Diels-Alder Reaction of β-Fluoro-β-nitrostyrenes. Synthesis of Mono-fluorinated Six-Membered Derivatives

Article abstract of DOI:10.1002/ejoc.202000054

The Diels-Alder reaction of β-fluoro-β nitrostyrenes with some linear dienes was investigated. A number of monofluorinated [4+2]-cycloadducts was prepared in up to 90 % yield. The kinetics of [4+2]-cycloaddition to 2,3-dimethyl-1,3-butadiene was studied i

Full text of DOI:10.1002/ejoc.202000054

DOI: 10.1002/ejoc.202000054
Full Paper
Fluorinated Nitrostyrenes
Diels-Alder Reaction of ꢀ-Fluoro-ꢀ-nitrostyrenes. Synthesis of
Mono-fluorinated Six-Membered Derivatives
Roman V. Larkovich,[a] Savva A. Ponomarev,[a] Alexander S. Aldoshin,[a] Andrey A. Tabolin,[b]
Sema L. Ioffe,[b] and Valentine G. Nenajdenko*[a]
Abstract: The Diels-Alder reaction of ꢀ-fluoro-ꢀ nitrostyrenes activation parameters of the reaction. It was demonstrated that
with some linear dienes was investigated. A number of mono-
fluorinated [4+2]-cycloadducts was prepared in up to 90 %
yield. The kinetics of [4+2]-cycloaddition to 2,3-dimethyl-1,3-
butadiene was studied in detail to reveal substituent effect and
base-induced elimination of nitrous acid followed by oxidative
aromatization can be used for the preparation of mono-fluorin-
ated biphenyls in up to 92 % isolated yield.
Introduction
carbo- and heterocycles using either dienes[7–9] or dieno-
philes[10–13] as fluorine-containing building blocks[5,6] (Figure 1)
Thus, the development of new protocols to relevant fluorinated
molecules based on application of novel versatile fluorine-
containing building blocks is of exceptional significance.
Organofluorine compounds play an exceptionally important
role in the development of new drugs and design of materials
with unique properties. Intensive research in organofluorine
chemistry is still a key trend of modern organic synthesis, de-
spite more than 150-year history of this area. About one-fourth
of currently manufactured agrochemical and pharmaceutical
products contains at least one fluorine atom and their number
tends to persistently rise. Indeed, only about 20 % of these
products appeared on the market in the first decade of the 21st
century.[1] One of the key problems in synthetic and medical
chemistry is the design of structures with a strictly prescribed
position of a fluorine. Incorporation of a fluorine into the mole-
cule can positively modulate a number of important pharmaco-
kinetic and physicochemical properties of the drug, such as li-
pophilicity, electrophilicity, conformation, pKa, metabolic and
chemical stability, membrane permeability and binding affinity
to a target protein.[2] Recently, significant advance on the direct
fluorination has been made due to the development of novel
fluorinating reagents and catalytic systems.[3] However, the ap-
plication of such the protocols are challenging and often lim-
ited.[4] The use of fluorinated building blocks is a very conve-
nient approach and in many cases indispensable alternative to
direct approaches.[5,6]
Figure 1. Selected examples of monofluorinated building blocks in Diels-Alder
reaction.
Recently, we have developed the efficient stereoselective
synthesis of ꢀ-fluoro-ꢀ-nitrostyrenes[14,15] and demonstrated
utility of these new building blocks for the synthesis of numer-
ous fluorinated compounds.[16] We proposed that due to elec-
tron deficient nature of nitrostyrenes these building blocks
could be efficient monofluorinated dienophiles. This study is
devoted to investigation of their reaction with some linear di-
enes to form cycloadducts 2 as well as subsequent aromatiza-
tion of 2 into the corresponding mono-fluorinated biphenyls 3.
In this regard, Diels–Alder reaction is a powerful tool which
has found wide application for assembling variety of fluorinated
[a] Department of Chemistry, Lomonosov Moscow State University,
Leninskie gory 1, Moscow, 119991, Russian Federation
Fax:, +7-495-9328846
E-mail: nenajdenko@org.chem.msu.ru
http://www.chem.msu.ru/eng/
[b] N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences
Leninsky prosp. 47, Moscow 119991, Russian Federation
http://zioc.ru/institute/laboratories/laboratory-of-functional-organic-
compounds-n8
RESULTS AND DISCUSSION
First, a set of ꢀ-fluoro-ꢀ-nitrostyrenes 1 bearing different sub-
stituents in benzene ring was prepared[14,15] to estimate the
reactivity of these fluorinated building blocks in [4+2]-cyclo-
addition. Having in hand the set of substrates, the Diels-Alder
reaction of ꢀ-fluoro-ꢀ-nitrostyrenes 1 with 2,3-dimethyl-1,3-
butadiene was investigated. The reactions were conducted in
screw-top vials in o-xylene media at 130 °C using 5-fold excess
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202000054.
Eur. J. Org. Chem. 0000, 0–0
1
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
of 2,3-dimethyl-1,3-butadiene (Scheme 1). It was found that the ln (C0/C) vs. time (Table 1). The overall second-order rate con-
reactions proceeded highly efficiently under these conditions stant k were calculated from k* and initial concentration of di-
to give the target cycloadducts 2 in high isolated yield (75– ene (Table 1).
90 %). Moreover, the reactions can be easily scaled-up to gram
amount (Scheme 1; 2h). All the structures were elucidated by
NMR and elemental analysis.
It was found that the reaction rate significantly depends on
substituents in the benzene ring of nitrostyrenes 2. We decided
to study a correlation with the Hammett constants for these
substituents. The effect of a substituent on the reaction rate
was estimated first by plotting log k against the Hammett con-
stants σp for p-substituent (Figure 2). A very good correlation
of the plot was obtained for a series of p-substituted nitrostyr-
enes 1 according to the Hammet Equation (Equation (1)):
log k = 1.00σp – 4.84(R = 0.984)
(1)
Scheme 1. Scope of nitrostyrenes in the reactions with 2,3-dimethyl-1,3-
butadiene; (nitrostyrene 1 = 0.5 mmol; (a) - 1.0 mmol; (b) - 2.5 mmol;
(c) - 5.0 mmol).
Additionally, we decided to have a deep insight on the reac-
tivity of ꢀ-fluoro-ꢀ-nitrostyrenes 1 in [4+2]-cycloaddition reac-
tions. Up to date there are very few works devoted to kinetic
studies of nitrostyrenes in Diels-Alder reactions.[17,18] In this
context, we aimed at detail study of kinetics of ꢀ-fluoro-ꢀ-nitro-
styrenes in [4+2]-cycloaddition on the example of symmetric
2,3-dimethyl-1,3-butadiene. To our best knowledge such the
multilateral investigations on the reactivity and application of
?-deficient ꢀ-fluoro-ꢀ-nitrostyrenes in [4+2]-cycloaddition are
unprecedented.
All the kinetic runs were performed using ca 35 molar excess
of 2,3-dimethyl-1,3-butadiene in o-xylene (1:1) to provide
pseudo-first order conditions. Conversions (F) of 1 were meas-
ured by 1H NMR analysis. First, the kinetic curves were obtained
for the reactions of 2,3-dimethyl-1,3-butadiene with differently
substituted in the benzene ring nitrostyrenes 1a – 1n at 130 °C.
Figure 2. Plot of log k vs. Hammet constants (σp).
Another parameter frequently used for estimation of reactiv-
ity is a global electrophilicity index (ω).[20] In contrast to the
Hammet approach it gives reliable predictions not only for
para- or meta-mono-substituted derivatives, but also for both
ortho-mono-substituted and multi-substituted derivatives.[21]
Ground-state geometries of nitrostyrenes 1 were optimized us-
ing DFT B3LYP/6-31G* level of theory. The values of ω were
evaluated from HOMO and LUMO energies for nitrostyrenes 1a-
1n (Figure 3, Equation (2)):[22]
ω = μ2/2η = 1/8 (EHOMO + ELUMO)2/(ELUMO – EHOMO
)
(2)
Next, the similar linear relationship was obtained between
The pseudo-first order rate constants k* were obtained with log k and ω. However, the correlation in this case was slightly
good correlation by plotting the experimental values of worse (Figure 4).
Table 1. Kinetic parameters for the reactions of 1 with 2,3-dimethyl-1,3-butadiene at 130 °C.
Entry
Substrate 1
Substituent R
k*, × 105 s–1
k, × 105 L/mol·s
Rcorr
σ[19]
ω, eV
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
4-CH3O
4-tBu
4-CH3
H
4-F
4-Cl
3.03
4.16
4.80
6.66
8.95
8.47
10.31
10.04
21.48
20.92
21.90
23.11
32.03
42.20
0.69
0.94
1.09
1.51
2.03
1.92
2.33
3.40
4.86
4.73
4.95
5.23
7.25
9.55
0.996
>0.999
0.999
0.997
0.999
0.998
>0.999
0.994
0.998
0.998
0.999
0.997
0.998
0.999
–0.27
–0.20
–0.17
0.00
0.06
0.23
0.23
0.45
0.54
–
2.66
2.76
2.78
2.87
2.94
3.10
3.11
3.21
3.25
3.27
3.41
3.43
3.56
3.82
4-Br
4-CO2Me
4-CF3
2,4-Cl2
2-NO2
3-NO2
4-CN
4-NO2
9
10
11
12
13
14
–
0.71
0.66
0.78
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
2
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Figure 3. FMO energies and global electrophilicity indexes (ω) of ꢀ-fluoro-ꢀ-nitrostyrenes 1a – 1n.
tween log k and ω (Figure 5) demonstrates that the experimen-
tal data is in full accordance with the theoretical DFT calcula-
tions.
Figure 4. Plot of log k vs. global electrophilicity indexes (ω).
The relationships (Equation (1); Equation (3)) suggest a simi-
lar structure of the transition state involved in all the reactions
studied. Indeed, the transition states have slightly polar charac-
ter as indicated by the value of the reaction constant (ρ = 1.00).
Moreover, positive value of ρ indicates that the reaction is fa-
vored by withdrawal of electron pairs from the reaction site.[23]
Thus, the charge transfer with transition state takes place from
the diene substructure towards the nitrostyrene substructure
that is in full accordance with the theoretical prediction.
Figure 5. Effect of position nitro-group in benzene ring of nitrostyrenes 1.
After, the relationship between the global electrophilicity (ω)
and the Hammett constants (both σp and σm) was studied (Fig-
ure 6).[24] The plot obtained confirms the existence of a good
linear correlation between both variable parameters from a
strong electron-donating OCH3 to a strong electron-withdraw-
ing NO2-group for a series of nitrostyrenes 1 (Equation (4)):
ω = 0.91 σ + 2.90 (R = 0.964)
(4)
log k = 1.02ω – 7.78 (R = 0.971)
(3)
Next, the substituent effect at the double bond was esti-
mated. The kinetics studies of reactions of nitrostyrenes bearing
H, F, Cl and Me at the ꢀ-carbon with 2,3-dimethyl-1,3-butadiene
were carried out at 130 °C (Scheme 2).
We also estimated the effect of position of nitro-group in the
benzene ring (Figure 5). The experimental kinetic data obtained
for the reaction of 2,3-dimethyl-1,3-butadiene with nitrostyr-
enes 1k, 1l, 1n at 130 °C showed that the reaction rate in-
creased for a following series: o-NO2 < m-NO2 < p-NO2. Most
The experimental data showed that ꢀ-unsubstituted nitro-
probably the least reactivity of o-substituted nitrostyrene 1k is styrene 1a-H proved to be the most reactive one instead of ꢀ-
related to the steric effect caused by the close position of nitro- fluorinated 1a expected according to DFT calculations (Table 2;
group to the reaction site. Noteworthy, the high correlation be- Figure 7). Besides, the replacement of H with CH3-group caused
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
3
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
was obtained for the plot of log k vs. Tafft-Kutter-Harsh steric
constants (Ês) (Equation (5); Figure 8). The latter are linear func-
tions of average van der Waals radii (R¯vdw) and were calculated
as defined by Equation (6).[25]
log k = 0.86 Ês - 5.80(R = 0.945)
(5)
Ês = 3.484–1.839 R¯vdw
(6)
Figure 6. Plot of Hammet constants (σ) vs. global electrophilicity (ω).
Figure 8. Plot of log k vs. Ês.
This data confirms that in case of substituent at the terminal
carbon the reactivity is mainly influenced by steric hindrance
of the reaction site.
Scheme 2. Kinetic study of substituent effect at ꢀ-carbon.
up to 22-fold decrease of the rate constant value (Table 2). It is
obvious that this cannot be explained only by electronic effect
of substituents. Indeed, a very low correlation between log k
and ω was obtained. However, the noticeably higher correlation
Finally, activation parameters for the reaction of the most
reactive p-NO2-substituted substrate 1n were estimated. The ki-
netic studies were conducted in the temperature range of 70–
130 °C. The calculated rate constants are presented in Table 3.
The data obtained were plotted in Arrhenius coordinates (ln k
vs. 1/T) as well as in Eyring coordinates (ln (k/T) vs. 1/T). The
regression analysis gave the following linear relationships
(Equation (7), Equation (8)):
ln k = 10.16–7886/T (R = 0.990)
(7)
ln (k/T) = 3.19–7514.8/T (R = 0.989)
(8)
The activation parameters were estimated by both Arrhenius
equation (Equation (9)) and Eyring equation[27] (Equation (10)).
ln k = ln A – EA/RT
(9)
ln (k/T) = ln (kb/Z) + ΔS#/R – ΔH#/RT
(10)
The values obtained (Table 3) were found to be typical for
concerted [4+2]-cycloaddition reactions.[18]
Figure 7. FMO energies and global electrophilicity indexes (ω) of ꢀ-nitrostyr-
enes 1a-H, 1a, 1a-Cl, 1a-Me.
Table 2. Kinetic parameters for the reactions of 4-MeO-nitrostyrenes with 2,3-dimethyl-1,3-butadiene.
