Radical Nitration-Debromination of α-Bromo-α-fluoroalkenes as a Stereoselective Route to Aromatic α-Fluoronitroalkenes - Functionalized Fluorinated Building Blocks for Organic Synthesis

Article abstract of DOI:10.1021/acs.joc.7b00578

A new highly efficient method for the synthesis of 2-fluoro-2-nitrostyrenes was described. Radical nitration of readily available 2-bromo-2-fluorostyrenes with Fe(NO₃)₃·9H₂O resulted in the formation of the corresponding α-fluoro-nitroalkenes in isolated yields up to 92%. The reaction proceeded as a nitration-debromination sequence to highly stereoselectively give α-fluoro-nitroalkenes as Z-isomers only. The broad scope of this method was demonstrated. Prepared monofluorinated alkenes were shown to be versatile building blocks for the synthesis of various fluorinated products.

Full text of DOI:10.1021/acs.joc.7b00578

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Article
Radical nitration-debromination of #-bromo-#-fluoroalkenes
as a stereoselective route to aromatic #-fluoronitroalkenes –
functionalized fluorinated building blocks for organic synthesis
Vladimir A. Motornov, Vasiliy M. Muzalevskiy, Andrey A. Tabolin, Roman A.
Novikov, Yulia V. Nelyubina, Valentine G. Nenajdenko, and Sema L. Ioffe
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 27 Apr 2017
Downloaded from http://pubs.acs.org on April 27, 2017
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Radical nitrationꢀdebromination of αꢀbromoꢀαꢀfluoroalkenes as a stereoselective route to
aromatic αꢀfluoronitroalkenes – functionalized fluorinated building blocks for organic
synthesis
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Vladimir A. Motornov,†,‡ Vasiliy M. Muzalevskiy,§ Andrey A. Tabolin,†,* Roman A. Novikov,
†,║ Yulia V. Nelyubina,┴ Valentine G. Nenajdenko,§,* Sema L. Ioffe†
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†
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp.
47, Moscow 119991, Russian Federation
‡
Higher Chemical College, D. I. Mendeleev University of Chemical Technology of Russia,
Miusskaya sq. 9, Moscow 125047, Russian Federation
§
Department of Chemistry, M. V. Lomonosov Moscow State University, Leninskie Gory 1,
Moscow, 119992 Russian Federation
║
V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str.
32, Moscow, 119991, Russian Federation
┴ A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
Vavilov str. 28, Moscow 119991, Russian Federation
Corresponding authors eꢀmails: tabolin87@mail.ru; nenajdenko@org.chem.msu.ru
Graphical abstract
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Abstract
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A new highly efficient method for the synthesis of 2ꢀfluoroꢀ2ꢀnitrostyrenes was described.
Radical nitration of readily available 2ꢀbromoꢀ2ꢀfluorostyrenes with Fe(NO3)3ꢁ9H2O resulted in
the formation of the corresponding αꢀfluoroꢀnitroalkenes in isolated yields up to 92%. The
reaction proceeded as a nitrationꢀdebromination sequence to highly stereoselectively give
αꢀfluoroꢀnitroalkenes as Zꢀisomers only. The broad scope of this method was demonstrated.
Prepared monofluorinated alkenes were shown to be versatile building blocks for the synthesis of
various fluorinated products.
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Introduction
Nitroalkenes are wellꢀknown versatile building blocks for organic synthesis.1 These
systems contain a highlyꢀpolarized alkene activated by a strongly electronꢀwithdrawing nitro
group. As a result, a broad spectrum of valuable synthetic transformations has been
demonstrated.2 Thus, nitroalkenes are superb Michael acceptors and a wide variety of
nucleophiles can be added to nitroalkenes to generate new CꢀC or Cꢀheteroatom bonds. A widely
used approach to prepare substituted amines is based on a Michael addition and/or subsequent
reduction.1b,f Stereoselective Michael additions with nitroalkenes provide access to the synthesis
of natural compounds, drugs and bioactive molecules. Nitroalkenes can be used as dienophiles
and dipolarophiles to participate in various cycloadditions.3 However, probably the most
important application of nitroalkenes is the construction of various heterocycles. For example,
pyrroles, pyrazoles, isoxazolines, 1,2ꢀoxazines, and many other derivatives can be prepared
using nitroalkenes as key starting materials.4 It should be noted that this constructive approach
allows substituents to be properly installed in desired positions of the heterocyclic core.
αꢀHalosubstituted nitroalkenes are especially interesting activated alkenes. Due to the presence
of additional halogen at the double bond, these alkenes can participate in various domino
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transformations.5,6 However, while αꢀchloro and αꢀbromo nitroalkenes are wellꢀknown
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compounds, αꢀfluoroꢀnitroalkenes 1 remain almost uninvestigated. Considering the importance
of fluorineꢀcontaining molecules as pharmaceuticals and agrochemicals, the synthesis of novel
fluorineꢀsubstituted building blocks is a very important task.7 αꢀFluoronitroalkenes 1 could be
used as valuable building blocks to prepare a variety of monofluorinated compounds. However,
despite the structural simplicity of αꢀfluoronitroalkenes 1, their synthesis can not be considered
as a trivial task. The classical and most straightforward method to prepare nitroalkenes is the
Henry reaction with aliphatic nitroalkanes.8 However, until now, the Henry reaction between
aldehydes and fluoronitromethane (Scheme 1) has not been reported. Apparently, this is due to
the low stability of fluoronitromethane in basic media.9 To our knowledge, only one general
method for synthesizing nitroalkenes 1 has been published: the HornerꢀWadsworthꢀEmmons
olefination of carbonyl compounds (Scheme 1) with diethyl fluoronitromethyl phosphonate has
been recently described by Beier.10 This new reagent for olefination was prepared by the
monofluorination of diethyl nitromethylphosphonate with Selectfluor. Despite its good substrate
scope, the method has low diastereoselectivity and thus gives the target nitroalkenes as E,Zꢀ
isomeric mixtures (generally in a 3:1 Z:Eꢀratio). Moreover, diethyl nitromethylphosphonate is
not commercially available and possesses low stability in the presence of bases.
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Therefore, new methods for the synthesis of αꢀfluoroꢀnitroalkenes are required, and novel
stereoselective protocols for the preparation of these alkenes are especially attractive. Recently,
some highly efficient procedures for radical nitration appeared in the literature.11 We envisioned
preparing nitroalkenes 1 from the corresponding 2ꢀbromoꢀ2ꢀfluoroalkenes 2 via a radical
nitrationꢀdebromination sequence (see below discussion of the reaction mechanism). Herein, we
report a new general and highly stereoselective synthesis of 2ꢀfluoroꢀ2ꢀnitrostyrenes 1.
Additionally, the broad synthetic scope of these building blocks was demonstrated by preparing
a variety of monofluorinated molecules.
Scheme 1. Approaches to αꢀfluoronitroalkenes 1
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Results and discussion
Starting alkenes 2 are readily available compounds that can be prepared from the
corresponding carbonyl compounds and CBr3F using either the CoreyꢀFuchs reaction or copper
chlorideꢀmediated catalytic olefination of hydrazones.12 Styrene 2a was chosen as the model
substrate to search for the optimal reaction conditions for radical nitration. Several types of
reaction conditions were used, focusing on the method of generating of NO2 radicals (Table 1).
To our delight, the reaction proceeded as a nitrationꢀdebromination sequence. As a rule, the
reaction of styrene 2a with all the studied nitration systems led to the formation of the target
nitroalkene 1a, thus confirming the possibility of our proposed process. Target nitroalkene 1a
can be prepared in moderate yields (up to 43%) using N2O4 (Entries 1,2) itself as a source of
NO2 radicals. Generation of NO2 radicals via the oxidation of sodium nitrite with some oxidants
resulted in the formation of 1a in up to 47% yields (Entries 3ꢀ10). Thermal decomposition of
transition metal nitrates was more efficient for the nitration of 2a. Various metal nitrates
including Cu(NO3)2ꢁ3H2O, Co(NO3)2ꢁ6H2O, AgNO3, Cr(NO3)3ꢁ9H2O, (NH4)2Ce(NO3)6,
Fe(NO3)3ꢁ9H2O gave target nitroalkene 1a in 28ꢀ53% yields (Entries 12ꢀ22).
Table 1. Optimization of reaction conditions
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Entry Reagent
Conditions
Yield 1a, %a
1
2
N2O4 (3 equiv.)
N2O4 (3 equiv.)
MeCN, r.t., 10 h
MeCN, 70 °C, 4 h
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NaNO2 (3 equiv.), FeCl3 (1 equiv.)
NaNO2 (3 equiv.), FeCl3 (1 equiv.)
NaNO2 (3 equiv.), PhI(OAc)2 (1
equiv.)
MeCN, 70 °C, 4 h
MeCN/H2O (5:1), 70 °C, 6 h
MeCN, 70 °C, 16 h
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7
NaNO2 (3 equiv.), K2S2O8 (0.5
equiv.)
MeCN, 70 °C, 16 h
DMSO, 80 °C, 4 h
14 (60)b
5 (69)b
44
NaNO2 (3 equiv.), K2S2O8 (0.5
equiv.)
8
NaNO2 (3 equiv.), (NH4)2Ce(NO3)6
(1 equiv.)
MeCN, 70 °C, 6 h
9
NaNO2 (3 equiv.), (NH4)2Ce(NO3)6
(1 equiv.)
MeCN/H2O (5:1), 70 °C, 8 h
MeCN, 70 °C, 4 h
18
ꢀ
10
Bu4N+NO2 (1 equiv.), FeCl3 (1
27
equiv.)
AgNO3 (1 equiv.)
