Nucleophilic pentafluorophenylation of nitroalkenes

Article abstract of DOI:10.1055/s-0032-1316553

The interaction of pentafluorophenylmagnesium bromide with conjugate nitroalkenes is described. The optimized conditions involve performing the reaction either in diethyl ether in the presence of chlorotrimethylsilane or in a tetrahydrofuran-diethyl ether

Full text of DOI:10.1055/s-0032-1316553

2436▌
PAPER
paper
Nucleophilic Pentafluorophenylation of Nitroalkenes
Pentafluorophenylation of Nitroalkenes
Nikolay S. Kondratyev, Artem A. Zemtsov, Vitalij V. Levin, Alexander D. Dilman,* Marina I. Struchkova
N. D. Zelinsky Institute of Organic Chemistry, Leninsky prosp. 47, 119991 Moscow, Russian Federation
Fax +7(499)1355328; E-mail: adil25@mail.ru
Received: 17.04.2012; Accepted after revision: 22.05.2012
cially available. When the Grignard reagent was added to
a suspension of nitrostyrene (1a) in diethyl ether at –78 °C
followed by warming and stirring overnight at room tem-
perature, product 2a was isolated in 43% yield (Scheme 1,
Abstract: The interaction of pentafluorophenylmagnesium bro-
mide with conjugate nitroalkenes is described. The optimized con-
ditions involve performing the reaction either in diethyl ether in the
presence of chlorotrimethylsilane or in a tetrahydrofuran–diethyl
ether solvent mixture. The addition products can be transformed Table 1, entry 1). Given the complete consumption of ni-
into 4,5,6,7-tetrafluoroindolines by means of a reduction and cycli-
zation sequence.
trostyrene (1a), we propose that initially formed magne-
sium nitronate 3 can react with 1a, thereby leading to
Key words: alkenes, nucleophilic addition, fluorine, nitro com-
pounds, pentafluorophenyl
oligomerization of the Michael acceptor. Indeed, poorly
soluble polymeric material was observed during the work-
up. Based on our earlier observation that chlorosilanes do
not react with C6F5MgBr in diethyl ether,12 we performed
Fluorinated aromatic compounds have attracted consider- the reaction in the presence of chlorotrimethylsilane
able attention as a result of their applications in various (TMSCl). Rewardingly, product 2a was obtained in 84%
fields.1 Having the highest number of fluorine atoms, the yield. We believe that the role of chlorosilane is to rapidly
pentafluorophenyl group possesses unique properties in trap magnesium nitronate 3 to generate silyl nitronate 4,
terms of steric requirements and electronic effects, as well which is hydrolyzed on work-up.13 As an alternative pro-
as its ability to engage in stacking interactions. As a result, cedure, we used a tetrahydrofuran–ether (3:1) solvent
substances bearing the C6F5-substituent have been inves- mixture, and obtained 2a in 80% yield (entry 4).
tigated in medicinal chemistry,2 supramolecular chemis-
try,3 and in surface and materials sciences.4 As an
additional synthetic benefit, the para- and ortho-positions
display enhanced reactivity towards nucleophilic substitu-
tion of fluorine, which allows for the synthesis of a wide
array of fluorinated aromatics.5
C6F5
C6F5MgBr (1.3 equiv)
NO2
NO2
Ph
Ph
solvent, additive;
then acidic work-up
2a
1a
C6F5 O–
N+
C6F5 O–
N+
Among several methods used for the direct introduction of
the C6F5-group,6 processes involving nucleophilic penta-
fluorophenylation appear to be most attractive. Whereas
the addition of the C6F5-carbanion to C=O and C=N bonds
is well-developed,7 the addition to electron-deficient al-
kenes is rare.8–10 Within the framework of our studies of
fluoroalkylation of various Michael acceptors,8 we turned
our attention to conjugate nitroalkenes.
TMSCl
Ph
OMgBr
Ph
OTMS
3
4
Scheme 1 Pentafluorophenylation of nitrostyrene (1a)
Table 1 Pentafluorophenylation of Nitrostyrene (1a)
Entry
Solvent
Additive
Time
(h)a
Yield
(%)b
Recently, we have shown that highly electrophilic α-nitro-
cinnamates undergo nucleophilic fluoroalkylation with
fluorinated silicon reagents activated by Lewis base.8d Us-
ing a similar methodology, 4-nitroisoxazoles formally
containing a nitroalkene fragment were successfully fluo-
roalkylated.11 However, under these conditions, conven-
tional nitroalkenes do not afford any product. Herein, we
describe an efficient method for nucleophilic pentafluoro-
phenylation of nitroalkenes.
1
2
3
4
Et2O
–
18
18
2
43
83
84
80
Et2O
TMSCl (1.1 equiv)
TMSCl (1.2 equiv)
–
Et2O
THF–Et2O
2
a Reagents were combined at –78 °C, then the mixture was stirred at
r.t. for the specified time.
b Isolated yield.