[26]
Entry
Substituent X
k* × 106 s–1
k × 106 L/mol·s
Rcorr
Rvdw
,
Å
Ês
ω, eV
1
2
3
4
H
F
Cl
Me
78.27
30.27
21.02
3.61
17.71
6.85
4.76
0.82
0.999
0.996
0.999
0.999
1.20
1.47
1.75
1.28
0.78
0.27
–0.14
2.44
2.66
2.64
2.27
1.93[a]
[a] Average between max (2.23) and min (1.715).
Table 3. Kinetic and thermodynamic data of the reaction 1h with 1,3-dimethylbutadiene.
Entry
T, °C
k* × 105 s–1
′
k × 105 L/mol·s
Rcorr
EA, kJ/mol
65.53
ΔH#, kJ/mol
ΔS#, J/mol·K
1
2
3
4
70
90
110
130
1.25
3.79
9.45
42.20
0.28
0.86
2.14
9.55
0.998
0.998
>0.999
0.999
62.45
–170.96
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
4
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Next, we decided to study elimination of nitrous acid under entries 3–4). However, the application of low nucleophilic
basic conditions. We expected that a family of highly attractive organic bases such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
monofluorinated biaryls could be prepared by this approach. 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) and 1,8-diazabicyclo-
Biphenyl is a key structural motif in a wide range of pharmaco- [5.4.0]undec-7-ene (DBU) demonstrated very good effective-
logical active compounds. Indeed, the biaryl structure is found ness. The corresponding mono fluorinated biaryl 4n was iso-
in 4.3 % of all known drugs which cover all therapeutic areas. lated in up to 82 % yield (Table 4, entries 5–7). Among the base
Moreover, biaryl groups can be useful templates for the discov- tested, DBU was selected as the most effective base. Moreover,
ery and design of therapeutics with high affinity and specificity the effectiveness of the process was noticeably enhanced when
for a broad range of protein targets.[28] The proposed sequence the reaction was conducted under pressure of air (Table 4, cf.
included two steps. After treatment with a base we expected entries 7, 10 with 8, 11). It should be emphasized that in all
the formation of the corresponding cyclohexadienes. However, cases the transformation of cycloadduct 2n into 3n occurred
due to potential low stability of these intermediate products, selectively; no formation of product 4n derived from the elimi-
we decided to perform aromatization in the presence of air to nation of HF was observed. However, when cycloadduct 2h
elaborate direct synthesis of the corresponding biphenyls.[29] In bearing p-methoxycarbonyl group was subjected to the aroma-
principle, competitive elimination of either HNO2 or HF can be tization, both products 3h and 4h were formed in 73 and 8 %
expected leading to the formation of either fluorine-substituted yield respectively (Table 4, entry 11). The change of the solvent
or nitro-substituted biphenyls (Scheme 3).
media did not affect the selectivity, but reduced the product
yield (Table 4, entries 12–13). Meanwhile, the use of MnO2 as
an oxidant was as effective as compressed air was. (Table 4,
entries 9,13).
We performed some optimization of the reaction conditions
for cycloadduct 2n as a model compound using various bases
(Table 4, entries 1–7). The reaction was performed in aceto-
nitrile at 60 °C in the presence of atmospheric air as an oxidant.
Having the optimized conditions in hand, the reaction was
The absence of solvent as well as the further increase of tem- performed with a set of cycloadducts 2 (Scheme 4). First, nitro-
perature led to the formation of undesirable and unidentified styrenes having strong electron-withdrawing group (EWG) sub-
side-products in the model reaction. When the reaction was stituents were tested (Scheme 4). In all cases only two products
performed in the presence of weak inorganic bases, only trace 3 and 4 were isolated. These results demonstrate that the cyclo-
amount of biphenyl 3n was detected by 19F NMR (Table 4, en- hexadiene intermediates are prone to oxidative aromatization.
tries 1–2). Low yields of the desired product 3n were observed To our delight, the elimination of HNO2 proceeds predomi-
when excess of cesium fluoride or tBuOK were used (Table 4, nantly. The corresponding monofluorinated biphenyls 3 were
Scheme 3. Elimination-aromatization of cycloadducts 2.
Table 4. Optimization of elimination-aromatization sequence.[a]
Entry
Substrate
base
oxidant
Solvent
Yield 3, %
Yield 4, %
1
2
3
4
5
6
7
8
9
2n
2n
2n
2n
2n
2n
2n
2n
2n
K2CO3 (10 equiv.)
KF (10 equiv.)
CsF (10 equiv.)
tBuOK (5 equiv.)
DBN (4 equiv.)
TBD (4 equiv.)
DBU (4 equiv.)
DBU (4 equiv.)
DBU (4 equiv.)
atm. air
atm. air
atm. air
atm. air
atm. air
atm. air
atm. air
air 1.5 bar
MnO2 (5 equiv.)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
trace
trace
16
14
76
80
82
92
86
0
0
0
0
0
0
0
0
0
10
11
12
13
14
2h
2h
2h
2h
2h
DBU (6 equiv.)
DBU (6 equiv.)
DBU (6 equiv.)
DBU (6 equiv.)
DBU (6 equiv.)
atm. air
MeCN
MeCN
EtOAc
THF
50
73
68
42
77
trace
8
8
trace
6
air 1.5 bar
air 1.5 bar
air 1.5 bar
MnO2 (5 equiv.)
MeCN
[a] Reaction conditions: 60 °C; concentration 2 = 0.4
M; 18–24 h.
Eur. J. Org. Chem. 0000, 0–0 www.eurjoc.org
5
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 4. Scope of strong EWG-substituted cycloadducts 2.
isolated in up to 92 % yield, whereas the nitro-containing deriv- oxidize by both oxygen and MnO2 in acetonitrile even at 80 °C.
atives 4 (elimination of HF) were isolated as minor products. However, the treatment of the reaction mixture with MnO2 in
Additionally, we investigated the effect of position of the nitro- toluene for 5 h at 80 °C made aromatization successful to give
group on the reaction selectivity. When the nitro-group is 3j in 15 % isolated yield. As result the formation of inseparable
posed at meta-position, the yield of the target 3l dropped to mixtures of fluorinated non-oxidized cyclohexadiene intermedi-
41–49 %, whereas the portion of 4l rose to 17–27 %. To our ates IM-1, IM-2 and biphenyl 3 were observed. On the contrary,
surprise, the elimination of adduct 2k with the nitro-group at the formation of ortho-nitro biphenyls 4 proceeds cleanly to
ortho-position led to the selective formation of non-fluorinated demonstrate that the presence of strong EWG is important to
biphenyl 4k in 49 % yield.
facilitate oxidative aromatization.
Further, the elimination for cycloadducts 2 bearing either no
EWG (2b–2d) or weak EWG (2e–2j) was studied (Table 5). It was
found that in this case the reaction is much more complicated.
Both the chemoselectivity and yields of monofluorinated bi-
phenyls 3 were significantly lower. In contrast, the elimination
of HF intensified to give nitro-substituted biphenyls 4 in 16–
41 % yield.
Next, the reactions of nitrostyrenes 1n, 1h with isoprene and
piperylene were studied. The corresponding cycloadducts 2
were isolated in high yield (64–85 %) confirming general char-
acter of the cycloaddition (Scheme 5). As expected, the reac-
tions are more complex due to unsymmetrical structure of both
reactants. According to analysis of NMR, the mixture of regio-
and stereoisomers is formed. Nevertheless, the subsequent
elimination-aromatization eventually gives the target product 3
as a mixture of two regioisomers having different position of
methyl groups.
Table 5. Scope of cycloadducts 2 with no or weak EWG.[a]
The aromatizaton of cycloadducts 2o–2s demonstrated the
similar pattern in terms of selectivity as that of cycloadducts
2h; 2n did. In case of piperylene derived cycloadducts 2o and
2p the yields of the desired products 3o and 3p were in range
25–46 %; the yields of the side products 4o and 4p did not
exceed 5 %. When isoprene based cycloadduct 2r underwent
to the aromatization process in the presence of MnO2, 37 % of
mono-fluorinated biphenyls 3r was obtained along with 11 %
of the side products 4r. On the contrary nitro-substituted cyclo-
adduct 2s was selectively transformed into the target products
3s in high yield (86 %) under compressed air.
[a] 60 °C, compressed air, DBU (8 mol. equiv.), 18–24 h. [b] 80 °C, MnO2
(5 mol. equiv.), DBU (8 mol. equiv.), 18 h.
Moreover, it was observed that the fluorine-containing cyclo-
Finally, the Diels-Alder reaction of nitrostyrene 1f with (E)-1-
hexadiene intermediates with no or weak EWG are difficult to methoxy-3-trimethylsilyloxy-buta-1,3-diene (Danishefsky's di-
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 5. Preparation of cycloadducts and biphenyls based on unsymmetrical 1,3-dienes.
Scheme 6. Diels-Alder reaction of nitrostyrene 1f with Danishefsky's diene.
ene) was studied (Scheme 6). Due to electron-rich nature of sequence for the synthesis of the corresponding mono-fluorin-
this diene the reaction was complete at 110 °C within 7.5 h. ated biphenyls was elaborated. It was found that the selectivity
Subsequent hydrolysis of TMS-group by THF/water solution of of the process and oxidizability of cycloadducts depends on the
HCl resulted in the formation of the mixture of regio- and ster- nature and position of substituents in the benzene ring. The
eoisomers of the corresponding cyclohexanones 5f in 76 % to- adducts bearing strong electron-withdrawing groups at para-
tal yield.
position can be transformed into the desired biphenyls in selec-
tive manner in up to 92 % isolated yield.
In summary, the Diels-Alder reaction of ꢀ-fluoro-ꢀ-nitro-
styrenes with linear dienes was investigated. A series of novel
monofluorinated [4+2]-cycloadducts was prepared in high yield
up to 90 %. The kinetic studies of [4+2]-cycloaddition reaction
of a series of nitrostyrenes with 2,3-dimethyl-1,3-butadiene
were carried out considering substituent effect in the benzene
ring and at the terminal ꢀ-carbon. The global electrophilicity
indexes were evaluated for a wide range of nitrostyrenes 1. The
experimental data demonstrated that the substituent effect in
the benzene ring was in agreement with both the Hammet
equation and DFT calculations. The activation parameters of the
reaction were found to be typical for concerted [4+2]-cyclo-
Experimental Section
All reagents were purchased from commercial sources and used
without any further purification except for piperylene and isoprene.
The latter were purified by distillation before use. Piperylene was
composed of 75 % of Z- and 25 % of E-isomer. All solvents were
dried before use by passing through a column charged with acti-
vated neutral alumina[30] or with the standard procedures. Melting
points (M.p.) were measured with a Büchi B-545 melting point appa-
ratus. NMR (1H, 13C and 19F) spectra were obtained with Bruker
addition reactions. In addition, the elimination-aromatization AV-400 and Agilent 400-MR spectrometers using deuterated chloro-
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
7
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
form (CDCl3). Chemical shifts for 1H NMR spectroscopic data were
referenced to internal tetramethylsilane (δ = 0.0 ppm) and the resid-
ual solvent resonance (δ = 7.26 ppm); chemical shifts for 13C NMR
spectroscopic data were referenced to residual solvent resonance
(δ = 77.16 ppm); chemical shifts for 19F NMR spectroscopic data
were referenced to PhCF3 (δ = –63.72 ppm). Data are reported as
follows: chemical shift, integration multiplicity (s = singlet, d = dou-
blet, t = triplet, q = quadruplet, qui = quintet, sext = sextet, sept =
septet, br = board, m = multiplet, dd = doublet of doublets, ddd =
doublet of doublet of doublets) and coupling constants (Hz). Start-
ing ꢀ-fluoro-ꢀ-nitrostyrenes were prepared according to the de-
scribed procedures.[14,15] Nitrostyrenes 1a, 1c, 1d, 1e, 1f, 1h, 1k,
1m, 1n;[14] 1b, 1g;[31]1i;[32] 1j[33] are known compounds.
analysis monitoring), the excess of the diene and o-xylene were
evaporated under vacuum. The pure product was isolated by col-
umn chromatography using mixture of Hex/DCM as eluent.
Synthesis of 2,3-dimethyl-1,3-butadiene based cycloadduts 2
(1R*,2R*)-2-Fluoro-4′-methoxy-4,5-dimethyl-2-nitro-1,2,3,6-
tetrahydro-1,1′-biphenyl (2a). Eluent: Hex/DCM (2:1); 0.115 g
(85 %), pale yellow solid; M.p. 102–103 °C (Hex/DCM, 2:1). Anal.
calcd. for C15H18FNO3 (%): C, 64.50; H, 6.50; N, 5.01; found C, 64.52;
H, 6.48; N, 4.97. 1H NMR (400 MHz, CDCl3): δ = 1.69–1.75 (m, 6H),
2
3
2.34 (dd, JH,H = 17.5 Hz, JH,H = 6.0 Hz, 1H), 2.47–2.71 (m, 2H), 3.19
(dd, 3JH,F = 34.9 Hz, JH,H = 18 Hz, 1H), 3.68 (ddd, 3JH,F = 31.5 Hz,
2
3JH,H = 12.2, 6.0 Hz, 1H), 3.77 (s, 3H), 6.79–6.85 (m, 2H), 7.19 (d,
3JH,H = 7.8 Hz) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.4, 18.5, 37.0
1-(2-Bromo-2-fluorovinyl)-3-nitrobenzene. 3-Nitrobenzaldehyde
(15.133 g, 100 mmol) was added portionwise to the solution of
hydrazine hydrate (5.3 mL, 110 mmol) in ethanol (400 mL) with
stirring. After completion of hydrazone formation (TLC monitoring),
the reaction mixture was cooled to 0 °C in ice-water bath and CBr3F
(14.7 mL, 150 mmol) was added. Then solution of ethylene diamine
(10 mL, 150 mmol) and CuCl (200 mg, 3 mmol) in ethanol (100 mL)
was added dropwise to the reaction mixture. The reaction mixture
was warmed to room temperature and stirred overnight. After the
reaction mixture was filtered and concentrated under vacuum. The
resulting mixture was dissolved in DCM (150 mL) and poured into
5 % aqueous HCl solution (150 mL). The product was extracted with
DCM, dried with anhydrous Na2SO4, and concentrated under vac-
uum. The product was isolated as E/Z-isomers mixture (74:26) by
column chromatography on silica gel using hexane/DCM (1:1) as
3
2
2
(d, JC,F = 3.6 Hz), 41.5 (d, JC,F = 24.3 Hz), 45.8 (d, JC,F = 19.6 Hz),
1
55.3, 114.1, 120.3, 121.0 (d, JC,F = 242.0 Hz), 126.0, 127.8, 129.9,
159.5 ppm. 19F NMR (376 MHz, CDCl3): δ = –140.85 – –140.58 (m)
ppm.
