Synthesis of N-Heterocycles by Reductive Cyclization of Nitroalkenes Using Molybdenum Hexacarbonyl as Carbon Monoxide Surrogate

Article abstract of DOI:10.1002/ejoc.202000580

The development of a method that uses molybdenum hexacarbonyl [Mo(CO)₆] as carbon monoxide (CO) surrogate for the palladium-catalyzed reductive cyclization of nitroalkenes into indoles or thienopyrroles is reported. Several types of nitroalkenes could be transformed into the desired products in excellent yields and in most cases with complete regioselectivities and higher yields than those previously reported with palladium/CO system.

Full text of DOI:10.1002/ejoc.202000580

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Synthesis of N-Heterocycles by Reductive Cyclization of
Nitroalkenes using Molybdenum Hexacarbonyl as Carbon
Monoxide Surrogate
Authors: Zhiyou Su, Bo Liu, Hongze Liao, and Hou-Wen Lin
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000580
Link to VoR: https://doi.org/10.1002/ejoc.202000580
01/2020

10.1002/ejoc.202000580
European Journal of Organic Chemistry
FULL PAPER
Synthesis of N-Heterocycles by Reductive Cyclization of
Nitroalkenes using Molybdenum Hexacarbonyl as Carbon
Monoxide Surrogate
Zhiyou Su+, Bo Liu+, Hongze Liao,* and Hou-Wen Lin*
Z. Su, B. Liu, Dr. H. Liao, Prof. Dr. H.-W. Lin
Research Center for Marine Drugs, State Key Laboratory of Oncogene and Related Genes,
Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
E-mail: franklin67@126.com；lhzseed@live.com
http://daoshi.shsmu.edu.cn/Pages/TeacherInformationView.aspx?uid=E0D919F8-C3F6-4B21-B5A8-3DA58DFB0A7C&from=s&pId=&tId=721
[+] These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
Abstract: The development of a method that uses molybdenum
hexacarbonyl [Mo(CO)6] as carbon monoxide (CO) surrogate for the
palladium-catalyzed reductive cyclization of nitroalkenes into indoles
or thienopyrroles is reported. Several types of nitroalkenes could be
transformed into the desired products in excellent yields and in most
case got higher yields and complete regioselectivities than those
previously reported with palladium/CO system.
the preparation of the starting substrates with two ortho-
substituted functional partners become the common limit to this
synthetic strategy. The direct catalytic deoxygenative cyclization
of nitroalkene has emerged as an attractive strategy for indole
synthesis, the pioneered elegant studies in this field by using CO
as stoichiometric reductant have been reported by Dong and
Ragaini’s group (Scheme 1).[6] Herein, we present a method for
the palladium-catalyzed synthesis of N-heterocycles from
nitroalkenes using Mo(CO)6 as the reductant.
Introduction
Results and Discussion
N-heterocycles are widely distributed in a broad range of
products, including natural alkaloids or bioactive pharmaceuticals,
ligands and functional materials.[1] Pyrrole-fused aromatic rings
are central to many natural and synthetic products that exhibit
biological and therapeutic activities.[2] Accordingly, numerous N-
heterocycles constructing methods have been developed in the
past decades,[3] especially the research about catalytic reductive
cyclization of nitroarenes by using CO as reductant.[4] However,
The nitroalkene 1a was easily prepared from benzaldehyde via
Wittig reaction and nitration, and initially investigated the
reductant cyclization in the presence of transition-metal catalysts
and reductants. At the outset, when substrate 1a was treated with
Pd(CH3CN)2Cl2, Mo(CO)6 and phenanathroline (phen) in 1,2-
dichloroethan (DCE), the indole 2a was obtained in 68% yield
(Table 1, entry 1). Different reductants were investigated and it
was found that other carbonyl complexes and phenyl formate
could also promote this reaction but gave lower yield (Table 1,
entries 2-4), which indicated that Mo(CO)6 did not act only as CO
surrogate. Inspired by these initial results, we further screened
different palladium sources and ligands. It was found that the
reaction catalyzed by Pd(OAc)2 gave better yield than those
catalyzed
by
Pd(CH3CN)2Cl2,
[Pd(CH3CN)4][BF4]2 and
Pd(dppf)Cl2 (Table 1, entries 5-7), and tmphen was less suitable
for this reaction than phen (Table 1, entry 8). Solvent screening
showed DCE was the optimal solvent for this reaction (Table 1,
o
entries 9, 10). Increasing the temperature to 140 C or reducing
the catalyst loading (5% mol palladium, 10% mol ligand) were
proved to be less detrimental for the reaction (Table 1, entries 11,
12).
With the optimal condition in hand, the scope of the reductive
cyclization was explored. The β, β-diaryl nitroalkenes, which were
synthesized from corresponding substituted benzophenones via
cascade Wittig reaction/nitrification were first investigated and
excellent yields were observed in most cases (Table 2).
Interestingly, the diaryl nitroalkenes with either electron-donating
or electron-withdrawing substituents in the para position of aryl
ring gave higher yields (Table 2, entries 2-4), despite the
substrate 1d required longer reaction time. It’s notable that
substrates bearing amino and carboxyl group could not get the
Scheme 1. Reported and current work on palladium-catalyzed
reductive cyclization.
