Stereoselective fluorination of methylenecyclopropanes with N-F reagents: A modular entry to γ-fluorohomoallylic sulfonimides and γ-fluorohomoallylic amides

Article abstract of DOI:10.1016/j.jfluchem.2009.07.020

A convenient and efficient method for fluorination of methylenecyclopropanes is reported. This is exemplified in the stereoselective preparation of N-[(E)-3-fluorobut-3-en-1-yl]-benzenesulfonimides by the reaction of methylenecyclopropanes with N-fluorobe

Full text of DOI:10.1016/j.jfluchem.2009.07.020

Journal of Fluorine Chemistry 130 (2009) 996–1000
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Stereoselective fluorination of methylenecyclopropanes with N-F reagents:
A modular entry to
g-fluorohomoallylic sulfonimides
and -fluorohomoallylic amides
g
Weijun Fu a, Guanglong Zou b, Mei Zhu a, Dongfeng Hong a, Dongsheng Deng a, Chen Xun a, Baoming Ji a,
*
a College of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang 471022, PR China
b School of Chemistry and Environmental Science, Guizhou University for Nationalities, Guiyang 550025, PR China
A R T I C L E I N F O
A B S T R A C T
Article history:
A convenient and efficient method for fluorination of methylenecyclopropanes is reported. This is
exemplified in the stereoselective preparation of N-[(E)-3-fluorobut-3-en-1-yl]-benzenesulfonimides by
the reaction of methylenecyclopropanes with N-fluorobenzenesulfonimide in good to excellent yields.
Received 23 April 2009
Received in revised form 25 July 2009
Accepted 28 July 2009
Moreover,
g-fluorohomoallylic amides are synthesized using Selectfluor in R3CN at 60 8C.
Available online 5 August 2009
ß 2009 Elsevier B.V. All rights reserved.
Keywords:
Fluorination
Methylenecyclopropanes
N-Fluorobenzenesulfonimide
Selectfluor
Stereoselective
1. Introduction
reactions because the relief of ring strain provides a potent
thermodynamic driving force for this process [18–22]. In the past
several years, a number of methods for construction of complex and
interesting organic molecules from MCPs have been developed.
Transition metal-catalyzed reactions of MCPs using transition metal
catalysts such as palladium complexes [23–25] or Lewis acids such
as metal triflates [26,27] have been most extensively investigated to
achieve numerous transformations. During our study on the
chemistryof MCPs[28–31], we imagined that the fluorinechemistry
of MCPs, which has not been well established, may be a nice way to
introduce fluorine atoms into organic molecules. In this paper, we
wish to describe our results on the reaction between MCPs and N-F
reagents under mild conditions to give the corresponding fluori-
nated derivatives in moderate yields (Scheme 1).
The presence of a fluorine atom to enhance biological and
therapeutic activities of organic compounds has led to wide spread
interest in selective introduction of fluorine atom and fluoroalkyl
groups into organic molecules [1,2]. Recently, the selective
introduction of a fluoro group into olefin-containing compounds
such as pheromones [3–6] and retinoids [7–10] has been proved to
be attractive due to the potential biological properties. Of paramount
importance in the synthesis of olefin-containing molecules is the
regio- and stereocontrol ofthe olefinicbond [11]. Inthis regard, there
exists an increasing demand for the efficient introduction of fluorine
atom into olefin-containing compounds. Among the many methods
used for the introduction of fluorine, electrophilic fluorination using
N-F reagents has grown in popularity and applications to the
selective fluorination of activated aromatics, alkenes, and enolates in
recent years [12–17]. Despite increased use of these regents, no
example on the reaction of electrophilic fluorinating agents with
methylenecyclopropanes has been disclosed thus far.
2. Results and discussion
Firstly, we conducted the reaction of methylenecyclopropane
1a with 1.0 equiv. of N-fluorobenzenesulfonimide (NFSI) in CH2Cl2
at room temperature. The reaction proceeded smoothly to give the
ring-opened product 2a in 65% yield along with 3a in 20% yield
(Table 1, entry 1). With this encouraging result, a systematic study
was undertaken to screen various solvents and reaction tempera-
tures for the fluorination process. The results are summarized in
Table 1. As can be seen from Table 1, under similar conditions, the
yields of 2a and 3a were similar with the use of 1.3 or 1.5 equiv. of
Methylenecyclopropanes (MCPs), which are highly strained but
readilyaccessible molecules, haveservedasusefulbuildingblocksin
organic synthesis. They can undergo a variety of ring-opening
* Corresponding author. Fax: +86 379 65523821.