(1R*,2R*)-4′-(tert-Butyl)-2-fluoro-4,5-dimethyl-2-nitro-1,2,3,6-
tetrahydro-1,1′-biphenyl (2b). Hex/DCM (6:1); 0.122 g (80 %), col-
orless solid; M.p. 108–110 °C (Hex/DCM, 6:1). Anal. calcd. for
C18H24FNO2 (%): C, 70.79; H, 7.92; N, 4.59; found C, 70.81; H, 7.95;
N, 4.62. 1H NMR (400 MHz, CDCl3): δ = 1.30 (s, 9H), 1.73 (s, 6H), 2.37
2
3
(dd, JH,H = 17.6 Hz, JH,H = 6.0 Hz, 1H), 2.50–2.73 (m, 2H), 3.20 (dd,
3JH,F = 35.0 Hz, 2JH,H = 17.8 Hz, 1H), 3.73 (ddd, 3JH,F = 31.6 Hz, 3JH,H
=
3
4
12.1, 6.0 Hz, 1H), 7.21 (dd, JH,H = 8.3 Hz, JH,H = 1.0 Hz, 2H), 7.30–
7.34 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.4, 18.5, 31.4,
3
2
2
34.6, 37.0 (d, JC,F = 3.4 Hz), 41.6 (d, JC,F = 24.3 Hz), 46.0 (d, JC,F
=
1
1
19.5 Hz), 120.3, 120.9 (d, JC,F = 242.4 Hz), 125.7, 126.1, 128.5 (d,
4JC,F = 0.9 Hz), 132.7, 151.0 ppm. 19F NMR (376 MHz, CDCl3): δ =
–135.73 – –135.46 (m) ppm.
eluent; 20.850 g (85 %); yellowish oil; Z-isomer: H NMR (400 MHz,
CDCl3): δ = 6.64 (d, 3JH,F = 14.5 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.69–
7.73 (m, 1H), 8.00–8.03 (m, 1H), 8.22 (t, J = 1.9 Hz, 1H) ppm; E-
1
3
isomer: H NMR (400 MHz, CDCl3): δ = 5.97 (d, JH,F = 32.0 Hz, 1H),
7.43 (t, J = 8.0 Hz, 1H), 7.56–7.60 (d, J = 7.8 Hz, 1H), 7.98 (ddd, J =
8.2, 2.2, 1.0 Hz, 1H), 8.05 (t, J = 1.9 Hz, 1H) ppm. Analysis of the
sample matched the previously reported data.[34]
(1R*,2R*)-2-Fluoro-4,4′,5-trimethyl-2-nitro-1,2,3,6-tetrahydro-
1,1′-biphenyl (2c). Eluent: Hex/DCM (3:1); 0.117 g (80 %); colorless
solid; M.p. 96–98 °C (Hex/DCM, 3:1); Anal. calcd. for C15H18FNO2
(%):C, 68.42; H, 6.89; N, 5.32; found C, 68.47; H, 6.83; N, 5.33. 1H
NMR (400 MHz, CDCl3): δ = 1.70–1.76 (m, 6H), 2.32 (s, 3H), 2.37 (dd,
(Z)-1-(2-Fluoro-2-nitrovinyl)-3-nitrobenzene (1l). Fe(NO3)3·9H2O
(99.20 g, 246 mmol) in dioxane (985 mL) was added into a flask
with 1-(2-bromo-2-fluorovinyl)-3-nitrobenzene (20.14 g, 82 mmol).
The reaction mixture was refluxed at 100 °C for 2.5 h with vigorous
stirring. After completion of the reaction (TLC control), the reaction
mixture was cooled to room temperature, filtered through a paper
filter and concentrated under vacuum. The residue was dissolved
in DCM (150 mL), poured into water (150 mL). The product was
extracted with DCM, dried with anhydrous Na2SO4, and concen-
trated under vacuum. The pure product was isolated by column
chromatography on silica gel using Hex/DCM (2:1; 1:1) as elution
mixture. 13.30 g (77 %); yellow solid; M.p. 95–97 °C (Hex/DCM, 1:1).
3
2
3
2JH,H = 17.0 Hz, JH,H = 5.8 Hz, 1H), 2.56 (dd, JH,H = 17.6 Hz, JH,F
=
17.3 Hz, 1H), 2.62–2.74 (dd, 2JH,H = 17.0 Hz, 3JH,H = 12.1 Hz, 1H), 3.21
3
2
3
(dd, JH,F = 35.0 Hz, JH,H = 17.6 Hz, 1H), 3.71 (ddd, JH,F = 31.5 Hz,
3JH,H = 12.1, 5.8 Hz, 1H), 7.12 (d, JH,H = 7.9 Hz, 2H), 7.18 (d, JH,H
=
3
3
7.9 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.4, 18.5, 21.2,
37.0 (d, 3JC,F = 3.6 Hz), 41.5 (d, 2JC,F = 24.3 Hz), 46.2 (d, JC,F
=
=
2
1
4
19.6 Hz), 120.3, 120.9 (d, JC,F = 242.5 Hz), 126.0, 128.7 (d, JC,F
1.9 Hz), 129.4, 132.8, 138.0 ppm. 19F NMR (376 MHz, CDCl3): δ =
–136.84 to –136.56 (m) ppm.
(1R*,2R*)-2-Fluoro-4,5-dimethyl-2-nitro-1,2,3,6-tetrahydro-1,1′-
biphenyl (2d). Eluent: Hex/DCM (3:1); 0.099 g (80 %), colorless solid;
M.p. 109–110 °C (Hex/DCM, 3:1). Anal. calcd. for C14H16FNO2 (%): C,
67.45; H, 6.47; N, 5.62; found C, 67.38; H, 6.31; N, 5.64. 1H NMR
(400 MHz, CDCl3): δ = 1.69–1.78 (m, 6H), 2.39 (dd, 2JH,H = 17.5 Hz,
Anal. calcd. for C8H5FN2O4: C, 45.29; H, 2.38; N, 13.21; found C, 45.13,
3
H, 2.25, N, 13.16; 1H NMR (400 MHz, CDCl3): δ = 7.49 (d, JH,F
=
25.0 Hz, 1H), 7.72 (t, J = 8.1 Hz, 1H), 7.98–8.03 (m, 1H), 8.31 (ddd,
J = 8.3, 2.2, 1.0 Hz, 1H), 8.48 (t, J = 1.8 Hz, 1H) ppm;13C NMR
3JH,H = 6.0 Hz, 1H), 2.50–2.76 (m, 2H), 3.22 (dd, 3JH,F = 34.7 Hz, 2JH,H
=
2
3
(100 MHz, CDCl3): δ = 107.5 (d, JC,F = 6.0 Hz); 125.1 (d, JC,F
=
3
3
17.0 Hz, 1H), 3.75 (ddd, JH,F = 31.7, JH,H = 12.1, 6.0 Hz, 1H), 7.30 (s,
8.0 Hz), 125.7 (d, 4JC,F = 2.3 Hz), 129.5 (d, 3JC,F = 6.3 Hz), 130.6, 136.1
3
5H) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.4, 18.5, 37.0 (d, JC,F
=
(d, 4JC,F = 7.7 Hz), 148.6, 153.1 (d, 1JC,F = 299.3 Hz) ppm; 19F NMR
3.3 Hz), 41.5 (d, 2JC,F = 24.3 Hz), 46.5 (d, 2JC,F = 19.5 Hz), 120.3, 120.8
3
(376 MHz, CDCl3): δ = –109.37 (d, JH,F = 25.0 Hz) ppm.
1
4
(d, JC,F = 242.6 Hz), 125.9, 128.3, 128.7, 128.8 (d, JC,F = 1.6 Hz),
135.9 ppm. 19F NMR (376 MHz, CDCl3): δ = –135.56 (ddd, J = 34.7,
31.7, 16.7) ppm.
General procedure for the Diels-Alder reaction of ꢀ-fluoro-ꢀ-
nitrostyrenes and dienes
In a typical experiment, ꢀ-fluoro-ꢀ-nitrostyrene 1 (0.5 mmol), o-xyl-
ene (0.2 mL) and diene (2.5 mmol) were successively loaded into a
screw-top vial filled with argon. After the cap was screwed tightly,
the reaction mixture was heated at 130 °C with vigorous stirring for
appropriate time (8–24 h). After completion of the reaction (1H NMR
(1R*,2R*)-2,4′-Difluoro-4,5-dimethyl-2-nitro-1,2,3,6-tetrahydro-
1,1′-biphenyl (2e). Eluent: Hex/DCM (3:1); 0.102 g (75 %); colorless
oil; Anal. calcd. for C14H15F2NO2 (%): C, 62.91; H, 5.66; N, 5.24; found
1
C, 62.89; H, 5.65; N, 5.18. H NMR (400 MHz, CDCl3): δ = 1.68–1.75
2
3
(m, 6H), 2.36 (dd, JH,H = 17.5 Hz, JH,H = 6.1 Hz, 1H), 2.50–2.68
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
8
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
3
2
(m,2H), 3.19 (dd, JH,F = 35.0 Hz, JH,H = 17.6 Hz, 1H), 3.74 (ddd,
3JH,F = 31.6 Hz, 3JH,H = 12.3, 6.1 Hz, 1H), 6.95–7.02 (m, 2H), 7.22–7.29
(m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.4, 18.5, 37.0 (d,
3JC,F = 3.2 Hz), 41.4 (d, 2JC,F = 24.3 Hz), 45.8 (d, 2JC,F = 19.6 Hz), 115.6
(85 %), colorless solid; M.p. 115–117 °C (Hex/DCM, 3:1). Anal. calcd.
for C14H14Cl2FNO2 (%): C, 52.85; H, 4.44; N, 4.40; found C, 52.81; H,
4.27; N, 4.19. 1H NMR (400 MHz, CDCl3): δ = 1.72 (s, 6H), 2.40 (d,
2
3
3JH,H = 9.0 Hz, 2H), 2.57 (dd, JH,H = 17.2 Hz, JH,F = 16.8 Hz, 1H),
2
1
(d, JC,F = 21.4 Hz), 120.4, 120.7 (d, JC,F = 242.3 Hz), 125.8, 130.5
3.19 (dd, 3JH,F = 35.3 Hz, 2JH,H = 17.2 Hz, 1H), 4.44 (dt, 3JH,F = 32.0 Hz,
3
4
4
3
4
(dd, JC,F = 8.2 Hz, JC,F = 1.7 Hz), 131.7 (d, JC,F = 2.9 Hz), 162.6 (d,
1JC,F = 247.0 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –136.02 (ddd,
J = 35.0, 31.6, 16.9 Hz), –114.02 to –113.92 (m) ppm.
3JH,H = 9.0 Hz, 1H), 7.21 (dd, JH,H = 8.5 Hz, JH,H = 2.2 Hz, 1H), 7.37
4
3
5
(d, JH,H = 2.2 Hz, 1H), 7.50 (dd, JH,H = 8.5 Hz, JH,H = 1.2 Hz, 1H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 17.9, 18.0, 36.5 (d, JC,F
=
3
2
2
3.2 Hz), 40.9 (d, JC,F = 18.5 Hz), 41.4 (d, JC,F = 24.6 Hz), 120.1 (d,
(1R*,2R*)-4′-Chloro-2-fluoro-4,5-dimethyl-2-nitro-1,2,3,6-tetra-
hydro-1,1′-biphenyl (2f). Eluent: Hex/DCM (3:1); 0.121 g (85 %),
colorless solid; M.p. 77–79 °C (Hex/DCM, 3:1); 1H NMR (400 MHz,
1JC,F = 243.0 Hz), 120.6, 125.8, 127.8, 129.6 (d, JC,F = 7.5 Hz), 129.8,
3
133.1 (d, JC,F = 1.9 Hz), 134.4, 135.1 ppm. 19F NMR (376 MHz,
4
CDCl3): δ = –134.64 (ddd, J = 35.3, 32.0, 16.8 Hz) ppm.
