 135.5, 123.0, 119.7, 112.0, 108.6, 102.9,
33.3, 28.6; HRMS Calcd. for C11H14N2O þ Hþ: 191.1184, found:
(1H, s), 7.45 (1H, dd, J ¼ 2.0, 1.5 Hz), 7.43 (1H, s), 7.41 (2H, m), 7.12
(1H, d, J ¼ 8.0), 7.03 (1H, td, J ¼ 7.5, 0.5 Hz), 6.90 (1H, m), 6.56 (1H,
191.1182.
dd, J ¼ 3.5, 2.5 Hz), 3.82 (3H, s); 13C NMR (125 MHz, DMSO):
d 157.6,
156.3,130.9,130.5,124.8,123.5,121.7,120.8,119.8,112.4,112.0,109.1,
107.4, 56.0; HRMS Calcd. for C14H12N2O2 þ Hþ: 241.0977, found:
241.0975.
4.4. General procedure for systhesis of 4
To a round-bottom flask (50 mL) was added 2a (780 mg,
2.0 mmol) in EtOH (15.0 mL), hydroxylamine hydrochloride
(276 mg, 4.0 mmol) and NaOAc (328 mg, 4.0 mmol). The mixture
was heated at 100 ꢀC for 6 h. After cooling off, the reaction was
quenched by water, the mixture was extracted with CH2Cl2
(3 ꢁ 4.0 mL), the organic layer was dried over anhydrous Na2SO4
and concentrated under reduced pressure, and then CH2Cl2
(15.0 mL) and triethylamine (TEA, 404 mg, 4.0 mmol) were added at
0 ꢀC. A solution of acetyl chloride (360 mg, 4.6 mmol) in CH2Cl2
(5.0 mL) was added dropwise to this stirred cooled solution. The
reaction mixture was stirred at room temperature for 2 h. After the
reaction was quenched by water, the mixture was extracted with
CH2Cl2 (3 ꢁ 10.0 mL), and the combined extracts were washed with
saturated NaHCO3 solution (10.0 mL) and brine (10.0 mL). The
organic layer was dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by column chroma-
tography on silica gel (hexane:EtOAc ¼ 10:1, Rf ¼ 0.4) to provide the
desired product 2a-1 as red solid (650 mg, 73% yield). To a round-
bottom flask (15 mL) was added 2a-1 (447 mg, 1.0 mmol) and
Fe(acac)3 (20 mol %) in acetic acid (3.0 mL). The mixture was heated
at 80 ꢀC for 4 h. After cooling off, the reaction was quenched by
water and neutralized with NaHCO3 (saturated solution), the
mixture was extracted with EtOAc (3 ꢁ 4.0 mL), the organic layer
was dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The concentrated residue was purified by column chro-
matography on silica gel (hexene:EtOAc ¼ 10:1, Rf ¼ 0.6) to provide
the desired product 4 as yellow solid (286.5 mg, 74% yield). And
without Fe(acac)3, the isolated yield was 54%. Mp: 116e118 ꢀC. 1H
4.3.9. 3-Methylpyrrolo[1,2-a]pyrazin-1(2H)-one (3i)
Following the general procedure, 1-(2-oxopropyl)-1H-pyrrole-
2-carbonitrile 1b-9 (29.6, mg, 0.2 mmol) was used. Purification via
column chromatography on silica gel (CHCl3:CH3OH ¼ 20:1,
Rf ¼ 0.7) afforded 3i as white solid (42.7 mg, 90% yield). Mp:
201e203 ꢀC. 1H NMR (500 MHz, DMSO):
d 10.44 (1H, s), 7.32 (1H,
dd, J ¼ 2.5, 1.5 Hz), 7.09 (1H, s), 6.80 (1H, m), 6.46 (1H, dd, J ¼ 4.0,
2.5 Hz), 2.01 (3H, d, J ¼ 1.0 Hz); 13C NMR (125 MHz, DMSO):
d 156.6,
123.7, 123.3, 119.1, 111.7, 108.8, 104.9, 16.0; HRMS Calcd. for
C8H8N2O þ Hþ: 149.0715, found: 149.0710.
4.3.10. 3-Cyclopropylpyrrolo[1,2-a]pyrazin-1(2H)-one (3j)
Following the general procedure, 1-(2-cyclopropyl-2-oxoethyl)-
1H-pyrrole-2-carbonitrile 1b-10 (34.8 mg, 0.2 mmol) was used.