Pentafluorophenylmagnesium bromide was selected as a
nucleophilic reagent because it can be readily prepared
from pentafluorophenyl bromide and magnesium in dieth-
yl ether. It is stable at room temperature and is commer-
The protocol involving the use of TMSCl (Method A) was
selected for further studies, and a series of nitroalkenes
were subjected to the pentafluorophenylation reaction
(Table 2). Aromatic and heteroaromatic substrates gave
nitro-containing compounds 2 in high yields (entries 1–7).
SYNTHESIS 2012, 44, 2436–2440
Advanced online publication: 27.06.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316553; Art ID: SS-2012-T0365-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Pentafluorophenylation of Nitroalkenes
2437
However, nitroalkenes 1i and 1j, bearing isopropyl and When β-morpholino-substituted nitroalkenes 1k and 1l
tert-butyl groups, respectively, reacted poorly under the were reacted with the C6F5MgBr and TMSCl system, ni-
standard conditions. In these cases, performing the reac- troalkenes 3k and 3l were obtained, respectively (Scheme
tion in a THF–diethyl ether solvent mixture without 2). Presumably, the initially formed silyl nitronates under-
TMSCl for 18 hours at room temperature afforded the de- went elimination of morpholine upon acidic work-up.
sired products in good yields (entries 9 and 11).
O
Table 2 Pentafluorophenylation of Nitroalkenes 1
C6F5MgBr
TMSCl
NO2
N
N
O–
N+
H+
C6F5MgBr (1.3 equiv)
TMSCl (1.2 equiv)
C6F5
O
R
NO2
R1
NO2
C6F5
OTMS
R1
–78 °C to r.t.;
then acidic work-up
R2
1k, R = H
1l, R = Et
R2
1
2
NO2
H+
C6F5
Entry
Substrate
Product Methoda Yield
(%)b
R
3k, 58 %
3l, 71 %
NO2
NO2
Scheme 2 Reaction of β-morpholino-substituted enamines
1
2
3
2b
2c
2d
A
A
A
83
88
87
O
We demonstrated that C6F5-substituted nitroalkanes can
be transformed into 4,5,6,7-tetrafluoroindolines (Scheme
3). Thus, reduction of the nitro group of product 2a under
an atmospheric pressure of hydrogen furnished amine 5.
Subsequent heating of the latter in N,N-dimethylform-
amide (DMF) in the presence of potassium fluoride effect-
ed substitution of ortho-fluorine leading to the formation
of 4,5,6,7-tetrafluoroindoline 6. It should be pointed out
that this approach to the synthesis of tetrafluoroindolines,
which starts from nitroalkene and C6F5 nucleophile, is
more general and efficient than previously reported meth-
ods.14
1b
S
1c
NO2
Cl
1d
NO2
4
5
2e
A
A
90
MeO
1e
F
Ph
F
Ph
NO2
C6F5
F
F
F
F
i
ii
NO2
2f
92c
Br
Ph
NH2
64%
80%
N
MeO
F
2a
H
F
F
5
6
1f
NO2
Scheme 3 Synthesis of 4,5,6,7-tetrafluoroindoline 6. Reagents and
conditions: (i) H2 (1 atm), Pd/C; (ii) KF, DMF, 150 °C, 4 h.
Ph
6
7
2g
A
A
82d
75
1g
In summary, a convenient protocol for the addition of
pentafluorophenylmagnesium bromide to conjugate ni-
troalkenes has been elaborated. The addition products,
C6F5-substituted nitro compounds, can be readily convert-
ed into fluorinated indolines.
NO2
Ph
2h
2i
1h
NO2
e
8
9
A
B
–
76
1i
1j
All reactions were performed under an argon atmosphere. Column
chromatography was carried out with Merck silica gel (Kieselgel
60, 230–400 mesh). Precoated silica gel plates F-254 were used for
thin-layer analytical chromatography; visualizing under UV light
and/or dipping in acidic aq KMnO4 solution. NMR spectra were re-
corded with a Bruker AM-300 instrument. Microanalyses were per-
formed with a KarloErba 1106 instrument. Nitroalkenes 1a, 1c–e,
and 1h,15 1f,16 1g,17 1i,18 1j,19 and 1l,20 were obtained according to
literature procedures.
NO2
10
11
2j
A
B
n.r
78
a Method A: C6F5MgBr, TMSCl, Et2O, –78 °C to r.t., 2 h; Method B:
C6F5MgBr, THF–Et2O (3:1), –78 °C to r.t., 18 h at r.t.
b Yield of isolated product.
c Mixture of isomers (dr = 1.2:1).
d Mixture of isomers (dr = 1.8:1).
2-[(E)-2-Nitrovinyl]furan (1b)21
e Approximately 50% conversion along with formation of byproducts. A solution of MeONa [prepared by dissolving of sodium (0.96 g,
41.0 mmol) in MeOH (10 mL)] was added to a mixture of nitro-
methane (2.14 mL, 39 mmol) and 2-furaldehyde (3.45 mL, 41.0
mmol) at 0 °C. After stirring for 10 min at 0 °C, the mixture was
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2436–2440

2438
N. S. Kondratyev et al.
PAPER
treated with H2O (5 mL), and then with cold HCl (prepared from 15
mL of conc. HCl and 25 mL of H2O). The precipitate was filtered,
washed with H2O (3 × 20 mL), dried, and recrystallized from
MeOH to give nitroalkene 1b.
