Phosphine-catalyzed dearomative (3 + 2) annulation of 2-nitrobenzofurans and nitrobenzothiophenes with allenoates

Article abstract of DOI:10.1039/c9ob00775j

An efficient Ph₂PMe-catalyzed dearomative (3 + 2) annulation of 2-nitrobenzofurans, 2-nitrobenzothiophenes, and 3-nitrobenzothiophenes with allenoates has been developed. With the developed protocol, a series of structurally important cyclopenta[b]benzofurans and cyclopenta[b]benzothiophenes were obtained in good to excellent yields (up to 98%) under mild conditions. In addition, preparative-scale experiments and transformations were conducted to exemplify the synthetic utility. The asymmetric version of this dearomative (3 + 2) annulation reaction was tentatively investigated by using chiral phosphine catalysts.

Full text of DOI:10.1039/c9ob00775j

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C9OB00775J
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ACTICLE
Phosphine-Catalyzed Dearomative (3+2) Annulation of 2-
Nitrobenzofurans and Nitrobenzothiophenes with Allenoate
Received 00th January 20xx,
Accepted 00th January 20xx
Jian-Qiang Zhao,a,* Lei Yang,b Yong You,a Zhen-Hua Wang,a Ke-Xin Xie,c Xiao-Mei Zhang,b Xiao-Ying
Xu,b and Wei-Cheng Yuanb,*
DOI: 10.1039/x0xx00000x
An efficient Ph2PMe-catalyzed dearomative (3+2) annulation of 2-nitrobenzofurans, 2-nitrobenzothiophenes, and 3-
nitrobenzothiophenes with allenoate has been developed. With the developed protocol, a series of structurally important
cyclopenta[b]benzofurans and cyclopenta[b]benzothiophenes were obtained in good to excellent yields (up to 98%) under
mild conditions. In addition, preparative-scale experiment and transformations were conducted to exemplify the synthetic
utility. The asymmetric version of this dearomative (3+2) annulation reaction was tentatively investigated by using chiral
phosphine catalysts.
www.rsc.org/
Cyclopentanoids are ubiquitous in numerous natural and
non-natural
compounds.6
Among
them,
Introduction
Dearomative annulation represents
cyclopenta[b]benzofurans, as an important and central
structural scaffolds, are present in a myriad of biologically
active natural products and pharmaceuticals (Figure 1).7 For
instance, beraprost is the first example of a drug with a
cyclopenta[b]benzofuran scaffold to enter the market for the
treatment of patients with pulmonary arterial hypertension
a
powerful and
straightforward strategy for the preparation of highly
functionalized three-dimensional molecules from readily
available feedstocks such as arenes and heteroarenes.1 In this
research area, the vast majority of the catalytic
transformations typically focus on adopting the nucleophilic
character of arenes and heteroarenes, including naphthol,
phenol, indole, and pyrrole.2 Nevertheless, installing suitable
electron-withdrawing group in these arenes or heteroarenes
can turn them into electron-deficient compounds thus
showing electrophilic nature. As a result, these electron-
deficient arenes or heteroarenes probably give rise to various
novel types of reactions to access structurally versatile cyclic
compounds. Recently, 3-nitroindoles serving as electrophilic
heteroarenes have demonstrated their interesting synthetic
potential in the dearomative cycloaddition reactions.3-4 In
contrast, we noted that 2-nitrobenzofurans and 2-
nitrobenzothiophenes, also belong to a class of electron-
deficient heteroarenes, are less explored in the
dearomatization process.5 In this context, exploring novel
types of reactions by taking advantage of the electrophilic
character of 2-nitrobenzofurans and 2-nitrobenzothiophenes
will be more promising and is highly desirable.
and
peripheral
artery
disease.8
Furthermore,
cyclopenta[b]annulated benzothiophenes are an important
class of three-ring heterocyclic compounds which possess
potential applications in medicinal chemistry and materials
science.9 Given their outstanding potential, the development
of efficient methodologies to rapidly construct the
cyclopenta[b]benzofuran and cyclopenta[b]benzothiophene
scaffolds has consequently become a primary target of
synthetic efforts.
a.Institute for Advanced Study, Chengdu University, Chengdu 610106, China
E-mail: zhaojianqiang@cdu.edu.cn
b.National Engineering Research Center of Chiral Drugs, Chengdu Institute of
Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China.
E-mail: yuanwc@cioc.ac.cn
Fig. 1 Examples of bioactive compounds with the core
structure of cyclopenta[b]benzofuran scaffold.
c. Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041,
China
† Electronic Supplementary Information (ESI) available: Experimental procedures,
spectral data of new compounds, and crystallographic data. CCDC 1900800. For
ESI and crystallographic data in CIF or other electronic format. See DOI:
10.1039/x0xx00000x
Phosphine-catalyzed cycloaddition reactions of allenoates
with electron-deficient olefins have emerged as one of
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powerful and efficient strategies for the generation of examined (Table 1, entries 10-11). It was obserVvieewdArtthicaletOntlhinee
molecular complexity and new molecular frameworks.10 Even reaction worked well in the presence of 20 mol % Ph2PMe
DOI: 10.1039/C9OB00775J
since Lu’s pioneering work on phosphine-catalyzed (3+2) under 0.05 M substrate concentration, giving 3a in 87% yield
annulation of allenoates with activated alkenes in 1995,11 this (Table 1, entry 10).
powerful mode of cyclization has attracted much research
interest from organic synthetic chemists for the construction Table 1 Optimization of reaction conditionsa
of structurally diverse cyclopentenes.12 However, during the
past two decades, although Lu’s classic (3+2) annulation has
been widely studied, the cycloaddition reaction involving
dearomatization
process
between
electron-deficient
Entry
1
2
3
4
cat.
PPh3
(n-Bu)3P CH2Cl2
MePPh2
DABCO
solvent T (oC) time (h) yield (%)b
heteroarenes and allenoates is unexplored so far. During our
preparation of this manuscript, the first phosphine-catalyzed
dearomative (3+2) annulation of 3-nitroindoles with allenoates
was reported.13 It is noteworthy that the reaction of 2-
nitrobenzofurans with allenoates is failed under the Zhang’s
reaction conditions.13a As part of our continuing efforts on the
dearomative cycloaddition reactions of electron-deficient
heteroarenes,4,5b-c, 5e, 5g herein we report phosphine-catalyzed
dearomative (3+2) annulation of 2-nitrobenzofurans and 2-
nitrobenzothiophenes with zwitterionic intermediate, in situ
generated from addition of tertiary phosphine to allenoate, for
synthesis of structurally diverse cyclopenta[b]benzofuran and
cyclopenta[b]benzothiophene derivatives. The extension of
the methodology to the dearomatization of 3-
nitrobenzothiophenes is also described (Scheme 1).
CH2Cl2
rt
rt
rt
rt
rt
rt
rt
0
20
20
2
48
9
9
9
4
24
8
44
55
74
N.R.
58
49
57
78
69
87
82
CH2Cl2
CH2Cl2
5
6
7
8
Ph2PMe toluene
Ph2PMe
Ph2PMe
Ph2PMe
Ph2PMe
Ph2PMe
Ph2PMe
MTBE
EtOAc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9c
10d
11e
0
0
0
9
aUnless specified, the reactions were carried out with 1a (0.2 mmol),
2a (0.3 mmol) and cat. (20 mol %) in 1.0 mL of solvent for indicated
b
c
d
time. Yield of isolated product. 10 mol % cat. was used. 2 mL of
solvent was used. e4 mL of solvent was used. N.R. = no reaction
With the optimal conditions in hand, we set out to
explore the substrate scope by using various 2-
nitrobenzofurans. To our delight, 2-nitrobenzofurans with
different steric and electronic constraints all could smoothly
undergo dearomatization (Scheme 2). For instance, 2-
nitrobenzofurans bearing various substituents at the C5
Scheme 1 Phosphine-catalyzed dearomative (3+2) annulation
of 2-nitrobenzofurans and nitrobenzothiophenes with
allenoate.