Purification via column chromatography on silica gel
(CHCl3:CH3OH ¼ 20:1, Rf ¼ 0.7) afforded 3j as white solid (31.0 mg,
89% yield). Mp: 212e214 ꢀC. 1H NMR (500 MHz, DMSO):
d 10.52
(1H, s), 7.29 (1H, t, J ¼ 2.0 Hz), 7.11 (1H, s), 6.80 (1H, m), 6.47 (1H, dd,
J ¼ 3.5, 2.5 Hz),1.68 (1H, m), 0.80 (2H, ddd, J ¼ 10.5, 4.0, 2.0 Hz), 0.68
(2H, ddd, J ¼ 10.5, 3.5, 1.5 Hz); 13C NMR (125 MHz, DMSO):
d 156.6,
129.6, 123.4, 119.2, 111.7, 108.8, 103.7, 11.0, 6.2; HRMS Calcd. for
C
10H10N2O þ Hþ: 175.0871, found: 175.0865.
4.3.11. 3-(Furan-2-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one (3k)
Following the general procedure, 1-(2-(furan-2-yl)-2-oxoethyl)-
1H-pyrrole-2-carbonitrile 1b-11 (40.0 mg, 0.2 mmol) was used.
Purification via column chromatography on silica gel
(CHCl3:CH3OH ¼ 20:1, Rf ¼ 0.7) afforded 3k as white solid (34.0 mg,
NMR (500 MHz, CDCl3):
d
7.70 (2H, dd, J ¼ 7.0, 1.0 Hz), 7.66 (1H, s),
7.46 (1H, t, J ¼ 7.5 Hz), 7.30 (2H, t, J ¼ 7.5 Hz), 7.24 (1H, m), 7.00 (5H,
m), 6.90 (1H, dd, J ¼ 4.0, 2.5 Hz), 6.75 (1H, d, J ¼ 4.0 Hz), 6.73 (1H,
dd, J ¼ 4.0, 1.0 Hz), 6.61 (1H, dd, J ¼ 2.5, 2.0 Hz), 6.02 (1H, dd, J ¼ 4.0,
85% yield). Mp: 230e232 ꢀC. 1H NMR (500 MHz, DMSO):
d 10.86
(1H, s), 7.81 (1H, s), 7.77 (1H, d, J ¼ 1.0 Hz), 7.54 (1H, dd, J ¼ 2.5,
1.5 Hz), 7.14 (1H, d, J ¼ 3.0 Hz), 6.92 (1H, m), 6.62 (1H, dd, J ¼ 3.5,
2.0 Hz), 6.58 (1H, dd, J ¼ 4.0, 2.5 Hz); 13C NMR (125 MHz, DMSO):
3.0 Hz); 13C NMR (125 MHz, CDCl3):
d 191.6, 135.6, 134.4, 132.3,
132.0,131.3,130.0,129.4,128.9,128.8,128.1,128.0,127.1,122.1,120.6,
119.0, 116.3, 113.9, 113.8, 109.0, 106.1, 103.1; HRMS Calcd. for
d
156.4, 146.2, 143.8, 123.3, 120.8, 119.0, 112.8, 112.3, 110.2, 108.1,
104.2; HRMS Calcd. for C11H8N2O2 þ Hþ: 201.0664, found: 201.0671.
C
26H17N3O þ Hþ: 388.1450, found: 388.1453.
Please cite this article in press as: N. Shao, et al., Functionalized N-containing heterocyclic scaffolds derived from N-substituted pyrroles via
inter- and intramolecular annulations, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.08.022

N. Shao et al. / Tetrahedron xxx (2018) 1e7
[2] a) J. Lee, I. Kim, J. Org. Chem. 78 (2013) 1283e1288;
7
Acknowledgement
b) G. Singh, E. Meatli, Eur. J. Med. Chem. 46 (2011) 5237e5257;
c) M. Kucukdisli, T. Opatz, J. Org. Chem. 78 (2013) 6670e6676;
d) D. Chai, M. Lautens, J. Org. Chem. 74 (2009) 3054e3061.
This work was supported by the National Key R&D Program of
China (2017YFE0102200), the National Natural Science Foundation
of China (No. 21472170, 21702183), the Zhejiang Provincial Fund for
Distinguished Young Scholars (LR15B020001) and the Fundamental
Research Funds for the Central Universities (2017FZA7016). We
appreciate Prof. Yongping Yu (Zhejiang University, China) for useful
discussion and Dr. Ellis O'Neill (Oxford University, UK) for critical
editing of the manuscript.
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Appendix A. Supplementary data
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Supplementary data associated with this article can be found in
the online version, at https://doi.org/10.1016/j.tet.2018.08.022.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
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Please cite this article in press as: N. Shao, et al., Functionalized N-containing heterocyclic scaffolds derived from N-substituted pyrroles via
inter- and intramolecular annulations, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.08.022