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14
MeCN, r.t., 8 h
EtOAc, 70 °C, 2 h
n.r.c
27
AgNO3 (1 equiv.)
AgNO3 (1 equiv.)
MeCN, 70 °C, 2 h
53
AgNO3 (1.1 equiv.), TEMPO (0.2
eq.)
MeCN, 4Å MS, 80 °C, 1.5 h
n.r.
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16
Cu(NO3)2ꢁ3H2O (1 equiv.)
Cu(NO3)2ꢁ3H2O (1 equiv.)
MeCN, 70 °C, 5 h
DMSO, 100 °C, 7 h
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Cu(NO3)2ꢁ3H2O (2 equiv.)
ClCH2CH2Cl, 80 °C, 8 h
MeCN, 70 °C, 8 h
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Cr(NO3)3ꢁ9H2O (1 equiv.)
(NH4)2Ce(NO3)6 (1 equiv.)
Co(NO3)2ꢁ6H2O (1 equiv.)
Fe(NO3)3ꢁ9H2O (1 equiv.)
Fe(NO3)3ꢁ9H2O (2 equiv.)
Cu(NO3)2ꢁ3H2O (2 equiv.),
TEMPO (0.2 eq.)
MeCN, 70 °C, 5 h
ClCH2CH2Cl, 80 °C, 18h
MeCN, 70 °C, 7 h
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ClCH2CH2Cl, 80 °C, 5 h
ClCH2CH2Cl, 4Å MS, 80 °C, 1.5 h
ClCH2CH2Cl, 4Å MS, 80 °C, 1.5 h
ClCH2CH2Cl, 80°C, 3 h
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Fe(NO3)3ꢁ9 H2O (2 equiv.),
TEMPO (0.2 eq.)
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Fe(NO3)3ꢁ9 H2O, (2 equiv.)
TEMPO (0.2 eq.)
Fe(NO3)3ꢁ9 H2O (2 equiv.),
TEMPO (0.1 eq.)
ClCH2CH2Cl, 4Å MS, 80 °C, 1.5 h
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Fe(NO3)3ꢁ9H2O (2 equiv.)
Fe(NO3)3ꢁ9H2O (2 equiv.)
Fe(NO3)3ꢁ9H2O (2 equiv.)
Fe(NO3)3ꢁ9H2O (2 equiv.)
Fe(NO3)3ꢁ9H2O (8 equiv.)
Fe(NO3)3ꢁ9H2O (3 equiv.)
acetone, 70 °C, 10 h
1,4ꢀdioxane, 80 °C, 10 h
1,4ꢀdioxaned, 100 °C, 0.5 h
1,4ꢀdioxanee, 100 °C, 0.5 h
1,4ꢀdioxanee, 100 °C, 0.5 h
1,4ꢀdioxanee, 100 °C, 0.5 h
50(20)b
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93
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a Determined by 19F NMR with PhCF3 as internal standard.
b Recovery of 2a is indicated in parentheses
c no reaction
d 0.3 M solution of 2a
e 0.08 M solution of 2a
The most promising results were obtained using inexpensive ferric nitrate nonahydrate
(Fe(NO3)3ꢁ9H2O). This reagent provided the target product in reasonable yields up to 54%. At
this point, attention was paid to the addition of TEMPO (Entries 23ꢀ26). Its use in the nitration of
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styrenes was recently demonstrated by Maiti11a followed by its successful application by his11b,c
and other research groups.11d,e Indeed, improvement of the yield to 68% was achieved using 0.2
equiv. of TEMPO as an additive to the ferric nitrate (Method A, Entry 24). There are two
possible explanations for the positive influence of TEMPO on the yield of 1a. The first reason is
that TEMPO inhibited the radical polymerization of either starting styrene 2 or product 1 by
trapping any intermediate radicals of type A. In the second case, TEMPO may facilitate the
release of NO2 radicals from the metal nitrate through coordination of TEMPO with the metal
atom.13 The decrease in the reaction time when TEMPO is added (Table 1, Entries 22, 24)
supports the latter proposal.
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Method A was the first one used to investigate the reaction scope. However, in some
cases (e.g., 1aꢀ1d) moderate yields were observed (see below, Table 2). Thus, additional
optimization of the reaction conditions was performed. According to the reaction scheme, the
elimination of a Br radical is expected (Table 1). Therefore, bromination of the starting alkene in
a side reaction is one possible reason for the lower yield of 1a. Careful analysis of the reaction
mixture confirmed this proposal. The formation of the corresponding bromination product 3a
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was observed (up to 20%). H, F NMR and GCꢀMS data supported the structure of tribromide
3a, although we did not manage to isolate it in an analytically pure form (a similar product was
also isolated in the reaction with pꢀmethoxyphenyl substituted substrate 2c, see Table 2).
Keeping in mind the ability of 1,4ꢀdioxane to form a complex with molecular bromine some
reevaluation of the procedure was made (Table 1, Entries 28ꢀ32). It was found that 1,4ꢀdioxane
forms a homogeneous solution with Fe(NO3)3ꢁ9H2O that is stable for 30 min. However, some
degradation and formation of a brown precipitate, likely Fe2O3 hydrate was observed at longer
time periods. Assuming that suppressing the formation of sideꢀproduct 3 can be achieved by
accelerating the target transformation, the reaction was run with an increased amount of
Fe(NO3)3ꢁ9H2O at higher temperatures. These conditions for the nitration of model alkene 2a
demonstrated very good results. The reaction proceeded in less time (30 min) to give target
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alkene 1a in 87% isolated yield (Method B, Entry 32). An even better yield of 1a (93%) was
reached using a larger excess of Fe(NO3)3 (8 equiv.) (Entry 31). However, we decided to use 3
equiv. of Fe(NO3)3 because the improvement was not very significant. We suppose that such
conditions favor increased rates of both the NO2 radical formation and the nitration reaction
while lowering or maintaining the rate of the sideꢀreaction, a bromination of 2a due to a possible
deactivation of bromine via complexation with 1,4ꢀdioxane.
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Crucial to our study was the stereochemical result of the reaction. To our delight, in all
cases the radical nitrationꢀdebromination reaction of 2a resulted in the formation of a single
diastereomer of 1a. The structure of 1a was determined unambiguously by 1H, 13C and 19F NMR
as well as massꢀspectrometry data. Accordingly to NMR data compound 1a has an HꢀF coupling
constant of 26 Hz, which corresponds to a transꢀarrangement of hydrogen and fluorine across the
CꢀC double bond.14 Therefore, only the Zꢀisomer of αꢀfluoronitrostyrene 1a is formed in this new
nitrationꢀdebromination reaction. The proposed protocol is highly stereoselective in contrast to
the previously reported method.10
Having optimized these reaction conditions, we next studied the scope of the reaction
using a diverse set of 2ꢀbromoꢀ2ꢀfluoroalkenes 2 (Table 2). As mentioned above, method A was
applied first. In the case of moderate (<75%) yields (see, e.g., 1aꢀd, 1m), method B was also
used. Gratifyingly, it was found that the nitrationꢀdebromination of alkenes 2 with
Fe(NO3)3ꢁ9H2O opens a general approach to fluoronitroalkenes 1. Styrenes with varying
electronic demand can be converted smoothly to the corresponding αꢀfluoronitroalkenes in yields
of up to 92%.15 For example, nitroꢀ, cyanoꢀ, carbomethoxyꢀ, methoxyꢀ, fluoroꢀ, chloroꢀ and
bromoꢀsubstituted 2ꢀbromoꢀ2ꢀfluorostyrenes 2 were converted to the target products very
efficiently. The naphthaleneꢀderived nitroalkene 1k was also prepared in high yield (90%)
confirming a broad scope for the reaction. High stereocontrol was observed in all cases and the
target nitrostyrenes were isolated as single Zꢀisomers.16 The reaction was also applicable for
synthesis of bisꢀnitroalkenes. Highly stereoselective nitration of bisꢀnitroalkene 2l provided the
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corresponding product 1l as a single isomer having a Z,Zꢀconfiguration despite the starting
material having a mixture of E,Eꢀ, E,Zꢀ and Z,Zꢀisomers in a 12:6:1 ratio.
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Likewise, the reaction can also be performed with tetraꢀsubstituted substrates derived
from ketones. Thus, the corresponding αꢀfluoronitroalkene 1m was prepared in 75% yield using
method B. Method A somehow resulted in a lower yield (50%) and a prolonged reaction time
was necessary to complete the nitration. Therefore, this nitration reaction is sensitive to steric
hindrance of the CꢀC double bond of the starting alkene. It should be noted that
αꢀfluoronitroalkene 1m was isolated as a mixture of E/Z isomers in a 1:2 ratio in contrast to all
the aldehydeꢀderived alkenes.
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Table 2. Synthesis of fluoronitroalkenes 1
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a 80 °C, 4 h; b Fe(NO3)3ꢁ9H2O (5 equiv.) and TEMPO (0.4 equiv.) were added in 3 portions. Total
reaction time – 5.5 h (see Experimental section)
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Some restrictions for this nitrationꢀdebromination cascade were observed for highly
electronꢀrich substrates. The nitration of 3,4ꢀdimethoxyphenylꢀ (2n) and 2ꢀthienyl (2o)
substituted substrates gave complex product mixtures and poor yields of the target
fluoronitroalkenes using both methods A and B. These results were predictable since the starting
alkenes 2n,o have highly reactive arene and hetarene rings, which are prone to participate in
nitration and bromination reactions. Thus, doubleꢀnitration product 1’n was isolated in the
reaction with the 3,4ꢀdimethoxyꢀsubstituted substrate 2n (Scheme 2). However, the use of milder
conditions for nitration (AgNO3 in acetonitrile, 65 °C) allowed the selective preparation of
nitroalkenes 1n and 1o in reasonable yields (Table 2).17
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Scheme 2. Double nitration of substrate 2n
1
Structures of all the obtained nitroalkenes 1aꢀo were determined unambiguously by H,
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13C and F NMR as well as mass spectrometry data. As discussed above, the highly selective
formation of Zꢀisomers was observed in all cases for trisubstituted alkenes (1aꢀl,n,o).