(dd, J = 8.7, 6.8 Hz, 1 H, CHPh), 6.21 (d, J = 2.8 Hz, 1 H, C=CH),
6.35 (dd, J = 2.8, 1.7 Hz, 1 H, OCH=CH), 7.38 (s, 1 H, OCH).
13C NMR (75 MHz, CDCl3): δ = 33.1, 74.7 (t, J = 3.5 Hz), 107.9,
110.7 (m), 110.8, 137.7 (dm, J = 250.0 Hz), 141.2 (dm,
J = 252.2 Hz), 143.0, 145.2 (dm, J = 250.0 Hz), 148.2.
Yield: 2.0 g (37%); brown crystals; mp 72–73 °C.
19F NMR (282 MHz, CDCl3): δ = –161.4 (ddd, J = 20.7, 20.3,
5.7 Hz, 2 F, meta), –154.0 (t, J = 20.7 Hz, 1 F, para), –142.1 (dd,
J = 20.3, 5.7 Hz, 2 F, ortho).
4-[(E)-2-Nitrovinyl]morpholine (1k)22
p-Toluenesulfonic acid (162 mg, 0.85 mmol) was added to a mix-
ture of morpholine (2.46 mL, 28.5 mmol), trimethyl orthoformate
(8.73 mL, 78.9 mmol) and nitromethane (7.76 mL, 142.5 mmol).
The mixture was heated at reflux for 7 h, then concentrated under
reduced pressure and the residue was recrystallized from MeOH to
give nitroalkene 1k.
Anal. Calcd for C12H6F5NO3 (307.17): C, 46.92; H, 1.97; N, 4.56.
Found: C, 46.84; H, 1.98; N, 4.47.
2-[2-Nitro-1-(perfluorophenyl)ethyl]thiophene (2c)
Yield: 284 mg (88%); pale-yellow oil; Rf = 0.26 (hexane–EtOAc,
15:1).
Yield: 1.58 g (35%); dark-green crystals; mp 140–141 °C.
Preparation of C6F5MgBr
1H NMR (300 MHz, CDCl3): δ = 5.11 (dd, J = 13.6, 7.9 Hz, 1 H,
CHAHBNO2), 5.19 (dd, J = 13.6, 8.6 Hz, 1 H, CHAHBNO2), 5.57
(dd, J = 8.6, 7.9 Hz, 1 H, CHAr), 6.92–7.07 (m, 2 H, C=CH-CH),
7.28 (dd, J = 4.9, 0.7 Hz, 1 H, SCH).
13C NMR (75 MHz, CDCl3): δ = 34.5, 76.8 (t, J = 4.3 Hz), 112.9
(m), 126.0, 126.3, 127.4, 137.9 (dm, J = 242.0 Hz), 138.0, 141.3
(dm, J = 243.1 Hz), 145.2 (dm, J = 248.1 Hz).
19F NMR (282 MHz, CDCl3): δ = –161.1 (ddd, J = 21.0, 20.7,
5.7 Hz, 2 F, meta), –154.1 (t, J = 20.7 Hz, 1 F, para), –142.2 (dd,
J = 21.0, 5.7 Hz, 2 F, ortho).
Bromopentafluorobenzene (6.2 mL, 50 mmol) was added dropwise
to a suspension of magnesium turnings (1.28 g, 52.5 mmol) in Et2O
(20 mL) at a rate that was sufficient to maintain gentle reflux. After
complete addition, the mixture was heated to reflux for an additional
1 h. The concentration of the Grignard reagent was determined by
19F NMR spectroscopy using PhCF3 as internal standard to be
1.92 M.
Reactions of Nitroalkenes with C6F5MgBr; General Procedure
Method A
Anal. Calcd for C12H6F5NO2S (323.24): C, 44.59; H, 1.87; N, 4.33.
Found: C, 44.64; H, 1.86; N, 4.23.
A Schlenk flask was evacuated, filled with argon, charged with ni-
troalkene (1.0 mmol), Et2O (1 mL) and TMSCl (152 μL, 1.2 mmol),
and the flask was cooled to –78 °C. A solution of C6F5MgBr (1.3
mmol) was added dropwise, then the temperature was allowed to
rise to r.t. during 1 h and the mixture was stirred for an additional
1 h. The mixture was quenched with AcOH (86 μL, 1.5 mmol), di-
luted with H2O (5 mL), and extracted with Et2O (3 × 5 mL). The or-
ganic phase was dried over Na2SO4, concentrated under vacuum,
and the residue was purified by chromatography.
1-[1-(4-Chlorophenyl)-2-nitroethyl]-2,3,4,5,6-pentafluoroben-
zene (2d)
Yield: 306 mg (87%); colorless oil; Rf = 0.26 (hexane–EtOAc,
15:1).