t
position (R = F, Cl, Br, NO2, Me, OMe, Bu, Ph) of the aromatic
ring could react efficiently with ethyl 2,3-butadienoate 2a, and
the reactions afforded the corresponding products 3b-i in good
yields (70-85%). Furthermore, substrates installing varied
electronic properties at the C6 or C7 position successfully
underwent the dearomative (3+2) annulation reaction and the
corresponding bromo-, methyl-, methoxy-, fluoro-, ethyoxyl-
and phenyl- substituted cyclopenta[b]benzofurans 3j-q were
isolated in yields ranging from 77% to 87%. The reaction of 2-
nitrobenzofuran 1r bearing substituent at C4 position and 2a
proved to be more sluggish, and the corresponding
cycloadduct 3r was obtained in only 40% yield, albeit with
adding the catalyst loading to 30 mol % and a specially
prolonged reaction time. This case suggests that an increase of
steric hindrance next to the electrophilic C3 position maybe
impede the dearomative (3+2) annulation process on certain
extent. Meanwhile, we found that the reaction for the di-
substituted substrate proceeded smoothly at room
temperature, affording product 3s in moderate yield. The
more sterically hindered 2-nitronaphtho[2,1-b]furan 1t also
proved to be amenable to this developed protocol, and the
expected product 3t could be obtained in 51% yield. It is worth
mentioning that the structure of product 3o was unequivocally
confirmed by means of single-crystal X-ray diffraction.14
Results and discussion
We began our investigation with the reaction of 2-
nitrobenzofuran 1a and ethyl 2,3-butadienoate 2a in the
presence of 20 mol % PPh3 in CH2Cl2 at room temperature for
20 h. To our delight, the desired (3+2) cycloadduct 3a was
obtained in 44% yield (Table 1, entry 1). Next,
tributylphosphine ((n-Bu)3P) and methyldiphenylphosphine
(Ph2PMe) were used to catalyze the dearomative (3+2)
annulation, giving 3a in 55% and 74% yield, respectively (Table
1, entry 2 and 3). However, it was found that DABCO could not
promote the reaction (Table 1, entry 4). Having identified
catalyst Ph2PMe as the best candidate, a screen of solvents
including toluene, methyl tert-butyl ether (MTBE), and EtOAc
were performed at room temperature. It revealed that CH2Cl2
was the most suitable reaction media for the reaction (Table 1,
entry 3 vs entries 5-7). Lowering the reaction temperature to 0
oC, the yield of product 3a was increased to 78% (Table 1,
entry 8). However, reducing the catalyst loading from 20
mol % to 10 mol %, the reaction provided 3a in decreasing
yield along with prolonging reaction time to 24 h (Table 1,
entry 9). Ultimately, the substrate concentration was
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(0.225 mmol) and Ph2PMe (20 mol %) in 1.5 mL of CH2Cl2
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DOI: 10.1039/C9OB00775J
indicated time.
Encouraged by the success of the above reactions, we
continued our attempt to investigate the dearomative (3+2)
annulation reaction of 3-nitrobenzothiophenes with allenoate
2a (Scheme 4). Substituents of different electronic natures on
the aromatic ring of 3-nitrobenzothiophene substrates, could
be tolerated in this dearomative (3+2) cycloaddition process,
and the reactions furnished their respective products 7a-g in
good to excellent yields (82-98%). Nevertheless, 3-
nitrothieno[2,3-b]pyridine also could react smoothly with ethyl
2,3-butadienoate, providing the desired dearomative
annulation product 7h in 83% yield.
Scheme
4 Substrates scope of 3-nitrobenzothiophenes.
Scheme 2 Substrates scope of 2-nitrobenzofuans. Reaction
conditions: the reactions were carried out with (0.2 mmol),
Reaction conditions: the reactions were carried out with
(0.15 mmol), 2a (0.225 mmol) and Ph2PMe (20 mol %) in 1.5
mL of CH2Cl2 for indicated time.
6
1
2a (0.3 mmol) and Ph2PMe (20 mol %) in 2.0 mL of CH2Cl2 for
indicated time. a30 mol % Ph2PMe was used. bRun at rt.
We further tried to develop a catalytic asymmetric
version of this annulation reaction using several common
Furthermore, we were keen on extending the
dearomative
(3+2)
annulation
reaction
to
2-
chiral phosphines. Using
I as the catalyst, the reaction gave
nitrobenzothiophenes to confirm the practicability of the
methodology. As shown in Scheme 3, this Ph2PMe-catalyzed
dearomative (3+2) annulation reaction proved to be well
compatible with the use of various 2-nitrobenzothiophenes.
Under the standard reaction conditions, the reaction of 2-
nitrobenzothiophene 4a and 2a could occur smoothly, and
delivered the expected product 5a in 78% yield. We also found
that diverse 2-nitrobenzothiophenes containing different
substituents (R = Cl, Me, Ph) on the aromatic rings could react
successfully with allenoate 2a, providing the corresponding
trace amount of product 3a. In the present of Dixon’s catalyst
II and chiral BINAP III, no product was detected. Using (R)-
SITCP (IV) as the catalyst, product 3a could be obtained in 63%
yield but with only 11% ee (Scheme 5). Despite the present
result is not satisfactory, this example indicates that the
catalytic enantioseclective dearomative (3+2) annulation is
promising.
products 5b-e with comparable results.
Scheme 5 Asymmetric version of the dearomative (3+2)
annulation.
To exemplify the synthetic utility of our developed
protocol, the reaction was scaled up to 4.6 mmol for 1a, which
is 23 times larger than the scale of the model reaction in Table
1. As showed in Scheme 6, the preparative-scale reaction
proceeded well and afforded 3a in 81% yield after 8 h. This
result revealed that the developed protocol was amenable to a
Scheme 3 Substrates scope of 2-nitrobenzothiophenes. Reaction
conditions: the reactions were carried out with 5 (0.15 mmol), 2a
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large-scale production. And then, product 3a was further strategy for the construction of cyclopenta[b]benzofuran and
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transformed into other compounds. The dihydroxylation of 3a cyclopenta[b]benzothiophene
could be conducted efficiently, affording product rac- in 49% extensively in biologically active natural products and
yield. Reduction of 3a using DIBAL-H in anhydrous THF gave pharmaceuticals. With the developed protocol, a range of
product in 77% yield (Scheme 6). structurally diverse cyclopenta[b]benzofurans and
scaffolDdOs,I: 10.1039/C9OB00775J
which exist
8
9
cyclopenta[b]benzothiophenes could be smoothly obtained in
good to excellent yields (up to 98%) under mild conditions.
Preparative-scale experiment and transformations were
conducted to exemplify the synthetic utility.The preliminary
attempt at the development of asymmetric version of this
dearomative (3+2) reaction was also conducted by using chiral
phosphines.
Experimental section
General Methods
Reagents were purchased from commercial sources and
were used as received unless mentioned otherwise. Reactions
were monitored by TLC. H NMR and 13C NMR spectra were
recorded in CDCl3 and DMSO-d6. H NMR chemical shifts are
1
1
Scheme 6 Preparative-scale experiment and transformations of the
product 3a.
reported in ppm relative to tetramethylsilane (TMS) with the
solvent resonance employed as the internal standard (CDCl3 at
7.26 ppm, DMSO-d6 at 2.50 ppm). Data are reported as follows:
chemical shift, multiplicity (s = singlet, br s = broad singlet, d =
doublet, t = triplet, q = quartet, m = multiplet), coupling
constants (Hz) and integration. 13C NMR chemical shifts are
reported in ppm from tetramethylsilane (TMS) with the
solvent resonance as the internal standard (CDCl3 at 77.00
ppm, DMSO-d6 at 39.51 ppm). Melting points were recorded
On the basis of previous literature reports13, 15 and our
own results, a plausible reaction mechanism was proposed in
Scheme 7. The reaction is initiated by the addition of catalyst
Ph2PMe to 2,3-butadienoate to generate the zwitterionic
intermediate
position of the 2-nitrobenzofurans or 2-nitrobenzothiophenes
through conjugate addition to form intermediate . And then,
an intramolecular annulation affords another intermediate
which upon an intramolecular [1,2] proton shift to give
A. Zwitterionic intermediate A attacks the C3
B
a
melting point apparatus. 2-Nitrobenzofurans,5a 2-
C
,
on
nitrobenzothiophenes,16 and 3-nitrobenzothiophenes17 in this
work are known compounds and prepared according to the
reported literature procedures.
intermediate
catalyst
D
. Ultimately, intermediate
D
releases the
the final
Ph2PMe and provides
cyclopenta[b]benzofurans and cyclopenta[b]benzothiophenes.
Typical experimental procedures for synthesis of 2-
nitrobenzothiophenes 16
A solution of benzothiophen (20
.
o
mmol) in THF (80 mL) was stirred at 0 C. Then NBS (5.4 g, 30
mmol) was added portionwise. After maintaining at 0 C for 30
o
min, the reaction was warmed to room temperature and
stirred for 48 h. Then the reaction was quenched with Na2S2O3,
and extracted with Et2O. The organic layer was washed with
brine, dried over Na2SO4, filtered and concentrated by rotary
evaporation. The crude product 3-bromobenzo[b]thiophene
was used directly without purification.