Additionally, Xꢀray analysis was performed for a single crystal of nitroalkene 1n (Figure 1)18 to
1
confirm the Zꢀconfiguration of these alkenes. An Hꢀ19F HOESY NMR experiment aided in
establishing the configuration of the tetrasubstituted product 1m.
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Figure 1. Singleꢀcrystal ORTEP drawing for 1n. Thermal ellipsoids are shown at 50 %
probability level.
We also proposed that this nitrationꢀdehalogenation sequence can be used as a new
general approach for the preparation of other αꢀhalogenated nitroalkenes. Several monoꢀ and
dihalogenated styrenes were subjected to the reaction (Scheme 3). It was found that 2ꢀchloroꢀ2ꢀ
fluoroꢀ and 2,2ꢀdichlorostyrenes (4a,b) failed to give the corresponding nitroalkenes with
Fe(NO3)3ꢁ9H2O, while the reaction with monobromoꢀ and 2,2ꢀdibromostyrenes (4c,d) afforded
the corresponding derivatives 5 in high yields. It should be noted that in these cases, the nitration
proceeded with high stereoselectivity to afford 5c,d as single diastereomers. The transꢀ
arrangement of aryl and NO2 groups was confirmed by comparison with literature data as well as
by its characteristic trans-coupling constant, 3JH,H = 13.7 Hz (for 5d).19
Scheme 3. Nitration of other halogenated styrenes 4.
A possible mechanism for the nitrationꢀdebromination sequence is depicted in Scheme 4.
Of course, this reaction is a complicated multistep transformation, but some details of the
sequence can be justified. We believe that the first step of the reaction probably includes
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generation of an NO2 radical from the selected precursor. The second step is an attack of an NO2
radical onto the C=C double bond to form the stabilized benzyl radical A which bears a
CBrFNO2 group in the adjacent position. Subsequent debromination proceeds either through the
elimination of a bromine radical (path (a)) or includes the participation of an Fe(III) species to
oxidize this radical to the corresponding benzyl cation B (path (b)) to facilitate the formation of
the final fluoronitrostyrenes 1. Eliminated Br+ can be reduced with Fe(II) to a bromide anion or
can participate in the bromination of a C=C double bond (sideꢀproduct 3). Thus, the iron salt is
an electron mediator in this reaction, which probably explain the efficacy of using iron nitrate in
this reaction over other nitrating agents such as N2O4 or AgNO3.20
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Considering the high stereoselectivity observed during similar radical nitration of
unsubstituted styrenes,11 we also envisioned high stereoselectivity for the nitrationꢀ
debromination of fluoroꢀbromostyrenes 2. The formation of simple nitrostyrenes in a transꢀ
configuration is quite predictable: however, to the best our knowledge, cisꢀisomers are much less
stable compounds.21 Stereoselective formation of 1ꢀfluoroꢀ1ꢀnitroalkenes 1 can be explained by
the formation of intermediate A (Scheme 4). It has been previously reported that βꢀbromoalkyl
radicals exist preferentially in the form of closed 3ꢀmembered bromo radicals C.22 Among
diastereomeric forms, C1 should be less favored than its diastereomer C2 due to the steric
repulsion between its large Rꢀgroup and NO2 moiety. Thus (Z)ꢀisomeric products 1 result from
the transformation of the more stable cyclic intermediate C2 by the elimination of bromine. This
proposal is in total agreement with the lower stereoselectivity observed for the nitration of tetraꢀ
substituted substrate 2m to form 1m, which made a mixture of Z/E isomers in a 2:1 ratio (see
above). Similar considerations are applicable for the elimination of Br+ from cation B and its
cyclic form D (path (b)).
Scheme 4. Rationale for the Zꢀselectivity of the nitration
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The ratio of isomers of the starting alkene appears to have no effect on the stereochemical
result of the reaction (see Experimental section). To confirm this observation, the reaction was
performed with samples of alkene 2h with different E/Zꢀratios (almost pure (E)ꢀisomer and ca.
1:1) (Scheme 5). Indeed, the stereochemical outcome of the reaction was independent on the
starting E/Zꢀratio and produced only the (Z)ꢀisomer of 1h in both cases.
Scheme 5. Comparison of the nitration of styrene 2h with different E,Zꢀratios
To demonstrate the synthetic utility of αꢀfluoronitroalkenes, we performed some
chemical transformations of substrate 1a. Due to the presence of the electronꢀwithdrawing nitroꢀ
group, the obtained nitrostyrenes 1 should be activated electrophiles and dienophiles and can be
used for the synthesis of valuable monofluorinated molecules. It should be noted that up to now
almost nothing has been known about the reactivity of αꢀfluoronitroalkenes.10 Accordingly, our
preliminary investigation of the synthetic utility of these very attractive building blocks included
reactions with Hꢀ, Nꢀ, Sꢀ, and Cꢀnucleophiles as well as cycloaddition with 2,3ꢀdimethylbutaꢀ
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1,3ꢀdiene and catalytic hydrogenation were studied (Scheme 6). We were pleased to find that
under unoptimized conditions all these reactions proceeded very efficiently to give the
corresponding products 6ꢀ10 in good isolated yields. Highly valuable monofluorinated products,
which are difficult to prepare using alternative methods, can be obtained in one synthetic step
from αꢀfluoronitroalkenes 1. For example, the Michael addition of hydride (NaBH4),10 dimethyl
malonate, amines (morpholine and isopropylamine) and thiophenol gave the corresponding αꢀ
fluorinated nitroalkanes 6ꢀ10, respectively. Two diastereomers can be formed in these reactions,
however, the diastereoselectivity of isolated Michael adducts 7ꢀ10 was not very high. Most likely,
these stereochemical results can be explained by the easy epimerization enabled by the high
acidity of the FCHNO2ꢀmoiety.23 In future work we will study these reactions more carefully.
Nitroalkenes are a popular type of activated alkenes in asymmetric synthesis. For example,
organocatalyzed Michael additions are a highly efficient approach for forming new stereocenters
with high enantioselectivity.1g,24
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αꢀFluoroamines are a very attractive but rather elusive type of organic molecules which
exhibit low stability. We attempted to prepare αꢀfluoroamine by the Pd/Cꢀcatalyzed
hydrogenation of 1a in the presence of Ac2O as a trapping agent. Unfortunately, only ester 11
was isolated as a main reaction product.25
Nitroalkene 1a was found to participate successfully in a DielsꢀAlder reaction with
2,3ꢀdimethylbutaꢀ1,3ꢀdiene, resulting in the corresponding monofluorinated cyclohexene 12 in
80% yield. As expected, DielsꢀAlder adduct 12 was formed as single diastereomer.
Especially interesting is the prospective use of αꢀfluoronitroalkenes in the synthesis of
monofluorinated heterocycles. In recent decades, the chemistry of fluorinated heterocycles has
received substantial attention due to their applications in pharmaceuticals, agrochemicals and the
synthesis of biologically active compounds.7 The domino sequence ꢀ Michael additionꢀ
heterocyclizationꢀaromatization by elimination of HNO2 at the last step can open access to a
large variety of highly attractive fluorinated heterocycles. Thus, nonfluorinated nitrostyrenes
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have found broad applications in the synthesis of different heterocycles.4 For example, the
BartonꢀZard reaction is a very useful method for the synthesis of pyrroles.26 It was demonstrated
that a fairly rare type of fluoroꢀsubstituted pyrrole,27 3ꢀfluorinated pyrrole derivative 13, can be
constructed very efficiently using the reaction of 1a with ethyl isocyanoacetate in the presence of
DBU as a base.
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Scheme 6. Selected chemical transformations of nitroalkene 1a
In conclusion, a new stereoselective method for the synthesis of βꢀfluoroꢀβꢀnitrostyrenes
from 2ꢀbromoꢀ2ꢀfluorostyrenes via a nitrationꢀdebromination sequence was described. Two
general protocols for the nitration, both based on the application of Fe(NO3)3, were proposed.
Method A employs a Fe(NO3)3/TEMPO system that allows milder reaction conditions (80 °C)
and Method B (Fe(NO3)3 in 1,4ꢀdioxane at 100 °C) allows a shorter reaction time. Additionally,
the radical nitration of highly electronꢀrich alkenes can be performed using AgNO3 in
acetonitrile (Method C). A rationale for the stereoselectivity of the reaction was proposed. The
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high synthetic utility of βꢀfluoroꢀβꢀnitrostyrenes was demonstrated. An investigation of the use
of these versatile building blocks to prepare small fluorinated molecules is currently underway.
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Experimental section
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All reactions were performed in ovenꢀdried (150 °C) glassware. Most of the chemicals were
acquired from commercial sources and used as received. Brine refers to a saturated aqueous
solution of NaCl. TLC were performed on silica coated on aluminium with UV254 indicator.
Visualization was accomplished with UV or ninhydrine. Column chromatography was
performed on silica (0.04–0.063 mm, 60 Å). NMR spectra were recorded at the following
spectrometer frequencies: 400 MHz, 300 MHz or 200 MHz (1H NMR), 100 MHz or 75 MHz
(13C NMR), 376 MHz or 282 MHz (19F NMR). Multiplicities are assigned as s (singlet),
d (doublet), t (triplet), q (quadruplet), hept (heptet), m (multiplet), br (broad). High resolution
mass spectra were acquired at TOF spectrometer using electrospray ionization (ESI).28 Low
resolution mass spectra were acquired using electron impact (EI) ionization (200 °C, ionization
energy – 70eV). Intensities relative to most intensive peak are reported in parentheses.