1H NMR (300 MHz, CDCl3): δ = 5.08–5.22 (m, 2 H, CH2NO2), 5.29
(dd, J = 8.0, 7.9 Hz, 1 H, CHPh), 7.26 (d, J = 7.4 Hz, 2 H, ArH),
7.35 (d, J = 7.4 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 38.6, 76.1 (t, J = 4.3 Hz), 112.9
(m), 128.8 (t, J = 1.6), 129.7, 134.6, 134.7, 138.0 (dm,
J = 254.9 Hz), 141.0 (dm, J = 255.8 Hz), 145.2 (dm, J = 249.7 Hz).
19F NMR (282 MHz, CDCl3): δ = –161.1 (dt, J = 20.9, 6.2 Hz, 2 F,
meta), –154.2 (t, J = 20.9 Hz, 1 F, para), –142.4 (dd, J = 20.9,
6.2 Hz, 2 F, ortho).
Method B
A Schlenk flask was evacuated, filled with argon, charged with ni-
troalkene (1.0 mmol) and THF (2 mL), and the flask was cooled to
–78 °C. A solution of C6F5MgBr (1.3 mmol) was added dropwise,
then the temperature was allowed to rise to r.t. during 1 h, and the
mixture stirred for an additional 18 h (reaction monitored by TLC
analysis). The mixture was quenched with aq HCl (0.5 M, 5.2 mL),
diluted with H2O (5 mL), and extracted with Et2O (3 × 5 mL). The
organic phase was dried over Na2SO4, concentrated under vacuum,
and the residue was purified by chromatography.
Anal. Calcd for C14H7ClF5NO2 (351.66): C, 47.82; H, 2.01; N, 3.98.
Found: C, 47.71; H, 1.94; N, 3.92.
1,2,3,4,5-Pentafluoro-6-[1-(4-methoxyphenyl)-2-nitroeth-
1,2,3,4,5-Pentafluoro-6-(2-nitro-1-phenylethyl)benzene (2a)
Yield: 266 mg (84%); colorless oil; Rf = 0.24 (hexane–EtOAc,
20:1).
1H NMR (300 MHz, CDCl3): δ = 5.07–5.37 (m, 1 H, CHC6F5), 5.22
(dd, J = 46.7, 13.3 Hz, 2 H, CH2), 7.25–7.44 (m, 5 H, PhH).
13C NMR (75 MHz, CDCl3): δ = 39.2, 76.3 (t, J = 4.3 Hz), 113.3
(m), 127.4 (t, J = 1.5 Hz), 128.6, 129.5, 136.1, 137.7 (dm,
J = 241.3 Hz), 140.9 (dm, J = 240.7 Hz), 145.1 (dm, J = 251.1 Hz).
19F NMR (282 MHz, CDCl3): δ = –161.4 (ddd, J = 21.2, 21.2,
7.4 Hz, 2 F, meta), –154.8 (t, J = 21.21 Hz, 1 F, para), –145.5 (dd,
J = 21.2, 7.4 Hz, ortho).
yl]benzene (2e)
Yield: 313 mg (90%); colorless oil; Rf = 0.20 (hexane–EtOAc,
10:1).
1H NMR (300 MHz, CDCl3): δ = 3.80 (s, 3 H, OCH3), 5.08 (dd,
J = 12.4, 6.5 Hz, 1 H, CHPh), 5.13–5.30 (m, 2 H, CH2NO2), 6.89
(d, J = 8.5 Hz, 2 H, ArH), 7.24 (d, J = 8.5 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 38.6, 55.3, 76.5 (t, J = 4.3 Hz),
113.6 (m), 114.8, 128.0, 128.6, 137.9 (dm, J = 254.0 Hz), 140.7
(dm, J = 254.6 Hz), 145.1 (dm, J = 247.0 Hz), 159.7.
19F NMR (282 MHz, CDCl3): δ = –161.4 (ddd, J = 21.2, 20.8,
6.2 Hz, 2 F, meta), –155.0 (t, J = 20.8 Hz, 1 F, para), –142.6 (dd,
J = 21.2, 6.2 Hz, 2 F, ortho).
Anal. Calcd for C14H8F5NO2 (317.21): C, 53.01; H, 2.54; N, 4.42.
Found: C, 53.11; H, 2.47; N, 4.29.
Anal. Calcd for C15H10F5NO3 (347.24): C, 51.88; H, 2.90; N, 4.03.
Found: C, 51.87; H, 2.76; N, 3.89.
2-[2-Nitro-1-(perfluorophenyl)ethyl]furan (2b)
Yield: 255 mg (83%); pale-yellow oil; Rf = 0.21 (hexane–EtOAc,
15:1).
1H NMR (300 MHz, CDCl3): δ = 5.04 (dd, J = 13.7, 8.7 Hz, 1 H,
CHAHBNO2), 5.15 (dd, J = 13.7, 6.8 Hz, 1 H, CHAHBNO2), 5.41
1-[2-Bromo-1-(4-methoxyphenyl)-2-nitroethyl]-2,3,4,5,6-penta-
fluorobenzene (2f)
Obtained as a mixture of isomers 1.2:1.