the widespread of this method is limited by the requirement of
safety measures for pressurized CO. Recently, much attention
has been paid to the use of CO surrogates and it was reported
that Mo(CO)6 could trigger this transformation in combination with
palladium catalysts.[4j, 5] Nonetheless, several synthetic steps for
1
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10.1002/ejoc.202000580
European Journal of Organic Chemistry
FULL PAPER
Table 1. Optimization of palladium-catalyzed reductive cyclization[a]
Table 2. Palladium-catalyzed reductive cyclization of β, β-diaryl nitroalkenes:
Reaction scope and limitations [a]
Entry
Reductant
Mo(CO)6
Cr(CO)6
Catalyst/Ligand
Pd(CH3CN)2Cl2/phen
Pd(CH3CN)2Cl2/phen
Pd(CH3CN)2Cl2/phen
Pd(CH3CN)2Cl2/phen
Pd(dppf)Cl2/phen
Solvent
DCE
DCE
DCE
DCE
DCE
Yield[d]
68
%
Entry
1
Substrate
Product
Yield[d]
%
1
2
3
4
5
42
80
W(CO)6
34
HCOOPh
Mo(CO)6
43
44
[Pd(Phen)2][BF4]2/
phen
6
Mo(CO)6
DCE
DCE
47
7
8
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Pd(OAc)2/ phen
Pd(OAc)2/tmphen
Pd(OAc)2/ phen
Pd(OAc)2/ phen
Pd(OAc)2/ phen
Pd(OAc)2/ phen
80
72
62
35
74
63
2
3
83
81
85
DMF
CH3CN
9
10
11[b]
12[c]
toluene
DCE
DCE
[a] Reaction conditions: 1a (0.1 mmol), Reductant (0.1 mmol), Pd catalyst (10
mol %), Ligand (20 mol %), solvent (2 mL), 120 oC, 4h; [b] The reaction was
carried out at 140 oC; [c] 5 mol % Pd(OAc)2, 10 mol % phen used; [d] isolated
yield.
corresponding products due to their strong activity in this catalytic
system (Table 2, entries 5, 6). Moreover, the α-H substituted
substrates 1g-1i with lower degree of conjugation of the π system
were also not stable and decomposed under the optimized
condition (Table 2, entries 7-9).
4[b]
Subsequently, the β-phenyl-α-alkyl nitroalkenes, which could
be easily prepared from aldehyde through Henry reaction, were
tested for this reaction (Table 3). To our delight, it was found that
this type of substrates also transformed into the desired products
with medium to good yields. The decrease in yield is due to the
lower reduction potential owing to the less extended system in this
type substrates (Table 3, entries 1-4). Both electron-withdrawing
and electron-donating groups could be present in the para
position of aryl ring and got the similar yields. The similar inactivity
of substrate with carboxyl group were observed (Table 3, entry 6).
It is notable that the cyclization of 3e, which contains a methoxyl
substituent in meta position of phenyl ring, may in principle take
place by activation of C-H bond at 2- or 4- position. Remarkably,
the cyclization was selective towards the 2-position and it could
be interpreted as partial coordination of the product to the metal
center (Table 3, entry 5).[7]
To further examine the substrate scope of this reaction, the
cyclization of β-thiopenyl-α-alkyl nitroalkenes to thienopyrroles
were studied (Table 3, entries 7-10). Similarly to the result of
indole synthesis, the desired products were obtained through
reductive cyclization under the optimized conditions in good yields.
The presence of substituted groups at the alkene or thiophene
ring did not affect the reactivity (Table 3, entries 8, 9). It should be
noted that the good result was obtained from substrate 3j with
good yield and complete regio selectivity, which could be ascribed
to the electrophilic cyclization process of the nitroso intermediate,
and attack on the electron rich 2-position of the thiophene ring
should be favored (Table 3, entry 10).
5
n.d.[c]
6
n.d.[c]
7
8
n.d.[c]
n.d.[c]
9
n.d.[c]
[a] Reaction conditions: 1 (0.1 mmol), Mo(CO)6 (0.1 mmol), Pd(OAc)2 (10
mol %), Phen (20 mol %), DCE (2 mL), 120 oC, 4h; [b] The reaction was
conducted for 12 h; [c] Not detected by GC-MS. [d] isolated yield.
In addition, a series of more complicated substrates were
rationally designed to study the regioselectivity of this type of
conditions, the amination of carbon-hydrogen bond was observed
only at the β position of the naphthalene ring, which indicated this
electrophilic substitution occurring under thermodynamic control
reaction.
As
seen
from
Table
4,
(E)-2-(2-nitro-
alkenyl)naphthalene 5a, 5b were subjected to the optimal
2
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10.1002/ejoc.202000580
European Journal of Organic Chemistry
FULL PAPER
(Table 4, entries 1, 2).[8] In the case of (E)-1-(2-nitro-
alkenyl)naphthalene 5c, the complete β selectivity was also
obtained and the benzo[de]quinoline skeleton was not detected
(Table 4, entry 3).[9]
underwent the reductive cyclization in the five-membered ring
manner (Table 5). Even for the reaction of substrate 7b (Table 5,
entry 2), containing two electron-donating methoxyl groups on the
isoquinoline ring and no substituent group on the phenyl ring,
furnished the N- biheteroarenes 8b in excellent yield and the
benzo[de]naphthyridine 8b’ was not detected. To rationalize the
Table 4. Palladium-catalyzed reductive cyclization of nitroalkenyl
naphthalenes[a]
Table 3. Palladium-catalyzed reductive cyclization of β-phenyl-α-alkyl
nitroalkenes: Reaction scope and limitations [a]
Entry
1
Substrate
Product
Yield[b]
72
%
2
63
Entry
1
Substrate
Product
Yield[b]
73
%
3
4
67
70
-
5
63
70
n.d.[c]
78
2
6
7
-
78
-
8
68
3
9
76
10
63
[a] Reaction conditions: 5 (0.1 mmol), Mo(CO)6 (0.1 mmol), Pd(OAc)2 (10
mol %), Phen (20 mol %), DCE (2 mL), 120 oC, 4h; [b] isolated yield.