To a solution of 3-bromobenzo[b]thiophene (20 mmol) in
65 mL of acetic anhydride at 0 oC, and then a mixture of 25 mL
of nitric acid and 20 mL of acetic acid was added dropwise with
vigorous stirring. Once the addition was complete, the ice bath
was removed and the reaction mixture stirred for 2 h at room
temperature. Then the mixture was poured into ice, filtered,
and washed with water. The solid was crystallized from
ethanol, yielding 3-bromo-2-nitrobenzo[b]thiophene.
Scheme 7 Proposed reaction mechanism.
3-Bromo-2-nitrobenzo[b]thiophene (5 mmol) and benzoic
acid (18.5 mmol, 3.7 equiv) were added to a 3-neck round-
bottom flask. The solids were mixed thoroughly with a
magnetic stir bar, and the reaction was purged 3 times before
heating to 150 °C. Under a cone of nitrogen, copper powder
Conclusions
In summary, we have developed Ph2PMe-catalyzed
dearomative (3+2) annulation of 2-nitrobenzofurans, 2-
nitrobenzothiophenes, and 3-nitrobenzothiophenes with
allenoate. This protocol provides a straightforward and useful
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(24 mmol, 4.8 equiv) was then added to the melt. The reaction 131.4, 133.2, 137.9, 142.9; HRMS (ESI-TOF) Calcd. for
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was stirred for an additional 1 h at 150 °C and then slowly C8H3ClNO2S [M-H]-: 211.9579; found: 211D.9O5I7: 140..1039/C9OB00775J
1
cooled to room temperature. The resulting solid was 5-Methyl-3-nitrobenzo[b]thiophene (6f). H NMR (400 MHz,
suspended in CH2Cl2, and the residual copper was removed by CDCl3) δ 2.57 (s, 3H), 7.36 (dd, J = 8.3, 1.7 Hz, 1H), 7.77 (d, J =
gravity filtration. The CH2Cl2 solution was washed three times 8.3 Hz, 1H), 8.38-8.49 (m, 1H), 8.67 (d, J = 1.8 Hz, 1H); 13C NMR
with saturated NaHCO3, once with water, and once with brine. (101 MHz, CDCl3) δ 21.8, 122.6, 123.8, 128.2, 130.2, 132.8,
This was then dried over MgSO4, filtered, and concentrated. 136.0, 137.4, 142.3; HRMS (ESI-TOF) Calcd. for C9H6NO2S [M-
The residue directly purified by flash chromatography on silica H]-: 192.0125; found: 192.0123.
gel (petroleum ether/ethyl acetate = 25:1
corresponding 2-nitrobenzothiophenes.
～
30:1) to give the
General experimental procedures for synthesis of
compounds 3. To a solution of 2-nitrobenzofurans
1 (0.2 mmol)
5-Chloro-2-nitrobenzo[b]thiophene (4b). 1H NMR (400 MHz, in CH2Cl2 (2.0 mL) were added ethyl-2,3-butadienoate 2a (0.3
CDCl3) δ 7.56 (dd, J = 8.7, 2.0 Hz, 1H), 7.80 (d, J = 8.7 Hz, 1H), mmol) and catalyst Ph2PMe (7.4 uL, 20 mol %). Then the
7.94 (d, J = 2.1 Hz, 1H), 8.16 (s, 1H); 13C NMR (101 MHz, CDCl3) mixture was stirred for specific time at 0 C. After completion,
o
δ 124.1, 124.5, 126.2, 129.7, 132.6, 137.1, 138.2, 152.8; HRMS the reaction mixture was directly purified by flash
(ESI-TOF) Calcd. for C8H3ClNO2S [M-H]-: 211.9579; found: chromatography on silica gel (petroleum ether/ethyl acetate =
211.9583.
20:1～25:1) to give the corresponding product 3.
1
5-Methyl-2-nitrobenzo[b]thiophene (4c). H NMR (400 MHz, Ethyl 3a-nitro-3a,8b-dihydro-3H-cyclopenta[b]benzofuran-1-
1
CDCl3) δ 2.51 (s, 3H), 7.43 (dd, J = 8.3, 1.8 Hz, 1H), 7.64-7.79 (m, carboxylate (3a). yellow oil; 87% yield (48.0 mg); H NMR (300
2H), 8.07-8.20 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 21.4, 122.5, MHz, CDCl3) δ 1.34 (t, J = 7.1 Hz, 3H), 3.32 (ddd, J = 19.7, 2.7,
125.4, 126.6, 131.2, 136.2, 136.4, 137.7, 151.4; HRMS (ESI-TOF) 1.7 Hz, 1H), 3.74 (ddd, J = 19.6, 2.5, 1.2 Hz, 1H), 4.12-4.43 (m,
Calcd. for C9H6NO2S [M-H]-: 192.0125; found: 192.0125.
2H), 5.13 (s, 1H), 6.75 (q, J = 2.4 Hz, 1H), 6.92-7.11 (m, 2H),
7-Methyl-2-nitrobenzo[b]thiophene (4d). H NMR (400 MHz, 7.16-7.35 (m, 1H), 7.45-7.69 (m, 1H); 13C NMR (75 MHz, CDCl3)
CDCl3) δ 2.59 (s, 3H), 7.34-7.50 (m, 2H), 7.80 (d, J = 7.8 Hz, 1H), δ 14.2, 44.2, 60.4, 61.1, 110.3, 121.4, 123.0, 123.9, 126.4,
8.24 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 19.9, 124.6, 126.3, 129.6, 135.0, 138.6, 157.7, 162.6; HRMS (ESI-TOF) Calcd. for
126.5, 129.2, 132.6, 136.0, 140.9, 151.1; HRMS (ESI-TOF) Calcd. C14H13NNaO5 [M+Na]+: 298.0686; found: 298.0685.
1
for C9H6NO2S [M-H]-: 192.0125; found: 192.0127.
Typical experimental procedures for synthesis of 3- furan-1-carboxylate
nitrobenzothiophenes 17
A mixture of benzothiophenes (20 NMR (300 MHz, CDCl3) δ 1.34 (t, J = 7.1 Hz, 3H), 3.31 (ddd, J =
Ethyl 7-fluoro-3a-nitro-3a,8b-dihydro-3H-cyclopenta[b]benzo
1
(3b). yellow oil; 81% yield (47.2 mg); H
.
mmol) and (NH4)2Ce(NO3)5·4H2O (7 mmol) in Ac2O (17 mL) was 19.7, 2.7, 1.7 Hz, 1H), 3.73 (ddd, J = 19.7, 2.5, 1.2 Hz, 1H), 4.13-
stirred at room temperature for 3 days. The reaction mixture 4.42 (m, 2H), 5.09 (s, 1H), 6.77 (q, J = 2.4 Hz, 1H), 6.84-7.03 (m,
was poured onto crushed ice and extracted with EtOAc. The 2H), 7.19-7.41 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 14.2, 44.2,
extracts were washed with water, dried and evaporated. The 60.4 (J = 1.9 Hz), 61.2, 110.7 (J = 8.6 Hz), 113.8 (J = 26.0 Hz),
residue directly purified by flash chromatography on silica gel 116.0 (J = 24.6 Hz), 122.0, 125.3 (J = 9.3 Hz), 134.4, 139.0,
and recrystallization to give the corresponding 3- 153.6 (J = 1.8 Hz), 158.7 (J = 239.0 Hz), 162.4; HRMS (ESI-TOF)
nitrobenzothiophenes.
Calcd. for C14H12FNNaO5 [M+Na]+: 316.0592; found: 316.0602.
5-Fluoro-3-nitrobenzo[b]thiophene (6b). 1H NMR (400 MHz, Ethyl 7-chloro-3a-nitro-3a,8b-dihydro-3H-cyclopenta[b]benzo
CDCl3) δ 7.28-7.35 (m, 1H), 7.86 (dd, J = 8.9, 4.7 Hz, 1H), 8.26- furan-1-carboxylate (3c). yellow solid; 81% yield (50.2 mg);
8.39 (m, 1H), 8.79 (d, J = 1.1 Hz, 1H); 13C NMR (101 MHz, CDCl3) m.p. 91.0-91.3 C; H NMR (300 MHz, CDCl3) δ 1.35 (t, J = 7.1
δ 110.2 (J = 27.2 Hz), 115.7 (J = 25.2 Hz), 124.4 (J = 9.6 Hz), Hz, 3H), 3.31 (ddd, J = 19.8, 2.7, 1.7 Hz, 1H), 3.74 (ddd, J = 19.7,
131.4 (J= 12.0 Hz), 134.1, 134.7, 140.9, 162.3 (J = 246.4 Hz); 2.4, 1.1 Hz, 1H), 4.15-4.42 (m, 2H), 5.08 (s, 1H), 6.77 (q, J = 2.4
HRMS (ESI-TOF) Calcd. for C8H3FNO2S [M-H]-: 195.9874; found: Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 7.17-7.25 (m, 1H), 7.47-7.62 (m,
o
1
195.9879.