Yield: 392 mg (92%); colorless crystals; mp 64–65 °C; Rf = 0.27
(hexane–EtOAc, 15:1).
Synthesis 2012, 44, 2436–2440
© Georg Thieme Verlag Stuttgart · New York

PAPER
Pentafluorophenylation of Nitroalkenes
2439
1H NMR (300 MHz, CDCl3): δ (major) = 3.78 (s, 3 H, OCH3), 5.30
(d, J = 11.9 Hz, 1 H, CHNO2), 6.83 (d, J = 11.9 Hz, 1 H, CHAr),
6.87 (d, J = 8.9 Hz, 2 H, ArH), 7.30 (d, J = 8.9 Hz, 2 H, ArH); δ
(minor) = 3.82 (s, 3 H, OCH3), 5.23 (d, J = 11.4 Hz, 1 H, CHNO2),
6.83 (d, J = 11.4 Hz, 1 H, CHAr), 6.93 (d, J = 8.9 Hz, 2 H, ArH),
7.33 (d, J = 8.9 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): δ (major) = 47.8, 55.2, 78.5 (t,
J = 5.0 Hz), 113.2 (m), 115.0, 126.1, 129.1, 137.7 (dm,
J = 249.3 Hz), 141.1 (dm, J = 249.9 Hz), 144.5 (dm, J = 249.9 Hz),
160.3; δ (minor) = 47.3, 55.3, 78.8 (t, J = 5.0 Hz), 112.2 (m), 114.8,
126.6, 129.5, 137.7 (dm, J = 249.3 Hz), 141.1 (dm, J = 249.9 Hz),
144.5 (dm, J = 249.9 Hz), 160.0.
19F NMR (282 MHz, CDCl3): δ (major) = –160.9 (ddd, J = 21.8,
21.2, 6.0 Hz, 2 F, meta), –154.1 (t, J = 21.2 Hz, 1 F, para), –141.9
(dd, J = 21.8, 6.0 Hz, 2 F, ortho); δ (minor) = –160.5 (ddd, J = 20.6,
20.5, 5.2 Hz, 2 F, meta), –153.6 (t, J = 20.5 Hz, 1 F, para), –141.9
(dd, J = 20.6, 5.2 Hz, 1 F, ortho).
2.20 [m, 1 H, CH(CH3)2], 3.99 (dt, J = 8.2, 8.2 Hz, 1 H, CHPh),
4.82 (d, J = 7.9 Hz, 2 H, CH2NO2).
13C NMR (75 MHz, CDCl3): δ = 20.6, 20.7, 30.0, 41.6, 76.2 (t,
J = 3.5 Hz), 112.8 (tm, J = 16.2 Hz), 137.7 (dm, J = 254.0 Hz),
140.5 (dm, J = 253.0 Hz), 145.4 (dm, J = 247.6).
19F NMR (282 MHz, CDCl3): δ = –162.2 (dt, J = 21.2, 6.4 Hz, 2 F,
meta) –155.4 (t, J = 21.2 Hz, 1 F, para), –141.8 (dd, J = 21.2,
6.3 Hz, 2 F, ortho).
Anal. Calcd for C11H10F5NO2 (283.19): C, 46.65; H, 3.56; N, 4.95.
Found: C, 46.54; H, 3.56; N, 4.97.
1-(3,3-Dimethyl-1-nitrobutan-2-yl)-2,3,4,5,6-pentafluoroben-
zene (2j)
Yield: 232 mg (78%); colorless oil; Rf = 0.31 (hexane–EtOAc,
15:1).
1H NMR (300 MHz, CDCl3): δ = 1.03 [s, 9 H, C(CH3)3], 3.89 (dd,
J = 10.9, 4.8 Hz, 1 H, CHC6F5), 4.82 (dd, J = 13.3, 4.8 Hz, 1 H,
CHAHB), 5.00 (dd, J = 13.3, 10.9 Hz, 1 H, CHACHB).
13C NMR (75 MHz, CDCl3): δ = 27.9 (d, J = 2.9 Hz), 35.2, 44.8 (dd,
J = 1.5, 1.4 Hz), 74.5 (d, J = 8.1 Hz).
19F NMR (282 MHz, CDCl3): δ = –162.3 (ddd, J = 21.8, 21.5,
7.1 Hz, 1 F, meta), –162.0 (ddd, J = 21.5, 21.4, 7.4 Hz, 1 F, meta),
–155.1 (t, J = 20.8 Hz, 1 F, para), –139.0 (d, J = 21.8 Hz, 2 F,
ortho), –138.3 (dm, J = 21.5 Hz, 2 F, ortho).
Anal. Calcd for C15H9BrF5NO3 (426.13): C, 42.28; H, 2.13; N, 3.29.
Found: C, 42.14; H, 2.07; N, 3.19.