[a] Reaction conditions: 3 (0.1 mmol), Mo(CO)6 (0.1 mmol), Pd(OAc)2 (10
mol %), Phen (20 mol %), DCE (2 mL), 120 oC, 4h; [b] isolated yield. [c] Not
detected by GC-MS.
observed regioselectivity of this reaction, density functional theory
(DFT) calculations were conducted. The distribution of Mulliken
atomic charge[11] from 7b showed much lower electronic density
on carbon 8 (0.087) of the isoquiloine ring than on carbon 2’ (-
0.063) and carbon 6’ (-0.299) of the phenyl ring when calculated
To explore whether five- or six-membered ring-closure is
favored in this reaction, (E)-1-(2-nitro-1-phenylvinyl)isoquinoline 7,
Scheme 2. Mulliken atomic charge distribution for 7b.
prepared through successive Bischer-Napieralski reaction and
one-step oxidation,[10] were evaluated under the optimized
conditions. To our surprise, this type diaryl nitroalkenes were all
transformed into isoquinoline-indole linked N-biheteroarenes 8
Scheme 3. Proposed reaction mechanism for the reductive cyclization of
nitroalkene.
3
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10.1002/ejoc.202000580
European Journal of Organic Chemistry
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using Gaussain 09 at B3LYP/6-31G+(d, p) level of theory Conclusion
(Scheme 2),[12] which suggested that the electrophilic cyclization
of the intermediate was favored at the phenyl ring.
In summary, we have developed an efficient and convenient
method for the preparation of N-heterocycles from nitroalkenes by
using Mo(CO)6 as CO surrogates. The increased operability by
avoiding the use of hazardous pressurized CO and concise
synthetic approach for substrates offered more application in
future studies. In most cases, the desired products could be
obtained with higher regioselectivities and yields than those
previously reported by using palladium/CO system. In addition,
the potential of employing this method to achieve the bioactive N-
biheteroarenes was also studied. Further efforts for mechanism
studies and pharmaceutical applications of this chemistry are
currently ongoing in our laboratories.
By analogy with the mechanism that previously proposed for
the reductive cyclization of nitroalkenes with carbon monoxide as
the reductant,[6b] we proposed the following mechanism: Firstly
Table 5. Palladium-catalyzed reductive cyclization of (2-nitro-1-
phenylvinyl)isoquinoline [a]
Experimental Section
Entry
1
Substrate
Product
Yield[b]
%
General information: Unless otherwise stated, all the reactions
were performed under nitrogen atmosphere. All reagents and
solvents were purchased commercially (Alfa Asear, Strem, Merck
and Sigma-Aldrich) and used as received. Evaporation of organic
solvent was achieved by rotary evaporation with a water bath
temperature below 36 °C. Thin layer chromatography (TLC) with
Merck TLC silica gel 60 F254 plate was used to check reaction
progress under the UV light at 254 nm. Flash column
chromatography with silica gel 60 (0.010-0.063 mm) was used for
76
2
73
1
product purification. H and 13C NMR spectra were obtained by
600 MHz Bruker Ascend 600 spectrometer. Tetramethylsilane
(TMS) was used as the internal standard for the measurement of
chemical shifts (δ) in ppm. Chemical shifts are reported in ppm
1
(δ). NMR experiments were run in CDCl3 as indicated, H NMR
3
4
78
81
spectra are referenced to the resonance from residual CHCl3 at
7.26 ppm. 13C NMR spectra are referenced to the central peak in
1
the signal from CDCl3 at 77.0 ppm. The multiplicities of H NMR
resonances are expressed by abbreviations: br s (broad singlet),
s (singlet), d (doublet), t (triplet), quartet (q), m (multiplet) and
combinations thereof for highly coupled systems. 13C NMR
spectra were run as proton decoupled experiments. H and 13C
1
signals where appropriate are described by chemical shift δ
(multiplicity, J (Hz), integration). HRMS (ESI) spectra were
obtained using a Waters Q-Tof premierTM mass spectrometer.
the palladium CO complex A is generated through the reduction
of Pd(OAc)2 by Mo(CO)6, which reacts with the nitroalkene
underwent single-electron transfer to lead the formation of radical
anion B. Reduction of intermediate B by CO/Mo(CO)6 affords the
nitroso intermediate C, which plays the role of aminating species
to form the N-hydroxy heterocycle D. Eventually, the palladium
catalyzed reduction of D by a second equivalent of CO forms the
desired N- heterocycle product (Scheme 3). To confirm this
mechanism, N-hydroxy heterocycle 9 was synthesized and
subjected to the optimized conditions, and the expected product
10 was obtained in 72.3% yield (Scheme 4).
General Procedure for Synthesis of N-Heterocycles.In an
oven-dried tube (15ml), Pd(OAc)2 (10 mol%), 1,10
-
phenanthroline (phen) (20 mol%) and Mo(CO)6 (0.1 mmol) was
added. Then under the nitrogen atmosphere, the nitroalkene(0.1
mmol) dissolved in the DCE (2 ml) was added using laboratory
syringe. Then the tube was heated in 120 °C for 2h with the
monitoring of TLC. The reaction was cooled to room temperature
and concentrated in vacuo to give the crude residue. The crude
reaction mixture was purified with silica gel column
chromatography with petroleum ether/ ethyl acetate as the eluent
to get the indole.
2, 2-diphenyl-1-nitroethylene (1a). 1H NMR (600 MHz,
Chloroform-d) δ 7.48 – 7.41 (m, 5H), 7.39 (t, J = 7.7 Hz, 2H), 7.31
– 7.27 (m, 2H), 7.23 (dd, J = 7.7, 1.6 Hz, 2H). 13C NMR (151 MHz,
Scheme 4. Reduction of N-hydroxy heterocycle 9.
4
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10.1002/ejoc.202000580
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Chloroform-d) δ 150.4, 137.0, 135.5, 134.4, 130.9, 129.3, 128.9
(2C), 128.8 (2C), 128.8 (2C), 128.5 (2C).
(E)- 2- thiophenyl-1-methyl-1-nitroethylene (3g). 1H NMR (600
MHz, Chloroform-d) δ 8.29 (s, 1H), 7.64 (d, J = 5.0 Hz, 1H), 7.43
(s, 1H), 7.19 (s, 1H), 2.55 (s, 3H). 13C NMR (151 MHz,
Chloroform-d) δ 144.3 , 135.1 , 134.7 , 131.7 , 128.1 , 127.2 , 14.2 .