1H); 13C NMR (75 MHz, CDCl3) δ 14.2, 44.1, 60.2, 61.3, 111.2,
5-Bromo-3-nitrobenzo[b]thiophene (6c). 1H NMR (400 MHz, 121.7, 125.7, 126.7, 128.1, 129.5, 134.4, 139.0, 156.4, 162.3;
CDCl3) δ 7.65 (dd, J = 8.7, 1.9 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), HRMS (ESI-TOF) Calcd. for C14H12ClNNaO5 [M+Na]+: 332.0296;
8.74 (s, 1H), 8.82 (d, J = 1.9 Hz, 1H); 13C NMR (75 MHz, DMSO) found: 332.0287.
δ 121.3, 125.0, 126.1, 129.4, 131.4, 136.0, 137.4, 141.2; HRMS Ethyl 7-bromo-3a-nitro-3a,8b-dihydro-3H-cyclopenta[b]benzo
(ESI-TOF) Calcd. for C8H4BrNNaO2S [M+Na]+: 279.9038; found: furan-1-carboxylate (3d). yellow solid; 85% yield (60.3 mg);
o
1
279.9032.
m.p. 86.0-86.3 C; H NMR (300 MHz, CDCl3) δ 1.35 (t, J = 7.1
5-Chloro-3-nitrobenzo[b]thiophene (6d)
.
1H NMR (300 MHz, Hz, 3H), 3.31 (ddd, J = 19.7, 2.7, 1.7 Hz, 1H), 3.74 (ddd, J = 19.7,
CDCl3) δ 7.38 (dd, J = 8.7, 2.1 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 2.4, 1.1 Hz, 1H), 4.10-4.44 (m, 2H), 5.08 (s, 1H), 6.77 (q, J = 2.4
8.47 (d, J = 2.1 Hz, 1H), 8.68 (s, 1H); 13C NMR (75 MHz, CDCl3) δ Hz, 1H), 6.89 (d, J = 8.6 Hz, 1H), 7.29-7.46 (m, 1H), 7.64-7.78 (m,
123.3, 123.8, 126.8, 130.7, 133.5, 134.3, 136.5, 141.4; HRMS 1H); 13C NMR (75 MHz, CDCl3) δ 14.2, 44.1, 60.2, 61.3, 111.8,
(ESI-TOF) Calcd. for C8H3ClNO2S [M-H]-: 211.9579; found: 115.2, 121.6, 126.2, 129.5, 132.4, 134.4, 139.0, 156.9, 162.3;
211.9577.
HRMS (ESI-TOF) Calcd. for C14H12BrNNaO5 [M+Na]+: 375.9791;
7-Chloro-3-nitrobenzo[b]thiophene (6e).
1H NMR (400 MHz, found: 375.9778.
CDCl3) δ 7.51-7.65 (m, 2H), 8.55 (dd, J = 8.1, 1.2 Hz, 1H), 8.76 (s, Ethyl 3a,7-dinitro-3a,8b-dihydro-3H-cyclopenta[b]benzofuran
1
1H); 13C NMR (101 MHz, CDCl3) δ 122.6, 126.0, 128.3, 128.4, -1-carboxylate (3e). yellow oil; 70% yield (45.1 mg); H NMR
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
(300 MHz, CDCl3) δ 1.38 (t, J = 7.1 Hz, 3H), 3.38 (ddd, J = 19.9, NMR (300 MHz, CDCl3) δ 1.34 (t, J = 7.1 Hz, 3H),V2iew.3A4rti(csle,O3nHlin)e,
2.7, 1.7 Hz, 1H), 3.83 (ddd, J = 19.9, 2.5, 1.1 Hz, 1H), 4.16-4.43 3.19-.39 (m, 1H), 3.64-3.82 (m, 1H), 4.16D-4O.I3: 610(.1m03,92/CH9)O, 5B.000777(5sJ,
(m, 2H), 5.16 (s, 1H), 6.83 (q, J = 2.4 Hz, 1H), 7.11 (d, J = 8.9 Hz, 1H), 6.67-6.77 (m, 1H), 6.78-6.92 (m, 2H), 7.43 (d, J = 8.0 Hz,
1H), 8.16-8.32 (m, 1H), 8.41-8.56 (m, 1H); 13C NMR (75 MHz, 1H); 13C NMR (75 MHz, CDCl3) δ 14.2, 21.4, 44.1, 60.3, 61.0,
CDCl3) δ 14.1, 43.9, 59.6, 61.6, 110.5, 122.2, 123.0, 125.6, 110.9, 120.9, 121.7, 123.8, 125.9, 135.1, 138.5, 140.1, 158.0,
126.6, 134.0, 139.5, 143.9, 162.0, 162.3; HRMS (ESI-TOF) Calcd. 162.6; HRMS (ESI-TOF) Calcd. for C15H15NNaO5 [M+Na]+:
for C14H12N2NaO7 [M+Na]+: 343.0537; found: 343.0542.
312.0842; found: 312.0842.
Ethyl 7-methyl-3a-nitro-3a,8b-dihydro-3H-cyclopenta[b]benz Ethyl 6-methoxy-3a-nitro-3a,8b-dihydro-3H-cyclopenta[b]ben
1
ofuran-1-carboxylate (3f). yellow solid; 83% yield (48.0 mg); zofuran-1-carboxylate (3l). yellow oil; 87% yield (53.0 mg); H
m.p. 102.8-103.0 oC; 1H NMR (300 MHz, CDCl3) δ 1.35 (t, J = 7.1 NMR (300 MHz, CDCl3) δ 1.33 (t, J = 7.1 Hz, 3H), 3.29 (ddd, J =
Hz, 3H), 2.30 (s, 3H), 3.19-3.39 (m, 1H), 3.72 (ddd, J = 19.6, 2.4, 19.5, 2.7, 1.6 Hz, 1H), 3.72 (ddd, J = 19.6, 2.4, 1.1 Hz, 1H), 3.77
1.2 Hz, 1H), 4.13-4.46 (m, 2H), 5.08 (s, 1H), 6.74 (q, J = 2.4 Hz, (s, 3H), 4.07-4.38 (m, 2H), 5.04 (s, 1H), 6.47-6.66 (m, 2H), 6.72
1H), 6.89 (d, J = 8.2 Hz, 1H), 6.98-7.13 (m, 1H), 7.38 (d, J = 1.8 (q, J = 2.3 Hz, 1H), 7.31-7.49 (m, 1H); 13C NMR (75 MHz, CDCl3)
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 14.2, 20.8, 44.2, 60.5, 61.0, δ 14.2, 44.1, 55.6, 60.0, 61.0, 96.8, 108.8, 115.8, 122.2, 126.5,
109.8, 121.7, 123.8, 126.9, 129.9, 132.6, 135.0, 138.6, 155.8, 135.2, 138.2, 159.0, 161.3, 162.7; HRMS (ESI-TOF) Calcd. for
162.7; HRMS (ESI-TOF) Calcd. for C15H15NNaO5 [M+Na]+: C15H15NNaO6 [M+Na]+: 328.0792; found: 328.0791.
312.0842; found: 312.0830.