Starting bromoalkenes were synthesized according to described procedures: 2,12f,g,28 4c,29 4d.30
Synthesis of fluoronitroalkenes 1,5.
Method A. 2ꢀbromoꢀ2ꢀfluorobromoalkene 2 was placed into 10 ml vial and dissolved in DCE (3
mL / 1 mmol of 2). Then Fe(NO3)3ꢁ9H2O (2 equiv), TEMPO (0.2 equiv) and 4Å MS (0.50 g /
mmol alkene 2) were added. Vial was closed and the reaction mixture was heated at 80°C (oil
bath) with stirring for 1ꢀ2 h (TLC monitoring). Mixture was cooled to rt and filtered through
Celite®. After that celite was washed with EtOAc. Combined filtrate was evaporated and crude
product was purified by column chromatography (eluent: PE/EtOAc, 7:1 – 15:1) to give target
nitroalkene 1.
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Method B. Fe(NO3)3ꢁ9H2O (3 equiv) was added to the solution of bromoalkene 2,4 in 1,4ꢀ
dioxane (12 mL / 1 mmol of 2) and the reaction mixture was heated at 100 °C (oil bath) with
stirring for 0.5 h (TLC monitoring). Mixture was cooled to rt and filtered through Celite®. After
that celite was washed with EtOAc or CH2Cl2. Combined filtrate was evaporated and crude
product was purified by column chromatography (eluent: PE/EtOAc, 7:1 – 15:1 or PE/CH2Cl2,
3:1) to give target nitroalkenes 1,5.
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Method C. 2ꢀBromoꢀ2ꢀfluoroalkene 2 was placed into 10 ml vial and dissolved in MeCN (5 mL
/ 1 mmol of 2), then AgNO3 (1.3 equiv.) was added. Vial was closed and the reaction mixture
was heated at 65 °C (oil bath) with stirring for 45ꢀ60 min (TLC monitoring). Mixture was cooled
to r.t. and filtered through celite®. After that celite was washed with EtOAc. Filtrate was
evaporated and crude product was purified by column chromatography (eluent: PE/EtOAc =
10:1) to give target nitroalkenes 1.
1ꢀChloroꢀ4ꢀ[(Z)ꢀ2ꢀfluoroꢀ2ꢀnitroethenyl]benzene (1a). A) Nitroalkene 1a was obtained from
bromofluorostyrene 2a (0.207 g, 0.88 mmol) (E/Z = 4:1) according to Method A. Column
chromatography (eluent: PE/EtOAc, 10:1) afforded 0.120 g (68 %) of target compound 1a. B)
Nitroalkene 1a was obtained from bromofluorostyrene 2a (0.470 g, 2 mmol) (E/Z = 4:1)
according to Method B. Column chromatography (eluent: PE/CH2Cl2, 3:1) afforded 0.354 g
(88 %) of target compound 1a. C) Nitroalkene 1a was obtained from bromofluorostyrene 2a
(0.172 g, 0.73 mmol) (E/Z = 4:1) according to Method C. Column chromatography (eluent:
PE/EtOAc, 7:1) afforded 0.067 g (46 %) of target compound 1a. Slightly yellow solid. Rf 0.27
(PE/CH2Cl2, 3:1) (UV). mp = 86ꢀ87 °C (CHCl3). NMR matched previously reported data.10
[(Z)ꢀ2ꢀFluoroꢀ2ꢀnitroethenyl]benzene (1b). A) Nitroalkene 1b was obtained from
bromofluorostyrene 2b (0.307 g, 1.55 mmol) (E/Z = 8:1) according to Method A. Column
chromatography (eluent: PE/EtOAc, 20:1) afforded 0.180 g (71 %) of target compound 1b. B)
Nitroalkene 1b was obtained from bromofluorostyrene 2b (0.402 g, 2 mmol) (E/Z = 8:1)
according to Method B. Column chromatography (eluent: PE/CH2Cl2, 3:1) afforded 0.261 g
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(78 %) of target compound 1b. Slightly yellow liquid, that solidifies upon storage. Rf 0.28
(PE/CH2Cl2, 3:1) (UV). mp = 40ꢀ41 °C (CHCl3). NMR matched previously reported data.10
1ꢀ[(Z)ꢀ2ꢀFluoroꢀ2ꢀnitroethenyl]ꢀ4ꢀ(methyloxy)benzene (1c). A) Nitroalkene 1c was obtained
from corresponding bromofluorostyrene 2c (0.523 g, 2.26 mmol) (E/Z = 5:1) according to
method A. Column chromatography (eluent: PE/EtOAc, 12:1) with subsequent crystallization
PE/EtOAc, 20:1) afforded 0.284 g (64 %) of target compound 1c. B) Nitroalkene 1c was
obtained from bromofluorostyrene 2c (0.462 g, 2 mmol) (E/Z = 5:1) according to Method B with
following change: reaction was maintained at 80 °C for 4 h. Column chromatography (eluent:
PE/CH2Cl2, 3:1) afforded 0.312 g (79 %) of target compound 1c. Yellow solid. Rf = 0.36
(PE/CH2Cl2, 1:1) (UV) mp = 100ꢀ102 °C (CHCl3). NMR matched previously reported data.10
1ꢀ[(Z)ꢀ2ꢀFluoroꢀ2ꢀnitroethenyl]ꢀ4ꢀmethylꢀbenzene (1d). A) Nitroalkene 1d was obtained from
bromofluorostyrene 2d (0.167 g, 0.77 mmol) (E/Z = 5:1) according to method A. Column
chromatography (eluent: PE/EtOAc, 10:1) afforded 0.098 g (70 %) of target compound 1d. B)
Nitroalkene 1d was obtained from bromofluorostyrene 2d (0.430 g, 2 mmol) (E/Z = 5:1)
according to Method B. Column chromatography (eluent: PE/CH2Cl2, 3:1) afforded 0.354 g
(74 %) of target compound 1d. Slightly yellow solid. Rf 0.59 (PE/EtOAc, 7:1) (UV). mp = 72ꢀ
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74 °C (PE). 1H NMR (300 MHz, CDCl3) δ 2.43 (s, 3H), 7.30 (d, J = 8.1 Hz, 2H), 7.40 (d, 3JHF
26.7 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 21.6, 110.1 (2JCF = 6.4 Hz),
=
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125.1 (d, JCF = 6.3 Hz), 130.1, 130.9 (d, 4JCF = 7.7 Hz), 142.4 (d, JCF = 2.8 Hz), 152.5 (1JCF
=
293.8 Hz). 19F NMR (282 MHz, CDCl3) δ ꢀ112.3 (d, J = 26.7 Hz). HRMS (ESIꢀTOF) m/z: [M +
Na]+ Calcd. for C9H8FNO2Na 204.0431; Found: 204.0432. MS (EI): m/z = 181 (M+, 76), 123
(100).
Methyl 4ꢀ[(Z)ꢀ2ꢀfluoroꢀ2ꢀnitroethenyl]benzoate (1e). A) Nitroalkene 1e was obtained from
bromofluorostyrene 2e (0.137 g, 0.53 mmol) (E/Z = 4:1) according to method A. Column
chromatography (eluent: PE/EtOAc, 10:1) afforded 0.110 g of target compound 1e (92 %) as
slightly yellow solid. B) Nitroalkene 1e was obtained from bromofluorostyrene 2e (0.159 g, 0.61
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mmol) (E/Z = 4:1) according to Method B. Column chromatography (eluent: PE/EtOAc, 5:1)
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compound 1e. Rf 0.48 (PE/EtOAc, 5:1) (UV). mp = 179ꢀ180 °C (PE/EtOAc, 10:1). H NMR
(300 MHz, CDCl3) δ 3.96 (s, 3H), 7.43 (d, 3JHF = 25.9 Hz, 1H), 7.73 (d, J = 8.3 Hz, 2H), 8.14 (d,
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J = 8.3 Hz, 2H). C NMR (75 MHz, CDCl3) δ 52.5, 108.5 (d, JCF = 6.2 Hz), 130.3, 130.6 (d,
4JCF = 8.1 Hz), 132.0 (d, 3JCF = 6.5 Hz), 132.4 (d, 6JCF = 2.6 Hz), 153.0 (1JCF = 294.6 Hz), 166.0.
19F NMR (282 MHz, CDCl3) δ ꢀ109.0 (d, J = 25.9 Hz). HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd.
for C10H8FNO4Na 248.0330; Found: 248.0322. MS (EI): m/z = 225 (M+, 76), 120 (100).