2, 2-di(4-methylphenyl)-1-nitroethylene (1b). 1H NMR (600
MHz, Chloroform-d) δ 7.41 (s, 1H), 7.24 (d, J = 7.8 Hz, 2H), 7.19
(s, 4H), 7.12 (d, J = 7.7 Hz, 2H), 2.42 (s, 3H), 2.40 (s, 3H). 13C
NMR (151 MHz, Chloroform-d) δ 150.9, 141.4, 139.4, 134.5,
(E)- 2- (2-methyl-thiophenyl)-1-ethyl-1-nitroethylene (3h). 1H
NMR (600 MHz, Chloroform-d) δ 8.17 (s, 1H), 7.24 (d, J = 3.6 Hz,
133.5, 132.7, 129.5 (2C), 129.1 (2C), 129.0 (2C), 128.9 (2C), 21.4, 1H), 6.88 – 6.81 (m, 1H), 2.98 (q, J = 7.4 Hz, 2H), 2.57 (s, 3H),
21.3.
1.24 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, Chloroform-d) δ
148.5, 147.9, 135.9, 132.6, 127.3, 126.7, 21.3, 15.8, 11.7.
1
2, 2-di(4-methoxyphenyl)-1-nitroethylene (1c). H NMR (600
MHz, Chloroform-d) δ 7.36 (s, 1H), 7.24 (dd, J = 9.3, 2.5 Hz, 2H),
7.16 (dd, J = 9.1, 2.4 Hz, 2H), 6.94 (dd, J = 9.2, 2.4 Hz, 2H), 6.89
(dd, J = 9.4, 2.4 Hz, 2H), 3.86 (s, 3H), 3.84 (s, 3H). 13C NMR (151
MHz, Chloroform-d) δ 162.0, 160.6, 150.8, 132.3, 131.0 (2C),
130.9 (2C), 129.8, 127.7, 114.2 (2C), 113.8 (2C), 55.4, 55.3.
1
(E)-3-(2-nitrobut-1-en-1-yl)thiophene (3i). H NMR (600 MHz,
Chloroform-d) δ 8.02 (s, 1H), 7.61 – 7.58 (m, 1H), 7.44 (dd, J =
5.1, 2.9 Hz, 1H), 7.26 (dd, J = 4.6, 1.6 Hz, 1H), 2.92 (q, J = 7.4
Hz, 2H), 1.28 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, Chloroform-
d) δ 151.6, 133.4, 129.9, 127.8, 127.2, 127.0, 21.0, 12.1.
2, 2-di(4-fluorophenyl)-1-nitroethylene (1d). 1H NMR (600 MHz, (E)- 2- naphthalenyl-1-ethyl-1-nitroethylene (5a). 1H NMR (600
Methylene Chloride-d2) δ 7.43 (s, 1H), 7.32 – 7.28 (m, 2H), 7.26–
7.20 (m, 2H), 7.18 – 7.08 (m, 4H). 13C NMR (151 MHz, Methylene
Chloride-d2) δ 165.7, 164.5, 164.0, 162.9, 148.8, 134.9, 133.5,
133.5, 131.9, 131.8, 131.5 (d, 3 Hz, C-F), 131.4 (d, 3 Hz, C-F),
116.5 (d, 90 Hz, C-F), 116.1 (d, 90 Hz, C-F).
MHz, Chloroform-d) δ 8.19 (s, 1H), 7.95 – 7.85 (m, 4H), 7.60 –
7.53 (m, 2H), 7.51 (dd, J = 8.5, 1.6 Hz, 1H), 2.96 (q, J = 7.4 Hz,
2H), 1.35 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, Chloroform-d)
δ 153.4, 133.6, 133.3, 133.1, 130.3, 129.8, 128.8, 128.5, 127.8,
127.6, 126.9, 126.0, 20.9, 12.6.
(E)- 2- phenyl-1-ethyl-1-nitroethylene (3a). 1H NMR (600 MHz,
Chloroform-d) δ 8.03 (s, 1H), 7.44 (m, 5H), 2.87 (q, J = 7.4 Hz,
2H), 1.28 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, Chloroform-d)
δ 153.3, 133.1, 132.3, 129.9, 129.6 (2C), 129.0 (2C), 20.7, 12.5.
(E)- 2- naphthalenyl-1-methyl-1-nitroethylene (5b). 1H NMR
(600 MHz, Chloroform-d) δ 8.25 (s, 1H), 7.96 – 7.83 (m, 5H), 7.60
– 7.54 (m, 2H), 7.52 (d, J = 8.5 Hz, 1H), 2.55 (s, 3H). 13C NMR
(151 MHz, Chloroform-d) δ 147.8 , 133.7 , 133.6 , 133.0 , 130.5 ,
129.8 , 128.6 , 128.5 , 127.8 , 127.6 , 126.9 , 126.4 , 14.2 .
(E)- 2- (4-methylphenyl)-1-ethyl-1-nitroethylene (3b). 1H NMR
(600 MHz, Chloroform-d) δ 8.00 (s, 1H), 7.33 (d, J = 8.1 Hz, 2H),
7.26 (d, J = 8.0 Hz, 2H), 2.88 (q, J = 7.4 Hz, 2H), 2.40 (s, 3H),
1.28 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, Chloroform-d) δ
152.4, 140.5, 133.2, 129.7 (2C), 129.7 (2C), 21.4, 20.7, 12.4.
(E)-1-(2-nitrobut-1-en-1-yl)naphthalene (5c). 1H NMR (600
MHz, Chloroform-d) δ 8.5 (s, 1H), 8.0 – 7.9 (m, 3H), 7.6 – 7.5 (m,
2H), 7.6 – 7.5 (m, 1H), 7.4 (d, J = 7.1 Hz, 1H), 2.8 (q, J = 7.4 Hz,
2H), 1.2 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, Chloroform-d) δ
154.9, 133.4, 131.5, 131.4, 130.1, 129.8, 128.7, 127.0, 126.6,
126.4, 125.2, 124.1, 20.9, 12.8.