E-mail address: fwjun1979@163.com (B. Ji).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.07.020

W. Fu et al. / Journal of Fluorine Chemistry 130 (2009) 996–1000
997
Scheme 1.
Table 1
Reaction of MCPs 1a with NFSI under various conditions.
a
Entry
1a/NFSI
Solvent
Temp (8C)
Time (h)
Yield (%)b
2a
3a
1
2
1/1
CH2Cl2
CH2Cl2
CH2Cl2
DCE
rt
36
36
36
12
12
20
36
36
30
65
69
68
72
80
45
48
69
44
20
14
11
15
–
1/1.3
1/1.5
1/1
rt
3
rt
4
60
60
60
rt
5
1/1
THF
6
1/1
toluene
Et2O
34
32
–
7
1/1
8
9c
1/1
THF
rt
1/1
CH3CN
60
16
a
Reaction conditions: 1a (0.5 mmol), NFSI (x mmol), solvent (5.0 mL) and the reactions were carried out at various temperatures.
b
c
Isolated yield.
In this case, compound 4a (see Table 3) was also obtained in 30% yield.
NFSI. When the reaction was carried out at 60 8C in dichloroethane
unexpected product 4a was obtained in 30% yield along with
the production of 2a and 3a in 44% and 16% yield, respectively
(Table 1, entry 9). Therefore, as the optimized conditions we chose
the reaction of 1.0 equiv. 1a with 1.0 equiv. NFSI in THF at 60 8C
(Table 1, entry 5).
(DCE), 2a and 3a were obtained in 72% and 15% yield, respectively.
Significantly, we found that in THF for 12 h, the ring-opened
product 2a was obtained in 80% yield as a sole product without the
isolation of compound 3a (Table 1, entry 5). On using other solvent
such as Et2O or toluene, the desired product 2a could be isolated in
slightly lower yield. Using acetonitrile as the solvent, the
With the optimized conditions in hand, we next carried out this
ring-opening reaction of a variety of methylenecyclopropanes 1
Table 2
Fluorination of methylenecyclopropanes with NFSI.
a
Entry
R1
R2
Time (h)
Yield (%)b
1
2
C6H5
C6H5
12
12
9
2a, 80
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
4-MeC6H4
3,4-(MeO)2C6H3
4-FC6H4
4-ClC6H4
-(CH2)5-
C4H9
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
H
2b, 84
3
2c, 90
4
30
36
12
12
36
36
24
24
24
2d, 65
5
2e, 48
6
2f, 77(4:1)c
2g, 93(>98:2)c
2h, 66(1:1)d
2i, 70(13:7)d
2j, complex
2k, complex
2l, NR
7
H
8
C6H5
9
C6H5
10
11
12
H
C4H9
C4H9
H
a
Reaction conditions: 1 (0.5 mmol), NFSI (0.5 mmol), solvent (5.0 mL), at 60 8C.
Isolated yield.
The ratio was determined by 1H NMR spectroscopic data.
The ratio was determined by 19F NMR spectroscopic data.
b
c
d

998
W. Fu et al. / Journal of Fluorine Chemistry 130 (2009) 996–1000
Table 3
Fluorination of Methylenecyclopropanes with Selectfluor.a
Entry
R1
R2
R3
Time (h)
Yields (%)b
1
2
3
4
5
6
C6H5
C6H5
CH3
24
24
24
24
36
30
4a, 67
4b, 89
4c, 91
4d, 65
4e, 70
4f, 63
Scheme 2. Configurations of E-2g.