1,2,3,4,5-Pentafluoro-6-(2-nitro-1-phenylpropyl)benzene (2g)
Obtained as a mixture of isomers 1.8:1.
Yield: 272 mg (82%); colorless crystals; mp 67–76 °C; Rf = 0.20
(hexane–EtOAc, 25:1).
1H NMR (300 MHz, CDCl3): δ = 1.62 (d, J = 6.7 Hz, 3 H, CH3),
5.01 (d, J = 11.7 Hz, 1 H, CHPh), 5.66–5.81 [m, 1 H,
CH(CH3)NO2], 7.22–7.54 (m, 5 H, PhH); δ (minor) = 1.57 (d,
J = 6.7 Hz, 3 H, CH3), 4.86 (d, J = 11.7 Hz, 1 H, CHPh), 5.66–5.81
[m, 1 H, CH(CH3)NO2], 7.22–7.54 (m, 5 H, PhH).
13C NMR (75 MHz, CDCl3): δ (major) = 19.3, 45.7, 84.1 (dd,
J = 4.3, 4.0 Hz); δ (minor) = 19.4, 46.4, 83.7 (dd, J = 3.6, 3.9 Hz);
δ (both isomers) = 113.4 (m), 127.5 (t, J = 1.8 Hz), 128.2 (t,
J = 2.1 Hz), 128.5 (d, J = 8.4 Hz), 128.6, 129.3, 129.6, 136.0,
136.5, 137.9 (dm, J = 249.9), 140.7 (dm, J = 257.0), 144.9 (dm,
J = 247.7).
19F NMR (282 MHz, CDCl3): δ (major) = –160.9 (dt, J = 21.2,
6.7 Hz, 2 F, meta), –154.6 (t, J = 21.2 Hz, 1 F, para), –142.2 (dd,
J = 21.2, 6.7 Hz, 1 F, ortho); δ (minor) = –161.6 (dt, J = 21.2,
6.4 Hz, 2 F, meta), –155.3 (t, J = 21.2 Hz, 1 F, para), –141.4 (dd,
J = 21.2, 6.4 Hz, 1 F, ortho).
Anal. Calcd for C12H12F5NO2 (297.22): C, 48.49; H, 4.07; N, 4.71.
Found: C, 48.29; H, 3.82; N, 4.54.
(E)-1,2,3,4,5-Pentafluoro-6-(2-nitrovinyl)benzene (3k)
Yield: 139 mg (58%); colorless oil; Rf = 0.24 (hexane–EtOAc,
25:1).
1H NMR (300 MHz, CDCl3): δ = 7.81 (d, J = 14.0 Hz, 1 H,
NO2HC=CH), 8.02 (d, J = 14.0 Hz, 1 H, PhCH=CH).
13C NMR (75 MHz, CDCl3): δ = 106.2 (ddd, J = 13.9, 14.1, 4.3 Hz),
123.0, 137.9 (dm, J = 253.7 Hz), 142.3 (dd, J = 9.8, 9.9 Hz), 143.2
(dm, J = 261.8 Hz), 146.0 (dm, J = 256.7).
19F NMR (282 MHz, CDCl3): δ = –161.0 (ddd, J = 20.4, 19.3,
5.8 Hz, 2 F, meta), –148.0 (dd, J = 20.4, 19.3 Hz, 1 F, para), –136.8
(m, 2 F, ortho).
Anal. Calcd for C8H2F5NO2 (239.10): C, 40.19; H, 0.84; N, 5.86.
Found: C, 40.33; H, 0.83; N, 5.88.
Anal. Calcd for C15H10F5NO2 (331.24): C, 54.39; H, 3.04; N, 4.23.
Found: C, 54.27; H, 2.91; N, 4.11.
(E)-1,2,3,4,5-Pentafluoro-6-(2-nitrobut-1-en-1-yl)benzene (3l)
Yield: 190 mg (71%); colorless oil; Rf = 0.36 (hexane–EtOAc,
25:1).
(E)-1,2,3,4,5-Pentafluoro-6-(1-nitro-4-phenylbut-3-en-2-
yl)benzene (2h)
1H NMR (300 MHz, CDCl3): δ = 1.17 (t, J = 7.3 Hz, 3 H, CH2CH3),
2.61 (q, J = 7.3 Hz, 2 H, CH2CH3), 7.55 (s, 1 H, PhCH).
13C NMR (75 MHz, CDCl3): δ = 11.3 (t, J = 1.5 Hz), 22.2 (t,
J = 1.8 Hz), 107.7 (td, J = 17.9, 4.0 Hz), 117.1, 138.1 (dm,
J = 257.4 Hz), 142.1 (dm, J = 258.7 Hz), 144.2 (dm, J = 249.5 Hz),
158.9.
19F NMR (282 MHz, CDCl3): δ = –161.2 (ddd, J = 20.9, 20.6,
6.2 Hz, 2 F, meta), –151.7 (t, J = 20.6 Hz, 1 F, para), –137.9 (dd,
J = 20.9, 6.2 Hz, 2 F, ortho).