(E)- 2- (4-methoxyphenyl)-1-ethyl-1-nitroethylene (3c). 1H
NMR (600 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.41 (d, J = 8.7 Hz,
2H), 6.98 (d, J = 9 Hz, 2H), 3.86 (s, 3H), 2.89 (q, J = 7.4 Hz, 2H),
1.28 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, Chloroform-d) δ
161.1, 151.2, 133.2, 131.8 (2C), 124.6, 114.5 (2C), 55.4, 20.8,
12.3.
(E)-1-(2-nitro-1-phenylvinyl)isoquinoline (7a). 1H NMR (600
MHz, Chloroform-d) δ 8.63 (dd, J = 5.8, 2.6 Hz, 1H), 7.92 (d, J =
8.1 Hz, 1H), 7.84 (d, J = 2.6 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.76
(d, J = 5.6 Hz, 1H), 7.71 (t, J = 7.5 Hz, 1H), 7.47 – 7.41 (m, 1H),
7.40 – 7.32 (m, 4H). 13C NMR (151 MHz, Chloroform-d) δ 155.5 ,
147.7 , 142.0 , 136.8 , 136.2 , 134.4 , 131.4 , 130.8 , 129.3(2C) ,
128.2 , 128.0(2C) , 127.4 , 126.7 , 125.3 , 121.2 .
1
(E)- 2- (4-fluorophenyl)-1-ethyl-1-nitroethylene (3d). H NMR
(600 MHz, Chloroform-d) δ 7.98 (s, 1H), 7.42 (ddd, J = 8.6, 5.0,
2.4 Hz, 2H), 7.18 – 7.12 (m, 2H), 2.85 (q, J = 7.4 Hz, 2H), 1.27 (t,
J = 7.4 Hz, 3H). 13C NMR (151 MHz, Chloroform-d) δ 164.3, 162.6, (E)-6,7-dimethoxy-1-(2-nitro-1-phenylvinyl)isoquinoline (7b).
153.0, 131.9, 131.7 (d, JC-F =34.2 Hz), 128.4, 128.4, 116.3 (d,
JC-F =27 Hz), 20.6, 12.4.
1H NMR (600 MHz, Chloroform-d) δ 8.48 (d, J = 5.6 Hz, 1H), 7.81
(s, 1H), 7.62 (d, J = 5.7 Hz, 1H), 7.47 – 7.43 (m, 1H), 7.40 – 7.34
(m, 4H), 7.15 (s, 1H), 6.94 (s, 1H), 4.04 (s, 3H), 3.80 (s, 3H). 13C
NMR (151 MHz, Chloroform-d) δ 153.4 , 152.4 , 151.0 , 147.4 ,
140.7 , 136.8 , 134.5 , 133.5 , 131.4 , 129.3(2C) , 128.1(2C) ,
122.6, 120.1 , 105.3 , 103.1 , 77.2 , 56.2 , 55.9 .
(E)- 2- (3-methoxyphenyl)-1-ethyl-1-nitroethylene (3e). 1H
NMR (600 MHz, Chloroform-d) δ 7.98 (s, 1H), 7.37 (t, J = 8.0 Hz,
1H), 7.01 (d, J = 7.6 Hz, 1H), 6.97 (dd, J = 8.3, 2.3 Hz, 1H), 6.94
– 6.92 (m, 1H), 3.84 (s, 3H), 2.87 (q, J = 7.4 Hz, 2H), 1.28 (t, J =
7.4 Hz, 3H). 13C NMR (151 MHz, Chloroform-d) δ 159.8, 153.5,
133.6, 133.0, 130.0, 121.9, 115.4, 115.1, 55.3, 20.8, 12.5.
(E)-6,7-dimethoxy-1-(2-nitro-1-(p-tolyl)vinyl)isoquinoline (7c).
1H NMR (600 MHz, Chloroform-d) δ 8.47 (d, J = 5.6 Hz, 1H), 7.81
(s, 1H), 7.61 (d, J = 5.7 Hz, 1H), 7.25 – 7.20 (m, 2H), 7.19 – 7.13
(m, 3H), 6.93 (s, 1H), 4.04 (s, 3H), 3.80 (s, 3H), 2.35 (s, 3H). 13
C
(E)- 2- thiophenyl-1-ethyl-1-nitroethylene (3f). 1H NMR (600
MHz, Chloroform-d) δ 8.24 (s, 1H), 7.63 (d, J = 5.1 Hz, 1H), 7.42
(d, J = 3.6 Hz, 1H), 7.18 (dd, J = 5.1, 3.7 Hz, 1H), 3.02 (q, J = 7.4
Hz, 2H), 1.27 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, Chloroform-
d) δ 149.9, 134.9, 134.7, 131.7, 128.2, 126.7, 21.4, 11.6.
NMR (151 MHz, Chloroform-d) δ 153.5 , 152.6 , 151.0 , 142.2 ,
140.6 , 136.1 , 133.4 , 131.6 , 130.0(2C) , 128.1(2C) , 122.7 ,
120.0 , 105.3 , 103.2 , 77.2 , 56.2 , 55.9 , 21.4 .
5
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10.1002/ejoc.202000580
European Journal of Organic Chemistry
FULL PAPER
(E)-6,7-dimethoxy-1-(1-(4-methoxyphenyl)-2-nitrovinyl)isoqu
inoline (7d). 1H NMR (600 MHz, Chloroform-d) δ 8.47 (d, J = 5.6
Hz, 1H), 7.81 (s, 1H), 7.61 (d, J = 5.6 Hz, 1H), 7.27 (d, J = 9.0 H
z, 2H), 7.14 (s, 1H), 6.93 (s, 1H), 6.87 (d, J = 9.0 Hz, 2H), 4.04 (s,
3H), 3.81 (s, 6H). 13C NMR (151 MHz, Chloroform-d) δ 162.4 , 1
53.4 , 152.9 , 150.9 , 140.9 , 134.9 , 133.3 , 129.9(2C) , 126.6 , 1
22.7 , 119.9 , 114.8(2C) , 105.3 , 103.2 , 56.2 , 56.0 , 55.5 .