2
3
CDCl3): δ = 1.68–1.75 (m, 6H), 2.36 (dd, JH,H = 17.5 Hz, JH,H
=
=
3
2
6.1 Hz, 1H), 2.46–2.67 (m, 2H), 3.18 (dd, JH,F = 35.1 Hz, JH,H
(1R*,2R*)-2-Fluoro-4,5-dimethyl-2,2′-dinitro-1,2,3,6-tetrahydro-
1,1′-biphenyl (2k). Eluent: Hex/DCM (2:1); 0.257 g (87 %) obtained
from 1.0 mmol of nitrostyrene 1k; pale orange solid; M.p. 149–
150 °C (Hex/DCM = 2:1); Anal. calcd. for C14H15FN2O4 (%): C, 57.14;
17.6 Hz, 1H), 3.72 (ddd, 3JH,F = 31.1 Hz, 3JH,H = 12.2, 6.1 Hz, 1H), 7.21
3
3
(d, JH,H = 8.5 Hz, 2H), 7.27 (d, JH,H = 8.5 Hz, 2H) ppm. Analysis of
the sample was consistent with the data reported in the litera-
ture.[14]
1
H, 5.14; N, 9.52; found C, 57.22; H, 5.20; N, 9.50. H NMR (400 MHz,
CDCl3): δ = 1.70 (s, 3H), 1.73 (s, 3H), 2.48–2.72 (m, 3H), 3.05 (dd,
(1R*,2R*)-4′-Bromo-2-fluoro-4,5-dimethyl-2-nitro-1,2,3,6-tetra-
hydro-1,1′-biphenyl (2g). Eluent: Hex/DCM (3:1); 0.128g (91 %),
colorless solid; M.p. 93–95 °C (Hex/DCM, 3:1). Anal. calcd. for
C14H15BrFNO2 (%): C, 51.24; H, 4.61; N, 4.27; found C, 51.21; H, 4.60;
3JH,F = 36.5 Hz, 2JH,H = 17.2 Hz, 1H), 4.49 (ddd, 3JH,F = 31.0 Hz, 3JH,H
=
11.6, 6.4 Hz, 1H), 7.37–7.43 (m, 1H), 7.51–7.57 (m, 1H), 7.70–7.77 (m,
3
2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.4, 18.5, 37.2 (d, JC,F
=
2
2
1
2
3.4 Hz), 40.1 (d, JC,F = 17.9 Hz), 42.0 (d, JC,F = 24.7 Hz), 120.0 (d,
N, 4.28. H NMR (400 MHz, CDCl3): δ = 1.71 (s, 6H), 2.35 (dd, JH,H
17.5 Hz, JH,H = 6.0 Hz, 1H), 2.49–2.67 (m, 2H), 3.17 (dd, JH,F
=
=
1JC,F = 244.0 Hz), 120.4, 124.7, 125.9, 128.9, 129.3 (d, JC,F = 7.7 Hz),
3
3
3
130.6 (d, JC,F = 2.2 Hz), 133.0, 150.7 ppm. 19F NMR (376 MHz,
4
2
3
3
35.0 Hz, JH,H = 17.9 Hz, 1H), 3.70 (ddd, JH,F = 31.0 Hz, JH,H = 12.2,
3
4
CDCl3): δ = –135.11 (ddd, J = 35.8, 31.0, 16.5 Hz) ppm.
6.0 Hz, 1H), 7.15 (dd, JH,H = 8.3 Hz, JH,H = 0.8 Hz, 2H), 7.39–7.44
(m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.4, 18.5, 36.8 (d,
(1R*,2R*)-2-Fluoro-4,5-dimethyl-2,3′-dinitro-1,2,3,6-tetrahydro-
1,1′-biphenyl (2l). Eluent: Hex/DCM (5:1); 0.236 g (80 %); pale yel-
low solid; M.p. 126–128 °C (Hex/DCM=, 5:1); Anal. calcd. for
3JC,F = 3.2 Hz), 41.4 (d, JC,F = 24.2 Hz), 46.0 (d, JC,F = 19.6 Hz),
2
2
1
4
120.4, 120.5 (d, JC,F = 242.7 Hz), 122.4, 125.7, 130.5 (d, JC,F
=
1.6 Hz), 131.9, 134.9 ppm. 19F NMR (376 MHz, CDCl3): δ = –135.91
C
14H15FN2O4 (%): C, 57.14; H, 5.14; N, 9.52; found C, 57.10; H, 5.12;
1
2
to –135.61 (m) ppm.
N, 9.47. H NMR (400 MHz, CDCl3): δ = 1.72 (s, 6H), 2.41 (dd, JH,H
=
=
3
3
17.4 Hz, JH,H = 5.8 Hz, 1H), 2.51–2.74 (m, 2H), 3.18 (dd, JH,F
Methyl (1R*,2R*)-2′-fluoro-4′,5′-dimethyl-2′-nitro-1′,2′,3′,6′-
tetrahydro-[1,1′-biphenyl]-4-carboxylate (2h). Eluent: Hex/DCM
(2:1); 0.118 g (78 %) obtained from 0.5 mmol of nitrostyrene 1h;
0.615 g (90 %) obtained from 2.5 mmol of nitrostyrene 1h; colorless
solid; M.p. 81–83 °C (Hex/DCM, 2:1); HRMS (ESI): calcd. for
35.4 Hz, JH,H = 17.6 Hz, 1H), 3.88 (ddd, JH,F = 30.5 Hz, 3JH,H = 12.2,
2
3
3
3
6.2 Hz, 1H), 7.47 (t, JH,H = 7.9 Hz, 1H), 7.62 (d, JH,H = 7.6 Hz, 1H),
8.09–8.20 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.3, 18.4,
3
2
2
36.6 (d, JC,F = 3.3 Hz), 41.2 (d, JC,F = 24.0 Hz), 46.1 (d, JC,F
=
=
1
4
C
16H19FNO4 [M + H]+ = 308.1298, found 308.1292; 1H NMR
19.7 Hz), 120.2 (d, JC,F = 243.0 Hz), 120.5, 123.3, 123.8 (d, JC,F
2.3 Hz), 125.4, 129.8, 135.1 (d, JC,F = 2.2 Hz), 138.0, 148.3 ppm. 19F
NMR (376 MHz, CDCl3): δ = –136.59 (ddd, J = 35.1, 30.5, 17.1 Hz)
ppm.
4
2
3
(400 MHz, CDCl3): δ = 1.70 (s, 6H), 2.35 (dd, JH,H = 17.4 Hz, JH,H
=
=
3
2
6.0 Hz, 1H), 2.47–2.70 (m, 2H), 3.16 (dd, JH,F = 35.1 Hz, JH,H
17.6 Hz, 1H), 3.78 (ddd, 3JH,F = 30.9 Hz, 3JH,H = 12.2, 6.0 Hz, 1H), 3.87
3
3
(s, 3H), 7.34 (d, JH,H = 7.5 Hz, 2H), 7.94 (d, JH,H = 8.4 Hz, 2H) ppm.
(1R*,2R*)-2′-Fluoro-4′,5′-dimethyl-2′-nitro-1′,2′,3′,6′-tetrahydro-
[1,1′-biphenyl]-4-carbonitrile (2m). Eluent: Hex/DCM (1:1); 0.232 g
(85 %) obtained from 1.0 mmol of nitrostyrene 1m; colorless solid;
M.p. 117–118 °C (Hex/DCM, 1:1). Anal. calcd. for C15H15FN2O2 (%):
13C NMR (100 MHz, CDCl3): δ = 18.3, 18.4, 36.7 (d, JC,F = 3.5 Hz),
3
2
2
1
41.4 (d, JC,F = 24.2 Hz), 46.4 (d, JC,F = 19.4 Hz), 120.4 (d, JC,F
=
3
4
243.1 Hz), 120.4 (d, JC,F = 0.5 Hz), 125.6, 128.9 (d, JC,F = 2.3 Hz),
129.9, 130.0, 141.0 (d, 3JC,F = 1.0 Hz), 166.7 ppm. 19F NMR (376 MHz,
CDCl3): δ = –135.67 to –135.32 (m) ppm.
1
C, 65.88; H, 5.51; N, 10.21; found C, 65.76; H, 5.55; N 10.28. H NMR
2
3
(400 MHz, CDCl3): δ = 1.70 (s, 6H), 2.35 (dd, JH,H = 17.5 Hz, JH,H
=
=
3
2
5.8 Hz, 1H), 2.48–2.69 (m, 2H), 3.16 (dd, JH,F = 35.1 Hz, JH,H
(1R*,2R*)-2-Fluoro-4,5-dimethyl-2-nitro-4′-(trifluoromethyl)-
1,2,3,6-tetrahydro-1,1′-biphenyl (2i). Eluent: Hex/DCM (5:1);
0.278 g (87 %) obtained from 1.0 mmol of nitrostyrene 1i; colorless
solid; M.p. 68–69 °C (Hex/DCM, 5:1). Anal. calcd. for C15H15F4NO2
(%): C, 56.78; H, 4.77; N, 4.41; found C, 56.76; H, 4.72; N, 4.41. 1H
17.8 Hz, 1H), 3.80 (ddd, 3JH,F = 30.8 Hz, 3JH,H = 12.1, 6.1 Hz, 1H), 7.39
(d, JH,H = 7.8 Hz, 2H), 7.53–7.61 (m, 2H) ppm. 13C NMR (100 MHz,
3
CDCl3): δ = 18.3, 18.4, 36.5 (d, 3JC,F = 3.4 Hz), 41.2 (d, 2JC,F = 24.0 Hz),
2
1
46.4 (d, JC,F = 19.4 Hz), 112.2, 118.4, 120.1 (d, JC,F = 243.2 Hz),
120.5, 125.3, 129.6 (d, JC,F = 2.3 Hz), 132.4, 141.3 ppm. 19F NMR
4
2
NMR (400 MHz, CDCl3): δ = 1.73 (s, 6H), 2.38 (dd, JH,H = 17.5 Hz,
3
3JH,H = 5.8 Hz, 1H), 2.51–2.74 (m, 2H), 3.20 (dd, JH,F = 35.1 Hz,
(376 MHz, CDCl3): δ = –136.47 (ddd, J = 35.1, 30.8, 17.0 Hz) ppm.
3
3
2JH,H = 17.7 Hz, 1H), 3.84 (ddd, JH,F = 30.9 Hz, JH,H = 12.2, 6.1 Hz,
(1R*,2R*)-2-Fluoro-4,5-dimethyl-2,4′-dinitro-1,2,3,6-tetrahydro-
1,1′-biphenyl (2n). Eluent: Hex/DCM (2:1); 0.107 g (73 %) obtained
from 0.5 mmol of nitrostyrene 1n; 1.120 g (75 %) obtained from
5.0 mmol of nitrostyrene 1n; colorless solid; M.p. 115–116 °C (Hex/
DCM, 2:1). Anal. calcd. for C14H15FN2O4 (%): C, 57.14; H, 5.14; N, 9.52;
1H), 7.43 (d, 3JH,H = 8.1 Hz, 2H), 7.57 (d, 3JH,H = 8.2 Hz, 2H) ppm. 13
C
3
NMR (100 MHz, CDCl3): δ = 18.3, 18.4, 36.8 (d, JC,F = 3.4 Hz), 41.4
(d, 2JC,F = 24.2 Hz), 46.3 (d, 2JC,F = 19.6 Hz), 120.4 (d, 1JC,F = 243.0 Hz),
1
3
120.5, 124.1 (q, JC,F = 272.1 Hz), 125.6, 125.7 (q, JC,F = 3.8 Hz),
129.3 (d, JC,F = 2.3 Hz), 130.4 (q, JC,F = 32.5 Hz), 140.2 ppm. 19F
NMR (376 MHz, CDCl3): δ = –136.51 (ddd, J = 35.1, 31.0, 17.0 Hz,
1F), –63.75 (s, 3F) ppm.
4
2
1
found C, 57.04; H, 5.02; N, 9.34. H NMR (400 MHz, CDCl3): δ = 1.72
2
3
(s, 6H), 2.38 (dd, JH,H = 17.4 Hz, JH,H = 5.9 Hz, 1H), 2.51–2.70 (m,
3
2
3
2H), 3.17 (dd, JH,F = 35.2 Hz, JH,H = 17.7 Hz, 1H), 3.87 (ddd, JH,F
=
3
3
(1R*,2R*)-2′,4′-Dichloro-2-fluoro-4,5-dimethyl-2-nitro-1,2,3,6-
tetrahydro-1,1′-biphenyl (2j). Eluent: Hex/DCM (3:1); 0.137 g
30.5 Hz, JH,H = 12.2, 5.9 Hz, 1H) 7.46 (d, JH,H = 8.7 Hz, 2H), 8.13
(dd, JH,H = 8.7 Hz, JH,H = 1.9 Hz, 2H) ppm. 13C NMR (100 MHz,
3
4
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
9
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
CDCl3): δ = 18.4, 18.5, 36.7 (d, 3JC,F = 2.8 Hz), 41.3 (d, 2JC,F = 24.1 Hz),
46.3 (d, JC,F = 19.6 Hz), 120.1 (d, JC,F = 243.5 Hz), 120.6, 123.8,
125.4, 129.9 (d, 4JC,F = 2.1 Hz), 143.4, 147.8 ppm. 19F NMR (376 MHz,
CDCl3): δ = –135.40 (ddd, J = 35.2, 30.5, 17.1 Hz) ppm.
7.38 (m, 4H), 7.91–7.97 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 22.6, 22.8, 30.6 (d, JC,F = 3.4 Hz), 35.4 (d, JC,F = 3.4 Hz), 36.1
2
1
3
3
2
2
2
(d, JC,F = 23.9 Hz), 40.2 (d, JC,F = 24.4 Hz), 45.9 (d, JC,F = 19.6 Hz),
46.2 (d, 2JC,F = 19.5 Hz), 52.2, 115.0, 120.0 (d, 1JC,F = 244.3 Hz), 120.2
1
(d, JC,F = 244.0 Hz), 120.3, 128.8, 128.9, 129.0, 129.7, 129.8, 129.9,
Synthesis of piperyline based cycloadduts 2
130.0, 130.1, 134.0, 141.0, 166.7 ppm. 19F NMR (376 MHz, CDCl3):
δ = –135.82 (ddd, J = 34.1, 31.3, 16.6 Hz, 1F), –134.73 (ddd, J = 34.0,
31.8, 16.6 Hz, 1F) ppm
(1′S*,2′S*)-Methyl 2′-Fluoro-3′-methyl-2′-nitro-1′,2′,3′,6′-tetra-
hydro-[1,1′-biphenyl]-4-carboxylate and (1′S*,2′S*)-Methyl 2′-
Fluoro-6′-methyl-2′-nitro-1′,2′,3′,6′-tetrahydro-[1,1′-biphenyl]-
4-carboxylate (2o). Eluent: Hex/DCM (1:1), DCM; 0.124 g (81 %);
colorless oil. Anal. calcd. for C15H16FNO4 (%): C, 61.43; H, 5.50; N,
4.78; found C, 61.72; H, 5.50; N, 4.72. Isomers ratio 35:11:7:29:8:10.