Ethyl 7-methoxy-3a-nitro-3a,8b-dihydro-3H-cyclopenta[b]ben furan-1-carboxylate
Ethyl 5-fluoro-3a-nitro-3a,8b-dihydro-3H-cyclopenta[b]benzo
1
(3m). yellow oil; 77% yield (45.3 mg); H
1
zofuran-1-carboxylate (3g). yellow oil; 82% yield (50.1 mg); H NMR (300 MHz, CDCl3) δ 1.33 (t, J = 7.1 Hz, 3H), 3.39 (ddd, J =
NMR (300 MHz, CDCl3) δ 1.34 (t, J = 7.1 Hz, 3H), 3.29 (ddd, J = 19.8, 2.7, 1.7 Hz, 1H), 3.78 (ddd, J = 19.8, 2.4, 1.1 Hz, 1H), 4.15-
19.6, 2.7, 1.7 Hz, 1H), 3.70 (ddd, J = 19.6, 2.5, 1.1 Hz, 1H), 3.76 4.37 (m, 2H), 5.15 (d, J = 2.0 Hz, 1H), 6.77 (q, J = 2.4 Hz, 1H),
(s, 3H), 4.15-4.43 (m, 2H), 5.09 (s, 1H), 6.68-6.85 (m, 2H), 6.91 6.90-7.10 (m, 2H), 7.28-7.43 (m, 1H); 13C NMR (75 MHz, CDCl3)
(d, J = 8.8 Hz, 1H), 7.14 (d, J = 2.7 Hz, 1H); 13C NMR (75 MHz, δ 14.2, 44.0, 60.8 (J = 2.2 Hz), 61.2, 116.8 (J = 15.7 Hz), 121.7 (J
CDCl3) δ 14.2, 44.2, 55.9, 60.7, 61.1, 110.4, 112.0, 114.9, 122.0, = 3.7 Hz), 121.9, 123.8 (J = 5.5 Hz), 127.3, 134.5, 138.9, 144.4 (J
124.8, 134.8, 138.8, 151.7, 155.8, 162.6; HRMS (ESI-TOF) Calcd. = 10.9 Hz), 146.8 (J = 247.5 Hz), 162.4; HRMS (ESI-TOF) Calcd.
for C15H15NNaO6 [M+Na]+: 328.0792; found: 328.0792.
for C14H12FNNaO5 [M+Na]+: 316.0592; found: 316.0598.
Ethyl 7-(tert-butyl)-3a-nitro-3a,8b-dihydro-3H-cyclopenta[b]b Ethyl 5-bromo-3a-nitro-3a,8b-dihydro-3H-cyclopenta[b]benzo
1
enzofuran-1-carboxylate (3h). yellow oil; 81% yield (53.8 mg); furan-1-carboxylate (3n). yellow oil, 78% yield (54.9 mg); H
1H NMR (300 MHz, CDCl3) δ 1.29 (s, 9H), 1.38 (d, J = 7.1 Hz, 3H), NMR (300 MHz, CDCl3) δ 1.33 (t, J = 7.1 Hz, 3H), 3.27-3.52 (m,
3.30 (ddd, J = 19.7, 2.7, 1.7 Hz, 1H), 3.72 (ddd, J = 19.6, 2.5, 1.2 1H), 3.80 (ddd, J = 19.8, 2.6, 1.4 Hz, 1H), 4.11-4.39 (m, 2H),
Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 5.12 (s, 1H), 6.76 (q, J = 2.4 Hz, 5.18 (s, 1H), 6.78 (q, J = 2.4 Hz, 1H), 6.85-6.99 (m, 1H), 7.33-
1H), 6.93 (d, J = 8.5 Hz, 1H), 7.18-7.39 (m, 1H), 7.57-7.69 (m, 7.46 (m, 1H), 7.47-7.62 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
1H); 13C NMR (75 MHz, CDCl3) δ 14.3, 31.6, 34.5, 44.3, 60.6, 14.2, 44.0, 61.1, 61.2, 102.9, 120.9, 124.4, 125.3, 125.4, 132.7,
61.0, 109.4, 121.8, 123.3, 123.5, 126.4, 135.1, 138.7, 146.2, 134.5, 139.0, 155.2, 162.4; HRMS (ESI-TOF) Calcd. for
155.5, 162.7; HRMS (ESI-TOF) Calcd. for C18H21NNaO5 [M+Na]+: C14H12BrNNaO5 [M+Na]+: 375.9791; found: 375.9783.
354.1312; found: 354.1308.
Ethyl 3a-nitro-7-phenyl-3a,8b-dihydro-3H-cyclopenta[b]benz
Ethyl 5-methoxy-3a-nitro-3a,8b-dihydro-3H-cyclopenta[b]ben
zofuran-1-carboxylate (3o). yellow solid; 82% yield (50.3 mg);
ofuran-1-carboxylate (3i). yellow oil; 85% yield (59.8 mg); H m.p. 98.1-98.3 oC; 1H NMR (300 MHz, CDCl3) δ 1.32 (td, J = 7.1,
NMR (300 MHz, CDCl3) δ 1.34 (t, J = 7.1 Hz, 3H), 3.27-3.45 (m, 0.9 Hz, 3H), 3.29-3.47 (m, 1H), 3.75 (ddd, J = 19.7, 2.5, 1.2 Hz,
1H), 3.71-3.84 (m, 1H), 4.18-4.37 (m, 2H), 5.20 (s, 1H), 6.78 (q, 1H), 4.13-4.36 (m, 2H), 5.12 (s, 1H), 6.64-6.81 (m, 1H), 6.85 (d,
J = 2.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.29-7.37 (m, 1H), 7.38- J = 8.2 Hz, 1H), 6.88-7.04 (m, 1H), 7.10-7.22 (m, 1H); 13C NMR
7.46 (m, 2H), 7.47-7.58 (m, 3H), 7.79-7.90 (m, 1H); 13C NMR (75 (75 MHz, CDCl3) δ 14.1, 44.0, 56.2, 60.9, 61.0, 112.8, 118.1,
MHz, CDCl3) δ 1.0, 14.2, 44.2, 60.5, 61.1 110.4, 111.8, 121.8, 121.6, 123.7, 125.2, 134.8, 138.8, 144.2, 146.1, 162.5; HRMS
124.6, 125.2, 126.9, 127.0, 128.6, 128.7, 134.9, 136.7, 138.7, (ESI-TOF) Calcd. for C15H15NNaO6 [M+Na]+: 328.0792; found:
140.5, 157.3, 162.6; HRMS (ESI-TOF) Calcd. for C20H17NNaO5 328.0785.
1
[M+Na]+: 374.0999; found: 374.1000.
Ethyl 6-bromo-3a-nitro-3a,8b-dihydro-3H-cyclopenta[b]benzo ofuran-1-carboxylate (3p). yellow oil; 83% yield (53.2 mg); H
Ethyl 5-ethoxy-3a-nitro-3a,8b-dihydro-3H-cyclopenta[b]benz
1
1
furan-1-carboxylate (3j). yellow oil; 84% yield (59.8 mg); H NMR (300 MHz, CDCl3) δ 1.33 (t, J = 7.1 Hz, 3H), 1.44 (t, J = 7.0
NMR (300 MHz, CDCl3) δ 1.33 (t, J = 7.2 Hz, 3H), 3.31 (ddd, J = Hz, 3H), 3.39 (ddd, J = 19.7, 2.7, 1.7 Hz, 1H), 3.76 (ddd, J = 19.7,
19.7, 2.7, 1.7 Hz, 1H), 3.75 (ddd, J = 19.7, 2.5, 1.1 Hz, 1H), 4.11- 2.5, 1.2 Hz, 1H), 4.09-4.21 (m, 2H), 4.21-4.34 (m, 2H), 5.11 (s,
4.40 (m, 2H), 5.05 (s, 1H), 6.75 (q, J = 2.4 Hz, 1H), 7.04-7.23 (m, 1H), 6.74 (q, J = 2.4 Hz, 1H), 6.82-6.89 (m, 1H), 6.89-6.98 (m,
2H), 7.33-7.50 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 14.2, 44.0, 1H), 7.09-7.21 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 14.1, 14.8,
60.0, 61.2, 114.0, 121.7, 122.7, 123.2, 126.2, 127.5, 134.5, 44.0, 60.9, 61.0, 64.9, 114.5, 118.2, 121.6, 123.7, 125.3, 134.8,
138.8, 158.5, 162.4; HRMS (ESI-TOF) Calcd. for C14H12BrNNaO5 138.8, 143.5, 146.5, 162.6; HRMS (ESI-TOF) Calcd. for
[M+Na]+: 375.9791; found: 375.9778.
C16H17NNaO6 [M+Na]+: 342.0948; found: 342.0943.