2-ethyl-6-methoxy-1H-indole (4c). 1H NMR (600 MHz,
Chloroform-d) δ 7.76 (s, 1H), 7.40 (d, J = 8.5 Hz, 1H), 6.81 (s, 1H),
6.76 (d, J = 8.5 Hz, 1H), 6.17 (s, 1H), 3.84 (s, 3H), 2.75 (q, J = 7.6
Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H). 13C NMR (151 MHz, Chloroform-
d) δ 155.7 , 140.2 , 136.5 , 123.0 , 120.2 , 109.0 , 98.3 , 94.5 ,
55.7 , 21.4 , 13.2 . HRMS (ESI): calcd. for [M+H]+, 176.0997;
found 176.1078.
2-ethyl-6-fluoro-1H-indole (4d). 1H NMR (600 MHz, Chloroform-
d) δ 7.84 (s, 1H), 7.42 (dd, J = 8.6, 5.4 Hz, 1H), 6.98 (dd, J = 9.6,
2.1 Hz, 1H), 6.87 – 6.82 (m, 1H), 6.21 (s, 1H), 2.77 (q, J = 7.5 Hz,
2H), 1.34 (t, J = 7.6 Hz, 3H). 13C NMR (151 MHz, Chloroform-d)
δ 160.1, 158.5, 141.7 (d, JC-F =3.0 Hz), 135.7 (d, JC-F =12.1 Hz),
125.2, 120.3 (d, JC-F =10.6 Hz), 108.1 (d, JC-F =6.0 Hz), 98.6,
96.8 (d, JC-F =24.7 Hz), 21.4, 13.1. HRMS (ESI): calcd. for
[M+H]+, 164.0797; found 164.0874.
Characterization Data for N-Heterocycles 3-phenylindole (2
a). 1H NMR (600 MHz, Chloroform-d) δ 8.13 (s, 1H), 8.02 (d, J =
7.9 Hz, 1H), 7.73 (d, J = 7.9 Hz, 2H), 7.51 (t, J = 7.5 Hz, 2H), 7.4
3 (d, J = 8.1 Hz, 1H), 7.39 – 7.22 (m, 5H) 13C NMR (151 MHz, C
hloroform-d) δ 136.6, 135.5, 128.7 (2C), 127.4 (2C), 125.9, 125.
7, 122.4, 121.8, 120.3, 119.8, 118.2, 111.4. HRMS (ESI): calcd. f
or [M+H]+, 194.0891; found 194.1038.
6-methyl-3-p-tolylindole (2b). 1H NMR (600 MHz, Chloroform-d)
δ 8.02 (s, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H),
7.31 – 7.25 (m, 3H), 7.21 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 2.51 (s,
3H), 2.43 (s, 3H). 13C NMR (151 MHz, Chloroform-d) δ 137.1,
135.4, 132.7, 132.1, 129.4 (2C), 127.2 (2C), 123.6, 121.9, 120.8,
119.5, 118.0, 111.2, 21.6, 21.1. HRMS (ESI): calcd. for [M+H]+,
222.1204; found 222.1279.
2-ethyl-7-methoxy-1H-indole (4e). 1H NMR (600 MHz,
Chloroform-d) δ 8.10 (s, 1H), 7.14 (d, J = 7.9 Hz, 1H), 6.98 (t, J =
7.8 Hz, 1H), 6.59 (d, J = 7.7 Hz, 1H), 6.22 (d, J = 1.2 Hz, 1H), 3.95
(s, 3H), 2.79 (q, J = 7.6 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H). 13C NMR
(151 MHz, Chloroform-d) δ 145.5, 140.9, 130.0, 126.0, 119.8,
112.7, 101.1, 99.0, 55.3, 21.4, 13.4. HRMS (ESI): calcd. for
[M+H]+, 176.0997; found 176.1079.
6-methoxy-3-(4-methoxyphenyl)-1H-indole (2c). 1H NMR (600
MHz, Chloroform-d) δ 8.08 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.57
(d, J = 8.8 Hz, 2H), 7.18 (d, J = 2.4 Hz, 1H), 7.00 (d, J = 8.8 Hz,
2H), 6.89 (d, J = 2.2 Hz, 1H), 6.86 (dd, J = 8.7, 2.3 Hz, 1H), 3.67
(s, 3H), 3.63 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 158.3,
156.8, 137.6, 128.6 (2C), 128.4, 120.6, 120.6, 120.0, 118.2, 114.5
(2C), 110.3, 95.0, 55.9, 55.6. HRMS (ESI): calcd. for [M+H]+,
253.1103; found 253.1181.
5-ethyl-4H-thieno[3,2-b]pyrrole (4f). 1H NMR (600 MHz,
Chloroform-d) δ 7.83 (s, 1H), 7.19 (d, J = 5.1 Hz, 1H), 6.99 – 6.94
(m, 1H), 6.77 (d, J = 3.4 Hz, 1H), 2.72 (q, J = 7.6 Hz, 2H), 1.25 (t,
J = 7.6 Hz, 3H). 13C NMR (151 MHz, Chloroform-d) δ 137.4, 130.4,
126.6, 126.1, 124.2, 113.1, 19.5, 14.5. HRMS (ESI): calcd. for
[M+H]+, 152.0456; found 152.0539.