1H NMR (400 MHz, CDCl3): δ = 0.83–1.27 (m, 6H), 1.45–1.83 – (m,
2H), 2.44–2.89 (m, 4H), 3.02–3.45 (m, 2H), 3.86–3.91 (m, 6H), 5.25–
5.96 (m, 4H), 7.15–7.46 (m, 4H), 7.92–8.04 (m, 4H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 13.0 (d, 3JC,F = 7.1 Hz), 15.9 (d, 3JC,F = 4.3 Hz),
(1S*,2S*)-2-fluoro-4-methyl-2,4′-dinitro-1,2,3,6-tetrahydro-1,1′-bi-
phenyl and (1S*,2S*)-2-fluoro-5-methyl-2,4′-dinitro-1,2,3,6-tetra-
hydro-1,1′-biphenyl (2s) (36:56). Eluent: Hex/DCM (1:1); 0.092 g; pale
brown oil. Anal. calcd. for C13H13FN2O4 (%): C, 55.71; H, 4.68; N,
10.00; found C, 55.85; H, 4.77; N, 9.89; 1H NMR (400 MHz, CDCl3):
δ = 1.78 (s, 6H), 2.33–2.86 (m, 6H), 3.05–3.31 (m, 2H), 3.70–4.00 (m,
2H), 5.37–5.45 (m, 1H), 5.58–5.64 (m, 1H), 7.42–7.51 (m, 4H), 8.09–
8.18 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.1, 22.3, 30.1
3
3
3
17.5 (d, JC,F = 7.4 Hz), 17.9 (d, JC,F = 4.8 Hz), 19.1, 31.0 (d, JC,F
=
3
3
2
(d, JC,F = 3.4 Hz), 34.9 (d, JC,F = 3.3 Hz), 35.5 (d, JC,F = 23.9 Hz),
3
3
3.6 Hz), 32.6 (d, JC,F = 4.2 Hz), 35.1 (d, JC,F = 2.8 Hz), 35.8, 36.1 (d,
2
2
2
39.6 (d, JC,F = 24.3 Hz), 45.3 (d, JC,F = 19.6 Hz), 45.6 (d, JC,F
19.8 Hz), 114.6, 119.2 (d, JC,F = 244.3 Hz), 119.4, 119.5 (d, JC,F
=
=
3JC,F = 3.7 Hz), 39.4 (d, JC,F = 22.2 Hz), 39.5 (d, JC,F = 24.6 Hz), 41.9
2
2
1
1
2
2
2
(d, JC,F = 19.4 Hz), 47.1 (d, JC,F = 20.1 Hz), 49.0 (d, JC,F = 17.7 Hz),
244.1 Hz), 123.1, 123.2, 123.3, 123.4, 128.5, 129.4, 133.2, 142.8,
147.4 ppm. 19F NMR (376 MHz, CDCl3): δ = –135.81 (ddd, J = 34.7,
30.6, 16.8 Hz, 1F), –134.72 (ddd, J = 34.6, 30.7, 16.8 Hz, 1F).
2
52.2, 52.3, 53.4 (d, JC,F = 19.3 Hz), 119.2, 119.5, 119.6, 120.1 (d,
1JC,F = 244.6 Hz), 120.8 (d, JC,F = 246.7 Hz), 124.9, 125.3, 126.7,
1
127.6, 127.8, 128.0 (d, JC,F = 4.9 Hz), 128.5 (d, JC,F = 4.2 Hz), 128.9
(d, JC,F = 2.2 Hz), 129.1 (d, JC,F = 2.9 Hz), 129.2 (d, JC,F = 3.0 Hz),
129.4, 129.5, 129.7, 129.9, 129.9, 130.0, 130.2, 130.6, 132.7, 132.8,
139.9, 140.5 (d, 3JC,F = 1.1 Hz), 141.0, 142.5, 166.6, 166.7, 166.8 ppm.
19F NMR (376 MHz, CDCl3): δ = –150.62 (dd, J = 31.4, 26.0 Hz),
–145.19 to –144.79 (m), 134.15 (ddd, J = 34.4, 32.2, 16.4 Hz), –132.55
(dq, J = 36.8, 17.9 Hz), –127.61 (dd, J = 31.6, 19.1 Hz), –126.59 (td,
J = 31.5, 16.4 Hz) ppm.
Synthesis of 3-(4-Chlorophenyl)-4-fluoro-5-methoxy-4-nitro-
cyclohexanone and 3-(4-Chlorophenyl)-4-fluoro-2-methoxy-4-
nitrocyclohexanone (5f).
ꢀ-Fluoro-ꢀ-nitrostyrene 1f (0.101 mg, 0.5 mmol), o-xylene (0.2 mL)
and Danishefsky's diene (0.48 mL, 2.5 mmol) were successively
loaded into a screw-top vial filled with argon. After the cap was
screwed tightly, the reaction mixture was heated at 110 °C with
vigorous stirring for 7.5 h. After completion of the cycloaddion (TLC
monitoring), the reaction mixture was treated with HCl/THF (1:1)
solution (2 mL) at 0 °C for 1h. Then the acid excess was neutralized
with saturated aqueous solution of NaHCO3. The resulting mixture
was extracted with DCM. The combined organic layer was dried
with Na2SO4, filtered and concentrated under vacuum. Purification
by column chromatography on silica gel using DCM as eluent gave
the product 5f (0.115 g, 76 %) as mixture of isomers. Yellowish oil;
isomers ratio: 56:29:6:4:4. Anal. calcd. for C13H13ClFNO4 (%): C, 51.75;
(1S*,2S*)-2-Fluoro-3-methyl-2,4′-dinitro-1,2,3,6-tetrahydro-1,1′-
biphenyl and (1S*,2S*)-2-Fluoro-6-methyl-2,4′-dinitro-1,2,3,6-
tetrahydro-1,1′-biphenyl (2p). Eluent: Hex/DCM (1:1), DCM;
0.195 g (69 %) obtained from 1.0 mmol of nitrostyrene 1n; pale
brown oil. Anal. calcd. for C13H13FN2O4 (%): C, 55.71; H, 4.68; N,
10.00; found C, 55.75; H, 4.58; N, 9.89. Isomers ratio: 42:10:5:28:6:10.
1H NMR (400 MHz, CDCl3): δ = 0.81–1.17 (m, 6H), 1.47–1.88 (m, 1H),
2.48–2.90 (m, 4H), 3.04–3.50 (m, 2H), 3.72–4.25 (m, 1H), 5.48–5.99
(m, 4H), 7.29–7.59 (m, 4H), 8.08–8.27 (m, 4H) ppm. 13C NMR
1
3
3
H, 4.34; N, 4.64; found C, 51.69; H, 4.30; N, 4.29; H NMR (400 MHz,
(100 MHz, CDCl3): δ = 13.0 (d, JC,F = 6.7 Hz), 15.9 (d, JC,F = 4.2 Hz),
3
3
3
CDCl3): δ = 2.59–2.71 (m, 2H), 2.76–2.87 (m, 2H), 2.88–3.11 (m, 4H),
3.37 (s, 3H), 3.38 (s, 3H), 3.67–3.83 (m, 1H), 4.12–4.19 (m, 1H), 4.29–
4.50 (m, 2H), 7.14–7.20 (m, 4H), 7.28–7.33 (m, 4H) ppm. 13C NMR
17.6 (d, JC,F = 7.4 Hz), 17.9 (d, JC,F = 6.7 Hz), 19.1, 31.0 (d, JC,F
=
=
3.7 Hz), 32.6 (d, 3JC,F = 4.0 Hz), 35.3 (d, 3JC,F = 2.8 Hz), 35.8 (d, 2JC,F
2
2
24.1 Hz), 35.9 (d, JC,F = 24.5 Hz), 36.1, 39.4 (d, JC,F = 22.1 Hz), 39.5
(d, JC,F = 24.0 Hz), 41.8 (d, JC,F = 19.6 Hz), 47.0 (d, JC,F = 20.0 Hz),
48.9 (d, JC,F = 17.8 Hz), 53.3 (d, JC,F = 19.3 Hz), 118.7, 119.3, 119.7,
120.5 (d, JC,F = 246.6 Hz), 122.3 (d, JC,F = 243.9 Hz), 123.8, 123.9,
123.9, 124.6, 125.0, 127.7, 128.0, 128.1, 128.9 (d, 3JC,F = 7.9 Hz), 129.9
(d, JC,F = 2.4 Hz), 130.1 (d, JC,F = 3.2 Hz), 130.2 (d, JC,F = 3.4 Hz),
2
3
2
2
2
(100 MHz, CDCl3): δ = 41.4, 42.3 (d, JC,F = 17.4 Hz), 42.8 (d, JC,F
=
=
1.2 Hz), 43.2 (d, 3JC,F = 2.8 Hz), 44.3 (d, 3JC,F = 1.8 Hz), 44.7 (d, 2JC,F
2
2
19.0 Hz), 58.4, 58.5, 78.8 (d, JC,F = 18.7 Hz), 80.1 (d, 2JC,F = 29.7 Hz),
2
1
1
1
1
117.6 (d, JC,F = 240.3 Hz), 118.6 (d, JC,F = 248.2 Hz), 129.2, 129.5,
4
4
129.8 (d, JC,F = 1.8 Hz), 130.6 (d, JC,F = 2.6 Hz), 130.8, 133.1, 134.6,
135.3, 201.7, 202.8 ppm. 19F NMR (376 MHz, CDCl3): δ = –157.98
(dd, J = 28.7, 20.8 Hz), –140.19 (d, J = 33.0 Hz), –134.09 (t, J =
11.1 Hz), –125.72 (t, J = 8.7 Hz), –116.78 (t, J = 10.3 Hz) ppm.
3
130.4 (d, JC,F = 2.9 Hz), 132.4, 132.5, 142.3, 142.9 (d, JC,F = 1.2 Hz),
144.9, 147.6, 148.0 ppm. 19F NMR (376 MHz, CDCl3): δ = –150.48
(dd, J = 30.7, 26.3 Hz), –145.01 (ddt, J = 43.1, 24.3, 18.5 Hz), –134.12
(ddd, J = 35.0, 31.0, 16.6 Hz), –133.75 to –133.21 (m), –127.86 (dd,
J = 31.3, 19.3 Hz), –126.87 (td, J = 31.5, 16.5 Hz) ppm.
General Procedure for Synthesis of Biphenyls
In a typical experiment, a solution of cycloadduct (0.20 mmol;
1 mol. equiv.) in acetonitrile (0.5 mL) was loaded into a glass tube
and treated with DBU (0.8–1.6 mmol; 4–8 mol equiv.) at 60 °C with
vigorous stirring using either compressed air (1.5 bar; Method 1) or
MnO2 (5 mol. equiv.; Method 2) as oxidant. After completion of the
reaction (TLC monitoring), the reaction mixture was concentrated
under vacuum. The resulting mixture was separated by column
chromatography using mixture of Hex/DCM as eluent.
Synthesis of Isoprene Based Cycloadducts 2
(1′S*,2′S*)-Methyl 2′-Fluoro-4′-methyl-2′-nitro-1′,2′,3′,6′-tetra-
hydro-[1,1′-biphenyl]-4-carboxylate and (1′S*,2′S*)-Methyl 2′-
Fluoro-5′-methyl-2′-nitro-1′,2′,3′,6′-tetrahydro-[1,1′-biphenyl]-
4-carboxylate (2r) (59:31). Eluent: Hex/DCM (1:1), DCM; 0.124 g
(85 %); colorless oil. Anal. calcd. for C15H16FNO4 (%): C, 61.43; H,
5.50; N, 4.78; found C, 61.51; H, 5.49; N, 4.77; 1H NMR (400 MHz,
CDCl3): δ = 1.76 (s, 6H), 2.24–2.77 (m, 6H), 2.98–3.30 (m, 2H), 3.60–
4′-(tert-Butyl)-4,5-dimethyl-2-nitro-1,1′-biphenyl (4b). Eluent:
3.93 (m, 2H), 3.87 (s, 6H), 5.34–5.41 (m, 1H), 5.54–5.63 (m, 1H), 7.30– Hex/DCM, 10:1; Hex/DCM, 5:1; Hex/DCM, 2:1, 0.015 g (27 %), pale-
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
10 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
yellow solid; M.p. 116–118 °C (Hex/DCM, 5:1). Anal. calcd. for.
C18H21NO2 (%): C, 76.29; H, 7.47; N, 4.94; found C, 76.05; H, 7.48; N,
4.75. 1H NMR (400 MHz, CDCl3): δ = 1.35 (s, 9H), 2.35 (s, 3H), 2.36
(s, 3H), 7.19 (s, 1H), 7.23 (d, JH,H = 8.4 Hz, 2H), 7.42 (d, JH,H = 8.4 Hz,
2H), 7.65 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.5, 19.9,
31.5, 34.8, 125.2, 125.6, 127.8, 133.2, 134.1, 134.8, 136.9, 142.0, 147.1,
151.0 ppm.
from 0.047 mmol of cycloadduct 2h; pale-yellow solid; M.p. 106–
108 °C (Hex/DCM, 3:2). Anal. calcd. for. C16H15NO4 (%): C, 67.36; H,
5.30; N, 4.91; found C, 67.33; H, 5.73; N, 4.90. 1H NMR (400 MHz,
CDCl3): δ = 2.37 (s, 3H), 2.38 (s, 3H), 3.94 (s, 3H), 7.16 (s, 1H), 7.33–
7.37 (m, 2H), 7.76 (s, 1H), 8.06–8.10 (m, 2H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 19.6, 19.9, 52.3, 125.6, 128.2, 129.7, 129.9, 132.9, 133.4,
138.0, 142.6, 142.9, 166.9 ppm.
4,4′,5-Trimethyl-2-nitro-1,1′-biphenyl (4c). Eluent: Hex/DCM, 10:1;
Hex/DCM, 5:1; Hex/DCM, 2:1. 0.036 g (41 %), pale yellow oil. Anal.
calcd. for. C15H15NO2 (%):C, 74.67; H, 6.27; N, 5.81; found C, 74.70;
Biphenyls 3i and 4i. purification by column chromatography on
silica gel with gradient elution (Hex/DCM, 5:1; Hex/DCM, 3:1) gave
the target product 3i and the side product 4i.
1
H, 6.25; N, 5.74 H NMR (400 MHz, CDCl3): δ = 2.36 (s, 3H), 2.37 (s,
2-Fluoro-4,5-dimethyl-4′-(trifluoromethyl)-1,1′-biphenyl (3i).