4-MeC6H4
4-MeOC6H4
4-ClC6H4
C6H5
4-MeC6H4
4-MeOC6H4
4-ClC6H4
C6H5
CH3
CH3
CH3
with NFSI. The results are summarized in Table 2. As indicated, the
substituents on the benzene ring of MCPs 1 significantly affect the
reaction. For MCPs 1 having an electron-donating group on the
benzene ring led to 2 in higher yields within shorter reaction time
than those with electron-withdrawing group. Unsymmetric MCPs
having a hydrogen group and an aromatic group (Table 2, entries 6
and 7) were converted to the corresponding ring-opened products
2 in good yields under mild conditions giving rise to E-2f or E-2g as
the major products. Although the unsymmetrical MCP 1 h having
phenyl and 4-fluorophenyl provided 1:1 mixture E- and Z-isomer
2h, the reaction of 4-chlorophenyl derivative 1i proceeded in a
highly stereoselective manner to give E-isomer 2i as a major
product (Table 2, entries 8 and 9). Configuration of the product E-
2g was established by the NOESY spectrum studies (Scheme 2). In
the cases of aliphatic MCP 1j and 1k, complicated reaction
products were formed without the isolation of the expected
products 2j and 2k (Table 2, entries 10 and 11). Using
unsymmetrical aliphatic MCP 1l as the substrate, no reaction
occurred (Table 2, entry 12).
C6H5CH2
n-Pr
C6H5
C6H5
a
Reaction conditions: 1 (0.5 mmol), Selectfluor (0.5 mmol), solvent (3.0 mL), at
60 8C.
b
Isolated yield.
benzene rings is significant on the reaction outcomes. With the
substrates 1b and 1c having electron-donating substituents on the
benzene ring, the corresponding products 4b and 4c were obtained
in 89 and 91% yields, respectively (Table 3, entries 2 and 3).
However, in the cases of methylenecyclopropanes 1d having
chlorine as an electron-inductive substituent on the benzene ring,
4d was formed in lower yield (Table 3, entry 4).
A plausible mechanism for the reaction of MCPs 1 with N-F
reagents is outlined in Scheme 3. Initially, the interaction between
NFSI and MCPs leads to the intermediate C and the anionic
intermediate A under the standard reaction conditions, in which
the anionic intermediate A can be transformed to another anionic
intermediate B [32,33]. In the intermediate C, if R1 is sterically
bulkier than R2, subsequently, the intermediate C is attacked by the
corresponding anion from the sterically smaller group R2 side to
give ring-opened products 2. Similarly, reaction of MCPs with
Selectfluor gives intermediate C. Then the ring-opening of the
cyclopropyl group would give intermediate D which would
produce the final products 4 after hydrolysis.
It was interesting to observe that the reaction of methylene-
cyclopropane 1a with 1.0 equiv. of Selectfluor (F-TEDA-BF4) in
acetonitrile afforded the amide derivative 4a in 67% yield (see
Scheme 1 and Table 3, entry 1). Then a series of methylenecyclo-
propanes were tested. The results in Table 3 show that the
reactions proceeded smoothly to give the corresponding products
4. We found the electronic nature of the substituents on the
Scheme 3. Proposed mechanism for the reaction of MCPs with N-F reagents.

W. Fu et al. / Journal of Fluorine Chemistry 130 (2009) 996–1000
999
3. Conclusion
Calcd for C28H22Cl2FNO4S2: (%) C, 56.95; H, 3.76; N, 2.37. Found: C,
56.80; H, 3.98; N, 2.45.
In conclusion, we have disclosed the reactions of methylene-
cyclopropanes with N-F reagents to give the corresponding
fluorinated derivatives 2 and 4 in moderate to excellent yields.
Further studies, including the reaction mechanism and synthetic
application of this methodology, are in progress.
Compound 2e: white solid, mp 112–114 8C. 1H NMR (400 MHz,
CDCl3):
d 2.67 (t, J = 8.4 Hz, 2H), 3.94 (t, J = 8.4 Hz, 2H), 6.87 (d,
J = 8.0 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 7.17–7.26 (m, 3H), 7.32 (d,
J = 8.0 Hz, 2H), 7.45–7.51 (m, 4H), 7.60 (t, J = 8.0 Hz, 2H), 7.94 (d,
J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 31.7 (d, JC–F = 27.8 Hz),
46.3, 122.2(d, JC–F = 15.4 Hz), 126.1, 127.3, 128.6, 128.9, 129.0, 129.5,
130.5, 131.3, 132.0, 133.6, 135.4, 138.0, 138.2, 139.0, 148.6, 154.6(d,
JC–F = 261.2 Hz);MS(EI)m/z557(M+).Anal.CalcdforC28H22F3NO4S2:
(%) C, 60.31; H, 3.98; N, 2.51. Found: C, 60.45; H, 4.20; N, 2.42.