5-methyl-4H-thieno[3,2-b]pyrrole (4g). 1H NMR (600 MHz,
Chloroform-d) δ 7.80 (s, 1H), 7.20 (d, J = 5.1 Hz, 1H), 7.01 – 6.97
(m, 1H), 6.78 (d, J = 3.5 Hz, 1H), 2.31 (s, 3H). 13C NMR (151 MHz,
Chloroform-d) δ 137.4 , 126.7 , 126.0 , 124.3 , 124.1 , 113.9 , 12.0 .
HRMS (ESI): calcd. for [M+H]+, 138.0299; found 138.0465.
6-fluoro-3-(4-fluorophenyl)-1H-indole (2d). 1H NMR (600 MHz,
Chloroform-d) δ 8.18 (s, 1H), 7.77 (dd, J = 8.7, 5.3 Hz, 1H), 7.58
(ddd, J = 8.4, 5.2, 2.5 Hz, 2H), 7.28 (s, 1H), 7.15 (t, J = 8.7 Hz,
2H), 7.11 (dd, J = 9.4, 2.2 Hz, 1H), 6.97 (td, J = 9.1, 2.3 Hz, 1H).
13C NMR (151 MHz, Chloroform-d) δ 162.4, 160.9 (d, JC-F =61.2
Hz), 159.3, 136.5 (d, JC-F =49.2 Hz), 131.1 (d, JC-F =12.6 Hz),
128.9 (d, JC-F =31.2 Hz), 122.4, 121.7 (d, JC-F =39.6 Hz), 120.4
(d, JC-F =39.6 Hz), 117.6, 115.7 (d, JC-F =84.6 Hz), 109.2 (d, JC-
F =24.5 Hz), 97.7 , 97.6. HRMS (ESI): calcd. for [M+H]+,
230.0703; found 230.0782.
5-ethyl-2-methyl-4H-thieno[3,2-b]pyrrole (4h). 1H NMR (600
MHz, Chloroform-d) δ 7.83 (s, 1H), 6.58 (s, 1H), 6.08 (s, 1H), 2.72
(q, J = 7.6 Hz, 2H), 2.51 (s, 3H), 1.28 (t, J = 7.6 Hz, 3H). 13C NMR
(151 MHz, Chloroform-d) δ 138.1, 136.6, 121.8, 109.3, 97.7, 29.7,
21.7, 16.4, 13.8. HRMS (ESI): calcd. for [M+H]+, 166.0612; found
166.0684.
2-ethyl-1H-indole (4a). 1H NMR (600 MHz, Chloroform-d) δ 7.85
(s, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.32 – 7.29 (m, 1H), 7.15 – 7.11
(m, 1H), 7.10 – 7.07 (m, 1H), 6.28 – 6.25 (m, 1H), 2.84 – 2.77 (m,
2H), 1.36 (t, J = 7.6 Hz, 3H). 13C NMR (151 MHz, Chloroform-d)
δ 141.3, 135.8, 128.8, 120.9, 119.7, 119.6, 110.2, 98.7, 21.4, 13.2.
HRMS (ESI): calcd. for [M+H]+, 146.0891; found 146.0968.
5-ethyl-6H-thieno[2,3-b]pyrrole (4i). 1H NMR (600 MHz,
Chloroform-d) δ 8.01 (s, 1H), 6.94 (d, J = 5.2 Hz, 1H), 6.78 (d, J
= 5.2 Hz, 1H), 6.19 – 6.15 (m, 1H), 2.74 (q, J = 7.5 Hz, 2H), 1.30
(t, J = 7.6 Hz, 3H). 13C NMR (151 MHz, Chloroform-d) δ 141.1,
131.9, 131.1, 128.5, 125.9, 122.8, 117.5, 116.9, 97.8, 44.0, 35.2,
21.8, 13.7. HRMS (ESI): calcd. for [M+H]+, 152.0456; found
152.0531.
2-ethyl-6-methyl-1H-indole (4b). 1H NMR (600 MHz,
Chloroform-d) δ 7.72 (d, J = 23.7 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H),
7.09 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.18 (s, 1H), 2.77 (q, J = 7.5
Hz, 2H), 2.44 (s, 3H), 1.33 (t, J = 7.6 Hz, 3H). 13C NMR (151 MHz,
Chloroform-d) δ 140.6, 136.3, 130.6, 126.5, 121.2, 119.4, 110.3,
98.4, 21.7, 21.4, 13.2. HRMS (ESI): calcd. for [M+H]+, 160.1048;
found 160.1127.
2-ethyl-1H-benzo[f]indole (6a). 1H NMR (600 MHz, Chloroform-
d) δ 8.59 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H),
7.67 (d, J = 8.5 Hz, 1H), 7.53 – 7.48 (M, 2H), 7.43 – 7.37 (m, 1H),
6.41(s, 1H), 2.91 (q, J = 7.6 Hz, 2H), 1.42 (t, J = 7.6 Hz, 3H). 13
C
NMR (151 MHz, Chloroform-d) δ 139.4, 129.9, 128.9, 125.2,
124.6, 123.2, 121.4, 120.3 (2C), 119.0, 100.5 (2C), 21.5, 13.5.
HRMS (ESI): calcd. for [M+H]+, 196.1048; found 196.1132.
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000580
European Journal of Organic Chemistry
FULL PAPER
2-methyl-1H-benzo[f]indole (6b). 1H NMR (600 MHz,
Chloroform-d) δ 8.58 (s, 1H), 7.92 (dd, J = 14.1, 8.2 Hz, 2H), 7.64
(d, J = 8.5 Hz, 1H), 7.50 (t, J = 7.8 Hz, 2H), 7.39 (t, J = 7.5 Hz,
1H), 6.37 (s, 1H), 2.55 (s, 3H). 13C NMR (151 MHz, Chloroform-
d) δ 133.0 , 130.1 , 129.8 , 128.9 , 125.2 , 124.8 , 123.2 , 121.3 ,
120.3 , 120.2 , 119.0 , 102.1 , 13.8 . HRMS (ESI): calcd. for [M+H]+,
182.0891; found 182.1036.