Ethyl 6-methyl-3a-nitro-3a,8b-dihydro-3H-cyclopenta[b]benz Ethyl 3a-nitro-5-phenyl-3a,8b-dihydro-3H-cyclopenta[b]benz
1
1
ofuran-1-carboxylate (3k). yellow oil; 85% yield (48.5 mg); H ofuran-1-carboxylate (3q). yellow oil; 84% yield (58.7 mg); H
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
Journal Name
ARTICLE
NMR (300 MHz, CDCl3) δ 1.36 (t, J = 7.1 Hz, 3H), 3.22-3.43 (m, Ethyl 7-chloro-3a-nitro-3a,8b-dihydro-3H-benzo[Vbie]wcyAcrtlioclepOennlitnae
1H), 3.68-3.84 (m, 1H), 4.21-4.41 (m, 2H), 5.19 (s, 1H), 6.75 (q, [d]thiophene-1-carboxylate (5b). yellowDoOilI;: 1802.1%03y9i/eCl9dO(B40007m75gJ);
J = 2.4 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.34-7.44 (m, 2H), 7.44- 1H NMR (400 MHz, CDCl3) δ 1.34 (t, J = 7.1 Hz, 3H), 3.42 (dt, J =
7.52 (m, 2H), 7.55-7.62 (m, 1H), 7.74-7.87 (m, 2H); 13C NMR (75 19.4, 2.3 Hz, 1H), 3.59 (dt, J = 19.4, 2.1 Hz, 1H), 4.14-4.37 (m,
MHz, CDCl3) δ 14.2, 44.1, 60.5, 61.1, 121.4, 123.6, 124.6, 124.7, 2H), 5.49 (d, J = 2.1 Hz, 1H), 6.72 (q, J = 2.5 Hz, 1H), 7.03 (d, J =
125.4, 127.6, 128.5, 129.6, 134.8, 135.9, 138.8, 154.8, 162.6; 8.3 Hz, 1H), 7.18-7.25 (m, 1H), 7.65-7.76 (m, 1H); 13C NMR (101
HRMS (ESI-TOF) Calcd. for C20H17NNaO5 [M+Na]+: 374.0999; MHz, CDCl3) δ 14.1, 44.3, 61.2, 62.9, 107.9, 121.7, 128.1, 129.0,
found: 374.0999.
131.6, 133.9, 135.7, 136.8, 138.3, 162.8; HRMS (ESI-TOF) Calcd.
Ethyl 8-chloro-3a-nitro-3a,8b-dihydro-3H-cyclopenta[b]benzo for C14H12ClNNaO4S [M+Na]+: 348.0068; found: 348.0080.
1
furan-1-carboxylate (3r). yellow oil; 40% yield (24.9 mg); H Ethyl 7-methyl-3a-nitro-3a,8b-dihydro-3H-benzo[b]cyclopean
NMR (300 MHz, CDCl3) δ 1.30 (t, J = 7.1 Hz, 3H), 3.31 (ddd, J = ta[d]thiophene-1-carboxylate (5c). yellow oil; 79% yield (36.0
19.0, 2.8, 1.5 Hz, 1H), 3.67 (ddd, J = 19.0, 2.4, 1.3 Hz, 1H), 4.15- mg); 1H NMR (400 MHz, CDCl3) δ 1.32 (t, J = 7.1 Hz, 3H), 2.32 (s,
4.34 (m, 2H), 5.22 (d, J = 1.7 Hz, 1H), 6.72 (q, J = 2.4 Hz, 1H), 3H), 3.41 (dt, J = 19.4, 2.3 Hz, 1H), 3.58 (dt, J = 19.3, 2.0 Hz, 1H),
6.90-6.97 (m, 1H), 7.02 (dd, J = 8.1, 0.9 Hz, 1H), 7.16-7.24 (m, 4.12-4.34 (m, 2H), 5.49 (d, J = 2.1 Hz, 1H), 6.68 (q, J = 2.4 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 14.1, 42.5, 59.4, 61.2, 109.0, 1H), 6.97-7.07 (m, 2H), 7.47-7.60 (m, 1H); 13C NMR (101 MHz,
121.5, 122.6, 124.5, 130.8, 131.8, 134.7, 138.6, 158.9, 163.0; CDCl3) δ 14.1, 21.1, 44.4, 60.9, 63.1, 107.9, 120.5, 128.5, 129.7,
HRMS (ESI-TOF) Calcd. for C14H12ClNNaO5 [M+Na]+: 332.0296; 133.7, 134.5, 135.0, 135.5, 137.8, 163.1; HRMS (ESI-TOF) Calcd.
found: 332.0301.
for C15H15NNaO4S [M+Na]+: 328.0614; found: 328.0620.
Ethyl 5,7-dibromo-3a-nitro-3a,8b-dihydro-3H-cyclopenta[b]b Ethyl 5-methyl-3a-nitro-3a,8b-dihydro-3H-benzo[b]cyclopean
enzofuran-1-carboxylate (3s). yellow solid; 50% yield (43.0 ta[d]thiophene-1-carboxylate (5d). yellow solid; 83% yield
mg); 172.5-173.2 oC; 1H NMR (300 MHz, CDCl3) δ 1.35 (t, J = 7.1 (38.0 mg); 82.1-82.4 oC; 1H NMR (400 MHz, CDCl3) δ 1.31 (t, J =
Hz, 3H), 3.41 (ddd, J = 19.8, 2.7, 1.7 Hz, 1H), 3.80 (ddd, J = 19.9, 7.1 Hz, 3H), 2.21 (s, 3H), 3.46 (dt, J = 19.4, 2.3 Hz, 1H), 3.61 (dt,
2.5, 1.2 Hz, 1H), 4.15-4.43 (m, 2H), 5.15 (s, 1H), 6.79 (q, J = 2.4 J = 19.4, 2.1 Hz, 1H), 4.06-4.34 (m, 2H), 5.59 (d, J = 2.1 Hz, 1H),
Hz, 1H), 7.50-7.60 (m, 1H), 7.61-7.73 (m, 1H); 13C NMR (75 6.67 (q, J = 2.4 Hz, 1H), 6.99-7.16 (m, 2H), 7.47-7.61 (m, 1H);
MHz, CDCl3) δ 14.2, 43.8, 61.0, 61.4, 103.6, 115.6, 121.1, 127.0, 13C NMR (101 MHz, CDCl3) δ 14.1, 20.4, 44.8, 60.9, 63.5, 107.0,
128.6, 134.0, 134.9, 139.4, 154.7, 162.2; HRMS (ESI-TOF) Calcd. 125.0, 126.0, 129.5, 130.6, 134.7, 134.8, 137.0, 137.5, 163.0;
for C14H11Br2NNaO5 [M+Na]+: 453.8896; found: 453.8896.
HRMS (ESI-TOF) Calcd. for C15H15NNaO4S [M+Na]+: 328.0614;
Ethyl 7a-nitro-8,10a-dihydro-7aH-cyclopenta[b]naphtho[1,2- found: 328.0617.
d]furan-10-carboxylate (3t). yellow oil; 51% yield (33.2 mg); 1H Ethyl 3a-nitro-6-phenyl-3a,8b-dihydro-3H-benzo[b]cyclopent
NMR (300 MHz, CDCl3) δ 1.25 (t, J = 7.1 Hz, 3H), 3.42 (ddd, J = a[d]thiophene-1-carboxylate (5e). yellow oil; 80% yield (44.0
1
19.2, 2.8, 1.4 Hz, 1H), 3.74 (ddd, J = 19.1, 2.4, 1.3 Hz, 1H), 4.07- mg); H NMR (400 MHz, CDCl3) δ 1.33 (t, J = 7.1 Hz, 3H), 3.46
4.29 (m, 2H), 5.58 (d, J = 1.7 Hz, 1H), 6.80 (q, J = 2.4 Hz, 1H), (dt, J = 19.4, 2.4 Hz, 1H), 3.64 (dt, J = 19.4, 2.1 Hz, 1H), 4.08-
7.29 (d, J = 8.9 Hz, 1H), 7.32-7.48 (m, 1H), 7.48-7.62 (m, 1H), 4.34 (m, 2H), 5.59 (d, J = 2.1 Hz, 1H), 6.71 (q, J = 2.4 Hz, 1H),
7.74-7.93 (m, 2H), 8.28-8.44 (m, 1H); 13C NMR (75 MHz, CDCl3) 7.33 (d, J = 1.7 Hz, 1H), 7.34-7.39 (m, 2H), 7.40-7.47 (m, 2H),
δ 14.1, 43.1, 59.6, 61.1, 111.6, 116.6, 122.2, 124.2, 125.1, 7.49-7.57 (m, 2H), 7.79 (d, J = 8.0 Hz, 1H); 13C NMR (101 MHz,
126.9, 128.5, 130.2, 130.7, 131.4, 135.4, 139.1, 156.1, 163.4; CDCl3) δ 14.1, 44.5, 61.0, 63.0, 107.9, 119.4, 124.8, 127.0,
HRMS (ESI-TOF) Calcd. for C18H15NNaO5 [M+Na]+: 348.0842; 127.7, 127.9, 128.8, 133.9, 134.4, 137.8, 138.0, 140.0, 142.4,
found: 348.0856.
General experimental procedures for synthesis of found: 368.0935.
compounds 5. To a solution of 2-nitrobenzothiophenes (0.15 General experimental procedures for synthesis of
mmol) in CH2Cl2 (1.5 mL) were added ethyl-2,3-butadienoate compounds 7. To a solution of 3-nitrobenzothiophenes (0.15
2a (0.225 mmol and catalyst Ph2PMe (5.6 uL, 20 mol %). Then mmol) in CH2Cl2 (1.5 mL) were added ethyl-2,3-butadienoate
163.0; HRMS (ESI-TOF) Calcd. for C20H18NO4S [M+H]+: 368.0951;
4
6
)
the mixture was stirred for specific time at 0 oC. After 2a (0.225 mmol
) and catalyst Ph2PMe (5.6 uL, 20 mol %). Then
completion, the reaction mixture was directly purified by flash the mixture was stirred for specific time at 0 oC. After
chromatography on silica gel (petroleum ether/ethyl acetate = completion, the reaction mixture was directly purified by flash
20:1
～
25:1) to give the corresponding product
5
.
chromatography on silica gel (petroleum ether/ethyl acetate =
25:1) to give the corresponding product
Ethyl 3a-nitro-3a,8b-dihydro-3H-benzo[b]cyclopenta[d]thioph 20:1
～
7.
ene-1-carboxylate (5a). yellow oil; 78% yield (34.0 mg); 1H Ethyl 8b-nitro-3a,8b-dihydro-1H-benzo[b]cyclopenta[d]thiop
NMR (300 MHz, CDCl3) δ 1.31 (t, J = 7.1 Hz, 3H), 3.42 (ddd, J = hene-3-carboxylate (7a). yellow oil; 83% yield (36.0 mg); 1H
19.4, 2.8, 1.9 Hz, 1H), 3.61 (ddd, J = 19.4, 2.4, 1.7 Hz, 1H), 4.07- NMR (300 MHz, CDCl3) δ 1.32 (t, J = 7.1 Hz, 3H), 3.44 (ddd, J =
4.38 (m, 2H), 5.55 (d, J = 2.1 Hz, 1H), 6.68 (q, J = 2.4 Hz, 1H), 19.2, 2.8, 2.0 Hz, 1H), 3.89 (ddd, J = 19.2, 2.5, 1.4 Hz, 1H), 4.15-
7.08-7.18 (m, 2H), 7.19-7.26 (m, 1H), 7.63-7.80 (m, 1H); 13C 4.37 (m, 2H), 5.75 (q, J = 1.6 Hz, 1H), 6.62-6.73 (m, 1H), 7.10-
NMR (75 MHz, CDCl3) δ 14.1, 44.5, 61.0, 63.2, 107.6, 120.8, 7.25 (m, 2H), 7.27-7.39 (m, 1H), 7.44-7.56 (m, 1H); 13C NMR
125.6, 127.7, 128.9, 134.5, 134.9, 137.2, 137.7, 163.0; HRMS (75 MHz, CDCl3) δ 14.13, 46.50, 59.33, 61.14, 105.40, 122.57,
(ESI-TOF) Calcd. for C14H13NNaO4S [M+Na]+: 314.0457; found: 125.17, 125.67, 131.59, 135.49, 135.80, 138.24, 142.31, 162.51;
314.0465.
HRMS (ESI-TOF) Calcd. for C14H13NNaO4S [M+Na]+: 314.0457;
found: 314.0458.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
Ethyl 7-fluoro-8b-nitro-3a,8b-dihydro-1H-benzo[b]cyclopenta 1H), 7.45-7.50 (m, 2H), 7.55 (q, J = 1.8 Hz, 1H), 7.56-7.62 (m,
View Article Online
13
DOI: 10.1039/C9OB00775J
[d]thiophene-3-carboxylate (7b). yellow oil; 91% yield (42.1 2H), 7.74 (d, J = 1.9 Hz, 1H); C NMR (101 MHz, CDCl3) δ 14.2,
1
mg); H NMR (300 MHz, CDCl3) δ 1.32 (t, J = 7.1 Hz, 3H), 3.40 46.6, 59.8, 61.3, 105.4, 122.9, 124.3, 126.9, 127.6, 129.0, 130.7,
(ddd, J = 19.2, 2.7, 1.9 Hz, 1H), 3.86 (ddd, J = 19.2, 2.5, 1.4 Hz, 135.5, 136.6, 138.4, 138.9, 139.8, 141.4, 162.6; HRMS (ESI-TOF)
1H), 4.17-4.36 (m, 2H), 5.75-5.85 (m, 1H), 6.64-6.73 (m, 1H), Calcd. for C20H17NNaO4S [M+Na]+: 390.0770; found: 390.0766.
7.01-7.16 (m, 2H), 7.19-7.25 (m, 1H); 13C NMR (75 MHz, CDCl3) Ethyl 4b-nitro-5,7a-dihydro-4bH-cyclopenta[4,5]thieno[2,3-b]
δ 14.1, 46.6, 60.0, 61.2, 105.0 (J = 2.2 Hz), 113.0 (J = 24.1 Hz), pyridine-7-carboxylate (7h). yellow oil;, 83% yield (36.0 mg);
119.3 (J = 23.0 Hz), 123.5 (J = 8.2 Hz), 135.5, 137.1 (J = 7.4 Hz), 1H NMR (400 MHz, CDCl3) δ 1.35 (t, J = 7.1 Hz, 3H), 3.40 (dt, J =
137.3 (J = 2.8 Hz), 138.0, 160.9 (J = 243.4 Hz), 162.4; HRMS 19.2, 2.4 Hz, 1H), 3.89 (ddd, J = 19.2, 2.6, 1.3 Hz, 1H), 4.23-4.37
(ESI-TOF) Calcd. for C14H12FNNaO4S [M+Na]+: 332.0363; found: (m, 2H), 5.81 (q, J = 1.5 Hz, 1H), 6.75 (q, J = 1.0 Hz, 1H), 6.98-
332.0357.
7.23 (m, 1H), 7.79-7.81 (m, 1H), 8.33-8.57 (m, 1H); 13C NMR
Ethyl 7-bromo-8b-nitro-3a,8b-dihydro-1H-benzo[b]cyclopenta (101 MHz, CDCl3) δ 14.2, 47.2, 57.1, 61.4, 102.9, 119.7, 130.1,
[d]thiophene-3-carboxylate (7c). yellow oil; 88% yield (49.1 133.9, 136.0, 138.3, 152.9, 162.3, 165.2; HRMS (ESI-TOF) Calcd.
1
mg); H NMR (300 MHz, CDCl3) δ 1.32 (t, J = 7.1 Hz, 3H), 3.42 for C13H12N2NaO4S [M+Na]+: 315.0410; found: 315.0424.
(ddd, J = 19.2, 2.7, 1.9 Hz, 1H), 3.87 (ddd, J = 19.2, 2.5, 1.4 Hz,
Scale-up experiment. To a solution of 2-nitrobenzofuran
1H), 4.20-4.33 (m, 2H), 5.77 (q, J = 1.6 Hz, 1H), 6.62-6.73 (m, 1a (4.6 mmol, 0.75 g) in CH2Cl2 (46 mL) were added ethyl-2,3-
1H), 7.06 (d, J = 8.4 Hz, 1H), 7.40-7.50 (m, 1H), 7.62 (d, J = 1.9 butadienoate 2a (0.3 mmol, 0.77 g) and catalyst Ph2PMe (184
o
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 14.1, 46.6, 59.9, 61.2, mg, 20 mol %). Then the mixture was stirred for 8 h at 0 C.
104.8, 118.1, 123.9, 128.8, 134.6, 135.3, 137.6, 138.1, 141.6, After completion, the reaction mixture was directly purified by
162.3; HRMS (ESI-TOF) Calcd. for C14H12BrNNaO4S [M+Na]+: flash chromatography on silica gel (petroleum ether/ethyl
391.9563; found: 391.9548.
acetate = 20:1) to give the corresponding product 3a in 81%
Ethyl 7-chloro-8b-nitro-3a,8b-dihydro-1H-benzo[b]cyclopenta yield (1.02 g).