4. Experimental
4.1. General
Compound 2f: oil. 1H NMR (400 MHz, CDCl3):
d 2.31 (s, 0.6H),
Chemicals used were obtained from commercial suppliers and
used without further purifications. 1H NMR spectra and 13C NMR
spectra were measured in CDCl3 and recorded on Bruker Avance-
400 spectrometer (400 MHz for 1H NMR, 100 MHz for 13C NMR)
with TMS as an internal standard. IR spectra were run on a Bruker
vector 22 spectrometer. EIMS were determined with a HP5989B
mass spectrometer. Elemental analyses were performed on an EA-
1110 instrument.
2.34 (s, 2.4H), 2.61–2.72 (m, 2H), 3.91–3.98 (m, 2H), 5.43 (, d,
J = 38.0 Hz, 0.8H), 6.25 (d, J = 22.8 Hz, 0.2H), 6.80 (d, J = 8.0 Hz,
0.5H), 6.95 (s, 1H), 7.11–7.18 (m, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.49–
7.56 (m, 5H), 7.61–7.68 (m, 3H), 7.98–8.05 (m, 5.5H); 13C NMR
(100 MHz, CDCl3):
d 21.1, 21.3, 34.1 (d, JC–F = 27.2 Hz), 46.3, 108.2,
108.4, 127.2, 127.3, 128.1, 128.2, 128.31, 128.34, 128.4, 128.5,
128.9, 129.1, 129.2, 129.3, 129.6, 130.0, 130.10, 130.14, 131.9,
133.9, 134.0, 134.1, 134.8, 137.0, 139.0, 139.5, 139.7, 155.6 (d, JC–
F = 265.0 Hz); MS (EI) m/z 459 (M+). Anal. Calcd for C23H22FNO4S2:
(%) C, 60.11; H, 4.83; N, 3.05. Found: C, 60.23; H, 4.58; N, 3.20.
4.2. Typical procedure for fluorination of methylenecyclopropane 1
with N-fluorobenzenesulfonimide
Compound 2g: oil. 1H NMR (400 MHz, CDCl3):
d 2.73 (t,
J = 8.0 Hz, 2H), 3.76 (s, 3H), 3.81 (s, 3H), 3.96 (t, J = 8.0 Hz, 2H), 5.81
(d, J = 40.0 Hz, 1H), 7.53 (t, J = 8.4 Hz, 5H), 7.63–7.66 (m, 4H), 8.05
N-Fluorobenzenesulfonimide (0.5 mmol) was added to a stirred
solution of the methylenecyclopropane 1 (0.5 mmol) in THF
(5 mL). The mixture was stirred at 60 8C until the reaction
completed. The solvent was removed under reduced pressure
and the residue was purified by SiO2 gel column chromatography
to give the corresponding products 2.
(d, J = 8.0 Hz, 4H); 13C NMR (100 MHz, CDCl3):
d 34.3 (d, JC–
F = 27.5 Hz), 46.1, 55.4, 55.6, 98.1, 101.6, 104.8, 114.9, 127.6, 128.1,
129.0, 130.3, 130.4, 133.9, 139.6, 155.6 (d, JC–F = 256.5 Hz), 157.1,
159.8; MS (EI) m/z 505 (M+). Anal. Calcd for C24H24FNO6S2: (%) C,
57.02; H, 4.78; N, 2.77. Found: C, 57.26; H, 4.50; N, 2.91.