1ꢀFluoroꢀ4ꢀ[(Z)ꢀ2ꢀfluoroꢀ2ꢀnitroethenyl]benzene (1f). Nitroalkene 1f was obtained from
bromofluorostyrene 2f (0.302 g, 1.38 mmol) (E/Z = 5:1) according to method A. Column
chromatography (eluent: PE/EtOAc, 10:1) afforded 0.210 g (83 %) of target compound 1f as
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slightly yellow solid. Rf 0.53 (PE/EtOAc, 5:1) (UV). mp = 48ꢀ49 °C (PE). H NMR (300 MHz,
CDCl3) δ 7.19 (t, J = 8.6 Hz, 2H), 7.40 (d, 3JHF = 26.1 Hz, 1H), 7.64ꢀ7.71 (m, 2H). 13C NMR (75
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MHz, CDCl3) δ 108.8 (d, JCF = 5.4 Hz), 116.8 (d, JCF = 22.1 Hz), 124.2, 133.1 (t, JCF = 7.9
19
Hz), 152.5 (1JCF = 291.5 Hz), 164.3 (1JCF = 255.7 Hz). F NMR (282 MHz, CDCl3): ꢀ106.9 ꢀ
ꢀ107.0 (m, 1 F), ꢀ113.2 (d, J = 26.1 Hz, 1 F). Anal. Calcd. for C8H5F2NO2: C, 51.90; H, 2.72; N,
7.57. Found: C, 51.57; H, 2.51; N, 7.39. MS (EI): m/z = 185 (M+, 62), 127 (100).
1ꢀBromoꢀ2ꢀ[(Z)ꢀ2ꢀfluoroꢀ2ꢀnitroethenyl]benzene (1g). Nitroalkene 1g was obtained from
bromofluorostyrene 2g (0.155 g, 0.56 mmol) (E/Z = 4:1) according to method A. Column
chromatography (eluent: PE/EtOAc, 7:1) afforded 0.112 g (82 %) of target compound 1g as
slightly yellow oil, that solidifies upon storage in a fridge. Rf 0.57 (PE/EtOAc, 7:1) (UV). mp =
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37ꢀ39 °C (PE). H NMR (300 MHz, CDCl3) δ 7.33 (td, J = 7.8, 1.4 Hz, 1H), 7.50 (t, J = 7.5 Hz,
3
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1H), 7.72 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.87 (d, JHF = 25.7 Hz, 1H). C NMR
(100 MHz, CDCl3) δ 108.1 (2JCF = 4.5 Hz), 126.2 (d, JCF = 2.0 Hz), 128.1, 128.2 (d, overlapped,
JCF = 8.7 Hz), 131.0 (d, 4JCF = 12.2 Hz), 132.3 (d, 6JCF = 1.5 Hz), 133.7, 153.0 (1JCF = 294.9 Hz).
19F NMR (282 MHz, CDCl3) δ ꢀ112.1 (d, J = 25.7). HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd. for
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C8H5 BrFNO2Na 267.9380; Found: 267.9383. MS (EI): m/z = 247 ([M+2]+, 16), 245 (M+, 18),
120 (100).
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1ꢀ[(Z)ꢀ2ꢀFluoroꢀ2ꢀnitroethenyl]ꢀ4ꢀnitrobenzene (1h). Nitroalkene 1h was obtained from
corresponding bromofluorostyrene 2h (0.067 g, 0.27 mmol) (E/Z = 19:1) according to method A.
Column chromatography (eluent: PE/EtOAc, 10:1) afforded 0.049 g (85 %) of target compound
1h as slightly yellow solid.
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The same procedure for bromofluorostyrene 2h (0.140 g, 0.57 mmol) (E/Z = 1.2:1) afforded
0.097 g (80%) of target compound 1h. NMR matched previously reported data.10
1ꢀ[(Z)ꢀ2ꢀFluoroꢀ2ꢀnitroethenyl]ꢀ2ꢀnitrobenzene (1i). Nitroalkene 1i was obtained from
bromofluorostyrene 2i (0.185 g, 0.75 mmol) (E/Z = 3:1) according to method A. Column
chromatography (eluent: PE/EtOAc, 10:1) afforded 0.137 g (86 %) of target compound 1i as
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yellow solid. Rf 0.26 (PE/EtOAc, 10:1) (UV). mp = 66ꢀ68 °C (PE/EtOAc, 10:1). H NMR (400
MHz, CDCl3) δ 7.67ꢀ7.71 (m, 1H), 7.78ꢀ7.82 (m, 2H), 7.94 (d, 3JHF = 23.7 Hz, 1H), 8.21 (d, J =
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7.9 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 105.3 (2JCF = 5.7 Hz), 122.9 (d, JCF = 5.0 Hz),
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125.6, 131.3 (d, JCF = 8.4 Hz), 131.5, 134.0, 148.2, 152.9 (1JCF = 296.7 Hz). 19F NMR (282
MHz, CDCl3) δ ꢀ112.1 (d, J = 23.7 Hz). HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd. for
C8H5FN2O4Na 235.0126; Found: 235.0135.
4ꢀ[(Z)ꢀ2ꢀFluoroꢀ2ꢀnitroethenyl]benzonitrile (1j). Nitroalkene 1j was obtained from
bromofluorostyrene 2j (0.215 g, 0.95 mmol) (E/Z = 4:1) according to method A. Column
chromatography (eluent: PE/EtOAc, 10:1) afforded 0.155 g (86 %) of target compound 1j as
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colorless solid. Rf 0.30 (PE/CH2Cl2, 1:1) (UV). mp = 119ꢀ120 °C (PE/EtOAc, 10:1). H NMR
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(300 MHz, CDCl3) δ 7.41 (d, JHF = 25.3 Hz, 1H), 7.75ꢀ7.81 (m, 4H). 13C NMR (75 MHz,
CDCl3) δ 107.5 (d, 2JCF = 6.1 Hz), 114.7 (d, 6JCF = 3.2 Hz), 117.8, 131.0 (d, 4JCF = 7.9 Hz), 132.2
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(d, JCF = 6.5 Hz), 132.9, 153.2 (1JCF = 298.2 Hz). F NMR (282 MHz, CDCl3): ꢀ107.6 (d, J =
25.3 Hz). HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd. for C9H5FN2O2Na 215.0227; Found:
215.0237. MS (EI): m/z = 192 (M+, 57), 134 (100).
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1ꢀ[(Z)ꢀ2ꢀFluoroꢀ2ꢀnitroethenyl]naphtalene (1k). Nitroalkene 1k was obtained from
bromofluorostyrene 2k (0.136 g, 0.54 mmol) (E/Z = 7:1) according to method A. Column
chromatography (eluent: PE/EtOAc, 15:1) afforded 0.106 g (90%) of target compound 1k as
yellow solid. Rf 0.60 (PE/EtOAc, 5:1) (UV). mp = 78ꢀ79 °C (PE). 1H NMR (400 MHz, CDCl3) δ
7.57ꢀ7.63 (m, 2H), 7.65ꢀ7.69 (m, 1H), 7.94 (dd, J = 8.1, 1.3 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H),
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8.00 (d, J = 8.2 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.20 (d, JHF = 24.7 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ 106.1 (2JCF = 6.7 Hz), 122.9, 124.0 (d, 3JCF = 6.1 Hz), 125.5, 126.7, 127.8, 129.2,
129.2 (d, JCF = 11.3 Hz), 131.7, 132.0 (d, JCF = 1.9 Hz), 133.7, 153.4 (1JCF = 290.8 Hz). F
NMR (282 MHz, CDCl3) δ ꢀ112.3 (d, J = 24.7 Hz). HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd. for
C12H8FNO2Na 240.0431; Found: 240.0431. MS (EI): m/z = 217 (M+, 39), 170 (100).
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1,3ꢀBisꢀ[(Z)ꢀ2ꢀfluoroꢀ2ꢀnitroethenyl]benzene (1l). Nitroalkene 1l was obtained from
bromofluorostyrene 2l (0.245 g, 0.76 mmol) (E,E/E,Z/Z,Z = 12:6:1) according to method A with
following change: 4 equiv Fe(NO3)3ꢁ9H2O and 0.4 equiv TEMPO were used. Column
chromatography (eluent: PE/EtOAc, 10:1) afforded 0.150 g (77 %) of target compound 1l as
slightly yellow solid. Rf 0.43 (PE/EtOAc, 5:1) (UV). mp = 108ꢀ109 °C (PE). 1H NMR (300 MHz,
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CDCl3) δ 7.44 (d, 2H, JHF = 25.7 Hz, 2H), 7.63 (t, J = 7.7 Hz, 1H), 7.80 (d, J = 7.7 Hz, 2H),
7.92 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 108.4 (d, 2JCF = 6.1 Hz), 129.3 (d, 3JCF = 6.4), 130.4,
132.5 (t, JCF = 7.6 Hz), 133.0 (dd, JCF = 7.9 Hz, JCF = 2.2 Hz), 153.0 (1JCF = 295.3 Hz). F
NMR (282 MHz, CDCl3) δ ꢀ109.6 (d, J = 25.7 Hz). Anal. Calcd. for C10H6F2N2O4: C, 46.89; H,
2.36; N, 10.94. Found: C, 46.72; H, 2.26; N, 10.71. MS (EI): m/z = 256 (M+, 71), 151 (100).
1ꢀBromoꢀ4ꢀ[2ꢀfluoroꢀ1ꢀmethylꢀ2ꢀnitroethenyl]benzene (1m). 1-Bromo-4-[2-bromo-2-fluoro-1-
methylethenyl]benzene (2m). In argon atmosphere the mixture of pꢀbromoacetophenone (0.39 g,
2.0 mmol), PPh3 (0.79 g, 3.0 mmol, 1.5 equiv.), Zn (0.26 g, 4.0 mmol, 2 equiv.) and CBr3F (0.49
mL, 5.0 mmol, 2.5 equiv.) in THF (6 mL) was vigorously stirred at 60 °C for 2 hours. After that
the mixture was evaporated, crude product was preadsorbed on silica and purified by column
chromatography (eluent: PE/CH2Cl2, 20:1) to give 0.55 g (95 %) of target compound 2m as
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colorless oil. E:Z = 1.1 : 1 (19F NMR). Assignment of E,Zꢀisomers was made considering JHF
value in H3CꢀC=CF scaffold: 4JHF = 3ꢀ4 Hz for transꢀarrangement of F and CH3 groups and 4JHF
= 4ꢀ5 Hz for cisꢀarrangement of F and CH3 groups.31 Rf 0.49 (PE/CH2Cl2, 20:1) (UV). 1H NMR
(300 MHz, CDCl3) (E+Z) δ 2.08 (d, 4JHF = 4.3 Hz, 3H, Zꢀisomer), 2.08 (d, 4JHF = 3.5 Hz, 3H, Eꢀ
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isomer), 7.16ꢀ7.20 (m, 2H), 7.22ꢀ7.62 (m, 2H), 7.48ꢀ7.53 (m, 2H). C NMR (75 MHz, CDCl3)
(E+Z) δ 17.6 (d, JHF = 4.7 Hz), 20.3, 116.7 (d, JCF = 8.7 Hz), 118.5 (d, 2JCF = 16.9 Hz), 121.6,
121.8, 129.4 (4JCF = 4.2 Hz), 130.0 (4JCF = 3.2 Hz), 131.0 (1JCF = 316.4 Hz), 131.5, 131.6, 132.6
(1JCF = 317.5 Hz), 135.3, 137.8 (d, 6JCF = 5.0 Hz). 19F NMR (282 MHz, CDCl3) (E+Z) δ ꢀ73.4 (q,
4JHF = 4.3 Hz, Zꢀisomer). ꢀ73.5 (qt, 4JHF = 3.5 Hz, 5JHF = 1.2 Hz, Eꢀisomer). MS (EI): m/z = 296
([M+4]+, 23), 294 ([M+2]+, 50), 292 (M+, 26), 134 (100). A) Nitroalkene 1m was obtained from
bromofluoroalkene 2m (0.157 g, 0.54 mmol) (E/Z = 1.1:1) according to method A with the
following changes: after 3 hour heating Fe(NO3)3ꢁ9H2O (2 equiv.) and TEMPO (0.2 equiv.) were
added. After additional heating at 80 °C for 1.5 h Fe(NO3)3ꢁ9H2O (1 equiv.) was added. After
additional heating for 1 h reaction was worked up as described. Column chromatography (eluent:
PE/EtOAc, 15:1) afforded 0.033 g (Zꢀisomer) and 0.037 g (Z/E = 1:1.5) of target compound 1m
(total yield – 50 %, Z/E = 2:1) as yellow oils. B) Nitroalkene 1m was obtained from
bromofluorostyrene 2m (0.171 g, 0.58 mmol) (E/Z = 1.1:1) according to Method B. Column
chromatography (eluent: PE/EtOAc, 10:1) afforded 0.113 g (74 %) of target compound 1m. Rf
0.36 (PE/EtOAc, 15:1) (UV) (Zꢀisomer) and 0.31 (PE/EtOAc, 15:1) (UV) (Eꢀisomer). Zꢀisomer:
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1H NMR (300 MHz, CDCl3) δ 2.54 (d, JHF = 3.7 Hz, 3H), 7.28ꢀ7.32 (m, 2H, CHAr), 7.57ꢀ7.62
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(m, 2H). C NMR (75 MHz, CDCl3) δ 19.3, 121.7 (d, JCF = 11.4 Hz), 124.1, 129.6 (4JCF = 3.4
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Hz), 132.0, 134.1, 150.7 (d, JCF = 277.4 Hz). F NMR (282 MHz, CDCl3) δ ꢀ108.6 (br s). Fꢀ
1H HOESY interaction: FꢀCHAr. Eꢀisomer: 1H NMR (400 MHz, CDCl3) δ 2.23 (d, 4JHF = 4.6 Hz,
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3H, Me), 7.07ꢀ7.10 (m, 2H), 7.54ꢀ7.57 (m, 2H). C NMR (100 MHz, CDCl3) δ 19.8, 121.3 (d,
2JCF = 17.9 Hz), 123.0, 128.4 (4JCF = 1.7 Hz), 132.1, 134.6, 149.7 (d, 1JCF = 279.4 Hz). 19F NMR
(282 MHz, CDCl3): ꢀ109.2 (br s). 19Fꢀ1H HOESY interaction: FꢀMe. HRMS (ESIꢀTOF) m/z: [M
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+ Na]+ Calcd. for C9H7 BrFNO2Na 281.9536; Found: 281.9534. MS (EI): m/z = 261 ([M+2]+,
16), 259 (M+, 16), 133 (100).
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4ꢀ[(Z)ꢀ2ꢀFluoroꢀ2ꢀnitroethenyl]ꢀ1,2ꢀbis(dimethyloxy)benzene (1n). Nitroalkene 1n was
obtained from bromofluorostyrene 2n (0.290 g, 1.11 mmol) (E/Z = 5:1) according to Method C.
Column chromatography (eluent: PE/EtOAc, 10:1) afforded 0.139 g (53 %) of target compound
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1n as orange crystals. Rf 0.25 (PE/EtOAc, 7:1) (UV). mp = 104ꢀ106 °C (15:1 PE/EtOAc). H
NMR (300 MHz, CDCl3) δ 3.93 (s, 3H), 3.96 (s, 3H), 6.95 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 2.0
Hz, 1H), 7.27 (dd, J = 8.4, 2.0 Hz, 1H), 7.39 (d, JHF = 26.7 Hz, 1H). 13C NMR (100 MHz,
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CDCl3) δ 55.9, 56.0, 110.5 (d, 2JCF = 6.2 Hz), 111.5, 112.7 (d, 4JCF = 8.8 Hz), 120.7 (d, 3JCF = 6.2
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Hz), 125.8 (d, JCF = 7.4 Hz), 149.5, 152.1 (d, JCF = 288.4 Hz), 152.2 (d, JCF = 3.3 Hz). F
NMR (282 MHz, CDCl3) δ ꢀ114.2 (d, J = 26.6 Hz). HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd. for
C10H10FNO4Na 250.0486; Found: 250.0485. MS (EI): m/z = 227 (M+, 100). Singleꢀcrystal Xꢀ
Ray diffraction data for 1n was deposited at Cambridge Crystallographic Data Centre (CCDCꢀ
1527014).
2ꢀ[(Z)ꢀ2ꢀFluoroꢀ2ꢀnitroethenyl]thiophene (1o). Nitroalkene 1o was obtained from
bromofluoroalkene 2o (0.139 g, 0.67 mmol) (E/Z = 3:1) according to Method C. Column
chromatography (eluent: PE/EtOAc, 15:1) afforded 0.043 g (37 %) of target compound 1o as
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yellow solid. Rf 0.50 (PE/EtOAc, 5:1) (UV). mp = 70ꢀ72 °C (PE/EtOAc, 10:1). H NMR (400
MHz, CDCl3) δ 7.21 (ddd, J = 5.1, 3.8, 1.4 Hz, 1H), 7.54 (d, J = 3.7 Hz, 1H), 7.69 (d, J = 25.4
Hz, 1H), 7.71 (d, J = 5.7 Hz, 1H). C NMR (100 MHz, CDCl3) δ 105.1 (2JCF = 9.9 Hz), 128.6,
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130.4 (d, JCF = 7.1 Hz), 133.2 (d, JCF = 8.1 Hz), 134.3, 151.6 (d, JCF = 288.1 Hz). F NMR
(282 MHz, CDCl3) δ ꢀ110.7 (d, J = 25.4 Hz). HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd. for
C6H4FNO2SNa 195.9839; Found: 195.9844. MS (EI): m/z = 173 (M+, 47), 83 (100).
1ꢀ[(Z)ꢀ2ꢀFluoroꢀ2ꢀnitroethenyl]ꢀ4,5ꢀbis(methyloxy)ꢀ2ꢀnitrobenzene (1’n). Nitroalkene 1’n was
obtained from bromofluorostyrene 2n (0.311 g, 1.19 mmol) (E/Z = 5:1) subjected to Method B.
Column chromatography (eluent: PE/EtOAc, 5:1) with subsequent crystallization (PE/EtOAc,
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15:1) afforded 0.054 g (20 %) of target compound 1’n as yellow solid. Rf = 0.20 (PE/EtOAc,
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3:1) (UV). mp = 142ꢀ144 °C (15:1 PE/EtOAc). 1H NMR (300 MHz, CDCl3): 4.02 (s, 6 H, OMe),
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7.14 (s, 1H, 6ꢀHCAr), 7.77 (s, 1H, 3ꢀHCAr), 8.08 (d, JHF = 24.4 Hz, 1H, =CH). C NMR (75
MHz, CDCl3): 56.6, 106.0 (d, 2JCF = 4.5 Hz), 108.6, 111.9 (d, 4JCF = 9.4 Hz), 116.9 (d, 3JCF = 5.2
Hz), 141.7, 150.7, 152.7 (d, 1JCF = 294.9 Hz), 153.2. 19F NMR (282 MHz, CDCl3): ꢀ113.0 (d, J =
24.4 Hz). Characteristic NOESY/HOESY interactions: OMe/3ꢀCHAr, OMe/6ꢀCHAr, F/6ꢀHCAr.
HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd. for C10H9FN2O6Na 295.0337; Found: 295.0332. MS
(EI): m/z = 272 (M+, 22), 44 (100).
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1ꢀ[(Z)ꢀ2ꢀBromoꢀ2ꢀnitroethenyl]ꢀ4ꢀchlorobenzene (5c). Nitroalkene 5c was obtained from
corresponding dibromostyrene 4c (0.148 g, 0.5 mmol) according to Method B with the following
change: reaction was maintained at 100 °C for 10 h. Column chromatography (eluent:
PE/CH2Cl2, 3:1) afforded 0.082 g (63 %) of target compound 5c as slightly yellow solid. Rf 0.31
(PE/CH2Cl2 = 3:1) (UV). NMR matched previously reported data.19b
1ꢀChloroꢀ4ꢀ[(E)ꢀ2ꢀnitroethenyl]benzene (5d). Nitroalkene 5d was obtained from corresponding
bromostyrene 4d (0.108 g, 0.5 mmol) (E/Z = 6:1) according to Method B. Column
chromatography (eluent: PE/CH2Cl2, 3:1) afforded 0.073 g (80 %) of target compound 5d as
slightly yellow solid. Rf = 0.46 (PE/CH2Cl2 = 1:1) (UV). NMR matched previously reported
data.11a
1ꢀChloroꢀ4ꢀ(2ꢀfluoroꢀ2ꢀnitroethyl)benzene (6). To the solution of nitroalkene 1a (90 mg, 0.45
mmol) in MeOH (4.4 mL) NaBH4 (26 mg, 0.67 mmol, 1.5 equiv.) was added at 0 °C with
stirring. Cooling bath was removed, the mixture was stirred for 30 min and diluted with EtOAc
(15 mL). Organic layer was washed with H2O (2 × 15 mL), brine (15 mL), dried over Na2SO4
and evaporated. Crude product was subjected to column chromatography (eluent: PE/EtOAc,
7:1) to give 71 mg (78 %) of target compound 6 as colorless oil. Rf = 0.21 (PE/EtOAc, 10:1)
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(UV). mp = 41ꢀ42 °C (pentane). H NMR (300 MHz, CDCl3): 3.34ꢀ3.57 (m, 2H), 5.95 (ddd, J =
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50.4 Hz, 6.2 Hz, 3.9 Hz, 1H), 7.19 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H). C NMR (75
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MHz, CDCl3): 38.8 (d, JCF = 19.7 Hz), 110.3 (d, JCF = 241.2 Hz), 129.2, 129.3 (d, JCF = 1.7
Hz), 130.9, 134.5. 19F NMR (282 MHz, CDCl3): ꢀ146.5 ꢀ ꢀ146.1 (m). Anal. Calcd. for
C8H7ClFNO2: C, 47.19; H, 3.47; N, 6.88. Found: C, 47.00; H, 3.63; N, 6.69. MS (EI): m/z = 205
([M+2]+, 7), 203 (M+, 18), 101 (100).
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4ꢀ[1ꢀ(4ꢀСhlorophenyl)ꢀ2ꢀfluoroꢀ2ꢀnitroethyl]morpholine (7). To the suspension of nitroalkene
1a (89 mg, 0.44 mmol) in EtOH (0.88 mL) morpholine (0.042 mL, 0.48 mmol, 1.1 equiv.) was
added. The reaction mixture was stirred for 15 min and evaporated. Column chromatography
(eluent: PE/EtOAc, 3:1) afforded 107 mg (84 %) of target compound 7 as colorless viscous oil.
d.r. = 1.6 : 1 (19F NMR). Relative configuration of stereocenters was not determined. Rf = 0.10
(PE/EtOAc, 5:1) (UV) 1H NMR (300 MHz, CDCl3): 2.36ꢀ2.69 (m, 4H, CH2ꢀN), 3.69 (t, J = 4.7
Hz, 4H, CH2ꢀO), 4.14 (dd, J = 21.9 Hz, 5.1 Hz, 1H, CHꢀN), 6.26 (dd, J = 50.5 Hz, 5.1 Hz, 1H,
CHꢀF), 7.23 (d, J = 8.5 Hz, 2H, CHAr), 7.38 (d, J = 8.5 Hz, 2H, CHAr). 13C NMR (75 MHz,
CDCl3): 50.9 (CH2ꢀN), 66.7 (CH2ꢀO), 69.9 (d, 2JCF = 19.9 Hz, CHꢀN), 109.8 (d, 1JCF = 245.6 Hz,
CHꢀF), 128.9 (CHAr), 129.5 (CAr), 130.7 (d, JCF = 0.8 Hz, CHAr), 135.3 (CAr). 19F NMR (272
MHz, CDCl3): ꢀ155.2 (dd, J = 50.5 Hz, 21.9 Hz). Minor isomer (characteristic signals): 1H NMR
(300 MHz, CDCl3): 2.36ꢀ2.69 (m, 4H, CH2ꢀN), 3.64 (t, J = 4.7 Hz, 4H, CH2ꢀO), 4.35 (dd, J =
28.5 Hz, 3.0 Hz, 1H, CHꢀN), 6.03 (dd, J = 49.4 Hz, 3.1 Hz, 1H, CHꢀF), 7.30 (d, J = 8.5 Hz, 2H,
CHAr), 7.41 (d, J = 8.5 Hz, 2H, CHAr). 13C NMR (75 MHz, CDCl3): 51.3 (d, 5JCF = 1.4 Hz, CH2ꢀ
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N), 66.9 (CH2ꢀO), 69.1 (d, JCF = 16.3 Hz, CHꢀN), 112.3 (d, JCF = 246.8 Hz, CHꢀF), 129.0
(CHAr), 130.8 (d, JCF = 2.6 Hz, CHAr), 135.3 (CAr). 19F NMR (272 MHz, CDCl3): ꢀ154.5 (dd, J =
49.4 Hz, 28.5 Hz). HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd. for C12H1535ClFN2O3 289.0750;
Found: 289.0747. MS (EI): m/z = 290 (M+, 5), 212 ([M+2–CHFNO2]+, 33), 210 ([M–CHFNO2]+,
100).
Nꢀ[1ꢀ(4ꢀСhlorophenyl)ꢀ2ꢀfluoroꢀ2ꢀnitroethyl]propanꢀ2ꢀamine (8). Mixture of nitroalkene 1a
(0.109 g, 0.54 mmol) and isopropyl amine (0.120 g, 2.03 mmol, 3.8 equiv.) in THF (2 mL) was
kept at room temperature for 48 h (TLC monitoring). Reaction mixture was evaporated in vacuo
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and the residue was purified by column chromatography on silica gel (eluent: PE/CH2Cl2, 3:1) to
give 0.051 g (d.r. = 1 : 9) and 0.072 g (d.r. = 18 : 1) of target compound 8 as colorless oils. Total
yield 87%. Total d.r. = 1.5 : 1 (19F NMR). Relative configuration of stereocenters was not
determined. Rf 0.13 (PE/CH2Cl2, 1:1) (UV). Major isomer: 1H NMR (400 MHz, CDCl3): 1.04 (d,
J = 6.3 Hz, 6 H), 1.60 (br s, 1H), 2.70 (hept, J = 6.3 Hz, 1H), 4.43 (dd, J = 21.9 Hz, 4.2 Hz, 1H),
5.94 (dd, J = 50.5 Hz, 4.2 Hz, 1H), 7.22 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H). 13C NMR
(100 MHz, CDCl3): 21.7, 23.7, 46.0, 60.7 (d, 2JCF = 19.4 Hz), 111.5 (d, 1JCF = 243.5 Hz), 129.1,
129.3, 133.0, 135.0. 19F NMR (376 MHz, CDCl3): ꢀ157.8 (dd, J = 50.5 Hz, 21.8 Hz). Minor
isomer: 1H NMR (400 MHz, CDCl3): 0.94 (d, J = 6.2 Hz, 3H), 1.00 (d, J = 6.2 Hz, 3H), 1.68 (br
s, 1H), 2.62 (hept, J = 6.2 Hz, 1H), 4.53 (dd, J = 25.2 Hz, 2.4 Hz, 1H), 5.78 (dd, J = 49.7 Hz, 2.6
Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): 21.4,
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23.8, 45.5, 60.6 (d, JCF = 17.6 Hz), 111.8 (d, JCF = 243.8 Hz), 128.9, 129.3, 134.2, 134.8. F
NMR (376 MHz, CDCl3): ꢀ161.9 (dd, J = 49.7 Hz, 25.1 Hz). HRMS (ESIꢀTOF) m/z: [M + H]+
Calcd. for C11H1535ClFN2O2 261.0801; Found: 261.0807. MS (EI): m/z = 247 ([M+2–Me]+, 6),
245 ([M–Me]+, 18), 184 ([M+2–CHFNO2]+, 30), 182 ([M–CHFNO2]+, 84), 156 (100).
1ꢀ(4ꢀСhlorophenyl)ꢀ2ꢀfluoroꢀ2ꢀnitroethyl phenyl sulfide (9). Mixture of nitroalkene 1a (0.101 g,
0.5 mmol), thiophenol (0.066 g, 0.6 mmol) and DIPEA (0.069 g, 0.6 mmol) in THF (2 mL) was
kept at room temperature for 24 h (TLC monitoring). Reaction mixture was evaporated in vacuo
and the residue was purified by column chromatography on silica gel (eluent: PE/CH2Cl2, 3:1) to
give 0.107 g (69 %) of compound 9 as colorless oil. d.r. = 1.5 : 1 (19F NMR). Relative
configuration of stereocenters was not determined. Rf 0.27 (PE/CH2Cl2, 1:1) (UV). Major
isomer: 1H NMR (400 MHz, CDCl3): 4.87 (dd, J = 26.7 Hz, 3.1 Hz, 1H), 5.92 (dd, J = 49.6 Hz,
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3.2 Hz, 1H), 7.25ꢀ7.39 (m, 8 H), 7.51ꢀ7.53 (m, 1H). C NMR (100 MHz, CDCl3): 54.1 (d, JCF
= 19.1 Hz), 109.4 (d, 1JCF = 246.1 Hz), 129.1, 129.2, 129.7, 130.2, 130.3 (d, J = 1.2 Hz), 130.9,
133.8, 135.4. 19F NMR (376 MHz, CDCl3): ꢀ157.8 (dd, J = 49.6 Hz, 26.6 Hz). Minor isomer: 1H
NMR (400 MHz, CDCl3): 4.80 (dd, J = 24.3 Hz, 3.8 Hz, 1H), 6.02 (dd, J = 49.6 Hz, 3.8 Hz, 1H),
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7.25ꢀ7.39 (m, 8 H), 7.51ꢀ7.53 (m, 1H). C NMR (100 MHz, CDCl3): 55.3 (d, JCF = 19.0 Hz),
111.2 (d, 1JCF = 245.0 Hz), 129.0, 129.3, 129.4, 129.7 (d, J = 1.1 Hz), 131.3, 132.9, 133.9, 135.0.
19F NMR (376 MHz, CDCl3): ꢀ150.8 (dd, J = 49.6 Hz, 23.9 Hz). Anal. Calcd. for
C14H11ClFNO2S: C, 53.94; H, 3.56; N, 4.49. Found: C, 53.89; H, 3.32; N, 4.32. HRMS (ESIꢀ
TOF) m/z: [M + Na]+ Calcd. for C14H1135ClFNO2SNa 334.0075; Found: 334.0062. MS (EI): m/z
= 313 ([M+2]+, 5), 311 (M+, 11), 156 (100).
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Dimethyl [1ꢀ(4ꢀchlorophenyl)ꢀ2ꢀfluoroꢀ2ꢀnitroethyl]propanedioate (10). To the solution of
K2CO3 (39 mg, 0.28 mmol, 0.5 equiv.) in MeOH (1.7 mL) at 0 °C dimethyl malonate (82 mg,
0.62 mmol, 1.1 equiv.) and nitroalkene 1a (113 mg, 0.56 mmol) were successively added. The
reaction mixture was maintained at the same temperature overnight and poured into EtOAc (25
mL) / H2O (15 mL). Organic layer was washed with brine (15 mL), dried over Na2SO4 and
evaporated. Column chromatography (eluent: PE/EtOAc, 5:1, 3:1) afforded 141 g (75 %) of
target compound 10 as colorless oil, that solidifies upon storage. d.r. = 2.3 : 1. Relative
configuration of stereocenters was not determined. Rf 0.28 (PE/EtOAc, 3:1) (UV, ninhydrine).
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mp = 111ꢀ114 °C (EtOAc). Major isomer: H NMR (300 MHz, CDCl3): 3.49 (s, 3H), 3.86 (s,
3H), 4.05 (d, J = 11.9 Hz, 1H), 4.37 (ddd, J = 31.3 Hz, 11.9 Hz, 2.3 Hz, 1H), 6.45 (dd, J = 50.7
Hz, 2.3 Hz, 1H), 7.13ꢀ7.18 (m, 2H), 7.27ꢀ7.31 (m, 2H). 13C NMR (75 MHz, CDCl3): 46.8 (d,
2JCF = 17.5 Hz), 52.2 (d, 3JCF = 2.9 Hz), 53.0, 53.5, 109.4 (d, 1JCF = 243.3 Hz), 129.1, 130.7 (d, J
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= 1.7 Hz), 135.4, 166.3, 167.3. F NMR (282 MHz, CDCl3): ꢀ157.6 (dd, J = 50.7 Hz, 31.3 Hz).
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Minor isomer (characteristic signals): H NMR (300 MHz, CDCl3): 3.54 (s, 3H), 3.83 (s, 3H),
4.22ꢀ4.27 (m, 2H), 6.33 (dd, J = 49.3 Hz, 3.3 Hz, 1H). 13C NMR (75 MHz, CDCl3): 51.9 (d, 3JCF
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= 5.3 Hz), 53.1, 53.4, 129.3, 130.1. F NMR (282 MHz, CDCl3): ꢀ146.9 (br d, J = 49.3 Hz).
HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd. for C13H1335ClFNO6Na 356.0308; Found: 356.0314.
MS (EI): m/z = 335 ([M+2]+, 1.5), 333 (M+, 3.3), 227 (100).
Methyl (4ꢀchlorophenyl)acetate (11). Nitroalkene 1a (128 mg, 0.64 mmol) and Ac2O (0.18 mL,
1.9 mmol, 3 equiv) in MeOH (3.2 mL) was hydrogenated over Pd/C (10%) (15 mg) under 1 atm
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of H2 (balloon) for 3 days with continuous stirring. Reaction mixture was filtered through celite
and evaporated. Column chromatography (eluent: PE/EtOAc, 9:1) afforded 37 mg (31 %) of
compound 11 as colorless oil. NMR matched previously reported data.32
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rel 1ꢀСhloroꢀ4ꢀ((1S,6S)ꢀ6ꢀfluoroꢀ3,4ꢀdimethylꢀ6ꢀnitrocyclohexꢀ3ꢀenꢀ1ꢀyl)benzene (12). Glass
tube with a Young’s tap was evacuated and filled with argon. Next, solution of nitroalkene 1a
(0.202 g, 1 mmol) in toluene (0.5 mL) and 2,3ꢀdimethylbutaꢀ1,3ꢀdiene (1 mL) were added in
argon flow and the tube was tightly sealed. After that the tube was heated at 135 °C for 5 h in oil
bath. The excess of the diene and toluene were evaporated at reduced pressure and the residue
was purified by column chromatography on silica gel (PE/CH2Cl2, 3:1) to give 0.228 g (80 %) of
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adduct 12 as colorless solid. Rf 0.25 (PE,CH2Cl2, 3:1) (UV). mp = 83ꢀ84 °C (CHCl3) H NMR
(400 MHz, CDCl3): 1.71 (s, 3H), 1.72 (s, 3H), 2.35 (dd, J = 17.5 Hz, 6.0 Hz, 1H), 2.52ꢀ2.65 (m,
2H), 3.18 (dd, J = 35.0 Hz, 17.5 Hz, 1H), 3.73 (dd, J = 31.3 Hz, 12.2 Hz, 6.1 Hz, 1H), 7.22 (d, J
= 8.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H). 13C NMR (100 MHz, CDCl3): 18.2, 18.3, 36.6 (d, J = 3.1
Hz), 41.2 (d, J = 24.2 Hz), 45.7 (d, J = 19.6 Hz), 120.2, 120.3 (d, 1JCF = 242.7 Hz), 125.5, 128.7,
130.0 (d, J = 1.8 Hz), 134.0, 134.3. 19F NMR (376 MHz, CDCl3): ꢀ136.9 (ddd, J = 35.0 Hz, 31.3
Hz, 16.9 Hz). Anal. Calcd. for C14H15ClFNO2: C, 59.26; H, 5.33; N, 4.94. Found: C, 59.40; H,
5.28; N, 4.82. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd. for C14H1535ClFNO2Na 306.0668;
Found: 306.0672. MS (EI): m/z = 238 ([M+2–HNO2]+, 33), 236 ([M–HNO2]+, 78), 125 (100).
Ethyl 3ꢀ(4ꢀchlorophenyl)ꢀ4ꢀfluoroꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (13). To a solution of ethyl
isocyanoacetate (0.028 g, 0.25 mmol) in THF (0.5 mL) DBU (0.038 g, 0.25 mmol) was added
and mixture thus obtained was cooled to ꢀ18 °C at fridge. After that solution of nitroalkene 1a
(0.051 g, 0.25 mmol) in THF (0.5 mL) was added and reaction mixture was left at room
temperature for 24 h (TLC monitoring). Volatiles were evaporated in vacuo and the residue was
purified by column chromatography on silica gel (eluent: PE/CH2Cl2 = 1:1) to give 0.040 g
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(61 %) of pyrrole 13 as colorless solid. Rf 0.50 (CH2Cl2) (UV). mp = 120ꢀ122 °C (CHCl3) H
NMR (400 MHz, CDCl3): 1.24 (t, J = 7.1 Hz, 3H), 4.27 (q, J = 7.1 Hz, 2H), 6.79 (t, J = 3.5 Hz,
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1H), 7.37 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 9.23 (br s, 1H). C NMR (100 MHz,
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CDCl3): 14.1, 60.7, 106.5 (d, 2JCF = 27.7 Hz), 115.4, 116.8, 127.9, 128.9, 131.7, 133.3, 149.8 (d,
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1JCF = 244.3 Hz), 160.7 (d, JCF = 2.6 Hz). 19F NMR (376 MHz, CDCl3): ꢀ167.3 (m). HRMS
(ESIꢀTOF) m/z: [M + H]+ Calcd. for C13H1235ClFNO2 268.0535; Found: 268.0536. MS (EI): m/z
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= 269 ([M+2]+, 16), 267 (M+, 50), 221 (100).
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Acknowledgements
The work was supported by Russian Science Foundation (grant 14ꢀ50ꢀ00126). The authors thank
Dr. N. G. Kolotyrkina (N. D. Zelinsky Institute of Organic Chemistry) and Dr. P. N. Sol’yev (V.
A. Engelhardt Institute of Molecular Biology) for registration of HRMS.
Supporting information
Copies of 1H and 13C NMR spectra of the compounds (.pdf).
Crystal data (.cif).
References
1. Selected reviews: (a) Ono, N. The Nitro Group in Organic Synthesis; John Wiley &
Sons: New York, 2002. (b) Sukhorukov, A. Yu.; Sukhanova, A. A.; Zlotin, S. G.
Tetrahedron 2016, 72, 6191ꢀ6281. (c) Yan, W.; Shi, X.; Zhong, C. Asian J. Org. Chem.
2013, 2, 904ꢀ914; (d) Kaur, K.; Namboothiri, I. N. N. Chimia 2012, 913ꢀ920. (e) Zard, S.
Z. Helv. Chim. Acta 2012, 95, 1730ꢀ1757. (f) Ballini, R.; Gabrielli, S.; Palmieri, A.;
Petrini, M. Curr. Org. Chem. 2011, 15, 1482ꢀ1506. (g) Berner, O. M.; Tedeschi, L.;
Enders, D. Eur. J. Org. Chem. 2002, 1877ꢀ1894.
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