Yield: 257 mg (75%); pale-yellow crystals; mp 99–101 °C; Rf =
0.28 (hexane–EtOAc, 15:1).
1H NMR (300 MHz, CDCl3): δ = 4.78–4.95 (m, 3 H, CHCH2NO2),
6.28 (dd, J = 16.0, 6.4 Hz, 1 H, PhCH=CH), 6.67 (d, J = 16.0 Hz,
1 H, PhCH=CH), 7.27–7.39 (m, 5 H, PhH).
13C NMR (75 MHz, CDCl3): δ = 37.8, 76.7, 112.3 (m), 122.2, 126.7,
128.7, 128.8, 135.5, 135.6, 138.0 (dm, J = 249.8 Hz), 144.5 (dm,
J = 262.2 Hz), 145.1 (dm, J = 247.8 Hz).
19F NMR (282 MHz, CDCl3): δ = –161.3 (ddd, J = 21.0, 20.7,
6.2 Hz, 2 F, meta), –154.6 (t, J = 20.7 Hz, 1 F, para), –142.6 (dd,
J = 21.0, 6.2 Hz, 2 F, ortho).
Anal. Calcd for C10H6F5NO2 (267.15): C, 44.96; H, 2.26; N, 5.24.
Found: C, 44.79; H, 2.24; N, 5.13.
Anal. Calcd for C16H10F5NO2 (343.25): C, 55.99; H, 2.94; N, 4.08.
Found: C, 55.84; H, 2.90; N, 4.01.
4,5,6,7-Tetrafluoro-3-phenylindoline (6)
Palladium on carbon (20 mg, 10% palladium content) and AcOH
(144 μL, 2.52 mmol) were added to a solution of 2a (533 mg, 1.68
mmol) in MeOH (3 mL). The flask was flushed with hydrogen and
connected to a hydrogen balloon (atmospheric pressure), and the
mixture was vigorously stirred for 24 h. After consumption of start-
ing compound (reaction monitored by TLC), the mixture was fil-
tered through the pad of Celite and concentrated. The residue was
1,2,3,4,5-Pentafluoro-6-(3-methyl-1-nitrobutan-2-yl)benzene
(2i)
Yield: 215 mg (76%); colorless oil; Rf = 0.28 (hexane–EtOAc,
15:1).
1H NMR (300 MHz, CDCl3): δ = 0.86 [d, J = 6.6 Hz, 3 H,
C(CH3)A(CH3)B], 1.10 [d, J = 6.6 Hz, 3 H, C(CH3)A(CH3)B], 2.02–
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2436–2440

2440
N. S. Kondratyev et al.
PAPER
dissolved in EtOAc (5 mL), washed with sat. aq NaHCO3 (3 × 5
mL), and the aqueous phase was washed with EtOAc (3 × 5 mL).
The combined organic phase was dried over Na2SO4 and concen-
trated under vacuum. The residue was passed through a short silica
gel pad (eluting with hexane–EtOAc, 1:1 containing 2 vol% Et3N),
to give amine 5 (307 mg), which was used without further purifica-
tion.
(6) (a) Korenaga, T.; Kosaki, T.; Fukumura, R.; Ema, T.; Sakai,
T. Org. Lett. 2005, 7, 4915. (b) Zhong, W.; Liu, Z.; Yu, C.;
Su, W. Synlett 2008, 2888. (c) Kovtonyuk, V. N.; Kobrina,
L. S.; Haufe, G. Russ. Chem. Bull. 2008, 57, 1686. (d) Chen,
Q. Y.; Li, Z. T. J. Org. Chem. 1993, 58, 2599.
(7) (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97,
757. (b) Brogan, S.; Carter, N. B.; Lam, H. W. Synlett 2010,
615. (c) Coe, P. L.; Stephens, R.; Tatlow, J. C. J. Chem. Soc.
1962, 3227. (d) Dilman, A. D.; Belyakov, P. A.; Korlyukov,
A. A.; Struchkova, M. I.; Tartakovsky, V. A. Org. Lett.
2005, 7, 2913. (e) Dilman, A. D.; Levin, V. V.; Belyakov, P.
A.; Struchkova, M. I.; Tartakovsky, V. A. Synthesis 2006,
447. (f) Levin, V. V.; Dilman, A. D.; Belyakov, P. A.;
Korlyukov, A. A.; Struchkova, M. I.; Antipin, M. Y.;
Tartakovsky, V. A. Synthesis 2006, 489.
(8) (a) Dilman, A. D.; Levin, V. V.; Belyakov, P. A.;
Struchkova, M. I.; Tartakovsky, V. A. Tetrahedron Lett.
2008, 49, 4352. (b) Zemtsov, A. A.; Levin, V. V.; Dilman,
A. D.; Struchkova, M. I.; Belyakov, P. A.; Tartakovsky, V.
A. Tetrahedron Lett. 2009, 50, 2998. (c) Zemtsov, A. A.;
Levin, V. V.; Dilman, A. D.; Struchkova, M. I.; Belyakov, P.