Method 1: 0.032 g (59 %); method 2: 0.029 g (55 %); colorless solid;
M.p. 56–58 °C (Hex/DCM, 5:1). Anal. calcd. for C15H12F4: C, 67.16; H,
3H), 2.40 (s, 3H), 7.17–7.25 (m, 5H), 7.67 (s, 1H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 19.5, 19.9, 21.3, 125.2, 127.9, 129.4, 133.1,
134.1, 134.9, 136.9, 137.8, 142.1, 146.9 ppm.
1
4.51; found C, 67.21; H, 4.59. H NMR (400 MHz, CDCl3): δ = 2.28 (s,
3
4
4,5-Dimethyl-2-nitro-1,1′-biphenyl (4d). Eluent: Hex/DCM, 10:1;
Hex/DCM, 5:1; Hex/DCM, 2:1, 0.007 g (16 %), yellow oil. Anal. calcd.
for. C14H13NO2 (%):C, 73.99; H, 5.77; N, 6.16; found C, 73.36; H, 5.78;
N, 5.99. 1H NMR (400 MHz, CDCl3): δ = 2.36 (s, 3H), 2.37 (s, 3H), 7.18
(s, 1H), 7.27–7.32 (m, 2H), 7.34–7.45 (m, 3H), 7.69 (s, 1H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 19.5, 19.9, 125.3, 128.0, 128.1, 128.7,
133.2, 134.2, 137.2, 138.0, 142.2, 147.0 ppm.
3H), 2.30 (s, 3H), 6.97 (d, JH,F = 11.4 Hz, 1H), 7.19 (d, JH,F = 8.0 Hz,
1H), 7.64 (d, 3JH,H = 8.5 Hz, 2H), 7.68 (d, 3JH,H = 8.5 Hz, 2H) ppm. 13
NMR (100 MHz, CDCl3): δ = 19.2, 19.8, 117.3 (d, JC,F = 22.3 Hz),
124.4 (q, JC,F = 272.0 Hz), 124.6 (d, JC,F = 12.9 Hz), 125.4 (q, JC,F
C
2
1
2
3
=
4
2
3.7 Hz), 129.3 (d, JC,F = 3.0 Hz), 129.4 (q, JC,F = 32.6 Hz), 131.4 (d,
3JC,F = 3.3 Hz), 132.8 (d, JC,F = 3.5 Hz), 139.0 (d, JC,F = 7.7 Hz),
3
3
139.8, 158.0 (d, JC,F = 246.1 Hz) ppm. 19F NMR (376 MHz, CDCl3):
1
δ = –123.43 to –123.34 (m, 1F), –62.50 (s, 3F) ppm.
4′-Fluoro-4,5-dimethyl-2-nitro-1,1′-biphenyl (4e). Eluent: Hex/
DCM, 10:1; Hex/DCM, 5:1; Hex/DCM, 2:1; 0.015 g (30 %), pale yellow
oil. Anal. calcd. for. C14H12FNO2 (%):C, 68.56; H, 4.93; N, 5.71 Found:
C, 68.48; H, 5.05; N, 5.68. 1H NMR (400 MHz, CDCl3): δ = 2.36 (s, 3H),
2.37 (s, 3H), 7.06–7.13 (m, 2H), 7.15 (s, 1H), 7.22–7.28 (m, 2H), 7.70
(s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.5, 19.9, 115.7 (d,
4,5-Dimethyl-2-nitro-4′-(trifluoromethyl)-1,1′-biphenyl (4i).
Method 1: 0.006 g (10 %); method 2: 0.011 (19 %); yellowish oil.
Anal. calcd. for C15H12F3NO2: C, 61.02; H, 4.10; N, 4.74; found C,
61.24; H, 4.23; N, 4.73; 1H NMR (400 MHz, CDCl3) δ = 2.37 (s, 3H),
2.39 (s, 3H), 7.15 (s, 1H), 7.40 (d, JH,H = 8.1 Hz, 2H), 7.66 (d, JH,H
=
3
2JC,F = 21.8 Hz), 125.4, 129.8 (d, JC,F = 8.2 Hz), 133.1, 133.9, 133.9,
8.1 Hz, 2H), 7.77 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ = 19.6,
1
137.5, 142.4, 146.8, 162.7 (d, JC,F = 247.1 Hz) ppm. 19F NMR
20.0, 121.5 (q, 1JC,F = 272.1 Hz), 125.5 (q, 3JC,F = 3.8 Hz), 125.6, 128.5,
2
(376 MHz, CDCl3): δ = –114.31 (tt, J = 8.6, 5.2 Hz) ppm.
128.6, 130.1 (q, JC,F = 32.6 Hz), 133.0, 138.2, 141.9, 142.8,
146.5 ppm; 19F NMR (376 MHz,CDCl3): δ = –63.55 ppm.
4′-Chloro-4,5-dimethyl-2-nitro-1,1′-biphenyl (4f). Eluent: Hex/
DCM, 10:1; Hex/DCM, 5:1; Hex/DCM, 2:1, 0.020 g (38 %), yellowish
oil. Anal. calcd. for. C14H12ClNO2 (%):C, 64.25; H, 4.62; N, 5.35; found
C, 64.59; H, 4.54; N, 5.38; 1H NMR (400 MHz, CDCl3): δ = 2.36 (s, 3H),
2.37 (s, 3H), 7.13 (s, 1H), 7.18–7.23 (m, 2H), 7.35–7.40 (m, 3H), 7.71
(s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.5, 19.9, 125.5, 128.9,
129.5, 133.0, 133.1, 134.2, 136.5, 137.7, 142.5, 146.6 ppm.
Biphenyls 3j and 4j. Separation by column chromatography on
silica gel with gradient elution (Hex/DCM, 10:1; Hex/DCM, 5:1; Hex/
DCM, 2:1) gave the fraction predominantly contained non-oxidized
intermediate of 3j (IM-1) and the fraction with the pure side prod-
uct 4j. Then the solid residue from the first fraction (0.011 g) was
treated with MnO2 (0.018 g, 5 mol. equiv.) in toluene (0.2 mL) at
80 °C for 5 h. Purification of the resulting mixture by column chro-
matography on silica gel using hexane as eluent afforded pure 3j.
4′-Bromo-4,5-dimethyl-2-nitro-1,1′-biphenyl (4g). Eluent: Hex/
DCM, 10:1; Hex/DCM, 5:1; Hex/DCM, 2:1; 0.019 g (32 %), yellow oil.
1H NMR (400 MHz, CDCl3): δ = 2.36 (s, 3H), 2.37 (s, 3H), 7.13 (s, 1H),
7.15 (d, JH,H = 8.4 Hz, 2H), 7.53 (d, JH,H = 8.4 Hz, 2H), 7.72 (s, 1H)
ppm. Analysis of the sample was consistent with the data reported
in the literature.[35]
2′,4′-Dichloro-2-fluoro-4,5-dimethyl-1,1′-biphenyl (3j). 0.008 g
(15 %); colorless oil; 1H NMR (400 MHz, CDCl3): δ = 2.26 (s, 3H), 2.30
3
4
(s, 3H), 6.94 (d, JH,F = 10.4 Hz, 1H), 7.01 (d, JH,F = 7.6 Hz, 1H), 7.24
3
3
4
(d, JH,H = 8.3 Hz, 1H), 7.29 (dd, JH,H = 8.3 Hz, JH,H = 2.0 Hz, 1H),
7.49 (d, JH,H = 2.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ =
4
Biphenyls 3h and 4h. Purification by column chromatography on
silica gel with gradient elution (Hex/DCM, 3:1; Hex/DCM, 3:2) gave
the target product 3h and the side product 4h.
2
2
19.1, 19.9, 116.7 (d, JC,F = 21.7 Hz), 122.9 (d, JC,F = 15.6 Hz), 127.1,
129.5, 132.1 (d, 3JC,F = 3.1 Hz), 132.2 (d, JC,F = 3.3 Hz), 132.6, 133.9,
3
134.3, 134.7, 139.2 (d, 3JC,F = 7.6 Hz), 157.7 (d, 1JC,F = 244.9 Hz) ppm.
19F NMR (376 MHz, CDCl3): δ = –119.72 to –119.62 (m) ppm.
Methyl 2′-fluoro-4′,5′-dimethyl-[1,1′-biphenyl]-4-carboxylate
(3h). Method 1: 0.031 g (73 %); method 2: 0.009 g (77 %) obtained
from 0.047 mmol of cycloadduct 2h; colorless solid; M.p. 99–101 °C
(Hex/DCM, 3:1). Anal. calcd. for C16H15FO2: C, 74.40; H, 5.85; found
C, 74.45; H, 5.81. 1H NMR (400 MHz, CDCl3): δ = 2.28 (s, 3H), 2.29 (s,
2′,4′-Dichloro-4,5-dimethyl-2-nitro-1,1′-biphenyl (4j). Method 1:
0.016 g (26 %); pale-yellow solid; M.p. 130–132 °C (Hex/DCM, 5:1).
Anal. calcd. for. C14H11Cl2NO2 (%):C, 56.78; H, 3.74; N, 4.73; found C,
56.72; H, 3.68; N, 4.72. 1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 3H),
3
4
3H), 3.94 (s, 3H), 6.96 (d, JH,F = 11.5 Hz, 1H), 7.21 (d, JH,F = 8.0 Hz,
2.40 (s, 3H), 7.06 (s, 1H), 7.18 (d, 3JH,H = 8.2 Hz, 1H), 7.31 (dd, 3JH,H
=
1H), 7.59–7.63 (m, 2H), 8.07–8.11 (m, 2H) ppm. 13C NMR (100 MHz,
8.2, 4JH,H = 2.1 Hz, 1H), 7.46 (d, 4JH,H = 2.1 Hz, 1H), 7.94 (s, 1H) ppm.
13C NMR (100 MHz, CDCl3): δ = 19.7, 20.0, 125.7, 127.3, 129.3, 130.8,
131.0, 133.3, 133.8, 134.4, 136.4, 138.6, 143.4, 146.1 ppm.
CDCl3): δ = 19.1, 19.8, 52.3, 117.3 (d, 2JC,F = 22.4 Hz), 124.9 (d, 2JC,F
=
=
4
3
12.9 Hz), 129.0 (d, JC,F = 3.3 Hz), 129.7, 129.8, 131.3 (d, JC,F
3
3
3.5 Hz), 132.7 (d, JC,F = 3.4 Hz), 138.9 (d, JC,F = 8.0 Hz), 140.8 (d,
4JC,F = 1.2 Hz), 158.0 (d, JC,F = 246.0 Hz), 167.1 ppm. 19F NMR
1
4,5-Dimethyl-2,2′-dinitro-1,1′-biphenyl (4k). Eluent: Hex/DCM
(4:1); Hex/DCM, 2:1; method 1: 0.023 g (42 %); method 2: 0.024 g
(44 %); pale brown solid; M.p. 100–102 °C (Hex/DCM, 2:1). Anal.
calcd. for C14H12N2O4: C, 61.76; H, 4.44; N, 10.29; found C, 61.68; H,
(376 MHz, CDCl3): δ = –123.18 to –123.07 (m) ppm.
Methyl 4′,5′-dimethyl-2′-nitro-[1,1′-biphenyl]-4-carboxylate
(4h). Method 1: 0.004 g (8 %); method 2: 0.001 g (6 %) obtained
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
11
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
3
3
4.57; N, 10.10. 1H NMR (400 MHz, CDCl3): δ = 2.35 (s, 3H), 2.40 (s, 3.4 Hz), 131.2 (d, JC,F = 3.0 Hz), 133.1 (d, JC,F = 3.3 Hz), 140.0 (d,
3
3
1
3H), 7.03 (s, 1H), 7.27 (d, JH,H = 7.4 Hz, 1H), 7.56 (dd, JH,H = 8.0,
3JC,F = 8.0 Hz), 142.9 (d, 4JC,F = 1.1 Hz), 147.0, 157.9 (d, JC,F
=
3
7.6 Hz, 1H), 7.66 (dd, JH,H = 7.6, 7.4 Hz, 1H), 8.02 (s, 1H), 8.18 (d,
246.9 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –122.85 (dd, J =
3JH,H = 8.0 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ = 19.7, 20.0,
124.8, 125.9, 128.9, 131.2, 131.7, 131.9, 133.4, 134.7, 138.3, 143.7,
145.0, 147.5 ppm.
11.0, 8.4 Hz) ppm.
Biphenyls 3o and 4o. Purification by column chromatography on
silica gel with gradient elution (Hex/DCM, 2:1; Hex/DCM, 1:1; DCM)
gave the target products mixture 3o and the side products mixture
4o.
Biphenyls 3l and 4l. purification by column chromatography on
silica gel with gradient elution (Hex/DCM, 4:1; Hex/DCM, 3:1) gave
the target product 3l and the side product 4l.
Methyl 2′-fluoro-3′-methyl-[1,1′-biphenyl]-4-carboxylate and
methyl 2′-fluoro-6′-methyl-[1,1′-biphenyl]-4-carboxylate (3o)
(48:52). Method 1: 0.023 g (25 %); method 2: 0.025 g (26 %), color-
less oil. Anal. calcd. for. C15H13FO2 (%):C, 73.76; H, 5.36; found C,
73.51; H, 5.60; 1H NMR (400 MHz, CDCl3): δ = 2.15 (s, 3H); 2.35 (d,
J = 2.2 Hz, 3H), 3.94 (s, 3H), 3.95 (s, 3H), 6.99 (t, J = 8.8 Hz, 1H), 7.07
(d, J = 7.6 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.18–7.29 (m, 3H), 7.37
(d, J = 8.1 Hz, 2H), 7.62 (dd, J = 8.4, 1.6 Hz, 2H), 8.08–8.14 (m, 4H)
2-Fluoro-4,5-dimethyl-3′-nitro-1,1′-biphenyl (3l). Method 1:
0.020 g (41 %), method 2: 0.024 g (49 %); colorless solid; M.p. 78–
80 °C (Hex/DCM, 4:1). Anal. calcd. for C14H12FNO2: C, 68.56; H, 4.93;
1
N, 5.71; found C, 68.60; H, 4.95; N, 5.55. H NMR (400 MHz, CDCl3):
3
δ = 2.29 (s, 3H), 2.31 (s, 3H), 6.98 (d, JH,F = 11.4 Hz, 1H), 7.22 (d,
4JH,F = 8.0 Hz, 1H), 7.59 (t, 3JH,H = 7.9 Hz, 1H), 7.88 (dd, 3JH,H = 7.9 Hz,
4JH,H = 1.0 Hz, 1H), 8.16–8.25 (m, 1H), 8.40 (s, 1H) ppm. 13C NMR
2
(100 MHz, CDCl3): δ = 19.2, 19.9, 117.4 (d, JC,F = 22.2 Hz), 122.2,
3
ppm. 13C NMR (100 MHz, CDCl3): δ = 14.9 (d, JC,F = 5.0 Hz), 20.2
2
4
123.5 (d, JC,F = 12.7 Hz), 123.8 (d, JC,F = 3.0 Hz), 129.4, 131.2 (d,
4
2
(d, JC,F = 2.9 Hz), 52.3, 52.4, 113.1 (d, JC,F = 22.8 Hz), 124.1 (d,
3JC,F = 3.0 Hz), 133.1 (d, JC,F = 3.4 Hz), 135.1 (d, JC,F = 3.6 Hz),
137.8, 139.5 (d, 3JC,F = 7.9 Hz), 148.5, 157.9 (d, 1JC,F = 246.4 Hz) ppm.