Compound 2a: white solid, mp 100–101 8C. 1H NMR (400 MHz,
Compound 2h: oil. 1H NMR (400 MHz, CDCl3):
2H), 3.96–3.99 (m, 2H), 6.93 (t, J = 8.8 Hz, 1H), 7.01–7.28 (m, 6H),
7.33–7.49 (m, 6H), 7.54–7.63 (m, 2H), 7.92 (, t, J = 9.6 Hz, 4H); 13
NMR (100 MHz, CDCl3): 31.5, 31.7 (d, JC–F = 26.8 Hz), 46.1, 46.2,
d 2.61–2.74 (m,
CDCl3):
(m, 7H), 7.36–7.41 (m, 7H), 7.60 (t, J = 7.6 Hz, 2H), 7.96 (d,
J = 7.6 Hz, 4H); 13C NMR (100 MHz, CDCl3):
31.7 (d, J = 27.2 Hz),
d 2.71 (t, J = 6.8 Hz, 2H), 3.97 (t, J = 6.8 Hz, 2H), 7.20–7.27
C
d
d
46.2, 122.8 (d, JC–F = 13.6 Hz), 127.2, 127.6, 128.0, 128.2, 128.5,
129.1, 129.4, 129.6, 130.0, 130.1, 134.0, 136.7, 138.0, 138.1, 139.5,
153.7 (d, JC–F = 260.2 Hz); MS (EI) m/z 521 (M+). Anal. Calcd for
114.8 (d, JC–F = 20.8 Hz), 115.6 (d, JC–F = 20.8 Hz), 121.80, 121.83,
121.93, 121.98, 127.0, 127.3, 127.8, 128.01, 128.06, 128.7, 129.1,
129.3, 129.4, 129.9, 130.0, 131.13, 131.18, 131.20, 131.26, 131.6,
131.72, 131.77, 132.7, 133.90, 133.93, 136.5, 137.7, 137.8, 139.50,
139.51, 153.6 (d, JC–F = 268.0 Hz), 153.7 (d, JC–F = 259.6 Hz), 161.7
(d, JC–F = 246.9 Hz), 162.2 (d, JC–F = 246.1 Hz); MS (EI) m/z 539 (M+).
Anal. Calcd for C28H23F2NO4S2: (%) C, 62.32; H, 4.30; N, 2.60. Found:
C, 62.25; H, 4.53; N, 2.71.
C28H24FNO4S2: (%) C, 64.47; H, 4.64; N, 2.69. Found: C, 64.41; H,
4.83; N, 2.58.
Compound 2b: oil, 1H NMR (400 MHz, CDCl3):
d 2.31 (s, 3H),
2.40 (s, 3H), 2.68 (t, J = 7.2 Hz, 2H), 3.99 (t, J = 7.2 Hz, 2H), 7.05–7.16
(m, 6H), 7.20 (d, J = 9.2 Hz, 2H), 7.44 (t, J = 8.0 Hz, 4H), 7.60 (d,
J = 8 Hz, 2H), 7.90 (d, J = 9.2 Hz, 4H); 13C NMR (100 MHz, CDCl3):
d
Compound 2i: oil. 1H NMR (400 MHz, CDCl3):
d 2.61–2.72 (m,
21.1, 21.2, 31.7 (d, JC–F = 27.2 Hz), 46.5, 122.4 (d, JC–F = 13.6 Hz),
128.0, 128.6, 129.1, 129.2, 129.4, 129.9, 133.7, 134.0, 135.1, 135.3,
136.8, 137.2, 139.5, 153.3 (d, JC–F = 259.1 Hz); MS (EI) m/z 549 (M+).
Anal. Calcd for C30H28FNO4S2: (%) C, 65.55; H, 5.13; N, 2.55. Found:
C, 65.48; H, 5.38; N, 2.62.
2H), 3.95–3.99 (m, 2H), 7.12 (d, J = 8.8 Hz, 1H), 7.15–7.36 (m, 6H),
7.35–7.45 (m, 2H), 7.44–7.53 (m, 4H), 7.54–7.64 (m, 2H), 7.88–7.91
(m, 4H); 13C NMR (100 MHz, CDCl3):
d 31.98 (d, JC–F = 25.8 Hz),
46.3, 121.7 (d, JC–F = 14.4 Hz), 127.3, 127.7, 127.8, 127.9, 128.6,
128.7, 128.9, 129.1, 129.3, 129.6, 130.4, 130.6, 131.2, 131.4, 132.8,
133.6, 133.7, 134.8, 136.1, 136.2, 136.3, 137.4, 139.3, 153.0 (d, JC–
F = 256.7 Hz), 153.8 (d, JC–F = 248.2 Hz); MS (EI) m/z 555 (M+). Anal.
Calcd for C28H23ClFNO4S2: (%) C, 60.48; H, 4.17; N, 2.52. Found: C,
60.45; H, 4.32; N, 2.61.
Compound 2c: oil. 1H NMR (400 MHz, CDCl3):
d2.69 (t,
J = 7.2 Hz, 2H), 3.78 (s, 3H), 3.84 (s, 3H), 4.02 (t, J = 7.2 Hz, 2H),
6.80 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.4 Hz,
2H), 7.22 (d, J = 8.4 Hz, 2H), 7.50 (t, J = 7.6 Hz, 4H), 7.61 (t, J = 7.6 Hz,
2H), 7.94 (d, J = 8.0 Hz, 4H); 13C NMR (100 MHz, CDCl3):
d
31.7 (d,
Compound 3a: white solid, mp 102–103 8C. 1H NMR (400 MHz,
JC–F = 27.9 Hz), 46.4, 55.0, 55.1, 113.2, 113.6, 114.0, 121.8(d, JC–
F = 13.4 Hz), 127.9, 128.4, 129.0, 129.3, 130.3, 130.4, 130.6, 130.7,
131.1, 133.7, 133.8, 139.5, 152.7 (d, JC–F = 257.8 Hz), 158.5, 158.9;
MS (EI) m/z 581 (M+). Anal. Calcd for C30H28FNO6S2: (%) C, 61.95; H,
4.85; N, 2.41. Found: C, 61.78; H, 5.10; N, 2.32.
CDCl3):
7.10 (m, 2H), 7.20–7.32 (m, 8H), 7.40–7.53 (m, 5H), 7.61–7.65 (m,
1H), 7.90–7.97 (m, 4H); 13C NMR (100 MHz, CDCl3):
30.3 (d, JC–
F = 27.8 Hz), 67.7, 126.7, 127.3, 127.7, 127.8, 128.6, 128.7, 129.2,
129.4, 130.0, 130.1, 132.5, 134.6, 135.5, 136.6, 142.6, 153.5 (d, JC–
F = 260.8 Hz); MS (EI) m/z 521 (M+). Anal. Calcd for C28H24FNO4S2:
(%) C, 64.47; H, 4.64; N, 2.69. Found: C, 64.36; H, 4.35; N, 2.78.
d 2.70 (dt, J = 20.0, 5.6 Hz, 2H), 4.41–4.50 (m, 2H), 7.07–
d
Compound 2d: white solid, mp 108–109 8C. 1H NMR (400 MHz,
CDCl3):
d 2.65 (t, J = 7.6 Hz, 2H), 3.95 (t, J = 7.6 Hz, 2H), 7.08 (d,
J = 8.0 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.22–7.30 (m, 3H), 7.35 (d,
J = 8.0 Hz, 2H), 7.44–7.52 (m, 4H), 7.64 (t, J = 8.0 Hz, 2H), 7.92 (d,
4.3. Typical procedure for fluorination of methylenecyclopropane 1
with F-TEDA-BF4
J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
31.8 (d, JC–
F = 27.0 Hz), 46.4, 122.6(d, JC–F = 14.2 Hz), 127.2, 127.5, 128.0,
128.1, 128.6, 129.0, 129.4, 129.5, 130.1, 130.2, 133.9, 136.8, 138.1,
138.2, 139.6, 153.7 (d, JC–F = 259.4 Hz); MS (EI) m/z 589 (M+). Anal.
1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis
(tetrafluoroborate) (0.5 mmol) was added to a stirred solution of

1000
W. Fu et al. / Journal of Fluorine Chemistry 130 (2009) 996–1000
methylenecyclopropane 1 (0.5 mmol) in R3CN(3 mL). The mixture
was stirred at 60 8C until the reaction completed. The solvent was
removed under reduced pressure and the residue was purified by
SiO2 gel column chromatography to give the corresponding
products 4.
C24H22FNO: (%) C, 80.20; H, 6.17; N, 3.90. Found: C, 80.29; H,
6.43; N, 4.04.
Compound 4f: solid, mp 101–103 8C. 1H NMR (400 MHz,
CDCl3):
d 0.90 (t, J = 7.2 Hz, 3H), 1.58–1.63(m, 2H), 2.08 (t,
J = 7.2 Hz, 2H), 2.57 (dt, J = 30.3, 8.4 Hz, 2H), 3.60 (dt, J = 8.4,
8.4 Hz, 2H), 5.63 (br s, 1H), 7.13–7.35 (m, 10H); 13C NMR (100 MHz,
Compound 4a: solid, mp 95–97 8C. 1H NMR (400 MHz, CDCl3):
d
1.96 (s, 3H), 2.56 (dt, J = 30.0, 8.8 Hz, 2H), 3.58 (dt, J = 8.8, 8.8 Hz,
CDCl3): d 13.8, 19.2, 23.3, 30.1 (d, JC–F = 26.4 Hz), 37.2, 39.3, 122.7
2H), 5.60 (br s, 1H), 7.16–7.39 (m, 10H); 13C NMR (100 MHz,
(d, JC–F = 12.0 Hz), 127.2, 127.5, 128.2, 128.6, 129.3, 129.5,130.0,
130.3, 137.4, 138.2, 138.3, 155.1 (d, JC–F = 258.2 Hz), 170.1; MS (EI)
m/z 311 (M+). Anal. Calcd for C20H22FNO: (%) C, 77.14; H, 7.12; N,
4.50. Found: C, 77.26; H, 7.35; N, 4.58.
CDCl3): d 23.3, 30.6 (d, JC–F = 26.0 Hz), 37.0, 122.5 (d, JC–F = 12.0 Hz),
127.1, 127.6, 128.0, 128.6, 129.4, 129.5,130.0, 130.1, 137.0, 138.2,
138.3, 155.4 (d, JC–F = 260 Hz), 169.9; MS (EI) m/z 283 (M+). Anal.
Calcd for C18H18FNO: (%) C, 76.30; H, 6.40; N, 4.94. Found: C, 76.45;
H, 6.21; N, 4.88.
Compound 4b: solid, mp 137–138 8C. 1H NMR (400 MHz,
References
CDCl3):
8.0 Hz, 2H), 3.55 (dt, J = 8.0, 8.0 Hz, 2H), 5.56 (br s, 1H), 7.10–7.14
(m, 8H); 13C NMR (100 MHz, CDCl3):
21.2, 21.3, 23.3, 30.5 (d, JC–
F = 25.6 Hz), 36.9, 123.0 (d, JC–F = 12.6 Hz), 128.5, 128.6, 128.9,
129.1, 129.5, 130.3,131.2, 131.4, 137.1, 137.5, 143.9, 154.8(d, JC–
F = 260 Hz), 170.0; MS (EI) m/z 311 (M+). Anal. Calcd for
d 1.96 (s, 3H), 2.31 (s, 3H), 2.33 (s, 3H), 2.54 (dt, J = 29.4,
[1] J.T. Welch, S. Eswarakrishnan, Fluorine in Bioorganic Chemistry, Wiley, NY, USA,
1991.
[2] I. Bennacef, S. Tymciu, M. Dhilly, M.C. Lasne, D. Debruyne, C. Perrio, L. Barre´,
Bioorg. Med. Chem. 12 (2004) 4533–4541.
[3] M.J. Hensel, P.L. Fuchs, Synth. Commun. 16 (1986) 1285–1295.
[4] F. Camps, G. Fabrias, A. Guerrero, Tetrahedron 42 (1986) 3623–3629.
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[6] A. Alcazar, F. Camps, J. Coll, G. Fabrias, A. Guerrero, Synth. Commun. 15 (1985)
819–827.
d
C
20H22FNO: (%) C, 77.14; H, 7.12; N, 4.50. Found: C, 77.27; H,
7.51; N, 4.62.
[7] A.E. Asato, H. Matsumoto, M. Denny, R.S.H. Liu, J. Am. Chem. Soc. 100 (1978) 5957–
5960.
Compound 4c: solid, mp 105–106 8C. 1H NMR (400 MHz,
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Srisethnil, J. Med. Chem. 22 (1979) 1059–1067.
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(1993) 3137–3147.
CDCl3):
J = 8.8, 8.8 Hz, 2H), 3.81 (s, 3H), 3.83 (s, 3H), 5.54 (br s, 1H), 6.82–
6.89 (m, 4H) 7.02–7.16 (m, 4H); 13C NMR (100 MHz, CDCl3):
23.1,
d 1.95 (s, 3H), 2.55 (dt, J = 30.2.4, 8.8 Hz, 2H), 3.56 (dt,
d
[10] T.M.T. Nguyen-Truong, H. Togo, M. Schlosser, Tetrahedron 50 (1994) 7827–
7836.
30.6 (d, JC–F = 26.0 Hz), 37.2, 55.2, 55.3, 113.6, 113.8, 124.5 (d, JC–
F = 12.2 Hz), 130.8, 131.2, 134.2, 136.9, 155.0(d, JC–F = 258.0 Hz),
159.4, 160.2, 170.2; MS (EI) m/z 343 (M+). Anal. Calcd for
[11] G.B. Hammond, D.J. Mendonca, J. Fluorine Chem. 102 (2000) 189–197.
[12] G.S. Lal, G.P. Pez, R.G. Syvret, Chem. Rev. 96 (1996) 1737–1756.
[13] K.L. Kirk, Org. Process Res. Dev. 12 (2008) 305–321.
[14] P. Liu, A. Sharon, C.K. Chu, J. Fluorine Chem. 129 (2008) 743–766.
[15] C.E. Stephens, J.A. Blake, J. Fluorine Chem. 125 (2004) 1939–1945.
[16] G. Verniest, E.V. Hende, R. Surmont, N.D. Kimpe, Org. Lett. 8 (2006) 4767–4770.
[17] J. Nie, H.W. Zhu, H.F. Cui, M.Q. Hua, J.A. Ma, Org. Lett. 9 (2007) 3053–3056.
[18] A. Brandi, A. Goti, Chem. Rev. 98 (1998) 589–636.
[19] A. Brandi, S. Cicchi, F.M. Cordero, A. Goti, Chem. Rev. 103 (2003) 1213–1270.
[20] I. Nakamura, Y. Yamamoto, Adv. Synth. Catal. 2 (2002) 111–129.
[21] E. Nakamura, S. Yamago, Acc. Chem. Res. 35 (2002) 867–877.
[22] S. Yamago, A. Takeichi, E. Nakamura, Synthesis (1996) 1380.
[23] M. Suginome, T. Matsuda, Y. Ito, J. Am. Chem. Soc. 122 (2000) 11015–11016.
[24] M. Itazaki, Y. Nishihara, K. Osakada, J. Org. Chem. 67 (2002) 6889–6895.
[25] I. Nakamura, A.I. Siriwardana, S. Saito, Y. Yamamoto, J. Org. Chem. 67 (2002)
3445–3449.
[26] M. Shi, Y. Chen, B. Xu, J. Tang, Tetrahedron Lett. 43 (2002) 8019–8024.
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[28] X. Huang, W.J. Fu, Synthesis (2006) 1016–1020.
[29] X. Huang, W.J. Fu, M.Z. Miao, Tetrahedron Lett. 49 (2008) 2359–2362.
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[31] W.J. Fu, X. Huang, Synlett (2007) 321–332.
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[33] B. Hill, Y. Liu, S.D. Taylor, Org. Lett. 6 (2004) 4285–4288.
C
20H22FNO3: (%) C, 69.95; H, 6.46; N, 4.08. Found: C, 69.78; H,
6.20; N, 4.12.
Compound 4d: solid, mp 95–97 8C. 1H NMR (400 MHz, CDCl3):
d
1.94 (s, 3H), 2.53 (dt, J = 30.4, 8.4 Hz, 2H), 3.56 (dt, J = 8.4, 8.4 Hz,
2H), 5.57 (br s, 1H), 7.15 (t, J = 8.2 Hz, 4H), 7.31–7.26 (m, 4H); 13
NMR (100 MHz, CDCl3): 23.1, 30.3 (d, JC–F = 26.0 Hz), 36.8, 122.0
C
d
(d, JC–F = 12.6 Hz), 128.5, 128.7, 130.1, 130.2, 133.4, 133.5, 137.9,
138.6, 155.1(d, JC–F = 262.2 Hz), 169.6; MS (EI) m/z 351 (M+). Anal.
Calcd for C18H16Cl2FNO: (%) C, 61.38; H, 4.58; N, 3.98. Found: C,
61.44; H, 4.29; N, 3.87.
Compound 4e: solid, mp 115–116 8C. 1H NMR (400 MHz,
CDCl3):
7.6 Hz, 2H), 5.41(br s, 1H), 7.01–7.33 (m, 15H); 13C NMR (100 MHz,
CDCl3): 30.3 (d, JC–F = 27.0 Hz), 37.4, 43.88, 122.7 (d, JC–
d 2.51 (dt, J = 29.4, 7.6 Hz, 2H), 3.53 (s, 2H), 3.59 (dt, J = 7.6,
d
F = 12.5 Hz), 127.1, 127.2, 127.4, 127.5, 128.0, 128.6, 129.0,129.3,
129.5,129.6, 131.2, 131.9, 136.3, 138.0, 138.7, 156.0 (d, JC–
F = 258.2 Hz), 170.3; MS (EI) m/z 359 (M+). Anal. Calcd for