[RuH2(PPh3)4]-catalyzed michael addition reaction of α-fluoronitroalkanes

Article abstract of DOI:10.1055/s-0032-1317526

The Michael addition reactions of α-fluoronitroalkanes with various electron-deficient olefins were realized by catalysis of low-valence ruthenium species through C_sp3-H activation, providing a useful way to construct a fluorinated quaternary c

Full text of DOI:10.1055/s-0032-1317526

PAPER
▌3815
paper
[RuH2(PPh3)4]-Catalyzed Michael Addition Reaction of α-Fluoronitroalkanes
Michael Addition of α-Fluoroalkanes
Qi Wang,a Qing-Yun Chen,b Xianjin Yang,*a Yong Guo*b
a
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology,
130 Meilong Road, Shanghai 200237, P. R. of China
Fax +86(21)64253074; E-mail: yxj@ecust.edu.cn
b
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: yguo@sioc.ac.cn
Received: 03.09.2012; Accepted after revision: 14.10.2012
rinated building blocks, but at the same time are less com-
Abstract: The Michael addition reactions of α-fluoronitroalkanes
mon (Scheme 1). A few reactions involving α-
with various electron-deficient olefins were realized by catalysis of
fluoronitroalkanes7 and allylic alkylated fluoronitroal-
low-valence ruthenium species through Csp3-H activation, provid-
ing a useful way to construct a fluorinated quaternary carbon center.
kanes with a quaternary carbon were reported to occur via
The reactions were carried out under neutral conditions, affording decarboxylation.8 Thus, together with the interesting ap-
plications and synthetic potential of nitro compounds,9
the desired products in moderate to excellent yields.
there is a need to develop new methodologies that provide
efficient routes to those valuable nitro molecules with a
fluorinated quaternary center.
Key words: Michael addition, fluoronitroalkanes, ruthenium, C-H
activation, fluorinated quaternary carbon
O
Introduction of fluorine atom(s) into organic molecules
leads to changes of biological activities, such as bioavail-
ability and metabolic stability.1 Synthesis of fluorinated
compounds with a fluorinated quaternary carbon center
has attracted much attention recently owing to their en-
hancing biological activities.2 For example, flurithromy-
cin, as a fluorinated analogue of erythromycin, showed
improved stability under the acidic conditions of the stom-
ach and a better bioavailability.1a In addition to some suc-
cessful efforts on direct fluorination,3 compounds with
more functionalities are usually accessed through trans-
formations of fluorinated building blocks,4 including gua-
nidine-promoted Michael addition reactions of α-
fluoronitroalkanes, which was recently reported by us.4g
However, we found that a large amount of N,N,N′,N′-tet-
ramethylguanidine was required to promote the Michael
addition reaction because of the negative fluorine effect,
which has been extensively discussed by Prakash and Hu
recently.5 Although ruthenium-catalyzed Michael addi-
tion was applied to nitroalkanes, research into their α-flu-
orinated analogues, to the best of our knowledge, has not
been done.6 In this article, we report Michael addition re-
actions of α-fluoronitroalkanes, which were realized by
catalysis of low-valence ruthenium species through a Csp3-
H activation. This approach could be used efficiently un-
der neutral conditions and could be applied to a broad
range of donors and acceptors.
F
OH
OH
NMe2
OH
HO
Et
F
NO2
R2
HO
O
O
O
R1
OMe
R1, R2 = alkyl, aryl
O
O
O
Flurithromycin
target with quaternary center
previous synthons
this work
F
NO2
F
R1
H
O2N
O2N
CO2R
SO2R
R1 = n-C5H11 (1a)
Bn (1b)
Ph (1c)
F
(1d)
CH2–
Scheme 1 New fluorinated targets and building blocks
Nitroalkanes 1a–d were prepared according to a known
procedure and,4f,7,10 with these starting materials in hand,
we screened reaction conditions with 1a as a model com-
pound. The reaction of 1a with one equivalent of Michael
acceptor in the presence of 5 mol% [RuH2(PPh3)4] under
a nitrogen atmosphere at room temperature was carried
out in a variety of solvents (Table 1, entries 1–9). Among
those solvents, the best was acetonitrile (76%; Table 1,
entry 8). When the amount of Michael acceptor was in-
creased to 1.2 equivalents and the reaction time was pro-
longed to 22 hours, the yield of 3a increased to 86%
(Table 1, entry 9).
Quaternary carbon centers with fluorine and nitro substit-
uents have been reported to be constructed by reactions of
α-fluoronitroesters and α-fluoronitrosulfones, which, with
two electron-withdrawing groups, are more reactive fluo-
SYNTHESIS 2012, 44, 3815–3821
Advanced online publication: 09.11.2012
DOI: 10.1055/s-0032-1317526; Art ID: SS-2012-H0701-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
The wide range of suitable nitroalkanes was demonstrated
by the good tolerance of the reaction towards variation of

3816
Q. Wang et al.
PAPER
Table 1 Conditions for the Reaction of 1a and 2aa
O
O
NO2
RuH2(PPh3)4 (5 mol%)
r.t.
+
F
F
NO2
1a
2a
3a
Entry
Solvent
Time (h)
Conv. of 1a (%)b
Yield of 3a (%)b
1
2
3
4
5
6
7
8
9c
MeOH
DMF
16
16
16
16
16
16
16
16
22
80
72
0
70
50
0
toluene
THF
0
0
1,4-dioxane
hexane
0
0
35
20
82
92
14
trace
76
86
CH2Cl2
MeCN
MeCN
a Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), solvent (0.8 mL), N2 atmosphere.
b The conversions and yields were determined by 19F NMR spectroscopic analysis.
c Reaction conditions: 1a (0.2 mmol) and 2a (0.24 mmol) were used.
R1, which could include alkyl, phenyl, benzyl, and allylic valence ruthenium species was realized. These reaction
alkyl groups (Table 2). The Michael addition reactions conditions were acid-base neutral and mild, which al-
were applied to many acceptors, including 1-aryl-2-pro- lowed the use of reactants with more sensitive substitu-
pen-1-one (2a, 2h, and 2i), acrylonitrile (2b), aryl acrylate ents. A range of potentially biologically active products
(2c, 2d, and 2e), ethyl vinyl ketone (2f), alkyl acrylate (2f with both fluorine and a nitro group at a quaternary carbon
and 2g), acrolein (2j), and phenyl vinyl sulfone (2k). center were provided.
These Michael acceptors gave excellent conversions of α-
fluoronitroalkanes, especially in the case of acrylates,
Unless otherwise stated, all reactions were carried out under N2. All
which gave 100% conversion of all α-fluoronitroalkanes
and excellent yields of 3 (entries 3–5, 7, 14, 16, and 18).
Either electron-donating or electron-withdrawing groups
on the aryl moiety of an aryl acrylate were tolerated (en-
tries 3–5). We found the reaction of 2a with 1c (entry 12)
and 1d (entry 17) and the reaction of 2i with 1c (entry 9)
were not efficient. However, 100% conversions of α-fluo-
ronitroalkanes were found when aryl vinyl ketone 2h was
used (entries 8 and 20). Interestingly, the reaction of acro-
lein (2j) with 1c gave a good result, with 100% conversion
of 1c and 72% yield of product 3j, which would be a use-
ful synthetic intermediate because of the existence of a
CHO group in the molecule.
solvents were purified according to standard methods prior to use.
Melting points were measured with a SDT Q600 Labsys Evo STA.
1H NMR spectra were recorded with a Bruker AM 300 (300 MHz)
spectrometer with TMS as an internal standard (negative for up-
field). 19F NMR spectra were recorded with a Bruker AM 300 (282
MHz) with CFCl3 as an external standard (negative for upfield). 13
C
NMR spectra were recorded with a Bruker AV-400 (100 MHz)
spectrometer with CDCl3 as an internal standard (negative for up-
field). MS and HRMS were recorded with a Hewlett-Packard HP-
5989A spectrometer and a Finnigan MAT-8483 mass spectrometer
and IonSpec 4.7T Maldi-HR. IR spectra were measured with a
Perkin–Elmer 983 spectrometer. Column chromatography was per-
formed using silica gel (mesh 300–400). The α-fluoronitroalkanes
were prepared as described previously.4f,7,10
Michael Addition Reaction; General Procedure
The mechanism was proposed to take place by activation
of the Csp3–H bond of the fluorinated starting material,
subsequent insertion into the double bond of the Michael
acceptor, and final reductive elimination to give the prod-
uct. The mechanism is different to the base-promoted ver-
sion and should overcome the negative fluorine effect,
which has been found to be problematic in the synthetic
utilization of monofluorinated carbanions.5
To a solution of [RuH2(PPh3)4] (11.5 mg, 0.01 mmol) in anhydrous
MeCN (0.8 mL) was added α-fluoronitroalkane (1; 0.2 mmol) under
an N2 atmosphere. Michael acceptor (2; 0.24 mmol) was added and
the mixture was stirred at r.t. for 22 h. The solvent was then re-
moved under vacuum and the residue was purified by flash column
chromatography on silica gel (petroleum ether–CH2Cl2, 95:5) to
give the desired addition product.
4-Fluoro-4-nitro-1-phenylnonan-1-one (3a)
Yield: 45 mg (80%); white solid; mp 77.9–78.7 °C.
In conclusion, a novel and efficient Michael addition re-
action of fluorinated nitroalkanes catalyzed by low-
IR (KBr): 3060.8, 2954.8, 2927.7, 2854.9, 1682.0, 1560.2, 1438.1,
1327.2, 1217.2, 1168.8, 1002.8, 913.6, 749.8, 690.6 cm–1.
Synthesis 2012, 44, 3815–3821
© Georg Thieme Verlag Stuttgart · New York

PAPER
Michael Addition of α-Fluoroalkanes
3817
Table 2 Michael Addition Reactions of α-Fluoronitroalkanes with Acceptorsa
R1
NO2
R1
F
R2
RuH2(PPh3)4 (5 mol%)
MeCN, r.t., 22 h
R2
+
NO2
F
1
2
3
Entry
α-Fluoronitroalkane
R2
Product
Conv. of 1 (%)b
Yield of 3 (%)b
1
2
3
1a R1 = n-C5H11
COPh (2a)
CN (2b)
3a
3b
3c
92
86 (80)
85 (78)
98 (95)
1a
1a
100
100
CO2Ph (2c)
O
4
5
1a
1a
3d
3e
100
100
93 (88)
90 (82)
O
MeO
2d
O
O
F3C
2e
6
7
1b R1 = Bn
COEt (2f)
3f
100
100
89 (80)
92 (88)
1b
CO2t-Bu (2g)
3g
O
8
9
1b
3h
3i
100
63
61 (51)
49 (37)
2h
O
MeO
1c R1 = Ph
2i
10
11
12
13
14
15
16
17
18
19
20
1c
CHO (2j)
3j
100
100
60
93 (72)
98 (90)
52 (43)
96 (90)
92 (87)
82 (73)c
85 (80)
63 (42)
75 (67)
76 (65)
70 (58)
1c
SO2Ph (2k)
3k
3l
1c
2a
2b
2c
2f
1c
3m
3n
3o
3p
3q
3r
3s
100
100
100
100
72
1c
1c
1c
2g
2a
2c
2k
2h
1d R1 = allyl
1d
1d
1d
100
100
100
3t
a Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), MeCN (0.8 mL), N2 atmosphere.
b The conversions and yields were determined by 19F NMR spectroscopic analysis; isolated yields are given in parentheses.
c Using MeOH as solvent instead of MeCN.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3815–3821

3818
Q. Wang et al.
PAPER
1H NMR (300 MHz, CDCl3): δ = 7.93 (d, J = 7.5 Hz, 2 H), 7.59 (t,
J = 7.5 Hz, 1 H), 7.47 (t, J = 7.5 Hz, 2 H), 3.28–3.16 (m, 1 H), 2.96–
2.62 (m, 3 H), 2.40–2.04 (m, 2 H), 1.33–1.25 (m, 6 H), 0.89 (t, J =
6.6 Hz, 3 H).
19F NMR (282 MHz, CDCl3): δ = –62.7 (s, 3 F), –130.2 (m, 1 F).
+
MS (ESI): m/z = 383 [M + NH4 ].
HRMS (ESI): m/z [M + Na+] calcd for C16H19F4NO4: 388.1142;
found: 388.1137.
13C NMR (100 MHz, CDCl3): δ = 196.9, 136.1, 133.6, 128.7, 128.0,
121.9 (d, JC–F = 250.9 Hz), 37.4 (d, JC–F = 22.4 Hz), 31.3 (d, JC–F
2.9 Hz), 31.1, 31.0, 22.2, 21.9 (d, JC–F = 3 Hz), 13.8.
=
6-Fluoro-6-nitro-7-phenylheptan-3-one (3f)
Yield: 40.5 mg (80%); white solid; mp 78.8–79.7 °C.
19F NMR (282 MHz, CDCl3): δ = –125.2 (m).
MS (ESI): m/z = 304 [M + Na+].
HRMS (ESI): m/z [M + Na+] calcd for C15H20FNO3: 304.1319;
IR (KBr): 3037.2, 2985.6, 2932.7, 1711.5, 1553.0, 1444.3, 1422.8,
1158.4, 1113.0, 879.2, 833.7, 730.0, 697.2, 587.8, 529.8 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.34–7.31 (m, 3 H), 7.21–7.18 (m,
2 H), 3.58–3.33 (m, 2 H), 2.73–2.26 (m, 6 H), 1.04 (t, J = 7.2 Hz,
3 H).
13C NMR (100 MHz, CDCl3): δ = 206.9, 130.0, 129.1, 127.7, 127.1,
120.0 (d, JC–F = 242.0 Hz), 42.3 (d, JC–F = 21.6 Hz), 35.0, 33.5, 29.4
(d, JC–F = 22.4 Hz), 6.6.
found: 304.1330.
4-Fluoro-4-nitrononanenitrile (3b)4g
Yield: 31.5 mg (78%); colorless oil.
1H NMR (300 MHz, CDCl3): δ = 2.80–2.02 (m, 6 H), 1.57–1.44 (m,
1 H), 1.33–1.18 (m, 5 H), 0.89 (t, J = 6.9 Hz, 3 H).
19F NMR (282 MHz, CDCl3): δ = –130.6 (m).
19F NMR (282 MHz, CDCl3): δ = –129.2 (m).
+
MS (ESI): m/z = 271 [M + NH4 ].
Phenyl 4-Fluoro-4-nitrononanoate (3c)
Yield: 56.5 mg (95%); colorless oil.
HRMS (ESI): m/z [M + Na+] calcd for C13H16FNO3: 276.1006;
found: 276.1014.
IR (KBr): 3043.5, 2958.7, 2872.4, 1762.6, 1561.2, 1492.8, 1363.2,
1196.2, 942.7, 689.7 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.38 (t, J = 7.5 Hz, 2 H), 7.23 (t,
J = 7.5 Hz, 1 H), 7.07 (d, J = 7.5 Hz, 2 H), 2.84–2.37 (m, 4 H),
2.29–2.02 (m, 2 H), 1.62–1.52 (m, 1 H), 1.49–1.20 (m, 5 H), 0.88 (t,
J = 6.6 Hz, 3 H).
tert-Butyl 4-Fluoro-4-nitro-5-phenylpentanoate (3g)
Yield: 52.3 mg (88%); colorless oil.
IR (KBr): 3034.8, 2980.1, 2933.5, 1731.5, 1567.5, 1496.9, 1455.9,
1368.4, 1155.9, 953.8, 843.7, 701.2, 592.3 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.33–7.30 (m, 3 H), 7.20–7.17 (m,
2 H), 3.56–3.32 (m, 2 H), 2.73–2.35 (m, 3 H), 2.24–2.12 (m, 1 H),
1.42 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 170.3, 131.0, 130.2, 128.7, 128.2,
120.8 (d, JC–F = 242.7 Hz), 81.3, 43.2 (d, JC–F = 20.9 Hz), 31.7 (d,
JC–F = 21.6 Hz), 28.3 (d, JC–F = 3.7 Hz), 27.9.
13C NMR (100 MHz, CDCl3): δ = 168.9, 149.4, 128.4, 125.0, 120.3
(d, JC–F = 241.2 Hz), 120.3, 36.0 (d, JC–F = 21.6 Hz), 31.0 (d, JC–F
21.6 Hz), 29.9, 26.5 (d, JC–F = 4.4 Hz), 21.2, 20.8, 12.7.
=
19F NMR (282 MHz, CDCl3): δ = –130.1 (m).
+
MS (ESI): m/z = 315 [M + NH4 ].
19F NMR (282 MHz, CDCl3): δ = –129.3 (m).
HRMS (ESI): m/z [M + Na+] calcd for C15H20FNO4: 320.1268;
found: 320.1256.
+
MS (ESI): m/z = 315 [M + NH4 ].
HRMS (ESI): m/z [M + Na+] calcd for C15H20FNO4: 320.1269;
4-Methoxyphenyl 4-Fluoro-4-nitrononanoate (3d)
Yield: 57.6 mg (88%); colorless oil.
found: 320.1271.
4-Fluoro-4-nitro-5-phenyl-1-(p-tolyl)pentan-1-one (3h)
IR (KBr): 3062.5, 2959.0, 2935.5, 2872.2, 1759.0, 1565.5, 1506.7,
1466.5, 1438.6, 1249.3, 1195.6, 1034.6, 945.3, 846.7, 521.6 cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.98 (d, J = 9.0 Hz, 2 H), 6.88 (d,
J = 9.0 Hz, 2 H), 3.79 (s, 3 H), 2.82–2.46 (m, 4 H), 2.38–2.02 (m,
2 H), 1.59–1.47 (m, 1 H), 1.33–1.19 (m, 5 H), 0.89 (t, J = 6.6 Hz,
3 H).
Yield: 32.2 mg (51%); white solid; mp 104.2–105.4 °C.
IR (KBr): 3041.6, 2892.7, 1676.6, 1609.9, 1552.0, 1439.9, 1323.2,
1161.2, 826.1, 774.6, 698.2, 590.6, 458.6 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.80 (d, J = 8.4 Hz, 2 H), 7.34–
7.20 (m, 7 H), 3.63–3.38 (m, 2 H), 3.22–3.10 (m, 1 H), 2.92–2.53
(m, 3 H), 2.40 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 196.3, 144.5, 133.6, 131.0, 130.2,
129.4, 128.8, 128.2, 128.1, 121.1 (d, JC–F = 241.2 Hz), 43.5 (d,
13C NMR (100 MHz, CDCl3): δ = 169.2, 156.4, 142.8, 121.1, 120.3
(d, JC–F = 240.4 Hz), 113.4, 54.5 (d, JC–F = 9.7 Hz), 36.0 (d, JC–F
=
21.6 Hz), 31.0 (d, JC–F = 22.3 Hz), 29.9, 26.4 (d, JC–F = 4.5 Hz),
21.1, 20.8, 12.7.
19F NMR (282 MHz, CDCl3): δ = –130.1 (m).
J
C–F = 20.8 Hz), 31.0, 30.9 (d, JC–F = 20.1 Hz), 21.6.
19F NMR (282 MHz, CDCl3): δ = –129.0 (m).
+
+
MS (ESI): m/z = 333 [M + NH4 ].
MS (ESI): m/z = 345 [M + NH4 ].
HRMS (ESI): m/z [M + Na+] calcd for C18H18FNO3: 338.1163;
found: 338.1161.
HRMS (ESI): m/z [M + Na+] calcd for C16H22FNO5: 350.1374;
found: 350.1384.
4-Fluoro-1-(3-methoxyphenyl)-4-nitro-4-phenylbutan-1-one
(3i)
4-(Trifluoromethyl)phenyl 4-Fluoro-4-nitrononanoate (3e)
Yield: 60 mg (82%); white solid; mp 43.2–43.9 °C.
Yield: 23.5 mg (37%); pale-yellow solid; mp 145.5–146.6 °C.
IR (KBr): 3082.3, 2962.3, 2876.7, 1767.3, 1613.7, 1566.2, 1513.8,
1438.9, 1326.1, 1210.7, 1131.1, 1065.3, 1018.0, 855.4, 592.5 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.65 (d, J = 8.4 Hz, 2 H), 7.21 (d,
J = 8.4 Hz, 2 H), 2.90–2.52 (m, 4 H), 2.39–2.03 (m, 2 H), 1.60–1.49
(m, 1 H), 1.33–1.20 (m, 5 H), 0.89 (t, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.4, 151.8, 127.3 (q, JC–F
32.8 Hz), 125.8, 122.7 (q, JC–F = 270.9 Hz), 120.9 (d, JC–F = 5.2 Hz),
120.2 (d, JC–F = 240.4 Hz), 36.1 (d, JC–F = 21.6 Hz), 30.8 (d, JC–F
21.6 Hz), 29.9, 26.4 (d, JC–F = 3.7 Hz), 21.1, 20.8, 12.7.
IR (KBr): 3089.1, 2948.7, 2841.6, 1691.6, 1597.0, 1556.7, 1330.4,
1259.4, 1192.2, 1178.1, 1036.3, 773.5, 711.0, 692.3, 645.1,
574.3 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.70 (d, J = 7.8 Hz, 2 H), 7.47 (t,
J = 7.2 Hz, 5 H), 7.36 (t, J = 8.1 Hz, 1 H), 7.12 (d, J = 8.4 Hz, 1 H),
3.85 (s, 3 H), 3.31–2.97 (m, 4 H).
=
13C NMR (100 MHz, CDCl3): δ = 196.6, 159.9, 137.5, 133.1 (d,
=
J
C–F = 23.8 Hz), 131.1, 129.7, 129.0 (d, JC–F = 1.5 Hz), 125.3 (d,
Synthesis 2012, 44, 3815–3821
© Georg Thieme Verlag Stuttgart · New York

PAPER
Michael Addition of α-Fluoroalkanes
3819
JC–F = 8.9 Hz), 120.6, 119.9, 119.6 (d, JC–F = 238.9 Hz), 112.3, 55.5,
31.9 (d, JC–F = 2.3 Hz), 31.6 (d, JC–F = 20.1 Hz).
19F NMR (282 MHz, CDCl3): δ = –128.2 (m).
MS (ESI): m/z = 340 [M + Na+].
HRMS (ESI): m/z [M + Na+] calcd for C17H16FNO4: 340.0956;
found: 340.0970.
1H NMR (300 MHz, CDCl3): δ = 7.69 (d, J = 7.8 Hz, 2 H), 7.51–
7.44 (m, 3 H), 7.37 (t, J = 7.8 Hz, 2 H), 7.23 (t, J = 7.5 Hz, 1 H),
7.05 (d, J = 7.5 Hz, 2 H), 3.29–2.96 (m, 2 H), 2.81–2.59 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 168.8, 149.3, 131.7 (d, JC–F
23.1 Hz), 130.2, 128.5, 128.0, 125.1, 124.2, 120.3 (d, JC–F
=
=
6.7 Hz), 118.7 (d, JC–F = 238.9 Hz), 31.3 (d, JC–F = 20.8 Hz), 27.0
(d, JC–F = 3.7 Hz).
19F NMR (282 MHz, CDCl3): δ = –129.2 (dd, J = 23.6, 17.7 Hz).
4-Fluoro-4-nitro-4-phenylbutanal (3j)
Yield: 30.4 mg (72%); pale-yellow oil.
+
MS (ESI): m/z = 321 [M + NH4 ].
HRMS (ESI): m/z [M + Na+] calcd for C16H14FNO4: 326.0799;
found: 326.0803.
IR (KBr): 3086.6, 2908.1, 2733.1, 1728.2, 1567.5, 1497.7, 1452.8,
1353.2, 1159.0, 1076.3, 995.4, 718.6, 693.9, 541.4 cm–1.
1H NMR (300 MHz, CDCl3): δ = 9.78 (s, 1 H), 7.68–7.64 (m, 2 H),
7.52–7.44 (m, 3 H), 3.11–2.91 (m, 2 H), 2.90–2.58 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 197.2, 131.8 (d, JC–F = 23.1 Hz),
6-Fluoro-6-nitro-6-phenylhexan-3-one (3o)
Yield: 34.9 mg (73%); colorless oil.
IR (KBr): 3082.6, 2979.7, 2941.4, 2908.4, 1719.5, 1566.8, 1452.7,
1355.4, 1115.2, 1026.7, 814.4, 770.9, 715.2, 694.2 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.65 (d, J = 7.8 Hz, 2 H), 7.49–
7.42 (m, 3 H), 3.14–2.81 (m, 2 H), 2.66–2.39 (m, 4 H), 1.05 (t, J =
7.2 Hz, 3 H).
130.2, 128.0, 124.1, 118.2 (d, JC–F = 234.5 Hz), 36.1, 28.5 (d, JC–F
=
20.8 Hz).
19F NMR (282 MHz, CDCl3): δ = –128.7 (q, J = 2.1 Hz).
+
MS (ESI): m/z = 229 [M + NH4 ].
HRMS (ESI): m/z [M + MeOH + Na+] calcd for C10H10FNO3:
266.0799; found: 266.0806.
13C NMR (100 MHz, CDCl3): δ = 207.0, 132.1 (d, J C–F = 23.8 Hz),
130.0, 127.9, 124.2, 118.2 (d, JC–F = 238.2 Hz), 35.0, 34.1 (d, JC–F
2.2 Hz), 30.0 (d, JC–F = 20.9 Hz), 6.7.
=
[1-Fluoro-1-nitro-3-(phenylsulfonyl)propyl]benzene (3k)
Yield: 58.2 mg (90%); white solid; mp 101.8–102.9 °C.
19F NMR (282 MHz, CDCl3): δ = –128.4 (dd, J = 25.8, 17.9 Hz).
MS (ESI): m/z = 262 [M + Na+].
HRMS (ESI): m/z [M + Na+] calcd for C12H14FNO3: 262.0849;
IR (KBr): 3070.1, 2980.8, 2939.9, 1560.6, 1447.3, 1308.0, 1191.7,
1151.4, 1087.4, 949.1, 797.8, 750.0, 720.8, 688.1, 530.5 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.93–7.89 (m, 2 H), 7.74–7.67 (m,
found: 262.0847.
1 H), 7.63–7.41 (m, 7 H), 3.19–3.02 (m, 4 H).
tert-Butyl 4-Fluoro-4-nitro-4-phenylbutanoate (3p)
13C NMR (100 MHz, CDCl3): δ = 137.1, 133.4, 130.7 (d, JC–F
23.1 Hz), 130.6, 128.6, 128.2, 127.0, 124.0, 117.0 (d, JC–F
239.6 Hz), 48.9 (d, JC–F = 2.2 Hz), 29.6 (d, JC–F = 21.6 Hz).
19F NMR (282 MHz, CDCl3): δ = –128.4 (m).
MS (ESI): m/z = 346 [M + Na+].
=
=
Yield: 44.8 mg (80%); colorless oil.
IR (KBr): 3070.2, 2982.6, 2933.0, 1732.7, 1568.5, 1453.9, 1369.0,
1297.3, 1153.9, 1075.4, 846.5, 693.7 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.66 (d, J = 7.8 Hz, 2 H), 7.49–
7.42 (m, 3 H), 3.11–2.80 (m, 2 H), 2.46–2.24 (m, 2 H), 1.44 (s,
9 H).
HRMS (ESI): m/z [M + Na+] calcd for C15H14FNO4S: 346.0519;
found: 346.0504.
13C NMR (100 MHz, CDCl3): δ = 169.4, 131.9 (d, JC–F = 23.1 Hz),
130.0, 127.9, 124.2, 118.2 (d, JC–F = 239 Hz), 80.3, 31.4 (d, JC–F
21.6 Hz), 27.8 (d, JC–F = 2.9 Hz), 26.9.
19F NMR (282 MHz, CDCl3): δ = –129.1 (dd, J = 22.7, 18.7 Hz).
=
4-Fluoro-4-nitro-1,4-diphenylbutan-1-one (3l)
Yield: 24.7 mg (43%); white solid; mp 97.9–99.2 °C.
IR (KBr): 3067.8, 2906.7, 1685.8, 1556.6, 1448.7, 1327.3, 1203.1,
1002.7, 886.4, 764.3, 711.8, 688.8, 647.6, 552.7 cm–1.
+
MS (ESI): m/z = 301 [M + NH4 ].
HRMS (ESI): m/z [M + Na+] calcd for C14H18FNO4: 306.1112;
found: 306.1110.
1H NMR (300 MHz, CDCl3): δ = 7.92 (d, J = 7.5 Hz, 2 H), 7.71 (d,
J = 7.8 Hz, 2 H), 7.58 (t, J = 7.5 Hz, 1 H), 7.49–7.43 (m, 5 H), 3.29–
2.99 (m, 4 H).
4-Fluoro-4-nitro-1-phenylhept-6-en-1-one (3q)
Yield: 21.1 mg (42%); white solid; mp 58.7–59.5 °C.
13C NMR (100 MHz, CDCl3): δ = 196.7, 136.1, 133.6, 133.2 (d,
J
C–F = 23.1 Hz), 131.1, 129.0 (d, JC–F = 1.5 Hz), 128.7, 128.0, 125.3
IR (KBr): 3071.3, 2923.6, 1685.7, 1561.9, 1439.2, 1322.4, 1261.8,
1218.7, 1166.7, 1133.0, 996.5, 931.4, 752.3, 688.9, 573.4 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.93 (d, J = 7.2 Hz, 2 H), 7.59 (t,
J = 7.2 Hz, 1 H), 7.47 (t, J = 7.2 Hz, 2 H), 5.79–5.67 (m, 1 H), 5.31–
5.24 (m, 2 H), 3.29–3.17 (m, 1 H), 3.10–2.56 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 195.7, 135.0, 132.6, 127.7, 127.0,
126.1, 121.5, 120.0 (d, JC–F = 240.4 Hz), 40.7 (d, JC–F = 21.6 Hz),
30.1 (d, JC–F = 3.0 Hz), 29.7 (d, JC–F = 28.0 Hz).
(d, JC–F = 8.2 Hz), 119.6 (d, JC–F = 238.2 Hz), 31.8 (d, JC–F
=
3.0 Hz), 31.5 (d, JC–F = 20.8 Hz).
19F NMR (282 MHz, CDCl3): δ = –129.5 (m).
+
MS (ESI): m/z = 305 [M + NH4 ].
HRMS (ESI): m/z [M + Na+] calcd for C16H14FNO3: 310.0850;
found: 310.0864.
4-Fluoro-4-nitro-4-phenylbutanenitrile (3m)4g
Yield: 37.5 mg (90%); colorless oil.
19F NMR (282 MHz, CDCl3): δ = –129.5 (m).
+
1H NMR (300 MHz, CDCl3): δ = 7.67–7.62 (m, 2 H), 7.55–7.46 (m,
MS (ESI): m/z = 269 [M + NH4 ].
HRMS (ESI): m/z [M + Na+] calcd for C13H14FNO3: 274.0850;
found: 274.0861.
3 H), 3.22–2.89 (m, 2 H), 2.59–2.37 (m, 2 H).
19F NMR (282 MHz, CDCl3): δ = –130.7 (t, J = 18.3 Hz).
Phenyl 4-Fluoro-4-nitrohept-6-enoate (3r)
Yield: 35.8 mg (67%); pale-yellow oil.
Phenyl 4-Fluoro-4-nitro-4-phenylbutanoate (3n)
Yield: 52.8 mg (87%); colorless oil.
IR (KBr): 3087.6, 2931.5, 1762.5, 1567.5, 1493.5, 1368.6, 1196.6,
1164.9, 946.4, 756.3, 692.1, 498.7 cm–1.
IR (KBr): 3065.9, 2945.7, 1762.7, 1570.3, 1492.8, 1452.9, 1353.3,
1195.9, 1164.3, 1073.2, 948.6, 760.1, 691.6, 497.3 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3815–3821

3820
Q. Wang et al.
PAPER
1H NMR (300 MHz, CDCl3): δ = 7.38 (t, J = 7.8 Hz, 2 H), 7.24 (t,
J = 7.8 Hz, 1 H), 7.07 (d, J = 7.8 Hz, 2 H), 5.80–5.65 (m, 1 H),
5.32–5.24 (m, 2 H), 3.07–2.49 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 168.8, 149.3, 128.5, 125.9, 125.1,
121.6, 120.3 (d, JC–F = 8.2 Hz), 119.4 (d, JC–F = 241.2 Hz), 40.4 (d,
Chemistry of Fluorine; Wiley: Hoboken, 2008.
(g) Uneyama, K. Organofluorine Chemistry; Blackwell:
Oxford, 2006. (h) Kirsch, P. Modern Fluoroorganic
Chemistry: Synthesis, Reactivity, Applications; Wiley-VCH:
Weinheim, 2004. (i) Chambers, R. D. Fluorine in Organic
Chemistry; Blackwell: Oxford, 2004. (j) Hiyama, T.
Organofluorine Compounds: Chemistry and Applications;
Springer: New York, 2000. (k) Müller, K.; Faeh, C.;
Diederich, F. Science 2007, 317, 1881.
JC–F = 21.6 Hz), 30.5 (d, J C–F= 21.6 Hz), 26.4 (d, JC–F = 4.4 Hz).
19F NMR (282 MHz, CDCl3): δ = –129.7 (m).
+
MS (ESI): m/z = 285 [M + NH4 ].
(2) (a) Guo, C.; Wang, R.-W.; Guo, Y.; Qing, F.-L. J. Fluorine
Chem. 2012, 133, 86. (b) Wang, W.; Chen, Q.-Y.; Guo, Y.
Synlett 2011, 2705; and references therein. (c) Davis, F. A.;
Kasu, P. V. N. Org. Prep. Proced. Int. 1999, 31, 125.
(d) Cahard, D.; Xu, X.; Couve-Bonnaire, S.; Pannecoucke,
X. Chem. Soc. Rev. 2010, 39, 558. (e) Lectard, S.;
HRMS (ESI): m/z [M + Na+] calcd for C13H14FNO4: 290.0799;
found: 290.0803.
[(3-Fluoro-3-nitrohex-5-en-1-yl)sulfonyl]benzene (3s)
Yield: 37.4 mg (65%); colorless oil.
IR (KBr): 3066.1, 2989.4, 2932.1, 1644.3, 1571.1, 1447.6, 1307.1,
1147.8, 1086.9, 938.4, 741.5, 688.5, 537.2 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.91 (d, J = 7.8 Hz, 2 H), 7.72 (t,
J = 7.8 Hz, 1 H), 7.61 (t, J = 7.8 Hz, 2 H), 5.73–5.59 (m, 1 H), 5.32–
5.24 (m, 2 H), 3.33–3.22 (m, 1 H), 3.02–2.54 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 137.2, 133.4, 128.6, 127.0, 125.4,
122.1, 118.3 (d, JC–F = 242.0 Hz), 48.4, 40.3 (d, JC–F = 21.6 Hz),
28.5 (d, JC–F = 22.3 Hz).
Hamashima, Y.; Sodeoka, M. Adv. Synth. Catal. 2010, 352,
2708. (f) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1.
(g) Brunet, V. A.; O’Hagan, D. Angew. Chem. Int. Ed. 2008,
47, 1179. (h) Shibata, N.; Ishimaru, T.; Nakamura, S.; Toru,
T. J. Fluorine Chem. 2007, 128, 469. (i) Prakash, G. K. S.;
Beier, P. Angew. Chem. Int. Ed. 2006, 45, 2172. (j) Pihko, P.
M. Angew. Chem. Int. Ed. 2006, 45, 544. (k) Bobbio, C.;
Gouverneur, V. Org. Biomol. Chem. 2006, 4, 2065.
(l) Hamashima, Y.; Sodeoka, M. Synlett 2006, 1467.
(m) Mikami, K.; Itoh, Y.; Yamanaka, M. Chem. Rev. 2004,
104, 1. (n) Smith, A. M. R.; Hii, K. K. Chem. Rev. 2011, 111,
1637. (o) Shibatomi, K. Synthesis 2010, 2679. (p) Bella, M.;
Gasperi, T. Synthesis 2009, 1583. (q) Ueda, M.; Kano, T.;
Maruoka, K. Org. Biomol. Chem. 2009, 7, 2005. (r) Cozzi,
P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem.
2007, 5969. (s) Marigo, M.; Jørgensen, K. A. Chem.
Commun. 2006, 2001. (t) Oestreich, M. Angew. Chem. Int.
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Khouzani, H.; Ranjbar-Karimi, R.; Sadeghi, M. M.
Tetrahedron 2007, 63, 11160. (b) Sadeghi, M. M.;
19F NMR (282 MHz, CDCl3): δ = –128.8 (m).
+
MS (ESI): m/z = 305 [M + NH4 ].
HRMS (ESI): m/z [M + Na+] calcd for C12H14FNO4S: 310.0519;
found: 310.0508.
4-Fluoro-4-nitro-1-(p-tolyl)hept-6-en-1-one (3t)
Yield: 30.8 mg (58%); colorless oil.
IR (KBr): 3034.7, 2922.1, 1685.6, 1607.8, 1563.7, 1435.3, 1359.1,
1320.7, 1182.3, 993.7, 934.7, 821.0, 779.1, 572.2 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.82 (d, J = 8.1 Hz, 2 H), 7.26 (d,
J = 8.1 Hz, 2 H), 5.81–5.66 (m, 1 H), 5.32–5.24 (m, 2 H), 3.25–3.13
(m, 1 H), 3.09–2.57 (m, 5 H), 2.41 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 195.3, 143.5, 132.6, 128.4 (d,
JC–F = 9.0 Hz), 127.1 (d, JC–F = 3.0 Hz), 126.2, 121.4, 120.0 (d,
JC–F = 240.4 Hz), 40.6 (d, JC–F = 21.5 Hz), 30.0 (d, JC–F = 8.2 Hz),
Loghmani-Khouzani, H.; Ranjbar-Karimi, R.; Golding, B.
T. Tetrahedron Lett. 2006, 47, 2455. (c) Chambers, R. D.;
Hutchinson, J. J. Fluorine Chem. 1998, 92, 45. (d) Wang, C.
M.; Mallouk, T. E. J. Am. Chem. Soc. 1990, 112, 2016.
(e) Barnette, W. E. J. Am. Chem. Soc. 1984, 106, 452.
(f) Freeman, J. P. J. Am. Chem. Soc. 1960, 82, 3869.
(g) Rozen, S.; Bar-Haim, S.; Mishani, E. J. Org. Chem.
1994, 59, 6800. (h) Lorand, J.; Ubran, J.; Overs, J.; Ahmed,
Q. A. J. Org. Chem. 1969, 34, 4176. (i) Adolph, H. G.;
Oesterling, R. E.; Sitzmann, M. E. J. Org. Chem. 1968, 33,
4296.
29.7, 20.6 (d, JC–F = 5.2 Hz).
19F NMR (282 MHz, CDCl3): δ = –129.6 (m).
MS (ESI): m/z = 288 [M + Na+].
HRMS (ESI): m/z [M + Na+] calcd for C14H16FNO3: 288.1006;
found: 288.1012.
Acknowledgment
This work was financially supported by the National Natural Sci-
ence Foundation (21172241), the 973 Program of China
(2012CB821600) and the Shanghai Science and Technology Com-
mission (11ZR1445700).
(4) (a) Cui, H.-F.; Li, P.; Wang, X.-W.; Chai, Z.; Yang, Y.-Q.;
Cai, Y.-P.; Zhu, S.-Z.; Zhao, G. Tetrahedron 2011, 67, 312.
(b) Wang, X.-W.; Cui, H.-F.; Wang, H.-F.; Yang, Y.-Q.;
Zhao, G.; Zhu, S.-Z. Tetrahedron 2011, 67, 2468.
(c) Takeuchi, Y.; Nagata, K.; Koizumi, T. J. Org. Chem.
1987, 52, 5061. (d) Takeuchi, Y.; Nagata, K.; Koizumi, T.
J. Org. Chem. 1989, 54, 5453. (e) Takeuchi, Y.; Kanada, A.;
Kawahara, S.; Koizumi, T. J. Org. Chem. 1993, 58, 3483.
(f) Hu, H.; Huang, Y.; Guo, Y. J. Fluorine Chem. 2012, 133,
108. (g) Huan, F.; Hu, H.; Huang, Y.; Chen, Q.; Guo, Y.
Chin. J. Chem. 2012, 30, 798. (h) Ullah, F.; Zhao, G.-L.;
Deiana, L.; Zhu, M.; Dziedzic, P.; Ibrahem, I.; Hammar, P.;
Sun, J.; Córdova, A. Chem.–Eur. J. 2009, 15, 10013. (i) Pan,
Y.; Zhao, Y.; Ma, T.; Yang, Y.; Liu, H.; Jiang, Z.; Tan, C.-
H. Chem.–Eur. J. 2010, 16, 779. (j) Kamlar, M.; Bravo, N.;
Alba, A.-N. R.; Hybelbauerová, S.; Císařová, I.; Veselý, J.;
Moyano, A.; Rios, R. Eur. J. Org. Chem. 2010, 5464.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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