A.; Tartakovsky, V. A.; Hu, J. Eur. J. Org. Chem. 2010,
6779. (d) Zemtsov, A. A.; Levin, V. V.; Dilman, A. D.;
Struchkova, M. I.; Tartakovsky, V. A. J. Fluorine Chem.
2011, 132, 378.
(9) An example of conjugate addition of C6F5MgBr to cyclic
unsaturated ester generated in situ was reported, see:
Claremon, D. A.; McClure, D. E.; Springer, J. P.; Baldwin,
J. J. J. Org. Chem. 1984, 49, 3871.
(10) Acylated Baylis–Hillman adducts also were subjected to
nucleophilic pentafluorophenylation and trifluoromethylation
reactions, which proceed through attack of the carbanion at
the C=C bond, see ref. 8c and (a) Furukawa, T.; Nishimine,
T.; Tokunaga, E.; Hasegawa, K.; Shiro, M.; Shibata, N. Org.
Lett. 2011, 13, 3972. (b) Li, Y.; Liang, F.; Li, Q.; Xu, Y.-c.;
Wang, Q.-R.; Jiang, L. Org. Lett. 2011, 13, 6082.
(11) Kawai, H.; Tachi, K.; Tokunaga, E.; Shiro, M.; Shibata, N.
Angew. Chem. Int. Ed. 2011, 50, 7803.
Anhydrous KF (93 mg, 1.6 mmol) was added to a solution of amine
5 (307 mg) in DMF (2 mL), and the suspension was heated at
150 °C for 5 h. The mixture was cooled to r.t., quenched with aq
HCl (5 M, 4 mL), and washed with hexane–EtOAc (1:1, 3 × 5 mL).
The combined organic phase was dried over Na2SO4, concentrated
under vacuum, and the residue was purified by chromatography on
silica gel (hexane–EtOAc, 10:1) to give indoline 6.
Yield: 228 mg (80% based on 5, 51% based on 2a); colorless oil;
Rf = 0.23 (hexane–EtOAc, 10:1).
1H NMR (300 MHz, CDCl3): δ = 3.67 (ddd, J = 9.2, 7.3, 2.0 Hz,
2 H, CHAHB), 3.96 (br, 1 H, NH), 4.09 (ddd, J = 9.2, 7.3, 2.0 Hz,
1 H, CHAHB), 4.69 (dd, J = 9.2, 7.3 Hz, 1 H, CHPh), 7.25–7.41 (m,
5 H, PhH).
13C NMR (75 MHz, CDCl3): δ = 45.9, 57.0, 114.6, 114.8, 126.8,
127.1, 128.6, 133.5 (dm, J = 249.3 Hz), 133.7 (dm, J = 250.1 Hz),
140.7 (dm, J = 250.7 Hz), 141.3, 143.9 (dm, J = 250.4 Hz).
19F (282 MHz, CDCl3): δ = –171.2 (ddd, J = 21.2, 21.2, 6.7 Hz,
1 F), –162.8 (ddd, J = 21.2, 21.2, 14.8 Hz, 1 F), –158.6 (dd,
J = 21.2, 21.2 Hz, 1 F), –164.8 (dd, J = 21.2, 14.8 Hz, 1 F).
Anal. Calcd for C14H9F4N (267.22): C, 62.93; H, 3.39; N, 5.24.
Found: C, 62.74; H, 3.35; N, 5.17.
Acknowledgment
This work was supported by the Russian Foundation for Basic Re-
search (project 10-03-91159) and the Ministry of Science (project
MD-1151.2011.3). We are grateful to Mr. A. Tabolin for providing
some nitroalkenes.
(12) Dilman, A. D.; Arkhipov, D. E.; Korlyukov, A. A.;
Ananikov, V. P.; Danilenko, V. M.; Tartakovsky, V. A.
J. Organomet. Chem. 2005, 690, 3680.
(13) Silylating reagents are typical additives in cuprate additions
to unsaturated carbonyl compounds, see: Dilman, A. D.;
Ioffe, S. L. Chem. Rev. 2003, 103, 733.
(14) (a) Filler, R.; Chen, W.; Woods, S. M. J. Fluorine Chem.
1995, 73, 95. (b) Filler, R.; Woods, S. M.; White, W. L. Can.
J. Chem. 1989, 67, 1837.
(15) Worrall, D. E. Org. Synth. 1929, 9, 66.
(16) Romashov, L. V.; Khomutova, Y. A.; Danilenko, V. M.;
Ioffe, S. L.; Lesiv, A. V. Synthesis 2010, 407.
(17) Heinzelman, R. V. Org. Synth. 1955, 35, 74.
(18) Melton, J.; McMurry, J. E. J. Org. Chem. 1975, 40, 2138.
(19) Mikesell, P.; Schwaebe, M.; DiMare, M.; Little, R. D. Acta
Chem. Scand. 1999, 53, 792.
(20) Node, M.; Nagasawa, H.; Naniwa, Y.; Fuji, K. Synthesis
1987, 729.
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Synthesis 2012, 44, 2436–2440
© Georg Thieme Verlag Stuttgart · New York