Keywords: Nitroalkenes • N-Heterocycles • Molybdenum
Hexacarbonyl • Reductive Cyclization
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2-ethyl-3H-benzo[e]indole (6c). 1H NMR (600 MHz, Chloroform-
d) δ 8.19 (d, J = 7.9 Hz, 2H), 7.89 (d, J = 8.1 Hz, 1H), 7.56 – 7.50
(m, 2H), 7.46 (d, J = 8.7 Hz, 1H), 7.42 – 7.37 (m, 1H), 6.80 (s, 1H),
2.89 (q, J = 7.5 Hz, 2H), 1.41 (td, J = 7.6, 1.5 Hz, 3H). 13C NMR
(151 MHz, Chloroform-d) δ 139.4, 131.8, 129.1, 128.4, 127.8,
125.4, 123.5, 123.0, 122.9, 121.7, 112.3, 98.2, 21.5, 13.5. HRMS
(ESI): calcd. for [M+H]+, 196.1048; found 196.1124.
1-(1H-indol-3-yl)isoquinoline (8a). 1H NMR (600 MHz,
Chloroform-d) δ 8.28 (d, J = 7.4 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H),
7.92 (s, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 7.9 Hz, 2H),
7.54 – 7.46 (m, 3H), 7.46 – 7.41 (m, 1H), 7.34 (t, J = 7.7 Hz, 1H),
7.02 (d, J = 7.4 Hz, 1H). 13C NMR (151 MHz, Chloroform-d) δ
141.8 , 134.0 , 133.7 , 130.0(2C) , 129.4 , 128.7 (2C) , 127.8 ,
127.4 , 127.3 , 127.2 , 126.6 , 125.1 , 123.4 , 116.8 , 112.5 . HRMS
(ESI): calcd. for [M+H]+, 245.1000; found 245.1206.
1-(1H-indol-3-yl)-6,7-dimethoxyisoquinoline (8b). 1H NMR
(600 MHz, Chloroform-d) δ 8.22 (d, J = 7.3 Hz, 1H), 7.91 (s, 1H),
7.58 (d, J = 7.9 Hz, 2H), 7.49 (t, J = 7.7 Hz, 2H), 7.43 – 7.37 (m,
2H), 7.07 (s, 1H), 6.93 (d, J = 7.3 Hz, 1H), 3.98 (s, 3H), 3.58 (s,
3H). 13C NMR (151 MHz, Chloroform-d) δ 149.7 , 149.1 , 141.4 ,
134.3 , 133.7 , 130.3(2C) , 128.5(2C) , 127.3 , 125.0 , 124.1 ,
119.3 , 115.1 , 111.8 , 107.6 , 104.7 , 55.9 , 55.6 . HRMS (ESI):
calcd. for [M+H]+, 305.1212; found 305.1414.
6, 7-dimethoxy-1-(6-methyl-1H-indol-3-yl)isoquinoline (8c).
1H NMR (600 MHz, Chloroform-d) δ 8.21 (d, J = 7.3 Hz, 1H), 7.88
(s, 1H), 7.47 (d, J = 7.8 Hz, 3H), 7.30 (d, J = 7.7 Hz, 2H), 7.07 (s,
1H), 6.92 (d, J = 7.3 Hz, 1H), 3.98 (s, 3H), 3.61 (s, 3H), 2.43 (s,
3H). 13C NMR (151 MHz, Chloroform-d) δ 149.6 , 149.1 , 141.5 ,
137.0 , 133.6 , 131.2 , 130.2(2C) , 129.1(2C) , 125.1 , 124.0 ,
119.5 , 115.0 , 111.7 , 107.5 , 104.8 , 55.9 , 55.6 , 21.3 . HRMS
(ESI): calcd. for [M+H]+, 319.1368; found 319.1573.
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6, 7-dimethoxy-1-(6-methoxy-1H-indol-3-yl)isoquinoline (8d).
1H NMR (600 MHz, Chloroform-d) δ 8.21 (d, J = 7.3 Hz, 1H), 7.87
(s, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.44 (s, 1H), 7.07 (s, 1H), 7.03
(d, J = 8.7 Hz, 2H), 6.92 (d, J = 7.3 Hz, 1H), 3.98 (s, 3H), 3.88 (s,
3H), 3.62 (s, 3H). 13C NMR (151 MHz, Chloroform-d) δ 159.0 ,
149.6 , 149.1 , 141.4 , 133.7 , 131.5(2C) , 126.4 , 125.1 , 124.0 ,
119.5 , 114.6 , 113.9(2C) , 111.7 , 107.6 , 104.6 , 55.9 , 55.7 ,
55.4 . HRMS (ESI): calcd. for [M+H]+, 335.1317; found 335.1527.
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Acknowledgements
We thank the financial support from the National Key Research
and Development Program of China (No. 2018YFC0310900),
National Natural Science Foundation of China (No. U1605221,
81903499), Shanghai Pujiang Program (18PJ1407000) and
Innovative research team of high-level local universities in
Shanghai（SSMU-ZLCX20180702）.
7
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8
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10.1002/ejoc.202000580
European Journal of Organic Chemistry
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Key Topic* Nitroalkenes • N-
Heterocycles • Molybdenum
Hexacarbonyl • Reductive Cyclization
Zhiyou Su+, Bo Liu+, Hongze Liao,* and
Hou-Wen Lin*
Page No. – Page No.
The development of a method that uses molybdenum hexacarbonyl [Mo(CO)6] as
carbon monoxide (CO) surrogate for the palladium-catalyzed reductive cyclization of
nitroalkenes into indoles or thienopyrroles is reported. Several types of nitroalkenes
could be transformed into the desired products in excellent yields and in most case
got higher yields and complete regioselectivities than those previously reported with
palladium/CO system.
Synthesis of N-Heterocycles by
Reductive Cyclization of Nitroalkenes
using Molybdenum Hexacarbonyl as
Carbon Monoxide Surrogate
9
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