Friedel–Crafts reaction of electron-rich (het)arenes with nitroalkenes

Article abstract of DOI:10.1016/j.mencom.2019.03.005

The Friedel–Crafts reaction between electron-rich (het)arenes and β-nitrostyrenes under MgI₂ or Ca(NTf₂)₂ catalysis affords 1-(het)aryl-2-nitro-1-phenylethanes in yields up to 94%.

Full text of DOI:10.1016/j.mencom.2019.03.005

Mendeleev
Communications
Mendeleev Commun., 2019, 29, 138–139
Friedel–Crafts reaction of electron-rich (het)arenes with nitroalkenes
Mikhail N. Feofanov,* Alexei D. Averin and Irina P. Beletskaya
Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation.
E-mail: feofanovmn@gmail.com
DOI: 10.1016/j.mencom.2019.03.005
X
X
NO2
NO2
cat.
The Friedel–Crafts reaction between electron-rich (het)arenes
and b-nitrostyrenes under MgI2 or Ca(NTf2)2 catalysis affords
1-(het)aryl-2-nitro-1-phenylethanes in yields up to 94%.
+
Ar
Ph
ArH
Ph
15 examples
up to 94%
X = H or CO2Et
cat. = MgI2 or Ca(NTf2)2
The Friedel–Crafts alkylation is one of the important reactions
for C–C bond formation in organic chemistry. The use of nitro-
alkenes as electrophiles in this reaction has attracted significant
interest in recent years. In fact, this process can be equally regarded
as the Friedel–Crafts alkylation of the aromatic compound and
the Michael addition at the double bond of nitroalkene. The
activating effect of NO2 group, as well as the ease of its trans-
formation into other functional groups, makes these compounds
promising building blocks for the synthesis of various pharma-
ceutical compounds.1 Generally, the Friedel–Crafts addition to
nitroalkenes is restricted to the reactions with indoles2–21 and
pyrroles,22–26 however cases with other electron-enriched arenes
are also documented.27–32 When strongly electron deficient
b-fluoro-b-nitrostyrenes were applied, the addition proceeded
without catalyst.33
In our previous works, we investigated the addition of indole
1a to activated olefins34 (including the asymmetric version35) and
to ethyl glyoxalate.36 We found out that the reaction conditions
(10% MgI2 in CH2Cl2) were suitable for a wide range of Friedel–
Crafts addition reactions characterized by high yields of the
products and short reaction time. In the present work, we studied
the addition of various electron-rich (het)arenes to trans-b-nitro-
styrene 2a and ethyl (Z)-3-nitro-2-phenylacrylate 2b.
since in our previous studies they provided good yields in relative
processes. Surprisingly, we discovered that MgI2/CH2Cl2 system
turned more suitable for Friedel–Crafts addition of indole to
trans-b-nitrostyrene 2a. In the case of ethyl (Z)-3-nitro-2-phenyl-
acrylate 2b, MgI2 was completely inactive and the reaction did
not proceed at all (see Scheme 1), whereas the use of Ca(NTf2)2
as the catalyst provided 90% yield of product 3h. The reactions
can be easily scaled up to a gram quantity: for 1 g scale of indole,
the yields of adducts 3a and 3h were 90 and 88%, respectively.
Next we investigated the effect of substituents in the indole
molecule on the yield of the addition product. N-Methylindole
formed an adduct 3b in a slightly lower yield (83%). The intro-
duction of fluorine or bromine atom at 5-position of indole almost
did not change the yield of the reaction products 3c,e, but in the
case of 5-chloroindole 1d the yield of 3d decreased to 74%.
5-Methylindole 1f afforded the corresponding product 3f in
91% yield. The introduction of the electron donor methoxy group
resulted in a lower yield (78%, product 3g). In the case of
4-methoxyindole, the reaction gave a complex mixture in which the
Friedel–Crafts addition product could not be identified. 5-Nitro-
and 6-carboxymethylindoles almost did not react under indicated
conditions due to their low reactivity, and after 48 h only traces
of corresponding addition products were detected.
In the first experiments on the addition of indole to nitro-
alkenes, calcium salts were tested as the catalysts (Scheme 1),
Further we studied various electron-enriched aromatic com-
pounds in this reaction. Benzenes with MeO and Et2N substituents
participated in the reactions with 2a in the presence of MgI2.
1,3-Dimethoxybenzene 4 provided 68% yield of product 4a
(Scheme 2), 1,3,5-trimethoxybenzene gave a slightly lower yield
(56%) of 4b, while in N,N-diethylaniline the para-hydrogen atom
was selectively substituted giving 62% yield of compound 4c.
As far as we know, this is the first example of the Lewis-acid
catalyzed addition of electron-rich benzenes to trans-b-nitro-
styrene. 2-Methylfuran also reacted with alkene 2, however the
yield of compound 4d was only 44% due to the formation of
various condensation products (see Scheme 2).
NO2
Ph
X
R2
R2
NO2
X
i
+
N
N
Ph
R1
R1
1a–g
1a R1 = R2 = H
2a,b
3a–h
Reactants Product Yield (%)
1b R1 = Me, R2 = H
1c R1 = H, R2 = F
1d R1 = H, R2 = Cl
1e R1 = H, R2 = Br
1f R1 = H, R2 = Me
1a + 2a
1b + 2a
1c + 2a
1d + 2a
1e + 2a
1f + 2a
1g + 2a
3a
3b
3c
3d
3e
3f
93 (90)
83
Ar
90
74
94
91
i
+
NO2
ArH
NO2
Ph
Ph
1g R1 = H, R2 = OMe
2a
4a Ar = 2,4-(MeO)2C6H3 (68%)
4b Ar = 2,4,6-(MeO)3C6H2 (56%)
4c Ar = 4-Et2NC6H4 (62%)
2a X = H
3g
78
2b X = CO2Et
1a + 2b 3h
0 (90)
4d Ar = 5-methylfuran-2-yl (44%)
Scheme 1 Reagents and conditions: i, 1a–g (0.5 mmol), 2a,b (0.25 mmol),
MgI2 (0.025 mmol), CH2Cl2 (0.5 ml), 20°C, 24 h.Yields given in parentheses
relate to the use of Ca(NTf2)2 as the catalyst in CHCl3 solution.
Scheme 2 Reagents and conditions: i, (het)arene (0.5 mmol), 2a (0.25 mmol),
MgI2 (0.025 mmol), CH2Cl2 (0.5 ml), 20°C, 24 h.
© 2019 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 138 –

Mendeleev Commun., 2019, 29, 138–139
Pyrrole reacted with trans-b-nitrostyrene to form mono- and
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arenes with trans-b-nitrostyrene and ethyl (Z)-3-nitro-2-phenyl-
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indoles to trans-b-nitrostyrene has been developed, this process
affords high yields of the target products (up to 94%). For the
first time, Lewis acid-catalyzed Friedel–Crafts addition of benzenes
with electron donor substituents was accomplished in the presence
of MgI2 for trans-b-nitrostyrene and in the presence of Ca(NTf2)2
for ethyl (Z)-3-nitro-2-phenylacrylate. This procedure can be
extended to the derivatives of 5-membered heterocycles, which
can be synthesized in 44–81% yields. The method is very simple as
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This work was supported by the Russian Science Foundation
(grant no. 14-23-00186P).
Online Supplementary Materials
Supplementary data associated with this article (experimental
details, 1H and 13C NMR spectra of compounds) can be found in
the online version at doi: 10.1016/j.mencom.2019.03.005.
Received: 3rd October 2018; Com. 18/5706
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