19F NMR (376 MHz, CDCl3): δ = –124.64 to –124.50 (m) ppm.
3
4
3JC,F = 4.4 Hz), 125.8 (d, JC,F = 18.1 Hz), 125.9 (d, JC,F = 3.3 Hz),
127.8 (d, JC,F = 14.3 Hz), 128.3 (d, JC,F = 3.1 Hz), 128.5 (d, JC,F
2
4
2
4
2
=
3
15.8 Hz), 129.0 (d, JC,F = 8.9 Hz), 129.1, 129.2, 129.4, 129.6, 129.7,
130.2, 131.5 (d, 3JC,F = 5.2 Hz), 138.4 (d, JC,F = 2.4 Hz), 139.9, 140.9,
3
4,5-Dimethyl-2,3′-dinitro-1,1′-biphenyl (4l). Method 1: 0.009 g
(17 %); method 2: 0.015 g (27 %), pale yellow solid; M.p. 158–160 °C
(Hex/DCM, 3:1). Anal. calcd. for C14H12N2O4: C, 61.76; H, 4.44; N,
1
1
158.3 (d, JC,F = 247.6 Hz), 158.9 (d, JC,F = 244.7 Hz), 167.0,
167.1 ppm. 19F NMR (376 MHz, CDCl3): δ = –121.97 to –121.86 (m,
1F), –115.36 (dd, J = 9.3, 5.8 Hz, 1F) ppm.
1
10.29; found C, 61.84; H, 4.52; N, 10.15. H NMR (400 MHz, CDCl3):
δ = 2.39 (s, 3H), 2.40 (s, 3H), 7.17 (s, 1H), 7.54–7.61 (m, 2H), 7.84 (s,
1H), 8.19 (s, 1H), 8.21–8.30 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3):
δ = 19.7, 20.0, 122.9, 123.3, 125.9, 128.2, 129.5, 132.1, 133.1, 134.4,
138.7, 140.0, 143.2, 143.3 ppm.
Methyl 2′-methyl-6′-nitro-[1,1′-biphenyl]-4-carboxylate and
methyl 3′-methyl-2′-nitro-[1,1′-biphenyl]-4-carboxylate (4o)
(23:77). Method 1: 0.005 g (5 %); method 2: 0.005 g (5 %); pale yel-
low oil. Anal. calcd. for. C15H13NO4 (%): C, 66.41; H, 4.83; N, 5.16;
Biphenyls 3m and 4m. Purification by column chromatography on
silica gel with gradient elution (Hex/DCM, 2:1; Hex/DCM, 1:1; Hex/
DCM, 1:2) gave the target product 3m and the side product 4m.
1
found C, 66.62; H, 4.92; N, 5.09; H NMR (400 MHz, CDCl3): δ = 2.11
(s, 6H), 3.90 (s, 3H), 3.94 (s, 3H), 7.26–7.30 (m, 4H), 7.34–7.37 (m, 1H),
7.41 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 7.6 Hz,
1H), 7.75 (d, J = 8.1 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 8.09–8.14 (m,
4H) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.7, 52.4, 121.6, 128.5,
128.7, 129.8, 130.0, 134.3, 134.8, 139.0, 141.3, 149.9, 166.9 ppm.
2′-Fluoro-4′,5′-dimethyl-[1,1′-biphenyl]-4-carbonitrile (3m).
Method 1:0.030 g (67 %); method 2: 0.032 (70 %); colorless solid;
M.p. 106–108 °C (Hex/DCM, 2:1). Anal. calcd. for C15H12FN: C, 79.98;
1
H, 5.37; N, 6.22; found C, 79.80; H, 5.32; N, 6.14. H NMR (400 MHz,
Biphenyls 3p and 4p. Purification by column chromatography on
silica gel with gradient elution (Hex/DCM, 2:1; Hex/DCM, 1:1) gave
the target products mixture 3p and the side products mixture 4p.
3
CDCl3): δ = 2.28 (s, 3H), 2.30 (s, 3H), 6.97 (d, JH,F = 11.5 Hz, 1H),
4
3
4
7.17 (d, JH,F = 8.0 Hz, 1H), 7.64 (dd, JH,H = 8.5 Hz, JH,H = 1.4 Hz,
2H), 7.67–7.73 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.1,
19.8, 111.0, 117.4 (d, 2JC,F = 22.4 Hz), 119.1, 124.0 (d, 2JC,F = 12.6 Hz),
2-Fluoro-3-methyl-4′-nitro-1,1′-biphenyl and 2-fluoro-6-methyl-
4′-nitro-1,1′-biphenyl (3p) (34:66). Method 1: 0.020 g (40 %);
method 2: 0.051 g (46 %) obtained from 0.47 mmol of cycloadduct
2p; pale yellow solid; M.p. 59–74 °C (Hex/DCM, 2:1). Anal. calcd. for.
4
3
129.6 (d, JC,F = 3.4 Hz), 131.1 (d, JC,F = 3.2 Hz), 132.3, 133.0 (d,
3JC,F = 3.3 Hz), 139.6 (d, 3JC,F = 8.0 Hz), 140.9 (d, 4JC,F = 1.0 Hz), 157.9
(d, JC,F = 246.7 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –124.07
1
(t, J = 9.3 Hz) ppm.
C
13H10FNO2 (%):C, 67.53; H, 4.36; N, 6.06, Found: C, 67.42; H, 4.36;
N, 5.91; 1H NMR (400 MHz, CDCl3): δ = 2.17 (s, 3H), 2.36 (d, J =
2.2 Hz, 3H), 7.01 (t, J = 8.8 Hz, 1H), 7.08–7.18 (m, 2H), 7.23–7.33 (m,
3H), 7.47 (d, J = 8.3 Hz, 2H), 7.71 (dd, J = 8.8, 1.5 Hz, 2H), 8.27–8.33
(m, 4H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.9 (d, 3JC,F = 4.8 Hz),
4′,5′-Dimethyl-2′-nitro-[1,1′-biphenyl]-4-carbonitrile (4m). Elu-
ent: Hex/DCM; method 1: 0.002 g (3 %); method 1: 0.005 g (10 %),
colorless solid; M.p. 161–163 °C (Hex/DCM, 1:2). Anal. calcd. for
C
15H12N2O2: C, 71.42; H, 4.79; N, 11.10; found C, 71.43; H, 4.72; N,
4
2
1
20.2 (d, JC,F = 2.8 Hz), 113.2 (d, JC,F = 22.5 Hz), 123.6, 123.7, 124.3
(d, JC,F = 4.5 Hz), 126.1 (d, JC,F = 3.3 Hz), 126.2 (d, JC,F = 18.1 Hz),
10.98. H NMR (400 MHz, CDCl3): δ = 2.38 (s, 3H), 2.39 (s, 3H), 7.13
(s, 1H), 7.36–7.41 (m, 2H), 7.68–7.72 (m, 2H), 7.80 (s, 1H) ppm; 13C
NMR (100 MHz, CDCl3): δ = 19.6, 19.9, 112.0, 118.7, 125.8, 129.0,
132.4, 132.7, 132.8, 138.6, 143.0, 143.1, 146.3 ppm.
3
4
2
2
2
4
126.6 (d, JC,F = 13.8 Hz), 127.3 (d, JC,F = 15.6 Hz), 128.1 (d, JC,F
=
2.8 Hz), 129.7 (d, 3JC,F = 9.0 Hz), 130.0 (d, 4JC,F = 3.5 Hz), 131.2, 132.3
(d, 3JC,F = 5.4 Hz), 138.2 (d, 3JC,F = 2.2 Hz), 142.0, 143.0, 147.2, 147.4,
2-Fluoro-4,5-dimethyl-4′-nitro-1,1′-biphenyl (3n); Eluent: Hex/
DCM (2:1); method 1: 0.045 g (92 %), method 2: 0.042 g (86 %);
yellow solid; M.p. 105–107 °C (Hex/DCM, 2:1). HRMS (ESI): calcd. for
158.2 (d, JC,F = 248.3 Hz), 159.6 (d, JC,F = 245.5 Hz) ppm. 19F NMR
(376 MHz, CDCl3): δ = –121.69 (td, J = 7.0, 2.1 Hz, 1F), –115.24 (dd,
J = 9.4, 5.8 Hz, 1F) ppm.
1
1
C
14H11FNO2 [M – H]– = 244.0774, found 244.0780; calcd. for
C14H13FNO2 [M + H]+ = 246.0930, found 246.0923; 1H NMR 2-Methyl-4′,6-dinitro-1,1′-biphenyl and 3-methyl-2,4′-dinitro-
3
(400 MHz, CDCl3): δ = 2.29 (s, 3H), 2.31 (s, 3H), 6.98 (d, JH,F
=
1,1′-biphenyl (4p) (87:13). Method 2: 0.005 g (4 %) obtained from
0.47 mmol of cycloadduct 2p; pale yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 2.12 (s, 3H), 2.20 (s, 3H), 7.19 (d, J = 8.0 Hz, 2H), 7.36–
7.41 (m, 2H), 7.45–7.59 (m, 4H), 7.83 (d, J = 8.0 Hz, 2H), 8.25–8.36
4
11.0 Hz, 1H), 7.21 (d, JH,F = 8.4 Hz, 1H), 7.65–7.73 (m, 2H), 8.25–
8.30 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.2, 19.9, 117.5
2
2
4
(d, JC,F = 22.3 Hz), 123.7 (d, JC,F = 10.1 Hz), 123.8, 129.7 (d, JC,F
=
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
12
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(m, 4H) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.8, 122.0, 123.7,
124.1, 129.1, 129.6, 131.2, 133.7, 134.8, 138.8, 143.7 ppm.
Acknowledgments
This work was supported by the Russian Science Foundation
(RSF) (grant No. 17-73-10358). The authors acknowledge the
partial support in measuring of NMR spectra from the M. V.
Lomonosov Moscow State University Program of Development.
The authors sincerely thank I. V. Smolyar for the DFT calcula-
tions.
Biphenyls 3r and 4r. Purification by column chromatography on
silica gel with gradient elution (Hex/DCM, 2:1; Hex/DCM, 1:1) gave
the target products mixture 3r and the side products mixture 4r.
Methyl 2′-fluoro-5′-methyl-[1,1′-biphenyl]-4-carboxylate and
methyl 2′-fluoro-4′-methyl-[1,1′-biphenyl]-4-carboxylate (3r)
(58:42). Method 1: 0.028 g (27 %); method 2: 0.031 g (37 %) (Method
2); viscous colorless oil. Anal. calcd. for. C15H13FO2 (%): C, 73.76; H,
Keywords: Diels-Alder reaction · ꢀ-Fluoro-ꢀ-nitrostyrene ·
1,3-Diene · Biphenyl · Kinetics · Hammet equation · Global
electrophilicity index
1
5.36; found C, 73.90; H, 5.50; H NMR (400 MHz, CDCl3): δ = 2.37 (s,
3H), 2.40 (s, 3H), 3.94 (s, 3H), 3.95 (s, 3H), 6.99 (d, J = 11.8 Hz, 1H),
7.02–7.09 (m, 2H), 7.11–7.17 (m, 1H), 7.22–7.25 (m, 1H), 7.34 (t, J =
8.0 Hz, 1H), 7.60–7.64 (m, 4H), 8.10 (d, J = 8.5 Hz, 2H), 8.11 (d, J =
8.5 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.8, 21.2 (d, 4JC,F
=
[1] L. V. Politanskaya, G. A. Selivanova, E. V. Panteleeva, E. V. Tretyakov, V. E.
Platonov, P. V. Nikul′shin, A. S. Vinogradov, Ya. V. Zonov, V. M. Karpov,
T. V. Mezhenkova, A. V. Vasilyev, A. B. Koldobskii, O. S. Shilova, S. M.
Morozova, Ya. V. Burgart, E. V. Shchegolkov, V. I. Saloutin, V. B. Sokolov,
A. Yu. Aksinenko, V. G. Nenajdenko, M. Yu. Moskalik, V. V. Astakhova, B. A.
Shainyan, A. A. Tabolin, S. L. Ioffe, V. M. Muzalevskiy, E. S. Balenkova, A. V.
Shastin, A. A. Tyutyunov, V. E. Boiko, S. M. Igumnov, A. D. Dilman, N. Yu.
Adonin, V. V. Bardin, S. M. Masoud, D. V. Vorobyeva, S. N. Osipov, E. V.
Nosova, G. N. Lipunova, V. N. Charushin, D. O. Prima, A. G. Makarov, A. V.
Zibarev, B. A. Trofimov, L. N. Sobenina, K. V. Belyaeva, V. Ya. Sosnovskikh,
D. L. Obydennov, S. A. Usachev, Russ. Chem. Rev. 2019, 88, 425–569.
[2] a) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008,
37, 320–330; b) P. Shah, A. D. Westwell, J. Enzyme, J. Enzyme Inhib. Med.