[d]thiophene-3-carboxylate (7d). yellow oil; 98% yield (48.1
mg); H NMR (300 MHz, CDCl3) δ 1.32 (t, J = 7.1 Hz, 3H), 3.41 distilled water (0.2 mL) were added to a test tube. The solution
Synthesis of compound 8. NaIO4 (89 mg, 2 equiv) and
1
(ddd, J = 19.2, 2.8, 2.0 Hz, 1H), 3.87 (ddd, J = 19.2, 2.5, 1.4 Hz, was cooled to 0 oC and RuCl3·3H2O (5.6 mg, 0.1 equiv) was
1H), 4.17-4.35 (m, 2H), 5.78 (d, J = 1.6 Hz, 1H), 6.63-6.74 (m, added. Then EtOAc (0.4 mL) was added. CH3CN (0.8 mL) and a
1H), 7.11 (d, J = 8.4 Hz, 1H), 7.26-7.32 (m, 1H), 7.48 (d, J = 2.1 solution of substrate 3a (55 mg, 0.2 mmol) in EtOAc (0.8 mL)
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 14.1, 46.6, 60.0, 61.3, was added in sequence. After 30 mins, 10% NaHCO3 (2.0 mL)
104.9, 123.5, 125.9, 130.9, 131.8, 135.4, 137.3, 138.1, 140.9, and saturated Na2SO3 solution (6.0 mL) were added. The
162.3; HRMS (ESI-TOF) Calcd. for C14H12ClNNaO4S [M+Na]+: solution was stirred for 10 mins at room temperature. Then it
348.0068; found: 338.0077.
was extracted with EtOAc three times. The combined organic
Ethyl 5-chloro-8b-nitro-3a,8b-dihydro-1H-benzo[b]cyclopenta layers were dried over anhydrous Na2SO4. After filtration, the
[d]thiophene-3-carboxylate (7e). yellow oil; 88% yield (43.0 solution was concentrated under reduced pressure and the
1
mg); H NMR (300 MHz, CDCl3) δ 1.33 (t, J = 7.1 Hz, 3H), 3.42 resulting crude mixture was purified by silica gel column
(ddd, J = 19.3, 2.7, 2.0 Hz, 1H), 3.90 (ddd, J = 19.3, 2.5, 1.3 Hz, chromatography (petroleum ether/AcOEt=15:1) to afford
1H), 4.22-4.34 (m, 2H), 5.76 (q, J = 1.7 Hz, 1H), 6.65-6.75 (m, compound 8.
1H), 7.12 (t, J = 7.9 Hz, 1H), 7.33 (dd, J = 7.9, 1.1 Hz, 1H), 7.40 Ethyl 1,2-dihydroxy-3a-nitro-2,3,3a,8b-tetrahydro-1H-cyclope
(dd, J = 7.8, 1.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 14.1, 46.8, nta[b]benzofuran-1-carboxylate (8). yellow oil; 49% yield
1
59.0, 61.3, 106.1, 123.8, 126.6, 128.1, 131.3, 135.5, 137.3, (30.0 mg); H NMR (400 MHz, CDCl3) δ 1.44 (t, J = 7.1 Hz, 3H),
138.4, 142.5, 162.3; HRMS (ESI-TOF) Calcd. for C14H12ClNNaO4S 2.50 (dd, J = 14.4, 10.6 Hz, 1H), 2.75 (d, J = 10.3 Hz, 1H), 3.16
[M+Na]+: 348.0068; found: 338.0059.
(dd, J = 14.3, 7.5 Hz, 1H), 3.42 (s, 1H), 4.33-4.58 (m, 3H), 5.05
Ethyl 7-methyl-8b-nitro-3a,8b-dihydro-1H-benzo[b]cyclopent (q, J = 9.3 Hz, 1H), 6.98-7.17 (m, 3H), 7.31-7.49 (m, 1H); 13C
a[d]thiophene-3-carboxylate (7f). yellow solid; 88% yield (40.0 NMR (101 MHz, CDCl3) δ 14.2, 42.8, 60.8, 63.4, 77.3, 81.7,
1
mg); m.p. 93.5-94.1 oC; H NMR (300 MHz, CDCl3) δ 1.32 (t, J = 110.7, 119.3, 120.6, 123.1, 124.7, 130.4, 159.9, 171.8; HRMS
7.1 Hz, 3H), 2.32 (s, 3H), 3.31-3.52 (m, 1H), 3.81-3.95 (m, 1H), (ESI-TOF) Calcd. for C14H15NNaO7 [M+Na]+: 332.0741; found:
4.18-4.33 (m, 2H), 5.74 (q, J = 1.7 Hz, 1H), 6.61-6.72 (m, 1H), 332.0743.
7.07 (d, J = 8.0 Hz, 1H), 7.11-7.16 (m, 1H), 7.27-7.31 (m, 1H);
Synthesis of compound 9. To compound 3a (110 mg, 0.4
13C NMR (75 MHz, CDCl3) δ 14.1, 20.9, 46.3, 59.6, 61.1, 105.5, mmol) in 4 mL of anhydrous THF was added DIBAL-H (170.4 mg,
o
122.3, 126.0, 132.6, 135.2, 135.5, 135.9, 138.2, 138.8, 162.6; 3.0 equiv) at 0 C. After being stirred at room temperature for
HRMS (ESI-TOF) Calcd. for C15H15NNaO4S [M+Na]+: 328.0614; 3 h, water (4 mL) was added to the reaction mixture and the
found: 328.0600.
aqueous layer was extracted with AcOEt. (6 mL × 3). The
Ethyl 8b-nitro-7-phenyl-3a,8b-dihydro-1H-benzo[b]cyclopent combined organic layers were dried over anhydrous Na2SO4.
a[d]thiophene-3-carboxylate (7g). yellow solid; 81% yield After filtration, the solution was concentrated under reduced
o
1
(45.1 mg); m.p. 112.8-113.1 C; H NMR (400 MHz, CDCl3) δ pressure and the resulting crude mixture was purified by silica
1.37 (t, J = 7.1 Hz, 3H), 3.54 (ddd, J = 19.2, 2.8, 2.0 Hz, 1H), 3.96 gel column chromatography (petroleum ether/AcOEt=4:1) to
(ddd, J = 19.2, 2.5, 1.4 Hz, 1H), 4.26-4.36 (m, 2H), 5.85 (q, J = afford compound 9.
1.7 Hz, 1H), 6.68-6.79 (m, 1H), 7.27-7.31 (m, 1H), 7.36-7.42 (m,
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
3
(a) B. Biolatto, M. Kneeteman, E. Paredes and P. M. E.
(3a-nitro-3a,8b-dihydro-3H-cyclopenta[b]benzofuran-1-yl)me
thanol (9). yellow oil 77% yield (71.5 mg); H NMR (300 MHz,
View Article Online
1
Mancini, J. Org. Chem., 2001, 66, 390D6O; I(:b1)0.I1.0C39h/aCt9aOigBn0e0r7,75CJ.
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CDCl3) δ 2.18 (s, 1H), 3.08-3.27 (m, 1H), 3.47-3.66 (m, 1H),
4.13-4.40 (m, 2H), 4.93 (s, 1H), 5.64 (q, J = 1.9 Hz, 1H), 6.94-
7.15 (m, 2H), 7.21-7.37 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
43.6, 59.2, 60.9, 110.5, 122.2, 122.4, 122.9, 124.0, 124.5, 129.3,
141.7, 157.6; HRMS (ESI-TOF) Calcd. for C12H11NNaO4 [M+Na]+:
256.0580; found: 256.0568.
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Conflicts of interest
There are no conflicts to declare.
and L. M. Stanley, Org. Chem. Front., 2016, 3, 339; (k) Y. Li, F.
Tur, R. P. Nielsen, H. Jiang, F. Jensen and K. A. Jørgensen,
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Babu, B. S. Simethy, G. Das, V. K. Praveen, S. Varughese and J.
John, J. Org. Chem., 2017, 82, 10537; (p) J.-Q. Zhang, F. Tong,
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A.Ying, H. Mo, D. Chen, G. Chen, Z. Wang and J. Yang, J. Org.
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The studies of our group about 3-nitroindoles, see: (a) J.-Q.
Zhao, M.-Q. Zhou, Z.-J. Wu, Z.-H. Wang, D.-F. Yue, X.-Y. Xu,
X.-M. Zhang and W.-C. Yuan, Org. Lett., 2015, 17, 2238; (b) J.-
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Yuan, Org. Lett., 2015, 17, 5020; (c) D.-F. Yue, J.-Q. Zhao, X.-Z.
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Acknowledgements
We are grateful for financial support from the National
NSFC (21572223, 21572224 and 21871252), Sichuan Youth
Science and Technology Foundation (2016JQ0024) and the
Start-up Fund of Chengdu University (2081916044)
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Organic & Biomolecular Chemistry
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(3o
)
contains
the
supplementary
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10 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C9OB00775J
Phosphine-Catalyzed Dearomative (3+2) Annulation of
2-Nitrobenzofurans and Nitrobenzothiophenes with allenoate
Jian-Qiang Zhao, Lei Yang, Yong You, Zhen-Hua Wang, Ke-Xin Xie, Xiao-Mei Zhang, Xiao-Ying Xu and
Wei-Cheng Yuan
An
efficient
Ph2PMe-catalyzed
dearomative
(3+2)
annulation
of
2-nitrobenzofurans,
2-nitrobenzothiophenes, and 3-nitrobenzothiophenes with allenoate was reported.