Chem. 2007, 22, 527–540; c) B. C. Wang, L. J. Wang, B. Jiang, S. Y. Wang,
N. Wu, X. Q. Li, D. Y. Shi, Mini-Rev. Med. Chem. 2017, 17, 683–692; d) E. P.
Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly, N. A. Meanwell, J. Med.
Chem. 2015, 58, 8315–8359.
[3] a) T. Furuya, A. S. Kamlet, T. Ritter, Nature 2011, 473, 470–477; b) T. Liang,
C. N. Neumann, T. Ritter, Angew. Chem. Int. Ed. 2013, 52, 8214–8264;
Angew. Chem. 2013, 125, 8372; c) J. Wu, Tetrahedron Lett. 2014, 55, 4289–
4294; d) M. G. Campbell, T. Ritter, Chem. Rev. 2015, 115, 612–633.
[4] Q. Cheng, T. Ritter, J. Wu, Trends Chem. 2019, 1, 461–470.
[5] I. S. Kondratov, N. A. Tolmachova, G. Haufe, Eur. J. Org. Chem. 2018, 2018,
3618–3647.
1.0 Hz), 52.2, 52.3, 116.1 (d, 2JC,F = 22.6 Hz), 116.9 (d, 2JC,F = 22.5 Hz),
2
3
2
125.0 (d, JC,F = 13.1 Hz), 125.4 (d, JC,F = 3.0 Hz), 127.6 (d, JC,F
=
3
4
13.4 Hz), 129.0 (d, JC,F = 3.3 Hz), 129.1 (d, JC,F = 3.1 Hz), 129.2,
4
129.7, 129.8, 130.3, 130.4, 130.4, 131.1 (d, JC,F = 3.0 Hz), 134.1 (d,
3JC,F = 3.7 Hz), 140.6 (d, JC,F = 1.1 Hz), 140.7 (d, JC,F = 8.2 Hz),
3
3
1
1
140.7, 158.1 (d, JC,F = 245.9 Hz), 159.7 (d, JC,F = 248.6 Hz), 167.0,
167.1 ppm. 19F NMR (376 MHz, CDCl3): δ = –123.02 to –122.92 (m,
1F), –118.51 to –118.43 (m, 1F) ppm.
Methyl 5′-methyl-2′-nitro-[1,1′-biphenyl]-4-carboxylate and
methyl 4′-methyl-2′-nitro-[1,1′-biphenyl]-4-carboxylate (4r)
(78:22). Method 1: 0.010 g (9 %); method 2: 0.011 g (11 %); yellow
solid; M.p. 109–122 °C (Hex/DCM, 1:1). Anal. calcd. for. C15H13NO4
(%): C, 66.41; H, 4.83; N, 5.16; found C, 66.65; H, 4.96; N, 5.06; 1H
NMR (400 MHz, CDCl3): δ = 2.47 (s, 3H), 2.48 (s, 3H), 3.94 (s, 6H),
7.21 (d, J = 1.1 Hz, 1H), 7.31 (d, J = 7.8 Hz, 2H), 7.35–7.38 (m, 4H),
7.45 (dd, J = 7.8, 0.5 Hz, 1H), 7.73 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H),
8.05–8.11 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.1, 21.6,
52.4, 52.4, 124.8, 124.9, 128.1, 128.2, 129.4, 129.5, 129.7, 129.8, 129.9,
130.0, 131.7, 132.5, 132.8, 133.5, 135.9, 139.6, 142.4, 142.8, 144.0,
148.9, 166.8, 166.8 ppm.
[6] A. S. Konev, A. F. Khlebnikov, Collect. Czech. Chem. Commun. 2008, 73,
1553–1611.
[7] a) T. Hayashi, Y. Usuki, Y. Wakamatsu, H. Iio, Synlett 2010, 19, 2843–2846;
b) G.-q. Shi, S. Cottens, S. A. Shiba, M. Schlosser, Tetrahedron 1992, 48,
10569–10574.
Biphenyls 3s and 4s. Purification by column chromatography on
silica gel with gradient elution (Hex/DCM, 2:1; Hex/DCM, 1:1) gave
the target products mixture 3s and the side products mixture 4s.
2-Fluoro-5-methyl-4′-nitro-1,1′-biphenyl and 2-fluoro-4-methyl-
4′-nitro-1,1′-biphenyl (3s) (42:58). Method 1: 0.064 g (86 %) ob-
tained from 0.32 mmol of cycloadduct 2s; method 2: 0.041 g (65 %)
obtained from 0.27 mmol of cycloadduct 2s; pale yellow oil. Anal.
calcd. for. C13H10FNO2 (%):C, 67.53; H, 4.36; N, 6.06; found C, 67.58;
[8] a) T. B. Patrick, J. Rogers, K. Gorrell, Org. Lett. 2002, 4, 3155–3156; b) T. B.
Patrick, K. Gorrell, J. Rogers, J. Fluorine Chem. 2007, 128, 710–713.
[9] a) F.-Q. Jin, Y.-Y. Xu, W.-Y. Huang, J. Fluorine Chem. 1995, 71, 1–4; b) G.-Q.
Shi, M. Schlosser, Tetrahedron 1993, 49, 1445–1456; c) H. Amii, T. Kobaya-
shi, H. Terasawa, K. Uneyama, Org. Lett. 2001, 3, 3103–3105.
[10] a) T. Hanamoto, K. Korekoda, K. Nakata, K. Handa, Y. Koga, M. Kondo, J.
Fluorine Chem. 2002, 118, 99–101; b) M. Sridhar, K. Leela Krishna, J. M.
Rao, Tetrahedron 2000, 56, 3539–3545; c) A. de Meijere, S. Teichmann, F.
Seyed-Mahdavi, S. Kohlstruk, Liebigs Ann. 1996, 12, 1989–2000.
[11] a) A. Arany, P. J. Crowley, J. Fawcett, M. B. Hursthouse, B. M. Kariuki, M. E.
Light, A. C. Moralee, J. M. Percy, V. Salafia, Org. Biomol. Chem. 2004, 2,
455–465; b) P. J. Crowley, J. M. Percy, K. Stansfield, Tetrahedron Lett. 1996,
37, 8237–8240; c) S. Yamada, M. Noma, T. Konno, T. Ishihara, H. Yaman-
aka, Org. Lett. 2006, 8, 843–845;.
1
H, 4.36; N, 6.20. H NMR (400 MHz, CDCl3): δ = 2.39 (s, 3H), 2.41 (s,
3H), 7.02 (d, J = 11.8 Hz, 1H), 7.05–7.12 (m, 2H), 7.16–7.27 (m, 2H),
7.35 (t, J = 8.0 Hz, 1H), 7.57–7.76 (m, 4H), 8.24–8.31 (m, 4H) ppm.
4
13C NMR (100 MHz, CDCl3): δ = 20.8, 21.3 (d, JC,F = 1.1 Hz), 116.3
2
2
(d, JC,F = 22.4 Hz), 117.1 (d, JC,F = 22.2 Hz), 123.7, 123.8, 123.9,
3
2
3
125.7 (d, JC,F = 3.3 Hz), 126.4 (d, JC,F = 13.1 Hz), 129.7 (d, JC,F
=
4
4
3.5 Hz), 129.9 (d, JC,F = 3.4 Hz), 130.3 (d, JC,F = 3.4 Hz), 131.0 (d,
4JC,F = 2.6 Hz), 131.2 (d, 4JC,F = 8.1 Hz), 134.4 (d, 3JC,F = 3.7 Hz), 141.7
[12] A. V. Shastin, V. G. Nenajdenko, V. M. Muzalevskiy, E. S. Balenkova, R.
Fröhlich, G. Haufe, Tetrahedron 2008, 64, 9725–9732.
[13] a) H. Ito, A. Saito, T. Taguchi, Tetrahedron: Asymmetry 1998, 9, 1979–1987;
b) S. Yamada, K. Hondo, T. Konno, T. Ishihara, RSC Adv. 2016, 6, 28458–
28469.
3
3
(d, JC,F = 8.4 Hz), 142.7 (d, JC,F = 7.4 Hz), 147.0, 147.2, 158.0 (d,
1JC,F = 247.0 Hz), 159.6 (d, 1JC,F = 249.3 Hz) ppm. 19F NMR (376 MHz,
CDCl3): δ = –124.10 to –121.62 (m, 1F), –118.25 to –118.17 (m, 1F)
ppm.
[14] V. A. Motornov, V. M. Muzalevskiy, A. A. Tabolin, R. A. Novikov, Yu. V.
Nelyubina, V. G. Nenajdenko, S. L. Ioffe, J. Org. Chem. 2017, 82, 5274–
5284.
[15] A. V. Shastin, V. M. Muzalevsky, E. S. Balenkova, V. G. Nenajdenko, Mende-
leev Commun. 2006, 16, 178–180.
5-Methyl-2,4′-dinitro-1,1′-biphenyl (4s). Method 2: 0.003 g (4 %);
pale yellow oil. H NMR (400 MHz, CDCl3): δ = 2.51 (s, 3H), 7.31 (d,
J = 7.8 Hz, 1H), 7.43–7.48 (m, 2H), 7.50 (dd, J = 7.8, 0.9 Hz, 1H), 7.81
(d, J = 0.7 Hz, 1H), 8.26–8.31 (m, 2H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.2, 124.0, 125.2, 129.2, 131.6, 131.8, 133.8, 140.5, 140.8,
142.9, 144.7 ppm.
1
[16] a) V. A. Motornov, A. A. Tabolin, R. A. Novikov, Yu. V. Nelyubina, V. G.
Nenajdenko, S. L. Ioffe, Org. Chem. Front. 2018, 5, 2588-2594; b) V. A.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
13
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Motornov, A. A. Tabolin, Yu. V. Nelyubina, V. G. Nenajdenko, S. L. Ioffe,
Org. Biomol. Chem. 2019, 17, 1442-1454;c) V. A. Motornov, A. A. Tabolin,
Yu. V. Nelyubina, V. G. Nenajdenko, S. L. Ioffe, Org. Biomol. Chem. 2020,
18, 1436-1448.
J. Med. Chem. 1969, 12, 647–652; c) C. Hansch, J. Org. Chem. 1970, 35,
620–621.
[26] K. Uneyama. Organofluorine Chemistry, Blackwell Publishing Ltd, New
Delhi, India, 2006, p. 82.
[27] R. Chang. Physical Chemistry for the Biosciences. USA: University Science
Books, 2005, p. 338–342.
[28] L. Yet, Privileged Structures in Drug Discovery: Medicinal Chemistry and
Synthesis, John Wiley & Sons, Inc., Hoboken, USA, 2018, p. 83.
[29] F. Fringuelli, R. Girotti, O. Piermatti, F. Pizzo, L. Vaccaro, Org. Lett. 2006, 8,
5741–5744.
[30] D. B. G. Williams, M. Lawton, J. Org. Chem. 2010, 75, 8351–8354.
[31] A. S. Aldoshin, A. A. Tabolin, S. L. Ioffe, V. G. Nenajdenko, Eur. J. Org.
Chem. 2018, 2018, 3816–3825.
[32] V. A. Motornov, A. A. Tabolin, R. A. Novikov, Yu. V. Nelyubina, S. L. Ioffe,
I. V. Smolyar, V. G. Nenajdenko, Eur. J. Org. Chem. 2017, 2017, 6851–6860.
[33] A. S. Aldoshin, A. A. Tabolin, S. L. Ioffe, V. G. Nenajdenko, Eur. J. Org.
Chem. 2019, 2019, 4384–4396.
[17]
[18]
R. Jasiński, M. Kwiatkowska, A. Barański, Monatsh. Chem. 2012, 143, 895–
899.
R. Jasiński, M. Kwiatkowska, A. Barański, J. Phys. Org. Chem. 2011, 24,
843–853.
[19]
[20]
C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991, 97, 165–195.
A. R. Jupp, T. C. Johnstone, D. W. Stephan, Inorg. Chem. 2018, 57, 14764–
14771.
[21] P. Pérez, L. R. Domingo, A. Aizman, R. Contreras in Theoretical Aspects of
Chemical Reactivity (Ed.: A. Toro-Labbé), 2007, Elveser, p. 139–291.
[22] R. G. Parr, L. V. Szentpaly, S. Liu, J. Am. Chem. Soc. 1999, 121, 1922–1924.
[23] J. D. Robert, M. C. Caserio, Basic Principles of Organic Chemistry, second
edition. W. A. Benjamin, Inc., Menlo Park, CA, 1977.
[24] H. B. El Ayouchia, H. Anane, M. L. El Idrissi Moubtassim, L. R. Domingo,
M. Julve, S.-E. Stiriba, Molecules 2016, 21, 1434.
[25] a) R. Todeschini, V. Consonni, Handbook of Molecular Descriptors, volume
11, Wiley-VCH, Weinheim, Germany, 2000, p. 414; b) E. Kutter, C. Hansch,
[34] J. Xu, D. J. Burton, J. Org. Chem. 2006, 71, 3743–3747.
[35] J. T. Kuethe, K. G. Childers, Adv. Synth. Catal. 2008, 350, 1577–1586.
Received: January 14, 2020
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
14
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Fluorinated Nitrostyrenes
R. V. Larkovich, S. A. Ponomarev,
A. S. Aldoshin, A. A. Tabolin,
S. L. Ioffe, V. G. Nenajdenko* ....... 1–15
Diels-Alder Reaction of ꢀ-Fluoro-ꢀ-
nitrostyrenes. Synthesis of Mono-
fluorinated Six-Membered Deriva-
tives
TOC Text: The Diels-Alder reaction of monofluorinated cyclohexenes 2 was
ꢀ-fluoro-ꢀ nitrostyrenes with some lin- prepared. The further transformation
ear dienes is reported. The kinetic of 2 into biphenyls 3 based on base-
studies were carried out to reveal sub- induced elimination of HNO2 followed
stituent effect and activation parame- by oxidative aromatization were de-
ters of the reaction. A new family of scribed.
DOI: 10.1002/ejoc.202000054
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
15
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim